Comprehensive Organic Functional Group Transformations, Volume 6 Elsevier, 2003 Editors-in-Chief: Alan R. Katritzky, Oth...
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Comprehensive Organic Functional Group Transformations, Volume 6 Elsevier, 2003 Editors-in-Chief: Alan R. Katritzky, Otho Meth-Cohn, and Charles W. Rees
Synthesis: Carbon with Three or Four Attached Heteroatoms Part I: Tetracoordinated Carbon with Three Attached Heteroatoms, RCXX′X″ 6.01 Trihalides, Pages 1-33, Richard D. Chambers and John Hutchinson 6.02 Functions Containing Halogens and Any Other Elements, Pages 35-66, Graham B. Jones and Jude E. Matthews 6.03 Functions Containing Three Chalcogens (and No Halogens), Pages 67-102, Glynn Mitchell 6.04 Functions Containing a Chalcogen and Any Other Heteroatoms Other Than a Halogen, Pages 103-136, Martin J. Rice 6.05 Functions Containing at Least One Group 15 Element (and No Halogen or Chalcogen), Pages 137-170, David P. J. Pearson 6.06 Functions Containing at Least One Metalloid (Si, Ge, or B) and No Halogen, Chalcogen or Group 15 Element; Also Functions Containing Three Metals, Pages 171-210, Vadim D. Romanenko, Michel Sanchez and Jean-Marc Sotiropoulos Part II: Tetracoordinated Carbon with Four Attached Heteroatoms, CXX′X″X‴ 6.07 Functions Containing Four Halogens or Three Halogens and One Other Heteroatom Substituent, Pages 211-247, Alex H. Gouliaev and Alexander Senning 6.08 Functions Containing Two Halogens and Two Other Heteroatom Substituents, Pages 249-270, Anastassios Varvoglis
by kmno4
6.09 Functions Containing One Halogen and Three Other Heteroatom Substituents, Pages 271-293, Angela Marinetti and Philippe Savignac 6.10 Functions Containing Four or Three Chalcogens (and No Halogens), Pages 295-318, Alex H. Gouliaev and Alexander Senning 6.11 Functions Containing Two or One Chalcogens (and No Halogens), Pages 319-358, Wolfgang Petz and Frank Weller 6.12 Functions Containing at Least One Group 15 Element (and No Halogen or Chalcogen), Pages 359-375, Duncan Carmichael, Angela Marinetti and Philippe Savignac 6.13 Functions Containing at Least One Metalloid (Si, Ge or B) and No Halogen, Chalcogen or Group 15 Element; Also Functions Containing Four Metals, Pages 377-406, Paul D. Lickiss Part III: Tricoordinated Carbon with Three Attached Heteroatoms, Y=CXX′ 6.14 Functions Containing a Carbonyl Group and at Least One Halogen, Pages 407-457, Geoffrey E. Gymer and Subramaniyan Narayanaswami 6.15 Functions Containing a Carbonyl Group and at Least One Chalcogen (but No Halogen), Pages 459-498, Heiner Eckert and Alfons Nestl 6.16 Functions Containing a Carbonyl Group and Two Heteroatoms Other Than a Halogen or Chalcogen, Pages 499-526, Anthony F. Hegarty and Leo J. Drennan 6.17 Functions Containing a Thiocarbonyl Group and at Least One Halogen; Also at Least One Chalcogen and No Halogen, Pages 527-567, Erich Kleinpeter and Kalevi Pihlaja 6.18 Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms Other Than a Halogen or Chalcogen, Pages 569-585, José Barluenga, Eduardo Rubio and Miguel Tomás 6.19 Functions Containing a Selenocarbonyl or Tellurocarbonyl Group—SeC(X)X′ and TeC(X)X′, Pages 587-599, Frank S. Guziec and Lynn J. Guziec 6.20 Functions Containing an Iminocarbonyl Group and at Least One Halogen; Also One Chalcogen and No Halogen, Pages 601-637, Thomas L. Gilchrist 6.21 Functions Containing an Iminocarbonyl Group and Any Elements Other Than a Halogen or Chalcogen, Pages 639-675, Ian A. Cliffe 6.22 Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B or a Metal, Pages 677-724, Vadim D. Romanenko, Michel Sanchez and Lydia Lamandé Part IV: Tricoordinated Stabilized Cations and Radicals, +CXYZ and ·CXYZ 6.23 Tricoordinated Stabilized Cations and Radicals, +CXYZ and ·CXYZ, Pages 725-734, Thomas L. Gilchrist 6.24 References to Volume 6, Pages 735-844
by kmno4
6.01 Trihalides RICHARD D. CHAMBERS University of Durham, UK and JOHN HUTCHINSON BNFL Fluorochemicals Ltd., Durham, UK 5[90[0 GENERAL METHODS
0
5[90[0[0 The Addition of Halo`ens and Interhalo`en Compounds to Fluoroalkenes 5[90[0[1 The Addition of Haloalkanes to Haloalkenes 5[90[0[1[0 Lewis acid!catalysed addition of trihalomethyl cations to haloalkenes*the Prins reaction 5[90[0[1[1 Additions initiated by free radicals\ heat or radiation 5[90[0[1[2 Additions catalysed by salts and complexes of transition metals 5[90[0[1[3 Additions induced electrochemically 5[90[0[2 The Preparation of C1 Chloro~uorohydrocarbons
1 3 3 3 5 6 6
5[90[1 TRIFLUOROMETHYL DERIVATIVES*RCF2 5[90[1[0 General 5[90[1[1 Aryl Derivatives 5[90[1[1[0 Conversion of `roups attached to an aromatic rin` into the tri~uoromethyl `roup 5[90[1[1[1 Substitution by tri~uoromethyl radicals 5[90[1[1[2 Substitution of hydro`en by the tri~uoromethyl `roup actin` as an electrophile 5[90[1[1[3 Substitution of halo`ens by the tri~uoromethyl `roup actin` as a nucleophile 5[90[1[1[4 Substitution of halo`ens by the tri~uoromethyl `roup usin` derivatives of metals 5[90[1[2 Derivatives of Alkanes\ Alkenes\ Alkynes and Other Saturated Compounds 5[90[1[2[0 Halo`en exchan`e 5[90[1[2[1 Conversions of other `roups to the tri~uoromethyl `roup 5[90[1[2[2 Transfer of tri~uoromethyl `roups as radicals 5[90[1[2[3 Reactions involvin` tri~uoromethyl derivatives of metals and metalloids
8 8 8 8 00 01 02 03 05 05 08 19 11
5[90[2 TRICHLOROMETHYL DERIVATIVES*RCCl2 5[90[2[0 Trichloromethyl Groups Attached to an Aliphatic Centre 5[90[2[0[0 Conversion of `roups attached to an aliphatic centre into the trichloromethyl `roup 5[90[2[0[1 Transfer of the trichloromethyl `roup to an aliphatic centre 5[90[2[1 Trichloromethyl Groups Attached to an Aromatic Rin` 5[90[2[1[0 Conversion of `roups attached to an aromatic rin` into the trichloromethyl `roup 5[90[2[1[1 Transfer of the trichloromethyl `roup to an aromatic rin`
12 12 12 12 16 17 18
5[90[3 TRIBROMOMETHYL DERIVATIVES*RBr2
20
5[90[4 MIXED SYSTEMS WITH FLUORINE*RCF1Hal
21
5[90[5 MIXED HALOFORMS*CHXY1 AND CHXYZ
21
5[90[0 GENERAL METHODS There are several general methods which can lead to trihalomethyl compounds where the halogen atoms can be the same or di}erent[ It will be seen that some of these methods lead to compounds 0
1
Trihalides
in which there are two such trihalomethyl groups[ For simplicity\ the general methods are discussed _rst[
5[90[0[0 The Addition of Halogens and Interhalogen Compounds to Fluoroalkenes The addition of halogens and interhalogen compounds to ~uoroalkenes a}ords a valuable method for the preparation of compounds containing the group 0CHal2 where the halogen atoms may be the same or di}erent[ The addition of halogens is conveniently carried out under ultraviolet irradiation "Equations "0# and "1## ð30JA2365\ 57JOC0905Ł\ but the addition of iodine to tetra~uoroethene occurs only at elevated temperatures "Equation "2## ð38JCS1837\ 38JOC636\ 42JCS0437\ 52USP2965930Ł[ Generally the yields of the adducts are high\ but when 0\0!di~uoroethene is treated with iodine a mixture of compounds is obtained\ the most abundant of which is CF2CH1I "Equation "3## ð47JOC211Ł[ F3C
Cl
F
Cl
F3C F Cl
Cl2, UV
Cl Cl Cl
OH
OH F
RF F F F
(1)
F
RF
Br2, UV
F Br
F F
i, ii or iii
F
F
I
I
F
F
(2)
F Br
(3)
F
i, I2, Et2O, 60 °C, 15 h; ii, I2, 150 °C, 24 h; iii, I2, KI, H2O, 100 °C, 5 h F
I2, 185 °C, 16 h
F
F
I
+ F
F
F
F
F
I
+
F
(4) F
F
F
I
+
The addition of the interhalogen compounds ICl and IBr to ~uoroalkenes also can be used to give compounds having the group 0CHal2[ With asymmetric alkenes\ the addition is regioselective\ but the precise composition of the product is in~uenced by the reaction conditions and the presence of catalysts[ The reactions shown in Equations "4#Ð"8# were carried out by several workers and thus under di}erent sets of conditions ð41JCS3312\ 43JCS812\ 50JCS2668\ 50JA1384\ 51JOC0371\ 53JOC141Ł^ the yields and\ where more than one isomer was obtained\ isomer ratios were correspondingly di}erent[ F
F
+ ICl F
Cl
F
F
+ ICl
F
Cl Cl
F
F
F
Cl
F
F
F F
F
F
Br Cl
I
+ IBr
I
Cl
+ IBr F
F
F
Cl
I
F
F
F
I
F
Cl
F
Cl
F
F
F
Cl
Cl
+
(5)
(6)
Cl
+
F
F
F Cl
Cl Cl Cl Cl
F
Cl
+
+ F
+ ICl
F
F
I
F F
F I
Br
I
(7)
I
(8)
I (9)
Br F
The elements bromine and ~uorine\ or iodine and ~uorine\ can be added to ~uoroalkenes by treating the alkene with a mixture of bromine tri~uoride and bromine\ or iodine penta~uoride and iodine "Equations "09#Ð"11##[ Here\ {IF| refers to a stoichiometric mixture of iodine penta~uoride
2
General Methods
and iodine "IF4 ¦1I1 04{IF|#\ and {BrF| to a stoichiometric mixture of bromine tri~uoride and bromine "BrF2 ¦Br1 02{BrF|#[ While the addition of {BrF| to ~uoroalkenes is vigorous and needs to be moderated\ the corresponding reactions of {IF| are carried out at elevated temperatures ð50JCS2668Ł\ and catalysts may be added ð50JA1272\ 73JAP4840114Ł[ The addition of {IF| to tetra! ~uoroethene is particularly important because the product\ penta~uoroiodoethane\ is a starting material in one of the commercial routes to ~uorochemical surfactants and surface treatments ðB! 68MI 590!90Ł[ Additions to hexa~uoropropene and 0\0!di~uoroethene give single isomers\ but additions to chlorotri~uoroethene and 0\0!dichlorodi~uoroethene yield mixtures of isomers whose composition is related to the reaction conditions[ The reaction of {IF| to tetrachloroethene results in ~uorination only "Equation "07##[ For the addition of {IF| to internal alkenes with the formula CF2"CF1#nCF1C"CF2#1\ special procedures are necessary "Equation "11##[ Either potassium ~uoride must be added to the {IF| mixture\ or the alkene may _rst be treated with AgF or AgF:KF in a polar aprotic solvent to make the silver salt\ which in turn is treated with iodine to give the desired product ð76JFC"26#112Ł[ These products are tertiary per~uoroiodoalkanes and are highly toxic\ so special care must be taken during their preparation[ F
F
+ 'IF' F
F
F 3C
+ 'IF'
F
F F
F
+ 'IF' F
Cl
F
Cl
F
F
Cl
F
Cl
Cl
F
Cl
F
F
F Cl
F
Cl
F
I
F
F
F
I
F
I
(14)
(15)
(16)
(17)
+ 'IF'
Cl Cl F
+ 'BrF'
F
Cl Cl
F
F F F
+ 'BrF' F
(13)
F
Cl
F3C
Cl F Cl
(12)
F
F
F
F
F Cl
F
F
Cl
F
F
F
+ 'IF'
F
I
Cl
+ 'IF'
(11)
F I
F
F I Cl
+ 'IF'
F F
+
F F
(10)
F
+
+ 'IF'
F
Cl
I
I F
F
F
I
F
Cl
F
F
F
+ 'IF'
F
F3C I F
F
F
F F
F
Cl Cl F
F
F
F
F Br
F3C F Br
(18)
(19)
F F F
(20)
3
Trihalides F
F
+ 'BrF' F
F
F
F
F Cl
Br
Cl
+ 'IF' CF3
F
F
F
F
Br Cl
F
CF3(CF2)n F F
CF3
CF3(CF2)n
+
CF3 CF3 I
(21)
(22)
5[90[0[1 The Addition of Haloalkanes to Haloalkenes The addition of haloalkanes to haloalkenes can be used to generate alkanes which bear a tri! halomethyl group "Equation "12##[ If the alkene is perhalogenated\ then it can be seen that the adduct will have two trihalomethyl groups[ These addition reactions can be initiated in four main ways\ that is\ by Lewis acids\ by free radical initiators\ by salts and complexes of certain transition metals\ and electrochemically[ RX
+
R
X
(23)
5[90[0[1[0 Lewis acid!catalysed addition of trihalomethyl cations to haloalkenes*the Prins reaction The aluminum chloride!catalysed addition of chloroalkanes to chloroalkenes has been known since the beginning of this century\ and is known as the Prins reaction ð03JPR304\ 24RTC138\ 24RTC296Ł[ More recently\ the reaction has been extended to include the addition of chloro~uoromethanes to ~uoroalkenes and chloro~uoroalkenes[ While most of the activity in this area occurred up to the early 0869s\ and was reviewed by Paleta ð66FCR28Ł and by Paleta and Posta ð61CLY826Ł\ interest has been renewed recently because the adducts may be intermediates in the manufacture of potential replacements for the higher!boiling chloro~uorocarbons "e[g[\ ð80MIP590!90\ 80EUP310211\ 81EUP362094\ 81JAP93053928Ł#[ Most commonly\ the halomethanes used in these reactions are CCl3\ CHCl2\ CFCl2 and CFHCl1\ and these have been added to the alkenes CF11CF1\ CF11CFCl\ CF11CCl1\ CFCl1CCl1\ CCl11CFCl\ C1Cl3\ CHCl1CHCl\ CF11CFH\ CF11CH1 and CF11CHCl "see Table 0#[ The addition of halomethanes to asymmetric perhalogenated ~uoroalkenes proceeds nonregiospeci_cally\ but corresponding additions to the hydrogen!containing alkenes CFCl1CFH\ CF11CFH\ CF11CH1 and CF11CHCl are highly regioselective\ with the electrophilic haloalkyl group becoming attached to the carbon which bears the hydrogen[ This suggests that the preferred isomer is that in which most of the ~uorine atoms on the precursor alkene are attached to the carbon where positive charge develops in the initial stages of the reaction[ In reactions with ~uorotrichloromethane\ both C0F and C0Cl bonds are cleaved\ although cleavage of the C0F bond is preferred due to the greater Al0F bond strength[ In its reaction with the alkenes CFCl1CHF and CF11CHCl the C0F bond is cleaved exclusively[ Some examples of these reactions are given in Table 0\ where it can be seen how the approach can be used to give a variety of propanes with various trihalomethyl groups attached to carbon atoms[ It is probable that the primary products in each of these reactions undergo rearrangement or further reaction\ and therefore the composition and nature of the observed products are dependent upon reaction conditions[
