Metallocenes in Regio- and Stereoselective Synthesis

Volume Editor Professor Tamotsu Takahashi Catalysis Research Center Hokkaido University Kita 21, Nishi 10, Kita-ku Sapporo 001-0021 Japan [email protected]

Editorial Board Prof. John M. Brown

Prof. Pierre H. Dixneuf

Dyson Perrins Laboratory South Parks Road Oxford OX1 3QY [email protected]

Campus de Beaulieu Université de Rennes 1 Av. du Gl Leclerc 35042 Rennes Cedex, France [email protected]

Prof. Alois Fürstner

Prof. Louis S. Hegedus

Max-Planck-Institut für Kohlenforschung Kaiser-Wilhelm-Platz 1 45470 Mühlheim an der Ruhr, Germany [email protected]

Department of Chemistry Colorado State University Fort Collins, Colorado 80523-1872, USA hegedus@lamar. colostate.edu

Prof. Peter Hofmann

Prof. Paul Knochel

Organisch-Chemisches Institut Universität Heidelberg Im Neuenheimer Feld 270 69120 Heidelberg, Germany [email protected]

Fachbereich Chemie Ludwig-Maximilians-Universität Butenandstr. 5–13 Gebäuse F 81377 München, Germany [email protected]

Prof. Gerard van Koten

Prof. Shinji Murai

Department of Metal-Mediated Synthesis Debye Research Institute Utrecht University Padualaan 8 3584 CA Utrecht, The Netherlands [email protected]

Faculty of Engineering Department of Applied Chemistry Osaka University Yamadaoka 2-1, Suita-shi Osaka 565, Japan [email protected]

Prof. Manfred Reetz Max-Planck-Institut für Kohlenforschung Kaiser-Wilhelm-Platz 1 45470 Mülheim an der Ruhr, Germany [email protected]

Preface

“Metallocenes” have been used for complexes which have sandwich structures with two cyclopentadienyl ligands since the discovery of ferrocene. Recently metal complexes having one cyclopentadienyl ligand have also been classified as a member of metallocene derivatives. One important discovery in this area is the olefin polymerization catalyzed by metallocene complexes of early transition metals such as zirconium and titanium. In particular, the structure of the metallocene catalyst has a remarkable effect on the structure of the polymers. This discovery has had a strong impact on the industry. The area of organic synthesis using metallocenes of early transition metals has been lagging behind synthesis using late transition metals. Many of the reactions have been stoichiometric for some time. Among them hydrozirconation of unsaturated compounds has been widely used. In the last two decades, however, a lot of catalytic reactions including asymmetric synthesis have been developed. Now this area has become quite attractive for many researchers in organic synthesis. This book is presented as a volume of Topics in Organometallic Chemistry, aiming at giving an overview of the chemistry of metallocenes. In particular, in this book we focused on, (i) hydrozirconation and its application to natural product synthesis, (ii) the asymmetric carboalumination reaction, (iii) the cyclization reaction using metallocenes, (iv) catalytic reactions using metallocenes, (v) olefin polymerization and (vi) carbon-carbon bond cleavage reactions using metallocenes. I would like to express my thanks to all contributors to this book. Sapporo, April 2004

Tamotsu Takahashi

Preface

Contents

Hydrozirconation and Its Applications P. Wipf · C. Kendall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Construction of Carbocycles via Zirconacycles and Titanacycles Z. Xi · Z. Li . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Metallocene-Catalyzed Selective Reactions M. Kotora . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Diastereoselective, Enantioselective, and Regioselective Carboalumination Reactions Catalyzed by Zirconocene Derivatives E. Negishi · Z. Tan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes N. Suzuki . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Carbon-Carbon Bond Cleavage Reaction Using Metallocenes T. Takahashi · K. Kanno . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Author Index Volumes 1–8 . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

Topics Organomet Chem (2004) 8: 1– 25 DOI 10.1007/b13144 © Springer-Verlag Berlin Heidelberg 2004

Hydrozirconation and Its Applications Peter Wipf (

) · Christopher Kendall

University of Pittsburgh, Department of Chemistry, Pittsburgh PA 15260, USA [email protected]

1

Introduction and Scope

. . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Preparation of Cp2ZrHCl and Related Reagents . . . . . . . . . . . . . . . .

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Functional Group Compatibility of Hydrozirconation . . . . . . . . . . . .

4

4

Alternative Methods for Generating Organozirconocenes . . . . . . . . . .

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Hydrozirconation Followed by Halogenation . . . . . . . . . . . . . . . . .

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Hydrogenation and Reduction . . . . . . . . . . . . . . . . . . . . . . . . .

7

7

Hydrozirconation Followed by C–C Bond Formation

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7.1 7.2 7.2.1 7.2.2 7.2.3

Silver-Catalyzed Ligand Abstraction . . . . . . . . Transmetalation . . . . . . . . . . . . . . . . . . . Zirconium Æ Palladium and Zirconium Æ Nickel Zirconium Æ Zinc . . . . . . . . . . . . . . . . . Zirconium Æ Copper . . . . . . . . . . . . . . . .

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10 12 12 15 17

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Miscellaneous Reactions of Organozirconocenes . . . . . . . . . . . . . . .

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References

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Abstract Next to hydroboration and hydrostannylation, hydrozirconation is among the few general methods available for the stoichiometric conversion of readily available alkenes and alkynes into stable, strongly nucleophilic synthetic intermediates. More significantly, the sterically shielded carbon–zirconium bond of organozirconocenes can participate in transmetalation schemes that link zirconium chemistry with many other elements in the periodic table, in particular with the highly functional group tolerant late transition metals. The in situ conversion of alkenes and alkynes into chain-extended synthetic building blocks by sequential hydrozirconation and further metal-catalyzed or metal-mediated condensations with electrophiles is thus characterized by experimental convenience and considerable strategic flexibility. In addition, the number of synthetic protocols that use organozirconocenes directly for intra- or intermolecular carbon–carbon and carbon–heteroatom bond formations is steadily increasing. As an extension of our comprehensive treatment of the topic in 1996, this review concentrates on the developments in hydrozirconation and its applications in synthesis from 1996 through mid-2002. Keywords Zirconocenes · Transmetalation · Cationic complexes · Alkenes · Alkynes

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1 Introduction and Scope The hydrozirconation of alkenes and alkynes with Cp2ZrHCl, a.k.a. Schwartz reagent [1], is one of two common methods for forming organozirconocenes (Scheme 1). According to the Pauling electronegativity scale, the ionic character of the C–Zr bond (26%) is almost equivalent to the C–Mg bond (27%), but organozirconocene complexes are intrinsically considerably weaker nucleophiles than Grignard reagents due to steric shielding at the metal atom by the two cyclopentadienyl ligands.While the preparations of Grignard and organolithium reagents mainly originate from the corresponding halides, the opportunity to use the more readily available, synthetically versatile alkenes and alkynes as starting materials is a great asset of zirconocene chemistry. Subsequent activation of the C–Zr bond by addition of catalytic or stoichiometric metal salts benefits from the ease of formation of bridged bimetallic complexes of early transition metals such as zirconium and the broad functional group compatibility and extraordinary synthetic utility of late transition metals. Figure 1 illustrates the ability of zirconocene to participate in mixed-metallic complex formation, often assisted by bridging chloride or oxygen atoms [2, 3].

Scheme 1 Formation of alkyl- and alkenylzirconium reagents by the hydrozirconation of alkenes and alkynes

Organozirconocene complexes can also be activated by ligand substitution or abstraction. In addition, small electrophiles such as halogens, dioxygen, protons, and isonitriles can be directly added to the Zr–C bond. This review will present a survey of many recent examples of hydrozirconation in organic synthesis, mostly focusing on material published since our last comprehensive review [4] on this subject [5–7]. The majority of examples for synthetic applications utilize alkenylzirconocenes, since the reaction of Cp2ZrHCl with alkynes is fast, regioselective, and quite functional group tolerant. Alkenes are not as reactive as alkynes, and furthermore internal alkenes are rapidly isomerized into terminal alkylzirconocenes [8–10], thus limiting the usefulness of this transformation. Some recent reactions of alkylzirconocenes are also covered. Cp2ZrHCl was first prepared in 1970 [11] and used to hydrozirconate alkenes [12] and alkynes [13] by Wailes and coworkers. Subseqently, Schwartz and coworkers treated the resulting alkylzirconocene [14] and alkenylzirconocene

Hydrozirconation and Its Applications

3

Fig. 1 Crystal structures of two zirconocene complexes with heteroatoms and carbon bridges to alanes

[15] products with inorganic electrophiles and used transmetalation from Zr to Al in order to increase reactivity towards organic electrophiles [16]. Due to these pioneering synthetic applications, Cp2ZrHCl is commonly referred to as “Schwartz reagent”.

2 Preparation of Cp2ZrHCl and Related Reagents The commercially available reagent is typically prepared by reduction of Cp2ZrCl2 with an aluminum hydride. Wailes and Weigold originally used one equivalent of LiAl(Ot-Bu)3H as the reducing agent in THF [11]. The insoluble zirconocene hydrochloride was isolated in 90% yield. The more practical LiAlH4 was at first not recommended as a reducing agent since it could lead to formation of significant quantities of Cp2ZrH2, a much more insoluble (and thus less reactive) complex than Cp2ZrHCl. For a solubilized version of zirconocene dihydride, see [17]. Schwartz and coworkers used Na[AlH2(OCH2CH2OCH3)2] (Red-Al) as the reducing agent in THF; however, this protocol contaminated the Cp2ZrHCl with ca. 30% NaCl [14]. Buchwald and coworkers discovered that the reaction, first reported by Wailes and Weigold [11], of Cp2ZrH2 with CH2Cl2 (forming Cp2ZrHCl and CH3Cl) was very rapid at room temperature, whereas the analogous reaction between Cp2ZrHCl and CH2Cl2 was slower [18]. Thus, by adding a CH2Cl2 wash to the workup of the LiAlH4 reduction of Cp2ZrCl2, the problem of over-reducing to Cp2ZrH2 was minimized.An important practical aspect of this process is the use of a filtered Et2O solution of LiAlH4, which is slowly added to the solution of zirconocene. The reaction of Cp2ZrCl2 with one equivalent of t-BuLi in toluene can also be used to prepare Cp2ZrHCl [19]. Since the reagent does not have a very long shelf-life, methods for its in situ generation have been developed, including the treatment of Cp2ZrCl2 with t-BuMgCl in benzene/Et2O which forms i-BuZrCp2Cl, a Cp2ZrHCl equivalent [20, 21], and reduction of Cp2ZrCl2 with LiEt3BH in THF which forms the Schwartz reagent, Et3B and LiCl, two by-

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products that do not interfere with hydrozirconation [22] but can be a problem for further transmetalation. Bu2ZrCl2, prepared by treatment of ZrCl4 with two equivalents of BuLi, can also serve as a hydrozirconating agent in hexane or toluene, but not in THF [23]. Many cyclopentadiene ring-substituted derivatives of Cp2ZrHCl have been prepared and tested in hydrozirconation schemes [24, 25]. Cp2ZrHCl is a moderately air-, moisture-, and light-sensitive amorphous colorless solid that can be handled and weighed on a balance without special precautions. In our hands, storage in a polyethylene bottle under N2 extends the shelf life of the reagent to at least 20 days without significant decrease in reactivity. The hydrozirconation of terminal alkynes and alkenes proceeds rapidly (5–15 min) at room temperature in CH2Cl2 or THF, and much more slowly in benzene or toluene [8]. The reaction is also very easily monitored visually since the colorless Cp2ZrHCl is insoluble in most common organic solvents whereas the colored organozirconocenes are highly soluble. If the reaction is performed under kinetic control with a slight excess of alkyne, the regioselectivity of hydrozirconation is actually quite low. However, if excess Schwartz reagent is employed, thermodynamic equilibration via double hydrozirconation-b-elimination leads to the highly regioselective formation of the terminal, sterically less hindered vinyl organometallic. Procedure: Schwartz Reagent [26]

To a dry, 1 L Schlenk flask equipped with a magnetic stirring bar Cp2ZrCl2 (100 g, 0.342 mol) is added under argon, followed by dry THF (650 mL). Dissolution of the solid is accomplished by gentle heating. To the solution is added dropwise, over a 45 min period, a filtered, clear solution of LiAlH4 (3.6 g, 94 mmol) in Et2O (100 mL). The resulting suspension is stirred at room temperature for 90 min, then Schlenk-filtered under argon using a “D” frit. The white solid is washed with THF (4¥75 mL), CH2Cl2 (2¥100 mL with stirring and a contact time of no greater than 10 min per wash), and then with Et2O (4¥50 mL), and dried in the dark under reduced pressure to yield 66 g (75%) of Cp2ZrHCl as a white powder.

3 Functional Group Compatibility of Hydrozirconation True to its nature as an early transition metal, zirconium displays considerable Lewis acidity and binds to hard Lewis bases such as carbonyl groups, thus facilitating hydride transfer and reduction. In general, amides, ketones, aldehydes, and nitriles are not compatible with alkene and alkyne hydrozirconation conditions. Alkynes are selectively hydrozirconated in the presence of esters, but only sterically hindered triisopropylsilylesters survive the slower hydrozirconation of alkenes. Acylsilanes are also readily tolerated in hydrozirconation, and carbamates, acetals, epoxides, silylethers, alkyl- and phenylethers,

Hydrozirconation and Its Applications

5

Scheme 2 Hydrozirconation of an electrophilic and easily deprotonated substrate

halides, and sulfides are recovered unchanged after exposure to Schwartz reagent. Alcohols and sulfonamides undergo an acid-base reaction with one equivalent of zirconocene hydrochloride but otherwise do not significantly interfere with alkene and alkyne hydrozirconation. An example for the considerable functional group compatibility and low basicity of hydrozirconation is shown in Scheme 2.

4 Alternative Methods for Generating Organozirconocenes Other widely used reagents for the formation of organozirconium complexes are Cp2ZrEt2 and Cp2ZrBu2. These “Cp2Zr(II)” equivalents can react with alkenes and alkynes to form zirconacyclopentanes, -cyclopentenes, and -cyclopentadienes, which react very similarly to the acyclic organozirconocenes formed by hydrozirconation. For a recent review, see [27] and references cited therein. Cp2ZrR2 reagents can also be inserted into vinyl halides [28], 2,2-difluorovinyltosylate [29], methoxy enol ethers [30], enolsilanes [31], and vinyl sulfides, sulfoxides, and sulfones [32] to form internal and terminal as well as cyclic alkenylzirconocenes.

5 Hydrozirconation Followed by Halogenation One of the most widely used applications in organozirconium chemistry is the preparation of (E)-vinyl halides via hydrozirconation and halogenation. Recent applications of this method in natural product synthesis include (+)-amphidinolide J [33], tedonolide [34, 35], and the CP-molecules (CP-263,114 and CP-225,917) [36]. For a fragment needed for (+)-acutiphycin, hydrozirconation of alkyne 5 followed by bromination afforded bromides 6 and 7 as a 94:6 mixture of regioisomers [37] (Scheme 3).Vinyl bromide 6 was then converted in 3 steps into Grignard reagent 8, and added to aldehyde 9, installing all carbons necessary for completion of the total synthesis.

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Scheme 3 Synthesis of the (+)-acutiphycin precursor (E)-vinyl bromide 6 by the hydrozirconation and bromination of alkyne 5

Procedure: Hydrozirconation, bromination of internal alkynes [37]

A solution of alkyne 5 (1.51 g, 5.50 mmol) in benzene (36.7 mL) was treated with Cp2ZrHCl (4.30 g, 16.5 mmol) in one portion, warmed to 40 °C for 1 h, and cooled to room temperature. NBS (1.96 g, 11.0 mmol) was then added, and the reaction mixture was stirred for 15 min and quenched with saturated NaHCO3. The biphasic mixture was stirred vigorously for 5 min and extracted with hexane/ethyl acetate (9:1). The combined organic extracts were washed with brine, dried (MgSO4), filtered through a pad of SiO2, and washed with hexane/ethyl acetate (4:1). Concentration and chromatography on SiO2 (hexanes/ethyl acetate, 95:5) afforded a 16.4:1 mixture of 6 to 7 as a colorless oil. (Z)-Vinyl halides can also be prepared from terminal alkynes via the hydrozirconation of stannylacetylenes [38]. In their total synthesis of myxalamide A (Scheme 4), Mapp and Heathcock reduced the triple bond of stannylacetylene 12 with Cp2ZrHCl [39]. Due to the higher reactivity of the zirconocene substituent over the stannyl group, aqueous workup and TBDMS-deprotection afforded (Z)-vinylstannane 14. Replacement of the tributyltin group with iodine led to iodotriene 15, which was isolated as a 15:1 ratio of Z/E isomers at the terminal alkene. The strategy of using both stoichiometric zirconium and tin was

Hydrozirconation and Its Applications

7

Scheme 4 Synthesis of a (Z)-vinyl iodide intermediate in the total synthesis of myxalamide A

preferred because Wittig olefination of aldehyde 17 afforded 15 with a Z/E ratio of 5:1 (which could not be improved by purification). Panek and coworkers used a similar difference in the reactivity of gembimetallic alkenes for the stereoselective synthesis of trisubstituted alkenes [40] (Scheme 5). Silylacetylenes react with Schwartz reagent much like stannylacetylenes, and again the zirconium moiety is selectively transformed first when quenched with inorganic electrophiles [41]. Thus, iodosilane 20 was formed after treatment of zirconocene 19 with I2. Negishi coupling of 20 and EtZnCl was very high yielding and was followed by iododesilylation to install the second vinyl iodide. Stille coupling with vinylstannane 23 afforded the trisubstituted alkene 24, a potential synthetic intermediate for the C1–C12 fragment of callystatin A.

6 Hydrogenation and Reduction Regiospecific deuterium labeling can be achieved by quenching organozirconocenes with D2O or by using Cp2ZrDCl for hydrozirconation.A nice demonstration of this concept is the synthesis of three deuterium-substituted analogues of dimethyl hept-1,6-dienyl-4,4-dicarboxylate [42] (Scheme 6). These compounds were used for the study of the mechanism of the transition metal-

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Scheme 5 Rapid stereoselective synthesis of trisustituted alkenes from silylacetylenes

Scheme 6 Regiospecific 2H-labelling using hydrozirconation

Hydrozirconation and Its Applications

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catalyzed 1,6-diene cycloisomerization. Diyne 25 was treated with sufficient Cp2ZrHCl to reduce both triple bonds, and quenched with D2O to afford 1,7(E,E)-bisdeuterodiene 26. A second regioisomer, 2,6-2H2-diene 27, was synthesized using Cp2ZrDCl for the hydrozirconation and quenching with H2O. The third regioisomer in this series, 1,7-(Z,Z)-2H2-diene 29, was prepared by a formal hydrogenation (hydrozirconation and H2O quench) of bisdeuterodiyne 28. A tritiated version of the Schwartz reagent has also been used for regioselectively labeling olefins with tritium [43]. In some cases, hydrozirconation and quenching with water is more selective and more efficient than catalytic hydrogenation protocols. For example, this strategy has been used for the hydrogenation of buckminsterfullerene C60 en route to organofullerenes [44]. Cp2ZrHCl has been used as a reducing agent by Ganem and coworkers for the deoxygenation of b-ketoesters to a,b-unsaturated esters [45], and for the reduction of amides to give imines [46]. Similarly, Schwartz reagent reduces N,Ndisubstituted amides to aldehydes [47]. This reagent has also been used by Majoral and coworkers for reducing phosphine oxides into phosphines [48] and dicyanophosphines into cyanophosphanes [49]. Trauner and Danishefsky used the Ganem reduction protocol in their synthesis of the spiroquinolizidine subunit of halichlorine [50] (Scheme 7).

Scheme 7 Deoxygenation of the lithium enolate of 30 using Cp2ZrHCl in the synthesis of a halichlorine fragment

7 Hydrozirconation Followed by C–C Bond Formation With the exception of direct insertion into CO and isocyanides [51], carbon–carbon bond formation from organozirconocenes requires the use of metal salts for transmetalation or (chloride) ligand abstraction. The former protocol has been successfully applied for many carbonyl additions and crosscouplings, whereas the latter strategy is particularly useful for conversions with electrophiles such as epoxides and aldehydes.

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7.1 Silver-Catalyzed Ligand Abstraction One way to increase alkenylzirconocene reactivity towards organic electrophiles is to reduce the steric congestion about zirconium by ligand (chloride) abstraction. Maeta et al. reported that cationic zirconocenes prepared in situ reacted rapidly with aldehydes to generate 1,2-addition products [52]. For example, when the product of the hydrozirconation of 1-hexyne was treated with hydrocinnamaldehyde in the presence of 5 mol% of AgClO4, alcohol 33 was isolated in 90% yield after a 10 min reaction time (Scheme 8). In the absence of the Ag(I) salt, only 17% conversion was observed after 2 h.AgAsF6 can also catalyze this transformation [53]; however, other Ag(I) salts such as AgOTf, AgSbF6, AgPF6, and AgBF4 were less effective. Wipf and Xu have shown that epoxides are rapidly activated by the cationic zirconocene obtained from treatment of the hydrozirconation product with catalytic amounts of AgClO4 [54]. After the cationic zirconocene-promoted epoxide rearrangement/[1,2]-H shift, carbon–ligand transfer to the resulting aldehyde provides access to secondary alcohols.

Scheme 8 Alkenylzirconocene addition to aldehydes catalyzed by AgClO4

Procedure: AgClO4-catalyzed alkenylzirconocene addition to aldehydes [52].

A mixture of Cp2ZrHCl (401 mg, 1.55 mmol) and 1-hexyne (132 mg, 1.61 mmol) in CH2Cl2 (4.0 mL) was stirred at room temperature for 10 min. To the resulting solution was added 3-phenylpropanal (174 mg, 1.30 mmol) in CH2Cl2 (4.0 mL) followed by AgClO4 (13 mg, 63 mmol, 5 mol%). The reaction mixture gradually turned dark brown. After stirring for 10 min, the mixture was poured into saturated NaHCO3. Extractive workup (EtOAc) followed by purification by preparative TLC (hexane/EtOAc, 80:20) gave allylic alcohol 33 as a colorless oil (255 mg, 90%). When epoxy ester 35 was subjected to these reaction conditions, acetal 36 was formed as a single diastereomer [55]. Hydrolysis of the acetal afforded an enone, thus the net transformation represented a new conversion of an ester into an a,b-unsaturated ketone. Wipf and Methot used this reaction in a synthesis of pyridazinones [56] (Scheme 9). The optimized conditions included addition of 5 mol% of triphenyl phosphite to the reaction mixture and adsorbing AgClO4 onto Celite to improve the stability and simplify the handling of the reagent. Conjugate addition to 36 followed by hydrolysis formed enone 37.A second cuprate addition, followed by cyclization using hydrazine and subsequent oxidation afforded pyridazinone 38 in 86% yield from 36.

Hydrozirconation and Its Applications

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Scheme 9 Synthesis of pyridazinones using the silver(I)-catalyzed addition of an alkenylzirconocene to epoxyester 35

The cationic zirconium-mediated aldehyde addition methodology has recently been used by Maier and coworkers in their study toward the taxol skeleton [57] (Scheme 10). The diene precursor to a planned cycloaddition was prepared by first adding zirconocene 40 to aldehyde 41 under silver(I)-catalysis, which afforded alcohol 42 as a 77:23 mixture of diastereomers. Protection of the

Scheme 10 Use of the silver(I)-catalyzed addition of alkenylzirconocene 40 to aldehyde 41 in the preparation of a potential precursor to a taxol-like skeleton

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newly formed alcohol followed by deprotection and elimination of the primary alcohol gave diene 43. The intramolecular Diels-Alder reaction of 44 to 45 was, however, unsuccessful. 7.2 Transmetalation While many other metals can be used for transmetalation from alkyl- and alkenylzirconocenes [4], the synthetically most important protocols include cross-couplings after zirconiumÆpalladium and zirconiumÆnickel transmetalations, and carbon–carbon bond formation after zirconiumÆzinc and zirconiumÆcopper transmetalations. Recent advances in these transformations and their synthetic scope are discussed in more detail below. 7.2.1 ZirconiumÆPalladium and ZirconiumÆNickel Negishi and coworkers discovered that alkenylzirconocenes could be coupled to aryl or alkenyl halides under Ni- [58] or Pd-catalysis [59]. The mechanism [60] is believed to be analogous to the cross-coupling cycles of organotin (Stille) [61] or organoboron (Suzuki-Miyaura) [62] coupling reactions.A recent total synthesis of lissoclinolide demonstrates a typical application of this methodology [63] (Scheme 11). Protected propargyl alcohol 47 was hydrozirconated with in situ generated i-BuZrCp2Cl and the resulting zirconocene was iodinated to afford vinyl iodide 49. Pd-catalyzed coupling of 49 with propargyl alcohol (46), Swern oxidation and then a Corey-Fuchs reaction gave 1,1-dibromoalkene 50. Pd-catalyzed coupling of 50 with zirconocene 48 occurred exclusively at the trans-position, and carboxylic acid 51 resulted from subsequent lithium–halogen exchange and a CO2 quench.Ag+-catalyzed lactonization of 51

Scheme 11 Total synthesis of lissoclinolide by use of the Pd-catalyzed cross-coupling of alkenylzirconocenes and vinyl halides

Hydrozirconation and Its Applications

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was quantitative, and finally deprotection gave the natural product in 9 steps and 32% overall yield from 46. Alkenylzirconocenes have also recently been coupled under Ni-catalysis with benzyl chlorides [64] and a-bromo-a,a-difluoro esters [65]. This group also found that the yield of Pd-catalyzed cross-couplings of sterically hindered alkenylzirconocenes and vinyl halides could be significantly improved by adding ZnCl2 to the reaction mixture [66]. A transmetalation from the bulky Cp2Zr to the sterically less demanding zinc salt was assumed to precede the normal catalytic coupling cycle. Negishi and Zeng used the combination of hydrozirconation and ZnCl2-mediated Pd-catalyzed cross-coupling to prepare all-E-oligoenes in a very selective and efficient fashion [67] (Scheme 12). For example, 1-octyne was converted into dienyne 53 and then tetraenyne 54 by repeated hydrozirconation-cross-coupling-deprotection operations, and similarly into trienyne 57 and pentaenyne 58 via enyne 56. The alkyne endgroup of the polyene was also converted into an ester function using known hydrozirconation methodology.

Scheme 12 Synthesis of all-E-oligoenes by iterative hydrozirconation and ZnCl2-mediated Pd-catalyzed cross-couplings

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Scheme 13 Successful and failed applications of the ZnCl2-mediated, Pd-catalyzed crosscoupling of alkenylzirconocenes with vinyl halides in the synthesis of N-Boc-ADDA

Panek and Hu further optimized this experimental protocol [68] and applied it towards the synthesis of the Adda amino acid side chain of the microcystin family of natural products [69] (Scheme 13). Hydrozirconation of alkyne 61 in THF at 50 °C gave zirconocene 62 as a single regioisomer. Pd-catalyzed coupling of 62 with vinyl iodide 63 in the presence of ZnCl2 afforded diene 64, which was deprotected and oxidized to yield the desired N-protected amino acid. In a second synthesis of Adda, coupling of 62 with vinyl iodide 65 (differing from 63 only in oxidation state) was not successful under ZnCl2-mediated Pd-catalysis [70]. Instead, 62 was iodinated and subjected to Stille coupling with the vinyl stannane derivative of 65. The Zr–Zn–Pd transmetalation has also been applied towards the total syntheses of (–)-motuporin [71], reveromycin B [72], pitiamide A [73], FR901464 [74], and eunicenone A [75]. Montgomery and coworkers found that ZnCl2 was an essential additive to promote their Ni-catalyzed inter- or partially intramolecular couplings of alkenylzirconocenes, alkynes, and either aldehydes or enones [76] (Scheme 14).

Scheme 14 ZnCl2 is crucial to promote the Ni-catalyzed cyclization of 66 and an alkenylzirconocene

Hydrozirconation and Its Applications

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Scheme 15 One-pot ZrÆZn transmetalation and addition to aldehydes

7.2.2 ZirconiumÆZinc Just as Pd-catalyzed cross-couplings of organozirconium reagents and vinyl or aryl halides can be greatly improved by addition of ZnCl2 to the reaction mixture, so can zinc reagents improve their reactivity towards other organic electrophiles. For a recent review of ZrÆZn transmetalation, see [77].Wipf and Xu have shown that addition of dialkylzincs (Me2Zn or Et2Zn) to alkenylzirconocenes promotes 1,2-addition to aldehydes [78] (Scheme 15). Presumably, a ZrÆZn transmetalation is followed by the zirconium-promoted carbonyl addition of the vinyl ligand of the mixed alkyl-alkenyl zinc reagent 70. ZnBr2 can also be used in this transformation [79]. Procedure: Zr–Zn transmetalation, aldehyde addition [80]

A Schlenk flask, fitted with a rubber septum and a magnetic stirring bar, was charged under N2 with alkyne 68 (5.55 g, 18 mmol) and dry CH2Cl2 (60 mL), immersed in a cold water bath and stirred. Within 20 min, Cp2ZrHCl (5.10 g, 19.8 mmol) was added in five portions. The water bath was removed and the reaction mixture was stirred at room temperature until a homogeneous solution formed. The resulting golden-yellow solution was stirred for another 20 min and then cooled to –60 °C. By syringe, Me2Zn (2.0 M solution in toluene, 10.4 mL, 20.8 mmol) was added dropwise over 45 min while the bath temperature was kept at –60 °C. The resulting orange-yellow solution was stirred for an additional 10 min at –60 °C, the reaction flask was immersed in an ice bath, and a solution of hexanal (2.16 g, 21.6 mmol) in dry CH2Cl2 (10 mL) was added via syringe over 45 min. The reaction mixture was stirred at 0 °C for another 6 h and poured slowly into an ice-cold aqueous 5% NaHCO3 solution.Vigorous stirring was continued at room temperature until the gas evolution subsided. The mixture was extracted with Et2O. The combined organic extracts were washed with brine, dried (Na2SO4), filtered through a pad of Florisil and concentrated. The residue was purified by chromatography on SiO2 (ethyl acetate/hexanes, 1:30 to 1:15) to yield 4.90 g (66%) of 71 as a colorless oil. MeLi can also be used in place of Me2Zn in this transformation; however, the reaction proceeds through a different mechanism [81] (Scheme 16). Treatment

16

P. Wipf · C. Kendall

Scheme 16 MeLi can promote the addition of alkenylchlorozirconocenes to aldehydes

of the alkenylzirconocene 40 with MeLi replaces the chloride with a methyl group. This complex loses methane upon heating thus forming an alkyne-zirconocene complex. Reaction with benzaldehyde affords oxazirconacyclopentene 77 with excellent regioselectivity. Protonolysis gives the allylic alcohol. Unbranched terminal alkynes give excellent regioselectivity in the aldehyde insertion step, however, the selectivity is reduced when unsymmetrical internal alkynes or trimethylsilylacetylene are used. Wipf and coworkers have used the Zr–Zn transmetalation, aldehyde addition methodology for the rapid, stereocontrolled preparation of all-(E)-polyenes [82] in the total syntheses of (+)-curacin A [83] and (±)-nisamycin [84]. Synthesis of the eastern side chain of (±)-nisamycin was accomplished in two steps from alkyne 79 (Scheme 17). Hydrozirconation of 79 followed by addition to cyclohexylcarboxaldehyde in the presence of dimethylzinc afforded the allylic alcohol 80. Elimination of the newly formed hydroxyl group was accomplished via the corresponding trifluoroacetate.Addition of alkenylzirconocenes

Scheme 17 Application of a one-pot hydrozirconation, ZrÆZn transmetalation, aldehyde addition toward the total synthesis of (±)-nisamycin

Hydrozirconation and Its Applications

17

to a,b-unsaturated aldehydes yields bis-allylic alcohols that are very easily eliminated to form all-(E)-trienes. The Zr–Zn transmetalation, aldehyde addition strategy has also been used in the total syntheses of (–)-ratjadone [85] and fostriecin. In the latter example, the substrate was a chiral epoxyketone, which was converted to a tertiary alcohol in excellent diastereoselectivity by chelation control [86]. More recently, the reaction scope has been extended to the addition to C=N electrophiles to form allylic amides [87] as well as allyl hydroxylamines [88], and to the preparation of trans-1,2-disubstituted cyclopropanes [87, 89]. Powell and Rychnovsky found that the BF3-mediated addition to in situ formed oxacarbenium ions led to a mixture of alkyl and alkenyl ligand transfers [90] (Scheme 18).

Scheme 18 Additions to oxacarbenium ions

Wipf and Ribe developed a catalytic asymmetric variant of the aldehyde addition process employing chiral aminoalcohols and aminothiols as catalytic ligands [91]. Danishefsky and coworkers used this methodology in a total synthesis of (+)-halichlorine [92], and Porco’s group applied it in a recent synthesis of the salicylate antitumor antibiotic lobatamide C [93]. 7.2.3 ZirconiumÆCopper Transmetalation from Zr to Cu is a highly beneficial process as it combines the ease of preparation of organozirconocenes from alkenes and alkynes with the wide scope of organocopper reagents in organic synthesis. Schwartz and coworkers were first to demonstrate transmetalation to Cu in their report on the reductive dimerization of alkenylzirconocenes [94]. Virgili et al. used this transformation to prepare dialkoxy-1,3-butadienes [95]. The copper-mediated coupling of alkenylzirconocene 85 and phenethynyl bromide was reported to yield 86 [96] (Scheme 19). The latter two reactions can also be mediated by oxovanadium complexes [97].

Scheme 19 Cu-mediated cross-coupling of alkynyl bromide 85 with an alkenylzirconocene

18

P. Wipf · C. Kendall

Wipf and coworkers reported the preparation of a,b-unsaturated ketones by the Cu(I)-catalyzed addition of alkenylzirconocenes to acid chlorides [98]. Analogously, saturated ketones were obtained from alkylzirconocenes. This group also developed a copper-catalyzed conjugate addition of alkylzirconocenes to enones [99] and a,b-unsaturated acyloxazolidinones [100]. Lipshutz and coworkers have worked extensively on the preparation of cyanocuprates by a hydrozirconation, transmetalation sequence [101]. These cuprate reagents can be alkylated with epoxides or activated (benzylic or allylic) halides [102]. They have also been used in conjugate additions to a,b-unsaturated ketones [103], and a large-scale, one-pot preparation of prostaglandins has been based on this process [104]. Lipshutz and Wood reported an elegant three-component coupling of cyanocuprates, prepared by transmetalation from alkenylzirconocenes, cyclopentenones and aldehydes or propargylic triflates for the synthesis of prostaglandin-like compounds [105] (Scheme 20). Disubstituted cyclopentanone 90 was prepared in one pot and 74% yield as a 12:1 mixture of stereoisomers using alkyne 87, 2-cyclopentene1-one and methyl 4-oxobutanoate. A solid-supported version of this sequence was recently reported [106].

8 Miscellaneous Reactions of Organozirconocenes After an initial discovery by Negishi and coworkers [107],Whitby and Kasatkin expanded the scope of the reaction of 1-lithio-1-haloalkenes and organozirconocenes [108] (Scheme 21). In this interesting process, the lithium reagent reacts with the zirconocene, presumably via an “ate-complex”, to generate a new alkenylzirconocene. 1-Lithio-1-chloroalkene 93 is formed by treatment of (Z)1-chloro-2-methyl-1-octene with LiTMP at –80 °C, and quenching of the alkenylzirconocene intermediate 94 provides a 93:7 ratio of trisubstituted alkenes 95 and 96. With (E)-1-chloro-2-methyl-1-octene as a starting material under the same conditions, the ratio of 95 to 96 is 63:37; however, if the corresponding (E)-iodide is used, the ratio is found to change to 16:84. Dienes are

Scheme 20 One-pot synthesis of prostaglandins by conjugate addition, enolate trapping

Hydrozirconation and Its Applications

19

Scheme 21 Insertion of vinyl lithium 93 into alkylzirconocene 92 to form an alkenylzirconocene

formed either by reacting 1-lithio-1-haloalkenes with alkenylzirconocenes, which results in poor E:Z selectivity in the insertion step, or by reacting 1lithio-1-halodienes with alkylzirconocenes, which can give much better selectivity. Trienes are formed by reacting the lithiohalodienes with alkenylzirconocenes, and alkynylzirconocenes, formed by treating zirconocene dichloride with alkynyl lithium reagents, can also be subjected to these reaction conditions to form enynes and dienynes. Similarly, homologation of alkenylzirconocenes into allylzirconocenes occurs when reagents such as LiCH(Cl)SiMe3 [109] or LiCH(Cl)OMe [110] are used in place of the lithioalkene, and lithioepoxynitriles are transformed into 2-cyano-1,3-dienes [111]. Wipf and Kendall have recently reported a multi-component allylation of aldimines in which the allylmetal species is generated in situ from a mixture of alkenylzirconocene, dimethylzinc and diiodomethane [112]. Suzuki and coworkers developed a method for the preparation of allylzirconocenes by hydrozirconation of allenes. The resulting allylzirconocenes readily converted aldehydes into homoallylic alcohols in high diastereoselectivities [113]. This group has also shown that allylzirconocenes can be used to carbometalate alkynes [114] (Scheme 22). The latter process was found to be very regiospecific; for example, the carbozirconation of alkyne 99 resulted in the isolation of naphthalene 103 as the sole product after protonolysis of the intermediate alkenylzirconocene 101. When iodoalkyne 100 was subjected to the same reaction conditions, a formal substitution took place and led to the formation of enyne 104 [115]. Alkylzirconocenes can also be used for the carbozirconation of alkynes if [Ph3C]+[B(C6F5)]– is used as the initiator in place of methylaluminoxane (MAO) [116]. Taguchi, Hanzawa and coworkers prepared cyclopropyl alcohols from vinyloxiranes by simply treating the substrate with Schwartz reagent in CH2Cl2 [117] (Scheme 23). This reaction was very diastereoselective (when R=Me) for cisvinyloxirane 105b since cyclopropyl alcohol 108b was the only diastereomer

20

P. Wipf · C. Kendall

Scheme 22 Carbozirconation of alkyne 99 catalyzed by MAO, and a spontaneous rearrangement of 102 into enyne 104

Scheme 23

Synthesis of cyclopropyl alcohols from vinyloxiranes

observed in the reaction mixture. When the corresponding trans-vinyloxirane was used, the diastereomeric ratio of the anti,trans-cyclopropane (vs. anti,cis) was 80:20.Allylic ethers were converted into cyclopropanes by the same mechanism; however, a Lewis acid was needed for deoxygenation [118].

Hydrozirconation and Its Applications

21

Scheme 24 Regioselective 1,2- or 1,4-addition of acylzirconocenes to a,b-unsaturated ketones

As initially reported by Schwartz and Bertelo [119], CO can be inserted into C–Zr bonds, resulting in acylzirconocenes. Hanzawa, Taguchi and coworkers have developed the synthetic utility of these complexes and demonstrated their reactivity in Lewis acid mediated additions to aldehydes [120], Pd-catalyzed cross-couplings with aryl halides, benzyl halides, acid chlorides and allylic acetates [121], and Pd-catalyzed conjugate or 1,2-additions to a,b-unsaturated ketones [122] (Scheme 24). The site of addition (1,4- vs. 1,2-) can be completely controlled by the choice of reaction conditions. For example, addition of acylzirconocene 110 to cyclohexenone afforded exclusively the 1,2-addition product a-hydroxyketone 111 under Pd-catalysis. Reaction of the same substrates under BF3·OEt2-mediated Pd-catalysis gave exclusively the 1,4-addition product. The yield and selectivity with acyclic ketone substrates is equally high. The use of chiral phosphine ligands for Pd under the 1,2-addition conditions afforded hydroxyl ketones with modest (up to 67%) enantiomeric excess [123]. Dupont and Donato have developed a synthesis of parasorbic acid and other 5,6–2H-pyran-2-ones by quenching an acylzirconocene intermediate with iodine followed by intramolecular lactonization [124]. Hypervalent aryl and vinyl iodonium salts have also been used as electrophiles for Pd-catalyzed coupling with acylzirconocenes [125]. Oxidation of the carbon–zirconium bond in organozirconocenes can be effected by a wide range of reagents and results in alcohols and carbonyl compounds in generally only moderate yields [126].