5[90[0[1[1 Additions initiated by free radicals\ heat or radiation When subjected to heat\ light\ or free radical initiators such as peroxides or azo compounds\ haloalkanes add to alkenes and haloalkenes "Scheme 0#[ Whether a simple adduct or a mixture of high molecular!weight telomers is obtained is determined by the relative rates of the propagation\ transfer and termination reactions[ Thus\ compounds with the weakest C0X bond\ that is\ iodides\ give lower molecular!weight products\ as do alkenes which are di.cult to polymerize under the conditions of the reaction[ But if the alkene is easily polymerized\ for example tetra~uoroethene\ or if the telogen is not particularly reactive\ high molecular!weight
4
General Methods Table 0 Lewis acid!catalysed addition of haloalkanes to haloalkenes[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * Yield Composition Reactants Conditions ")# Products ")# Ref[ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * CF1CF1 ½14>C:2 h 69 CF2CF1CCl2\ CF1ClCF1CFCl1 72\ 06 60CCC0756 CFCl2 CHFCl1 CF1CF1 04>C:2[4 h 47 CF2CF1CHCl1\ CF1ClCF1CHFCl 48\ 30 60CCC0756 CF1CCl1 11>C:06 h 31 CF2CCl1CCl2\ CFCl1CF1CCl2\ 34\ 37\ 6 55CCC2473 CFCl2 CF1ClCCl1CFCl1 CHFCl1 CF1CCl1 6>C:01 h 67 CFCl1CF1CHCl1\ 70\ 08 56CCC2777 CF2CCl1CHCl1\ CCl2CF1CHFCl\ CF1ClCCl1CHFCl\ CF1ClCFClCHCl1 CFCl2 CF1CHF 9Ð03>C:6 h 54 CF2CHFCCl2\ CF1ClCHFCFCl1 69\ 29 63CCC0229 CHFCl1 CF1CHF 9>C:6 h 72 CF2CHFCHCl1\ 47\ 31 63CCC0229 CF1ClCHFCHFCl ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ *
Initiation R • + X•
RX
2 In•
or In2 In• + RX
R• + InX •
Propagation R• +
n
R n
Transfer •
+ RX
R
R
n
X
+ R•
n
Termination •
•
+
R
R
R
n
n
X• + X• •
X2
+ X•
R
R 2n
R
n
X n
Scheme 1
material is obtained[ With easily polymerized alkenes\ the telomerization can be controlled by using a large excess of the telogen "preferably an iodide or diiodide# and recycling the lower telomers[ This addition of a haloalkane is often regioselective\ and it is observed that the incoming radical generally attacks the least sterically hindered carbon[ However\ there is still debate on the factors which control the products of these reactions and the relative stability of the potential intermediate radicals\ and polar e}ects "note that trihalomethyl radicals are electrophilic# as well as steric e}ects all play their part[ This approach is used in the manufacture of C7 or C8 per~uoroalkyl iodides\ which are inter! mediates in the preparation of per~uorocarbon surfactants and surface treatments ðB!68MI 590!90Ł[ Illustrative examples of these addition reactions are given in Equations "13#Ð"24# "NB[ Higher telomers are also produced in these reactions# ð36JA0099\ 89JFC"36#150\ 49JA1102\ 42JOC217\ 42JCS811\ 42JCS2650\ 41JCS2389\ 53JOC0087\ 47JA740\ 76IZV797\ 44JA657\ 74T3492Ł "references refer to the respective Equations "13#Ð"24##\ but many more are recorded elsewhere ð52OR"02#80\ B!63MI 590!90\ B!65MI 590! 90Ł[ It is noteworthy that\ unlike other polyhaloalkanes\ trichloromethane adds to alkenes by hydrogen transfer "Equation "15##[
5
Trihalides R
+
CCl4
Cl
Cl
R (24)
Cl F
F
n-C6H13
+
Cl
F
F
F
Cl
Cl
Ph
+
(26) n-C6H13
Cl
Cl
Br (27)
Cl
+
CCl3I
F
F
F
Cl
F
Cl
F
F
Cl
I F
F
F
F
CN
F
F
F
I (30)
F
CF2Br2
OEt
+
F
CN Br
Br (31)
F
F CF2Br2
+
F
OEt
F
Br
F
Br F
F F
F
F CBr4
F
F
(29)
F F
+
F
Br F
F
F
Br
Br
F
F
Br
F F
+ F
CCl3Br
+
EtO2C
Cl
Br
F
(32)
F
(33)
F
F
CF2BrCl
(28)
F
I
F
F
+
CF3I
Ph
F
+
CF3I
(25)
RF
Cl
CCl3Br
Cl
Cl
RF
F
CCl3H
Cl
+
CCl4
Cl
F
(34)
F
EtO2C
CO2Et
Br
Cl Cl
CO2Et Cl
(35)
5[90[0[1[2 Additions catalysed by salts and complexes of transition metals In 0845 ð45CI"M#260Ł\ unexpected results were obtained when the thermal additions of CCl3 and CCl2H to acrylonitrile were carried out using a steel autoclave[ More of the 0 ] 0 adduct was obtained than expected\ and trichloromethane gave the adduct CHCl1CH1CHClCN rather than
6
General Methods
CCl2CH1CH1CN\ which is normally obtained in free radical additions to alkenes "vide supra#[ Later ð52JCS0776Ł\ it was established that copper"II# and iron"III# both catalysed the addition of tetrachloromethane to a variety of vinylic monomers\ and that 0 ] 0 adducts were frequently the sole products\ even with easily polymerized alkenes[ This discovery led to extensive work in the area\ and copper"II# has now been used to catalyse the addition of CCl3\ CCl2Br\ CCl1Br1\ CF2CCl2 and other chloro compounds to a large variety of alkenes and dienes[ It is worth noting that the addition of CF2CCl2 followed by hydrogenation of the adduct can be used to introduce a CF2CH1 group[ While most investigations in this area have used copper! and iron!based catalysts\ other metal salts such as samarium diiodide ð89JCS"P0#1920Ł and vanadium dichloride ð89SL106Ł have been used more recently[ As well as alkenes which contain only hydrogen\ halogenated alkenes and those which contain other groups have also been used[ Generally the 0 ] 0 adduct is the only product\ but higher telomers are produced when the alkene is halogenated[ However\ this method of initation always gives lower molecular!weight material than the corresponding peroxide initiated reaction[ Amines are often added to form complexes and {increase the solubility| of the copper\ and consequently to increase the reaction rate[ The following is not a comprehensive list of references but will serve to lead the reader into the area] ðB!63MI 590!90\ 64ACR054\ 65T1184\ 66TL3204\ 79CCC2377\ 79CCC2491\ 74PAC0716\ 76JPS"A#2914\ 78JFC"34#104\ 89JFC"36#84\ 80MI 590!90\ 81CCC0180\ 81JMOC40\ 82JFC"50#022Ł[ As well as metal oxides\ salts and their complexes with amines\ other transition metal complexes such as carbonyls of iron ð56JCS"C#0049\ 79JOC2846Ł and cobalt ð69JOC1871Ł\ carbonyl complexes of molybdenum ð71JCS"D#1170\ 89JOM"286#40Ł\ iron ð89JOM"275#118Ł and chromium ð73JOM"159#C64Ł\ and phosphine complexes of ruthenium ð62TL4036\ 64TL788\ 67JOC0623\ 74JOM"179#286\ 76JCS"P0#0404\ 81JOM40Ł\ rhodium ð70AG"E#364Ł\ rhenium ð76JCS"P0#0404Ł and palladium ð70CL0058\ 74T282Ł have all been found to be e.cient catalysts in this reaction[ When the chiral Ru2Cl3"diop#2 "diop\ 1\2!O! isopropylidene!1\2!dihydroxy!0\3!bis"diphenylphosphino#butane# was the catalyst\ chiral adducts were obtained ð76BCJ2576Ł[ Clearly the metal!catalysed additions of haloalkanes to haloalkenes proceed by a di}erent mechanism to those promoted by free radical initiators such as peroxides[ Any mechanism needs to be able to explain the {abnormal| addition of trichloromethane\ the suppression of the propagation step "0 ] 0 adducts are the main products#\ and the fact that the addition of tetrachloromethane to cyclohexene is highly stereoselective "with a ruthenium catalyst# compared with the situation which obtains when conventional radical initiators are used[ It is unlikely that the details of the mechanism will be the same for all the catalysts that have been identi_ed\ but it is generally believed that it is not a simple redox process but one in which "e[g[\ for CCl3# a trichloromethyl radical is formed on and bound to the catalyst prior to the addition to the alkene which is itself coordinated to the complex[
5[90[0[1[3 Additions induced electrochemically The free radical chain addition of various polyhalomethanes to alkenes has been initiated by electrochemically in situ generated manganese salts used in a catalytic amount associated with an equimolecular amount of a manganese"III# oxidizable compound such as methyl cyano! or acetoacetate[ In particular\ tetrabromomethane\ bromotrichloromethane\ dibromodi~uoromethane and n!heptadeca~uorooctyl iodide have been added to a variety of alkenes in high yield by this means "Equation "25## ð81TL102Ł[ X X R
+ CX3Y
Mn(II)
Y
X
(36)
anodic oxidation
R CX3 = CBr3, Y = Br; CX3 = CCl3, Y = Br; CX3 = CBrF2, Y = Br; CX3 = C7F15, Y = I
5[90[0[2 The Preparation of C1 Chloro~uorohydrocarbons The manufacture of saturated compounds having the general formula C1HxClyFz represents an important part of the ~uorochemical industry[ These compounds "x O# "chloro~uorocarbons* {CFC|s# have been used as refrigerants\ solvents and foam!blowing agents[ However\ because they
7
Trihalides
have been implicated in the destruction of ozone in the earth|s upper atmosphere\ they are being replaced\ under the terms of the Montreal Protocol\ by hydro~uorocarbons "y O# "{HFC|s# and\ for an interim period\ by hydrochloro~uorocarbons "{HCFC|s#[ The manufacture of these compounds is largely brought about by treating a chlorocarbon with hydrogen ~uoride and sometimes chlorine[ Other reactions in the process may include isomerization and hydrogenation[ The ~uorinations are carried out in either the liquid phase using an antimony"V# catalyst "Swarts| catalyst# or in the gas phase using a chromia!based catalyst[ The main routes to the C1 chloro~uorocarbons and those compounds which are replacing them are outlined in Scheme 1[ 0\0\0\1!Tetra~uoroethane "R023a# is to be the main {high!temperature| refrigerant "e[g[\ mobile air conditioning\ and domestic and industrial refrigeration# while 0\0\0!tri~uoroethane "R032a# and 0\0\0\1\1!penta~uoroethane "R014# will be used in compositions for {low!temperature| refrigeration and static air conditioning "e[g[\ ð82MI 590!90Ł#[ As well as having the uses outlined above\ some of these compounds are intermediates in the manufacture of products such as the anaesthetic halothane "CF2CHClBr#\ and monomers such as 0\0!di~uoroethene and chlorotri~uoroethene[
Cl
Cl
F
Cl
Cl
F
F F
F
F R134a
F R133a
F
Cl
F F Br Halothane Cl
Cl
Cl F Cl
F Cl
Cl
F
Cl
F
Cl
F
F
F
F
Cl R115
R114
Cl Cl F Cl R113a F
F
F F
F F
Cl
R113
F
F
F Cl
Cl R123
F F F
F
F F R125
Cl F Cl
R114a
F
F
F F
F
F
F R134a Cl Cl
F
F
R143a F Cl Cl
+
R141b Scheme 2
F F Cl R142b
F
+
F F R143a
8
Tri~uoromethyl 5[90[1 TRIFLUOROMETHYL DERIVATIVES*RCF2 5[90[1[0 General
There is a very considerable literature relating to the synthesis of organic compounds containing the tri~uoromethyl group\ and this stems principally from the importance of such compounds in the plant protection industry ð80MI 590!91Ł and\ to a lesser extent\ the pharmaceutical industry ðB! 80MI 590!92\ B!71MI 590!90Ł[ Amongst other e}ects\ the introduction of the tri~uoromethyl group increases the lipophilicity of bioactive molecules\ enhancing transport across cell walls\ and can reduce metabolism of a drug[ A major review ð81T5444Ł is focused on the synthesis of tri~uoromethyl derivatives\ and others ð80T2196\ 81T078\ 83TA826Ł include discussions of relevant methodology[ In considering this area\ it is appropriate to draw attention to the fact that processes which involve halogen exchange for ~uorine\ using anhydrous hydrogen ~uoride "AHF# as the source of ~uorine\ will be the most economically favourable for large!scale manufacture by industry\ which is remark! ably adept at handling AHF[ Such procedures are not\ however\ particularly easy on the laboratory scale\ and other approaches described here will frequently be preferred[ Furthermore\ the sensitivity of the molecule under consideration may well dictate the route that is most appropriate[ The considerations described above relate to compounds containing the tri~uoromethyl group as the only halocarbon unit\ but\ of course\ there is a very wide range of applications for more highly ~uorinated systems\ including their use as refrigerants and for other volatile inert ~uid applications\ membranes\ polymers and anaesthetics[
5[90[1[1 Aryl Derivatives 5[90[1[1[0 Conversion of groups attached to an aromatic ring into the tri~uoromethyl group Only the most reactive of organic halides will react with anhydrous hydrogen ~uoride without catalysis "see Section 5[90[0[2#\ but benzotrichloride is converted to the tri~uoride "Equation "26## ð41MI 590!90Ł\ and analogous systems\ including heterocyclic compounds\ may be obtained in this way "Equation "27## ð70AHC"17#0Ł[ More sophisticated techniques have been used in processes to chloro~uorinate side chains in a continuous process "Equation "28## ð79GEP2997970Ł[ Alternatively\ antimony tri~uoride may be used in classical ~uorination processes "Equation "39# ðB!65MI 590!91Ł\ where the product is obtained by simply distilling from the ~uorinating agent\ but the trichloroethyl moiety is much less e.cient for conversion to the tri~uoroethyl group "Equation "30## ð77JOC2526Ł[ A clever {one!pot| methodology is available for acid!induced trichloromethylation accompanied by exchange of chlorine for ~uorine "Equation "31## ð70JFC"07#170Ł[ CCl3
CF3 AHF
(37) 40 °C, autoclave 70%
CF3
CCl3 HF
(38) N
CCl3
204 °C 45%
Cl2, HF
N
300–600 °C 33%
N
CF3
N
Cl
F3C (39)
CF3
CCl3 SbF3 125 °C 58–66%
(40)
09
Trihalides F
Cl
Cl
CF3
CCl3
Cl
Cl
SbF3
+
Cl
+