9 Conclusions As amply demonstrated by the success of the metathesis reaction [127], alkenes and alkynes are synthetically extraordinarily versatile functional groups for transition metal-mediated transformations. Hydrozirconation with readily available zirconocene hydrides allows the direct reductive conversion of

22

P. Wipf · C. Kendall

alkenes and alkynes into reactive nucleophiles under mild reaction conditions that are compatible with the presence of many functional groups. While in the past most synthetic uses of organozirconocenes have been limited to halide formation, transmetalation protocols provide for a far greater value by selective carbon–carbon bond formations. In particular, cross-coupling and multi-component reactions have greatly extended the scope of the sterically hindered organozirconocene complexes. As a consequence, use of alkenyl- and alkylzirconocenes in natural product synthesis has considerably increased in the past 10 years. Much of the incentive for future method development with hydrozirconation products is likely to derive from new reaction discovery and the evolution of older, racemic protocols into catalytic enantioselective transformations.

References 1. Schwartz J, Labinger JA (1976) Angew Chem, Int Ed Engl 15:333 2. Hartner FM, Clift SM, Schwartz J (1987) Organometallics:1346 3. Waymouth RM, Santarsiero BD, Coots RJ, Bronikowski MJ, Grubbs RH (1986) J Am Chem Soc 108:1427 4. Wipf P, Jahn H (1996) Tetrahedron 52:12853 5. Wipf P, Xu W, Takahashi H, Jahn H, Coish PDG (1997) Pure Appl Chem 69:639 6. Labinger JA (1991) In: Trost BM, Fleming I (eds) Comprehensive organic synthesis, vol 8. Pergamon, Oxford, p 667 7. Takacs JM (1995) In: Abel EW, Stone FGA, Wilkinson G (eds) Comprehensive organometallic chemistry II: A review of the literature 1982–1994, vol 12. Pergamon, Oxford, UK, p 39 8. Wipf P, Takahashi H, Zhuang N (1998) Pure Appl Chem 70:1077 9. Annby U, Karlsson S, Gronowitz S, Hallberg A, Alvhall J, Svenson R (1993) Acta Chem Scand 47:425 10. Chirik PJ, Day MW, Labinger JA, Bercaw JE (1999) J Am Chem Soc 121:10308 11. Wailes PC, Weigold H (1970) J Organomet Chem 24:405 12. Wailes PC, Weigold H, Bell AP (1972) J Organomet Chem 43:C32 13. Wailes PC, Weigold H, Bell AP (1971) J Organomet Chem 27:373 14. Hart DW, Schwartz J (1974) J Am Chem Soc 96:8115 15. Hart DW, Blackburn TF, Schwartz J (1975) J Am Chem Soc 97:679 16. Carr DB, Schwartz J (1979) J Am Chem Soc 101:3521 17. Wipf P, Wang X (2000) Tetrahedron Lett 41:8237 18. Buchwald SL, LaMaire SJ, Nielsen RB, Watson BT, King SM (1987) Tetrahedron Lett 28:3895 19. Pool JA, Bradley CA, Chirik PJ (2002) Organometallics 21:1271 20. Swanson DR, Nguyen T, Noda Y, Negishi E (1991) J Org Chem 56:2590 21. Makabe H, Negishi E (1999) Eur J Org Chem 969 22. Lipshutz BH, Keil R, Ellsworth EL (1990) Tetrahedron Lett 31:7257 23. Eisch JJ, Owour FA, Shi X (1999) Oganometallics 18:1583 24. Annby U, Gronowitz S, Hallberg A (1990) Acta Chem Scand 44:862 25. Luinstra GA, Rief U, Prosenc MH (1995) Organometallics 14:1551 26. Buchwald SL, LaMaire SJ, Nielsen RB, Watson BT, King SM (1993) Org Synth 71:77 27. Negishi E, Takahashi T (1998) Bull Chem Soc Jpn 71:755

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28. Takahashi T, Kotora M, Fischer R, Nishihara Y, Nakajima K (1995) J Am Chem Soc 117:11039 29. Ichikawa J, Fujiwawa M, Nawata H, Okauchi T, Minami T (1996) Tetrahedron Lett 37:8799 30. Liard A, Kaftanov J, Chechik H, Farhat S, Morlender-Vais N, Averbuj C, Marek I (2001) J Organomet Chem 624:26 31. Ganchegui B, Bertus P, Szymoniak J (2001) Synlett 123 32. Farhat S, Marek I (2002) Angew Chem Int Ed 41:1410 33. Williams DR, Kissel WS (1998) J Am Chem Soc 120:11198 34. Matsushima T, Mori M, Zheng BZ, Maeda H, Nakajima N, Uenishi J,Yonemitsu O (1999) Chem Pharm Bull 47:308 35. Zheng BP, Maeda H, Mori M, Kusaka S, Yonemitsu O, Matsushima T, Nakajima N, Uenishi J (1999) Chem Pharm Bull 47:1288 36. Nicolaou KC, Jung JK, Yoon WH, He Y, Zhong YL, Baran PS (2000) Angew Chem Int Ed 39:1829 37. Smith III AB, Chen SSY, Nelson FC, Reichert JM, Salvatore BA (1997) J Am Chem Soc 119:10935 38. Lipshutz BH, Keil R, Barton JC (1992) Tetrahedron Lett 33:5861 39. Mapp AK, Heathcock CH (1999) J Org Chem 64:23 40. Arefolov A, Langille NF, Panek JS (2001) Org Lett 3:3281 41. Xu X-H, Zheng W-X, Huang X (1998) Synth Commun 28:4165 42. Bray KL, Lloyd-Jones GC (2001) Eur J Org Chem 1635 43. Zippi EM, Andres H, Morimoto H, Williams PG (1994) Synth Commun 24:1037 44. Ballenweg S, Gleiter R, Krätschmer W (1993) Tetrahedron Lett 34:3737 45. Godfrey AG, Ganem B (1992) Tetrahedron Lett 33:7461 46. Schedler DJA, Li J, Ganem B (1996) J Org Chem 61:4115 47. White JM, Tunoori AR, Georg GI (2000) J Am Chem Soc 122:11995 48. Zablocka M, Delest B, Igau A, Skowronska A, Majoral J-P (1997) Tetrahedron Lett 38:5997 49. Maraval A, Igau A, Lepetit C, Chrostowska A, Sotiropoulos J-M, Pfister-Guillouzo G, Donnadieu B, Majoral J-P (2001) Organometallics 20:25 50. Trauner D, Danishefsky SJ (1999) Tetrahedron Lett 40:6513 51. Negishi E, Swanson DR, Miller SR (1988) Tetrahedron Lett 29:1631 52. Maeta H, Hashimoto T, Hasegawa T, Suzuki K (1992) Tetrahedron Lett 33, 5965 53. Suzuki K, Hasegawa T, Imai T, Maeta H, Ohba S (1995) Tetrahedron 51:4483 54. Wipf P, Xu W (1993) J Org Chem 58:825 55. Wipf P, Xu W (1993) J Org Chem 58:5880 56. Wipf P, Methot J-L (1999) Org Lett 1:1253 57. Richter F, Bauer M, Perez C, Maichle-Mössmer C, Maier ME (2002) J Org Chem 67:2474 58. Negishi E, Van Horn DE (1977) J Am Chem Soc 99:3168 59. Okukado N, Van Horn DE, Klima WL, Negishi E (1978) Tetrahedron Lett 1027 60. Negishi E, Takahashi T, Baba S, Van Horn DE, Okukado N (1987) J Am Chem Soc 109:2393 61. Stille JK (1986) Angew Chem Int Ed 25:508 62. Miyaura N, Suzuki A (1995) Chem Rev 95:2457 63. Xu CD, Negishi E (1999) Tetrahedron Lett 40:431 64. Lipshutz BH, Bülow G, Lowe RF, Stevens KL (1996) Tetrahedron 52:7265 65. Schwaebe MK, McCarthy JR, Whitten JP (2000) Tetrahedron Lett 41:791 66. Negishi E, Okukado N, King AO, Van Horn DE, Spiegel BI (1978) J Am Chem Soc 100:2254 67. Zeng F, Negishi E (2002) Org Lett 4:703

24 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116.

P. Wipf · C. Kendall Panek JS, Hu T (1997) J Org Chem 62:4912 Panek JS, Hu T (1997) J Org Chem 62:4914 D’Aniello F, Mann A, Schoenfelder A, Taddei M (1997) Tetrahedron 53:1447 Hu T, Panek JS (1999) J Org Chem 64:3000 Drouet KE, Theodorakis EA (2000) Chem Eur J 6:1987 Ribe S, Kondru RK, Beratan DN, Wipf P (2000) J Am Chem Soc 122:4608 Thompson CF, Jamison TF, Jacobsen EN (2000) J Am Chem Soc 122:10482 Lee TW, Corey EJ (2001) J Am Chem Soc 123:1872 Ni YK, Amarasinghe KKD, Montgomery J (2002) Org Lett 4:1743 Wipf P, Kendall C (2002) Chem Eur J 8:1778 Wipf P, Xu W (1994) Tetrahedron Lett 35:5197 Zheng B, Srebnik M (1995) J Org Chem 60:3278 Wipf P, Xu W (1997) Org Synth 74:205 Maier ME, Oost T (1995) J Organomet Chem 505:95 Wipf P, Coish PDG (1997) Tetrahedron Lett 38:5073 Wipf P, Xu W (1996) J Org Chem 61:6556 Wipf P, Coish PDG (1999) J Org Chem 64:5053 Williams DR, Ihle DC, Plummer SV (2001) Org Lett 3:1383 Chavez DE, Jacobsen EN (2001) Angew Chem Int Ed 40:3667 Wipf P, KendallC, Stephenson CRJ (2001) J Am Chem Soc 123:5122 Pandya SU, Garçon C, Chavant PY, Py S, Vallée Y (2001) Chem Commun 1806 Yachi K, Shinokubo H, Oshima K (1998) Angew Chem Int Ed 37:2515 Powell NA, Rychnovsky SD (1999) J Org Chem 64:2026 Wipf P, Ribe S (1998) J Org Chem 63:6454 Trauner D, Schwarz JB, Danishefsky SJ (1999) Angew Chem Int Ed 38:3542 Shen R, Lin CT, Porco JA (2002) J Am Chem Soc 124:5650 Yoshifuji M, Loots MJ, Schwartz J (1977) Tetrahedron Lett 1303 Virgili M, Moyano A, Pericàs MA, Riera A (1997) Tetrahedron Lett 38:6921 Hara R, Liu Y, Sun W-H, Takahashi T (1997) Tetrahedron Lett 38:4103 Ishikawa T, Ogawa A, Hirao T (1999) J Organomet Chem 575:76 Wipf P, Xu W (1992) Synlett 718 Wipf P, Xu W, Smitrovich JH, Lehmann R, Venanzi LM (1994) Tetrahedron 50:1935 Wipf P, Takahashi H (1996) Chem Commun:2675 Lipshutz BH, Bhandari A, Lindsley C, Keil R, Wood MR (1994) Pure Appl Chem 66: 1493 Lipshutz BH, Kato K (1991) Tetrahedron Lett 32:5647 Lipshutz BH, Ellsworth EL (1990) J Am Chem Soc 112:7440 Babiak KA, Behling JR, Dygos JH, McLaughlin KT, Ng JS, Kalish VJ, Kramer SW, Shone RL (1990) J Am Chem Soc 112:7441 Lipshutz BH, Wood MR (1994) J Am Chem Soc 116:11689 Manzotti R, Tang S-Y, Janda KD (2000) Tetrahedron 56:7885 Negishi E, Akiyoshi K, O’Connor B, Takagi K, Wu G (1989) J Am Chem Soc 111:3089 Kasatkin A, Whitby RJ (1999) J Am Chem Soc 121:7039 Kasatkin AN, Whitby RJ (1999) Tetrahedron Lett 40:9353 Kasatkin AN, Whitby RJ (2000) Tetrahedron Lett 41:6211 Kasatkin AN, Whitby RJ (2000) Tetrahedron Lett 41:6201 Wipf P, Kendall C (2001) Org Lett 3:2773 Chino M, Matsumoto T, Suzuki K (1994) Synlett 359 Yamanoi S, Imai T, Matsumoto T, Suzuki K (1997) Tetrahedron Lett 38:3031 Yamanoi S, Matsumoto T, Suzuki K (1999) Tetrahedron Lett 40:2793 Yamanoi S, Seki K, Matsumoto T, Suzuki K (2001) J Organomet Chem 624:143

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117. Harada S, Kowase N, Tabuchi N, Taguchi T, Dobashi Y, Dobashi A, Hanzawa Y (1998) Tetrahedron 54:753 118. Gandon V, Szymoniak J (2002) Chem Commun 1308 119. Bertelo CA, Schwartz J (1975) J Am Chem Soc 97:228 120. Harada S, Taguchi T, Tabuchi N, Narita K, Hanzawa Y (1998) Angew Chem Int Ed 37:1696 121. Hanzawa Y, Tabuchi N, Taguchi T (1998) Tetrahedron Lett 39:6249 122. Hanzawa Y, Tabuchi N, Taguchi T (1998) Tetrahedron Lett 39:8141 123. Hanzawa Y, Tabuchi N., Saito K, Noguchi S, Taguchi T (1999) Angew Chem Int Ed 38:2395 124. Dupont J, Donato AJ (1998) Tetrahedron: Asymmetry 9:949 125. Kang S-K, Yoon S-K (2002) J Chem Soc, Perkin Trans I 459 126. Nagashima T, Curran DP (1996) Synlett:330 127. Trnka TM, Grubbs RH (2001) Acc Chem Res 34:18

Topics Organomet Chem (2004) 8: 27– 56 DOI 10.1007/b13143 © Springer-Verlag Berlin Heidelberg 2004

Construction of Carbocycles via Zirconacycles and Titanacycles Zhenfeng Xi (

) · Zhiping Li

Peking University, College of Chemistry, 100871 Beijing, China [email protected]

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

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29

1

Introduction

2

Preparative Methods for Metallacyclic Intermediates

2.1 2.2 2.3 2.4

Metallacyclopropanes and Metallacyclopropenes . . . . . . . . . . . . . . Metallacyclobutanes and Metallacyclobutenes . . . . . . . . . . . . . . . Metallacyclopentanes, Metallacyclopentenes, and Metallacyclopentadienes Six-Membered Metallacycles . . . . . . . . . . . . . . . . . . . . . . . . .

. . . .

29 31 32 34

3

Preparation of Carbocyclic Compounds via Metallacycles . . . . . . . . . .

36

3.1 3.2 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.4 3.4.1 3.4.2 3.4.3 3.5

Three-Membered Carbocycles . . . . . . . . . . . . . . . . . . . Four-Membered Carbocycles . . . . . . . . . . . . . . . . . . . . Five-Membered Carbocycles . . . . . . . . . . . . . . . . . . . . Carbon Monoxide as One-Carbon Unit Affording Cyclic Ketones Isocyanides as One-Carbon Unit . . . . . . . . . . . . . . . . . . Other One-Carbon Unit Equivalents . . . . . . . . . . . . . . . . Preparation of Five-Membered Heterocycles . . . . . . . . . . . Six-Membered Carbocycles . . . . . . . . . . . . . . . . . . . . Benzene Derivatives . . . . . . . . . . . . . . . . . . . . . . . . Pyridine Derivatives and Related Compounds . . . . . . . . . . Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Seven-Membered Carbocycles and Others . . . . . . . . . . . .

. . . . . . . . . . . .

36 38 40 40 43 44 46 47 47 50 50 52

4

Concluding Remark

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53

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53

References

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Abstract Metal-mediated selective construction of useful carbocyclic compounds from multi-component reaction systems has attracted much attention in recent years. Zirconocene (containing a Cp2Zr unit) and titanocene (containing a Cp2Ti unit) mediated reactions have made significant contributions to the development of synthetically useful methodologies for construction of carbocyclic compounds from different components. This review surveys applications of zirconacycles and titanacycles on construction of useful carbocyclic compounds from multi-components. A brief introduction into preparative methods for zirconacycles and titanacycles is also given. Keywords Zirconacycle · Titanacycle · Carbocycles · Methodology · Selectivity

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1 Introduction The preparation and reaction chemistry of metallacyclic compounds have attracted much attention in recent years because many synthetically important transition-metal-assisted reactions proceed via metallacyclic intermediates.As a consequence, metallacyclic compounds have become a large family in organometallic chemistry, and are normally generated in situ in a reaction that involves reductive coupling of two unsaturated organic substrates on a low valent transition metal center. Metallacycles of group 4 metals, especially Zr and Ti with cyclopentadienyl (Cp) ligands, have proven very useful as reagents in synthetic chemistry (Fig. 1). Existence of the two identical or different M–C bonds in such metallacycles provides various opportunities to design and construct a large diversity of compounds. Carbocycles are important compounds in natural products and functional materials. The traditional preparative methods for cyclic compounds include the Diels–Alder addition reaction, and cyclization mediated by Lewis acid and base. With the aid of metallacycles, carbocycles are often prepared in high yields with high selectivity from different components (Scheme 1). Among many metallacycles, zirconacycles and titanacycles with Cp ligands have been most widely used in stoichiometric reactions to prepare carbocycles.

Scheme 1 Preparation of carbocyles mediated by stoichiometric amounts of metallacycles via intermolecular reaction patterns

Fig. 1

Some representatives of metallacycles of zirconocene and titanocene. M=Zr or Ti

Construction of Carbocycles via Zirconacycles and Titanacycles

29

There have been several excellent reviews and books dealing with preparation methods of zirconacycles and titanacycles, especially on the formation of 3- and 5-membered zirconacycles [1–5]. Therefore, this paper will not describe details of preparation of 3- and 5-membered zirconacycles, which are the most popular metallacycles of zirconocene and titanocene. In order for readers to find appropriate references, a brief introduction into preparative methods of these metallacycles is given. Applications of zirconacycles and titanacycles in the construction of useful carbocyclic compounds from multi-components are summarized.

2 Preparative Methods for Metallacyclic Intermediates Generation of zirconocene (II) and titanocene (II) species is a prerequisite since zirconocene (IV) and titanocene (IV) are the stable oxidation states. A ligand-free zirconocene (II) species, [Cp2Zr(II)], a 14-electron species with d2 configuration, has been well accepted as a highly reactive intermediate, although it has never been isolated as a discrete chemical compound. Zirconocene (II) complexes are generally prepared by the reduction of zirconocene (IV) dichloride in the presence of stabilizing ligands such as carbon monoxide, phosphines, alkenes, alkynes, and so on [1–5]. Either heterogeneous or homogeneous procedures have been reported. As reducing reagents, Na, Li, Mg, Mg/HgCl2, Na–Hg, and so on, had been commonly used before Negishi and coworkers reported the convenient method for generating Cp2Zr(II) species by treatment of Cp2ZrCl2 with two equivalents of n-BuLi (Eq. 1) [6].

(1)

2.1 Metallacyclopropanes and Metallacyclopropenes Excellent reviews or chapters in books have been published dealing with chemistry of metallocene–alkene complexes, metallocene–alkyne complexes, and their corresponding three-membered metallacyclic compounds of zirconocene and titanocene [1–5]. Zirconocene(II)–alkene complexes and zirconocene (II)–alkyne complexes are often also viewed as zirconocene (IV) comple-

30

Z. Xi · Z. Li

(2)

(3)

(4)

xes (resonance hybrids) [2a]; their corresponding three-membered zirconacyclopropanes and zirconacyclopropenes are shown below (Eqs. 2–4, M=Zr, Ti). The first X-ray structure of a zirconocene(II)-–alkene complex, zirconocene(II)–stilbene stabilized by phosphine, was reported by Takahashi and coworkers [7]. Basically, the formation of zirconocene alkene or alkyne complexes may be achieved in three different ways: (a) by a reductive elimination process starting from alkyl, alkenyl or aryl zirconocene(IV) complexes (Eq. 1, and Eqs. 5–6) [1–5, 8, 9], or (b) by ligand exchange reactions involving carbonyl or phosphine complexes (Eq. 7), or (c) by b,b¢-C–C bond cleavage of zirconacyclopentanes or zirconacyclopentenes (Eqs. 8–9) [10, 11].

(5)

(6)

(7)

Construction of Carbocycles via Zirconacycles and Titanacycles

31

(8)

(9)

Oxazirconacyclopropanes, silazirconacyclopropanes, and other three-membered zirconacycles containing heteroatoms have been prepared via transmetallation and migratory insertion (Eqs. 10–11) [12]. (10)

(11) 2.2 Metallacyclobutanes and Metallacyclobutenes Four-membered titanacycle intermediates have been often involved in titanium carbene mediated olefin metathesis and related reactions (Eqs. 12–13). Both titanacyclobutanes and titanacyclobutenes have been reported and are useful intermediates for the synthesis of various organic compounds. Since many reviews have appeared [13], no details will be described in the paper. (12)

(13)

Except the well-known olefin-metathesis protocol, generally, there is lack of preparative methods for four-membered metallacycles. Takahashi and coworkers reported formation of zirconacyclobutene–silacyclobutene fused ring compound via a novel skeletal rearrangement of zirconacycles (Eq. 14) [14]. The structure of this compound has been characterized by X-ray analysis [14b]. (14)

32

Z. Xi · Z. Li

Fig. 2

Rosenthal and coworkers reported a series of interesting reactions of bis(trimethylsilyl)acetylene–zirconocene and –titanocene complexes.A variety of metallacyclobutene derivatives were prepared via metallacycocumulenes from 1,3-diynes, linear tetraynes, and tetraalkynylsilanes (Fig. 2). Cleavage of C–C single bonds in conjugated diynes was observed [5]. 2.3 Metallacyclopentanes, Metallacyclopentenes, and Metallacyclopentadienes There have been many reports on the preparation and applications of fivemembered zirconacycles, namely, zirconacyclopentanes, zirconacyclopentenes and zirconacyclopentadienes [1–5]. For the preparation of 5-membered zirconacycles, although it is possible to use di-Grignard or dilithium reagents for the preparation of zirconacyclopentanes [10], the reductive coupling of unsaturated organic substrates, either intramolecular or intermolecular, on a zirconocene(II) species is the most common way. Generally, intramolecular coupling pattern can afford bicyclic metallacycles in excellent yield with perfect regioselectivity. Treatment of zirconocene(II) species, generated in situ either by Cp2ZrCl2/2 n-BuLi (Negishi reagent) or Cp2ZrCl2/Mg/HgCl2, with a diene, a nonconjugated enyne, or a diyne affords high yield formation of corresponding bicyclic zirconacyclopentane, zirconacyclopentene, and zirconacyclopentadiene, respectively (Eqs. 15–18) [10, 15–17]. Titanacyclopentadienes could be prepared in a similar way [18, 19]. It is noteworthy that terminal acetylenes are generally not applicable for this reaction. Messy mixtures are normally obtained.

(15)

(16)

Construction of Carbocycles via Zirconacycles and Titanacycles

33

(17)

(18)

Coupling reaction of an alkene with a zirconocene(II)–alkene complex may give a zirconocyclopentane (and regioisomers). Similarly, formation of zirconacyclopentenes can be expected when zirconocene(II)–alkene complexes are treated with alkynes or when zirconocnene(II)–alkyne complexes are treated with alkenes. Takahashi has reported a very convenient procedure for the preparation of zirconacyclopentenes by warming of Cp2ZrEt2 to 0 °C in the presence of an alkyne or a conjugated diyne (Eq. 19) [11]. Although titanacyclopentenes could be similarly prepared (Eq. 20) [18], the reaction should be carried out at –30 °C. When the reaction is done at 0 °C, as the case for zirconocene, low yields of titanacyclopentenes are obtained.

(19)

(20)

Compared with symmetrical metallacyclopentadienes, unsymmetrical metallacyclopentadienes from two different alkynes are not always easily prepared. Several methods have been reported for preparation of unsymmetrical zirconacyclopentadienes in which the key step is the addition of a second alkyne to zirconocene–alkyne complexes generated in situ [20]. Formation of homocoupling products from the same alkyne is often the biggest problem (Eq. 21).

(21)

34

Z. Xi · Z. Li

(22)

A highly selective and practical alkyne–alkyne cross-coupling using Cp2ZrBu2 and ethylene gas was developed by Takahashi and coworkers (Eq. 22) [20]. A first alkyne was added to zirconacyclopentanes, generated in situ from the reaction of Cp2ZrBu2 and ethylene gas, affording zirconacyclopentenes with high selectivities at room temperature under ethylene atmosphere. Subsequent addition of a second alkyne to the solution of zirconacyclopentenes at 50 °C gave unsymmetrical zirconacyclopentadienes selectively from two different alkynes. For unsymmetrical titanacyclopentadienes, there is still no selective preparative method. Cyclic gem-metallozirconocene compounds such as a-lithiated zirconacyclopentadienes, a-stannyl or gallio-zirconacyclopentenes, and a,a¢bis(trimethylstannyl) zirconacyclopentadienes have been prepared (Fig. 3) [21–25]. These multifunctionalized zirconacycles can be expected to have useful applications in organic synthesis. 2.4 Six-Membered Metallacycles Compared with five-membered metallacycles, relatively fewer reports are known on the preparative methods and reaction chemistry of six-membered metallacycles.Whitby and coworkers have systematically investigated insertion of carbenoids into five-membered zirconacycles and developed a number of interesting six-membered zirconacycles [17, 26]. Isonitriles, 1-halo-1lithioalkenes, allenyl carbenoids, allyl carbenoids, propargy carbenoids, benzyl carbenoids, and 1-nitrile-1-lithio epoxides can all insert into zirconacyclopentanes and zirconacyclopentenes to afford various six-membered zirconacycles (Eqs. 23, 24).

Fig. 3

Construction of Carbocycles via Zirconacycles and Titanacycles

35

(23)

(24)

Lithiated chloromethyltrimethylsilane was reported to insert into zirconacyclopentadienes to give zirconacyclohexadiene derivatives (Eq. 25) [27]. This has been so far the only example of carbenoid insertion into 5-membered metallacyclopentadienes.

(25)

The first example of intramolecular alkyne insertion into zirconacyclopentadienes was reported by Takahashi and coworkers (Eq. 26) [14b]. The structure of the zirconacyclohexadiene–silacyclobutene fused ring compound was determined by single crystal X-ray analysis. Xi and coworkers recently reported an alternative method for the preparation of analogous zirconacyclohexadiene–silacyclobutene fused ring compound via an unprecedented alkyne-induced C–C bond and C–Si bond cleavage pattern (Eq. 27) [14c].

(26)

(27)

In a similar manner, reactions of zirconocene–benzyne complexes with bis(phenylalkynyl)phosphine afforded benzocyclozirconacyclohexadiene derivatives (Eq. 28) [28].

36

Z. Xi · Z. Li

(28)

A dibenzotitanacyclohexadiene, the first example of this kind, was prepared in 1988 from the reaction of 2,2¢-dilithiobiphenyl and Cp2TiCl2 and structurally characterized (Eq. 29) [29].

(29) Obviously, titanocene analogues of six-membered metallacycles are very rare, due to lack of preparative methods. More preparative methods are desirable and interesting reaction chemistry can be expected of six-membered metallacycles.

3 Preparation of Carbocyclic Compounds via Metallacycles Construction of carbocycles from metallacycles is attractive. Theoretically, for example, reaction of a five-membered metallacycle with a one-carbon unit may afford a five-membered carbocycle. A six-membered carbocycle may be formed from insertion of a two-carbon unit into a five-membered metallacycle. However, in many cases, skeletal rearrangement of in situ generated metallacycles takes place, thus making prediction of structures of products very difficult. Accordingly, in this section, we focus on the carbocycles formed, regardless of the starting metallacycles. 3.1 Three-Membered Carbocycles Formation of three-membered carbocycles from the reaction of three-membered metallacycles (or metallocene–alkyne or –alkene complexes) with a onecarbon unit can be considered to be the most straightforward way (Scheme 2). However, such a preparative route has not been reported. Takahashi and coworkers have reported three types of formation of cyclopropane derivatives from five-membered zirconacycles. One is via reaction of carbenes or carbenoids with carbon–carbon double bond in zirconcyclopentadienes (Eq. 30) [30], the second via b-elimination from zirconacyclopentenes (Eq. 31) [31] and the third via intramolecular Michael addition (Eq. 32) [32].

Construction of Carbocycles via Zirconacycles and Titanacycles

37

Scheme 2

Both of the carbene species, :CX2 and :CH2, which were generated in situ by the standard procedures, could smoothly react with one a,b-C=C bond in zirconacyclopentadienes without interference with Zr–C bonds to give cyclopropane derivatives after hydrolysis (Eq. 30) [30]. This was the first example of reaction of the a,b-C=C bond in metallacyclopentadienes.

(30)

The reaction of zirconacyclopentenes with homoallyl bromides afforded allylcyclopropane derivatives with diastereoselectivity through intramolecular alkylation (Eq. 31) [31]. A a-substituted homoallylic bromide produced predominantly the cis-isomer for the disubstituted cyclopropane moiety, while a b-substituted one gave the trans-isomer as a main product.

(31)

38

Z. Xi · Z. Li

(32)

Titanacyclopentenes are formed from the reaction of Cp2TiEt2 and alkynes as described above (Eq. 20) [18]. However, interestingly, when a silylated acetylene such as 1-trimethylsilyl-1-propyne was used, 1-methyl-1-(trimethylsilyl)methyl cyclopropane, other than the expected titanacyclopentene, was formed (Eq. 33) [18]. This reaction chemistry is different from that of analogous zirconocene. Formation of a titanocene–carbene complex is proposed via Michael addition-type reaction in the titanacyclopentene intermediates.

(33)

3.2 Four-Membered Carbocycles Cyclobutadiene is one of the most attractive molecules.A conceptually new and simple method using intramolecular coupling of 1-metallo-4-halobutadiene was reported to form cyclobutadiene derivatives by Takahashi and coworkers (Eq. 34). 1-Zircona-4-halobutadiene derivatives, generated in situ by treatment of zirconacyclopentadienes with one equivalent of iodine, react in the presence

Construction of Carbocycles via Zirconacycles and Titanacycles

39

(34)

(35)

of CuCl to produce cyclobutadiene derivatives that afford their dimmers, or Diels–Alder adducts with dimethyl maleate or fumarate (Eq. 35) [33]. Following the same concept as described above, a convenient one-pot procedure to arylcyclobutenes from arylacetylenes via zirconacyclopentenes was reported (Eq. 36) [34]. By using this method, conjugated cyclobutenes such as 1,2-diarylcyclobutenes can be readily prepared.

(36)

Negishi and coworkers reported an alternative method for 1,2-disubstituted cyclobutene derivatives from the reaction of t-BuLi and 1,4-diiodo-1-alkenes (Eq. 37) [35], which are isolated from treatment of zirconacyclopentes with iodine. However, the use of t-BuLi does not tolerate other functional groups in the starting diiodides. As described in Eq. 14 and Eqs. 26 to Eq. 28, and Fig. 2, along with formation of metallacycles, silacyclobutene derivatives and the phosphorus analogues are formed. These methods represent general routes for silacyclobutene derivatives. Interesting reaction chemistry of such silacycles can be expected.

(37)

40

Z. Xi · Z. Li

3.3 Five-Membered Carbocycles Conversion of the five-membered metallacycles into five-membered carbocycles, where the metal is eventually replaced with one carbon atom, is an attractive method for the construction of five-membered carbocycles (Eq. 38). In fact, such transformation is very popular using five-membered metallacycles of titanocenes and zirconocenes [1–5].

(38)

3.3.1 Carbon Monoxide as One-Carbon Unit Affording Cyclic Ketones The carbonylation reactions are very important in synthesis and for industrial applications as well. The Pauson–Khand reaction, the well-known cobalt-mediated procedure, combines an alkyne, an alkene, and a carbon monoxide ligand into cyclopentenones (Eq. 39) [36].

(39)

Zirconocene or titanocene mediated intramolecular cyclization reactions of enynes followed by CO insertion into their corresponding five-membered metallacycles led to the formation of bicyclic cyclopentenones (Eqs. 40, 41) [37, 38]. Intermolecular coupling of alkynes, alkenes, and CO mediated by zirconocene or titanocene affording cyclopentenone derivatives have also been achieved (Eq. 39) [18, 39, 40]. It is noteworthy that, in order to obtain the desired cyclopentenones from the reaction of zirconacyclopentenes with CO, termination of the reaction mixture with I2 is necessary.Alcohols are normally formed if the reaction mixture is treated with aqueous acid. However, in case of titanacyclopentenes, quenching with 3 N HCl gave cyclopentenones exclusively [18]. Under pressure of CO, cyclopentenones can be obtained in good yields in the presence of a catalytic amount of the titanocene Cp2Ti(CO)2 (Eq. 42) [41]. By using an enantiomerically pure analogue, Buchwald was able to perform a highly enantioselective catalytic Pauson–Khand type reaction (Eq. 42) [42].

(40)

Construction of Carbocycles via Zirconacycles and Titanacycles

41

(41)

(42)

In addition to CO, isocyanides and bis(trichloromethyl)carbonate were also applied as a one-carbon unit to transform five-membered metallacycles into cyclopentenones [41–44]. Carbonylation of five-membered zirconacycles has been applied for synthesis of complexed and natural products. Stereocontrolled one-pot synthesis of tricyclic ketone with only cis isomer was achieved by Negishi and coworkers (Eq. 43) [45].

(43)

Mori and coworkers successfully synthesized the optically active alkaloid (–)-dedrobine by a short sequence using zirconocene-promoted carbonylation and reductive cyclization (Eq. 44) [46].

(44)

42

Z. Xi · Z. Li

Wender and coworkers had established a methodology for the synthesis of a family of simple tigliane–daphnane analogues, based on the zirconocene-mediated enyne carbocyclization, demonstrating both the extension of the carbocyclization methodology to cycloheptanoid synthesis and the control of stereochemistry from a pre-existing ring system with the zirconocene-mediated carbocyclization reaction (Eq. 45) [47].

(45)

g-Butyrolactones are ubiquitous in nature. An attractive route to this ring system is the [2+2+1] approach. Although a similar approach has been successfully employed for the construction of five-membered carbocycles, the application of this route to heterocycle synthesis is rare. Crowe and coworkers firstly reported a titanocene-mediated synthesis of g-butyrolactones that proceeds via the reaction sequence of reductive coupling-carbonylation-reductive elimination (Eq. 46) [48].

(46)

Cyclopentenones could be also prepared from the BuLi-mediated reaction of zirconacyclopentadienes with CO (Eq. 47) [49]. The work reported by Takahashi represents the first example of cyclopentenone formation from two alkynes and CO mediated by metallocenes.

(47)

Construction of Carbocycles via Zirconacycles and Titanacycles

43

3.3.2 Isocyanides as One-Carbon Unit Insertion of isocyanides into zirconacyclopentanes and zirconacyclopentenes affords the corresponding zirconocene h2-imine complexes. Cyclopentylamine derivatives could be prepared by trapping of the insertion intermediates using alkenes, alkynes, and carbonyl compounds [50]. For example, insertion of phenylisocyanide into bicyclic zirconacyclopentenes affords iminoacyl complexes that rearrange to give a, b-unsaturated zirconocene h2-imine complexes. These complexes react with alkenes or alkynes to give cyclopententylamines (Eq. 48) [51].

(48)

Isocyanides can also insert into metallacyclopentadienes [52]. Majoral and coworkers reported insertion of isocyanides into indenylzirconacyclopentadienes and proved the formation of h1-imine zirconocene complex, which is intramolecularly stabilized by a phosphino group. Elimination of the metal fragment “Cp2Zr” give the corresponding b-phosphino imine derivatives or the unexpected b-iminophosphine by hydrolysis with HCl (Eq. 49) [53].

(49)

44

Z. Xi · Z. Li

(50)

If a sterically hindered isocyanide was used, only iminocyclopentadienes were formed in the presence of CuCl or NiCl2(PPh3)2 (Eq. 50) [54]. 3.3.3 Other One-Carbon Unit Equivalents 1,1-Dihalo-1-lithio species (halogenocarbenoids) undergo double insertion into the carbon–zirconium bonds of a zirconacyclopentane to produce, after hydrolysis, bicyclo[3.3.0]octanes (Eq. 51) [55].

(51)

Allenyl carbenoids (3-chloro-1-lithioalk-1-ynes) insert into zirconacyclopentanes and zirconacyclopentenes to afford cyclic h3-allenyl/prop-2-ynyl zirconocene complexes which give cyclized-alcohol products on addition of aldehydes activated with boron trifluoride-diethyl ether (Eq. 52) [56].

(52)

Xi and coworkers reported a one-pot procedure for the preparation of highly substituted indenes, tetrahydroindenes, and cyclopentadienes via Lewis acid mediated reactions of zirconacyclopentadienes with aldehydes. The carbonyl groups of aldehydes were deoxygenated in the reaction and behaved formally as a one-carbon unit (Eq. 53) [57].

Construction of Carbocycles via Zirconacycles and Titanacycles

45

(53)

Acyl chloride was found to behave as a one-carbon unit when treated with zirconacyclopentanes and zirconacyclopentenes in the presence of CuCl. Cyclopentene and cyclopentadiene derivatives were obtained, respectively (Eqs. 54, 55) [58, 59].

(54)

(55)

Interestingly, propynoates and iodopropenoates can also behave as one-carbon unit equivalents to form 1,1-addition products. In the presence of CuCl, zirconacyclopentadienes react with iodopropenoatesto give cyclopentadiene derivatives (Eq. 56) [60, 61].

(56)

In conclusion, five-membered metallacycles of titanocene and zirconocene are convenient starting materials for the construction of five-membered carbocyclic compounds. The formation of five-membered carbocycles can be accomplished by addition reactions (or insertion reactions) of a variety of electrophiles, such as CO, RCN, RNC, bis(trichloromethyl)carbonate, allenyl carbenoids, halogencarbenoids, aldehyde, acyl chlorides, propynoates, and iodopropenoatesthe to the five-membered metallacycles.

46

Z. Xi · Z. Li

3.3.4 Preparation of Five-Membered Heterocycles Replacement of the Cp2Zr or Cp2Ti units in five-membered metallacycles by a different metal or by an atom such as N and S provides an important route to other five-membered metallacycles or five-membered heterocycles containing N or S and so on (Eq. 57) [62, 63].

(57)

Me2SiCl2 does not react with zirconacyclopentadienes. When MeHSiCl2 or H2SiCl2 is used as a silyl electrophile, the reaction proceeds at room temperature to give the corresponding siloles in high yields [64]. Tilley and coworkers have reported a general and efficient method for the synthesis of various functionalized thiophene-1-oxide derivatives, via the reaction of zirconacyclopentadienes with SO2 [65]. Thiophenes were also obtained by the reaction of zirconacyclopentadienes with S2Cl2 [66]. When nitrosobenzene was used, Lewis acids were found to be effective for the promotion of formation of pyrrole derivatives from the reaction of zirconacyclopentadienes with nitrosobenzene (Eq. 58) [67].

(58)

Homocoupling of a conjugated diyne proceeded to give the single titanacyclopentadiene, which was utilized for the preparation of a heterocyclic compound (Eq. 59) [68].

(59)

Construction of Carbocycles via Zirconacycles and Titanacycles

47

3.4 Six-Membered Carbocycles Insertion of a two-carbon unit into a five-membered metallacycle may afford formation of a six-membered carbocycle (Eq. 60), such as a benzene derivative via a formal [2+2+2] aromatization of three alkynes. Similarly, insertion of a C–X unit such as a nitrile into a five-membered metallacycle may afford formation of a six-membered heterocycle, such as a pyridine derivative (Eq. 60). In recent years, Takahashi laboratory and other laboratories have developed a number of synthetically useful methods for six-membered cyclic compounds by taking advantage of five-membered metallacycles of zirconocenes and titanocenes [1–5].

(60)

3.4.1 Benzene Derivatives In the presence of CuCl or NiBr2(PPh3)2, the unsymmetrically substituted zirconacyclopentadienes generated in situ react smoothly with a third alkyne to afford benzene derivatives of three different alkynes (Eq. 61) [69, 70]. As a whole, this is the first example of highly selective, one-pot and high-yield preparation of benzene derivatives from three different alkynes. It should be pointed out that in the case of CuCl-mediated reactions the third alkyne should have at least one electron-withdrawing group. In the case of NiBr2(PPh3)2, the third alkyne could be normal alkynes bearing both electron withdrawing groups and electron donating groups. Reaction of zirconacyclopentadienes with carbenes affords zirconacyclopentene–cyclopropane fused ring intermediates, which further react with CO to generate 1,2,3,5-tetrasubstituted benzenes via a novel skeletal rearrangement (Eq. 62) [30].

(61)

48

Z. Xi · Z. Li

(62)

Naphthalene derivatives could be prepared by the reactions of zirconaindenes with allyl halides in the presence of ZnX2 (X=Br or Cl) and a catalytic amount of Pd(PPh3)4 (Eq. 63) [71].

(63)

2,3,4,5-Tetraalkyl styrenes were obtained when zirconacyclopentadienes were treated with 1,4-dihalo-2-butyne in the presence of CuCl, representing the first example of construction of styrene derivatives from three molecules of alkynes (Eq. 64) [72].

(64)

Buta-2,3-diene-1-yl benezene derivatives were obtained when zirconacyclopentadienes reacted with two propargyl halides in the presence of CuCl (Eq. 65) [73].

(65)

Formation of multi-substituted arylalkynes was achieved via Ni-catalyzed coupling reaction of zirconacyclopentadienes with two alkynyl halides (Eq. 66) [74].

(66)

Construction of Carbocycles via Zirconacycles and Titanacycles

49

Scheme 3 Homologation

Fused aromatic compounds such as polyacenes have attracted much attention as organic conductive materials. However, established methods are very limited. Lack of general and convenient synthetic methods for fused aromatic compounds and their very poor solubility in organic solvents are the most serious problems that control further advances in this very important field. Takahashi and coworkers have recently developed a synthetically useful method for preparation of fused aromatic compounds, by using the zirconocene-mediated aromatization of alkynes. In order to solve the solubility problem, alkyl substituents are introduced into to the skeletons. In principle, two types of synthetic protocols have been used. Type I protocol is via the homologation starting from a functionalized benzene derivative (Scheme 3) [75]; the Type II protocol is via the intermolecular cycloaddition of two alkynes to an arene (Scheme 4) [76].

Scheme 4 Intermolecular cycloaddition

50

Z. Xi · Z. Li

3.4.2 Pyridine Derivatives and Related Compounds Six-membered heterocycles were obtained from two different alkynes and other unsaturated organic substrates involving C=O and C=N moieties. The Reppe-type cyclotrimerization can be also applied for preparation of pyridine derivatives when one of the alkynes is replaced by a nitrile. The pyridine formation from two alkynes and a nitrile with Co complexes was originated by Wakatsuki and Yamazaki [77].Although this method is effective, there is a critical problem for the selective intermolecular coupling of two different alkynes with a nitrile. As shown in Eq. 67, two isomers of pyridine derivatives are formed when a metallacyclopentadiene reacts with a nitrile, due to the two possible orientations of the nitrile in its coupling with the unsymmetrically substituted metallacyclopentadienes.

(67)

Takahashi and coworkers reported a novel coupling reaction of azazirconacyclopentadienes, which were prepared in situ from an alkyne and a nitrile, with a different alkyne in the presence of NiX2(PPh3)2 to afford only single isomer of pyridine (Eq. 68) [78]. Pyridine derivatives with five different substituents from two different unsymmetrical alkynes and a nitrile were prepared with high regioselectivity and in good to excellent yields [78].

(68)

This method could also be applied for the formation of iminopyridines and pyridones using carbodiimide derivatives and isocyanate instead of nitriles (Eq. 69) [78b]. 3.4.3 Others Cyclohexadiene derivatives were obtained in high yields via the reaction of zirconacyclopentadienes with dimethyl maleate, dimethyl fumarate or allylic chlorides in the presence of CuCl (Eq. 70) [69b, 79].

Construction of Carbocycles via Zirconacycles and Titanacycles

51

(69)

(70)

Highly substituted pyran derivatives were synthesized with high regioselectivity from the reaction of zirconacycloipentadienes with diethyl ketomalonate in the presence of two equivalents of BiCl3 (Eq. 71) [80]. When zirconacyclopentadienes were treated with azodicarboxylates in the presence of CuCl, dihydropyridazine derivatives could be prepared (Eq. 71) [80].

(71)

52

Z. Xi · Z. Li

3.5 Seven-Membered Carbocycles and Others There are fewer examples concerning the formation of higher ring compounds, such as seven-, eight- and nine-membered cyclic compounds, from metallacycles of titanocene and zirconocene. 3-Chloro-2-chlorometheyl-1-propene acted as a three-carbon unit building block that after the reaction with zirconacyclopentadienes afforded methylenecycloheptadienes (Eq. 72) [79].

(72)

The first example of cyclooctatetraene formation from metallacyclopentadienes was reported by Takahashi and coworkers [81]. Sequential treatment of zirconacyclopentadiene with two equivalents of CuCl and one equivalent of NBS afforded cyclooctatetraenes in good yields (Eq. 73).

(73)

In similar protocol, the coupling of certain bicyclic zirconacyclopentadienes with diiodo compounds also gave cyclooctatetraene derivatives (Eq. 74) [82]. This reaction depends on the size of the side ring of the bicyclic zirconacyclopentadiene. Both simple zirconacyclopentadienes and bicyclic zirconacyclopentsdienes with a six-membered side ring do not give the desired eightmembered ring compounds [82].

(74)

The formation of eight- and nine-membered cyclic compounds has been achieved by a copper-catalyzed intermolecular [4+4] and [4+5] coupling of zirconacyclopentadienes with bis(halomethyl)arenes (Eq. 75) [83].

Construction of Carbocycles via Zirconacycles and Titanacycles

53

(75)

4 Concluding Remark Metallacycles, mainly five-membered ones of zirconocene and titanocene, have contributed significantly to the development of synthetically useful methods for cyclic compounds, especially to the selective construction of complexed cyclic compounds from different components. More applications of these useful protocols can be expected. Five-membered metallacycles are very popular. However, on the contrary, six-membered metallacycles are very rare. General and practical methods for six-membered metallacycles are desirable, since interesting and rich reaction chemistry and applications of these metallacycles can be expected.

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53. Cadierno V, Zablocka M, Donnadieu B, Igau A, Majoral JP, Skowronska A (1999) J Am Chem Soc 121:11086 54. Takahashi T, Tsai F, Li Y, Nakajiama K (2001) Organometallics 20:4122 55. Vicart N, Whitby RJ (1999) Chem Commum 1241 56. Gordon GJ, Whitby RJ (1997) Chem Commum 1321 57. (a) Xi Z, Li P (2000) Angew Chem Int Ed 39:2950. (b) Zhao C, Li P, Cao X, Xi Z (2002) Chem Eur J 8:4292 58. Takahashi T, Kotora M, Xi Z (1995) J Chem Soc Chem Commun 1503 59. Takahashi T, Xi Z, Kotora M, Xi C (1996) Tetrahedron Lett 37:7521 60. Kotora M, Xi C, Takahashi T (1998) Tetrahedron Lett 39:4321 61. Takahashi T, Sun W, Xi C, Kotora M (1997) Chem Commun 2069 62. (a) Fangan PJ, Nugent WA (1988) J Am Chem Soc 110:2310. (b) RajanBabu TV, Nugent WA, Taber DF, Fangan PJ (1988) J Am Chem Soc 110:7128 63. (a) Buchwald SL, Qun F (1989) J Org Chem 54:2793. (b) Buchwald SL, Fisher RA, Foxman BM (1990) Angew Chem Int Ed 29:771. (c) Spence REV, Hsu DP, Buchwald SL (1992) Organometallics 11:3492. (d) Fangan PJ, Nugent WA, Calabrese JC (1994) J Am Chem Soc 116:1880. (e) Ura Y, Li Y, Xi Z, Takahashi T (1998) Tetrahedron Lett 39:2787. (f) Ura Y, Li Y, Tsai F, Nakajima, Kotora M, Takahashi T (2000) Heterocycles 52:1171 64. Kanno K, Kira M (1999) Chem Lett 1127 65. Jiang B, Tilley TD (1999) J Am Chem Soc 121:9744 66. Suh M, Jiang B, Tilley TD (2000) Angew Chem Int Ed 39:2870 67. Nakamoto M, Tilley TD (2001) Organometallics 20:5515 68. Burlakov VV, Peulecke N, Baumann W, Spannenberg A, Kempe R, Rosenthal U (1997) Collect Czech Chem Commun 62:331 69. (a) Xi Z, Takahashi T (2000) Acta Chimica Sinica 58:1177. (b) Takahashi T, Xi Z,Yamazaki Y, Liu Y, Nakajima K, Kotora M (1998) J Am Chem Soc 120:1672. (c) Takahashi T, Kotora M, Xi Z (1995) J Chem Soc Chem Commun 361 70. Takahashi T, Tsai FY, Li Y, Nakajima K, Kotora M (1999) J Am Chem Soc 121:11093 71. Duan Z, Nakajima K, Takahashi T (2001) Chem Commun 1672 72. Xi Z, Li Z, Umeda C, Guan H, Li P, Kotora M, Takahashi T (2002) Tetrahedron 58:1107 73. (a) Takahashi T, Kotora M, Kasai K, Suzuki N (1994) Organometallics 13:4183. (b) Kotora M, Noguchi Y, Takahashi T (1999) Collect Czech Chem Commun 64:1119 74. Wang H, Tsai F, Takahashi T (2000) Chem Lett 1410 75. Takahashi T, Kitamura M, Shen B, Nakajima K (2000) J Am Chem Soc 122:12876 76. (a) Takahashi T, Hara R, Nishihara Y, Kotora M (1996) J Am Chem Soc 118:5154. (b) Takahashi T, Li Y, Stepnicks P, Kitamura M, Liu Y, Nakajima K, Kotora M (2002) J Am Chem Soc 124:576 77. Wakatsuki Y, Yamazaki H (1973) J Chem Soc Chem Commun 280 78. (a) Takahashi T, Tsai FY, Kotora M (2000) J Am Chem Soc 122:4994. (b) Takahashi T, Tsai FY, Li Y, Wang H, Kondo Y, Yamanaka M, Nakajima K, Kotora M (2002) J Am Chem Soc 124:5059 79. Kotora M, Umeda C, Ishida T, Takahashi (1997) Tetrahedron Lett 38:8355 80. Takahashi T, Li Y, Ito T, Xu F, Nakajima K, Liu Y (2002) J Am Chem Soc 124:1144 81. Takahashi T, Sun W, Nakajima K (1999) Chem Commun 1595 82. Yamamoto Y, Ohno T, Itoh K (1999) Chem Commun 1543 83. Takahashi T, Sun W, Liu Y, Nakajima K, Kotora M (1998) Organometallics 17:3841

Topics Organomet Chem (2004) 8: 57– 137 DOI 10.1007/b96002 © Springer-Verlag Berlin Heidelberg 2004

Metallocene-Catalyzed Selective Reactions Martin Kotora (

)

Charles University, Department of Organic Chemistry, Faculty of Science, Hlavova 8 128 43 Prague 2, Czech Republic [email protected]

1

Introduction

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2.1 2.1.1 2.1.2 2.2 2.3 2.3.1 2.3.2 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11

Carbometallation of Alkenes . . . . . . . . . . Carbomagnesation . . . . . . . . . . . . . . . Carboalumination . . . . . . . . . . . . . . . Carbometallation of Alkynes . . . . . . . . . . Dimerization of Alkenes and Alkynes . . . . . Dimerization of Alkenes . . . . . . . . . . . . Dimerization of Alkynes . . . . . . . . . . . . Conjugate Addition . . . . . . . . . . . . . . . Hydroacylation . . . . . . . . . . . . . . . . . Hydroboration . . . . . . . . . . . . . . . . . Hydrosilylation . . . . . . . . . . . . . . . . . Hydration of Alkynes . . . . . . . . . . . . . . Intramolecular Addition of Alcohols to Alkynes Allylic Amination . . . . . . . . . . . . . . . . Reaction of Diazocompounds with C=X Bonds

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60 60 67 69 72 72 74 74 75 77 78 79 79 80 81

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Coupling of Two or More Multiple Bonds . . . . . . . . . . . . . . . . . . .

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3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11

Coupling of Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydridic Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkylative Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metallacyclopentane Mechanism . . . . . . . . . . . . . . . . . . . . . . . . Coupling of Alkynes and Alkenes . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intermolecular Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . Coupling of Alkenes with Carbonyl Group . . . . . . . . . . . . . . . . . . Coupling of Alkenes and Alkynes with Epoxides . . . . . . . . . . . . . . . [2+2+2] Cyclotrimerization of Alkynes . . . . . . . . . . . . . . . . . . . . [2+2+2] Cyclotrimerization of Alkynes with C–Heteroatom Multiple Bonds [2+2+2] Cyclotrimerization of Alkynes with Alkenes . . . . . . . . . . . . . [4+2] Cycloaddition (Diels–Alder Reaction) . . . . . . . . . . . . . . . . . [5+2] Cycloaddition Reaction . . . . . . . . . . . . . . . . . . . . . . . . . Coupling of Allenes with Alkenes . . . . . . . . . . . . . . . . . . . . . . . Multicomponent Couplings of Alkenes with Alkynes . . . . . . . . . . . . .

84 84 86 87 90 90 93 99 101 103 108 111 111 113 113 118

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4

C–C Bond Cleavage Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 123

4.1 4.2

Alkene Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 C–C Bond Cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

5

Substitution Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

5.1 5.2

Allylic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Propargylic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

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Isomerization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

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Isomerization of Allyl Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . 128 Isomerization of Propargyl Alcohols . . . . . . . . . . . . . . . . . . . . . . 129

7

Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

7.1 7.2 7.3 7.4 7.5

Cyclization of Dienynes . . . . . . . . . . . . Annulation of Alkynes with Nitrosoaromatics Hydrodechlorination of Aryl Chlorides . . . Reductive Amination of Ketones . . . . . . . Oxidative Cyclization of Amino Alcohols . .

8

Conclusion

References

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131 131 131 132 132

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Abstract Transition metal cyclopentadienyl complexes constitute a large family of compounds that can be used as catalyst for a number of organic transformations such as additions of various organics to double and triple bonds, inter- and intramolecular coupling of double and triple bonds, substitution reactions, functional group interconversions, isomerizations, and C–C bond cleavage reactions. These reactions usually proceed with high degree of regio-, stereo- and enantioselectivity under mild reaction conditions. Moreover, they often display broad tolerance to the presence of other functional groups in the substrates. Keywords Cyclopentadiene · Metallocene · Homogenous catalysis · C–C bond formation

Abbreviations Ac Acetyl BINAP 2,2¢-Bis(diphenylphosphino)-1,1¢-binaphthyl Bn Benzyl Boc tert-Butyloxycarbonyl BTMSA Bis(trimethylsilyl)acetylene Bu Butyl i-Bu iso-Butyl t-Bu tert-Butyl cat Catalytic COD 1,4-Cyclooctadiene Cp Cyclopentadienyl CSA Camphorsulfonic acid

Metallocene-Catalyzed Selective Reactions Cy C5H5 C5Me5 D DMF dppe dppm dr E EBTH eq Et Hex c-Hex Ind Me Oct Ph Pr i-Pr TBS TBAF Tf TFA THF TIPS TMS Ts

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Cyclohexyl Cyclopentadienyl Pentamethylcyclopentadienyl Heat N,N-Dimethylformamide Bis(diphenylphosphino)ethane Bis(diphenylphosphino)methane Diastereoisomer ratio Electrophile Ethylenebis(4,5,6,7-terahydro-1-indenyl) Equivalent Ethyl Hexyl Cyclohexyl Indenyl Methyl Octyl Phenyl Propyl iso-Propyl tert-Butyldimethylsilyl Tetrabutylammonium fluoride Trifluoromethansulfonyl Trifluoroacetic acid Tetrahydrofuran Triisopropylsilyl Trimethylsilyl Tosyl, 4-toluensulfonyl

1 Introduction The discovery of the first cyclopentadienyl transition metal compound – ferrocene [1] – and the confirmation of its structure [2] opened a new era in chemistry. It showed the direct relationship between organic chemistry and inorganic chemistry of transition metals, and provided the necessary impetus for development of a new area: organometallic chemistry. Although, the cyclopentadienylmetal compounds seemed to be rather a chemical curiosity, further research soon revealed their useful potential in chemistry. Namely, it has been shown that many of them can be used as catalysts to facilitate a plethora of reactions and transformation under mild reaction conditions that would be otherwise difficult or even impossible to achieve by using classical organic processes. Cyclopentadienyl ligands have considerable advantage over other ligands based, e.g., on compounds with N- or P-coordination to the central metal atom in complexes, in that they usually remain for the most part uninvolved in the transformation mediated by the central metal atom. They can be considered as

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rather chemically inert ligands that do not interfere or react with reactants during the reaction. This is clearly a consequence of the strong h5-coordination mode between the cyclopentadienyl ring and the metal, and the energetic cost of disrupting this very stable unit. Also, it is possible to tune and change the properties of the metal center by careful changes to the structure of the corresponding cyclopentadienyl moiety. Various degrees of substitution on the cyclopentadienyl ring may change both electronic as well as steric properties of the metal complex. This provides delicate means to control the properties and behavior of the whole complex and also the environment in the close vicinity of the metal atom [3, 4, 5]. Both steric as well as electronic properties have a profound effect on the course of the reaction. These effects have been observed, e.g., in carboalumination of alkenes, [2+2+2]-cyclotrimerization of alkynes, hydroboration, etc. A number of other examples can be found as well. The main goal of this chapter is to give a brief overview of reactions that have been catalyzed by cyclopentadienylmetal complexes and to show their potential and application in organic synthesis. The reactions have been classified into seven types according to their similar features. The tables give some representative examples of chemical transformations. In some cases presumed reaction mechanisms are also shown for better understanding of the course of the reaction. It is necessary to emphasize that the list of the reactions and possible applications is by no means final and many new interesting applications and reactions can be expected to appear in the near future.

2 Additions to Multiple Bonds 2.1 Carbometallation of Alkenes Generally speaking, carbometallation of alkenes results in the formation of substituted alkanes. In this process two new bonds at each terminus of the double bond are formed. 2.1.1 Carbomagnesation One of the first practical reactions was the zirconocene (h5–C5H5)2ZrCl2 1 catalyzed carbometallation of simple alkenes with Grignard reagents. Simple alkenes such as 1-decene and styrene underwent ethylmagnesation in high yields to give the new Grignard reagent 2 that after the reaction with an electrophile gave 3 (Scheme 1). The key intermediate of this reaction is the zirconocene–ethylene complex 4 that reacts with the alkene to give the substituted zirconacyclopentane 5. Its transmetallation with another equivalent of EtMgBr

Metallocene-Catalyzed Selective Reactions

61

Scheme 1

Scheme 2

results in the transmetallation of the more sterically hindered Zr–C bond to 6, which decomposes into 2 with the regeneration of the zirconocene–ethylene complex 4 (Scheme 2) [6, 7, 8]. The use of higher alkyl Grignard reagents leads to alkylmagnesation [9]. Although this reaction is of considerable synthetic interest its applicability in organic synthesis is rather limited. Nevertheless, it has been recently shown that the zirconocene 1 catalyzed ethylzincation of alkenes with a mixture composed of Et2Zn/EtMgBr(cat) can be done with high yields of the products (Scheme 3). The reaction mechanism is the same as the above mentioned one. A stoichiometric amount of EtMgBr with respect to the amount of the zirconocene 1 is used only to generate the zirconocene–ethylene complex 4. The transmetallation itself proceeds with diethylzinc to the organozinc intermediate 7. A few examples of ethylzincation followed by iodonolysis are shown in Table 1 [10]. A considerable advance in this area was a discovery that styrene can be catalytically alkylated with various alkyl tosylates in the presence of (cyclohexyl)ethylmagnesium bromide to give the new Grignard reagent 8. Its reaction with oxygen furnishes after hydrolysis the alcohols 9 (Scheme 4).Authors claim that the reaction mechanism does not proceed through a metallacycle formation, instead that the ate-complex 10 is the species responsible for the alkylation (Scheme 5). This procedure enables addition of various linear, branched,

Scheme 3

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Table 1 Zr-catalyzed ethylmagnesation of allyl ethers followed by iodination

Alkene

a

Product

Yield (%) a

GC yields. Isolated yields are given in parentheses.

Scheme 4

Scheme 5

Metallocene-Catalyzed Selective Reactions

63

and cycloalkyl groups to alkenes [11]. The intramolecular variant has been developed as well and it allows preparation of various benzocycloalkenes [12]. The use of alkenes bearing a functional group in the near vicinity of the double bond opens new possibilities for the control of carbomagnesation. Ethylmagnesation of allylic alcohols with the terminal or internal double bond proceeds by different reaction pathways to give different kinds of products. Zirconocene-catalyzed ethylmagnesation of protected and unprotected allylic alcohols with the terminal double bond proceeds through the Grignard reagents 11 and 12 to give the diols 13 and 14 with the opposite diastereoselectivity in high yields (Scheme 6). The advantage of this reaction is that by simple means, such as the choice between the protected and unprotected allylic alcohol, it is possible to control diastereoselectivity in the products. The best diastereoselectivity for ethylmagnesation of unprotected allylic alcohols was achieved in Et2O; on the other hand, better yields of the products 13 and 14 were obtained in THF (Table 2). Ethylmagnesation of the protected allylic alcohols proceeded in both media with similar results (Table 3). Homoallylic alcohols undergo ethylmagnesation under the same conditions as well [13].

Scheme 6

Zirconocene-catalyzed carbomagnesation of internal allylic ethers proceeds by a different pathway. The carbometallation of allylic ethers with the internal double bond gives formally the Sn2¢ substitution product 15 with the loss of the ether moiety (Scheme 7). A few examples are given in Table 4. Especially interesting, from the synthetic point of view, is ethylmagnesation of cyclic ethers (the last entry in Table 4), because it opens a pathway to the synthesis of functionalized homoallylic alcohols [14]. An asymmetric variant of this reaction gives products with ees>90% [15]. Also the titanocene (h5-C5H5)2TiCl2 16 has proved to be an excellent catalyst for a number of various alkylation reactions of alkenes and dienes: such as regioselective double alkylation, Mizoroki–Heck type alkylation, carbosilylation, carbomagnesation, and double silylation [16]. Of special interest are the first

Scheme 7

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Table 2 Zr-catalyzed ethylmagnesation of allylic alcohols

Alkene

a

Major Product

dr

Yield (%) c

In Et2O. b In THF. c Isolated yields.

two cases: regioselective double alkylation and Mizoroki–Heck type alkylation. The regioselective double alkylation of vinylarenes enables functionalization of the double bond either by the same two alkyl chains (2 equivalents of alkyl bromide) or two different alkyl chains (two different alkyl bromides) to give 17 (Scheme 8) [17]. It is assumed that the reaction mechanism is series of oneelectron transfer reactions. Some typical examples are given in Table 5. The Mizoroki–Heck type reaction proceeds under similar reaction conditions to give 18 (Scheme 8). However, the change of the solvent from THF to Et2O is required for the successful course of the reaction [16]. Some typical examples are given in Table 6. A plausible reaction pathway for double alkylation of alkenes is outlined in Scheme 9. It is assumed that 16 reacts with RMgX to generate the titanium(III) complex 19. One-electron transfer from 19 to alkyl bromide leads to the cleav-

Scheme 8

Metallocene-Catalyzed Selective Reactions

65

Table 3 Zr-catalyzed ethylmagnesation of allylic ethers

Alkene

Major Product

Yield (%) c

dr

Table 1 Z

a

In Et2O. b In THF. c Isolated yields.

Table 4 Zr-catalyzed ethylmagnesation of allyl ethers

Alkene

Product

Yield (%)

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Scheme 9 Table 5 Ti-catalyzed double alkylation of alkenes

Alkene

a

R1-Br

R2-Br

Product

Yield (%) a

Isolated yields.

age of the C–Br bond to give alkyl radical along with the dibutyltitanocene 20, which readily forms 21 through b-hydrogen elimination. Addition of the formed alkyl radical to styrene affords a benzyl radical species, which recombines with 21 to give the benzyltitanium compound 22. Subsequent transmetallation of 22 with RMgX gives the corresponding benzyl Grignard reagent 23, which after the reaction with alkyl bromide gives the doubly alkylated product 18. The reaction mechanism of the Mizoroki–Heck reaction proceeds through a similar reaction pathway [16].

Metallocene-Catalyzed Selective Reactions

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Table 6 Ti-catalyzed Mozoroki-Heck reaction

Alkene

a

R-Br

Product

Yield (%) a

Isolated yields. b 16 (20 mol%).

2.1.2 Carboalumination Another type of alkene functionalization is carboalumination. Cyclopentadienylamidotitanium dichlorides such as 24 catalyzed carboalumination of alkenes with triethylaluminium with subsequent oxygenation to furnish the 1,4-diols 25 (Scheme 10) [18]. Some representative examples are given in Table 7. It has been proposed that triethylaluminium initially reacts with 24 to give 26, which after b-hydrogen elimination affords the titanium(II)-ethylene complex 27. Its reaction with alkene gives the titanacycloalkane 28 that after transmetallation with triethylaluminium furnishes the ethyl-alkyl intermediate 29, which releases the catalytically active species 26 and the organoalumium intermediate 30. Its treatment with oxygen followed by acidic workup affords the diols 25 (Scheme 11). Zirconocene also catalyzes carboalumination of alkenes with trimethylaluminium and subsequent oxygenation affords the alcohols 31 (Scheme 12). The successful course of the reaction requires the use of sterically hindered zir-

Scheme 10

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Scheme 11

Scheme 12

Table 7 Ti-catalyzed carboalumination of alkenes

Alcohol

Product

Yield (%) a

a

Isolated yields. b 24 (10 mol%), solvent CH3CHCl2. c dr 1/1. d dr 2/1.

a

Isolated yields. b 24 (10 mol%), solvent CH3CHCl2 . c dr 1/1. d dr 2/1.

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Table 8 Ti-catalyzed methylalumination of alkenes

Alkene

a

Product

dr

Yield (%) a

Isolated yields.

conocene such as (h5-C5Me5)2ZrCl2 32 bearing pentamethylcyclopentadiene ligands [19]. In this instance the reaction mechanism proceeds by a somewhat different pathway: it is assumed that the reaction mechanism proceeds through the cationic methylzirconocene intermediate [(h5-C5Me5)2ZrMe+]. Some typical examples are given in Table 8. The use of other zirconocenes bearing bulky cyclopentadienyl ligand with chiral centers resulted in the development of an asymmetric variant of this reaction [19a, 20]. 2.2 Carbometallation of Alkynes Carbometallation of alkynes provides one of the possible routes to stereoselectively substituted alkenes. There is no doubt that one of the most useful functionalizations of alkynes is Negishi methylalumination of terminal alkynes [21]. This reaction is catalyzed by the zirconocene 1 and the addition of trimethylaluminium proceeds regioselectively through a stereoselective syn-addition to give the cismethylalkenylalanes 33, which can be used in further reactions with electrophiles or cross-coupling reactions (Scheme 13). This method will not be

Scheme 13

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dealt with in this section and its scope and application will be presented in a separate chapter. Generally speaking, other cyclopentadienylmetal complex catalyzed carbometallations of alkynes are rather rare but a few interesting examples have been reported. The first one is the zirconocene 1 catalyzed ethylmagnesation of dialkyldiynes with ethylmagnesium bromide to afford a mixture of isomeric enynes 34 (Scheme 14). The ethylation proceeds regioselectively on the terminal carbon atom of the diyne moiety. However, the addition is not stereoselective: a mixture of cis and trans isomers is obtained [22].

Scheme 14

The key steps of the reaction mechanism (Scheme 15) follow those proposed for carbometallation of alkenes. It is noteworthy that the transmetallation with EtMgBr proceeds at the Zr–sp2C bond, which is a rare phenomenon, and at the end of the catalytic cycle vinylmagnesium bromide 35 is obtained, which after hydrolysis affords the enyne 34.

Scheme 15

Interesting carbometallation was reported for the vanadocene (h5C5H5)2VCl2 36 catalyzed addition of trimethylaluminium to bis(trimethylsilyl)butadiyne. The reaction resulted in the formation of the dimethylated enyne 37 (Scheme 16) [23]. Although, the reaction itself was unprecedented and afforded purely the Z-isomer, its synthetic applicability at the present state is negligible because of the low overall yield of the product (27%) and its limited scope. No reasoning for a possible reaction mechanism was given.

Metallocene-Catalyzed Selective Reactions

71

Scheme 16

A second one is the zirconocene 1 catalyzed reaction of chloroalkynes with ethylmagnesium bromide to give substituted the cyclobutenes 38 (Scheme 17). Some typical examples are given in Table 9. The reaction mechanism is outlined in Scheme 18. It is assumed that the first step is the formation of the zirconacyclopentene 39 by the reaction of ethylene-zirconocene complex with chloroalkyne followed by subsequent rearrangement to the chlorocyclobutenylzirconium intermediate 40.Alkylation of 40 with EtMgBr followed by b-hydrogen elimination affords the cyclobutene 38 [24].

Scheme 17

Scheme 18

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Table 9 Zr-catalyzed formation of cyclobutenes

Chloroalkyne

a

Product

Yield (%) a

GC yields.

2.3 Dimerization of Alkenes and Alkynes

2.3.1 Dimerization of Alkenes Transition metal complex catalyzed tail-to-tail dimerization of acrylates represents an attractive and alternative route to adipic acid and has received considerable attention. Among many catalytic systems the ones with substituted cyclopentadienyl or indenyl ligands exhibit high activity under mild reaction conditions.Acrylates are dimerized to a mixture of cis and trans isomers of the methyl hexenedioates 41 and 42 (Scheme 19). Turnover (TO) frequencies for different catalysts varied to a considerable extent: 43a (h5-C5Me5)Rh(CH2= CH2)P(OMe)3 (slow), 43b (h5-C5Me5)Rh(CH2=CH2)2 (6.6 TO/min), 43c (11 TO/min), 43d (11 TO/min), 43e (h5-C5H5)Rh(CH2=CH2)2 (0.1 TO/min), 43f (1 TO/min). The catalytically active species for acrylate dimerization were usually cationic hydride species generated from the corresponding neutral complexes by the reaction with H(Et2O)B(3,5-(CF3)2Ph)4 [25]. Iridium analogs were completely catalytically inactive. On the other hand, efficient catalytic dimerization of simple alkenes can be usually achieved by early transition metal alkene or diene complexes. For example the niobium-butadiene complexes 44 and 45 also showed good catalytic activity for dimerization of isoprene into a mixture of the head-to-tail and head-to-head dimers 46 and 47 (Scheme 20). The former catalyst gave products in 85:15 ratio and the latter one gave rise to 70:30 ratio [26].

Metallocene-Catalyzed Selective Reactions

73

Scheme 19

Scheme 20

The cycloolefin–tantalum complex (h5-C5Me5)Ta(cyclooctene)Cl 48 is capable of dimerization of various olefins into a mixture of the head-to-tail and head-to-head dimers 49 and 50 (Scheme 21) [27]. Some representative results are summarized in Table 10. It was shown that the dimerization process proceeds through series of reversible metallacycle formations such as tantalacyclopentanes and tantalacyclobutanes, and b-hydrogen eliminations. The dimerization ends in reductive elimination of the organyl moiety from the intermediate alkylhydridotantalum species.

Scheme 21

Selective dimerization of ethene to 1-butene was reported for the tantalum hydride 51 [28]. The reaction proceeds through hydrotantalation of ethene to give alkyl tantalum compound, followed by the insertion of another molecule of ethene and b-hydrogen elimination.

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Table 10 Ta-catalyzed dimerization of alkenes

Alkene

Ratio of 49/50

2.3.2 Dimerization of Alkynes Dimerization of terminal alkynes has been extensively explored with numerous transition metal catalysts. Nevertheless, tertiary propargyl alcohols can be dimerized in an unprecedented way into the dienones 52 under catalysis of [(h5-C5H5)Ru(MeCN)3]+PF6- 53 (Scheme 22). The course of the reaction depends on the solvent used, which influences the stereochemistry of the double bond as well as regioselectivity of the dimerization. The best results for the formation of Z-dienones were obtained in a mixture of THF/acetone at low temperatures (–20 to 0 °C). E-isomers were obtained by carrying out the reaction in acetone at 60 °C. Table 11 demonstrates the broad scope of this unusual dimerization. A number of functional groups is tolerated [29].

Scheme 22

2.4 Conjugate Addition The late transition metal hydrides may behave like mild redox Lewis acid and base catalysts. This makes them useful for the generation of carbon nucleophiles from protonucleophiles by activation of the a-C–H bond adjacent to electron withdrawing groups (CN, COR). One of such catalysts is the iridium hydride 54 that can reversibly abstract a proton from an active methylene compound and act as a catalyst for Michael addition. The reaction of ethyl acetoacetate and cyanoacetate with acrylonitrile

Metallocene-Catalyzed Selective Reactions

75

Table 11 Ru-catalyzed dimerization of propargyl alcohols

Propargyl alcohol

a

T (°C)

Product

Yield (%) a

Isolated yields.

Scheme 23

at room temperature afforded almost quantitatively the products of twofold addition 55 (Scheme 23) [30]. On the other hand, ruthenium hydrides selectively promote monoaddition. The ruthenium hydrides (h5-C5H5)RuH(PPh3)2 56 and (h5-C5Me5)RuH(PPh3)2 57 are efficient catalysts for conjugate addition of various carbonyl compounds to activated alkenes to furnish the polycarbonyl compounds such as 58 and 59 (Scheme 24) [31]. 2.5 Hydroacylation Hydroacylation of alkenes with aldehydes is convenient method for the construction of C–C bonds under mild and neutral reaction conditions. Both intra and intermolecular variants are known. Hydroacylation proceeds through activation of the C–H bond of the aldehyde moiety followed by the addition to the double bond.

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Scheme 24

Scheme 25

Table 12 Co-catalyzed hydroacylation of trimethylsilylethene

Aldehyde

a

TOF (TO/h)

Conversion of the starting material.

Con. (%) a

Metallocene-Catalyzed Selective Reactions

77

Intermolecular hydroacylation of the electron-rich alkene (trimethylsilylethene) with various aldehydes to give the ketones 60 was catalyzed by the cobalt complex 61 at 35 °C with high yields (Scheme 25 and Table 12) [32]. Cyclopentadienylrhodium complexes were used for tandem Claisen rearrangement-hydrocylation of the allylenolethers 62 to the pentenals 63, which were subsequently cyclized to the cyclopentanones 64 (Scheme 26). Activity of the monomeric (h5-C5H5)Rh(CO)2 65 and the polystyrene supported catalyst 66 was compared. The results clearly showed that the latter one gave the better results (Table 13) [33].

Scheme 26

Table 13 Rh-catalyzed rearrangement-hydroacylation of allylenolethers

Ether

Solvent

Cat. (mol%)

dppe (mol%)

Yield (%) a 63/64

62a 62a 62a 62ab 62b

PhCN DMF decane PhCN PhCN

1.5 1.5 1 2 1.5

3 1.5 1 2 1.5

2/96 8/68 97/<1 31/61 10/67

a

GC yields. b The reaction was carried out with 65.

2.6 Hydroboration The substituted indenyl rhodium and iridium complexes 67 and 68 are convenient catalysts for donor-directed stereoselective hydroboration of alkynes. A typical example is the directed hydroboration of 4-(benzyloxy)cyclohexene to the cis-1,3-substituted cyclohexane 69 (Scheme 27).With the unsubstituted indenylrhodium complex (h5-C9H7)Rh(CH2=CH2)2 67a 75% cis-selectivity [34] was achieved, whereas the introduction of electron-deficient indenes (trifluoromethyl substitution) increased cis-selectivity by ~10% [35]. Considerable improvement in the selectivity up to 98% was achieved when the electron-deficient iridium complexes 68 were used (Table 14).

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Scheme 27

Table 14 Rh and Ir-catalyzed hydroboration

Catalyst

cis 1,3-selectivity (%)

Yield (%) a

67a 67b 67c 67d 67e 68a 68b 68c 68d

75 74 81 81 84 93 96 96 98

78 70 59 58 59 72 69 62 60

a

Isolated yields.

2.7 Hydrosilylation Hydrosilylation of multiple bonds has not often been catalyzed by cyclopentadienylmetal complexes. Nevertheless, several methods concerning hydrosilylation of terminal and internal alkynes catalyzed by the ruthenium complex 53 and [(h5-C5Me5)Ru(MeCN)3]+PF6 70 have been recently reported [36]. Of special interest is the complex 70, which has a high preference for the formation of the branched 71 over the linear product 72 (Scheme 28). The reaction of the Si–H bond with the triple bond is stereoselectively trans-addition. In the case of alkynyl silanes the reaction proceeds through endo-dig hydrosilation to the silacycles 73 with endocyclic double bond (Scheme 29) [36b]. There has also been a recent report of hydrosilylation and hydrogermylation of phenylacetylene catalyzed by the rhodium complexes [(h5-C5Me5)RhCl2]2 74 and (h5-C5Me5)Rh(BINAP)SbF6 75. The former catalyst promotes the unusual cis-addition whereas the latter promotes trans-addition [37].

Scheme 28

Metallocene-Catalyzed Selective Reactions

79

Scheme 29

In contrast to hydrosilylation of alkynes, hydrosilylation of alkenes by cyclopentadienylmetal complexes has not attracted considerable attention. The lonely report on such a process is the zirconocene 1 catalyzed hydrosilylation of terminal alkenes [38]. 2.8 Hydration of Alkynes anti-Markovnikov hydration of alkynes to give aldehydes is a rare but synthetically interesting process. It has been shown that this reaction can be affected by various cyclopentadienylruthenium phosphine complexes. Among them the highest activity is displayed by the complex 76, which regioselectively transforms terminal alkynes to aldehydes 77 in high yields under mild reaction conditions (Scheme 30) [39]. Some representative examples are shown in Table 15. The reaction conditions tolerate a number of functional groups, for example the alkyne moiety can be transformed even in the presence of a nitrile group in high yield.

Scheme 30

2.9 Intramolecular Addition of Alcohols to Alkynes A related reaction to hydration of alkynes is intramolecular addition of alcohols to a triple bond. This reaction was used for cycloisomerization of homopropargyl alcohols to the butyrolactones 79 and it was catalyzed by the ruthenium complex (h5-C5H5)Ru(COD)Cl 78 in a combination with tris(furyl) phosphine (TFP), an ammonium salt and an oxidant (NOHS=N-hydroxysuccinimide) (Scheme 31).

Scheme 31

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Table 15 Ru-catalyzed hydration of alkynes to aldehydes

Alkene

a

Cat. Product (mol%)

Yield (%) a

Isolated yields. b GC yield. c In 2-methoxyethanol, 130 °C.

The reaction conditions tolerate various functional groups and can be easily applied to substrates with complex structure such as sugars and steroids. Some typical examples are shown in Table 16. The reaction mechanism proceeds through alkylideneruthenium intermediates that are similar to reconstitutive coupling of alkynes with allylic alcohols [40]. In a similar fashion, cycloisomerization of bis-homopropargylic alcohols into d-lactones [41] was also carried out.Applicability of this methodology for the synthesis of g-lactones is quite general and is nicely demonstrated in the concise synthesis of (–)-muricatacin (Scheme 32) [40].

Scheme 32

2.10 Allylic Amination A very interesting reaction is allylic amination of nitrocompounds that afforded the disubstituted amines 80 (Scheme 33). Co-reactants are simple alkenes and carbon monoxide, and the whole process is catalyzed by the iron

Metallocene-Catalyzed Selective Reactions

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Table 16 Ru-catalyzed cycloisomerization of homopropargyl alcohols to lactones

Alcohol

a

Product

Yield (%) a

Isolated yields.

Scheme 33

complexes [h5-(C5H5)Fe(CO)2]2 81 or [h5-(Me5C5)Fe(CO)2]2 82. This reaction is quite general with respect to the alkene as well as the aromatic nitrocompound and provides a simple pathway to a variety of substituted anilines (Table 17) [42]. 2.11 Reaction of Diazocompounds with C=X Bonds Cyclopentadienyliron compounds have been mainly used as Lewis acids and have found applications in a few catalytic processes. [h5-(C5H5)Fe(CO)2 (THF)]

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Table 17 Fe-catalyzed allylic amination of nitroarenes

Alkene

a

ArNO2

Product

Yield (%)

GC yields. b Isolated yields.