(41)
SbCl5
NO2
NO2
NO2 48%
NO2
10%
33%
HF, CCl4
(42)
CF3 α:β=2:3
One of the most versatile methods available for introducing the tri~uoromethyl group involves reactions of benzoic acid derivatives and corresponding heterocyclic compounds with sulfur tetra~uoride "Equations "32#\ "33# and "34## ð74OR"23#208\ 70AHC"17#0\ 76JOM"214#02\ 82JFC"59#122Ł\ or the more convenient but less reactive diethylaminosulfur tri~uoride "DAST# ð64USP2803154\ 65USP2865580Ł and related systems "Equation "35## ð77OR"24#402Ł[ CF3
CO2H SF4, 150 °C
(43)
6h
HO2C
F3C
CO2H
CF3
33% conversion
HO2C
CO2H
HO2C
CO2H
SF4, 150–200°C 16 h
F F3C
CF3
F3C
CF3
F3C
+
O F3C F
66–76%
F
F
F
+
F
F
CO2H
F O
O F
8–12%
F 0.8–1.7%
(44)
F
CF3 SF4, HF 80–140 °C autoclave 55–92%
X
F
(45) X
X = OMe, Me, H, Cl, NO2 CO2H
CF3 Et2NSF3
(46)
NaF 50%
Thio derivatives "e[g[\ ortho!thioesters# may also be used for conversion to the tri~uoro! methyl moiety\ using NBS\ or its equivalent\ followed by pyridineÐhydrogen ~uoride "Equation "36## ð75TL3750Ł[ Dithiocarboxylate esters are converted in a similar process "Equation "37## ð81CL716Ł\ and dithiocarboxylate derivatives are also converted in an interesting process that involves xenon di~uoride "Equation "38## ð89TL2246Ł[ A very unusual conversion of a nitrile to the tri~uoromethyl derivative occurs\ using carbonyl ~uoride\ accompanied by other products "Equation "49## ð67IJ018Ł[
00
Tri~uoromethyl C(SMe)3
CF3 i, DBH
(47) ii, HF–pyridine 34%
NO2
NO2
DBH = 1,3-dibromo-5,5-dimethylhydantoin CS2Me
CF3 DBH, Bu4N+H2F3–
(48)
CF3
i, Mg, Et2O ii, CS2
(49)
Ar-X iii, XeF2 40–77%
X Ar = Ph, p-MeC6H4, m-CF3C6H4, α-naphthyl X = halogen (e.g., Br)
HF, NaF
+
(50)
COF2 4 d, 50 °C 20%
CN
CF3
5[90[1[1[1 Substitution by tri~uoromethyl radicals Primary sources of tri~uoromethyl radicals include tri~uoroethanoic acid and tri~uoro! methanesulfonic acid\ but iodo! or bromotri~uoromethanes are important sources that have been used extensively[ Various methods have been applied to generate tri~uoromethyl radicals from these sources ð81T5474\ 80TL6414Ł\ and these radicals are\ of course\ electrophilic in character[ Conse! quently\ a wide range of radical aromatic substitutions occur\ and these probably proceed more e}ectively with the more electron!rich aromatic compounds\ but\ in general\ they are not high! yielding processes "Equations "40#Ð"47## ð70JFC"06#234\ 76CC0690Ł[ hν
+
CF3I
O
N
NH
+
hν
CF3I
F3C
NH
N
(51)
CF3
O
DMF 24%
+ N
CF3 32%
Br
NH
(52)
47%
Br
+
(53)
CF3I CF3 61%, o : m : p = 40 : 30 : 22
NH2
NH2
+
CF3Br
Zn, SO2
(54) CF3
56%, o : p = 1.8 : 1
01
Trihalides OH
OH ButOOH
+
(55)
CF3SO2Na Cu(II)
CF3
45%, o : m : p = 4 : 1 : 6 70 °C
+
C6H6
(56)
C6H5CF3
(CF3CO)2O 54%
[CF3(CO)O]2
X
X = O (53%), NH (65%)
O
O CF3CO2H
HN
CF3
HN
electrolysis 60%
N H
O
(57)
CF3
X
(58) N H
O
Bis"tri~uoroacetyl# peroxide decomposes thermally and can be used to tri~uoromethylate elec! tron!rich aromatic compounds "Equations "48# and "59## ð89JFC"35#312Ł[ An atmosphere of ammonia has been used to promote the reaction of iodotri~uoromethane with pyridine "Equation "50## ð68JAP68172Ł[ Remarkably\ some cross!coupling between hexa~uorobenzene and bromotri~uoro! methane occurs over copper chromite "Equation "51## ð82JFC"50#0Ł\ and\ in other high!temperature chemistry\ polytetra~uoroethylene is used as a source of di~uorocarbene\ which\ under the con! ditions used\ is able to insert into carbonÐ~uorine bonds "Equation "52## ð58IZV085\ 63JCS"P0#097Ł[ 60 °C
+
[CF3(CO)O]2
S
70 °C
[CF3(CO)O]2
+
(59)
CF3
S
72%
(60)
CF3
71%
+
NH3
CF3I
(61)
CF3
180 °C, 24 h 60%
N
N α : β : γ = 46 : 40 : 13
copper chromite
+
C6F6
(62)
C6F5CF3
CF3Br 600 °C, flow 40%
F N
+
(–CF2–)n
CF3
550 °C
N 6%
CF3
F3C
+
F
F
(63)
N 60%
5[90[1[1[2 Substitution of hydrogen by the tri~uoromethyl group acting as an electrophile Nucleophilic attack at a saturated carbon contained in a highly halogenated system is\ in general\ very di.cult\ but Umemoto and co!workers have demonstrated that with superior leaving groups it is possible to e}ect what is\ formally\ nucleophilic attack on the tri~uoromethyl group "Equation "53##[ Very powerful per~uoroalkylating agents are available through so!called {FITS| reagents ""per~uoroalkyl#phenyliodonium iodides# ð73TL70\ 75JFC"20#26Ł[ So far\ the corresponding reagents
02
Tri~uoromethyl
are not available for the introduction of the tri~uoromethyl group\ although this may be a practical di.culty\ rather than a fundamental di}erence in reactivity between tri~uoromethyl and other per~uoroalkyl systems[ However\ a less powerful but e}ective series of salts of tellurium\ selenium and sulfur heterocycles has been developed which will transfer the tri~uoromethyl moiety ð82JA1045Ł\ and it is concluded that the process involves nucleophilic attack on the tri~uoromethyl group[ The overall process is illustrated in Scheme 2\ where the reactivity of the salts "0# varies in the series X Te³Se³S\ while electron!withdrawing substituents in the aromatic ring also increase reac! tivity "1#[ Examples of tri~uoromethyl transfer from the salts "0# are shown "Equations "54#Ð"56##[ The tri~uoromethylation of hydroquinone "Equation "55## e}ectively rules out a free radical process because hydroquinone is known to be an e.cient radical scavenger[ [Ar
H]
+
F3C
[ArHCF3]+ + L–
L
+
ArCF3 + H+ + L–
(64)
F2, CF3SO2OH
CF3I
0 °C
X–
XCF3 O2N
CF3SO2ONO2
NO2
+
+
X CF3 (1)
X
CF3SO2–
CF3 (2)
X = S, Se, Te Scheme 3
CF3
CF3
OH
+
i
(2) (X = S)
OH
OH (65)
+
52% i, DMF (+ 4-dimethylaminopyridine)
6%
OH
OH
+
(2) (X = S)
OH CF3
i
+
(CF3)2
OH 61%
OH
(66)
OH 11%
i, DMF (+ pyridine)
NH2
NH2
+ Reactant (1) (X = S) (2) (X = S)
(1) or (2) Conditions 80 °C, 1 h RT, 0.5 h
CF3
(67)
Products o-CF3 (31%) + p-CF3 (15%) o-CF3 (54%) + p-CF3 (20%)
5[90[1[1[3 Substitution of halogens by the tri~uoromethyl group acting as a nucleophile Tri~uoromethyllithium and !magnesium derivatives are unstable and\ therefore\ a methodology for the transfer of a tri~uoromethyl anion to electrophilic centres via silanes has been developed "Equation "57## ðB!81MI 590!90Ł[ A convenient synthesis of trimethyltri~uoromethylsilane has been
03
Trihalides
reported "Equation "58## ð79ZOB0786\ 73TL1084\ 82RHA121\ 81MI 590!91Ł\ and a process using tetra! kis"dimethylamino#ethene has also been described "Equation "69## ð78JFC"31#318Ł[ The key step involves displacement of the tri~uoromethyl group from silicon\ using tetrabutylammonium ~uoride "which inevitably contains amine#[ Understandably\ reaction only occurs with the more activated aromatic systems "Equations "60# and "61## ðB!81MI 590!92Ł[ CF3–
+
Ar
[ArLCF3]–
L
ArCF3 + L– PhCN
TMS-Cl + CF3Br + (Et3N)3P Me2N
NMe2
TMS-CF3
(69)
PhCN
+ TMS-Cl Me2N
(68)
TMS-CF3
(70)
or CH2Cl2
NMe2
NO2 F
+ TMS-CF3
tbaf, 0 °C, 0.5 h, RT
(71)
C6F5NO2 + CF3C6F4NO2 90%
10%
F NO2
+ TMS-CF3
tbaf, 0 °C, THF
mixture of trifluoromethylated products
(72)
NO2
5[90[1[1[4 Substitution of halogens by the tri~uoromethyl group using derivatives of metals As indicated above\ lithium and magnesium derivatives are unstable and\ therefore\ are not viable reagents for the introduction of the tri~uoromethyl group[ Metals that form weaker bonds to ~uorine generally give more stable tri~uoromethyl derivatives\ and consequently copper\ cadmium and zinc compounds are particularly useful in synthesis ð81T078\ 81T5444Ł[ Therefore\ access to tri~uoromethyl derivatives of these metals is of some importance[ Easily accessible sources for the e}ective use of the tri~uoromethyl moiety include CF2CO1H\ CF2SO1OH\ CF2I "usually made from tri~uoroacetic acid by Hunsdiecker processes#\ CF2Br and CF1Br1[ Tri~uoromethylation of aryl halides occurs using CF2I or CF2Br in the presence of copper powder in aprotic solvents at elevated temperatures "Equation "62## ð79JCS"P0#1644Ł\ but direct reaction of sodium tri~uoroacetate with CuI in N!methyl!1!pyrrolidone "NMP# is also possible ð70CL0608Ł\ and it has been concluded that the reaction proceeds via an intermediate like ðCF2CuIŁ=− rather than ðCF2CuIŁ = "Equations "63#Ð"65## ð77JCS"P0#810Ł[ Tri~uoromethanesulfonyl chloride can be used in an analogous way "Equation "66## ð78JFC"34#75Ł[ NH2
NH2 N
N
HMPA
N
N AcO
N
N
I
+
CF3Cu 46%
O
CF3 N
N AcO
AcO OAc
(73)
O
AcO OAc HMPA = hexamethylphosphoramide I
CF3 CF3CO2Na, Cu, NMP
(74) 160 °C, 4 h 98%
Cl
Cl
04
Tri~uoromethyl CF3
CF3
Br CF3CO2Na, Cu, NMP
+
(75)
160 °C, 4 h
Br
F3C
Br
CF3
CF3
48%
I
F3C
CF3CO2Na, Cu, NMP
N
41%
(76)
160 °C, 4 h 85%
Cl
N
Cl
Cl
CF3 NO2
NO2
Cu, DMF
+
(77)
CF3SO2Cl 100 °C 73%
NO2
NO2
A fascinating route to tri~uoromethylcadmium and !zinc has been developed by Burton and co! workers ð74JA4903Ł in which reaction of dihalodi~uoromethanes with cadmium or zinc powders in DMF gives stable solutions of the corresponding tri~uoromethyl derivatives "Scheme 3#\ which then react further[ Copper reacts in an analogous way but a mixture of homologues is obtained unless ~uoride ion is added\ or other procedures used to prevent the di~uorocarbene generated reacting further with CF2MX "Scheme 3#[ Cadmium derivatives can also be converted to copper reagents ð75JA721Ł\ and these can be stabilized against formation of higher homologues by adding HMPA ð78JA7491Ł "Equations "67# and "68##[ Tri~uoromethylation in dimethylacetamide "DMA# is also e.cient "Equation "79## ð77CC527Ł[ Transfer of the tri~uoromethyl group to amines\ using dibromo! di~uoromethane\ has also been reported ð80JFC"41#118Ł "Equation "70##[ Methyl ~uoro! sulfonyldi~uoroacetate in the presence of copper"I# iodide functions in a similar way ð78JCS"P0#1274Ł\ and the corresponding iodide has also been used "Equations "71# and "72##[ The source of the starting materials in the latter cases is tetra~uoroethene\ via formation and ring opening of a b! sulfone "Scheme 4# ð59JA5070Ł^ this is an attractively direct but\ unfortunately\ potentially hazardous process for laboratory application[
DMF, RT
CF2XY + M
[CF3MX + (CF3)2M] 80–95%
X = Br, Cl; Y = Br, Cl; M = Cd, Zn, Cu
MXY + [CF2]
F
DMF
Me2N
+
+ CO
Me2N
F
F– + [CF2]
CF3–
CF3– + MXY
CF3MX + (CF3)2M
CF3CuX + [CF2]
CF3CF2CuX
[CF2]
CuY
[CF3CdX + (CF3)2Cd]
[CF3Cu] –40 °C
90–100%
Y = I, Br, Cl, CN Scheme 4
etc.
F
F–
05
Trihalides I
CF3 DMF
NO2
+
NO2
CF3Cu
(78)
HMPA 70 °C, 4–6 h 75%
I
F3 C
I
+
CF3Cu
CF3
DMF
I
I
S
(79)
HMPA 70 °C
F3C
Cl
S
CF3
CF3 NO2
NO2
Cu, DMA
+
(80)
CF2Br2 100 °C, 4 h 93%
NO2
CF2Br2
NO2 Me2N
NMe2
Me2N
NMe2
+
+ R2NH
R2NCF3
I
CF3 CuI, DMF
+
FO2SCF2CO2Me
(81)
(82)
60–80 °C, 3 h 80%
NO2
NO2
ICF2SO2F +
Ph
F
Cu, DMF
Br
Ph
80 °C 83%
F
F
< 80 °C
+ F
SO3
F
~3 atm 93%
F F
F
(83)
F
F F
F–
FCOCF2SO2F
O SO2 Scheme 5
5[90[1[2 Derivatives of Alkanes\ Alkenes\ Alkynes and Other Saturated Compounds 5[90[1[2[0 Halogen exchange These reactions ð52AFC"2#070\ B!78MI 590!90\ 30JA2367\ 36JA0719Ł involve\ essentially\ the nucleophilic displacement of other halogens by ~uorine using a metal ~uoride ðB!62MI 590!90\ B!65MI 590!92Ł\ frequently in combination with hydrogen ~uoride[ An important part of the function of the metal ~uoride is to act as a Lewis acid\ to assist the removal of the halogen as a halide ion[ Some of the reactions could involve carbocations "Scheme 5#[ As the number of ~uorine atoms attached to the chlorine!bearing carbon increases\ it becomes progressively more di.cult to e}ect further ~uorination "Equation "73# and "Scheme 6##[ Never! theless\ the inhalation anaesthetic CF2CHBrCl may be obtained by an exchange process "Scheme 7# ð46BRP656668Ł[ For a carbocation!type process\ it is understandable that the introduction of unsaturated sites makes such exchange reactions much easier "Equations "74# ð30JA2367Ł and "75# ð36JA0719Ł#[ Fluorination of hexachlorobutadiene provides an accessible route to hexa~uoro!1! butyne "Equations "75# and "76## ð38JA187Ł[ Functional derivatives are also accessible by these procedures\ for example halo!ethers and !thioethers "Equation "77## ð41JA2483Ł as well as hexa! ~uoroacetone\ which is made commercially by this route "Equation "78## ð53FRP0258673Ł[ Antimony ~uorides and various other ~uorides have been used to promote exchange with hydrogen ~uoride\
06
Tri~uoromethyl [MFxCl]–
+
F– (HF)
Cl + MFx
F + MFx-1Cl
or
δ+
Cl
δ–
MFx-1 F Scheme 6
and very e.cient catalysts have been developed by industry\ including chromia catalysts for use in vapour phase processes^ these are particularly important in the refrigerant industry "see Section 5[90[0[2#[ HF, SbCl3, Cl2
CCl4
CCl3CCl3
CCl3CCl2F
(84)
CCl3F + CCl2F2 + CClF3
110 °C, 3 atm
9%
CCl2FCCl2F
90%
0.5%
CCl2FCClF2
CClF2CClF2
CF3CClF2
Scheme 7
HF, SbF5
CCl3Me
Br2
Cl2
CF3Me
CF3CH2Cl
CF3CHBrCl 425–475 °C
Scheme 8
Cl Cl
F
Cl Cl
SbF3
Cl F
F
F
Cl
+
F Cl
(85)
150 °C
Cl
Cl
Cl
Cl
Cl
43%
Cl
Cl
Cl
Cl Cl
Cl
SbF3Cl2
Cl
Cl Cl
Cl
F
F
F
F Cl
F
Cl
Cl
Cl
F
F
+
F
Cl
28%
Cl
Cl
F
F
F
F Cl
F
(86)
F
F
F
Cl Cl
Zn, Ac2O
F F
F
63%
F
F
F
F
F
F
(87)
07
Trihalides Cl Cl Cl
SbF3, SbCl5
SMe
Cl +
90 °C
F SMe
F
73%
Cl
SMe
(88)
F
O
O
Cl
Cl
Cl
Cl
Cl
Cl
HF, 350 °C Cr (cat.)
F
F
F
F
F
F
(89)
Alkali metal ~uorides\ although easily used\ have limited application for saturated sites "Equation "89## ð52JOC001Ł\ but such systems are extremely e}ective for attack at unsaturated sites "Equation "80##\ where even lithium ~uoride\ normally the least reactive of the alkali metal ~uorides\ can give some ~uorination "Equation "81## ð48JA1967\ 59JA2980Ł[ These reactions probably involve nucleo! philic attack with allylic rearrangement\ and other metal ~uorides will also promote this process "Equation "82## ð59BRP712408Ł[ Terminal ~uorinated alkenes are rearranged to the thermo! dynamically more stable isomers by the ~uoride ion "Equation "83## ðB!62MI 590!91Ł[ Furthermore\ hexa~uorobutadiene is converted into hexa~uoro!1!butyne by ~uoride ion "Equation "84## ð50JA0656Ł and\ more surprising\ hexa~uorocyclobutene also gives hexa~uoro!1!butyne when passed over hot caesium ~uoride or potassium ~uoride "Equation "85## ð68CC853Ł[ An even more remarkable rearrangement induced by hot metal ~uorides involves conversion of per~uorobicyclobutylidene to a product containing three tri~uoromethyl groups "Equation "86##[ Cl
Cl
Cl
Cl Cl
Cl
KF, 190 °C
F
Cl
NMP ~60%
F
Cl
Cl Cl
F
Cl F
F F
F LiF, cellosolve
F
Cl
F
F
90–95%
F
CsF, 100 °C
C4F9
F
no solvent
F
F
F
F
+
C4F9
F–
F–
F
+
F C3F7
F F
(94)
F
F
F
F F
F
F
F
+
F C4F9
F
F–
(93)
F
–
F
F
F
(92)
F
F
F
F
F
F HF, CoF2, 250 °C
Cl
F
F
F
Cl
F– +
(91)
F
F
F
(90)
Cl
F
90%
Cl Cl
F F
F
F
F
Cl
(C2H5)4NF, CHCl3 27 °C, 12 h
F
F
F
CsF, 100 °C, no solvent
F
F
F
F F
F
+ F–
(95)
08
Tri~uoromethyl F
F
i
F
F
F
80–90%
F
F
F
F
F
F
F
F
(96)
i, CsF or KF, 510–590 °C, flow system in N2
F
F F
i
F F
F
(97)
F
F
70%
F
F
F F
F
i, KF, 510 °C, flow system in N2
5[90[1[2[1 Conversions of other groups to the tri~uoromethyl group Use of sulfur tetra~uoride ð59JA432Ł to convert the carboxyl group to the tri~uoromethyl group proceeds well\ except where formation of anhydrides is in competition "Equations "87# and "88## ð67PJC60Ł and in some cases other functional groups present also react preferentially "Scheme 8# ðB! 78MI 590!91Ł[ Treatment of ~uorinated enols with DAST gives tri~uoromethyl derivatives with a high degree of regio! and stereoselectivity "Equation "099## ð80TL4852Ł[ An interesting in situ electrophilic formylation and subsequent reaction with sulfur tetra~uoride has been reported "Equa! tion "090## ð71ZOR117Ł[ HO2C
( )8
CO2H
HO2C
F
F
F ( )3
F
( )3
SF4, 120 °C, 6 h
F
87%
F
F
+
F
+
F
F
F F
O 10%
34%
F ( )8
F
(98)
F
SF4, 5 °C, 48 h
CO2H
F
F
F
F
F
F F
( )3
F
F ( )3
O
F
(99)
F
16% 100 °C
F
50%
F
HF, 20 °C
F
60%
F
F
F
F COF
O
+ SF4
CO2H
HO2C
F
F
F
F
F F
Scheme 9 Ph
F
F
Ph
+ Et2NSF3 OH
F
F
SF4, HCO2H, HF
F
(100)
(101) CF3
Although halogen exchange to form the tri~uoromethyl group proceeds well "see above#\ pro! cedures to convert the methyl group to the tri~uoromethyl moiety directly are limited[ High!valency metal ~uorides\ for example cobalt tri~uoride\ will carry out this conversion at high temperatures\
19
Trihalides
but the rest of the molecule is also ~uorinated in the process\ leading to very useful inert ~uids "Equation "091## ð59AFC"0#055Ł[ Various direct ~uorination procedures can also be used for such transformations "Equation "092## ðB!62MI 590!92Ł[ CF3 CoF3
(102) F
F
CF3 F2
(103) F
Au on Cu
CF3
Electrochemical ~uorination "ECF# is a procedure for converting C0H bonds to C0F bonds at the anode of an electrochemical cell during the electrolysis of hydrogen ~uoride ð56FCR66Ł under conditions that do not generate elemental ~uorine[ The process is operated on an industrial scale and is particularly e}ective for polar systems\ for example the synthesis of tri~uoromethanesulfonic acid "Scheme 09# and other functions "Equation "093# and Scheme 00#[ An interesting conversion of the amino group to the tri~uoromethyl group involves conversion to an azo derivative\ using nitrosotri~uoromethane\ followed by photolytic elimination of nitrogen "Scheme 01# ð66AG"E#743Ł[ ECF
MeSO2F
H2O
CF3SO2F
CF3SO2OH
96%
Scheme 10
ECF
CS2
CF3SF5
(104)
90%
ECF
MeCOF
H2O
CF3COF
CF3CO2H
Scheme 11
CF3 C8H17NH2 + CF3NO
N N C8H17
hν 69%
C8H17CF3
Scheme 12
5[90[1[2[2 Transfer of tri~uoromethyl groups as radicals One of the most e}ective and e.cient procedures for transferring tri~uoromethyl radicals involves the use of iodo! or bromotri~uoromethane for addition to an unsaturated unit "see Section 5[90[0[1#[ These are generally radical chain reactions\ and they proceed with very high e.ciency when a relatively nucleophilic centre is involved\ and a range of catalytic procedures have been developed\ as illustrated in Table 1[ Electrolysis of tri~uoroacetic acid is a very direct and attractive route for generation of tri~uoro! methyl radicals[ Mixed Kolbe processes lead to tri~uoromethyl derivatives by combination of radicals "Equation "094## ð64CJC418Ł\ although the process is not e.cient[ Similarly\ addition of tri~uoromethyl radicals\ generated this way\ to alkenes and derivatives leads to mixtures of products where dimerization of the radical arising from addition of the tri~uoromethyl group can be a signi_cant pathway "Equation "095## ð63CC212\ 67JCS"P0#191Ł[ Products that arise from cyclization of the intermediate radical "Equation "096## ð80T438Ł and from di!addition have been observed "Equa! tions "097# ð68CJC1506Ł and "098# ð78TL098Ł#[ Enzymes have been used to promote radical additions
10
Tri~uoromethyl Table 1 Addition of halo~uoromethanes to alkenes[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * Yield Reactants Catalyst:conditions Product ")# Ref[ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * Ru2"CO#01 CF2CH1CHISiMe2 78 73TL292 CH1 CHSiMe2 ¦CF2I CH2CO"CH1#7CH Et2B CH2OCO"CH1#7CHICH1CF2 75 78TL2048 CH1 ¦CF2I CH1 CHC5H02 ¦CF2Br NaSePh CF2CH1CH"SePh#C5H02 ¦ 15\ 23\ 20 80TL264\ 80TL6314 CF2SePh¦PhSeSePh Na1S1O3 NaHCO2 CF2CH1CHIR B!83MI 590!90 CH1 CHR¦CF2I CH1 CHR "R Ph\ Ru"PPh2#2Cl1 CF2CH1CHClR 78CC0448 CO1Et\ alkyl#¦CF2SO1Cl ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ *
"Equation "009## ð77JOC1249Ł\ and it is probable that these are reacting as electron transfer agents\ in the manner that various other transition metal systems behave[ Reactions of plasma!generated radicals can be very e.cient "Scheme 02# ð68CC017Ł[ F EtO2C
CO2H
electrolysis
F
EtO2C
+ CF3CO2H
electrolysis
+ CF3CO2H F
F
F
+ F
F major
F
F
F
+
F
(105)
F
46%
F
F
+
F
F (106)
F
F
F H N
electrolysis
+ CF3CO2H
F
F
F F
F
(107)
N H O NEt
electrolysis
F
40%
F
O
+ CF3CO2H
NEt F
O
F
electrolysis
CONH2
F
F
+ CF3CO2H
O
F
F
F
F
F (110)
39%
F
Ph F
CI4
plasma
CF3I
F
urease
Ph
(109)
CONH2
F CF3I +
F
F
35%
(108)
CF3• 97%
F3C F3C F3C
CF3 1
Scheme 13
F
+ :
F3C F3C F3C
I 3
11
Trihalides
5[90[1[2[3 Reactions involving tri~uoromethyl derivatives of metals and metalloids Electrophilic tri~uoromethylating agents "see Section 5[90[1[1[2# can be applied to transferring the tri~uoromethyl group to an alkyne "Equation "000## ð89TL2468Ł\ and acidic sites derived from alkyl pyridines may be tri~uoromethylated using tri~ic anhydride\ together with formation of corresponding tri~ates "Equation "001## ð72JOC0665Ł[
Ph
+
Li
+
Se CF3
Ph
46%
CF3SO2O–
(111)
CF3
CF3
+
(112)
+
(CF3SO2)2O N
N
CH2OSO2CF3
N 62%
5%
Nucleophilic tri~uoromethylation has been carried out directly with a system that is highly susceptible to nucleophilic attack "Equation "002## ð89IZV380Ł\ although the nature of the inter! mediate is not clear[ Displacement of the tri~uoromethyl group from trimethyltri~uoromethylsilane\ using the ~uoride ion "see Section 5[90[1[1[3#\ is applicable to a range of systems "Scheme 03# ðB! 81MI 590!90Ł\ and\ used in conjunction with copper"I# salts\ trimethyltri~uoromethylsilane functions as a tri~uoromethylcopper reagent which will tri~uoromethylate aryl\ benzyl and allyl halides "Equation "003## ð80TL80Ł[
F
F
F
F
F
F F
F
F
F F
+ CF3Br/P[NC2H5)2]3
CH2Cl2, –78 °C, argon
F
45%
F
F
F
TMS-O R1 F3C
F– THF
R1 = alkyl, aryl R2 = alkyl
F
F F
HO R1 F3C
HCl
CO2R2
F
F
F
F F
F
R1COCO2R2 + TMS-CF3
F
68–83%
(113)
F
CO2R2
Scheme 14 KF, Cu(I)
R1X + CF3SiR23
R1CF3
(114)
DMF, 60–80 °C 23–94%
Tri~uoromethylcopper reagents\ made by other routes\ react with various substrates "Equations "004# ð81CC42Ł\ "005# ð68TL3960Ł and "006# ð71CL0342Ł#\ and zinc reagents are also useful ð81T078Ł in a variety of contexts[ Cl Ph
Br
+ F
F–, CuI
PhCF3
CO2Me
Ph
Br
+ CuCF3
(115)
84%
F
HMPA (CF3I + Cu)
Ph
F
65%
F
F
(116)
12
Trichloromethyl OH
Zn, CuI
F
61%, (E):(Z) = 3:7
F
+ CF3I
(117)
OH F
5[90[2 TRICHLOROMETHYL DERIVATIVES*RCCl2 5[90[2[0 Trichloromethyl Groups Attached to an Aliphatic Centre Trichloromethyl compounds can be prepared either by converting an existing group into a trichloromethyl group or by introducing a trichloromethyl group on to a carbon atom in an existing molecule "see also Section 5[90[0#[
5[90[2[0[0 Conversion of groups attached to an aliphatic centre into the trichloromethyl group As with chloro~uorocarbons\ the manufacture of many chlorinated solvents is being phased out[ Of these\ only 0\0\0!trichloroethane is relevant to this chapter[ Several routes are available\ and the choice\ which makes use of permutations of chlorination\ hydrochlorination and dehydro! chlorination\ is outlined in Scheme 04[ Hydrochlorination is usually e}ected by Lewis acid catalysis "e[g[\ FeCl2#\ and dehydrochlorination by thermal cracking or by the action of base[ Chlorination is catalysed by free radical sources in the liquid or gas phase[ The route chosen depends in part on how much hydrogen chloride the operator is prepared to make[
H2C
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH2
Cl Cl Cl
Cl Cl
C2H6
Cl Scheme 15
5[90[2[0[1 Transfer of the trichloromethyl group to an aliphatic centre "i# Preparation of trichloromethylalkanes Trichloromethyl anions are an unstable species and decompose to give dichlorocarbenes[ However\ the problem of their instability can be minimized by running reactions at low temperature and by generating the trichloromethyl anion in the presence of the substrate[ Trichloro! methyllithium\ which can be made at about −099>C from trichloromethane and butyllithium in THF\ reacts successfully with iodoalkanes at this same temperature to give a series of trichloromethyl alkanes "Equation "007## ð89JOC0170Ł[ Cl R
I
BuLi, CHCl3, THF, –100 °C HMPA
R = –(CH2)nCH=CH2 (n = 2 or 3), –CH2
R
Cl Cl
(118)
13
Trihalides
The trichloromethylation of activated alkyl halides can also be carried out by a cross!coupling reaction with tetrachloromethane in an undivided electrochemical cell with a sacri_cial anode[ The preferred anode is zinc\ with a stainless steel cathode\ and the preferred solvent is a mixture of THF and tetramethyl urea "Scheme 05# ð77TL0588Ł[ Mn+ + ne–
M
Anode
Cathode
CCl4 + 2e–
CCl3– + Cl–
CCl3– + RX
CCl3R + X–
RX = PhCH2Br, MeCHClOCO2Et, BrCH2CO2Me, Me(CH2)9Br Scheme 16
Trichloromethylated compounds can also be prepared by the action of trichloromethyl anions generated by the action of a base on trichloromethane[ Thus\ by using catalytic amounts of electrochemically generated base\ a relatively stable anion is produced which reacts with a\b! unsaturated esters and nitriles to give the corresponding b!trichloromethyl adducts in good yield[ The base is made by the electroreduction of 1!pyrrolidone in DMF using tetraalkylammonium salts as supporting electrolytes "Scheme 06# ð89TL6070Ł[ +e–, 1.8 F mol–1
O
N H
R = Et, X = OTs; R =
CHCl3
–
N
DMF, R4NX Pt cathode
Bun,
–
X = BF4
R4
eg.