BF4 83 catalyzes reaction of aromatic aldehydes with various diazo-compounds. For example, the reaction of phenyldiazomethane with 4-substituted benzaldehydes gave a mixture of the epoxides 84 and ketones 85 in various ratios (Scheme 34). From the experimental results the following conclusion has been drawn: benzaldehydes with electron-withdrawing substituents (e.g. Cl) give a mixture of both products, whereas those with electron-donating substituents give only ketones [43]. A different reaction pathway was observed when ethyl diazoacetate was used: a mixture of the ethyl 3-hydroxy-2-acrylates 86 and ketones 87 was obtained (Scheme 35) [44]. However, switching from an aldehyde to N-benzilidene aniline, the formation of mainly the cis-aziridines 88 was achieved (Scheme 36). Interestingly, the reaction did not proceed with 4methoxybenzilidene aniline [45]. The ruthenium complexes 89 are efficient catalysts for cyclopropanation of alkenes with diazocompounds to give the cis- 90 and trans-cyclopropanes 91 (Scheme 37). The reaction of diazoacetate with styrene and other electron-rich alkenes proceeded with high cis-stereoselectivity (Table 18) [46].

Scheme 34

Metallocene-Catalyzed Selective Reactions

83

Scheme 35

Scheme 36

Scheme 37

Table 18 Influence of Ru-catalysts stereoselectivity in cyclopropanation of styrene with ethyl diazoacetate

Catalyst

T (°C)

t (h)

90 (%) a

91 (%) a

89a 89b 89c 89d 89e 89f 89g 89h

45 60 59 25 50 40 80 80

4 3 2 4 4 4 3 3

65 40 55 46 52 48 36 38

31 33 35 33 32 40 60 40

a

GC yields.

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3 Coupling of Two or More Multiple Bonds 3.1 Coupling of Alkenes Cyclization of dienes is synthetically a very useful transformation that allows construction of cyclic compounds from a simple starting material. The cyclization of dienes can proceed through several reaction mechanisms depending on the reaction conditions, the nature of a catalytic species, as well as the substitution pattern of reactant. 3.1.1 Hydridic Mechanism Titanium hydrides are good catalysts for cyclization of a,w-dienes into the cyclic compounds. Generally, the cyclization starts with hydrotitanation of one of the double bonds, and because it can proceed in both Markovnikov and antiMarkovnikov mode it may result in the formation of two kinds of products: the 1-methylene-2-methylcycloalkanes 92 and methylenecycloalkanes 93 (Scheme 38).

Scheme 38

One of the first cyclizations was carried out with the titanium(III)hydride (h5-C5H5)2TiH 94. Owing to anti-Markovnikov addition of the titanium hydride to the double bond, this type of reaction is suitable for the cyclization of 1,5dienes such 1,5-hexadiene and 1,2-divinylcyclohexadiene to give methylenecyclopentanes.A typical example is cyclization of cis 1,2-divinylcyclohexane into a mixture of the cis 95c and trans products 95t (Scheme 39) [47, 48]. From a practical point of view, it is more convenient to use catalytic systems composed of cyclopentadienyltitanium complexes and Grignard reagents that generate the active titanium hydride in situ. These systems are able to cyclize 1,6-heptadienes (X=CH2) into carbocycles. By varying the cyclopentadienyl

Scheme 39

Metallocene-Catalyzed Selective Reactions

85

moiety of the catalyst, either the 1,2-methylenecyclopentanes 92 or methylenecyclohexanes 93 can be obtained. The use of the simple titanocene 16 mainly affords products with the cyclopentane ring whereas the more sterically encumbered (±)-EBTHI-TiCl2 96 gives cyclohexanes. Some typical examples are given Table 19 [49]. The catalytically active species is assumed to be a Ti(III) hydride formed by alkylation-reduction of a titanocene dichloride.As mentioned above, the course of the reaction is governed either by Markovnikov or anti-Markovnikov addition to the double bond that produces the intermediates 97a and 97b. Intramolecular carbometallation gives the alkyltitanium compounds 98a and 98b that after b-hydrogen elimination afford the corresponding products 92 and 93 (Scheme 40). Table 19 Ti-catalyzed cyclization of dienes

Diene

a

Catalyst

Product

Yield (%) a

Isolated yields. b 10% of the catalysts and 30% n-BuMgBr. c The reaction was carried out in toluene. d 1H NMR yield.

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Scheme 40

Analogically to the titanocene(III) hydride catalyzed reactions, the zirconocene 1 can be used as well. However, in this case the active species is assumed to be a cationic zirconium(IV) hydride generated by the reaction of the zirconocene 1 with MAO. The reaction mechanism copies the one described in Scheme 40. However, the course of the reaction favors anti-Markovnikov addition of the zirconium hydride to the double bond to give solely the methylenecycloalkanes 93 [50, 51]. 3.1.2 Alkylative Mechanism When considering the above-mentioned reaction mechanism, it is obvious that a simple substitution of the hydrogen atom in the hydride by an alkyl group could lead to alkylative cyclization of dienes. Zirconocenes with bulky cyclopentadienyl ligands such as 32 are capable of efficient catalysis of cyclization of a,w-dienes into the 1,3-substituted cycloalkanes 99 (Scheme 41). Some typical examples are given in Table 20 [19].

Scheme 41

Metallocene-Catalyzed Selective Reactions

87

Table 20 Zr-catalyzed methylalumination of dienes

Diene

a

Product a

dr b

Yield (%) c

The major isomer. b cis/trans ratio. c Isolated yields.

3.1.3 Metallacyclopentane Mechanism An alternative procedure for the cyclization is oxidative/reductive dimerization of dienes on low-valent metal centers. It is followed by the cleavage of the formed metal–carbon bonds to release the product and the catalytically active metal species that again joins the catalytic cycle. There are several possible reaction pathways to achieve this process and they depend on the nature of the transition metal. For early transition-metal catalyzed processes catalytic cyclization in the presence of an excess of organometallic compounds is characteristic. Such a typical reaction system is 1 (cat)/BuMgX that catalyzes cyclization a,w-hepta-

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M. Kotora

Scheme 42

and a,w-octadienes to give, after hydrolysis, the corresponding 1,2-dimethylcyclopentane and 1,2-dimethylcyclohexane derivatives 100 (Scheme 42) [52, 53, 54]. The products are usually obtained as a mixture of cis and trans isomers. Generally, the cyclization of 1,6-heptadienes gives mainly trans products, whereas the cyclization of 1,7-cyclooctadienes affords mainly cis products. Nevertheless, in some cases, such as the cyclization of 1,4,7-octatrienes, the products are obtained stereoselectively with the cis geometry 101 (Scheme 43) [53]. Catalytic enantioselective cyclization of a,w-dienes [55] was developed as well and will be discussed in a different chapter.

Scheme 43

The reaction mechanism proceeds through the cleavage of the Zr–C bond of the zirconacyclopentane 102 to give 103. Then there are two possible pathways depending on the rate of transmetallation with another molecule of BuMgX to give either 104 or 105 (Scheme 44). The course of the reaction depends on the solvent used: path A, resulting in the formation of the dimagnesium intermediate 105, is favored in Et2O [52, 53], whereas path B gives the monomagnesium intermediate 104 in THF [54]. Hydrolysis of both intermediates gives the corresponding 1,2-dimethylcycloalkanes 100.

Scheme 44

Metallocene-Catalyzed Selective Reactions

89

Although the zirconium-catalyzed cyclization of a,w-dienes is suitable only for cyclization of 1,6-hepta-and 1,7-octadienes, it has been shown that by using a catalytic amount of the tantalocene (h5-Me5C5)TaCl2(styrene) cyclization of 1,8-nonadiene to 1-methylene-2-methylcycloheptane can be achieved in up to 90% yield [56].Also, cyclopentadienyl compounds of the late transition metals such as (h5-Me5C5)RuCl(COD) 106 are capable of catalysis of cyclization of a,w-dienes [57]. The zirconocene 1 catalyzed cyclization is also convenient for cyclization of dienes bearing a leaving group in the allylic position with respect to the one of the double bonds. In this process the 1-vinyl-2-methylcyclopentanes 107 (Scheme 45) are formed. The reaction can be carried out both in Et2O and THF [58, 59]. Formation of the 1-vinyl-2-methyl-cyclohexenes proceeds stereospecifically to give cis-substituted products when the leaving group OR is the part of the cis-substituted double bond [53].

Scheme 45

The first step of the reaction mechanism is similar to the previously mentioned one and begins with reductive dimerization of the diene on a reduced metal center to give the zirconacyclopentane 108 (Scheme 46). However, owing to the presence of the leaving group in b-position to the metal, elimination ensues to give the mono-organozirconium compound 109. Substitution of the alkoxy group with BuMgCl to give 110 followed by b-hydrogen elimination from the butyl group affords a mixture of the isomeric 107.

Scheme 46

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Scheme 47

Zirconocene-catalyzed cyclizations are also suitable for cyclization of 2halodienes into the 1-methylene-2-methylcycloalkanes 111 (Scheme 47) [60, 61]. The reaction proceeds under the same condition as mentioned above through the identical reaction mechanism. The only exception is that the belimination of the halogen atom proceeds from the intermediate 112. 3.2 Coupling of Alkynes and Alkenes 3.2.1 Intramolecular Coupling Recently, it has been shown that the titanocene dicarbonyl (h5-C5H5)2Ti(CO)2 113 is a convenient complex that catalyzes a number of cyclization reactions. Among suitable substrates are enynes that can be easily cyclized into the corresponding vinylmethylenecycloalkanes 114 (Scheme 48) in the presence of this compound. Representative examples are shown in Table 21 [62]. The reaction mechanism is outlined in Scheme 49 and proceeds through the formation of the titanacyclopentene 115, which is followed by b-hydrogen elimination to 116 and, finally, by reductive elimination to 114. Formally, it resembles cyclization of dienes via metallacycle formation.

Scheme 48

The same reaction can be carried out under catalysis of the ruthenium complex 53. The reaction mechanism is identical with the one depicted in Scheme 49. The advantage of ruthenium catalysis is that enynes with various degree of the substitution of the double bond can be used for the construction of both five- and six-membered rings, and strikingly mild reaction conditions (in many cases the reaction proceeds at room temperature). Also, a number of functional groups are tolerated. Some typical examples are given in Table 22 [63]. Under the similar reaction conditions the catalyst 113 is able to cyclize enynes in the presence of CO into the corresponding cyclopentenone deriva-

Metallocene-Catalyzed Selective Reactions

91

Scheme 49 Table 21 Ti-catalyzed cyclization of enynes

Enyne

Product

Yield (%) a

97

85

79

87

89

54

a

Isolated yields.

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Table 22 Ru-catalyzed cyclization of enynes

Enyne

a

Conditions a

Product

Yield (%) b

A: acetone, rt. B: DMF, rt. C: 2-butanone, rt. b Isolated yields. c dr 1.1/1. d dr 8/1.

Scheme 50

tives 117 (Scheme 50) [64]. Some representative examples are given in Table 23. The reaction mechanism is shown in Scheme 51. An enantioselective variant of this reaction is known as well. The use of the chiral titanocene complex (S,S)-EBTHI-Ti(CO)2 118 resulted in the formation of cyclopentenone derivatives with ees up to 96% [65]. Enynes were also

Metallocene-Catalyzed Selective Reactions

93

Scheme 51

cyclized into cyclopentanone derivatives by using trimethylsilylcyanide (Me3SiCN) instead of CO and a catalytic amount of (h5-C5H5)2Ti(PMe3)2 119 [66]. 3.2.2 Intermolecular Coupling Catalytic intermolecular coupling of alkene and alkyne is quite a challenging task. Nevertheless, cyclopentadienyl rutheniumcomplexes are able to catalyze alkyne–alkene coupling (an Alder-ene type reaction) to a mixture of the regioisomeric products 120 and 121 (Scheme 52). The most efficient catalysts are the complexes 78 or 53. The latter is more reactive. The scope of the reaction with respect to substituents attached to the both reactants is enormous: ester, hydroxy, nitrile, ether, amino, and arylhalide groups are tolerated. Both terminal and internal alkynes and alkenes can be used. Some typical examples are summarized in Table 24 [67, 69]. Ruthenium-catalyzed coupling was utilized also in the synthesis of natural compounds. The underlying strategy was the coupling of a terminal alkene with a disubstituted alkyne. Thus coupling of methyl 3-hydroxybutynoate with dodecadiene produced the tetraene 122 in good yield (75%). Chemoselective hydrogenation of the unconjugated double bonds of 122 produced naturally oc-

Scheme 52

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Table 23 Ti-catalyzed carbonylative cyclization of enynes

Enyne

a

Product

Yield (%) a

Isolated yields. b 4/1 trans/cis. c 5psig of CO.

curring ancepsenolide 123 [67c] (Scheme 53).A similar approach has also been used for the synthesis of more complex acetogenins [67d]. The reaction mechanism (Scheme 54) proceeds as follows: after coordination of the alkyne and alkene by the coordinatively unsaturated ruthenium(+2) catalyst, the ruthenacyclopentenes 124 are formed by oxidative coupling of the two ligands. Two regioisomeric ruthenacycles are possible, depending on the orientation of the alkyne. These ruthenacycles undergo a syn-b-hydrogen elimination to generate the vinylruthenium(+4) hydrides 125. These complexes undergo a reductive elimination to form the 1,4-diene products 120 and 121 and regenerate the ruthenium(+2) catalyst.

Metallocene-Catalyzed Selective Reactions

95

Scheme 53

Scheme 54

An analogical reaction is coupling of alkynes with N-allylamides to give enamides. In this instance the linear products 126 are favored over the branched ones 127 (Scheme 55). Some representative results are given in Table 25. The coupling of internal alkynes bearing a trimethylsilyl group at one end of the triple bond gives exclusively the branched product 128 with a trimethylsilyl group attached at the least substituted terminus of the double bond (Scheme 56). It is presumed that preference for the branched product is

Scheme 55

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Table 24 Ru-catalyzed coupling of alkynes and alkenes

R1

R2

R3

Yield (%)

Scheme 56 Table 25 Ru-catalyzed coupling of alkynes and allyl amines

R1

Ratio of 126/127

Yield (%)

Metallocene-Catalyzed Selective Reactions

97

caused by lesser steric hindrance in the intermediate 129 over the intermediate 130 [68]. Alkynes can also be coupled with allylic alcohols; however, the reaction mechanism and therefore also the structure of products depends on the catalysts used. The first process is the coupling of alkynes with allylic alcohols to produce the g,d-unsaturated ketones and aldehydes 131 and 132 (Scheme 57). The second process is reconstitutive addition of allylic alcohols to terminal alkynes to give the g,d-unsaturated ketones 133 (Scheme 58).

Scheme 57

Scheme 58

The former is usually catalyzed by various ruthenium complexes such as 106 or more reactive 53. Some representative examples are given in Table 26. The reaction mechanism is the same as the one mentioned above. The carbonyl group is formed by syn-b-hydrogen elimination that affords vinyl alcohol that rearranges to ketone or aldehyde [69, 70]. When allylsilyl ethers are used in place of alcohols the reaction affords silylenol ethers [71]. Table 26 Ru-catalyzed coupling of alkynes and allyl alcohols

R1

R2

R3

Ratio of 131/132

Yield (%)

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Table 27 Ru-catalyzed reconstitutive coupling of alkynes and allyl alcohols

Alkyne

Alcohol

Product

Yield (%)

The latter process is catalyzed by the ruthenium complexes bearing phosphine ligands such as (h5-C5H5)Ru(PPh3)2Cl 89a and NH4PF6 and involves formal migration of the oxygen atom from the allyl alcohol moiety onto the alkyne moiety. Some representative examples are given in Table 27 [72]. The reconstitutive addition was also used as a method to form functionalized steroid side chains from acetylenic steroids, for example, the coupling of the alkynyl steroid with methallyl alcohol afforded 134 (Scheme 59) [73]. There has also been modest success rendering this reaction enantioselective by using chiral cyclopentadienylruthenium catalyst [74, 75].

Scheme 59

Metallocene-Catalyzed Selective Reactions

99

Scheme 60

The mechanism (Scheme 60) involves coordination of the terminal alkyne to the ruthenium atom followed by the formation of the vinylidene complex 135. Coordination of the allyl alcohol followed by addition of the alcohol to the ruthenium vinylidene complex leads to the ruthenium carbene complex 136. Metalla-Claisen rearrangement produces the p-allyl-acylruthenium complex 137, which undergoes a reductive elimination to give the product 133 and regenerates the catalytically active ruthenium species. The regioselectivity of the coupling is independent of the site of ionization and the new bond formation occurs on the more substituted terminus of the double bond of the p-allylruthenium complex. 3.3 Coupling of Alkenes with Carbonyl Group Titanium catalysis is suitable not only for combining of compounds with the C–C multiple bonds but also for combining C–heteroatom double bonds. Such an example is reductive cyclization of a,w-enones in the presence of silanes (Ph2SiH2, Si(OEt)3H) and a catalytic amount of the complex 119 into the corresponding silylated cycloalkanols 138, which after deprotection afford the alcohols 139 (Scheme 61). Some representative examples are given in Table 28 [76].

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Scheme 61

Table 28 Ti-catalyzed reductive cyclization of enones

Enone

a

Work-up a Product b

cis/trans c

Yield (%) d

Is

a A: HCl/acetone, 3h. B: TFA/H O/THF/CH Cl , 0°C, 12h. C: TBAF/THF, 15 min. D: Purified 2 2 2 by distillation. b Major isomer (cis). c GC ratio. d Isolated yields. e PhMeSiH2 was used. Isolated as mixture of the cis product and reduced ketone. f Isolated as a mixture of both isomers.

Metallocene-Catalyzed Selective Reactions

101

Scheme 62

The key step of the reaction mechanism is reaction of the titanium complex 118 with the a,w-enone to give the titanaoxacyclopentane 140, which reacted with diphenylsilane by the cleavage of the Ti-O bond to afford the alkyltitanium compound 141. Reductive elimination furnished the siloxane 138 and the catalyst entered the cycle again (Scheme 62). Analogously to cyclization-carbonylation of dienes, it is possible to carry out synthetically attractive cyclization-carbonylation of a,w-enones into the butyrolactones 142 (Scheme 63). The reaction can be catalyzed either by the titanocenes 113 or 119. Interestingly, the catalytic cyclization proceeded well only with allylaryl ketones (Table 29). In the case of alkyl ketones or aldehydes only the stoichiometric cyclization was successful [77].

Scheme 63

3.4 Coupling of Alkenes and Alkynes with Epoxides Reductive opening of epoxides with concomitant hydrogen atom abstraction followed by inter- or intramolecular C–C bond coupling with double or triple bonds is catalyzed by the titanocene 16 in the presence of 2,4,6-collidine hydrochloride and zinc or manganese as reductants (Scheme 64). The reaction proceeds well with both en-epoxides as well as with yn-epoxides to give the 1hydroxymethyl-2-methylcycloalkanes 143 and 1-hydroxymethyl-2-alkylidenecycloalkanes 144, respectively. Some typical examples are given in Table 30 and Table 31. This system is also good just for simple opening of epoxide [78].

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Table 29 Ti-catalyzed carbonylative cyclization of enones

Enone

a

Product

A: 119, CO (15 psig). B: 113, (5 psig). b Isolated yields.

Scheme 64

Yield (%) a, b A (B)

Metallocene-Catalyzed Selective Reactions

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Table 30 Ti-catalyzed cyclization of en-epoxides

En-epoxide

a

dr

Product

dr

Yield (%) a

Isolated yields. b Yield of pure trans isomer.

3.5 [2+2+2] Cyclotrimerization of Alkynes There are no doubts that one of the most useful application of transition metal cyclopentadienyl complexes of the type CpM(L)n (M=Co, Rh, L=CO, ethene, COD) has been in cyclotrimerization of alkynes into benzene derivatives. In this regard, the most general application has found (h5-C5H5)Co(CO)2 145 because of its availability, activity and reasonable price. Cyclotrimerization reactions and their application have been thoroughly investigated and several comprehensive reviews have been reported [79]. Therefore, this chapter will briefly mention some basic principles of [2+2+2] cyclotrimerization and its scope will be limited only to the use of some new catalytic systems, to a few interesting aspects that are not generally known, and to recent applications of this methodology. Cyclotrimerization is one of a few reactions in which the influence of the substituents attached to the cyclopentadienyl ring has been studied. Thus a

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Table 31 Ti-catalyzed cyclization of yn-epoxides

Yn-epoxide

a

dr

Product

dr

Yield (%) a

Isolated yields. b 20 mol% of the catalyst. c 55/45 ratio of the double bond isomers.

study of the variously substituted rhodium complexes (h5-C5R5)Rh(COD) 146 showed that the reaction rate of cyclotrimerization can be controlled by the electronic tuning of the catalysts by introducing electron-donating or -accepting groups to the cyclopentadienyl ring. Generally, the complex with electronaccepting groups (R=Cl) was more active for the cyclotrimerization of alkynes with electrondonating groups (3-hexyne) and the complex with electrondonating groups (R=Me) was more active for the cyclotrimerization of dimethylacetylene dicarboxylate [80]. As far as other catalytic systems are concerned, a cyclopentadienylrhodium complex supported on silica has been show to be efficent cyclotrimerization catalyst [81] and a cyclopentadienylcobalt complex bearing hydrophilic group in the side chain was efficient catalyst for cyclotrimerizations carried out in aqueous media [82]. From synthetic point of view, an attractive process is co-trimerization of a diyne with an alkyne that results in the formation of benzocycloalkanes. The required condition for successful course of the reaction is that the alkyne under the given reaction conditions does not homocyclotrimerize. Such an alkyne is bis(trimethylsilyl)acetylene (BTMSA), which has reduced tendency for ho-

Metallocene-Catalyzed Selective Reactions

105

mocoupling because of its bulky trimethylsilyl groups. On the other hand, it readily participates in the co-cyclotrimerization with sterically less hindered diynes in the presence of cyclopentadienylcobalt catalysts. Its success owes to the fact that Co-complexes readily form intermediate cobaltacyclopentadienes with 1,5-hexadiynes, 1,6-heptadiynes, 1,7-octadiynes, and 1,8-nonadiynes that co-cyclotrimerize with alkynes to give the corresponding benzocycloalkanes with 4,5,6, and 7-membered rings. Detailed discussion can be found elsewhere [79c]. As far as other cyclopentadienylmetal complexes are concerned, the ruthenium complex 106 seems to be an emerging promising catalyst for this type of transformation [83]. Cyclotrimerization of alkynes into the benzene ring has found numerous applications in the syntheses of natural compounds such as protoberberine skeleton [84], precursors of aromatic steroids [85], and tetracyclic terpenes [86].A typical example is the short synthesis of estrone 147, in which the whole steroid framework 149 was assembled from the starting diyne 148 in one step (Scheme 65) [87].

Scheme 65

Co-cyclotrimerization is also an effective method for the preparation of various classes of polyphenylenes [88]. One of the most illustrative examples is preparation of the C3-symmetric phenylene 150. The method is based on iterative cyclotrimerization of the starting hexadiyne 151 with 1,6-bis(triisopropylsilyl)-1,3,5-hexatriyne 152 that allows growth of the molecules simultaneously in three directions (Scheme 66). Here only the first step is shown; the hexadiyne 153 formed was used in one more co-cyclotrimeration to give an even larger molecule [89]. Intramolecular cyclization of triynes is the underlying strategy for the preparation of helicenes. Cyclotrimerization of a suitable starting material resulted in the formation of various [5], [6], and [7]-helicenes with 5–7 rings. Some representative examples are given in Table 32 [90]. Among other catalysts capable of alkyne cyclotrimerization are some cyclopentadienyl complexes of early transition metals. Thus a catalytic system composed of (h5-C5H5)NbCl4 154 and excess of Mg is capable of cyclotrimerization of terminal alkynes to a mixture of the 1,3,5- 155 and 1,2,4-substituted benzenes 156 (Scheme 67). The preferential formation of the 1,3,5-substituted isomers was observed in all cases (Table 33). Internal alkynes and trimethylsi-

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Scheme 66

Scheme 67

lylethyne under these conditions did not cyclotrimerize and this enabled their use in co-cyclotrimerization with diynes into the indane derivatives 157 and 158, respectively (Scheme 68) [91]. The niobium-diene complexes 57 and 58 are also known to be good catalysts for cyclotrimerization of terminal alkynes [26]. Interestingly, the former complex shows preference for the formation of 1,2,4-substituted benzenes, whereas the latter exhibits selectivity for 1,3,5-substituted isomers.

Metallocene-Catalyzed Selective Reactions

107

Table 32 Co-catalyzed cyclotrimerization of triynes into helicenes

Triyne

a

Yield (%) a

Helicene

Isolated yields.

Table 33 Nb-catalyzed cyclotrimerization of alkynes

R

Yield (%) a (155 + 156)

Ratio of 155/156

Ph n-Bu TBSOCH2CH2CH2 i-BuCOOCH2CH2

90 91 95 83

7/1 1.22/1 1.17/1 1.15/1

a

Isolated yields.

157

Scheme 68

158

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3.6 [2+2+2] Cyclotrimerization of Alkynes with C–Heteroatom Multiple Bonds Among transition-metal complex catalyzed reactions of alkynes with carbon–heteroatom unsaturated compounds the most studied is co-cyclotrimerization of alkynes with nitriles to pyridines. For this process the same complexes can be used as for the cyclotrimerization of alkynes. The first report of a cyclopentadienylcobalt complex catalyzed co-cyclotrimerization of alkynes with nitriles appeared in 1973 [92] and was soon followed by other papers [93]. Co-cyclotrimerization of alkynes and nitriles with all its aspects has been recently reviewed [94] and because of that we will focus only on recent developments in this area. In this regard, advances have been made in simple co-cyclotrimerization of ethyne with various nitriles [95], combinatorial synthesis of substituted pyridines [96], and co-cyclotrimerization of hydroxyalkynes with nitriles in aqueous media catalyzed by cobalt complex with hydrophobic chain attached to the cyclopentadienyl ring [97]. Cobalt-catalyzed co-cylotrimerization of alkynes with nitriles has also been used for the preparation of various bipyridines. Since the first report [93b], this reaction was extended to synthesis bi- or terpyridines with various degrees of complexity. The chiral bipyridines 159 were obtained from chiral nitriles by sequential double co-cyclotrimerization catalyzed by (h5-C5H5)Co(COD) 160 (Scheme 69) [98]. One-step synthesis of bipyridines was based on double cocyclotrimerization of ynnitriles with alkynes or diynes. Such a general approach was the underlying strategy for the preparation of the bicyclic bipyridines 161 (Scheme 70) [99], terpyridines [100], and the spirobipyridines 162 (Scheme 71) [101].

Scheme 69

Scheme 70

Metallocene-Catalyzed Selective Reactions

109

Scheme 71

Although there are the same problems with the regioselectivity as in the case of the trimerization of terminal alkynes [79], a certain degree of control can be achieved by varying the electron-withdrawing or -donating substituent at the cyclopentadienyl ring of the rhodium complexes 163, 43e and (h5C5H4CF3)Rh(CH2=CH2)2 43f. Generally, there was tendency of the complexes with electron-donating groups (R=NMe2, etc.) to prefer formation of 2,3,6-isomers 164, whereas in the case of the complexes with electron-withdrawing groups (R=COOMe, etc.) the formation of 2,4,6-isomers 165 was marginally favored (Scheme 72) [102]. The similar trend in regioselectivity was also observed for the complexes (h5-C5Me5)Rh(CH2=CH2)2 43b, and 166 [103].

Scheme 72

Recently, it has been shown that co-cyclotrimerization of diynes with electron-deficient nitriles can be successfully achieved with the ruthenium complex 106 in high yields to give the bicyclic pyridines 167 (Scheme 73) [104]. The same reaction conditions were used for the preparation of bipyridines from dinitriles [105]. Co-cylotrimerization of diynes with nitriles or ynnitriles with alkynes was a crucial step for total synthesis of several natural compounds. The former ap-

Scheme 73

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Scheme 74

proach of co-cyclotrimerization of the diyne 168 and acetonitrile has been also used in the synthesis of vitamin B6 169 (Scheme 74) [106]. The latter was used for the synthesis of (±)-lysergene and (±)-LSD [107]. Cyclopentadienylcobalt complexes are also good for co-cyclotrimerization of alkynes with other unsaturated compounds containing the carbon–heteroatom double bonds, especially when they are part of the cumulene system such as isocyanates, diimides, and carbon dioxide. The reaction conditions are essentially the same as in the previously mentioned processes. However, the biggest problem remains the selectivity for the formation of heterocycles, because of the strong competition for the formation of benzene derivatives. Whereas co-cyclotrimerization of diimides and isocyanates results in the formation of reasonable yields of the corresponding heterocycles 170 and 171 (Scheme 75), in the case of carbon dioxide the yields are generally low [108, 109]. Recently, it has been shown that the ruthenium complex 106 is capable of efficient catalysis of co-cyclotrimerization of diynes and isocyanates [110] and isothiocyanates [111] under mild reaction conditions.

Scheme 75

Although co-cyclotrimerization of alkynes with heterocumulenes has not been widely utilized in organic synthesis, it has been used as the essential step in the total synthesis of camptothecine 173. For the construction of the required heterocyclic ring was used co-cyclotrimerization of the yn-isocyanate 172 and 1-trimethylsilylpentyne (Scheme 76) [108].

Metallocene-Catalyzed Selective Reactions

111

Scheme 76

3.7 [2+2+2] Cyclotrimerization of Alkynes with Alkenes The cyclopentadienylcobalt complexes CpCo(L)n are also good catalysts for cocyclotrimerization of diynes with alkenes [79a]. Recently, it has been shown that the similar catalytic activity is exhibited by the ruthenium complex 106, which efficiently catalyzed cycloaddition of diynes with cyclic alkenes to the conjugated cyclohexadienes 174 (Scheme 77) [112].

Scheme 77

3.8 [4+2] Cycloaddition (Diels–Alder Reaction) Several cationic cyclopentadienylrhodium and iridium complexes 175 with attached chiral ligands behave like Lewis acids and have found their way as catalysts for Diels–Alder reaction. The complexes with chiral iminopyridine 175a,b [113], chiral oxazoline 175d,e [114], and chiral phosphine ligands 175c [115] were studied in the cycloaddition of cyclopentadiene with methacrolein into 176 (Scheme 78). Some typical examples are given in Table 34. Table 34 Rh- and Ir-catalyzed Diels-Alder reaction

Catalyst

mol%

T (°C)

exo/endo

ee (%) a

Yield (%) a

175a 175b 175c 175d 175e

5 5 10 5 2

20 –50 –50 20 0

93/7 94/6 98/2 94/6 95/5

8 46 71 29 68

72 21 73 62 81

a

The major product. b Isolated yields.

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Scheme 78

Table 35 Ru-catalyzed enantioselective Diels-Alder reaction

Acrolein

a

Isolated yields.

Diene

Product

Yield (%) a ee (%)

Metallocene-Catalyzed Selective Reactions

113

The monocyclopentadienyliron complexes with chiral bidentate phosphorus ligand such as 177 and 178 are suitable Lewis acid catalysts for Diels–Alder reaction of dienes with acryl aldehydes. The reaction proceeds under mild conditions with high yields and ees. In some cases the complex 178 gave better results than 177. Some representative examples of enantioselective Diels–Alder reaction of various acroleins with dienes are given in Table 35 [116]. Similar results can be achieved with the ruthenium complexes 179 [117]. Recently, the iron and ruthenium complexes 178 and 179 were use for enantioselective Diels–Alder reaction of methacrolein with nitrones [118]. 3.9 [5+2] Cycloaddition Reaction Higher order cycloaddition reactions provide unique tools for the construction of complex molecules through the formation of several C–C bonds in one reaction sequence. Such a case is intramolecular [5+2]-cycloaddition of cyclopropylenynes to seven-membered ring compounds 180 catalyzed by the ruthenium complex 53 (Scheme 79). The reaction conditions tolerate various functional groups (ether, amine, aldehyde, ketone, ester, amide, etc.) and the reaction proceeds under mild reaction conditions with high yields of the corresponding products. Some representative examples are given in Table 36 [119].

Scheme 79

The use of the proper starting material, such as one of the cyclopropylenynes 181, 182, and 183, results after the cycloaddition in the formation of the corresponding tricyclic systems 184, 185, and 186 that constitute the basic framework of several natural compounds (Scheme 80) [120]. The reaction mechanism of [5+2]-cycloaddition is likely to proceed through the following steps: initially, the cyclopropylenyne reacts with the Rucomplex to form the ruthenacyclopentene 188 through the intermediate complex 187, then ensues the C–C cleavage of the cyclopropane ring to give the ruthenacyclooctadiene 189. Finally reductive elimination affords the product 180 (Scheme 81). 3.10 Coupling of Allenes with Alkenes Analogically to the coupling of alkynes with alkenes (enones) there is also coupling of allenes with enones to give the dienones 190 (Scheme 82). This process is catalyzed by a number of ruthenium complexes such as 78 or 53 in the presence of a catalytic amount of cerium chloride. The former catalyst is suitable

114

Scheme 80

Scheme 81

Scheme 82

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Metallocene-Catalyzed Selective Reactions

115

Table 36 Ru-catalyzed [5+2]-cycloaddition of cyclopropylenynes

Cyclopropyleyne

a

Product

Yield (%) a

Isolated yields. b A product with the cyclopentane ring is also present.

for the coupling of monosubstituted allenes, whereas the latter is more convenient for the coupling of 1,1-disubstituted allenes. The reaction tolerates a wide range of functional groups [121]. The coupling of the monosubstituted allenes with enones proceeds specifically with the internal double bond of the allene moiety and some representative examples are given in Table 37. The use of di and higher substituted allenes usually gives a mixture of isomers, although in some cases predominant formation of one of the possible products may be observed. In case of 1,1-substituted allenes, only one regioisomer is formed when one of the b-hydrogens is acidified by being a to an ester or amido group (Table 38).

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Table 37 Ru-catalyzed coupling of allenes with enones

Allene

R3

Product

Yield (%)

The first step of the reaction mechanism is the formation of the ruthenacyclopentene 191, then b-hydrogen elimination proceeds to 192, which after reductive elimination releases the product 190 and the ruthenium complex goes back to the catalytic cycle (Scheme 83). The coupling of allenyl alcohols bearing a hydroxy group in the g- or d-position to the allenyl moiety results in the formation of the cyclic ethers 193 (Scheme 84). Some representative examples are given in Table 39. The reaction mechanism is the same as above. The difference is in facility of the nucleophilic attack versus b-hydrogen elimination. The presence of a free hydroxyl group in 194 juxtaposed such that either a five or six-membered cyclic ether can form allows nucleophilic substitution to proceed to give 195 (Scheme 85) [122].

Metallocene-Catalyzed Selective Reactions

117

Table 38 Ru-catalyzed coupling of 1,1-substituted allenes with 2-butenone

Allene

Scheme 83

Product

Yield (%)

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Scheme 84

Scheme 85

In a similar fashion, g- and d-aminoallenes can also be cyclized into the corresponding pyrrolidines and piperidines. However, in this instance the presence of a stronger Lewis acid such as TiCl4 and Et2AlCl is necessary for the successful course of the reaction [123]. 3.11 Multicomponent Couplings of Alkenes with Alkynes The first multicomponent coupling was a three-component coupling of vinylketones with alkynes and water resulting in the formation of the 1,5-diketones 196 (Scheme 86). The reaction was catalyzed by the ruthenium complex 78 and the successful course of the reaction required the presence of a Lewis acid (indium(III)triflate). Some typical examples are given Table 40 [124]. An intramolecular variant of this process allows preparation of the cyclic diketones 197 from starting yn-enones (Scheme 87) [125]. Some typical ex-

Scheme 86

Metallocene-Catalyzed Selective Reactions

119

Scheme 87

Table 39 Ru-catalyzed coupling of w-allenols with enones

w-Allenol

R1

Product

Yield (%)

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Table 40 Ru-catalyzed coupling of alkynes and 2-butenone

Alkyne

a

Product

Yield (%) a

GC yields. Isolated yields are in parentheses.

amples are given in Table 41. The reaction mechanism is rather complex with several possible reaction pathways; it is outlined in Scheme 88. Further inquiry into the reaction mechanism resulted in the development of a new three-component coupling that led to the formation of the E-vinyl chlorides 198. This was achieved by carrying out the ruthenium-catalyzed coupling of alkynes with vinylketones in the presence of ammonium chloride and a cat-

Scheme 88

Metallocene-Catalyzed Selective Reactions

121

Table 41 Ru-catalyzed cyclization of yn-enones

Alcohol

Product

dr

Yield (%)

alytic amount of a Lewis acid (SnCl4) in a mixture of DMF and H2O (Scheme 89) [126]. The same set of reaction conditions could also be used for the preparation of vinyl bromides; however, in this instance a mixture of E and Z isomers was obtained. Optimizing co-catalyst concentration, bromide source, and solvent allowed finding reaction conditions that gave the valuable Z-isomers 199 as the major products (Scheme 90) [127]. Some typical examples are represented in Table 42.

Scheme 89

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Table 42 Ru-catalyzed coupling of alkynes and vinyl ketones

Alcohl

R2

Product

Z/E

Yield (%)

Scheme 90

Under the same reaction conditions disubstituted alkynes can participate as well to give tetrasubstituted vinyl bromides. The three-component coupling to the Z vinyl bromides was later used as the underlying strategy for the development of a new approach into cyclopentanoids [128]. A hypothetical reaction mechanism is presented in Scheme 91. It is assumed that the cationic ruthenium complex initially reacts with metal halide to give the ruthenium species with the covalently bound halide 200. Then cishaloruthenation proceeds to give the alkenyl ruthenium species 201 followed by insertion of an enone resulting in the formation of the ruthenium enolate 202. Its decomposition by protonation releases the product 199 and the ruthenium complex goes back into the catalytic cycle.

Metallocene-Catalyzed Selective Reactions

123

Scheme 91

The above mentioned three-component coupling was also the basis for the development of four-component coupling of alkynes, vinylketones, and aldehydes in the presence of metal halides to give 203 (Scheme 92). The key step is again the formation of the ruthenium enolate 202, which reacts with the aldehyde present in the reaction mixture. The formation of chloro-derivatives proceeds through trans-chlororuthenation and affords E-vinyl chlorides. The formation of bromo-derivatives proceeds through cis-bromoruthenation and affords Z-vinyl bromides [129].

Scheme 92

4 C–C Bond Cleavage Reactions 4.1 Alkene Metathesis Cyclopentadienyl complexes of transition metals have rarely been used in the carbon–carbon double bond metathesis. So far only various cyclopentadienylcarbonyl complexes of molybdenum in a combination with Lewis acids (organoaluminium compounds) such as CpMo(CO)3I/NO/(CH3)3Al2Cl3 203a [130], CpMo(NO)2(O-i-Pr)2/EtAlCl2 203b [131], [CpMo(CO)3]2/EtAlCl2 203c and [CpMo(CO)3]2/NO/EtAlCl2 203d [132] showed certain activity for intermolecular metathesis of terminal alkenes (Scheme 93). However, the reaction

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Scheme 93

is not selective and is plagued by side reactions such as dimerization and oligomerization of the alkenes. 4.2 C–C Bond Cleavage The coordinatively unsaturated binuclear iridium hydride 54 is capable of catalysis of the C–C bond cleavage of aromatic diols that disproportionate into the ketone 205 and the alcohol 206 (Scheme 94) [30]. The ruthenium complex 106 is capable of cleaving the C–C bond through ballyl elimination in tertiary homoallylic alcohols to give the ketones 207 and propene 208 (Scheme 95) [133].

Scheme 94

Scheme 95

5 Substitution Reactions 5.1 Allylic Substitution The ruthenium complex 78 is a good catalyst for allylic substitution of various allyl derivatives (acetates, carbonates, etc.) to give the allylated products 209 (Scheme 96). These reactions were classified as an electrophilic and a nucleophilic allylation. It has been concluded that there exists the possibility that the intermediate (h3-allyl)ruthenium complexes can alternately function as a nucleophile and an electrophile, i.e., as an ambiphile, depending on the reactivity of the substrates [134]. Table 43 gives some typical examples of the allylation of N- and C-nucleophiles with allylic carbonates [134d].