R4N+ CCl3–
O
N
2
R4N+
DMF
+
+ –1 H2
O
CO2Me CN
or
N+
Cl Cl
CO2Me
Cl or
Cl
Cl
CN Cl
Scheme 17
b!"Trichloromethyl#nitroalkanes can be prepared in good yield by the reaction between trichloro! methyl anions\ generated from trichloromethyltrimethylsilane and caesium ~uoride "see also 5[90[0[1#\ and nitroalkenes "Equation "008## ð80SC1078Ł[ R3
Cl
i, TMS-CCl3, CsF, THF, 25 °C
R1
NO2 R2
R3
R1
R2
Cl
ii, H+
R1 Bun Ph Me Et Me
Cl
R2 Me H H H Me
NO2
(119)
R3 H H Et H Me
Closely related to the trichloromethyl radical additions outlined in Section 5[90[0[1[2 is the reaction of trichloromethylsufonyl chloride with 0!alkenes in the presence of ruthenium complexes such as dichlorotris"triphenylphosphine#ruthenium"II#[ In this reaction\ the elements of CCl2 and chlorine are added to the double bond in high yield under mild conditions with the extrusion of sulfur dioxide ð72SUL020Ł[ When the chiral Ru2Cl3"diop#2 is the catalyst\ chiral adducts are obtained ð76BCJ2576Ł[
14
Trichloromethyl "ii# Preparation of a!trichloromethyl carbinols
a!Trichloromethyl carbinols are valuable intermediates for making compounds in which the trichloromethyl group is preserved and also for making those in which the trichloromethyl group has been transformed into other functions "e[g[\ ð60S020\ 71TL0598\ 77M0316\ 78S355\ 80RCR0207\ 81TL2324Ł#[ Essentially\ their preparation comprises the formation of a trichloromethyl anion followed by its attack on an aldehyde or ketone "Scheme 07#[ CCl3–
AcCl3 R1
O CCl3– +
R2 R1
R2
–O
Cl Cl Cl
R1 R2 HO
H+
Cl Cl Cl
Scheme 18
Carbonyl compounds have been treated successfully with trichloromethyllithium\ but because the reactions have to be carried out at −099>C\ only the more reactive carbonyls can be used ð53AG"E#402\ 56JOC0106\ 77M0316\ 89JOC0170Ł[ Reactions can be carried out at higher temperatures "−67>C# if lithium dicyclohexylamide is used to generate the trichloromethyllithium from trichloro! methane in the presence of the carbonyl "Equations "019#Ð"012##[ Equation "012# gives equally good results with tribromomethane in place of trichloromethane ð63JA2909Ł[ i
Ph2CO
Ph2COHCCl3
(120)
ii
i, BunLi, CHCl3, –110 °C, THF/Et2O, petroleum ether; ii, H+ i, BunLi, CHCl3, –100 °C, THF
(CF3)2CO
R
( )n
CHO
(CF3)2COHCCl3
ii, H+
i, BunLi, CHCl3, –100 °C, HMPA
R
COHCCl3 ( )n
(121)
(122)
ii, H+
R H H Me O
n 2 3 2 HO
CCl3
i
(123)
i, Lithium dicyclohexylamide, CHCl3, –78 °C, THF, hexane
Trichloromethane and a base have been used extensively to generate the trichloromethyl anion[ The base may be sodium or potassium hydroxide ð33JCS63\ 49JA4901\ 72M702\ 76JOC833Ł\ an alkali metal alkoxide ð47CB1553\ 53JOC0037Ł\ or potassium ~uoride supported on alumina ð75TL2734Ł[ The amount of base\ its nature and also the choice of solvent are particularly important when the carbonyl compound is inclined to undergo an aldol condensation or the Cannizzaro reaction[ Reactions are generally carried out below 9>C to help suppress dichlorocarbene formation[ Phase transfer catalysts have been used in these reactions\ but they were only really successful with higher aldehydes and ketones ð79JOC4103\ 68TL0362Ł[ The thermal decomposition of sodium trichloroacetate in a solvent yields dichlorocarbene ð48PCS118Ł[ However\ the intermediate trichloromethyl anion can be trapped by aldehydes to yield trichloromethyl carbinols[ Under similar conditions\ anhydrides react to give trichloromethyl lactols or their tautomeric keto acids "Equation "013## ð56JOC1055Ł[ Trichloromethyl carbinols are also obtained in high yield when\ in the presence of an aldehyde\ trichloroacetic acid decomposes in DMSO ð72CC172\ 73JCS"P1#0136\ 78JCS"P1#140Ł or HMPA ð89S216Ł\ or a 0 ] 0 mixture of the trichloro!
15
Trihalides
acetic acid and its sodium salt decomposes in DMF ð81TL2324Ł[ These reactions are successful with aliphatic as well as aromatic aldehydes[ They are less successful with ketones unless the ketone is "partially# ~uorinated and therefore more electrophilic\ in which case the yields are high ð81BAU269Ł[ O
O
HO
O
CCl3
CCl3
CCl3CO2Na
O
OH
DME
O
(124)
O
O
Trichloromethyl compounds of silicon and tin have been used as sources of trichloromethyl anions in reactions with carbonyl compounds[ For example\ the reaction of trichloro! methyltrimethylsilane and trimethylsilyl trichloroacetate in the presence of the ~uoride ion with aromatic and aliphatic aldehydes ð74JA3974\ 76SC0936\ 77T3024Ł\ trimethylsilyl trichloroacetate in the presence of potassium carbonate and 07!crown!5 with aromatic aldehydes and ketones ð74TL0064Ł\ and tributyl"trichloromethyl#stannane with aliphatic and aromatic aldehydes ð64JOM"091#312Ł all give the corresponding trichloromethylcarbinols in good yield "Equations "014#Ð"017##[ Equation "017# proceeds with equal success to give tribromomethylcarbinols when tribromomethyltributyltin is used instead of the trichloromethyl tin compound[ R
i, TMS-CCl3, tas-F, THF, 0 °C
Cl Cl Cl
RCHO ii, H+
HO
(125)
R = Ph, n-C10H21, PhCH(Me); tas = tris(diethylamino)sulfonium
R1 O
i, CCl3CO2-TMS, F–, THF
R1
ii, H+
R2
Cl Cl Cl
HO R2
(126)
F = KF or tas-F R1 O = cyclohexanone, benzaldehyde, pivaldehyde, 2-cyclohexenone, crotonaldehyde R2 R1 O
i, CCl3CO2-TMS, K2CO3, 18-crown-6
R1 HO
ii, H+
R2
R2
Cl Cl Cl
(127)
R1 R2
O = e.g. benzaldehyde, 3,5-dichlorobenzaldehyde, 4-hydroxybenzaldehyde, cyclobutanone, cyclopentanone, cyclohexanone
RCHO
i, Bu3SnCCl3, 80 °C ii, H+
R HO
Cl Cl Cl
(128)
R = Me, Et, Pri, Ph, PhCH = CH
The reductive addition of tetrachloromethane to aldehydes using a lead:aluminum bimetal redox system has been reported to give high yields of trihalocarbinols[ While a variety of aliphatic and aromatic aldehydes give good yields\ ketones give less satisfactory results[ The use of bromo! trichloromethane instead of tetrachloromethane gives exclusively the same product "Scheme 08# ð78JOC333Ł[ A variety of aldehydes have been treated with trichloromethyl anions generated by the cathodic reduction of tetrachloromethane in trichloromethane[ Only relatively small amounts of tetra! chloromethane are used in this reaction\ since it is the trichloromethane which supplies the proton to the intermediate anion and thereby generates another trichloromethyl anion*steps "ii# and "iii# in Scheme 19[ The use of vinyl acetate instead of an aldehyde yields the acetate MeCH"OAc#CCl2 ð70TL760\ 71TL0598\ 71TL3790Ł[ These same workers oxidized trichloromethyl carbinols with chromic oxide to give the corresponding trichloromethyl ketones ð71TL0598Ł[
16
Trichloromethyl R
X
HO
X
PbX2 (cat.)/Al, DMF
RCHO + CX4
Pb(0)
Pb(II)
Al(III)
Al(0)
X
X = Cl or Br; R = alkyl, aryl Scheme 19
+2e–
CCl4
CCl3– + Cl– –O
Cl Cl Cl
CCl3– + RCHO R –O
HO
Cl Cl + CHCl3 Cl
R
Cl Cl Cl
R
(i)
(ii)
+ CCl3–
(iii)
Scheme 20
The other approach to making trichloromethyl carbinols is to start with trichloroacetaldehyde "chloral#[ This compound will condense with aromatic hydrocarbons with FriedelÐCraft catalysts "e[g[\ H1SO3\ HCl\ AlCl2\ BF2 and ZnCl1# ð12CB868\ 31JA1404\ 55CJC464\ 57CJC1122\ 79CJC374Ł or under the in~uence of basic catalysts "e[g[\ potassium hydroxide\ potassium carbonate and pyridine# ð45CB1467\ 14JPR014\ 41CB890Ł to yield trichloromethyl carbinols[ Certain Grignard reagents will react with chloral to give trichloromethyl carbinols\ although reduction of the chloral to trichloroethanol can be a problem "Equation "018## ð40M0997\ 45BSF0330Ł[ Finally\ silanes\ R!TMS\ in which the group R is electron!withdrawing\ have been shown to react with chloral in the presence of a Lewis acid to give the corresponding trichloromethyl carbinols "Scheme 10# ð64JOM"82#32Ł[ RMgBr
R-TMS
+
Cl Cl Cl
CHO
+
Cl Cl Cl
R CHO HO R
Al, Ga or InCl3
TMS-O
Cl Cl Cl
Cl Cl Cl MeOH
(129)
R HO
Cl Cl Cl
R = allyl, aryl, vinyl, ethynyl, propargyl Scheme 21
5[90[2[1 Trichloromethyl Groups Attached to an Aromatic Ring The high reactivity of trichloromethylarenes makes them valuable intermediates in the synthesis of acids and their derivatives\ heterocyclic compounds and the tri~uoromethyl group "which we have seen is of great interest to the pharmaceutical and agrochemical industries#[ Similarly to trichloromethyl aliphatic compounds\ trichloromethylarenes may be made by converting a group which is already attached to a ring into a trichloromethyl group or by transferring a trichloromethyl group on to a ring[
17
Trihalides
5[90[2[1[0 Conversion of groups attached to an aromatic ring into the trichloromethyl group Methyl groups in arenes can be trichlorinated using chlorine\ by a free radical mechanism "Equation "029## ð51HOU"4:2#624Ł[ 1! and 3!Methylpyridines and 1! and 3!methylquinolines are also readily trichlorinated\ but here reactions are best carried out by passing the halogen into a solution of the substrate in glacial acetic acid\ optionally acetic anhydride\ and sodium or potassium acetate\ where the reaction is believed to proceed by an ionic process\ with the acetate acting as a base ð12JCS1771\ 28JCS670\ 40JCS0034Ł[ 2!Methylpyridine cannot be trichlorinated by this method\ but when its vapour and chlorine are passed over a chromia catalyst\ pretreated with hydrogen ~uoride\ 2! trichloromethylpyridine is produced ð71EUP54247Ł in reasonable yield[ CCl3 Cl2
(130)
heat or UV
While these methods are fairly general\ there are situations where other methods are necessary^ for example\ in the preparation of methylbenzotrichlorides where chlorination of dimethyl com! pounds leads to chlorination in both side chains\ and in the preparation of compounds such as 3!nitrobenzotrichloride where the electron!withdrawing group inhibits chlorination[ Thus\ car! boxylic acid groups in aromatic and heteroaromatic rings are converted into trichloromethyl groups by treatment with phosphorus pentachloride in thionyl chloride ð66JHC770\ 67JHC782Ł\ or with phosphorus pentachloride alone ð78JCS"P0#172Ł[ This conversion can also be accomplished by treating acids with chlorine in a mixture of phosphorus trichloride and phenylphosphonic dichloride ð72USP3308403Ł or phenyl dichlorophosphorane and phenylphosphonic dichloride ð78USP3722149Ł[ Substituted benzal chlorides\ which can be prepared from the corresponding aldehydes ð67JOC3256Ł\ can be chlorinated further to trichloromethyl compounds by treatment with isobutyl hypochlorite in aqueous sodium hydroxide\ optionally in the presence of an alcohol\ and a phase transfer agent ð67USP3987720Ł[ Substituted benzyl and benzal chlorides are also converted into the corresponding benzotrichlorides when they are treated with tetrachloromethane or hexachloroethane and aqueous sodium hydroxide in the presence of a phase transfer catalyst "PTC# by a process which probably involves nucleophilic attack on chlorine "Equation "020## ð75S113Ł[ Cl
X
CCl3 CCl4 or CCl3CCl3
(131)
50% aqueous , NaOH, PTC, reflux
R R X = H; R = 2-NO2, 2-NO2, 3-Me X = Cl; R = 2-NO2, 2-NO2, 3-Me, 2-Me, 3-Me, 4-Me, 2-Me, 2-Cl, 4-Et
A similar range of compounds is made by treating appropriate dibenzyl sulphides with chlorine or sulfuryl chloride "Equation "021## ð71S840Ł^ or by chlorinating with sulfuryl chloride the product obtained from treating an aldehyde with a dithiol in the presence of acid "Scheme 11# ð75USP3464454Ł[ Dichlorine monoxide can be used to chlorinate methyl groups in methylnitrobenzenes and other methylbenzenes which have electron!withdrawing groups on the aromatic ring "Equation "022## ðB! 71MI 590!91Ł[ While 3!nitrotoluene and highly deactivated compounds such as 1!chloro!3!nitro!\ 2\3! dinitro! and 2\4!dinitrotoluene are converted into the corresponding benzotrichlorides in very high yield\ 1!nitrotoluene is only dichlorinated by dichlorine monoxide to give the benzal chloride[ "NB[ This compound could be chlorinated further by methods outlined above[# In the case of the other substituted toluenes with deactivating groups in the 3 position\ chlorination takes place exclusively in the methyl group with the exception of p!toluenesulfonic acid\ which undergoes chlorination on the ring[ R
R
R
Cl2 or SO2Cl2
2 S
CCl4, POCl3 or o-dichlorobenzene
R = 2-Mea, 3-Meb,c, 4-Mea, 2-Bra, 4-NO2d,e, 2,3-CH=CH–CH=CHa aCl2/CCl4, bCl2, cSO2Cl2/CCl4, dCl2/POCl3, eCl2/o-dichlorobenzene
CCl3
(132)
18
Trichloromethyl R
S ( ) n S
R
CHO
HS
( )n
SH
R SO2Cl2
HCl in CHCl3
CCl3
CCl4
R = 3-Me, 4-NO2, 2-Cl, 4-MeO; n = 2 or 3 Scheme 22 NO2 2
NO2
+ 3Cl2O
CCl4
2
+ 3H2O
(133)
CCl3
5[90[2[1[1 Transfer of the trichloromethyl group to an aromatic ring Aromatic compounds can be trichloromethylated by reaction with tetrachloromethane in the presence of excess Lewis acid\ which is most commonly aluminum trichloride "e[g[\ ð76JPR0020Ł#[ Whilst the trichloromethyl compounds can be the main product\ diaryldichloromethanes are also produced in signi_cant amounts "Equation "023##\ although it is claimed that the addition of mordenite can reduce dimer formation ð81JAP93038032Ł[ The reaction is fairly general\ but there are complications when polymethyl aromatics are trichloromethylated[ Thus\ while m!xylene gives the expected 1\3!dimethyltrichloromethylbenzene\ a Jacobson!type rearrangement occurs in the reaction with p!xylene to give 1\3!dimethyltrichloromethylbenzene as the main product "o!xylene gives no trichloromethyl compounds but yields the dichloromethane\ "2\3!Me1C5H2#1CCl1# ð78CS70Ł[ Similarly\ the trichloromethylation of mesitylene gives the expected product ð50JA3359Ł\ but during the trichloromethylation of pseudocumene ð78CS70Ł both the expected 1\3\4!trimethyltrichloro! methylbenzene and about 04) of the rearranged 1\3\5 isomer are produced "Scheme 12#[ Although mesitylene itself gives only the expected trichloromethylmesitylene\ 0\2\4!trimethylhalobenzenes give signi_cant amounts of the rearranged product "Scheme 13^ in this scheme the products were isolated as the corresponding methyl benzoates# ð69JOC2526Ł[ In the case of the tetramethylbenzenes "Scheme 14#\ durene gives almost exclusively the rearranged product\ 1\2\3\4!tetramethyltrichloromethyl! benzene "a small amount of disproportionation took place under the conditions used#\ whereas isodurene gives predominantly 1\2\3\5!tetramethyltrichloromethylbenzene\ some of the 1\2\3\4 iso! mer and a trace of the 1\2\4\5 isomer ð50JA3359Ł[ It was suggested that rearranged products in these reactions could arise by the trichloromethyl group attacking a ring carbon that is already substituted followed by a 0\1!methyl migration and proton loss\ but rearrangements induced by acid\ HCl:AlCl2\ are also possible[ Cl CCl4, AlCl3
CCl3
+
(134)
CCl3 CCl4, AlCl3 100%
mesitylene
CCl4, AlCl3 15% CCl4, AlCl3 85%
pseudocumene Scheme 23
Cl
CCl3
29
Trihalides X
X
X AlCl3, CCl4
+ CCl3 CCl3
X H F Cl Br
100 70 88 93
: : : :
0 30 12 7
Scheme 24
CCl3 CCl4, AlCl3
durene
CCl4, AlCl3 23%
CCl3
CCl4, AlCl3 2% CCl4, AlCl3
isodurene
73%
CCl3
Scheme 25
Highly chlorinated trichloromethyl and tri~uoromethyl aromatics are quite di.cult to prepare\ but Castaner et al[ ð80JOC092Ł found that treatment of polychlorinated benzenes with aluminum trichloride and ~uorotrichloromethane gives the tri~uoromethyl compound[ Treatment of this with more aluminum trichloride in carbon disul_de yields the corresponding trichloromethyl compound[ This reaction is reversed by treating the trichloromethyl compound with aluminum trichloride and ~uorotrichloromethane[ Bis"trichloromethyl# and bis"tri~uoromethyl# compounds were also made by these methods "Scheme 15#[ CF3 Cl
CCl3F, AlCl3
Cl
Cl3 AlCl3, CS2
Cl
CCl3F, AlCl3
Scheme 26
Trichloromethyl anions can be used to prepare trichloromethylated aromatics ð89TL5720\ In a one!pot reaction sequence\ a cyclopentadieneyliron!complexed arene is added to a solution made from potassium t!butoxide and chloroform in THF at −67>C[ The mixture is allowed to warm to room temperature\ and the intermediate is demetallated in situ with iodine to give the trichloromethylarene in good yield "Scheme 16#[ Aromatic compounds that are susceptible to nucleophilic attack\ such as 0\2\4!trinitrobenzene\ can be trichloromethylated by reaction with trichloromethyl anions generated by the decomposition of trichloroacetic acid in DMSO[ The _rst step is the formation of the Meisenheimer complex\ which is then oxidized to give the trichloromethylated product "Scheme 17# ð72CC039\ 73JCS"P1#0128Ł[ 80JOM"308#246Ł[
20
Tribromomethyl Cl3C R1
R1 HCCl3, ButOK
H
R1
CCl3
I2
–78 °C, THF
R2
R2
FeCpPF6
FeCp
R2
R1 Me Me Me H NO2 H Cl
R2 2-Me 3-Me 4-Me p-TolSO2 4-Me But 4-Cl indane tetralin benzosuberane Scheme 27
Similarly\ hexachloroacetone can be used as the source of trichloromethyl anions[ The decompo! sition of hexachloroacetone in DMSO is slower than that of trichloroacetic acid\ but it is accelerated by the addition of water[ It is believed that it is actually the hexachloroacetone hydrate that decomposes into the trichloromethyl anion\ and trichloroacetic acid which in turn decomposes to generate a second trichloromethyl anion ð75JCS"P1#360Ł CCl3 NO2
O2N
CCl3CO2H
CCl3 NO2
O2N
NO2
O2N
–
DMSO
NO2
NO2
NO2
Scheme 28
5[90[3 TRIBROMOMETHYL DERIVATIVES*RBr2 Considerably less work has been carried out on making compounds bearing a tribromomethyl group than on those bearing a trichloromethyl group[ With few exceptions\ the essentials of the methods for making tribromomethyl compounds are the same as those for making the trichloro! methyl analogues[ Thus\ tribromomethyl carbinols are produced when cyclohexanone is treated with tribromomethyl lithium at −67>C in THF ð63JA2909Ł\ or when various 2!pyridyl ketones are reacted at −099>C ð77M0316Ł[ Corresponding to the decarboxylation of trichloroacetic acid and its sodium salt to give the trichloromethyl anion is the decarboxylation of the analogous tribromo compounds[ The main di}erence between the two systems is that the tribromo compounds are less stable[ Thus\ tribromo! methyl carbinols are obtained when sodium tribromoacetate decomposes in the presence of alde! hydes[ In a similar reaction\ anhydrides react to give tribromolactols or their tautomeric keto acids ð56JOC1055Ł[ Tribromomethyl carbinols are also obtained when\ in the presence of aldehydes\ tribromoacetic acid decarboxylates in DMSO ð72CC172\ 73JCS"P1#0136Ł\ or a mixture of the acid and its sodium salt decarboxylates in DMF ð81TL2324Ł[ Again corresponding to the trichloromethyl case\ the reaction between tributyl"tribromo! methyl#stannane and an aldehyde gives a tribromomethyl carbinol[ The main di}erence between the two reactions is that tribromomethylation is exothermic at room temperature whereas trichloro! methylation requires some heating ð64JOM"091#312Ł[ Finally\ tribromomethyl carbinols can be made by the reductive addition of tetrabromomethane to aldehydes using a lead:aluminum bimetal system ð78JOC333Ł[
21
Trihalides
5[90[4 MIXED SYSTEMS WITH FLUORINE*RCF1Hal Per~uoroalkyl iodides*CnF1n¦0I*are some of the most important intermediates in the prep! aration of compounds which bear the per~uoroalkyl group "e[g[\ ð73JFC"14#58\ 77MI 590!90Ł#[ Some methods for the preparation of these compounds have been described previously "see Sections 5[90[0[0 and 5[90[0[1[1#\ but there are others which need to be noted[ Most of these methods take a per~uorocarboxylic acid as their starting point[ For example\ the thermal decomposition of the acid in the presence of iodine ð42USP1536822Ł\ the decomposition of per~uoroacyl chlorides in the presence of potassium iodide at 199>C ð47JOC1905Ł\ the decomposition of per~uoroacyl anhydrides in the presence of iodine at 249Ð399>C ð46BRP646782Ł and the thermal decomposition of dry metal salts in the presence of iodine all give per~uoroalkyl iodides[ Sodium\ potassium\ barium\ mercury and lead salts have all been used in this last reaction\ but it is silver salts which give the best yields ð40JCS473\ 41JA737\ 41JA738Ł[ This is known as the Hunsdiecker reaction\ and it can also be used to obtain {dihalides| from the corresponding diacid salts\ although lactone formation can be a problem ð41JA737\ 41JA0863Ł[ More recently\ it has been shown that treatment of sodium and potassium salts of per~uorocarboxylic acids with iodine in re~uxing DMF gives per~uoroalkyl iodides in high yield ð56JOC722Ł[ One compound in this class which has attracted a lot of interest of late is per~uorooctyl bromide "PFOB# because of its potential use as a contrast agent for diagnostic imaging[ The telomerization reaction between bromopenta~uoroethane and tetra~uoroethylene does not a}ord a convenient route to PFOB because the propagation step is so much faster than chain transfer\ and a mixture of high telomers is obtained[ Most of the practical routes for the manufacture of PFOB start from per~uorooctyl iodide\ which of course is manufactured on a substantial scale\ and replace the iodine by bromine[ For example\ iodides can be treated with bromine in the vapour phase at 299Ð249>C ð80EUP349473\ 81EUP404147Ł\ or with ultraviolet irradiation for 09 h ð73MI 590!90Ł[ Also\ PFOB can be made by re~uxing per~uorooctyl iodide with tetraalkylphosphonium bromide ð81GEP3914116Ł\ or with sodium bromide ð80GEP2826456Ł in DMF "a certain amount of reduction to the monohydro compound occurs here#\ and by heating with metal "Cs\ Mn"II#\ Fe"II# Fe"III# or Co"II## bromides to 299>C in an autoclave ð80EUP350452Ł[
5[90[5 MIXED HALOFORMS*CHXY1 AND CHXYZ Most methods for the preparation of mixed haloforms take the simple haloforms and replace one or two of the original halogens by others[ Trichloromethane "chloroform# is ~uorinated on an industrial scale in the liquid phase using Swarts| catalyst or in the vapour phase using chromia! based catalysts with hydrogen ~uoride as the ~uorinating agent "see also Section 5[90[0[2#[ The compound of greatest interest to the manufacturer is chlorodi~uoromethane\ since it is used in the manufacture of tetra~uoroethene\ but dichloro~uoromethane can also be made by this method[ Similarly\ tribromomethane "bromoform# can be ~uorinated using antimony tri~uoride and bromine ð54BRP0903141Ł\ or a ~uoride!type ion exchange resin ð51NKZ825Ł\ to give dibromo~uoromethane "Equation "024##[ CHBr3
i, ii
CHBr2F
(135)
i, SbF3, Br2, reflux; ii, amberlite IRA-400 (F type), 80 °C
Chloroform\ bromoform and iodoform can all be treated with an alkali metal halide and a base in the presence of a phase transfer agent to give mixed haloforms "e[g[\ Equations "025#Ð"039## ð78LA076\ 76TL1658Ł\ but satisfactory yields are not always obtained[ A single iodine in iodoform can be replaced by bromine simply by stirring a mixture of iodoform and bromine in tetrachloromethane for some 04 h "Equation "030## ð71CB2783Ł[ NaBr, NaOH, PTC
CHCl3
CHCl3
NaI, NaOH, PTC
CHBrCl2
(136)
CHCl2I + CHClI2
(137)
22
Mixed Haloforms NaCl, NaOH, PTC
CHBr3 NaI, NaOH, PTC
CHBr3
NaCl, NaOH, PTC
CHI3 CHI3
Br2, CCl4
CHBr2Cl
(138)
CHBr2I
(139)
CHClI2 + CHCl2I
(140)
CHBrI2
(141)
Dibromochloromethane reacts with sodium iodide and sodium methoxide in methanol to give bromochloroiodomethane "Equation "031## ð47JA3171Ł\ and with mercuric ~uoride to give bromo! chloro~uoromethane "Equation "032## ð45JA368\ 74JA5882Ł[ Bromochloro~uoromethane having high optical purity has been made by pyrolysing the optically pure strychnine salt of bromochloro! ~uoroacetic acid ð78JA7409Ł[ NaI, NaOH, MeONa
CHBr2Cl
CHBr2Cl
CHBrClI HgF2
CHBrClF
(142)
(143)
The thermal decarboxylation of silver salts of halogenated acetic acids in the presence of a halogen "the Hunsdiecker reaction*see Section 5[90[4# has been used to make the haloforms CHCl1F\ CHClF1\ CHClBrF\ CHClFI\ CHBr1F\ CHBrFI\ CHFI1\ CHBrF1 and CHF1I "e[g[\ Equations "033# and "034## ð41JCS3148Ł[
Copyright
#
CHF2CO2Ag + I2
CHF2I
(144)
CHClFCO2Ag + Br2
CHClBrF
(145)
1995, Elsevier Ltd. All R ights Reserved
Comprehensive Organic Functional Group Transformations
6.02 Functions Containing Halogens and Any Other Elements GRAHAM B. JONES and JUDE E. MATTHEWS Clemson University, SC, USA 5[91[0 FUNCTIONS CONTAINING HALOGEN AND A CHALCOGEN 5[91[0[0 Halo`en and Oxy`en Derivatives "R0CHal1OR1 and R0CHal"OR1#1# 5[91[0[0[0 Tetracoordinated carbon atoms with two identical halo`en and one oxy`en function attached "R0CHal1OR1# 5[91[0[0[1 Tetracoordinated carbon atoms bearin` mixed halo`ens and one oxy`en function "R0CHal1OR1# 5[91[0[0[2 Tetracoordinated carbon atoms bearin` one halo`en and two oxy`en functions "R0CHal"OR#11# 5[91[0[1 Halo`en and Sulfur Derivatives "R0CHal1SR1 and R0CHal"SR1#1# 5[91[0[1[0 Tetracoordinated carbon atoms with two identical halo`en and one sulfur function attached "R0CHal1SR1# 5[91[0[1[1 Tetracoordinated carbon atoms bearin` mixed halo`ens and one sulfur function "R0CHal1SR1# 5[91[0[1[2 Tetracoordinated carbon atoms bearin` one halo`en and two sulfur functions "R0CHal"SR1#1# 5[91[0[2 Halo`en and Se or Te Derivatives "R0CHal1SeR1 or R0CHal1TeR1# 5[91[0[2[0 Tetracoordinated carbon atoms bearin` two halo`ens and one selenium function "R0CHal1SeR1# 5[91[0[2[1 Tetracoordinated carbon atoms bearin` two halo`en and one tellurium function "R0CHal1TeR1# 5[91[0[3 Halo`en and Mixed Chalco`en Derivatives "R0CHal"OR1#"SR2## 5[91[1 FUNCTIONS CONTAINING HALOGEN AND A GROUP 04 ELEMENT AND POSSIBLY A CHALCOGEN 5[91[1[0 Halo`en and Nitro`en Derivatives] General Considerations 5[91[1[0[0 Tetracoordinate carbon atoms bearin` two halo`ens and one nitro`en function 5[91[1[0[1 Tetracoordinate carbon atoms bearin` one halo`en and two nitro`en functions 5[91[1[0[2 Tetracoordinate carbon atoms bearin` one halo`en\ one nitro`en and one oxy`en function 5[91[1[0[3 Tetracoordinate carbon atoms bearin` one halo`en\ one nitro`en and one sulfur function 5[91[1[1 Halo`en and Phosphorus Derivatives 5[91[1[1[0 Tetracoordinate carbon atoms bearin` two halo`en and one phosphorus function and one halo`en and two phosphorus functions 5[91[1[2 Halo`en and Arsenic Derivatives 5[91[1[2[0 Tetracoordinate carbon atoms bearin` two halo`ens and one arsenic function 5[91[2 FUNCTIONS CONTAINING HALOGEN AND A METALLOID AND POSSIBLY A CHALCOGEN AND:OR GROUP 04 ELEMENT