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Scheme 96

Table 43 Ru-catalyzed allylic substitution of cyclic carbonates

Carbonate

Nucleophile

Product

Yield (%)

Recently, it was shown that the cyclopentadienylruthenium aminidate complexes 210 are good catalysts for allylic substitution with various nucleophiles. The advantage over the other catalytic systems is that malonates do not have to be used as their C-salts [134e]. 5.2 Propargylic Substitution The thiolate bridged diruthenium complex [(h5-C5Me5)RuCl(m-SR)2Ru(h5C5Me5)Cl] 211, or its derivative with various anions, proved to be a very efficient catalyst for substitution of propargylic alcohols with a number of nucleophiles. The substitution of propargylic alcohols proceeds with heteroatom nucleophiles such as alcohols, thiols, amines, amides, and phosphineoxides to give the corresponding ethers 212, thioethers 213, amines 214, amides 215, and phosphineoxides 216 (Scheme 97) [135]. Carbon nucleophiles such ketones and

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Scheme 97 Table 44 Ru-catalyzed substitution of propargylic alcohols with ketones

Propargyl alcohol

a

Ketone

Product

Isolated yields. b Regioisomer ratio 97/3.

Yield (%) a

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Table 45 Ru-catalyzed substitution of propargylic alcohols with aromatic compounds

Propargyl alcohol Ketone

a

Product

Yield (%) a

Isolated yields.

aromatic compounds could also be used to give the homopropargyl ketones 217, and the aryl- and heteroaryl alkynes 218 (Scheme 98) [136]. Some representative examples of the formation of homopropargyl ketones and alkynylarenes are given in Tables 44 and 45.

Scheme 98

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6 Isomerization Reactions 6.1 Isomerization of Allyl Alcohols A double bond isomerization in alkenes possessing hydroxy groups can occur to generate ketones. Such a process represents a more economical approach to redox chemistry than processes involving sequential oxidation and reduction. Isomerization of allyl alcohols to the saturated ketones 219 can be catalyzed by the cyclopentadienyl- or indenylruthenium complexes 89a or 220 in the presence of triethylammonium hexafluorophosphate under mild reaction conditions (Scheme 99). Some representative results of the isomerization of allyl alTable 46 Ru-catalyzed isomerization of allylic alcohols into carbonyl compounds

Allyl alcohol

a Yields

Product

Yield (%) a

were based on the recovered starting material.

Metallocene-Catalyzed Selective Reactions

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Scheme 99

cohols with 89a to ketones 219 are summarized in Table 46. Comparison of both catalysts for isomerizations showed that the former catalyst provides excellent selectivity but at the sacrifice of reactivity. Use of the latter catalyst allows maintenance of most of the selectivity but with a significantly higher expansion of the scope [137]. The same reaction was studied for cyclopentadienylruthenium complexes bearing diphopshine ligands, which showed much lower reactivity [138]. The proposed reaction mechanism is outlined in Scheme 100 and proceeds through the formation of the biscoordinated ruthenium complex 221, followed by b-hydrogen elimination and the formation of ruthenium hydride and with simultaneous coordination of the formed enone 222. Hydrometallation of the intermediate 222 will afford the enolate 223, which after protonolysis will furnish the ketone 219.

Scheme 100

6.2 Isomerization of Propargyl Alcohols The use of a,b-unsaturated carbonyl compounds 224 in organic synthesis and the ease of access to propargyl alcohols makes conversion of the latter into the

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Scheme 101

former a useful transformation (Scheme 101). Such a process is analogic to the isomerization of allylic alcohol to ketones and is catalyzed under the similar reaction conditions by the same indenylruthenium complex 220 in the presence of hexafluorophosphate salt and indium chloride as a co-catalyst. The reaction proceeds well with mono- and disubstituted propargyl alcohols to give the corresponding a,b-unsaturated aldehydes and ketones [139]. Some typical examTable 47 Ru-catalyzed isomerization of propargylic alcohols into a,b-unsaturated carbonyl compounds

Alcohol

a

Isolated yields.

Product

Yield (%) a

Metallocene-Catalyzed Selective Reactions

131

ples are given in Table 47. The reaction mechanism follows the one mentioned in Scheme 100.

7 Other Reactions 7.1 Cyclization of Dienynes Some cyclopentadienylruthenium complexes such as (h5-C5H5)Ru(L)nCl (L=PPh3, dppm, dppe, P(OEt)3) 89 and 76 in combination with NH4PF6 are capable of catalyzing the cyclization of dienynes into the tricyclic compounds 225 (Scheme 102). It was proposed that the reaction mechanism proceeds through an alkylidene ruthenium intermediate [140].

Scheme 102

7.2 Annulation of Alkynes with Nitrosoaromatics An interesting process that leads to the formation of the indoles 226 is the reaction of nitrosoaromatics with alkynes catalyzed by (h5-C5Me5)Ru(CO)2 227 (Scheme 103) [141].

Scheme 103

7.3 Hydrodechlorination of Aryl Chlorides Dechlorination of chloroaromatics is an important chemical transformation from the synthetic as well as environmental point of view. Facile dehydrochlorination of aryl chlorides can be affected by a catalytic amount of the rhodium complex 74 under basic conditions and 2-butanol as a hydrogen source (Scheme 104). The reaction tolerates both electron-donating and electron-accepting substituents and gives high yields of the products 228 [142].

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Scheme 104

7.4 Reductive Amination of Ketones Reductive amination of carbonyl compounds is a synthetically attractive process because it directly transforms aldehyde and ketones into the primary and secondary amines 229 (Scheme 105). Among a number of screened catalysts, the best proved to be the rhodium complex 74. The reaction proceeded with a high selectivity in the presence of HCOONH4 as hydride and amine source with linear and cyclic ketones, and also with ketoacids [143].

Scheme 105

7.5 Oxidative Cyclization of Amino Alcohols Amino alcohols can be conveniently transformed into the corresponding heterocyclic compounds in the presence of a catalytic amount of the iridium complex [(h5-C5Me5)IrCl2]2 230. Oxidative cyclization of 2-aminophenethyl alcohols yields the indols 231, whereas oxidative cyclization of 3(2-aminophenyl) propanols and 4(2-aminophenyl)butanol furnished the 1,2,3,4-tetrahydroquinolines 232 and the 2,3,4,5-terahydro-1-azepine 233 (Scheme 106). Reaction conditions tolerate various functional groups attached to the aromatic ring, such as Cl, MeO. Products bearing substituents on N-heterocyclic ring could be synthesized from the aminoalcohols with substituents on the methylene chain [144].

Scheme 106

Metallocene-Catalyzed Selective Reactions

133

8 Conclusion This brief overview clearly shows the potential of cyclopentadienylmetal complexes in organic synthesis. Examples of catalysis by more then 70 cyclopentadienyl transition metal complexes are mentioned. They are able to catalyze various processes ranging from a simple C–C or C–heteroatom bond formation or cleavage to a cascade assembly of several building blocks into a product with high molecular complexity. Moreover, the structural features of those complexes allow subtle tuning of their properties by changing electronic, steric, or both effects by varying substituents on the cyclopentadienyl ring. In cases when other ligands (e.g., phopshines) are also coordinated to the central metal atom there is an additional site for tuning of the catalyst’s properties. The results presented show that the use of cyclopentadienyl complexes in organic synthesis has many advantages, such as selectivity for a certain process, mild reaction conditions, and also tolerance for various functional groups. In addition, many of these reactions have no counterparts in classical organic synthesis and thus provide unique tools for the selective manipulation of defined bonds. In view of the forgoing, it is not surprising that the last two decades have witnessed an enormous increase in the use of cyclopentadienyl complex catalyzed reactions in organic synthesis. Moreover, this trend still continues with steadily increasing pace and there is no doubt that even more applications of cyclopentadienyl complexes will appear in the near future.

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113. (a) Carmona D, Lahoz FJ, Elipe, S, Oro LA, Lamata MP, Viguri, F, Mir C, Cativiela C, de Viu, MPLR (1998) Organometallics 17:2986. (b) Carmona D, Vega C, Lahoz FJ, Elipe, S, Oro LA, Lamata MP, Viguri, F, Garcia-Correas R, Cativiela C, de Viu, MPLR (1999) Organometallics 18:3364 114. Davenport AJ, Davies DL, Fawcett J, Garratt SA, Lad L, Russell DR (1997) Chem Commun 2347 115. Carmona D, Cativiela C, Garcia-Correas R, Lahoz FJ, Lamata MP, Lopez JA, de Viu, MPLR, Oro LA, San Jose E, Viguri, F (1996) Chem Commun 1247 116. (a) Kundig EP, Bourdin B, Bernardinelli G (1994) Angew Chem Int Ed Engl 33:1856. (b) Bruin ME, Kundig EP (1998) Chem Commun 2635 117. Kundig EP, Sauda CM, Bernardinelli G (1999) Angew Chem Int Ed 38:1220 118. Viton F, Bernardinelli G, Kündig EP (2002) J Am Chem Soc 124:4968 119. Trost BM, Toste FD, Shen H (2000) J Am Chem Soc 122:2379 120. Trost BM, Shen HC (2001) Angew Chem Int Ed 40:2313 121. Trost BM, Pinkerton AB, Seidel M (2001) J Am Chem Soc 123:12466 122. Trost BM, Pinkerton AB (1999) J Am Chem Soc 121:10842 123. Trost BM, Pinkerton AB, Kremzow D (2000) J Am Chem Soc 122:12007 124. Trost BM, Portnoy M, Kurihara H (1997) J Am Chem Soc 119:836 125. Trost BM, Brown RE, Toste FD (2000) J Am Chem Soc 122:5877 126. Trost BM, Pinkerton AB (1999) J Am Chem Soc 121:1988 127. Trost BM, Pinkerton AB (2000) Angew Chem Int Ed 39:360 128. (a) Trost BM, Pinkerton AB (2000) Org Lett 2:1601. (b) Trost BM, Pinkerton AB (2001) J Org Chem 66:7714 129. Trost BM, Pinkerton AB (2000) J Am Chem Soc (2000) 122:8081 130. Zuech EA, Hughes WB, Kubicek DH, Kittleman EJ J Am Chem Soc 92:528 131. Keller A (1990) J Organomet Chem 385:285 132. du Plessis JAK, van Sittert CGCE, Vosloo HCM (1994) J Mol Cat 90:11 133. Kodo T, Kodoi K, Nishinaga E, Okada T, Morisaki Y,Watanabe Y, Mitsudo T (1998) J Am Chem Soc 120:5587 134. (a) Kondo T, Mukai T, Watanabe Y (1991) J Org Chem 56:487. (b) Kondo T, Ono H, Satake N, Mitsudo T, Watanabe Y (1995) Organometallics 14:1945. (c) Kondo T, Morisaki Y, Wada K, Mitsudo T (1999) J Am Chem Soc 121:8567. (d) Morisaki Y, Kondo T, Mitsudo T (1999) Organometallics 18:4742. (e) Kondo H, Kageyama A,Yamaguchi Y, Haga M, Kirschner K, Nagashima H (2001) Bull Chem Soc Jpn 74:1927 135. (a) Nishibayashi Y, Wakiji I, Hidai M (2000) J Am Chem Soc 122:11019. (b) Inada Y, Nishibayashi Y, Hidai M, Uemura S (2002) J Am Chem Soc 124:15172 136. (a) Nishibayashi Y, Wakiji I, Ishii Y, Uemura S, Hidai M (2001) J Am Chem Soc 123:339. (b) Nishibayashi Y, Yoshikawa M, Inada Y, Hidai M, Uemura S (2002) J Am Chem Soc 124:11846 137. Trost BM, Kulawiec RJ (1993) J Am Chem Soc 115:2027 138. van der Drift RC, Vailati M, Bouwman E, Drent E (2000) J Mol Cata A Chem 159:163 139. (a) Trost BM, Livingston RC (1995) J Am Chem Soc 117:9586. (b) Trost BM, Lee C (2001) J Am Chem Soc 123:12191 140. Merlic CA, Pauly ME (1996) J Am Chem Soc 118:11319 141. Penoni A, Volkmann J, Nicholas KM (2002) Org Lett 4:699 142. Fujita K, Owaki M, Yamaguchi R (2002) Chem Commun 2964 143. Kitamura M, Lee D, Hayashi S, Tanaka S, Yoshimura M (2002) J Org Chem 67:8685 144. Fujita K, Yamamoto K, Yamaguchi R (2002) Org Let 4:2691

Topics Organomet Chem (2004) 8: 139– 176 DOI 10.1007/b96003 © Springer-Verlag Berlin Heidelberg 2004

Diastereoselective, Enantioselective, and Regioselective Carboalumination Reactions Catalyzed by Zirconocene Derivatives Ei-ichi Negishi (

) · Ze Tan

Purdue University, Herbert C. Brown Laboratory of Chemistry, 560 Oval Drive,West Lafayette, Indiana 47907–2084 USA [email protected] 1

General Discussion of Carbometallation . . . . . . . . . . . . . . . . . . . 140

2

Zr-Catalyzed Methylalumination of Alkynes . . . . . . . . . . . . . . . . . 142

2.1 2.2 2.3

Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Synthetic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Mechanism of the Zr-Catalyzed Methylalumination of Alkynes . . . . . . . 145

3

Zr-Catalyzed Ethyl- and Higher Alkylalumination of Alkynes . . . . . . . . 152

3.1 3.2 3.2.1 3.2.2

Earlier Investigation . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism of Zr-Catalyzed Ethylalumination of Alkynes . . . . . Cyclic Mechanism for the Dzhemilev Ethylmagnesation of Alkenes Zr-Catalyzed Cyclic Bimetallic Ethylalumination of Alkynes. Scope, Limitations, and Mechanisms . . . . . . . . . . . . . . . . . . . .

. . . . . 152 . . . . . 152 . . . . . 152 . . . . . 153

4

Hydrogen-Transfer Hydroalumination and Hydrozirconation . . . . . . . . 157

5

Effects of Metal Countercations on Stoichiometric and Catalytic Carbozirconation. Zr-Catalyzed Carbozincation . . . . . . . . . . . . . . . 158

5.1 5.2 5.3 5.4

Comparison of Stoichiometric and Catalytic Carbometallation Reactions with Al–Zr and Mg–Zr Reagent Combinations . . . . Zr-Catalyzed Carbozincation . . . . . . . . . . . . . . . . . . . Carbozirconation Induced by Alkyllithiums . . . . . . . . . . . Summary of the Effects of Metal Countercations . . . . . . . .

6

Zr-Catalyzed Asymmetric Carboalumination of Alkenes

6.1

Discovery of Zr-Catalyzed Asymmetric Methyl-, Ethyl-, and Higher Alkylalumination of Alkenes . . . . . . . . . . . . . . . . . . . . . . . Zr-Catalyzed Asymmetric Alkylation with Alkylmagnesium Reagents via Cyclic Carbozirconation . . . . . . . . . . . . . . . . . . . . . . . Zr-Catalyzed Asymmetric Methylalumination of Ordinary Unactivated Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zr-Catalyzed Asymmetric Ethyl- and Higher Alkylalumination of Ordinary Unactivated Alkenes . . . . . . . . . . . . . . . . . . . . . Synthetic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . Future Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.1.1 6.1.2 6.1.3 6.2 6.3

References

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

158 159 162 163

. . . . . . . . . . 164 . . . 164 . . . 164 . . . 165 . . . 167 . . . 168 . . . 170

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

140

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Abstract Coordinatively unsaturated alkylzirconocene derivatives can undergo stereo-, and regioselective carbometallation reactions of synthetic utility via either bimetallic activation or formation of active three-membered zirconacycles. The Zr-catalyzed carboalumination of alkynes is an example of the former. The Zr-catalyzed methylalumination, in particular, has been developed into a generally applicable reaction of high synthetic utility, and it has been applied to the synthesis of about 100 complex natural products. Highly promising is the Zr-catalyzed asymmetric carboalumination of alkenes featuring novelty and high efficiency. With further improvements, it promises to become another synthetically useful reaction of widespread use. Use of isoalkylalanes in the above-mentioned reactions leads to potentially attractive and useful hydrogen-transfer hydrometallation reactions. Unlike Al, other metals including Li, Mg, and Zn have tended to participate in the reactions proceeding via zirconacycles. Some of these reactions also provide highly efficient routes to compounds that are otherwise difficult to access. Structural and mechanistic aspects of these carbometallation reactions are discussed in some detail. Keywords Zr-catalyzed carboalumination of alkynes · Zr-catalyzed asymmetric carboalumination of alkenes · Hydrogen-transfer hydrometallation · Cyclic carbozirconation · Bimetallic activation of C–M bonds

1 General Discussion of Carbometallation Carbometallation may be defined as a chemical process involving addition of carbon–metal bonds (C–M bonds, hereafter) to carbon–carbon p-bonds (C–C p-bonds, hereafter). This term was most probably first suggested in 1978 [1]. Earlier examples of carbometallation involved oligomerization and polymerization of alkenes and alkynes that are of major significance in materials chemistry but of very limited utility in the synthesis of fine chemicals. One of the prototypical examples of controlled single-stage carbometallation is Normant’s carbocupration of alkynes reported in the early 1970s [2, 3]. In this sense, controlled single-stage carbometallation is barely 30 years old. Fundamentally, controlled carbometallation is complementary with conventional organometallic C–C bond formation with polar organometals containing Li, Mg, and so on. Their relationships with each other are indicated in Scheme 1. Although they closely resemble each other at first glance, some major differences have also been noted. In essence, most of the conventional reactions are dominated by polar processes involving polar sigma (s) C–M and carbon–heteroatom (C–X, hereafter) bonds. On the other hand, synthetically useful and facile carbometallation reactions must generally involve concerted processes of non-polar pbonds, i.e., C=C and C
C, in which the presence or ready availability of at least one valence-shell empty orbital is thought to be important. Just as the simultaneous presence of a metal-centered empty orbital serving as a LUMO and a filled non-bonding orbital serving as a HOMO is critically important in p-complexation of metals (or even carbenes, nitrenes, and so on) with p-bonds (De-

Diastereoselective, Enantioselective, and Regioselective Carboalumination

141

Scheme 1

war-Chatt-Duncanson model; for the seminal work by Dewar, see [4]), the simultaneous availability of a metal-centered empty orbital and a H–M or C–M s-bond serving as a HOMO is thought to be critically important for facile, concerted hydrometallation or carbometallation, respectively (Scheme 2). With the simplistic notion presented above in mind, the controlled singlestage carbotitanation [5] and the synthetically much more useful Zr-catalyzed carboalumination of alkynes [1, 6, 7, 8, 9, 10] were both discovered in 1978. For a recent review, see [10]. It soon became clear that none of these reactions would proceed with just one metal, i.e., Ti, Zr, or Al. They are unmistakably bimetallic at the crucial C–C bond-forming step, and a bimetallic mechanism

Scheme 2

142

E. Negishi · Z. Tan

involving three-centered M1–X–M2 bonds [7, 9, 11, 12, 13, 14] was proposed as early as 1981 [7, 12]. This mechanistic notion, which has been termed the twois-better-than-one principle [14], appears to be widely observable and has undoubtedly manifested itself in the Friedel–Crafts reaction [15] and the more closely related Ziegler–Natta alkene polymerization. For a recent review, see [16]. As important as the bimetallic activation of C–Zr or C–Ti bonds is, this only represents part of the mechanistic diversity displayed by Zr or Ti. Only within the last decade or so have the mechanisms of some of the Zr-catalyzed carboalumination proceeding via cyclic carbozirconation been adequately clarified [13, 14, 17], following the unexpected clarification of the cyclic mechanism of the Zr-catalyzed ethylmagnesation of alkenes [18, 19]. For a review, see [19]. Some mechanistic details of these various carbometallation reactions vis-à-vis metal countercations will be presented later.

2 Zr-Catalyzed Methylalumination of Alkynes 2.1 Discovery With the meager theory presented above and a remote analogy between the multi-step Ziegler–Natta alkene polymerization in mind, PhC
CPh was reacted with a 2:1 mixture of Me3Al and Cp2TiCl2. The reaction led to nearly quantitative formation of the desired product (1), which was essentially 100% Z, upon protonolysis of the initially formed alkenylmetal (2) [5]. A few years later, Tebbe [20] reported the reaction of the same three reagents except that Me3Al and Cp2TiCl2 were premixed for a couple of days before addition of PhC
CPh. This led to the formation of a titanacyclobutene (3) (Scheme 3). This seeming puzzle has been resolved recently [21]. In essence, all reported results were correct. The former is thought to be an acyclic bimetallic carbotitanation, whereas the latter involves the intermediacy of the Tebbe reagent (4)

Scheme 3

Diastereoselective, Enantioselective, and Regioselective Carboalumination

143

[22]. Thus, the acyclic–cyclic dichotomy, which is one of the main themes of this chapter, was observed as early as 1978–1980. Unfortunately, the carbotitanation reaction was not only stoichiometric in Ti but also of very limited synthetic utility. With the goal of discovering a synthetically more useful and generally applicable carbometallation, the Ti triad, i.e., Ti, Zr, and Hf, was screened, and the Zr-catalyzed carboalumination of alkynes often called the Negishi carboalumination [1] was thus discovered and reported in 1978 (Scheme 4). Under the conditions employed, the reaction was unquestionably bimetallic as indicated earlier. Omission of either Al or Zr led to no reaction. The reaction is (i) generally high-yielding, (ii) about 95% regioselective in the methylalumination of terminal alkynes, (iii) essentially 100% stereoselective, and (iv) tolerant of some useful heterofunctional groups, such as OH, halogens, and amines [6]. The reaction has been most extensively studied and carried out with Me3Al as a reagent, but it works well with alanes containing allyl and benzyl groups [8]. Higher alkylalanes also react [17], but further improvements are desirable, as discussed in Sect. 3.

Scheme 4

Some synthetically useful variations of the reaction have also been observed. Thus, the reaction of 1-metallo-4-halo-1-butynes with Me3Al and a catalytic amount of Cp2ZrCl2 produced 2-methyl-1-cyclobutenylalanes in high yields [23, 24, 25]. On the other hand, the presence of a 4-hydroxy group in place of halogens led to a nearly complete stereoinversion of the trisubstituted alkene moiety thereby providing a useful route to otherwise difficultly accessible trisubstituted alkenes [26] (Scheme 5).

Scheme 5

144

E. Negishi · Z. Tan

2.2 Synthetic Applications (E)-b-Methyl-substituted alkenylalanes (5) generated in situ by the Zr-catalyzed carboalumination can now be directly or indirectly converted to a myriad of organic compounds. Only some of the seminal and representative examples are summarized in Schemes 6, Scheme 7 and Scheme 8. As summarized in Scheme 6, the Al atom of 5 can be readily substituted with heteroatoms including H, D, halogens [27], S, and metals, such as B [28], Hg [29], and Zr [28].

Scheme 6

Carbon–carbon bond formation via alkenylalanes (5) can be achieved by conventional polar reactions (Scheme 7) [30, 31] and by more modern Pd- or Ni-catalyzed and related cross-coupling reactions (Scheme 8) [32, 33, 34, 35, 36, 37, 38, 39]. As the products in Schemes 7 and 8 represent a large number of natural products including terpenoids and carotenoids, the reaction has indeed been

Scheme 7

Diastereoselective, Enantioselective, and Regioselective Carboalumination

145

Scheme 8

applied to their syntheses.A recent survey summarized in Table 1 suggests that the number of applications in the synthesis of natural products and related compounds may have exceeded 100. The structures of only a limited number of representative examples are shown at the end of Table 1. 2.3 Mechanism of the Zr-Catalyzed Methylalumination of Alkynes Earlier investigations of the Zr-catalyzed carboalumination of alkynes has indicated that the reaction is bimetallic, requiring both Al and Zr at the critical stage of the reaction [1, 7, 9, 11, 12].Although mechanisms involving Al-assisted C–Zr bond addition were thought to be plausible, experimental findings pointing to alternative mechanisms involving Zr-assisted C–Al bond addition were also observed in some cases, such as the reaction of alkynes with Me2AlCl catalyzed by Cl2ZrCp2 [7, 9, 11]. In addition to the results shown in Scheme 4, those stoichiometric carbozirconation reactions shown in Scheme 9 further point to the need for enhancing the Lewis acidity of the Zr center through bimetallic polarization by another metal, such as Al and B [9, 11, 131, 132].

Scheme 9

146

E. Negishi · Z. Tan

Table 1 Applications of the Zr-catalyzed carboalumination of alkynes to the stereoselective syntheses of natural products

Year

Natural product

Molecular formula Major author

Ref.

1978

Geraniol Ethyl geranate Monocyclofarnesol Mokupalide (6) Dendrolasin Farnesol Brassinolide (7) a-Farnesene Verrucarin J (8) Udoteatrial Verrucarin J (8) Brassinolide (7) Castasterone Dolicholide Dolichosterone Verrucarin B Zoapatanol Mycarose epi-Axenose Aurodox Efrotomycin Lophotoxin (9) Methyl kolavenate (10) Milbemycin b3 (11) Brassinolide (7) (+)-Sterpurene FK-506 (12) Lophotoxin (9) Pukalide Ageline A Lacrimin A (13) Milbemycin b1 Lacrimin A (13) Avermectin B1a (14) FK-506 (12) Avermectin B1a (14) Vitamin A Phytol Aboa of theonellamide F Inhibitor of 2,3-oxidosqualene-lanoosterol cyclase Milbemycin K C(1)-C(14) tetraene unit of calyculin A

C10H18O C12H20O2 C15H26O C30H46O2 C15H22O C15H26O C28H48O6 C15H24 C27H32O8 C20H30O3 C27H32O8 C28H48O6 C28H48O5 C28H46O6 C28H48O5 C27H32O9 C20H34O4 C7H24O4 C7H24O4 C44H64N2O12 C59H88N2O20 C22H24O8 C21H34O2 C31H42O5 C28H48O6 C15H24 C44H63NO12 C22H24O8 C21H24O6 C26H40N5 C31H42O5 C32H48O7 C31H42O5 C48H72O14 C44H63NO12 C48H72O14 C20H30O C20H40O C15H18O3Br C29H48OS

Negishi E

30

Negishi E Negishi E

40 41

Negishi E Siddall JB Negishi E Roush WR Whitesell JK Roush WR Mori K

36 42 34 43 44 45 46

Roush WR Cookson RC Roush WR

47 48 49

Nicolaou KC

50

Tius MA Tokoroyama T Kocienski PJ Mori K Okamura WH Smith AB III Paterson I

51 52 53 54 55 56 57

Tokoroyama T Kocienski P Ley SV Kocienski P Ley SV Ireland R Ley SV Negishi E Takano S Hamada Y, Shioiri T Oehlschlager AC

58 59 60 61 62 63 64 65 66 67 68

C32H44O7 C50H87N4O15P

Takano S Barrrett AG

69 70

1980 1980 1980 1980 1981 1983 1983 1984 1984

1984 1985 1985 1985 1986 1987 1987 1988 1988 1989 1989 1989 1989 1989 1990 1990 1990 1991 1991 1991 1992 1992 1992 1992

Diastereoselective, Enantioselective, and Regioselective Carboalumination

147

Table 1 (continued)

Year

Natural product

Molecular formula Major author

Ref.

1993

1233A

C18H32O5

71

1993 1993 1993 1994

Forskolin Milbemycin E Callosobruchusic acid Suspensolide (15) Anastrephin and epianastrephin Inhibitors of 2,3-oxidosqualene-lanosterol cyclase Manoalide Curacin A (16) Curacin A (16) Vitamin A Pateamine A (17) Pateamine (17) Hygrolidin Phomactin D CoQ3 CoQ4 CoQ5 Vitamin K1 Vitamin K2 Concanamycin A (18) (–)-PI-091 (+)-Curacin (16) (3z)-a-Farnesene FK-506 (12) Freelingyne (19) 1233A (+)-Curacin A Concanolide A Concanoamycin A (18) (–)-Pateamine A (17) Aurisides (+)-Calyculin A (20) (–)-Calyculin B Okinonellin B (21) Menaquinone-3 CoQ5 Elenic acid (–)-Bafilomycin A (22) 1233A Amphidinolide B (23) Epolactaene

C22H34O7 C34H52O7 C10H16O4 C12H18O2 C12H18O2

1994 1994 1995 1995 1995 1995 1996 1996 1996 1996

1997 1997 1997 1997 1997 1997 1998 1998 1998 1998 1998 1998 1998 1998 1998 1999 1999 1999 1999 1999

Wovkulich PM, Uskokovic MR Welzel P Thomas EJ Carpita A Oehlschlager AC

72 73 74 75

C29H48OS

Oehlschlager AC

76

C25H36O5 C23H35NOS C23H35NOS C20H30O C31H45N3O4S C31H45N3O4S C38H58O11 C20H30O3 C24H34O4 C29H42O4 C34H50O4 C30H44O2 C31H50O2 C46H75NO14 C17H31NO4 C15H18Cl2O7 C15H24 C44H63NO12 C15H12O3 C18H32O5 C23H35NOS C39H64O10 C39H64O10 C31H45N3O4S

Kocienski P Gerwick WH White JD de Lera AR Romo D Pattenden G Hashimoto S Yamada Y Lipshutz BH

77 78 79 80 81 82 83 84 85

Paterson I Iwasawa N White JD Negishi E Ireland RE Negishi E Langlois Y Pattenden G Toshima K Toshima K Romo D Yamada K Smith AB III

86 87 88 26 89 90 91 92 93 94 95 96 97

Romo D Lipshutz BH

98 99

Hoye RC Roush WR Ley SV Chakraborty TK Kobayashi S

100 101 102 103 104

C50H87N4O15P C50H87N4O15P C25H36O4 C26H32O2 C34H50O4 C30H50O3 C35H58O9 C18H32O5 C32H50O8 C21H27NO6

148

E. Negishi · Z. Tan

Table 1 (continued)

Year

Natural product

Molecular formula Major author

Ref.

1999

CoQ6 CoQ7 CoQ8 (+)-Calyculin A (20) (–)-Calyculin B Pateamine (17) Phomactin D CoQ10 (24) Scyphostatin (25) (S)-Methanophenazine (R)-Methanophenazine Aplyronines Methanophenazine Phomactin core Bafilomycin A1 (22) Concanamycin F Formamicin (+)-Ratjadone (26) (+)-Calyculin A (20) (10R,11S)-(+)-Juvenile hormones Bis-deoxylophotoxin b-Carotene (27) g-Carotene Vitamin A (–)-Bafilomycin A1 (22) Bafilomycin V1 Rhizoxin D (28) Meneaquinone-3 CoQ3 CoQ10 (24) Vicenistatin (29) CoQ10 (24) CoQ10 (24) Callipeltosides Aurisides

C39H58O4 C44H66O4 C49H74O4 C50H87N4O15P C50H87N4O15P C31H45N3O4S C20H30O3 C59H90O4 C29H43NO5 C37H50N2O C37H50N2O C59H107N3O14 C37H50N2O C20H30O3 C35H58O9 C39H64O10 C44H72O13 C28H40O5 C50H87N4O15P C18H30O3

Lipshutz BH

105

Smith AB III

106

Pattenden G Halcomb RL Negishi E Hoye TR Beifuss U

107 108 109 110 111

Marshall JA Beifuss U Rawal VH Hanessian S Toshima K Roush WR Bhatt U Barrett AG Mori K

112 113 114 115 116 117 118 119 120

Pattenden G Negishi E

121 122

Roush WR Marshall JA White JD Negishi E

123 124 125 126

Kakinuma K Lipshutz BH Lipshutz BH Olivo HF

127 128 129 130

1999 2000 2000 2000 2000 2000 2000 2000 2001 2001 2001 2001 2001 2001 2001 2001 2001

2002 2002 2002 2002

2002 2002 2002 2002

C22H24O6 C40H56 C40H56 C20H30O C35H58O9 C35H58O9 C34H45NO7 C26H32O2 C24H34O4 C59H90O4 C30H48N2O4 C59H90O4 C59H90O4 C35H48NO10Cl C37H57O14Br

Diastereoselective, Enantioselective, and Regioselective Carboalumination

149

150

E. Negishi · Z. Tan

Diastereoselective, Enantioselective, and Regioselective Carboalumination

151

Even though the simple MO theory pointing to the presence or ready availability of a valence-shell empty orbital as the crucial requirement for facile and concerted carbometallation must still be judged to be fundamentally correct, it may not be sufficient for certain types of carbozirconation, such as those discussed herein. In this context, it is instructive to note that, whereas hydroboration [133], hydroalumination [134] and hydrozirconation [135] are all very facile and observable even at or below room temperature, carboboration is essentially unknown except for allylboration that can proceed via a six-centered process and some other special cases [133]. Terminal alkynes react with alkylalanes at elevated temperatures (≥80 °C) to undergo terminal alumination via H abstraction [134]. Internal alkynes do undergo carboalumination at elevated temperatures, but the reaction typically produces dimeric and oligomeric products [134]. So, the situation observed with Zr is, in fact, quite similar to those observed with B and Al. The sterically more demanding and more directional carbon–metal bonds as compared with those of hydrogen–metal bonds may be judged to be two potentially significant differences that can account for the observed differences between hydrometallation and carbometallation. In the formation of the Tebbe reagent (4), one of three hydrogen atoms of a Me group bonded to Ti must be abstracted, presumably through a-agostic interaction between C–H and Ti [136, 137]. Formation of this cyclic reagent (4) would then lead to the formation of a titanacyclic product (3). Thus, agostic C–H activation can provide a mechanism for cyclic carbometallation. Coordinatively unsaturated methylzirconocene species must also be capable of participating in a-agostic interaction. However, little or nothing appears to be known about the formation of Zr-carbene species by this process. Nor has there been any reported indication for cyclic carbozirconation of methylzirconicum species. It may thus be tentatively concluded that all currently known carbometallation reactions of methylzirconium derivatives are most probably acyclic. One molar equivalent each of Me3Al and Cl2ZrCp2 readily undergo Me–Cl exchange in chlorinated hydrocarbons, such as CH2Cl2 and ClCH2CH2Cl, to generate reversibly a doubly bridged complex consisting of Me3AlCl and MeZrCp2Cl but only to the extent of 70%. Under these conditions, formation of Me2ZrCp2 was not detected [7, 9]. Similarly, little or no Me–Cl exchange was detected between Me2AlCl and Cl2ZrCp2 [7, 9] (Scheme 10). On the bases of these and other experimental observations, an acyclic, bimetallic, and Al-assisted carbozirconation mechanism (Eq. 1 in Scheme 11) has been proposed for the carboalumination of alkynes with Me3Al and a cat-

Scheme 10

152

E. Negishi · Z. Tan

(1)

(2)

Scheme 11

alytic or stoichiometric amount of Cl2ZrCp2. For the reaction with Me2AlCl, however, an alternate acyclic, bimetallic, and Zr-assisted direct carboalumination mechanism appears to be plausible (Eq. 2 in Scheme 11).

3 Zr-Catalyzed Ethyl- and Higher Alkylalumination of Alkynes 3.1 Earlier Investigation The reactions of both terminal and internal alkynes with Et3Al in the presence of Cl2ZrCp2 were investigated as early as 1978 [1].As expected, ethyl-substituted alkenes were produced upon protonolysis of the initially produced alkenylalanes. One notable difference between methylalumination and ethylalumination was that, whereas methylalumination was about 95% regioselective, ethylalumination was only about 70% regioselective. Because of this shortcoming, ethyl- and higher alkylalumination reactions were not extensively investigated, and they were assumed to proceed by the same acyclic bimetallic carbometallation mechanism as that for methylalumination. 3.2 Mechanism of Zr-Catalyzed Ethylalumination of Alkynes 3.2.1 Cyclic Mechanism for the Dzhemilev Ethylmagnesation of Alkenes During the 1980s, extensive investigations were conducted on the chemistry of Cp2ZrII derivatives. In addition to the authors’ group [10, 19, 138, 139, 140, 141,

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142, 143], a number of others including those of Bercaw [144, 145], Buchwald [146], Dzhemilev [147, 148, 149], Erker [150, 151, 152], Nakamura–Yasuda [153, 154], Nugent [155, 156], and Takahashi [10, 19, 140, 157] made extensive and significant contributions to this field. As these are the topics of some other chapters in this volume, their extensive discussions are not included here. However, one important link between them and the topics discussed in this chapter is that many of the reactions of Cp2ZrII derivatives do involve carbozirconation of three-membered zirconacycles, even though these reactions were and may still be viewed as processes that are quite discrete from the Zr-catalyzed carboalumination discussed herein. Systematic investigations of the chemistry of Cp2ZrII derivatives initiated at Purdue in the early 1980s and jointly pursued later by the groups of Negishi and Takahashi led to the discoveries, developments, as well as structural and mechanistic clarification of the four stoichiometric reactions shown in Scheme 12 [18, 158, 159, 160, 161, 162]. The use of an excess of EtMgBr (≥3 equivalents relative to Cl2ZrCp2) in the preparation of zirconacyclopentane derivatives via Eq. 1–3 in Scheme 12 unexpectedly led to the transformation shown in Eq. 4 in Scheme 12 [18]. It was soon realized that these four stoichiometric reactions could be added up to come up with an overall catalytic reaction shown at the bottom of Scheme 12. After a while, however, it became evident that, whereas most of the findings shown in Eq. 2–4 in Scheme 12 were due to the joint investigations of the Negishi–Takahashi groups, the overall catalytic process was the discovery of Dzhemilev made in 1983 [147]. Thus, the Negishi–Takahashi groups [18] unintentionally clarified the mechanism of the Dzhemilev Zrcatalyzed ethylmagnesation of alkenes [147]. In 1991, related reactions and their mechanisms were also reported by Hoveyda [163] and Waymouth [164], but these workers did not reach the mechanism shown at the bottom of Scheme 12. A later related study by Whitby further confirmed the mechanism [165]. Clarification of the cyclic mechanism for the apparently acyclic Zr-catalyzed ethylmagnesation of alkenes was an important turning point in the development of various Zr-catalyzed carbometallation reactions. In essence, it has clearly indicated that carbozirconation with ethyl- and higher alkylmetals can proceed via cyclic mechanisms involving b-H abstraction even in cases where both starting compounds and products are acyclic. 3.2.2 Zr-Catalyzed Cyclic Bimetallic Ethylalumination of Alkynes. Scope, Limitations, and Mechanisms With the unexpected mechanistic findings discussed in the preceding section in mind, the Zr-catalyzed alkyne carboalumination reactions with ethyl- and higher alkylalanes were reinvestigated in the mid-1990s. The reaction of terminal and internal alkynes with Et2AlCl in the presence of a catalytic amount of Cl2ZrCp2 in ClCH2CH2Cl appeared to be acyclic, as

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(1)

(2)

(3)

(4)

Scheme 12

judged by the incorporation of only one D atom in the expected position (Eq. 1 in Scheme 13). The reaction of 5-decyne with n Pr2AlCl also proceeded similarly to give (Z)-5-(n-propyl)-5-decene in 75% yield (Eq. 2 in Scheme 13). These results summarized in Scheme 13 suggest that the mechanism of these reactions most probably is the same as that for the reaction with Me2AlCl (Eq. 2 in Scheme 11). In sharp contrast, the reaction of both terminal and internal alkynes with Et3Al in the presence of 10 mol% of Cl2ZrCp2 yielded dideuterated products after deuterolysis with DCl-D2O. In ClCH2CH2Cl, the reaction produced both mono- and dideuterated products along with 1,4-dideuterio-1,3-dienes, suggesting that there are at least three discrete reactions occurring concurrently

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(1)

(2) Scheme 13

[17]. The formation of dideuterated products in which two D atoms are in a 1,4relationship was judged to be an indication of some cyclic processes. On the basis of a reasonable assumption that aluminacyclopentenes and aluminacyclopentadienes were converted to the dideuterated products, the reactions of 5-dcyne with Et3Al catalyzed by Cl2ZrCp2 in ClCH2CH2Cl and hexanes may be represented as shown in Scheme 14.