25 25 25 32 32 33 33 36 37 38 38 38 49 49 49 40 44 46 46 47 47 59 59 59 59 50 51
5[91[2[0 Halo`en and Silicon Derivatives 5[91[2[1 Halo`en and Boron Derivatives 5[91[2[2 Halo`en and Germanium Derivatives 5[91[3 FUNCTIONS CONTAINING HALOGEN AND A METAL AND POSSIBLY A GROUP 04 ELEMENT\ A CHALCOGEN OR A METALLOID
51 51 52 52
5[91[3[0 Halo`en and Lithium Derivatives 5[91[3[1 Halo`en and Ma`nesium Derivatives 5[91[3[2 Halo`en and Copper Derivatives
24
25
Halo`ens and any other Elements 5[91[3[3 5[91[3[4 5[91[3[5 5[91[3[6 5[91[3[7 5[91[3[8
52 53 53 53 54 54
Halo`en and Silver Derivatives Halo`en and Zinc Derivatives Halo`en and Cadmium Derivatives Halo`en and Mercury Derivatives Halo`en and Tin Derivatives Halo`en and Lead Derivatives
5[91[0 FUNCTIONS CONTAINING HALOGEN AND A CHALCOGEN A general review on ortho!ester derivatives covering the literature up to 0873 has been published ð74HOU"E4#Ł and provides a broad overview of several categories of haloalkyl systems relevant to this chapter[
5[91[0[0 Halogen and Oxygen Derivatives "R0CHal1OR1 and R0CHal"OR1#1# 5[91[0[0[0 Tetracoordinated carbon atoms with two identical halogen and one oxygen function attached "R0CHal1OR1# "i# From ethers Direct halogenation of ethers has proved a versatile technique for the synthesis of a variety of perhalogenated compounds of this class[ Novel per~uorinated ethers have been obtained by direct ~uorination of low molecular weight ethers with product ratios a function of the ~ow rate of ~uorine and carrier gas "usually helium# "Scheme 0# ð62JOC2506Ł[ The method has also been applied successfully to the preparation of per~uorinated polymers\ although in these cases the mixtures required heating up to 009>C for e.cient conversion ð66CC148\ 70JCS"P0#0210Ł[ Electrochemical ~uorination has also been investigated\ but it was found that\ under the optimum conditions used\ primary alcohols were converted into cyclic per~uorinated ethers in only moderate yield "Equation "0## ð65BCJ0777Ł[ The electrochemical ~uorination of ethylene glycol ethers has also been reported\ yielding complex mixtures of linear and cyclic per~uorinated compounds ð63ZOR1920Ł[
Me
Me
O
O
O
O
O
Me
F
20 ml/min He, 0.5 ml/min F2, –78 °C, 12 h
F3C
21%
O
F
F3C
16%
CF3
F F
20 ml/min He, 0.5 ml/min F2, –40 °C
Me
F
O
F
FF
O
O
O
F
F
F
CF3
F
Scheme 1
F F OH
HF, 3.5 A/1; 5 °C, 0–10 V
F F
F F
18%
F
O
(1)
CF3
Photochlorination of mixed halogenated ethers has been used in the synthesis of a number of anaesthetic agents "Scheme 1#[ Yields of the chlorinated systems are moderate to good\ reactivity being a function of carbon substitution patterns\ with monochlorinated carbon atoms being more reactive than the corresponding ~uoro!substituted carbons as expected ð41JA1181\ 60JMC406\ 60JMC482Ł[ Fluorination via direct substitution of chloro ethers has been accomplished using either HF or HF in the presence of SbF2 "Equation "1##[ Selectivity can be achieved by controlling HF introduction\ monitoring the progress of the substitution reaction by the HCl liberated ð60JMC482Ł[ Halogenation of heterocycles is a well!studied route to compounds of this class with trisubstituted
26
Halo`en and a Chalco`en
carbon atoms[ Electrochemical ~uorination of a range of oxanes gave the corresponding per! ~uorinated systems in moderate yield "Equation "2## ð68JFC"02#408\ 68JFC"04#242Ł[ F Cl
O
F
F
Cl F
Cl2, hν
F
80%
Cl
F F
O F Cl
Cl2, hν
F3C
O
Cl
Cl
F3C
80%
F O
F
F3C
75%
Cl
Cl F
Cl
Cl2, hν
F 3C
O
O
F Cl
Cl2, hν
F3C
O
Me 60%
F 3C
O
Cl
Scheme 2
CF3 F3C
Cl
O
CF3
HF, SbCl5, 0 °C, 12 min
Cl
or SbF3, SbCl5, 53 °C, 3 h 62%
F3C
O
electrochemical fluorination, HF 5.0–6.2 V, 3.5 A/dm2, 7 h
O
F
(3)
F
R
O
(2) F
Rf
R = Me, 28%; Et, 26%; Prn, 30%; Pri, 23%; Bun, 30%; Amn, 23%
Direct ~uorination of dioxane using elemental ~uorine is reported to give the per~uorinated system in moderate yield "Scheme 2# ð64JOC2160Ł\ whereas treatment with a mixture of sulfur tetra~uoride and hydrogen ~uoride gave the 1\1\2!tri~uorodioxane in high yield "Scheme 2# ð72JFC"11#094Ł[ The same product is also reported using the potassium salt of cobalt tetra~uoride ð60T3422Ł[ Finally\ ~uorination of 3!methylmorpholine using cobalt tri~uoride is reported to give the di~uoromethyl derivative shown in moderate yield "Scheme 2# ð67T086Ł[ O
SF4, 185 °C, 8 h; S2Cl2
O F
89%
O
O O
O
F
KCoF4, 220 °C
F 65%
O
O
F F
N
Me CoF3, 100 °C
F
N
F
31%
Scheme 3
"ii# From mixed trihalomethanes Chlorodi~uoromethane has been used extensively as a source of di~uoromethylene\ which can be intercepted by alkoxide nucleophiles to give alkoxydi~uoromethane adducts[ The conditions used
27
Halo`ens and any other Elements
are similar to those employed in the ReimerÐTiemann reaction\ and give good yields of product di~uoro ethers "Equation "3## ð47JA2991\ 59JOC1998Ł[ A phase transfer method has also been used to generate di~uorocarbene from chlorodi~uoromethane ð77JFC"30#136Ł[
R OH
i, NaOH, H2O, dioxane, 70 °C ii, CHFCl2
R
F (4)
O F
R = Ph, 65%; 4-MeC6H4, 66%; 4-MeOC6H4, 53%; 2,4-Me2C6H3, 56%; 2,4-Cl2C6H3, 44%; 2-naphthyl, 66%; Pri, 60%
The range of functionality tolerated by the reaction includes substituted primary and secondary alkyl halides\ which provides access to heavily functionalized systems "Scheme 3# ð65CB1240Ł[ Trihalomethylmercury compounds have also been used to deliver the dihalomethyl moiety to alcohols and carboxyl groups ð53JA1850\ 63JOM"56#230Ł[ Phenyl"bromodichloromethyl#mercury thus adds to carboxylic acids to yield the dichloromethyl esters shown "Scheme 4#\ and with butanol to give the dichloro ether shown in high yield\ producing phenylmercuric bromide as by!product in both cases[ Di~uorocarbene has also been generated from FSO1CF1CO1H\ and it inserts into alcohols in the presence of CuI ð78JFC"33#322Ł[ Cl
F
Cl
O
Cl
HClCF2
Cl
O
F
97%
F
OH
Cl
F
Cl
Cl
Cl HClCF2
O
O
OH Cl
Cl
F
98%
F F
F
Scheme 4
O PhHgCCl2Br + RCO2H
R
benzene, 60 °C, 45 min
Cl O
+ PhHgBr
Cl R = Ph, 86%; Me, 92%; ClCH2, 86%; But, 81%
PhEt, 80 °C, 30 min
Bu
O
PhHgCCl2Br + BuOH
Cl 85%
+ PhHgBr
Cl
Scheme 5
"iii# From dihalo ethers Treatment of dichloro ethers and bromochloro ethers with antimony tri~uoride results in halogen substitution to yield the corresponding di~uoro ether "Scheme 5# ð52AFC"2#070\ 69ZOR033\ 61JMC593\ 61JMC595Ł[ Alternatively\ anhydrous hydrogen ~uoride can be used in the presence of antimony penta~uoride giving high yields of the di~uoro adducts "Equation "4## ð61JMC593Ł[ Treatment of
28
Halo`en and a Chalco`en
cyclic per~uorinated ethers with aluminum trichloride is reported to give the corresponding a\a\a?! trichloro ether in good yield "Equation "5## ð67JFC"01#248Ł[ Cl Cl
Cl O
Cl
75%
CF3
Cl F
F
SbF3, 60 °C
Cl
F
O F
F
O
F
SbF3, 60 °C
F
70%
CF3
F
F F
O
Cl F Me
Cl
Br
O
Br
F
51%
Br
CF3 Cl
F
SbF3, 117 °C
Me
O
Br
F
F
CF3 F
Cl
SbF3, ∆
O
Br
F O
67%
Cl
C F3Cl Cl
CF3 F SbF3, ∆
Cl
Cl3C
O
Me 84%
F Cl3C
F
F O
Me
Scheme 6
Cl F Cl
F
F F
O
HF, SbCl3, 0 °C 80%
F
F
F F
O
F
F3C
F O
(5)
F
AlCl3, 143 °C, 19 min 53%
Cl F3C
F O
Cl
(6)
Cl
"iv# From carbonyl derivatives Electrochemical ~uorination of acyl chlorides and esters has been used to prepare compounds of this class[ The process gives moderate yields of cyclic per~uorinated ethers\ but often results in formation of mixtures "Scheme 6# ð67JFC"01#0\ 72JFC"12#012Ł[ Sulfur tetra~uoride has been shown to be e}ective for the conversion of the carbonyl group to a di~uoromethylene group[ Thus\ treatment of a variety of anhydrides\ esters\ and formate esters with sulfur tetra~uoride yields the corresponding di~uoromethylene systems\ often in high yield "Scheme 7# ð59JA432\ 53JOC0\ 69ZOR033\ 64ZOR0561\ 65ZOR0176\ 65ZOR0687\ 72JFC"11#196Ł[ Exposure of aryl!ortho! diacid systems to the same conditions results in ring formation in addition to partial per~uorination "Scheme 8# ð69ZOR1387Ł[ Phosphorus pentachloride has been shown to react with a variety of formate esters to yield the corresponding a\a!dichloro ethers "Equation "6## ð52CB0276\ 56OS"36#36\ 60RTC445Ł[ The analogous addition reactions are also applicable to oxalates and other carboxylic esters\ which constitute high! yielding routes to dichloro ethers\ trichloro ethers\ and dichloroacetates "Scheme 09# ð40JA4057\ 45M212\ 64S416Ł[ a!Chlorination of a!chloro!a!alkoxyacyl chlorides has also been employed\ giving the corresponding dichloroalkoxyacyl chloride in good yield "Scheme 09# ð48CB2069Ł[
39
Halo`ens and any other Elements O
C3F7 HF/3.5 A/dm2, 5 °C, 6.4 V, He 100 ml/min
Cl 20%
F O
F3C
C4H9
HF/3.5 A/dm2, 5 °C, 6.4 V, He 100 ml/min
OMe 21%
F O
C2F5
O OMe
CF3
HF/3.5 A/dm2, 5 °C, 6.4 V, He 100 ml/min
O
19%
F
F O
Scheme 7
Cl
Cl
Cl SF4, 300 °C, 10 h
O
O X
F
F
46%
O
O
F CF3
Cl
O
F O
SF4, HF, ∆
X
O
CF3
F
F
X = H, 61%; 4-NO2, 69%; 3-NO2, 83%; 2-Cl, 71%; 4-Cl, 74%; 4-F, 69%; 3-Me, 63%; 4-Me, 46%; 2-MeO, 36%
OCOCF3
OC2F5
OCOCF3
OC2F5
SF4, HF, ∆ 79%
OCOCF3
OC2F5
OCOCF3
OC2F5 Scheme 8
CF3
CO2H CO2H
SF4, ∆
CO2H
SF4, ∆
O
F O
76%
F
CF3 F
CO2H
CF3 F
O
CF3 F
F
Scheme 9
O R
O
Cl
PCl5, ∆
R
+ POCl3 O
(7)
Cl
R = Me, 84%; But, 68%; Ph, 85%
Another versatile route is o}ered using a\a!dichloromethyl methyl ether as a transfer agent\ in the presence of mercuric chloride[ A variety of aryl formate esters have been converted to the corresponding dichloromethyl ethers using this very high!yielding method "Equation "7## ð60RTC445Ł[
30
Halo`en and a Chalco`en O
PCl5, 80 °C
OPh
Cl
Cl
>50%
OPh
O R
O
O
Cl
PCl5, 85–90 °C, 12 h
R
R
O Et
O
Et
O
R
Cl
R = Me, 75%; Et, 85%
O
Cl
O
Cl
PCl5, 110 °C, 15 h
Et
65%
Cl
O
O
O
Et
O Cl Cl
EtO
Cl
Cl2, 150 °C
Cl Cl
EtO
70%
O
O Scheme 10
O
O MeOCHCl2, HgCl2
X
X
O
Cl Cl
(8)
X = H, 85%; 2-Me, 94%; 3-Me, 90%; 4-Me, 90%; 3-Cl, 90%; 4-NO2, 86%; 3-HCl2CO, 90%
"v# From haloalkoxyalkenes Chlorination of chloroalkoxyalkenes has been used successfully to give the corresponding dichloroalkoxyalkanes in good yield "Scheme 00#[ Typical conditions involve exposure of the alkene to a stream of chlorine gas or dry hydrogen chloride "generated in situ# at −4>C followed by distillation of the product ð46RTC858\ 47CB795Ł[ OEt Cl OEt Cl
Cl
Cl
OEt
EtO
Cl
OEt Cl Cl
dry HCl, –5 °C 73%
Cl
OEt Cl Cl
Cl Cl EtO
OEt Cl Cl
dry HCl, 0 °C 88%
dry Cl2, –5 °C 74%
Scheme 11
"vi# From haloalkenes The addition of primary alcohols to halogenated alkenes proceeds rapidly\ giving dihaloalkoxy! alkanes in high yield[ The reactions are often catalyzed by trace amounts of the corresponding metal alkoxide^ this is often required for addition of less reactive secondary and tertiary alcohols\ which usually give mixtures of products "Scheme 01# ð59JOC882\ 54AFC"3#49\ 63BSF1961Ł[ Electron! withdrawing substituents on the alkene also accelerate the reaction^ thus\ methyl tri~uoroacrylate
31
Halo`ens and any other Elements
reacts faster than methyl acrylate ð62CCC55\ 75ZOR0723Ł[ Addition of oximes has also been accomplished\ merely requiring more elevated temperatures "Scheme 01# ð62CCC55Ł[ Addition of alkyl and trihaloalkyl hypohalites to haloalkenes is another useful route to this class[ A variety of primary and tertiary alkyl hypohalites add cleanly at low temperature "Scheme 01# to give high yields of the adducts ð69JOC2629\ 64JA02\ 64JFC"4#14Ł[ Bis"tri~uoromethyl#trioxide has also been employed for this type of addition reaction\ which is applicable both to acyclic and cyclic alkenes "Scheme 01# ð63JOC0187Ł[ Per~uorinated alkenes are reported to react with sulfur trioxide to give cyclic per~uoro! 1!b!sulfones in excellent yield ð75ZOR0731Ł[ Per~uoroalkenes also react with halogen mono~uoro! sulfates to yield both 1!haloalkyl~uoroalkyl ~uorosulfates and vicinal bis"halosulfonyloxy# ~uoroalkanes ð74IZV548Ł[
F
F
F
F
Cl
F
F
BunOH, 10% Na, 0–38%
F
F
F
OBun
81%
OH
F
F
O
, 5% Na, THF, –10 °C
F
75%
F
F Cl
Br
F
Br
F
EtCO2
O
Br
79%
F N
F
F
Br
EtOH, 10% Na, –10 °C–>16 °C
F OH , DME, 10% Na, 25 °C
F
ClOMe, –80 °C
F
96%
F
F
F
O
O F
CF3 CF3 CF3 , –62 °C–>25 °C
F
CF3
F O F
CF3OO2CF3, 67 °C, 8 h
F
F
N
F
F 3C
95%
F
F O
Cl
F3C
F
EtCO2
92%
F
Et
F
F
CF3 CF3 CF3
O2CF3
F
80%
OCF3
F Scheme 12
Epoxidation of ~uoroalkenes is a convenient route to a\a!di~urorooxiranes[ High yields are attainable at low temperature using moderate to high strength hydrogen peroxide "Equation "8## ð55JOC1201\ 69JOC1943\ 61MI 591!90\ 62ZOR1902Ł[ C4F9
F
F
F
60% H2O2, MeOH, –20 °C, 8 h 82%
F
C4F9 F
F
(9)
O