(1)

(2) Scheme 14

Initially, a cyclic monometallic mechanism involving reversible double transmetallation similar to that for the ethylmagnesation of alkenes (Scheme 12) was considered. The mechanism shown in Scheme 15, however, was soon ruled out, when preformed zirconecyclopentene (32) added to a 3:1 mixture of Et3Al and 5-decyne failed to induce the expected catalytic process. Although reversible transmetallation between trialkylalanes and Cl2ZrCp2 is

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Scheme 15

widely observable, there has been little or no indication for double alkylation of Cl2ZrCp2 by trialkylalanes. Thus, a long arduous search for the mechanism of the Zr-catalyzed cyclic carboalumination of alkynes was undertaken, and a most intricate mechanism involving a cyclic bimetallic process (Scheme 16)

Scheme 16

was clarified [17]. It is striking that, despite its complexity, this mechanism closely parallels those of both the Zr-catalyzed carbomagnesation (Scheme 12) and the formation of the Tebbe reagent (Scheme 3). At the foundation, they all must undergo a- or b-agostic-interation-induced C–H activation to generate reactive metal-carbenes or three-membered metallacycles, respectively. They then undergo carbometallative ring expansion to produce four- or five-membered metallacycles, respectively.With Cp2Zr derivatives, some catalytic cycles involving regeneration of three-membered zirconacycles have been observed, although the Tebbe Ti reactions appear to have remained stoichiometric. Despite clarification of the intriguing cyclic bimetallic carboalumination mechanisms, the cyclic version of ethyl- and higher alkylalumination remains to be further developed. Although the reaction of dialkylchloroalanes, which appears to proceed by an acyclic process, looks more useful and promising, the regioselectivity problem needs to be overcome before its widespread use. The Cl2ZrCp2-catalyzed reaction of alkynes with i Bu3Al did not undergo carbometallation under the conditions employed. It instead underwent a hydrogen-transfer hydroalumination [17].As it could be not only a synthetically useful reaction but also intimately related to the Zr-catalyzed carboalumination of alkenes discussed later, a brief discussion of this reaction will be presented in the following section.

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4 Hydrogen-Transfer Hydroalumination and Hydrozirconation As briefly discussed in the preceding section, a combination of i Bu3Al and Cl2ZrCp2 has thus far failed to transfer the i Bu group to undergo isobutylmetallation with alkynes or alkenes. This is in surprising contrast with the Ziegler–Natta and related alkene polymerization reactions [16] in which a series of isoalkylmetallation must occur very rapidly. In the meantime, a synthetically interesting Zr-catalyzed hydrogen transfer hydroalumination of alkenes with i Bu3Al was reported as early as 1980 [166] (Scheme 17). Noting

Scheme 17

that t BuMgCl would not dialkylate Cl2ZrCp2 but cleanly monoalkylate and rapidly isomerizes to produce Al-free i BuZrCp2Cl (33), the hydrogen-transfer hydrozirconation of alkenes was also developed [167] (Scheme 18). Several years later, its scope was expanded by its application to hydrozirconation of alkynes [168] (Scheme 18). Since this procedure avoids the cumbersome preparation of HZrCp2Cl, it has provided a convenient alternative to the original method of hydrozirconation [135]. Several other alternatives for in situ generation of HZrCp2Cl are known [167, 169, 170]. However, they all display some obvious and/or subtle differences, and their merits and demerits must be carefully evaluated. The hydrogen-transfer hydrozirconation of alkynes has been successfully applied to the synthesis of various natural products including freelingyne [90] and lissoclinolide [171]. One of the shortcomings associated with the hydrogen-transfer hydrozirconation is that it is generally much slower than that with preformed HZrCp2Cl.

Scheme 18

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Scheme 19

Since the hydrogen-transfer hydroalumination with i Bu3Al is catalyzed with Cl2ZrCp2 presumably through bimetallic activation, hydrogen-transfer hydrozirconation might, in turn, be catalyzed by Al compounds. This indeed was the case. Moreover, a variety of metal compounds including Al, Zn, Ag, Pd, and even Si were shown to catalyze the reaction, as indicated by the results summarized in Scheme 19 [172]. Further simplification and improvements are desirable and appear to be feasible.

5 Effects of Metal Countercations on Stoichiometric and Catalytic Carbozirconation. Zr-Catalyzed Carbozincation 5.1 Comparison of Stoichiometric and Catalytic Carbometallation Reactions with Al–Zr and Mg–Zr Reagent Combinations The results presented in the preceding sections indicate that alkylalanes can participate in (i) acyclic bimetallic carbometallation reactions and (ii) cyclic bimetallic carbometallation reactions proceeding via b-agostic interaction-induced b-H abstraction. In either case, bimetallic three-centered bond polarization represented by Zr–Cl+–Al– or Al–Cl+–Zr– is thought to be critically important for activation of the carbon-metal bond undergoing carbometallation. On the other hand, ethylmagnesium and other alkylmagnesium derivatives can induce (i) stoichiometric cyclic carbozirconation producing five-membered zirconacycles and (ii) Zr-catalyzed ethylmagnesation producing acyclic b-ethylalkylmagnesium derivatives. All of these reactions are thought to proceed via cyclic monometallic carbozirconation unassisted by Mg at the critical stage of C–Zr bond addition to a p-bond. Some of the critical factors and features associated with the carbometallation reactions observed with Al–Zr and Mg–Zr reagent combinations are summarized in Table 2. Although the bewildering mechanistic diversity observed

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Table 2 Comparison of carbometallation reactions involving Al–Zr and Mg–Zr reagents

Metal

Acyclic processes

Cyclic processes

Al

With R3Al (i) Reversible monoalkylation of Zr (no dialkylation observed) (ii) Bimetallic activation R-Zr-Cl+-Al–

(i) Reversible monoalkylation of Zr (no dialkylation observed) (ii) Formation of active cyclic reagents via b-H abstraction induced by b-agostic interaction (iii) Bimetallic b-CH bond activation (iv) Bimetallic activation of C–Zr bond

With R2AlCl (i) No alkylation of Zr (ii) Bimetallic activation R-Al-Cl+-Zr– Mg

Carbometallation via acyclic carbozirconation not observed even with MeMgX, where X is Cl or Me

Stoichiometric carbozirconation and Zr-catalyzed carbomagnesation (i) (a) Products in the stoichiometric carbozirconation (five-membered zirconacycles). (b) Products in Zr-catalyzed ethylmagnesation (2-ethylalkylmagnesium derivatives) (ii) Dialkylation of Zr (iii) Formation of active three-membered zirconacycles via b-H abstraction induced by b-agostic interaction (iv) Monometallic b-CH bond activation

in these reactions was initially quite puzzling, a few critical factors responsible for the mechanistic diversity have since been identified and reasonably wellunderstood. In this section, the reaction profiles of those of alkylzinc and alkyllithium reagents will be delineated both for further exploring the synthetic scope of carbozirconation and for further reinforcing our mechanistic knowledge and interpretations. 5.2 Zr-Catalyzed Carbozincation The intrinsic nucleophilicity and electrophilicity of alkylmetals containing Li, Mg, Zn, and Al may be ranked more or less as shown in Scheme 20. In this scheme, Zn lies between Mg and Al. It might therefore be expected to participate in some cyclic carbometallation reactions since both Mg and Al do participate in cyclic carbometallation reactions. Furthermore, if Zn resembles Al,

Scheme 20

Nucleophilicty: Li > Mg > Zn > Al Electrophilicty: Al > Zn > Mg > Li

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it might also participate in Zr-catalyzed acyclic bimetallic carbozincation as well. With these simple notions in mind, the reaction of terminal alkenes with Et2Zn (0.5 molar equivalents) was carried out in THF in the presence of 10 mol% of Cl2ZrCp2, but the expected carbozincation was not observed. It was soon found, however, that addition of 20 mol% of EtMgBr to the above reaction mixture would induce a smooth carbozincation to produce diisoalkylzincs in good yields except with styrene with which the product yield was 58%. The representative experimental results are summarized in Scheme 21, and a plausible mechanism is shown in Scheme 22 [173]. It should be pointed out here that this carbozincation is generally significantly cleaner and higher yielding than the corresponding ethylmagnesation.

Scheme 21

Scheme 22

The products can be directly used as useful isoalkylating agents in the Pdcatalyzed cross-coupling (Scheme 23). Although not fully clarified, the requirement for EtMgBr indicates that Et2Zn most probably does not readily dialkylate Cl2ZrCp2. Nor does it participate in the Zr-catalyzed bimetallic carbometallation in a manner of Al. These facts may be explained in terms of its lower nucleophilicity relative to EtMgBr and lower electrophilicity relative to Et3Al, respectively. Once Et2ZrCp2 is generated by the

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Scheme 23

reaction of EtMgBr with Cl2ZrCp2, however, Et2Zn must be capable of sustaining the catalytic cycle shown in Scheme 21 in a manner of EtMgBr. This has indeed been established by treating a preformed zirconacyclopentane containing a b-nOct group with one equivalent each of Et2Zn and PMe3 to produce the expected (CH2CH2)ZrCp2·PMe3 and 2-ethyldecyl(ethyl)zinc in good yields. Treatment of the latter with I2 gave 2-ethyldecyl iodide in 80% yield [173]. In fact, the first carbozincation promoted by Cp2Zr derivatives was reported as early as 1983 [174]. Some representative results are shown in Scheme 24. Unlike the Zr-catalyzed carbozincation of alkenes discussed above, this carbozincation proceeded with Me2Zn, suggesting an acyclic process at least for this case. The high regioselectivity figures shown in Eq. 2 and Eq. 3 in Scheme 24 are most likely due to competitive terminal zincation of alkynes favoring the formation of 1,1-dimetalloalkenes. The use of I2ZrCp2 in place of Cl2ZrCp2 was desirable, as it permitted a much faster and higher yielding reaction.Although the reaction did proceed with a substoichiometric amount of I2ZrCp2, its catal-

(1) (2)

(3) Scheme 24

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ysis is still marginal. Despite various shortcomings presented above, the reaction clearly deserves to be further investigated. At this point, however, any mechanistic discussion is premature. 5.3 Carbozirconation Induced by Alkyllithiums Treatment of Cl2ZrCp2 with 2 equivalents of nBuLi gives at low temperatures n Bu2ZrCp2 that decomposes via b-H abstraction to give (1-butene)zirconocene, often called the Negishi reagent [158, 159, 175, 176]. This can, in turn, undergo cyclic carbozirconation with or without displacement of 1-butene to produce five-membered zirconacycles [19, 139, 142, 158, 159, 162, 177, 178, 179]. So, the ability of alkyllithiums to induce stoichiometric cyclic monometallic carbozirconation has been well established and used widely in both organic and organometallic syntheses. In this sense, alkyllithiums are often equivalent to the corresponding alkylmagnesium derivatives. The fact that either alkyllithium or alkylmagnesium derivatives can be used interchangeably to induce virtually the same stoichiometric cyclic carbozirconation is a clear indication that this carbozirconation must be monometallic with little or no influence of Li or Mg at the critical stage of carbometallation. In marked contrast with Mg, however, little or nothing appears to be known about Zr-catalyzed carbolithiation. To further probe this puzzle, Cl2ZrCp2 was treated with an excess (≥3 molar equivalents) of nHexLi to partially simulate catalytic conditions. With 3.3 molar equivalents of nHexLi, the reaction produced in nearly quantitative yield nHex3ZrCp (35). Thus, one of the two Cp groups was displaced as LiCp formed in 98% yield. Interestingly, addition of one equivalent of 1-hexene to the mixture of 35 and LiCp produced zirconacyclopentane (36) in ≥80% yield. Evidently, the mixture of 35 and LiCp must exist in equilibrium with small quantities of nHex2ZrCp2 and nHexLi and serve as a reservoir of nHex2ZrCp2 [175]. Even more intriguing was the reaction of 36

Scheme 25

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163

prepared by the well-established reaction of nHex2ZrCp2 with 1-hexene [162], with two equivalents of nHexLi once again to partially simulate catalytic conditions. The reaction produced a formally 14-electron lithium zirconate, which could be represented only by a fluxional structure (37).Although it was not feasible to obtain its X-ray structure, its NMR data indicated the presence of two nonequivalent nHex groups and 2,3-dibutyl-1,4-butylidene moiety undergoing a rapid transmetallation to make the two halves equivalent on the NMR time scale. The results presented above are summarized in Scheme 25. 5.4 Summary of the Effects of Metal Countercations Regardless of which metal countercation is used, the crucial requirement for an empty valence-shell orbital of Zr is evident in all of the stoichiometric and catalytic carbozirconation reactions discussed in this chapter. With highly nucleophilic alkyllithium and alkylmagnesium reagents, dialkylation of Cl2ZrCp2 occurs readily to produce dialkylzirconocenes. These products are often thermally unstable and decompose via b-H abstraction leading to the formation of three-membered zirconacycles. These zirconacycles can undergo cyclic monometallic carbozirconation to produce five-membered zirconacycles. Alkylmagnesium reagents can then undergo exquisite metathetical ring opening of zirconacyclopentanes accompanied by b-H abstraction to regenerate three-membered zirconacycles, thereby permitting Zr-catalyzed carbomagnesation. This ring opening and b-H abstraction processes can also be induced by alkylzincs, but they are not sufficiently nucleophilic to undergo the initially required dialkylation of Cl2ZrCp2, which must therefore be performed with alkylmagnesiums or perhaps even with alkyllithiums, although the latter remains untested. Alkyllithiums are most probably too nucleophilic to sustain Zr-catalyzed carbometallation via dialkylzinconcene derivatives and five-membered zirconacycles, presumably because alkyllithiums can readily and strongly interact with such Zr species to convert them into catalytically inactive species through “ate” complexation and displacement of Cp and other ligands. In short, they tend to act as catalyst poisons. At present, the carbometallation reactions of Al–Zr reagents appear to be all bimetallic, whether they are acyclic or cyclic. The Zr-catalyzed acyclic bimetallic methylalumination is the only well-established Zr-catalyzed carbometallation reaction permitting introduction of a Me group in a satisfactory manner, although the reaction of the Zn–Zr combination appears to be promising. At present, alkylalanes are also the only class of compounds that undergo Zr-catalyzed cyclic bimetallic carbometallation. The reactivity profiles of Li, Mg, Zn, and Al have been reasonably well delineated. The experimental findings and interpretations presented above may now be extended and applied to the development of those carbometallation re-

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actions involving other mono-, bi-, and multimetallic reagents as well as other related carbometallation reactions, such as the Zr-catalyzed enantioselective carboalumination of alkenes discussed in the following section.

6 Zr-Catalyzed Asymmetric Carboalumination of Alkenes 6.1 Discovery of Zr-Catalyzed Asymmetric Methyl-, Ethyl-, and Higher Alkylalumination of Alkenes 6.1.1 Zr-Catalyzed Asymmetric Alkylation with Alkylmagnesium Reagents via Cyclic Carbozirconation Shortly after the discovery of the Zr-catalyzed carboalumination of alkynes in 1978, attempts were made briefly to observe the corresponding carboalumination of alkenes, but no more than traces of the desired products were formed. This puzzle was soon resolved when the Zr-catalyzed hydrogen-transfer hydroalumination with i Bu3Al was discovered in 1980 [166]. Since the expected products of carboalumination of alkenes would be isoalkylalanes, they could then undergo hydrogen-transfer hydroalumination in competition with the desired carboalumination. With this rationalization, attempts to develop the Zrcatalyzed asymmetric carboalumination were postponed. In 1993, a Zr-catalyzed asymmetric carbometallation proceeding via cyclic carbozirconation induced by alkylmagnesium derivatives was disclosed [180]. This and related reactions sharing a common cyclic carbozirconation process have since been developed by various groups including those of Hoveyda [180, 181, 182, 183, 184, 185], Whitby [186, 187], and Mori [188]. As they are mostly outside the scope of this chapter on Zr-catalyzed carboalumination, no systematic discussion of them is intended here, and the interested readers are referred to recent reviews and references therein [189, 190]. It should however be noted here that the cyclic carbozirconation-based asymmetric C–C bond formation reactions suffer from two significant limitations. One is that highly enantioselective (> 90% ee) C–C bond formation has been observed exclusively with allylically hetrosubstituted alkenes. Although very little has been reported about the use of other simple alkenes, the enantioselectivity in these cases appears to be rather low (< 50% ee). Efforts to develop highly stereoselective procedures applicable to simple ordinary alkenes are clearly desirable. Another noteworthy limitation is that, whereas incorporation of Et by the use of ethylmagnesium derivatives is generally high yielding, that of Pr, Bu, and higher alkyls appears to be low-yielding, typically 35–40%.

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6.1.2 Zr-Catalyzed Asymmetric Methylalumination of Ordinary Unactivated Alkenes With the goal of discovering and developing a Zr-catalyzed asymmetric methylmetallation of alkenes represented by Eq. 1 in Scheme 26, the reaction of terminal alkenes with Me3Al-Cl2ZCp2 was reinvestigated [191]. However, the reaction of 1-octene with 1 molar equivalent of Me3Al and 8 mol% of Cl2ZrCp2 yielded just a trace (<1–2%) of the desired 2-methyloctane after protonolysis only to confirm earlier failures. Two products obtained were 2-(n-hexyl)-1decene (38) and 2-methyl-1-octene (39), their approximate yields being 60 and 20%, respectively. Evidently, the desired methylmetallation must have occurred, but the methylmetallation product (40) must have undergone the suspected Htransfer hydrometallation (Eq. 2) to produce 2-methyl-1-octene and 41, which could then undergo competitive and presumably faster n-octylmetallation to produce 42 (Eq. 3). Its H-transfer hydrometallation would then produce the major product 38 and regenerate 41 (Eq. 4), thereby completing a catalytic cycle consisting of Eq. 3 and Eq. 4 [191] (Scheme 26). The experimental results and interpretations presented in this and preceding sections have clearly indicated that the discovery and development of the desired Zr-catalyzed asymmetric carboalumination of alkenes must avoid the following undesirable processes:

(1)

(2)

(3)

(4) Scheme 26

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1. Oligomerization and polymerization of the starting alkenes 2. Hydrogen-transfer hydrometallation depleting the desired methylmetallation product 3. Cyclic carbozirconation that would not only limit the scope largely to ethylmetallation but also lead to low ee figures with unactivated alkenes The only question was how to avoid them all. Despite apprehension and pessimism, up to a dozen known and previously unknown chiral zirconocene derivatives were prepared, and the reaction of 1octene with one molar equivalent of Me3Al was run in their presence (8 mol%). The use of (–)-dichlorobis(1-neomenthylindenyl)zirconium (43), (–)Cl2Zr(NMI)2 hereafter [192], led to the most favorable reaction producing the desired product in 88% yield in 72% ee [191]. A novel Zr-catalyzed asymmetric methylalumination of unactivated alkenes was thus discovered. Neither alkene oligomerization nor H-transfer hydrometallation significantly interfered with the desired carbometallation. Although not yet fully clarified, the steric bulk of the NMI ligand and/or the presence of a fused benzene ring rather than its chirality must be largely responsible for suppressing unwanted H-transfer hydrometallation. In the Zr-catalyzed methylalumination, cyclic processes may not be observed.As the initially reported results summarized in Scheme 27 indicate, the reaction is reasonably general with respect to R in terminal alkenes. Despite the modest ee range of 65–85%, the reaction appeared highly promising. With (–)-Cl2Zr(NMI)2, the re face of the vinyl group of 1-octene was selectively attacked, leading to the predominant formation of

Scheme 27

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167

(R)-2-methyl-1-octanol. Similar yields and ee figures were observed for the conversion of 1-alkenes into (S)-2-methyl-1-alkanols by using (+)-Cl2Zr(NMI)2. The same sense of asymmetric induction has been observed in all cases thus far reported. Although the highest ee of 85% was observed with styrene, its reaction was very slow, requiring weeks to produce only a 30% yield of the desired product. This difficulty has been solved by Wipf either with the use preformed methylaluminoxane (MAO) or by addition of H2O to in situ generate MAO [193]. In cases where the desired reaction is slow, addition of H2O, MAO, or other alkylaluminoxanes, such as IBAO (isobutylaluminoxane) [194], appears to be generally effective. On the other hand, acceleration of faster reactions with alkylaluminoxanes has, for the first time, revealed some oligometric side reactions [195]. Although rate acceleration permitting the use of lower reaction temperatures has led to somewhat higher ee figures, e.g., 90% in the case of styrene, the intrinsic enantioselectivity at a given temperature appears to remain essentially the same. Very analogous but generally somewhat inferior results have also been reported by using cationic chiral zirconocene catalysts such as those derived from Me2Zr(NMI)2 and B(C6F5)3 as well as Me2Zr(EBTHI) and B(C6F5)3 [196]. 6.1.3 Zr-Catalyzed Asymmetric Ethyl- and Higher Alkylalumination of Ordinary Unactivated Alkenes Unlike the Zr-catalyzed methylalumination of alkynes, the corresponding ethyland higher alkylalumination of alkynes has not yet been developed into a synthetically useful reaction (Sect. 3). Acyclic–cyclic dichotomy, modest regioselectivity, and attendant modest yields are some of the pending problems to be overcome. It was therefore thought that the promising and favorable scope of the Zr-catalyzed asymmetric carboalumination of alkenes might also be practically limited to asymmetric methylalumination. This pessimistic view was, in fact, initially confirmed by running the reaction of 1-decene with Et3Al in the presence of 8 mol% of (–)-Cl2Zr(NMI)2 (43) in hexanes. Upon oxidation with O2 2-(noctyl)-1,4-butanediol was obtained in 65% yield and only in 33% ee [197]. The use of hexanes as solvents was influenced by the results observed in the corresponding reaction of 5-decyne in which the use of hexanes led to cleaner and higher-yielding results than that of ClCH2CH2Cl (Scheme 14 in Sect. 3.2.2). It was soon found, however, that the course of the reaction could be altered from cyclic to acyclic by merely changing the solvent to chlorinated hydrocarbons, such as CH2Cl2, ClCH2CH2Cl, and CH3CHCl2. Furthermore, the ee figure jumped from 33% to 90–95%. The Zr-catalyzed H-transfer hydroalumination evidently competed to minor extents of 5–15%, and the yields of the alkylalumination products were accordingly somewhat lower (60–90%) than the corresponding methylalumination. The initially obtained results are summarized in Scheme 28 [197].

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Scheme 28

It should be noted that the reaction appears to be reasonably general as long as primary alkylalanes represented by (RCH2CH2)3Al are used and promises to be of considerable synthetic utility. Although not fully established, the Zr-catalyzed asymmetric alkylalumination of alkenes including methylalumination appears to proceed via acyclic bimetallic carbozirconation in which Zr–Cl+–Al– polarization must be significant. This mechanism is indeed consistent with (i) the exclusive formation of monools, (ii) high ee figures pointing to the chirally modified Zr atom as the active center rather than more remote Al atoms, and (iii) the highly contrasting solvent effects. 6.2 Synthetic Applications Although the synthetic potential of the Zr-catalyzed asymmetric carboalumination appears to be considerable, its application to the synthesis of natural

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Scheme 29

products has so far been very limited. Phytol (44), [194], vitamin E (45) [194, 195], vitamin K (46) [194], and (3S, 7S)-dianeackerone [198] have been efficiently and asymmetrically synthesized by the authors’ group (Scheme 29 and 30). Synthesis of pitiamide A by Wipf [199] is another prototypical example of its application to natural products synthesis (Scheme 30). Although they are not natural product syntheses, the reactions shown in Scheme 31 are noteworthy because they involve the Zr-catalyzed asymmetric carboalumination of allylic ethers [200, 201]. In marked contrast with the Zrcatalyzed asymmetric ethylmagnesation and related reactions of allylically heterosubstituted alkenes discussed in Sect. 6.1.1, the corresponding cases of the Zr-catalyzed asymmetric carboalumination have often been problematic.

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Scheme 30

Scheme 31

6.3 Future Outlook Despite its novelty, reasonable generality, high efficiency, and considerable synthetic potential, the Zr-catalyzed asymmetric carboalumination of alkenes has not yet been widely used. Clearly, further systematic investigations are desirable and necessary. The reaction still suffers from a few critical deficiencies. One is the somewhat modest level of asymmetric induction, especially the 70–80% ee range observed in most of the methylalumination reactions. Another is the relatively high catalyst loading of about 5 mol%.Yet another would be the rather low yields (40–60%) for each of the two steps in the synthesis of Cl2Zr(NMI)2. They do present serious practical problems. However, they all are matters of degree for which some satisfactory solutions are expected to emerge. It would be desirable to demonstrate in the near future its synthetic usefulness in many additional natural products synthesis in competition with some of the best known methods for given asymmetric transformations. In this respect, commercialization of Cl2Zr(NMI)2 and other chiral zirconocene derivatives would be very desirable. Extensive efforts along all of these lines are being made in the authors’ group.Although a few other groups, notably those of Waymouth and Wipf, have also investigated in this area, the reaction appears to deserve participation by many additional research groups.

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Acknowledgments The authors acknowledge financial support from the National Science Foundation (CHE-0309613), the National Institutes of Health (GM 36792), and Purdue University.

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Topics Organomet Chem (2004) 8: 177– 215 DOI 10.1007/b13142 © Springer-Verlag Berlin Heidelberg 2004

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes Noriyuki Suzuki (

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RIKEN, Chemical Analysis Division, 351–0198 Wako Saitama, Japan [email protected]

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Background . . . . . . . . . . . . . . . . . . . Scope of Review . . . . . . . . . . . . . . . . . Active Species and Polymerization Mechanism Cationic Active Species . . . . . . . . . . . . . Propagation Reaction . . . . . . . . . . . . . . Termination Reactions . . . . . . . . . . . . . Stereoregularity in Polyolefins: Tacticity . . . . Catalytic-Site Control or Chain-End Control .

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Polypropylene and Polymers of Higher a -olefins

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Metallocene Catalysts for Isotactic Polyolefins . . . . . Stereo-Control Mechanism in Isospecific Polymerization Racemo-Selective Synthesis . . . . . . . . . . . . . . . . Syndiotactic Polypropylene . . . . . . . . . . . . . . . Hemiisotactic and Iso-Block Polypropylene . . . . . . . Regioselectivity: 2,1- and 1,3-Insertion . . . . . . . . .

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Abstract Metallocene complexes that serve as stereoselective olefin polymerization catalysts are described. The polymerization of propylene, styrene, methyl methacrylate, 1,3-dienes, non-conjugated dienes and cycloolefins is discussed. The stereochemistry of monomer insertion is governed by the chiral steric environment of catalysts derived from a ligand structure (catalytic-site control) or a chiral center in the polymer chain (chain-end control). The mechanism of formation of isotactic and syndiotactic polymers in each monomer and catalyst is explained. Non-metallocene catalysts for stereospecific polymerization are also mentioned. Keywords Olefin polymerization · Isotactic · Syndiotactic · Polyolefin · Ansa-Metallocene

Abbreviations Cp Cyclopentadienyl Cp* Pentamethylcyclopentadienyl Cp¢ Substituted or non-substituted cyclopentadienyl Flu Fluorenyl Ind Indenyl MAO Methylaluminoxane MMA Methyl methacrylate ROMP Ring-opening metathesis polymerization THInd Tetrahydroindenyl TIBA Triisobutylaluminum

1 Introduction 1.1 Background Since the discovery of Ziegler–Natta catalysts for olefin polymerization in 1954, this organometallic catalyst has contributed to a great deal of industry [1, 2, 3]. Conventional heterogeneous Ziegler–Natta catalysts typically consist of titanium chloride and trialkylaluminum as co-catalysts. In initial studies, group 4 metallocene complexes showed low catalytic activity because trialkylaluminum was used as a co-catalyst; yet it was found that they exhibit surprisingly high activity in the presence of water [4, 5]. Kaminsky reported that trimethylaluminum was partially hydrolyzed by water to give methylaluminoxane (MAO), and that it serves as a very effective co-catalyst [6, 7]. Thus, MAO has become a key compound for the development of homogeneous polymerization catalysts. After this finding, research on metallocene catalysts has developed ex-

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plosively. Typical group 4 metallocene catalysts comprise metallocene dichloride and a co-catalyst such as MAO and borane compounds. A homogeneous catalyst is a single-site catalyst and produces polymers of narrow molecular weight distribution (Mw/Mn=2). This results in ease of analysis and mechanistic studies. In addition, free ligand design makes it possible to adjust the steric environment of a coordination sphere. The advantage of single-site catalysts is evident in copolymerization. Copolymers in which each monomer unit is homogeneously distributed can be obtained. Thus, much attention has been focused on the industrial application of metallocene catalysts. 1.2 Scope of Review There is a large amount of literature and many patents in this area, as well as many good reviews and books [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. The recent review by Coates [10] describing stereoselective polymerization overlaps considerably with this chapter, and is recommended for consultation. In this chapter, metallocene-catalyzed olefin polymerization is discussed, focusing on the synthesis of stereoregulated polymers. The aim of this review is not to be a complete survey; the outline and some recent topics in polymerization of propylene, higher a-olefins, styrene, acrylate esters such as methyl methacrylate (MMA), 1,3-butadienes, and cycloolefins will be described. Polyethylene is one of the most important commercially manufactured polymers. The homopolymer, as well as the copolymer with ethylene and other olefins, is an important subject in the polyolefin industry. However, it will be only briefly mentioned because the stereochemistry is less involved. Half-metallocene complexes are included because they play an important role, particularly in the synthesis of syndiotactic polystyrene. Much interest in non-metallocene complexes of group 4 metals, Ni, Pd, Fe, and Co for polymerization catalysts has recently been shown. They will be described with regard to stereoregular polymerization. Ring-opening polymerization of lactones, lactams, and lactides is excluded in this chapter. Ring-opening metathesis polymerization (ROMP) has received much interest recently; however, it is not discussed here because few metallocene complexes are used for ROMP. 1.3 Active Species and Polymerization Mechanism 1.3.1 Cationic Active Species The active species for olefin polymerization is believed to be cationic [9, 20, 21, 22, 23]. When the precursor chloride complex is activated with MAO, it is formed in situ. The role of MAO is to methylate metal chlorides, abstract the

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Scheme 1

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Formation of cationic species by methylaluminoxane (MAO)

methyl group to form a cationic complex and then to stabilize it (Scheme 1). It often requires a large excess over the metallocene precursors (Al/metal= 100–10,000). An induction period (usually 10–20 min, at laboratory scale) is observed before showing high catalytic activity, and generation of active species from catalyst precursors is not always quantitative. Starting from dimethyl derivatives of metallocenes with activators such as B(C6F5)3, [Ph3C][B(C6F5)4], and [PhMe2NH][B(C6F5)4] results in efficient and immediate generation of active species (Fig. 1) [24, 25]. However, since the concentration of catalyst is usually very low due to its extraordinary activity and because it is highly sensitive towards a trace of water and oxygen, the practical procedure often requires a scavenger such as triisobutylaluminum (TIBA). The activity of borane-activated catalysts rapidly decreases due to decomposition of the active species. Thus MAO is still very useful and commonly used, despite some drawbacks. The alane co-catalyst has also been reported [26, 27]. Trivalent lanthanocene complexes that are isoelectronic (14e, d0) to cationic group 4 metallocenes are also active for olefin polymerization, although their activity is much less than that of Ti and Zr [28, 29]. Mashima et al. have reported monocyclopentadienyl h4-diene complexes of tantalum and niobium that are isoelectronic to group 4 metallocenes. These complexes catalyze ethylene polymerization, albeit with low activity [30].

Fig. 1 Borane-activated zirconium cations

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1.3.2 Propagation Reaction The cationic group 4 metallocenes are 14-electron d0 complexes, and the alkyl species accept coordination of an olefin and allow its insertion into the metal–carbon bond (Scheme 2). The coordination site for monomers switches alternately, and it is important for an understanding of stereoselective polymerization. Highly active metallocene catalysts allow more than 1000 ethylene insertions per second at one catalyst molecule.

Scheme 2 Propagation reaction in metallocene-catalyzed ethylene polymerization

1.3.3 Termination Reactions In metallocene-catalyzed olefin polymerization, the propagation reaction is terminated usually by chain transfer. It is generally believed that three major chain-transfer reactions exist in homogeneous Ziegler–Natta catalysts (Scheme 3) [8]: i. b-Hydrogen elimination from propagating polymer chain to the metal ii. b-Hydrogen transfer to the coordinated olefin iii. Transmetallation of polymer chain to aluminum metal Process (i) is a unimolecular process, while (ii) is a bimolecular process and the rate depends on monomer concentration. Frequent chain-transfer reactions bring about low molecular weight polyolefins. If chain transfer is negligible or very slow, the polymerization can be “living”, as observed in group 5 metallocene–diene complexes [30, 31]. b-Methyl elimination is also reported in bis(pentamethylcyclopentadienyl)metallocene catalysts [32, 33]. 1.4 Stereoregularity in Polyolefins: Tacticity Because a-olefins are prochiral, the selectivity of their re-face and si-face in coordination and insertion is reflected in the stereoselectivity of polymer prop-

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Scheme 3 Termination processes of olefin polymerization

agation. Figure 2 describes stereoregularity in polyolefins. If a catalyst consistently selects one of the re- or si-faces in every insertion, isotactic polyolefins are formed. Isotactic polypropylene is of importance in industry and practical use. If insertion alternately occurs on the re-face and si-face, syndiotactic polymers are produced. Syndiotactic polypropylene and polystyrene have received increasing interest in the industry. The stereochemical relationship between adjacent substituents is described by the terms meso and racemi, abbreviated as m and r, respectively. If five sequential substituents stand in a meso relationship, it is described as an mmmm pentad, and the probability of mmmm is often used to evaluate the isotacticity of polymers. In addition, [m] dyad for two sequential substituents and [mm] triad for three are used. Indeed, in order to achieve 99% of [mmmm], the probability of each [m] needs to be more than 99.8%. It can be understood that excellent stereoselectivity of the insertion reaction is required to produce highly stereoregular polyolefins. The ease of ligand design in metallocene catalysts has made possible novel stereoregulated polymers that have not been seen with conventional Ziegler–Natta catalysts. Hemi-isotactic polyolefins, and isotactic-atactic block polymers are examples that will be discussed in Sect. 2.5. 1H and 13C NMR spectroscopies are powerful tools to estimate the tacticity of polymers [34]. An example of a 13C NMR spectrum for isotactic polypropy-

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Fig. 2 Stereochemistry in polyolefins produced by metallocene catalysts

lene produced by a chiral ansa-zirconocene catalyst is shown in Fig. 3 [35]. Signals for the methine carbon that appear at 20–22 ppm are usually used to determine probabilities of pentad sequences. As well as the main signal of [mmmm], three small signals assignable to [mmmr], [mmrr], and [mrrm] are observed. Stereoregular polymers are highly crystalline and poorly soluble in common solvents. The NMR spectra of isotactic polypropylene are often measured at 120–130 °C using polar solvents such as o-dichlorobenzene-d4 and 1,3,5trichlorobenzene-d3. It takes more than several hours (sometimes a few days) to achieve a good S/N ratio that allows estimation of the very small signals due to stereoerrors. An alternative method for evaluating stereoregularity is extraction of a soluble part from the obtained polymer. Extraction with boiling hydrocarbyl solvents, such as toluene or heptane, using a Soxhlet extractor leaves an insoluble crystalline polymer. The percentage of the residue is the isotactic index or syndiotactic index that is used for indices of stereoregularity.

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Fig. 3 trol

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13C NMR spectroscopy of

isotactic polypropylene produced under catalytic-site con-

This procedure is, however, not applicable for polymers of higher olefins, such as polyhexene, because isotactic polymer is also soluble in hydrocarbyl solvents. 1.5 Catalytic-Site Control or Chain-End Control Stereoselectivity in the insertion of olefins is brought about by a chiral environment of the coordination sphere. When the selectivity is predominantly governed by chirality of the catalyst itself, stereospecificity shows “catalytic-site control”, also called “catalyst control” or “enantiomorphic-site control”. Catalysts must have chiral structures (but need not be homochiral) in this case. Even though a catalyst is achiral, an inserted a-olefin can make a chiral center at the end of a polymer chain. When this chirality controls the stereoselectivity of the next monomer insertion, it is called “chain-end control”. These two mechanisms can be distinguished by observation of the stereoerrors found in the polymers. Catalytic-site controlled isotactic polymers have an error described in Fig. 4. One misinsertion has little effect on the face selectivity of the next insertion, because it is governed by the catalyst structure. It results in a sequence of mmmrrmmm. Thus mmmr, mmrr and mrrm pentads are found besides mmmm. On the other hand, in chain-end control, once a monomer is misinserted, the opposite chirality governs the next monomer insertion. It gives an mmmrmmm sequence, as shown in Fig. 4, and mmmr and mmrm appear in the spectra.

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Fig. 4 Stereoerrors in polyolefins: catalytic-site control and chain-end control

2 Polypropylene and Polymers of Higher a -olefins 2.1 Metallocene Catalysts for Isotactic Polyolefins Isotactic polypropylene produced with conventional heterogeneous Ziegler–Natta catalysts is now widely used for various purposes. Catalysts commonly comprise titanium chloride impregnated in magnesium chloride and trialkylaluminum as co-catalyst. In addition, functional additives such as esters and alkoxysilanes are added as internal and external donors. These donors are very important in controlling stereoregularity of the polymers. Homogeneous metallocene catalysts produce types of polypropylene that could not be obtained with traditional catalysts, such as a narrow molecular weight distribution. It allowed us to design the ligand structure and to tailor the microstructure of the polymers. An excellent review on metallocene-catalyzed propylene polymerization by Resconi appeared recently [36]. The first preparation of isotactic polypropylene using a metallocene catalyst was reported by Ewen, although the isotacticity of the crystalline polymer was not satisfactory ([mm]=0.71) [37]. They employed a C2-symmetrical titanium catalyst 1a as a meso/racemi mixture, which was first reported by Brintzinger [38]. Brintzinger and Kaminsky achieved highly isospecific polymerization (I.I=91%, [mm]=0.95) using the racemic ansa-zirconocene complex 2 [39]. Thereafter, extensive efforts have been devoted to the development of highly isospecific catalysts for polypropylene. Many of these examples employed indenyl and related ligands that are bridged with C1, C2 or silylene units. Figure 5 shows some typical C2-symmetric complexes for isospecific polymerization. Introduction of various substituents onto the indenyl groups leads to improvement in the stereoselectivity. Extremely high isotacticity ([mmmm] > 0.99) was achieved using 3 (R1=Me, R2=1-naphthyl) [40]. Substituted cyclopentadienyl

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Fig. 5 C2-Symmetric ansa-metallocenes for isospecific olefin polymerization

ligands bridged by a silicon atom were found to be effective for the construction of isospecific ansa-metallocenes (4, [mmmm]=0.98) [41, 42].Yamazaki recently reported that furyl substituents on cyclopentadienyl rings greatly increase catalytic activity of the ansa-zirconocene and hafnocene complexes [43]. Some C1-symmetric ansa-metallocenes also produce isotactic polypropylene, although it is difficult to predict their stereoselectivity in the polymerization. For example, 5 reported by Marks [44] and 6 by Miyake [45] give highly isotactic polypropylene (Fig. 6, 5: M=Hf, [mmmm]=0.95; 6: [mmmm]>0.98).

Fig. 6 C1-Symmetric ansa-metallocenes and a non-bridged metallocene for isospecific polymerization

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There are few examples of non-bridged metallocenes acting as isoselective catalysts. Erker reported metallocenes with chiral auxiliaries on cyclopentadienyl or indenyl ligands [46, 47]. The polymerization proceeds by catalyst control. However, large substituents and a low reaction temperature are necessary to suppress fast rotation of the Cp/indenyl ligands, otherwise tacticity decreases. This limitation also leads to low activity, and it is a drawback of this type of catalyst. It was reported that 1-methylfluorenyl ligands are more effective for isoselective polymerization even at 60 °C (7: [mmmm]=0.83) [48]. Isorich polymerization with the achiral catalyst, Cp2TiPh2, by chain-end control was reported, although a low polymerization temperature was needed and the tacticity was not satisfactory [37]. Of course, catalyst structure is very important for highly isoselective polymerization. However, tacticity of polyolefins depends not only on catalyst structures but also on co-catalysts, reaction conditions such as temperature, monomer concentrations and Al/metal ratios. For example, in the case of a certain catalyst, isotacticity of polymers can strongly depend on the temperature for pre-mixing MAO and a catalyst precursor. The effect of reaction pressure up to 1500 MPa was also reported in hexene polymerization [49]. Group 3 metallocene hydrides, which usually form dimers, are known to be “single-component” catalysts for ethylene polymerization [50]. The olefin inserted species, Cp¢2Ln-R, is isoelectronic to active cationic species of group 4 metallocenes, and it can catalyze polymerization without such co-catalysts as MAO and borane compounds. Examples of isospecific a-olefin polymerization catalysts are, however, rather rare. Bercaw and Yasuda independently reported ansa-yttrocene complexes with bulky substituents on Cp rings (8 and 9 in Fig. 7) that catalyze polymerization of propylene and a-olefins in a highly isospecific manner, although their activity and molecular weight are moderate (8: polypropylene, [mmmm]=0.97, Mn=4200) [51, 52]. It is interesting that achiral monocyclopentadienylaryloxyyttrium 10 gives isotactic polymerization of hexene ([mmmm]>85%), presumably by chain-end control [53]. Divalent ansa-samarocene analogues, on the other hand, exhibited poor activity, albeit with high isotacticity ([mmmm]>0.95) [54].

Fig. 7 Lanthanide complexes for isospecific propylene polymerization

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2.2 Stereo-Control Mechanism in Isospecific Polymerization In isospecific polymerization by catalytic-site control, the ligand-induced chiral environment in ansa-metallocene complexes is responsible for stereoselectivity. Theoretical studies have shed light on the mechanism of stereoselective insertion, as illustrated in Fig. 8 [55, 56, 57].An olefin approaches the metal from side A with its alkyl (R) group up, while it inserts with the substituents down from side B. Thus insertion occurs only at a si-face in this case. This is explained by steric repulsion between the R group and the propagating polymer chain, which rotates avoiding the sterically demanding ligand. Steric repulsion between the alkyl group and ligand are of little importance for stereoselectivity. This mechanism is supported by experimental work. Propylene inserts into a Zr–CH3 bond with no stereoselectivity at all (re/si=1:1), while insertion of butene occurs with 1:2 selectivity [58]. On the other hand, the selectivity in propylene insertion into Zr-CH2CH3 is excellent [59]. Experimental studies show that the face selectivity during polymerization is complete, and that stereoerrors observed in polypropylene are not due to misinsertion but rather to chain-end epimerization [60, 61, 62].

Fig. 8 Face selectivity in olefin approach

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2.3 Racemo-Selective Synthesis The usual preparative method of bridged group 4 metallocenes that involves a dimetallated (typically, dilithium salt) ligand and a metal halide often gives a mixture of racemi and meso isomers. The ansa-metallocenes for isospecific polymerization, however, must be racemic, and the concomitant meso isomer causes formation of atactic polymers. Separation of the racemic isomers from the racemo/meso mixtures often requires tedious operations. For example, group 4 metallocene chlorides barely survive the usual column chromatograph separation (although a column technique at low temperature under an inert atmosphere may give good results), and occasionally several recrystallizations are required. Introduction of bulky substituents on Cp/indenyl ligands or bridging moieties can improve the racemo/meso ratios in the synthesis of ansa-metallocenes [42, 63, 64, 65]. Exclusive synthesis of the racemic isomer was even achieved using tert-butyl and trimethylsilyl substituents. However, polymerization using the corresponding ansa-zirconocene was not described [66], although the ansa-yttrocene complex 8 produced isotactic polypropylene [51]. There are many examples of ansa-metallocenes designed for stereoselective synthesis [67, 68, 69, 70]. In order to construct a racemo-selective structure, rigid bridging moieties such as biaryl groups or double bridges were used, whereas it does not seem easy to satisfy both a highly racemo-selective structure and a high isospecific catalyst ability. The preparation of a single stereoisomer of the ligand prior to complexation can result in predominant formation of racemic metallocenes. Brintzinger reported an S4-symmtric silylene–stannylene double bridged bis(cyclopentadienyl) ligand, which reacts with zirconium chloride to give a C2-symmetric complex exclusively [71]. Jordan reported a new preparative method that starts with metal amides. Non-metallated ligands react with M(NR2)4 to give ansa-metallocene bisamide complexes [72, 73, 74]. The use of bulky amides results in racemo-rich formation of ansa-metallocene complexes due to steric repulsion, although it requires chlorination to obtain more stable dichlorides. Yamazaki reported meso-selective formation of binuclear m-oxo-ansa-metallocenes [75]. This can be a convenient method for separating meso and racemo-isomers of ansa-bis(substituted cyclopentadienyl)metallocenes, although it might be less effective for non-substituted ansa-bisindenyl complexes [76]. 2.4 Syndiotactic Polypropylene Syndiotactic polypropylene was prepared by a heterogeneous vanadium catalyst with low tacticity. Preparation of highly syndiotactic polypropylene

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Fig. 9 Cs-Symmetric metallocenes for syndiospecific catalysts

([rrrr]=0.86) using the homogeneous catalyst 11 was first reported by Ewen (Fig. 9) [77]. Complex 11 has a Cs-symmetric structure, and propylene inserts to a metal–carbon bond alternately by the re-face and si-face (Fig. 10). It is believed that the monomer approaches the metal with its methyl group down, to avoid repulsive interaction with the propagating polymer chain [78]. A stereoerror found in the metallocene-produced syndiotactic polyolefin is rmmr, which is due to insertion from the wrong face (or chain-end epimerization). Another error, rmr, is formed by “skipped insertion”, which results from migration of the polymer chain without monomer insertion. Although syndiotactic polypropylene is less attractive in industry because of its slow crystallization rate, it still has attracted many chemists for academic

Fig. 10 Formation of syndiotactic polyolefins

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Fig. 11 Catalyst system for iso-block polypropylene

reasons. There have appeared many Cs-symmetric metallocenes derived from 11, and some have succeeded in improving syndiotacticity. Bercaw reported doubly bridged biscyclopentadienyl zirconium 14, which serves as a highly syndiospecific catalyst ([rrrr]=0.99 at 0 °C) [79]. It was also reported that (C5Me5)2MCl2 (M=Zr, Hf) gives syndio-rich polypropylene at low temperature (Zr, [rr]=0.68; Hf, [rr]=0.77 at –20 °C) by chain-end control [80]. 2.5 Hemiisotactic and Iso-Block Polypropylene Metallocene catalysts that allow various ligand designs made possible novel stereoregular polymers that could not be prepared with heterogeneous catalysts. Hemiisotactic polyolefin produced by 12 is an example [81]. Isoselective and aspecific insertion occur alternately in 12. It is of interest that the catalyst without a methyl group (11) gives syndiotactic polymer and the one with a tertbutyl group (13) gives isotactic polymer. Waymouth et al. reported that the non-bridged complex 15 produces iso-block polymers that consist of isotactic sequences and atactic sequences [82]. One rotamer of 15 has C2-symmetry and is thus isospecific, while another is aspecific. Slow isomerization between the two rotamers brings about iso-block polymers. These polypropylenes contain crystalline and amorphous parts, and have an elastomeric character (Fig. 11). 2.6 Regioselectivity: 2,1- and 1,3-Insertion In metallocene-catalyzed propylene polymerization, propagation proceeds via 1,2-insertion of the monomer. 2,1-Insertion gives rise to a secondary alkyl species. This species is known to be much less active for the next insertion and tends to be involved in chain transfer or isomerization into 1,3-inserted species. As shown in Scheme 4, b-hydrogen elimination followed by rotation and re-in-

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Scheme 4 1,3-Insertion of propylene via 2,1-inserted species

sertion resulted in 1,3-insertion of propylene. This trimethylene unit decreases crystallinity of the polymer, and is responsible for the lower melting point compared with those produced by heterogeneous catalysts, despite the high [mmmm].

3 Polystyrene 3.1 Catalysts for Syndiotactic Polystyrene Commonly used polystyrene is produced by radical polymerization in industry and its stereochemistry is atactic. Isotactic polystyrene was achieved by Natta using traditional Ziegler–Natta catalysis in 1956 [83]. Isotactic polystyrene, however, is less interesting in industry because of its slow crystallization rate. Ishihara et al. reported highly syndiotactic polystyrene using halfmetallocene complexes of titanium [84, 85]. Since syndiotactic polystyrene is a highly crystalline polymer with a rather fast crystallization rate, it is a promising material, leading many polymer chemists to investigate the catalysts. Some reviews have appeared and may be consulted [13, 86, 87, 88, 89, 90, 91]. The syndiotactic index, which is a percentage of the insoluble part in refluxing 2-butanone or acetone, is also often used to estimate syndiotacticity of polymers as well as [rr] triad and [rrrr] pentad. Ishihara et al. reported that CpTiCl3– and Cp*TiCl3–MAO catalyst systems synthesize syndiotactic polystyrene [84, 85]. Various styrene derivatives that have alkyl groups or halogens give syndiotactic polymers using these catalysts. CpTiCl2, a Ti(III) species, also shows high catalytic activity and stereospecificity. Zirconium and hafnium complexes are not only less active than titanium but also produce atactic polystyrene. Many studies on the catalysts based on Cp¢TiX3 have appeared, where Cp¢ is a substituted (or non-substituted) cyclopentadienyl, indenyl or related h5-ligand and X can be halogens, alkoxy or

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Fig. 12 Precatalysts for stereospecific polymerization of styrene

alkyl groups.Among the complexes with substituted cyclopentadienyl ligands, the catalytic activity of Cp¢Ti(OMe)3 is in the order C5Me4Et>C5Me5>C5Me4H> C5H5 [89, 92]. Indenyl, benz[e]indenyl and their phenyl-substituted ligands increase activity and stability of the catalysts (16, 17 in Fig. 12) [93, 94]. Brintzinger et al. reported that cyclopenta[1]phenanthrene titanium trichloride 18 exhibits the highest activity among Cp¢TiCl3-type catalysts [95]. Kaminsky et al. showed that fluorinated complexes Cp¢TiF3 exhibit much higher activity than Cp¢TiCl3 [96]. The catalytic activity of Cp*TiX3 decreases in the order F>OMe>Cl. Although titanocene complexes are less active than half-titanocenes, Miyashita et al. showed that a methylene-bridged titanocene 19 is effective for syndiospecific styrene polymerization [97]. A large gap aperture is probably necessary for coordination of styrene. Boranes can be used as activators instead of MAO [98], while the use of dry trialkylaluminum led to atactic polystyrenes [85]. The TiX4-type compounds (X=halogen, alkoxy, alkyl, etc.) aldo can catalyze syndiospecific styrene polymerization, although their activities are lower than Cp¢TiX3. 3.2 Active Species Ti(IV), Ti(III), and even Ti(II) are employed as catalyst precursors, but it is most probable that Ti(III) is the active species [99]. MAO and/or trialkylaluminum

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contained in MAO has been believed to be responsible for reducing Ti(IV) to Ti(III). Recently, Waymouth et al. reported that Cp*Ti(CH2Ph)3/[NHMe2Ph] [B(C6F5)4] did not polymerize styrene in the dark, although it generated syndiotactic polystyrene in the light [100]. They suggested that the light plays an important role in reducing Ti(IV) to Ti(III), which is active for syndiospecific polymerization of styrene. Indeed, Cp*Ti(allyl)2/[NHMe2Ph][B(C6F5)4] is highly active in the dark. 3.3 Mechanism of Syndiospecific Polymerization The propagation of styrene polymerization can be illustrated as in Scheme 5. Contrary to the a-olefin polymerization, the initiation and propagation reactions of styrene proceed via 2,1-insertion of monomers into the Ti–C bond [89, 101, 102]. The monomer inserts with high regioselectivity, and b-hydrogen elimination that terminates the propagation also occurs on 2,1-inserted species. Zambelli showed that molecular weight does not strongly depend on monomer concentration, showing that b-hydrogen elimination to the metal is the predominant chain-transfer process [103]. Its stereochemistry is regulated in chain-end control [104]. p-Coordination of a phenyl group in the last-inserted styrene to titanium in an agostic fashion seems important to control the approach of the next monomer [91].

Scheme 5 Polymerization of styrene catalyzed by half-titanocene complexes

The Cp*TiMe3-B(C6F5)3 catalyst gives syndiotactic polystyrene, while it produced atactic polystyrene in halogenated solutions such as CH2Cl2 or 1,2dichloroethane [105]. In accord with these results, Baird et al. proposed a carbocationic mechanism for styrene polymerization.

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3.4 Isotactic Polystyrene by Metallocene Catalysts Recently, Arai et al. reported preparation of isotactic polystyrene using some ansa-zirconocene complexes [106, 107]. For example, 20 gives isotactic polystyrene with [mmmm]>0.90. Although the isotactic homopolymer of styrene is less attractive for practical use, the catalysts would be useful in the production of stereoregulated styrene–ethylene copolymer. 3.5 Other Catalyst Systems Emulsion polymerization that uses water as a reaction medium is commonly employed for radical polymerization of styrene. Recently, application of Cp*Ti(OR)3/NHMe2Ph+B(C6F5)–4 for emulsion polymerization was reported [108]. The use of transition metals other than group 4 metals is rather rare. Some half-metallocenes of lanthanides can catalyze styrene polymerization without co-catalysts, although atactic polystyrene is obtained [86, 109, 110, 111]. A few non-cyclopentadienyl lanthanocenes are known to be capable of syndio and iso-rich polymerization of styrene [112, 113], whereas activity and stereoregularity are inferior to Ti catalysts. Calcium half-metallocene for syndiospecific “living” polymerization of styrene has been recently reported, although activity and stereoselectivity are not very good [114].

4 Poly(Methyl Methacrylate) 4.1 Background Methyl methacrylate (MMA) is one of the most common polar monomers. Poly(MMA) as commonly used is manufactured by a radical polymerization process. Syndio-rich poly(MMA) ([rr]=0.5–0.7) is obtained by the radical process. This clear transparent polymer is versatile and widely used. Synthesis of highly stereoregular poly(MMA) was achieved by anionic polymerization using organometallic compounds such as alkylaluminum, alkyllithium, and Grignard reagents as initiators. Both isotactic and syndiotactic poly(MMA) can be prepared by careful choice of initiators, additives, solvents, and reaction conditions [115, 116, 117]. Some of these reactions proceed in a living polymerization. However, high molecular weight and high stereoregularity were difficult to simultaneously accomplish by a single initiator system. Yasuda first reported that organolanthanides could efficiently initiate syn-

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diospecific polymerization of MMA in a living manner [118]. Collins showed that cationic zirconocenes are capable of polymerizing MMA [119]. There are several reviews on lanthanocene-catalyzed polymerization of MMA and acrylates [120, 121, 122]. 4.2 Lanthanocene Catalysts Yasuda reported some classes of organolanthanide(III) complexes that efficiently initiate stereoregular polymerization of MMA [118, 124]. In their first report, they employed samarocene hydride dimer, [SmH(C5Me5)2]2 (21),

Fig. 13 Lanthanide complexes for stereospecific MMA polymerization

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monoalkyllanthanides, LnR(C5Me5)2 (22, 23), and their m-bridged complexes (24, 25), as shown in Fig. 13. These catalysts achieved the following features for the first time [124]: i. High molecular weight (Mn), greater than 1¥106 ii. Very narrow polydispersity (Mw/Mn <1.05) iii. High syndiotacticity, reaching 0.80 in [rr] triad at room temperature and 0.95 at –95 °C iv. High polymerization rate An NMR investigation on the syndiotactic poly(MMA) indicated that the stereochemistry is determined by chain-end control. Interestingly, they succeeded in isolating a key intermediate (30), in which the first two MMA molecules are incorporated in (C5Me5)2SmH. X-ray analysis showed its eight-membered structure (Fig. 14). This species, 30, is catalytically active, and it strongly supports the belief that the propagation proceeds via eight-membered intermediates (Scheme 6). It was proposed that steric repulsion between C7 and C9 (or the polymer chain) would regulate stereochemistry during the formation of the eight-membered intermediate. Thereafter, many reports on lanthanocenes for stereoselective MMA polymerization have appeared (Fig. 15). Table 1 summarizes some examples of lanthanide-catalyzed stereoselective polymerizations of MMA. Marks et al. developed C1-symmetric ansa-metallocenes of lanthanides that give isotactic poly(MMA) [125]. They introduced a (+)-neomenthyl group on a Cp ring and achieved high isotacticity (31, [mm]=0.94, Mn=1.04¥105, Mw/Mn≥1.8). Similar

Fig. 14 Molecular structure of the eight-membered Sm intermediate (30) for MMA polymerization

Scheme 6 Initiation and propagation in Sm-catalyzed MMA polymerization

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Fig. 15 Lanthanide complexes for MMA polymerization

complexes with a (–)-menthyl group (32), however, provided syndiotactic-rich poly(MMA). They described that NMR analysis of the polymer cannot be associated with either chain-end control or catalytic-site control, and proposed an “isomerization mechanism” for iso-rich propagation. Do reported that the yttrium complex 33 gave iso-rich poly(MMA) despite its Cs-symmetric structure [126]. Similar Cs-symmetric complexes 34 and 35, on the contrary, gave syndio-rich polymer [127, 128].

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Table 1 Stereoregular polymerization of MMA catalyzed by organolanthanides

Entry Catalysts

Temp Mw

1 2 3 4 5 6 7 8 9 10 11 12 13

0 –95 0 0 –35 25 25 –78 0 –40 –40 –78 0

a

21 21 24 (Ln=Y) (R,S)-31a (R)-31c (R)-32b 33 34c 36 36 37 27 29

479,000 896,000 1,645,000 113,000 nd

Mn

Mw/Mn

58,000 187,000 53,000 262,000 134,000 521,000

1.02 1.05 1.03 1.8 6.7 3.2 1.39 Bimodal 259,500 1.31 224,200 1.42 244,100 1.62 53,400 1.02a 2,550,000 2.01a

rr

mr

0.824 0.953 0.847 0.20 0.01 0.73

0.168 0.008 124 118 0.145 0.008 124 0.23 0.57 125 0.05 0.94 125 0.17 0.10 125 0.58 126 0.18 0.00 127 0.19 0.40 129 0.11 0.72 129 0.24 0.72 129 0.725 131 0.885 131

0.82 0.41 0.17 0.04

mm

Ref

Bimodal and another peak is for atactic polymer.

Not only bridged metallocenes but also non-bridged lanthanocenes 36, 37 give iso-rich poly(MMA). There are racemo and meso isomers in 36, and both 36 and 37 have several kinds of rotamers. Although the rotation is too fast to be detected by NMR at low temperature, stereomultiblock polymers were obtained [129]. It was also described that the tacticity is not consistent with either catalytic-site control or chain-end control. In regard to these reports, isospecific MMA polymerization seems not simply regulated as in the case of propylene polymerization. The non-metallocene ytterbium compound 26 gives highly isotactic poly(MMA) of high molecular weight in toluene, whereas syndiotactic polymer was obtained in THF [130]. Diaza-pentadienyl 27 and azaallyl lanthanides 28, 29 produce highly isotactic poly(MMA), although the polymer was bimodal and another peak consisted of atactic polymer [131]. Organolanthanides are able to initiate living polymerization of alkyl acrylates such as methyl, ethyl, n-butyl, and tert-butyl to give high molecular weight polymers with narrow polydispersity [132]. However, the stereochemistry of the polymers is atactic. It is proposed that acrylates as well as methacrylates polymerize via the eight-membered intermediates, and the lack of stereocontrol by steric repulsion observed in methacrylates might result in atactic polymers. 4.3 Group 4 Metallocenes Polymerization of MMA by zirconocene catalysts was first reported by Collins et al. in 1992 [119]. Their catalyst system, which consists of two components,

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes

201

cationic [Cp2ZrMe(thf)]+[BPh4]– and neutral Cp2ZrMe2 (38), gives syndio-rich poly(MMA) ([r]=0.80). Cationic alkylzirconocene alone did not polymerize MMA under their conditions. Soga and Shiono showed that ZnEt2 is an effective additive for cationic Cp2ZrMe+ to afford syndio-rich poly(MMA) [133, 134]. It was reported by several groups that attempts to polymerize MMA using cationic zirconium species such as [Cp2ZrMe(thf)]+[BPh4]–, Cp2ZrMe2/B(C6F5)3 or Cp2ZrMe2/Ph4C·B (C6F5)4 in the absence of neutral additives were unsuccessful [119, 133, 134, 135]. Bandermann reported that Cp2ZrMe(OCMe=CMe2) is inert for initiating polymerization, while it started immediately on the addition of cationic Cp2ZrMe+ [136]. On the other hand, Gibson demonstrated that the additional component is not essential and that the Zr cationic species, Cp2ZrMe2/B(C6F5)3, itself can catalyze the polymerization of MMA [137]. The reaction conditions, particularly the order of addition of catalyst precursors, activators and monomers, seem to be important. Marks et al. reported that Cp2ZrMe2-B(C6F5)3 did not polymerize MMA under their conditions, probably due to low monomer and catalyst concentrations, while the dimeric cation with (2,2¢,2≤-nonafluorobiphenyl)borane (PBB, 39) and [(Cp2ZrMe)2(m-Me)]+MePBB– gave poly(MMA) [135]. Höcker et al. independently reported single-component catalysts that consist of methylene-bridged zirconocene complexes 40 and 41 [138, 139]. It is noteworthy that these catalysts polymerize MMA with the BPh4– anion instead of fluorinated boranes. The advantage of a methylene bridge seems to be its large gap aperture [140]. It is thought that polymerization proceeds in the same way as proposed for lanthanide catalysts, and the catalyst systems using non-bridged bis(cyclopentadienyl)zirconium also afford syndiotactic poly(MMA). Some examples of stereospecific polymerization of MMA are summarized in Table 2 and Fig. 16. Complexes with non-bridged indenyl or fluorenyl ligands, 42 and 43, were explored, but syndiotacticity did not depend on the ligands [134]. Soga and Shiono used some C2-symmetric ansa-metallocenes for their ZnEt2-assisted system. Typical catalyst precursors for isospecific propylene polymerization, such as 44, 45 and 46, produced highly isotactic poly(MMA) with catalyst control [141, 142]. Marks showed that the binuclear cationic species [(rac-Me2Si(Ind)2Zr)2(m-Me)]+ with PBB anion gave highly isotactic poly(MMA) ([mm]=0.93) [135]. Catalyst-controlled isospecific polymerization of MMA by single-component systems was reported independently by two groups [137, 138, 139]. Achiral 40 gave syndio-rich poly(MMA) while isotactic poly(MMA) was obtained with the C1-symmetric complex 41. C2-Symmetric 44 with B(C6F5)3 afforded highly isotactic poly(MMA), as well as 41. Methyl substituted 47 gave polymer with low mm triad probability. The large gap aperture of ligands in methylenebridged ansa-metallocenes must give an advantage both in activating a monomer and its insertion. However, contrary to the results of lanthanides, 48B(C6F5)3 did not give polymers. Interestingly, 49 derived from a Cs-symmetric

202

Fig. 16 Group 4 metallocenes for stereoselective polymerization of MMA

N. Suzuki

b

Additives

Cp2ZrMe2 ZnEt2 ZnEt2 ZnEt2 ZnEt2 Zn(C4H7)2a Zn(C4H7)2a Zn(C4H7)2a None None None None None None

Counter anions

[BPh4]– B(C6F5)3 Ph3CB(C6F5)4 Ph3CB(C6F5)4 Ph3CB(C6F5)4 Ph3CB(C6F5)4 Ph3CB(C6F5)4 Ph3CB(C6F5)4 B(C6F5)3 B(C6F5)3 B(C6F5)3 PBB– [BPh4]– [B(C6F5)4]–

Zn(CH2)2CH=CH2. Probably at ambient temperature.

Cp2ZrMe(thf) Cp2ZrMe2 Cp2ZrMe2 42 43 44 45 46 44 41 47 46 41 49

14 15 16 17 18 19 20 21 22 23 24 25 26 27

a

Catalysts

Entry

0 –30 –60

b

b

b

0 0 0 0 0 0 0 0

Temp/ °C

57,300 19,600

149,000 480,000 260,000 190,000 23,000 599,000 339,000 345,000 48,700 33,400 25,000

Mn

1.21 1.10

1.32 1.38 1.23 1.30 1.17 1.30 1.25 1.34 1.20 1.49 1.51

Mw/Mn

Table 2 Stereoselective polymerization of MMA catalyzed by group 4 metallocene catalysts

[r]=0.80 0.649 0.74 0.72 0.72 0.007 0.012 0.023 0.01 0.08 0.23 0.022 0.014

[rr]

0.264 0.22 0.25 0.25 0.013 0.033 0.053 0.04 0.11 0.23 0.048 0.031

[mr]

0.087 0.04 0.03 0.03 0.98 0.955 0.914 0.95 0.81 0.54 0.93 0.947 0.955

[mm]

119 133 134 134 134 142 142 142 137 137 137 135 139 143

Refs

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes 203

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precursor gave isotactic MMA [143]. The active species 49 is chiral at the Zr metal, and the triad distribution of the polymer was consistent with a catalyticsite control mechanism. Chen et al. showed that stereoregularity greatly depends on co-catalysts: 44 and 46 with borane give isotactic poly(MMA) by catalytic-site control, while these catalysts with the alane Al(C6F5)3 give syndio-rich poly(MMA) by chainend control [144]. They achieved iso-b-syndio stereoblock poly(MMA) using the borane and the alane in one pot [145]. Stereospecific polymerization of acrylates is rare. Isotactic polymerization of tert-butyl acrylate by 44 (or 46)–Ph3CB(C6F5)3-ZnEt2 system gives 0.742 and 0.759 mm triad of poly(tert-butyl acrylate) at 0 °C [146]. 4.4 Group 5 Metals Mashima et al. reported group 5 cylopentadienyl–butadiene complexes that are “isoelectronic” to group 4 metallocenes, and capable of ethylene polymerization [30] (Fig. 17). The tantalum bis(diene) complex 50 was ineffective for MMA polymerization when combined with MAO, while it initiated MMA polymerization using bis(aryloxy)aluminum 51 as a co-catalyst ([rr]=0.68). The analogous 1,4-diaza-1,3-butadiene (DAD) tantalum complexes 52 also give syndiotactic poly(MMA) ([rr]=0.70–0.73) [147, 148]. Interestingly, the MMA-coordinated complexes 53 showed activity with trialkylaluminums, such as AlMe3, AlEt3 or AlEt2Cl, as co-catalysts [149]. The corresponding dichloro

Fig. 17 Group 5 metal complexes for MMA polymerization

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes

205

complex [Cp*TaCl2(h4-Cy-DAD)] or dimethyl complexes [Cp*TaMe2 (h4-CyDAD)] are inactive.

5 Polymerization of 1,3-Dienes Polymerization of 1,3-dienes potentially gives the stereoregularity illustrated in Fig. 18. 1,4-cis-Poly(butadiene) is of importance as a synthetic rubber. Isoprene gives some more possible stereoregular polymers. For commercial production, conventional Ziegler–Natta type catalysts that contain Ti, Co, Ni or Nd salts are used with alkylaluminum [150, 151, 152]. Most of these catalysts are halides, alkoxides, carboxylates, and alkyl(allyl) compounds without cyclopentadienyl ligands. The monomer and polymers coordinate to metal during the polymerization to form sterically encumbered species that control its steric environment. Thus the steric bulkiness of Cp ligands does not seem essential. Titanium [153] and vanadium [154] monocyclopentadienyl complexes are known to serve as catalysts for 1,4-cis polymerization, although bis(cyclopentadienyl) complexes are less active [155]. Ricci et al. investigated various diene monomers using CpTiCl3–MAO catalysts and showed that stereoselectivity of polymerization depends on the monomer employed [156]. Soga reported that half-titanocene with an oxy-coordinating pendant 54 produces cis-rich polybutadiene [157, 158]. Recently, Longo et al. reported that the ansa-zirconocene complex 55 gives a novel polymer with cyclopropyl moieties from butadiene. The polymer structure strongly depends on reaction temperatures [159].

Fig. 18 Stereoregularity in poly(1,3-butadiene)

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N. Suzuki

Fig. 19 Stereoselective catalysts for butadiene polymerization

Kaita and Hou reported samarocene-catalyzed highly 1,4-cis-selective butadiene polymerization. This is a rare example of stereospecific catalysts of non-bridged metallocene complexes for the polymerization of butadiene [160, 161, 162] (Fig. 19).

6 Polymerization of Non-Conjugated Dienes Some non-conjugated dienes, such as 1,5-hexadiene, 1,6-heptadiene, and 1,7octadiene, polymerize in the presence of metallocene catalysts to give polymers with cyclic structures. The stereochemistry of the cyclic units involves cis and trans rings (Fig. 20). They also polymerize in a 1,2-manner, resulting in poly-

Fig. 20 Stereoregularity in poly(1,5-hexadiene)

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes

207

Fig. 21 Catalytsts for polymerization of non-conjugated dienes and substituted dienes

mer with vinyl-ended branches. 1,5-Hexadiene tends to give cyclic units more selectively, and 1,6-heptadiene and 1,7-octadiene give more 1,2-insertion units, although the selectivity depends on catalysts and reaction conditions [163]. Highly substituted 1,5- and 1,6-dienes such as 56–58 give only 1,2-insertion units (Fig. 21) [164]. Waymouth et al. extensively explored stereoselectivity in the polymerization of 1,5-hexadiene using a variety of metallocene catalysts [165, 166, 167, 168, 169, 170].Achiral metallocenes can give cis- and trans-rich poly(methylene-1,3-cyclopentane)s, although they are atactic. For example, Cp2ZrCl2/MAO gives 80–91% trans-polymer, while Cp*2ZrCl2/MAO gives 70–86% cis-polymers. A zirconocene with bulky ferrocenyl ligands, 59, polymerizes 1,5-hexadiene with more trans-selectivity (91–98% trans) [171]. trans-Isotactic polymers can be optically active (chiral) if homochiral catalysts are used.Waymouth et al. showed that the homochiral ansa-zirconoceneBINOL complex , 60, with MAO polymerized 1,5-hexadiene giving optically active trans(72%)-polymer [166, 167]. There are a few examples of monocyclopentadienyl compounds that catalyze non-conjugated dienes. The cationic titanium compound [Cp*TiMe2]+ [172] and mono(pentamethylcyclopentadienyl)yttrium alkoxides [53] catalyzed cyclopolymerization of 1,5-hexadiene, whereas neither of them gave highly stereoregulated polymers. Copolymerization of non-conjugated diene with other olefins has been also studied. In copolymerization with ethylene [173, 174], 1,5-hexadiene selectively gives methylenecyclopentane units, and 1,7-octadiene partly gives methylenecycloheptane, although 1,9-decadiene exclusively gives a 1,2-inserted sequence [175]. Shiono et al. reported copolymerization of 1,5-hexadiene and 1,7-octadiene with

208

N. Suzuki

propylene using isospecific and syndiospecific zirconocenes [176]. Single-component ansa-samarocene catalyst 61 allows copolymerization of 1,5-hexadiene or 1,7-octadiene with isoprene [177]. 1,5-Hexadiene is cyclopolymerized by the samarium catalyst, whereas 1,7-octadiene inserted in a 1,2-fashion.

7 Polymerization of Cycloolefins Metallocene catalysts are capable of polymerization of cycloolefins such as cyclobutene, cyclopentene and norbornene, whereas conventional heterogeneous Ziegler–Natta catalysts are unable to polymerize cycloolefins without ring opening [178]. Polymerization of cyclopentene proceeds via 1,3-insertion, while cyclobutene and norbornene undergo 1,2-enchainment. Their stereochemistry involves cis and trans in ring enchainment and tacticity of its sequence (Fig. 22). The stereoregulated polymers are highly crystalline and show high melting points. The melting point of poly(cyclobutene) is 485 °C, 395 °C for poly(cyclopentene) and >500 °C for poly(norbornene). This makes structural analysis difficult, and hydrooligomerization products are often used for determination of the stereochemistry.Although homopolymers of cycloolefins cause difficulty in industrial manufacturing because of their high melting points, their copolymers with ethylene are of interest as optical materials, such as compact disks [179]. The mechanism of 1,3-enchainment of cyclopentene is similar to that of propylene. After 1,2-insertion of the monomer, b-hydrogen elimination and reinsertion resulted in 1,3-insertion.An achiral catalyst Cp2ZrCl2 produces cisrich but atactic poly(cyclopentene) that is amorphous polymer [180, 181].A few chiral zirconocenes such as rac-Me2Si(Ind)2ZrCl2 (3, R1=R2=H) [181] and racC2H4(Ind)2ZrCl2 (1b) [180] give highly cis-isotactic polymer, while racC2H4(THInd)2ZrCl2 (2) gives cis- (60%) trans-mixed polymer [182, 183]. The Cs-symmetric complex Ph2C(Cp)(Flu)ZrCl2 (11)/MAO showed low stereoselectivity [181].

Fig. 22 Stereoregularity in cyclopolymers

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes

209

Fig. 23 Hydrotrimers of norbornenes

Studies on hydrooligomerization of norbornene revealed that 3 predominantly gave the meso,meso-isomer (66–71%), and 11 gave the rac,rac-trimer in 55–78% selectivity (Fig. 23) [184].

8 Post-Metallocene Catalysts Homogeneous polymerization catalysts that have non-metallocene structures, so-called “post-metallocene” catalysts, have been extensively explored. Stereoselective polymerization using these catalysts has also been reported, although most examples describe polypropylene. Complex 62, a so-called constrained geometry catalyst (CGC), which has a bridged half-metallocene structure and thus is usually not considered a postmetallocene catalyst, is of much interest in ethylene polymerization and copolymerization. Its Zr-enolate complex 49 gives isotactic poly(MMA) despite the Cs-symmetric structure, although it shows in principle no stereoselectivity in propylene polymerization. The titanium–bisamide complex 63 reported by McConville is capable of living polymerization of a-olefins [185]. Formation of isotactic polypropylene ([mmmm]=0.79) using a 63-Al-i-Bu3-[Ph3C][B(C6F5)4] system by catalytic-site control has been reported [186]. Recently Fujita et al. reported that bis(phenoxyimine) complexes 64 show a significant high catalytic activity [187, 188, 189, 190]. Although the complexes 64 have C2-symmetric structures, it was found that the fluorinated derivatives (M=Ti, R1=C6F5, R2=t-Bu, R3=H, t-Bu) produce syndiotactic polypropylene under chain-end control ([rr]=0.98 [191], [rrrr]=0.96 at 0 °C [192]). It is noteworthy that the propylene inserts in a 2,1-fashion [193, 194, 195]. Benzamidinate complexes 65 and 66 also give isotactic polypropylene (66, [mmmm]=0.95–0.98) [196, 197]. Late transition metal catalysts that are highly active and produce high molecular weight polyolefins were recently reported [198, 199]. For example, nickel and palladium–diimine catalysts 67 produce highly branched polyethylene that is totally different from those produced by conventional or homogeneous Ziegler–Natta catalysts [200]. On the other hand, iron and cobalt 2,6-pyridine bis(imine) complexes 68 give linear polyethylene [201, 202]. These catalysts are used with co-catalysts such as MAO, and the active species are cationic. Neu-

210

Fig. 24 Post-metallocene catalysts for olefin polymeriation

N. Suzuki

Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes

211

tral nickel catalyst 69 was also reported [203]. There have been some examples, albeit few, of stereospecific polymerization using them. Syndiotactic polypropylene is formed by the nickel(II)–diimine complex 67 (M=Ni) at low temperature ([rrrr]=0.80 at –78 °C, 0.65 at 0 °C) [204, 205]. Polymerization proceeds by 1,2-insertion and the stereochemistry is regulated under chain-end control. On the other hand, isotactic polypropylene can be prepared using the iron complexes 68 (M=Fe; [mmmm]=0.55–0.67 at –20 °C) despite the low molecular weight of the polymer [206]. Polymerization proceeds via a 2,1-insertion mechanism by chain-end control.

9 Conclusion It has been shown that a variety of metallocene complexes serve as effective homogeneous, stereoselective polymerization catalysts. They achieve unprecedented polymers that could not be produced by traditional catalysts. Many examples of non-metallocene catalysts have also been studied. In industry, however, conventional heterogeneous catalyst systems are still major processes for the production of polyolefins. In order to apply homogeneous catalysts for commercial processes, practical improvements are needed. Heterogenization of homogeneous catalysts by adsorption on solid supports such as silica gel is one strategy allowing the existing process to be used [207, 208]. Economic drawbacks also must be overcome; the cost of the precatalyst complex is reduced by improvement in its activity. Further, MAO is also expensive, and decreasing this co-catalyst or exploring other inexpensive co-catalysts is being pursued. These technologies will provide increasing numbers of metallocene-produced polyolefins to the market in the near future.

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189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207. 208.

Topics Organomet Chem (2004) 8: 217– 236 DOI 10.1007/b96004 © Springer-Verlag Berlin Heidelberg 2004

Carbon–Carbon Bond Cleavage Reaction Using Metallocenes Tamotsu Takahashi (

) · Ken-ichiro Kanno

Hokkaido University, Catalysis Research Center, Kita 21, Nishi 10, Kita-ku 001-0021 Sapporo, Japan [email protected]

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Introduction

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C–C Bond Cleavage of the Cyclopentadienyl Ligand of Metallocenes . . . . 218

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C–C Single Bond Cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

3.1 3.2 3.3 3.4 3.5

C–C Bond Cleavage of Alkyl Metal Compounds . C–C Bond Cleavage of Metallacyclic Compounds C–C Bond Cleavage of Olefin, Diene, and Arene . C–C Bond Cleavage of Alkynes . . . . . . . . . . C–C Bond Cleavage of Nitriles . . . . . . . . . .

4

C–C Double Bond Cleavage

4.1 4.2

C–C Double Bond Cleavage by the Multi-Metallic System . . . . . . . . . . 230 C–C Double Bond Cleavage in the Coupling with Alkyne (Enyne Cyclization) 231

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C–C Triple Bond Cleavage

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Conclusion

References

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Abstract Among a lot of transition metal mediated or catalyzed C–C bond cleavage reactions, metallocene mediated C–C bond cleavage reactions, in particular, are attractive since many cases show the intermediates or the C–C bond cleavage steps in the reactions. Organic compounds are classified into three groups by the bond order of the C–C bond: (1) C–C single bond, (2) C–C double bond, and (3) C–C triple bond. Keywords C–C bond cleavage · Metallacycles · Cyclopentadienyl ligand · b,g-C–C bond · Multi-metallic system

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1 Introduction Carbon–carbon bond cleavage is a new area in organic and organometallic chemistry [1]. It has been generally believed that once a carbon–carbon bond is formed, it cannot be easily cleaved. Therefore, introduction of selectivities, such as regio-, stereo-, and enantioselectivity has to be done when a new carbon–carbon bond is formed.After formation of the carbon–carbon bond there is almost no chance to introduce new selectivity into it. However, what if we can easily cleave the carbon–carbon bond in a molecule? This will widen the scope of organic chemistry and organometallic chemistry. (1) Some carbon–carbon bond cleavage reactions have already been known as classic chemistry, such as opening small ring strained molecules (three-membered ring or four-membered ring), decarboxylation, and retro-Diels–Alder reaction and so on. Also, some mechanisms of cleavage reactions such as metathesis have been elucidated [2]. Recently, new C–C bond cleavage reactions have been reported for unstrained molecules using transition metal complexes. In particular, the number of reports on C–C bond cleavage has increased since the 1980s. Such C–C bond cleavage reactions of unstrained molecules with transition metal complexes are interesting, mysterious, and attractive. The mechanisms for those reactions still remain unclear. What is the driving force of the C–C bond cleavage of unstrained molecules? This should be the target of study. In order to study the C–C bond cleavage step, the best way is by monitoring the cleavage reaction or investigating the structure of the starting complex and the final metal-containing product. This means that metallocenes or metal complexes with cyclopentadienyl or related ligands are quite useful. In many C–C bond cleavage reactions, some metal-containing intermediates have been isolated and the structures of those complexes with cyclopentadienyl ligands have been determined either before or after the C–C cleavage reaction. Therefore, this chapter focuses on the C–C bond cleavage using metallocenes or metal complexes with cyclopentadienyl ligands or related ligands.

2 C–C Bond Cleavage of the Cyclopentadienyl Ligand of Metallocenes The first question regarding the C–C bond cleavage using metallocenes is the following.“Is the C–C bond of a cyclopentadienyl ligand cleaved by itself?” The answer is yes in some cases.

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The first direct C–C-bond cleavage reaction of the cyclopentadienyl ligand on metal was reported by Rosenthal et al. [3]. As shown in Eq. 2, titanacyclopentadiene derivatives, which can be prepared from a low valent titanocene and 3,9-dodecadiyne, gave a dihydroindene titanium complex.When the structure of the product is checked carefully, it is found that one C–C bond of the cyclopentadienyl ligand was cleaved and three new C–C bonds were formed in this transformation. The structure of the dihydroindene titanium complex was determined by X-ray analysis.

(2)

An interesting C–C bond cleavage of Me-substituted Cp ligand was reported by Stryker et al. for a CpCo derivative as shown in Eq. 3 [4]. 2-Butyne was inserted into a Cp ligand to form a seven-membered ring compound. It is notable that the allyl group in the starting complex reacted with 2-butyne to be converted into a dimethylcyclopentadienyl ligand to stabilize the complex as shown below.

(3)

Takahashi, Xi, and coworkers reported double C–C bond cleavage of the cyclopentadienyl ligand [5]. As shown in Scheme 1, one cyclopentadienyl ligand was torn into two parts, a 2-carbon unit and a 3-carbon unit that were converted into two different cyclic compounds, a benzene derivative and a pyridine derivative. Addition of a nitrile to a titanacyclopentadiene gave a 1,2,3,4-tetrasubstituted benzene derivative and a pyridine derivative (Eq. 4). A labeling reaction using a 13C-enriched Cp2Ti species clearly indicated that two carbons of the

Scheme 1

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benzene derivative and three carbons of the pyridine derivative came from the cyclopentadienyl ligand. Monitoring the reaction revealed that the benzene derivative was formed first and that there was a time-lag for the pyridine formation.

(4)

Although the mechanism has not yet been elucidated and is now under investigation, a coupling of the Cp ligand and the titanacyclopentadiene moiety is the important step, as Rosenthal has shown above. The subsequent double C–C bond cleavage giving a benzene derivative is not clear yet, but the allyl-titanium species might be formed after the double C–C bond cleavage. Reaction of the allyl-titanium with two nitrile molecules produces a pyridine derivative and a titanium nitride derivative, which is converted into ammonia after hydrolysis. This is a tentative explanation for this reaction. Some reports have shown that Cp ligands were converted into cyclopentadiene derivatives on metal complexes and then the C–C bonds were cleaved on the metal. Such reactions are discussed later.

3 C–C Single Bond Cleavage In most cases, cyclopentadienyl ligands do not incorporate in the reactions. In the following sections, we classify the organic unstrained molecules by the bond order in the cleavage reaction: (i) C–C single bond,( ii) C–C double bond, and (iii) C–C triple bond in the starting molecules. For the C–C single bond cleavage reaction, compounds were classified by their functional groups such as alkyl-metals, metallacycles, olefins, dienes, arenes, alkynes, and nitriles. The C–C single bond cleavage reaction by transition metal complexes requires the interaction of the bond with the metal center; in other words, coordination of the functional group (an anchor) in the molecule to the metal center. The cleavage of the single C–C bond occurs very often at the b,g-C–C bond in the intermediate, as shown in Scheme 2, via three patterns where X is carbon or heteroatom. 3.1 C–C Bond Cleavage of Alkyl Metal Compounds The C–C bond cleavage of alkyl metal occurs on the b,g-carbon–carbon bond in the alkyl group. The C–C bond cleavage of alkyl metal compounds always

Carbon–Carbon Bond Cleavage Reaction Using Metallocenes

221

Scheme 2

competes with b-hydrogen elimination. Therefore, such C–C bond cleavage reaction was usually observed in neopentylmetal compounds which do not have the b-hydrogen. Trineopentylaluminum is not a metallocene but this compound is important to show an example of the b,g-C–C bond cleavage reaction [6]. Although it is slow, elimination of isobutene and formation of Al(CH2CCMe3)2Me were detected (Eq. 5). (5) In 1982,Watson et al. reported the carbon–carbon bond cleavage reaction of an isobutyl group on metallocene of Lu, as shown in Eq. 6 [7]. The b,g-carbon– carbon bond was cleaved and the methyl group stayed on Lu in this reaction. The metallocene compound is very powerful at showing the structure of the

(6)

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final product. The product Lu–Me complex was fully characterized by X-ray analysis. The Lu–Me complex was a dimer. The structure clearly showed that one Me group stayed on Lu metal after the cleavage. Another important point is the competition with b-hydrogen elimination. Both the C–C bond cleavage and the b-hydrogen elimination are in equilibrium with the starting compound. The isobutyl group has b-hydrogen. Generally, it is believed that b-hydrogen elimination is much more favorable compared with C–C bond cleavage. However, it is interesting to note that the total amount of Cp*2Lu-CH3 in the reaction mixture, which is formed by C–C bond cleavage, increased and the rate is faster than the formation of isobutene by b-hydrogen elimination. This type of C–C bond cleavage is important for olefin polymerization chemistry. Metallocenes are well known for olefin polymerization. In a polymerization reaction of propene, formation of vinyl end groups is sometimes observed [8]. This reaction can be explained by the carbon–carbon bond cleavage reaction with elimination of the terminal olefin. This fact suggests that such a C–C bond cleavage reaction over b-hydrogen elimination is not so special for the metallocenes. A similar type of C–C bond cleavage was also observed for zirconium cation compounds [9]. The complex, as shown in Eq. 7 with a neopentyl group, showed the elimination of isobutene and the formation of the methylzirconocene complex.

(7)

This type of reaction is called b-methyl elimination or b-alkyl elimination. The methyl group or alkyl group on b-carbon is eliminated. Therefore, it is called b-methyl elimination or b-alkyl elimination. These terms are related to “b-hydrogen elimination”. However, the term,“b-carbon elimination”, is not appropriate. It is very confusing, since the carbon that is eliminated is not the b-carbon but the g-carbon. Therefore, b,g-cleavage, b-alkyl elimination, and bmethyl elimination are better terms for this type of reaction. 3.2 C–C Bond Cleavage of Metallacyclic Compounds

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C–C bond cleavage reactions of titanacyclopentanes and titanacyclohexane were independently studied by Grubbs [10] and Whitesides [11]. In the case of titanacyclopentane, ethylene was eliminated via a titanocene-bis(ethylene) complex as shown in Eq. 8. According to the deuterium labeling reaction, the real mechanism is more complicated, since scrambling of D was observed (Eq. 9) [10].

(8)

(9)

This type of C–C bond formation was used for the formation of hafnacyclopentene and hafnacyclopentadiene by Erker and his coworkers [12]. Takahashi et al. introduced regioselective and stereoselective transformation in the C–C bond cleavage reaction [13]. As shown in Scheme 3, a,a’-dimethylzirconacyclopentane was prepared in situ starting from 2,5-dibromohexane. This compound was selectively converted into b,b¢-dimethylzirconacyclopentane at room temperature in THF within 1 h. Since this reaction was too fast, it could not be followed by NMR. However, the transformation of a Hf analogue was slow enough for monitoring the reaction by NMR. As shown in Fig. 1, Cp signals of dimethylhafnacyclopentane in its 1H NMR spectrum are gradually changed to b,b¢-dimethylhafnacyclopentane cleanly and the stereochemistry of the final product was completely controlled. Two methyl groups at the a position of hafnacyclopentane were converted stepwise into the b-position. Further application of the b,g-C–C bond cleavage of zirconacycles has been done for the formation of benzene derivatives [14] and pyridine derivatives

Scheme 3

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Fig. 1 Isomerization of hafnacyclopentadiene monitored by 1H NMR

[15] via zirconacyclopentenes and zirconacyclopentadienes, as shown in Scheme 4 and Eq. 10, respectively. By this method, the first example of benzene formation from three different alkynes in one-pot was achieved [14].

Scheme 4

(10)

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All substituted and all different substituted pyridine derivatives could be prepared by the C–C bond cleavage of the zirconacyclopentane reaction in onepot from two different alkynes and one nitrile with excellent selectivity and high yields [15]. This is the only method for the penta-substituted and all different substituted pyridine from two unsymmetrical internal alkynes and one nitrile so far. 3.3 C–C Bond Cleavage of Olefin, Diene, and Arene In 1974, Green reported a reversible C–C bond formation and cleavage of the cyclopentadienyl ligand of Cp2MoEtCl [16]. The ethyl group moved from Mo to a Cp ligand by addition of a phosphine to give h4-cyclopentadiene derivatives. The ethyl group of the cyclopentadiene ligand on molybdenum, in turn, was eliminated by the C–C bond cleavage which was initiated by abstraction of the Cl anion. Then the Et group moved back to Mo as shown in Eq. 11. One important factor is the formation of a cyclopentadienyl ligand. The cyclopentadienyl ligand itself can be formed by elimination of either Et or H. Elimination of H is energetically much more favorable than that of the Et group. The reason why the elimination of Et is more favorable than that of H is not clear but one possible mechanism is as follows. Probably, elimination of H occurs very rapidly and reversibly. On the other hand, the elimination of Et is irreversible, or its reversible reaction might be slow, even though the reaction itself is a minor reaction. Therefore, elimination of the Et group is observed as the total reaction.

(11)

A similar type of alkyl group elimination from alkyl-substituted cyclopentadienes giving cyclopentadienyl ligands has been reported for W [17], Mo [18], and Ir [19]. The starting compounds are not Cp complexes but the final products are CpM compounds. Non-alkyl substituted cyclopentadiene showed the ring-opening reaction. Suzuki et al. reported that cyclopentadiene reacted with a trinuclear Ru complex to open the ring and that a ruthenacyclopentadiene derivative is formed as a product (Eq. 12) [20]. Reaction of norbornadiene with a bimetallic Ru complex also gave a ringopening product (Eq. 13). In this reaction two C–C bonds were cleaved. The cleaved C–C bonds were both single bonds in the starting material [21]. There is a report for the C–C bond cleavage of cyclooctadiene on cobalt by treatment with HBF4 as shown in Scheme 5[22]. The first step of this reaction is protonation of one double bond which converts the complex to the corre-

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(12)

(13)

Scheme 5

sponding h3-(p-allyl) cobalt compound. The p-allyl cobalt complex was isolated and characterized. The C–C bond cleavage occurred from this p-allyl complex. The b,g–C–C bond was cleaved.

(14)

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This result suggests that diene itself is not involved in the cleavage reaction. A p-allyl-metal species with agostic interaction of H with Co is the key intermediate. The same type of reaction also proceeds in 5-membered ring compounds on Co (Eq. 14) [23].A simple cobalt p-allyl complex reacted with 2-butyne to give a 7-membered ring cobalt complex where one carbon and two carbons of the allyl moiety were separated in the final product [11]. The mechanism is not yet clear. Bercaw reported an interesting reversible branching reaction of 1,4-pentadiene derivatives catalyzed by a scandocene hydride complex as shown in Scheme 6 [24].

Scheme 6

The C–C bond cleavage of an unstrained single bond of olefins is difficult. Activated ofefins, such as dienes, and a p-allyl system are needed for the cleavage reaction. The following example in Scheme 7 is also C–C bond cleavage of enones. The driving force of the cleavage is aromatization of the 6-membered ring. And the methyl group on the ring is eliminated as shown below [25, 26]. This reaction was applied in the synthesis of a steroid derivative. Catalytic C–C bond cleavage of neohexene has been reported using the [Cp*Ru(OMe)2]/CF3SO3H system (Eq. 15) [27]. The products were 2,3-di-

Scheme 7

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(15) methyl-2-butene, 2,3-dimethyl-1-butene and a small amount of CH4. Migration of one methyl group is the major reaction. Although it is not an unstrained compound, it is noteworthy that a C–C single bond of biphenylene was cleaved by (C5Me5)RhPh(H)PMe3 to give Rh containing a 5-membered ring complex as shown in Eq. 16 [28, 29].

(16)

3.4 C–C Bond Cleavage of Alkynes

Mach and coworkers reported the single bond cleavage of 2,4-disilyldiyne in the presence of a low-valent titanium complex that was produced by the reduction of (C5Me4H)2TiCl2 with Mg (Eq. 17). The final product [(C5Me4H)2Ti (CCSiMe3)2][MgCl(thf)] was characterized by X-ray analysis [30]. (17)

Similarly, Rosenthal showed the selective cleavage of the C–C bond of octatetraynes with titanocene and zirconocene bis(trimethylsilyl)acetylene complexes. The final product was also characterized by X-ray analysis (Eq. 18) [31].

(18)

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229

3.5 C–C Bond Cleavage of Nitriles

C–C bond cleavage of a nitrile on metal proceeds at the b,g-bond of the nitrile. As shown in Eq. 19, photolysis of [Me2Si(C5Me4)2]MoH2 gives a very active species that reacts with acetonitrile to give the methyl-cyanide complex Me2Si(C5Me4)2Mo(Me)CN [32]. This product was characterized by X-ray analysis. The usual molybdocene analogue affords an h2-nitrile complex but not the C–C bond cleavage complex. This suggests the coordination of nitrile to Mo in a side-on mode is the first step.

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4 C–C Double Bond Cleavage Several reactions can be expected for the reaction of olefin with transition metals. For example: i. ii. iii. iv. v. vi.

Oxidative addition of a vinyl C–H bond Oxidative addition of allylic C–H bond b,g-C–C single bond cleavage of olefins g,d-C–C single bond cleavage of olefins Insertion reaction Coupling reaction

Direct cleavage of the C–C double bond of olefins is not usually observed. The C–C double bond coordinates to transition metals first and a formal metallacyclopropane derivative is produced. If the C–C bond is cleaved in the metallacyclopropane, two metal-carbene moieties are formed on one metal center. Due to the unstability of bis(carbene) compounds, the direct and simple cleavage reaction of the C–C double bond does not easily occur (Eq. 20). (20)

230

T. Takahashi · K. Kanno

The cleaved fragment should be stabilized somehow. One method is stabilization of the cleaved species by multi-metallic systems. Another method is a combination with other functional groups in the molecule. 4.1 C–C Double Bond Cleavage by the Multi-Metallic System The multi-metallic system was reported by Suzuki et al. as shown in Eq. 21.Advantages of the multi-metallic system over a mono-metallic system are the existence of a multi-coordination site, the possibility of multi-electron transfer, and the stabilization of the fragmented species. The tri-ruthenium system Suzuki et al. developed showed an interesting C–C double bond cleavage [33]. As shown in Scheme 8, the C–C double bond of methyl methacrylate was cleaved when it was treated with {(h5-C5Me5)Ru}3(m-H)3(m3-H)2 at 80°C for 48 h. The structure of the final product was determined by X-ray single crystal analysis. Under milder conditions a m-vinylidene complex was isolated and its structure was also determined by X-ray analysis. The first step of this cleavage reaction is oxidative addition of the two terminal C–H bonds of alkenes. The following elimination of allylic hydrogen of the m-vinylidene complex afforded a bimetallic bridged allyl system. The b,g-C–C bond was cleaved in the bimetallic system to give the final product.

(21)

Scheme 8

Carbon–Carbon Bond Cleavage Reaction Using Metallocenes

231

4.2 C–C Double Bond Cleavage in the Coupling with Alkyne (Enyne Cyclization) C–C double bond cleavage of an enyne derivative using a metallocene derivative was reported by Takahashi and coworkers [34]. When an alkyne was treated with Cp2ZrEt2 and vinyl bromide or vinyl ether in this order; after hydrolysis a 2,3-disubstituted diene derivative was obtained (Eqs. 22 and 23). Bissilyl acetylene, aryl-substituted acetylene or cyclohexyl-substituted alkyne could be used as internal alkynes. (22)

(23)

This reaction was applied for intramolecular reactions.As shown in Eq. 24, a diene was formed. The structure of the final product clearly showed that the C–C double bond of enyne was cleaved. The use of vinyl ether gave vinylzirconation of alkynes without C–C bond cleavage. Therefore, the key point for this reaction is the use of the vinyl halide moiety.

(24)

Following the reaction of diphenylacetylene with vinyl bromide suggested the formation of two kinds of cyclobutene derivatives as intermediates (Scheme 9). Table 1 shows the hydrolysis product of the intermediates during the reaction. First, a cyclobutene derivative was formed in high yield, which gradually decreased. The amount of the second cyclobutene derivative increased with a decrease in the amount of the first cyclobutene derivative.Again it also decreased and the final diene accumulated. The structure of one of the zirconium-containing cyclobutene intermediates with trimethylsilyl substituted Cp ligands was determined by X-ray analysis. Judging from the results, the mechanism in Scheme 10 is plausible. The coupling of one alkyne and vinyl bromide occurs on zirconocene to give a-bromozirconacyclopentene. Elimination of Br via 1,2-shift of the Zr–C bond affords the first cyclobutene derivative. The zirconium moiety attaches to the

232

T. Takahashi · K. Kanno

Scheme 9

Table 1 Formations of Cyclobutenes and Butadienes in Scheme 9

T/°C

rt rt 50 50 50 50 50

time/h

1 3 1 3 6 15 24

ratio (%)

Combined yields

I

II

III

IV

98 95 36 25 18 1 tr

tr 1 38 17 3 1 tr

tr 2 21 48 66 84 86

tr 1 5 10 13 13 13

84 93 93 90 89 90 87

allylic carbon with R2 substituent. Allylic rearrangement to the second cyclobutene derivative, of which the structure was determined, occurs. Ringopening of the cyclobutene proceeds to afford a dienyl zirconocene derivative. Deuterolysis and iodinolysis of the dienylzirconocene showed the stereochemistry of the diene moiety was completely controlled by this reaction.

Scheme 10

Carbon–Carbon Bond Cleavage Reaction Using Metallocenes

233

5 C–C Triple Bond Cleavage C–C triple bond cleavage has some similarity to the C–C double cleavage. Several examples are known for the C–C triple bond cleavage in the multi-metallic system. A C–C triple bond easily coordinates to transition metals giving an alkyne complex. The alkyne complex can also be formally described as a metallacyclopropene. The second coordination of the C–C double bond moiety of the metallacyclopropene to another transition metal center provides a more strained two metallacyclopropane fused ring system. When the C–C bond is cleaved, the fragment can be stabilized in the multi-metallic system. Most reported reactions of this type used the Cp ligand in the system. An acetylide cluster, CpWRu2(CO)8(CCPh), was treated with 1 equivalent of Ru3(CO)12 to give two carbido-alkylidyne cluster complexes, CpWRu4(m5C)(CO)12(m-CPh) and CpWRu5(m6-C)(CO)14(m-CPh), as shown in Scheme 11 [35]. It is interesting to note that this cleavage is reversible.

Scheme 11

A diiron polyyne complex, Cp*Fe(CO)2-(CC)n-Fe(CO)2Cp* (n=3 or 4) showed site-selective cleavage reaction of the C–C triple bond when it reacted with Fe2(CO)9 or Fe3(CO)12 (Eq. 25) [36]. The second C–C triple bond from the terminal was selectively cleaved at room temperature, although the yield was relatively low. The cleaved fragment was stabilized by three iron metals. Similar (25)

234

T. Takahashi · K. Kanno

C–C triple bond cleavage by the (h5-C5R5)M system has been reported for Co [37], Rh [38] and Fe [39]. Usually, the C–C triple bond is cleaved in multi-metal systems. An unusual example of the C–C triple bond cleavage by mononuclear metal complex has been reported [40]. This occurs when the alkyne is very bulky as shown in Eq. 26.

(26)

The following reaction of an alkyne with an Ir complex looks like the C–C triple bond cleavage (Eq. 27) [41]. It is not the direct C–C triple bond cleavage by the reaction with metals. The first step of this reaction is addition of water to the triple bond forming an aldehyde. Elimination of CO from the resulting acyl complex gives the product.

(27)

6 Conclusion Metallocene or metal complexes with Cp or related ligands provide considerable important information about the mechanistic aspects of C–C bond cleavage reactions. At the same time, metallocenes sometimes show catalytic reactions. We believe that development of novel types of C–C bond cleavage reactions and elucidation of their mechanism will be accomplished using metallocenes and their related complexes.

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32. Churchill D, Shin JH, Hascall T, Hahn JM, Bridgewater BM, Parkin G (1999) Organometallics 18:2403 33. Takemori T, Inagaki A, Suzuki H (2001) J Am Chem Soc 123:1762 34. Takahashi T, Xi Z, Fischer R, Huo S, Xi C, Nakajima K (1997) J Am Chem Soc 119:4561 35. Hwang SF, Chi Y, Chiang SJ, Peng SM, Lee GH (2001) Organometallics 20:215 36. Akita M, Sakurai A, Moro-oka Y (1999) Chem Commun: 101 37. (a) King RB, Harmon CA (1976) Inorg Chem 15:879; (b) Yamazaki H, Wakatsuki Y, Aoki K (1979) Chem Lett:1041; (c) Fritch JR, Vollhardt KPC (1980) Angew Chem Int Ed Engl 19:559; (d) Tallison N, Fritch JR, Vollhardt KPC, Walborsky EC (1983) J Am Chem Soc 105:1384 38. Clauss AD, Shapley JR, Winker CN, Hoffmann R (1984) Organometallics 3:619 39. (a) Nuel D, Dahan F, Mathiu R (1985) Organometallics 4:1436; (b) Hriljac JA, Shriver DF (1987) J Am Chem Soc 109:6010; (c) Cabrera E, Daran JC, Jeannin Y (1988) J Chem Soc Chem Commun: 607 40. Hayashi N, Ho DM, Pascal Jr RA (2000) Tetrahedron Lett 41:4261 41. Chin CS, Chong D, Maeng B, Ryu J, Kim H, Kim M, Lee H (2002) Organometallics 21:1739

Author Index Volumes 1 – 8

Abdel-Magid AF see Mehrmann SJ (2004) 6: 153–180 Alper H see Grushin VV (1999) 3: 193–225 Anwander R (1999) Principles in Organolanthanide Chemistry. 2: 1–62 Armentrout PB (1999) Gas-Phase Organometallic Chemistry 4: 1–45 Beak P, Johnson TA, Kim DD, Lim SH (2003) Enantioselective Synthesis by Lithiation Adjacent to Nitrogen and Electrophile Incorporation. 5: 139–176 Bien J, Lane GC, Oberholzer MR (2004) Removal of Metals from Process Streams: Methodologies and Applications. 6: 263–284 Böttcher A see Schmalz HG (2004) 7: 157–180 Braga D (1999) Static and Dynamic Structures of Organometallic Molecules and Crystals. 4: 47–68 Brüggemann M see Hoppe D (2003) 5: 61–138 Chlenov A see Semmelhack MF (2004) 7: 21–42 Chlenov A see Semmelhack MF (2004) 7: 43–70 Clayden J (2003) Enantioselective Synthesis by Lithiation to Generate Planar or Axial Chirality. 5: 251–286 Dedieu A (1999) Theoretical Treatment of Organometallic Reaction Mechanisms and Catalysis. 4: 69–107 Delmonte AJ, Dowdy ED, Watson DJ (2004) Development of Transition Metal-Mediated Cyclopropanation Reaction. 6: 97–122 Dowdy EC see Molander G (1999) 2: 119–154 Dowdy ED see Delmonte AJ (2004) 6: 97–122 Fürstner A (1998) Ruthenium-Catalyzed Metathesis Reactions in Organic Synthesis. 1:37–72 Gibson SE (née Thomas), Keen SP (1998) Cross-Metathesis. 1: 155–181 Gisdakis P see Rösch N (1999) 4: 109–163 Görling A see Rösch N (1999) 4: 109–163 Goldfuss B (2003) Enantioselective Addition of Organolithiums to C=O Groups and Ethers. 5: 12–36 Gossage RA, van Koten G (1999) A General Survey and Recent Advances in the Activation of Unreactive Bonds by Metal Complexes. 3: 1–8 Gotov B see Schmalz HG (2004) 7: 157–180

238

Author Index

Gras E see Hodgson DM (2003) 5: 217–250 Grepioni F see Braga D (1999) 4: 47–68 Gröger H see Shibasaki M (1999) 2: 199–232 Grushin VV, Alper H (1999) Activation of Otherwise Unreactive C–Cl Bonds. 3: 193–225 Harman D (2004 Dearomatization of Arenes by Dihapto-Coordination. 7: 95–128 He Y see Nicolaou KC, King NP (1998) 1: 73–104 Hidai M, Mizobe Y (1999) Activation of the N–N Triple Bond in Molecular Nitrogen: Toward its Chemical Transformation into Organo-Nitrogen Compounds. 3: 227–241 Hodgson DM, Stent MAH (2003) Overview of Organolithium-Ligand Combinations and Lithium Amides for Enantioselective Processes. 5: 1–20 Hodgson DM, Tomooka K, Gras E (2003) Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Subsequent Rearrangement. 5: 217–250 Hoppe D, Marr F, Brüggemann M (2003) Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Electrophile Incorporation. 5: 61–138 Hou Z, Wakatsuki Y (1999) Reactions of Ketones with Low-Valent Lanthanides: Isolation and Reactivity of Lanthanide Ketyl and Ketone Dianion Complexes. 2: 233–253 Hoveyda AH (1998) Catalytic Ring-Closing Metathesis and the Development of Enantioselective Processes. 1: 105–132 Huang M see Wu GG (2004) 6: 1–36 Hughes DL (2004) Applications of Organotitanium Reagents. 6: 37–62 Iguchi M, Yamada K, Tomioka K (2003) Enantioselective Conjugate Addition and 1,2-Addition to C=N of Organolithium Reagents. 5: 37–60 Ito Y see Murakami M (1999) 3: 97–130 Ito Y see Suginome M (1999) 3: 131–159 Jacobsen EN see Larrow JF (2004) 6: 123–152 Johnson TA see Break P (2003) 5: 139–176 Jones WD (1999) Activation of C–H Bonds: Stoichiometric Reactions. 3: 9–46 Kagan H, Namy JL (1999) Influence of Solvents or Additives on the Organic Chemistry Mediated by Diiodosamarium. 2: 155–198 Kakiuchi F, Murai S (1999) Activation of C–H Bonds: Catalytic Reactions. 3: 47–79 Kanno K see Takahashi T (2005) 8: 217–236 Keen SP see Gibson SE (née Thomas) (1998) 1: 155–181 Kendall C see Wipf P (2005) 8: 1–25 Kiessling LL, Strong LE (1998) Bioactive Polymers. 1: 199–231 Kim DD see Beak P (2003) 5: 139–176 King AO, Yasuda N (2004) Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals. 6: 205–246 King NP see Nicolaou KC, He Y (1998) 1: 73–104 Kobayashi S (1999) Lanthanide Triflate-Catalyzed Carbon–Carbon Bond-Forming Reactions in Organic Synthesis. 2: 63–118 Kobayashi S (1999) Polymer-Supported Rare Earth Catalysts Used in Organic Synthesis. 2: 285–305 Kodama T see Arends IWCE (2004) 11: 277–320 Kondratenkov M see Rigby J (2004) 7: 181–204 Koten G van see Gossage RA (1999) 3: 1–8 Kotora M (2005) Metallocene-Catalyzed Selective Reactions. 8: 57–137 Kumobayashi H, see Sumi K (2004) 6: 63–96

Author Index

239

Kündig EP (2004) Introduction 7: 1–2 Kündig EP (2004) Synthesis of Transition Metal h6-Arene Complexes. 7: 3–20 Kündig EP, Pape A (2004) Dearomatization via h6 Complexes. 7: 71–94 Lane GC see Bien J (2004) 6: 263–284 Larrow JF, Jacobsen EN (2004) Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 6: 123–152 Li Z, see Xi Z (2005) 8: 27–56 Lim SH see Beak P (2003) 5: 139–176 Lin Y-S, Yamamoto A (1999) Activation of C–O Bonds: Stoichiometric and Catalytic Reactions. 3: 161–192 Marr F see Hoppe D (2003) 5: 61–138 Maryanoff CA see Mehrmann SJ (2004) 6: 153–180 Maseras F (1999) Hybrid Quantum Mechanics/Molecular Mechanics Methods in Transition Metal Chemistry. 4: 165–191 Medaer BP see Mehrmann SJ (2004) 6: 153–180 Mehrmann SJ, Abdel-Magid AF, Maryanoff CA, Medaer BP (2004) Non-Salen Metal-Catalyzed Asymmetric Dihydroxylation and Asymmetric Aminohydroxylation of Alkenes. Practical Applications and Recent Advances. 6: 153–180 Mizobe Y see Hidai M (1999) 3: 227–241 Molander G, Dowdy EC (1999) Lanthanide- and Group 3 Metallocene Catalysis in Small Molecule Synthesis. 2: 119–154 Mori M (1998) Enyne Metathesis. 1: 133–154 Muñiz K (2004) Planar Chiral Arene Chromium (0) Complexes as Ligands for Asymetric Catalysis. 7: 205–223 Murai S see Kakiuchi F (1999) 3: 47–79 Murakami M, Ito Y (1999) Cleavage of Carbon–Carbon Single Bonds by Transition Metals. 3: 97–130 Nakamura S see Toru T (2003) 5: 177–216 Namy JL see Kagan H (1999) 2: 155–198 Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carboalumination Reactions Catalyzed by Zirconocene Derivatives. 8: 139–176 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products. 1: 73–104 Normant JF (2003) Enantioselective Carbolithiations. 5: 287–310 Oberholzer MR see Bien J (2004) 6: 263–284 Pape A see Kündig EP (2004) 7: 71–94 Pawlow JH see Tindall D, Wagener KB (1998) 1: 183–198 Prashad M (2004) Palladium-Catalyzed Heck Arylations in the Synthesis of Active Pharmaceutical Ingredients. 6: 181–204 Richmond TG (1999) Metal Reagents for Activation and Functionalization of Carbon– Fluorine Bonds. 3: 243–269 Rigby J, Kondratenkov M (2004) Arene Complexes as Catalysts. 7: 181–204 Rodríguez F see Barluenga (2004) 13: 59–121 Rösch N (1999) A Critical Assessment of Density Functional Theory with Regard to Applications in Organometallic Chemistry. 4: 109–163

240

Author Index

Schmalz HG, Gotov B, Böttcher A (2004) Natural Product Synthesis. 7: 157–180 Schrock RR (1998) Olefin Metathesis by Well-Defined Complexes of Molybdenum and Tungsten. 1: 1–36 Semmelhack MF, Chlenov A (2004) (Arene)Cr(Co)3 Complexes: Arene Lithiation/Reaction with Electrophiles. 7: 21–42 Semmelhack MF, Chlenov A (2004) (Arene)Cr(Co)3 Complexes: Aromatic Nucleophilic Substitution. 7: 43–70 Sen A (1999) Catalytic Activation of Methane and Ethane by Metal Compounds. 3: 81–95 Shibasaki M, Gröger H (1999) Chiral Heterobimetallic Lanthanoid Complexes: Highly Efficient Multifunctional Catalysts for the Asymmetric Formation of C–C, C–O and C–P Bonds. 2: 199–232 Stent MAH see Hodgson DM (2003) 5: 1–20 Strong LE see Kiessling LL (1998) 1: 199–231 Suginome M, Ito Y (1999) Activation of Si–Si Bonds by Transition-Metal Complexes. 3: 131–159 Sumi K, Kumobayashi H (2004) Rhodium/Ruthenium Applications. 6: 63–96 Suzuki N (2005) Stereospecific Olefin Polymerization Catalyzed by Metallocene Complexes. 8: 177–215 Takahashi T, Kanno K (2005) Carbon-Carbon Bond Cleavage Reaction Using Metallocenes. 8: 217–236 Tan Z see Negishi E (2005) 8: in preparation Tindall D, Pawlow JH, Wagener KB (1998) Recent Advances in ADMET Chemistry. 1: 183–198 Tomioka K see Iguchi M (2003) 5: 37–60 Tomooka K see Hodgson DM (2003) 5: 217–250 Toru T, Nakamura S (2003) Enantioselective Synthesis by Lithiation Adjacent to Sulfur, Selenium or Phosphorus, or without an Adjacent Activating Heteroatom. 5: 177–216 Uemura M (2004) (Arene)Cr(Co)3 Complexes: Cyclization, Cycloaddition and Cross Coupling Reactions. 7: 129–156 Wagener KB see Tindall D, Pawlow JH (1998) 1: 183–198 Wakatsuki Y see Hou Z (1999) 2: 233–253 Watson DJ see Delmonte AJ (2004) 6: 97–122 Wipf P, Kendall C (2005) Hydrozirconation and Its Application. 8: 1–25 Wu GG, Huang M (2004) Organolithium in Asymmetric Process. 6: 1–36 Xi Z, Li Z (2005) Construction of Carbocycles via Zirconacycles and Titanacycles. 8: 27–56 Yamada K see Iguchi M (2003) 5: 37–60 Yamamoto A see Lin Y-S (1999) 3: 161–192 Yasuda H (1999) Organo Rare Earth Metal Catalysis for the Living Polymerizations of Polar and Nonpolar Monomers. 2: 255–283 Yasuda N see King AO (2004) 6: 205–246

Subject Index

Acetylide cluster 233 Acrylates 72, 200, 204 Acutiphycin 5 Acylsilane 4 Acylzirconocene, ketone addition, asymmetric 21 Adda 14 Addition, cis/trans 78 –, Markovnikov 79, 84–86 –, Michael 74 Aldehyde vinylation, silver(I)-catalyzed 10, 11 Alkene polymerization, Ziegler-Natta 142 Alkenes, carboalumination 164 –, Dzhemilev ethylmagnesation 151 Alkenylalanes, (E)-b-methyl-substituted 144 Alkenylzirconocene, aldehyde addition 10, 15 –, homologation 19 –, imine addition 17 Alkyl metal compounds, C-C bond cleavage 220 Alkylation 61, 63, 64, 71, 85 –, double 63, 64 –, Mizoroki-Heck 63, 64 –, regioselective 64 Alkylmagnesation 61 Alkylzirconocene, isomerization 2 Alkynes, alkylalumination 152 –, C-C bond cleavage 228, 231 –, Normant’s carbocupration 140 –, Zr-catalyzed carboalumination 141 Allyl-titanium 220 Allylzirconocene, aldehyde addition 20 Ansa-metallocenes 177 Arenes, C-C bond cleavage 225

B(C6F5)3 167 Benzamidinate 209 Benzene derivatives 47–49 Bimetallic complex 2, 7 Bipyridines 108, 109 Buchwald, S. 2 Butadienes 232 2-Butyne 219 C1/C2-symmetric complexes 185, 186, 201 Callystatin A 7 Carboalumination 139 Carbolithiation, Zr-catalyzed 162 Carbometallation, controlled single-stage 140 Carbon mononoxide 20 Carbonylation 101 Carbosilylation 63 Carbotitanation 143 Carbozincation, Zr-catalyzed 158, 159 Carbozirconation 19, 139 –, alkyllithiums 162 – mechanism, Al-assisted 151 Catalysts, chiral 98 –, single-site 179 Catalytic-site control 184 C-C double bond cleavage 229 C-C triple bond cleavage 233 C-H bond, activation 74, 75 Chain-end control 184, 194, 197, 211 Chain-transfer 181 Chirality 69, 108, 111 Claisen rearrangement 77 Compounds, natural 93, 105, 113 Conjugate addition 18 Corey-Fuchs olefination 12 Coupling, four-component 123 –, three component 118–123

242

Cp2ZrII derivatives 152 Cumulene 110 Cyclization 84, 86–90, 101, 105, 131 –, enantioselective 88 –, oxidative 132 –, reductive 99 Cycloaddition, higher order 113 Cyclobutadienes 38–39 Cyclobutenes 39, 71, 208, 232 Cycloisomerization 79, 80 Cyclooctatetraenes 52 Cyclopentadienyl ligand 217, 218 Cyclopentene 208 Cyclopentenones 40–42 Cyclopropane 17–20 Deuterium labeling 7 Dewar-Chatt-Duncanson model 140 Diastereoselectivity 63 1,4-Diaza-1,3-butadiene 204 Dichlorobis(1-neomenthylindenyl)zirconium 166 Diels-Alder reaction 111, 113 Diene complexes, h4 180 Dienes, C-C bond cleavage 225 1,3-Dienes, polymerization 205 Diiron polyyne 233 Dimerization 17 –, head-to-head/head-to-tail 72, 73 Dimethylcyclopentadienyl ligand 219 3,9-Dodecadiyne 219 Dyad 182 Dzhemilev ethylmagnesation 151 Electronegativity 2 b-Elimination 90 –, b-allyl 124 –, b-hydrogen 66, 67, 71, 73, 85, 89, 90, 94, 97, 116, 129 Enantioselective reactions 92, 98, 113 Enantioselectivity 88, 92, 98, 112 Enyne cyclization 231 Epimerization 188 Ethylmagnesation 60, 63, 70, 151 Ethylzincation 61 Friedel-Crafts reaction 142

Subject Index

Ganem, B. 9 Gap aperture 193, 201 Grignard reagent 2, 5, 60–63, 66, 84 Hafnacyclopentadiene 223 Halichlorine 9, 17 Hanzawa, Y. 19, 20 Heathcock, C. 6 Helicene 105 1,6-Heptadiene 206 Heterocumulenes 110 1,5-Hexadiene 206 Hydroalumination 157 b-Hydrogen elimination 181, 194, 208 Hydrometallation, hydrogen-transfer 140, 165 Hydrooligomerization 209 Hydrozirconation 157 HZrCp2Cl 157 IBAO 167 Isobutene 222 Isobutylaluminoxane 167 Lactonization, silver(I)-catalyzed 12 Lanthanocene catalysts 196 Lewis acid 74, 81, 111, 113, 118, 121, 123 Ligand, chiral 111 Lipshutz, B. 18 Lissoclinolide 12 Lithium aluminum hydride 3 Living polymerization 195 Maeta, H. 10 Maier, M. 11 Majoral, J.-P. 9 MAO 19, 167, 178 Me2Zr(NMI)2 167 Metal countercations 163 Metalla-Claisen rearrangement 99 Metallacycles 61, 73, 90, 217 Metallacyclic compounds, C-C bond cleavage 222 Metallacyclopropane 233 Metallocenes, ansa- 177 –, C-C bond cleavage 217 –, Cs-symmetric 191

Subject Index

(S)-2-Methyl-1-alkanols 167 2-Methyl-1-cyclobutenylalanes 143 Methylalumination 142 Methylaluminoxane (MAO) 19, 167, 178 Methylenecycloheptadienes 52 Methylenecycloheptane 207 Methylzirconocene 222 Microcystin 14 Misinsertion 188 Mizoroki-Heck reaction 64, 65 MMA 195 Montgomery, J. 14 Multi-component reactions 21 Multi-metallic systems 217, 230 Myxalamide A 6 Negishi, E. 12, 13, 18 Negishi coupling 7, 12 Negishi reagent 162 Nisamycin 16 Nitriles, C-C bond cleavage 229 Norbornadiene 225 Norbornene 208 1,7-Octadiene 206 Olefin polymerization, stereospecific, metallocene-catalyzed 177 Olefins, C-C bond cleavage 225 Oxovanadium complex 18 Oxygenation 67 Panek, J. 7, 14 Pauling electronegativity 2 Pentad 182, 183 Phenoxyimine 209 Phytol 169 Pitiamide A 169 PMMA 195 all-E-Polyenes 13, 16, 17 Polyolefins 177 –, hemiisotactic 191 –, isotactic/syndiotactic 182 Polystyrene 192 Porco Jr., J. 17 Propagation 181 Prostaglandins 16 Pyridazinone 10 2,6-Pyridine bis(imine) 209 Pyridine derivatives 50

243

Reaction, asymmetric 69 Rearrangement 71 –, Claisen 77 –, metalla-Claisen 99 Regioisomer 115 Regioselectivity 70, 74, 99, 109 Rychovsky, S. 17 Samarocene 187, 196, 206 Scandocene 227 Schwartz reagent 3, 4, 12 Schwartz, J. 2, 3, 17, 20 Selectivity 77, 106, 110, 129, 132 Silver perchlorate 10 – – on Celite 10 Silylacetylene 7, 16 Skipped insertion 190 Spiroquinolizidine 9 Stannylacetylene 6, 7 Stereoerrors 188, 190 Stereoselectivity 82 Steroids 227 Stille coupling 7, 12, 14 Suzuki, L. 19 Suzuki-Miyaura coupling 12 Swern oxidation 12 Taguchi, T. 19, 20 Taxol 11 Tebbe reagent 142, 156 Titanacyclopentadienes 32, 220 Titanacyclopentenes 33, 38, 41 Titanocene-bis(ethylene) 223 Transmetallation 60, 61, 66, 67, 70, 88 Triad 182 Trineopentylaluminum 221 Tritium labeling 9 Tunning, electronic 104 Vinyl halides 5, 6 Vinyl oxiranes 19, 20 Virgili, M. 17 Vitamin E 169 Wailes, P. 2, 3 Whitby, R. 18 Wipf, P. 10, 15–19 Wittig olefination 7

244

Yttrocene 187, 189 Ziegler-Natta catalysts 278 Zirconacycles, three-membered 163 Zirconacyclobutenes 31 Zirconacyclohexadienes 35 Zirconacyclopentadienes 32–35, 46–53

Subject Index

Zirconacyclopentanes 32–34 Zirconacyclopentenes 32–45, 51, 224 Zirconacyclopropanes/zirconacyclopropenes 30 Zirconocene(II)-alkene/ and -alkyne complexes 29 ZnEt2 201