a\a!Dichlorooxiranes have been used by Corey in the enantioselective synthesis of azido and amino acids "Scheme 02#[ The oxiranes\ generated in situ from trichloromethyl carbinols\ are immediately ring!opened by the SN1 attack of aqueous azide\ subsequent oxidation giving a!azido acids in high yield ð81JA0895Ł[
32
Halo`en and a Chalco`en H R
OH
H
NaOH, NaN3
CCl3
O
R
then KH2PO4
Cl Cl
N3
H
R
CO2H
R = n-C5H11, 89%; C6H5(CH2)2, 91%; c-C6H11, 89%; But, 80% Scheme 13
5[91[0[0[1 Tetracoordinated carbon atoms bearing mixed halogens and one oxygen function "R0CHal1OR1# Selective mono~uorination of dichloro ethers has been used to prepare chloro~uoro ethers in moderate to good yield "Scheme 03# ð60JMC482\ 61JMC593\ 64JFC"5#26Ł[ Another useful strategy is addition of tri~uoromethyl hypochlorite to mixed 0\0!dihaloalkenes giving the dihalo ethers in excellent yield "Scheme 03# ð69JOC2629\ 61JMC595Ł[ The ester BrCF"OPh#CO1Et has been prepared by bromination of ethyl~uoro"phenoxy#acetate ð75JOC844Ł[ Cl F Cl
F
F F
O F
F F
anhydrous HF, SbCl5 (cat.), 0 °C
F Cl
Cl
80%
F
F
F F
O F F
ClOCF3, –80 °C 90%
F3C
O F
F
Cl F
Cl
Scheme 14
5[91[0[0[2 Tetracoordinated carbon atoms bearing one halogen and two oxygen functions "R0CHal"OR#11# Numerous examples of compounds of this class exist\ as the corresponding carbenium ion halide salt\ a consequence of stabilizing in~uence of the alkoxy functions ð61CRV246\ 71S0\ 74HOU"E4#Ł[ The following examples described are clear!cut cases where the chemistry is best described by the covalent species[
"i# From 0\2!dioxolanes Direct formation of 1!~uoro!1!tri~uoromethyl!0\2!dioxolanes has been accomplished by treating aryl ortho!bis"tri~uoroacetic# esters with a mixture of sulfur tetra~uoride and hydrogen ~uoride ð65ZOR0176Ł[ Formation of 1!chloro!0\2!dioxolanes has been achieved using a variety of protocols ð56LA"696#24Ł[ Chlorination of derived ortho!esters with phosphorus pentachloride at elevated tem! peratures is a high!yielding process\ as is direct chlorination of unsubstituted 0\2!dioxolanes "Scheme 04# ð50CB433\ 55CB1514\ 56LA"696#24\ 57LA"619#035Ł[ A related procedure used substitutive chlorination of a 1!acetoxy!0\2!dioxolane using dichloromethyl ether ð58TL4992Ł[ Alternatively\ displacement of chloride from 1\1!dichloro!0\2!dioxolanes has been used ð55CB1514Ł[
"ii# From ortho!formates Decomposition of vinyl ortho!formates is a versatile route to dialkoxymethyl halides[ Treatment of dialkoxy vinyl ortho!formates with either hydrogen chloride or hydrogen bromide results in
33
Halo`ens and any other Elements Cl
O
SOCl2, 80 °C
Cl
O
92%
Cl
O
Cl
O
Cl
O
R1
O
OR2
PCl5, 110 °C
R1
O
R1
O
Cl
R2
= Ph, = Me, 88% R1 = CO2Et, R2 = Et, 53% R1 = H, R2 = Et, 87% Scheme 15
liberation of the dialkoxyhalomethane "Scheme 05# ð60RTC0012Ł[ Alternatively\ substitution of triaryl ortho!formates with acetyl chloride has been reported to give good yields of the chloro! diaryloxymethane ð51CB0748Ł[ OR
OR
HCl or HBr, Et2O, 25 °C, 15 min
O
RO
X
RO R = CH=CH2, X = Cl, 50% R = Ph, X = Cl, 60% R = Ph, X = Br, 50% R = p-Tol, X = Cl, 65% R = C(Me)=CH2, X = Cl, 90% OPh
PhO
OPh
MeCOCl
OPh
81%
Cl
PhO
Scheme 16
5[91[0[1 Halogen and Sulfur Derivatives "R0CHal1SR1 and R0CHal"SR1#1# 5[91[0[1[0 Tetracoordinated carbon atoms with two identical halogen and one sulfur function attached "R0CHal1SR1# "i# From sul_des a!Chlorination of sul_des is a popular route to these compounds\ and a variety of di}erent protocols have proved e}ective including photochemical chlorination and use of thionyl chloride "Scheme 06# ð41JA2483\ 42LA"470#022\ 47LA"505#0\ 48LA"510#7\ 54JOC3900Ł[ The ester MeSCH1CO1Me has been converted into the corresponding a\a!dichloro ester using thionyl chloride and into the dibromo ester by reaction with bromine ð70AG"E#474Ł[
Me
SOCl2, 0 °C, 1.5 h then 95 °C, 4 h
Me
S
Cl Me
Cl
Cl2, CCl4, –20 °C
Me
S
Cl
Me 57%
Scheme 17
Cl
S
77%
S
Cl
34
Halo`en and a Chalco`en "ii# From iodo~uoroalkanes
The photochemical reaction of ~uoroiodo alkanes with both methyl sul_de and dimethyl disul_de has been investigated extensively\ and the radical addition process was found to give good yields of the corresponding di~uoro sul_des "Scheme 07#\ the only drawback being the sluggishness of the reaction ð61JCS"P0#044\ 61JCS"P0#048\ 61JCS"P0#0495\ 61JCS"P0#1327Ł[ Metallation of terminal iodo~uoro! alkanes with methyllithium at −67>C\ followed by addition of sulfur dioxide\ results in formation of a lithium di~uoroalkylsul_nate by attack of the intermediate organolithium species ð78S352Ł[ F
F
F3C F I
F F
F Me
48%
I
S F
MeSSMe, UV, 30 d
F
F
F3C
93%
F
F
F
MeSSMe, UV, 21 d
I
Me
F F S
S F
Me
F
Scheme 18
"iii# From a\a!dichloroalkyl sul_des Dichloroalkyl sul_des react smoothly with antimony tri~uoride in the presence of catalytic quantities of antimony penta~uoride to yield the corresponding di~uoro sul_des "Scheme 08# ð41JA2483\ 54JOC3900Ł[ The substitutions are regioselective for the carbons alpha to the sulfur center as shown by control reactions[ F S
Me
Br
Cl
F
SbF3, SbF5 (cat.) 75%
Me
Cl
Cl
Br
F
S Cl
S
Cl Cl
SbF3, SbF5 (cat.)
Cl
46%
F
F
S F
F F
F
Scheme 19
"iv# From chlorodi~uoromethane Substitution of the chloro group of this haloform with thiols has been achieved using a variety of conditions\ typically involving addition of a sodium thiolate followed by thermolysis "Scheme 19# ð46JA4382\ 68JOC0697\ 74S386Ł[ Some debate exists concerning the mechanism of the substitution\ which appears to have both a carbene and SN1 type character[ A phase!transfer method\ which undoubtedly involves di~uorocarbene\ has been described for preparation of sul_des ArSCHF1 from aromatic thiols ð77JFC"30#136Ł[ Cl
F
PhCH2SH, NaOH 50%, DMF, 65 °C
Ph
S
F
75%
F Cl
F F
Na, MeOH then PhSH, 7 h 63%
Scheme 20
F Ph
S
F F
35
Halo`ens and any other Elements
"v# From thioformates Thioformates react cleanly with phosphorus pentachloride in carbon tetrachloride to yield the corresponding a\a!dichloromethyl sul_des in high yield "Scheme 10#[ An alternative but slightly less e.cient route to such compounds is via halomethylene transfer from dichloromethyl methyl ether\ catalyzed by mercuric chloride ð61RTC238Ł[ O R
R
+ POCl3
R
76–87%
S O
Cl
PCl5, CCl4, –40 °C–>25 °C
S Cl
MeOCCl2, HgCl2, reflux 4 h
R
75–93%
S
Cl
+ MeOCHO S
Cl
Scheme 21
"vi# From alkenes "a# Vinyl sul_des[ Chlorination of 0!chlorovinyl sul_des has been used to generate bis"alkylthio#tetrachloroethanes "Scheme 11#[ In this example the alkene is readily available via thiolate!induced substitution and elimination from the corresponding hexachloroethane ð47CB795Ł[
Cl3C
CCl3
NaSEt
EtS Cl
SEt Cl
Cl2 52%
Cl EtS Cl
Cl SEt Cl
Scheme 22
"b# 0\0!Dihaloalkenes[ Addition of thiols and disul_des to halogenated alkenes proceeds rapidly when they are subjected to either ultraviolet or x!ray radiation to give the corresponding addition products "Scheme 12#[ As expected\ addition of thiolates proceeds without photolytic conditions\ but the reaction rates are heavily dependent on the nature of the haloalkene substitutents[ Mixed chloro! and bromo~uoroalkenes are far more reactive than tetra~uoroethylene\ which requires forcing conditions ð59JA4005\ 50JA739\ 54JOC3900\ 55BCJ1080\ 61JCS"P0#23\ 63JFC"3#096\ 65JCS"P0#0067Ł[ Free! radical addition of tri~uoromethanesulfonyl chloride to haloalkenes under UV irradiation has been employed and gives moderate yields of the tri~uoromethylsul_de adducts "Scheme 12# ð51JA2037Ł[ Thermolysis of tetra~uoroethylene with elemental sulfur is reported to produce _ve!\ and six! membered cyclic sul_des bearing a\a!di~uoromethyl groups in yields ranging from 09) to 59) ð51JOC2884Ł[ Addition of thiols to di~uoroalkenes catalyzed by Triton B is also reported to produce a\a!di~uoroalkyl sul_des in high yield ð49JA2531Ł[ Activated haloalkenes\ including penta~uoro! propene!1!sulfonyl ~uoride\ undergo rapid addition of alkyl hydrosul_des\ yielding 0!alkylthio!1H! penta~uoropropane!1!sulfonyl ~uorides "Scheme 12# ð75ZOR0723Ł[
"vii# From carbon disul_de Treatment of carbon disul_de with elemental ~uorine at −019>C is reported to yield octa~uoro! ethyl methyl sul_de in 59) yield ð66IC1863Ł[
"viii# From a!~uoroalkyl sulfoxides The reaction of the sulfoxide of 3!MeOC5H3SOCH1F with "diethylamino#sulfur tri~uoride gives the di~uorosul_de 3!MeOC5H3SCHF1 "57)# by a Pummerer!type reaction ð89JOC3646Ł[ The sul_de
36
Halo`en and a Chalco`en F
Cl
F
Cl
F
RS
RSH, x-rays, 3–4 weeks, 25 °C
Cl
F
F
R = Me, 71%; Et, 61%; Pri, 74%
F
F
S
O
F
F
PhSH, dioxane, 60–80 °C
F
F
91%
F
F
F
S
Me
90%
Cl
F
F
F
F F
S Ph
F
F
ClSCF3, hν, 2 h (R = H)
F F
S F F
R
F
CF3
R = H, 50%; CF3, 63%
CF3
S
C4H9
66%
Cl
R
CF3
C4H9SH, Et2O, –60 °C
SO2F
Me
F
MeSH, 4M NaOMe
Cl
F
F3C
71%
F
F
F
CF3SH, UV irradiation 15 min
OMe F
Cl
SO2F
F
F
Scheme 23
can be oxidized to the corresponding sulfoxide and sulfone[ The reaction is\ however\ unsuccessful with PhSOCH1F[ 5[91[0[1[1 Tetracoordinated carbon atoms bearing mixed halogens and one sulfur function "R0CHal1SR1# Thiolate additions to mixed chloro~uoroalkenes under both radical and ionic conditions have been employed to synthesize mixed dihalo sul_des of this class "see Section 5[91[0[1[0#[ Typical conditions parallel those for identically substituted haloalkenes\ and product yields are comparable "Scheme 13# ð48LA"510#7\ 51JA2037\ 55BCJ1080\ 63JFC"3#096\ 65JCS"P0#0067Ł[ Alternatively\ treatment of dichloro sul_des with antimony tri~uoride results in monosubstitution of chlorine\ giving the mixed "chloro~uoro#sul_de in good yield "Scheme 13# ð48LA"510#7Ł[ The esters BrCF"SR#CO1Et "R Et and Ph# have been prepared by NBS bromination of the corresponding "ethylthio#~uoroacetate or ~uoro"phenylthio#acetate ð75JOC844Ł[ MeS–, MeSSMe
F
F
F
56%
F
Cl
ClSMe, hν, 26 h
Cl
42%
S
Me
F S
S
Cl Cl
SbF3 72%
Scheme 24
F 3C
F F F
Me
F3C
S Me
Cl
F
S
Cl
Cl F
37
Halo`ens and any other Elements
5[91[0[1[2 Tetracoordinated carbon atoms bearing one halogen and two sulfur functions "R0CHal"SR1#1# As in the case of many compounds described in Section 5[91[0[0[2\ much of the chemistry of compounds of this class is represented by the corresponding halothiolium salts ð55AHC"6#28\ 79AHC"16#040Ł[ Cases illustrated below are con_ned to systems where the chemistry is best represented by the covalently bound species[ "i# From thioacetals Chlorination of 0\2!dithianes has been used to generate versatile 1!chloro!0\2!dithianes which are useful for coupling reactions of this masked carbonyl[ Typical conditions involve either sulfuryl chloride or N!chlorosuccinimide\ and recovered yields are high "Scheme 14# ð65BCJ442\ 66TL774\ 68JOC0736Ł[ SO2Cl2, CHCl3
S
S
95%
S
S Cl
S
S NCS, PhH, 20 °C, 30 min
S
S
95%
S
S Cl
Scheme 25
"ii# From thioformates and ortho!thioesters Ortho!thioesters can be monochlorinated successfully using either phosphorus chlorides or acetyl chloride as donors\ giving moderate yields at elevated temperatures "Scheme 15# ð50LA"537#10\ 66JPR06Ł[ An alternative procedure involves treatment of thioesters with a dichloromethyl aryl ether in the presence of mercuric chloride "Scheme 15#[ This procedure\ however\ is less e.cient in that it requires 1 equivalents of thioester ð61RTC238Ł[ SMe SMe
MeS
SMe
MeCOCl, 70 °C 63%
SMe
Cl
O
SEt SEt
EtS
O
PCl3 O CCl4, 78 °C, 1 h 70%
SEt SEt
Cl
SPh
0.5 PhOCHCl2, HgCl2, 90 °C
SPh
80%
SPh
Cl CF3
S
UV irradiation, 3 h, Cl2CF2
Cl
F 3C
Cl
S Cl
S
93%
CF3 CF2Cl S ClF2C
UV irradiation, 3 h, Cl2CF2
F
83%
F
S S
F CF2Cl
Scheme 26
Halo`en and a Chalco`en
38
"iii# Dimerization of thiocarbonyl compounds A variety of substituted thiocarbonyl compounds are reported to undergo rapid dimerization on irradiation with UV light ð54JOC0264Ł[ The corresponding 0\2!dithietanes are formed in high yields\ and are easily puri_ed by distillation "Scheme 15#[
5[91[0[2 Halogen and Se or Te Derivatives "R0CHal1SeR1 or R0CHal1TeR1# 5[91[0[2[0 Tetracoordinated carbon atoms bearing two halogens and one selenium function "R0CHal1SeR1# A variety of examples of compounds from this class have been reported\ and their preparation often involves transmetallation reactions of metal selenyl dihalomethyl derivatives[ Bis"penta~uoroethyl# monoselenide has been prepared by reaction of selenium powder with the corresponding penta~uoroethyl silver salt ð52JCS0157\ 62JCS"D#1203Ł[ Thermolysis of selenium metal with tetra~uoroethylene in the presence of catalytic amounts of iodine\ however\ results in the formation of a mixture of octa~uoroselenolane and octa~uoro!0\3!diselenane "Scheme 16# ð51JOC2473Ł[ Tetra~uoroethylene also reacts with tetraselenium bis"hexa~uoroarsenate"V## over extended periods of time to yield bis"per~uoroethyl# diselenide in good yield "Scheme 16# ð66CJC2025Ł[ Similar reactions have been perfomed using Se7"AsF5#1\ and Se7"Sb1F00#1\ which both react with tetra~uoroethylene to give the bis"per~uoroethyl# diselenide in nearly quantitative yield ð62JCS"D#1203Ł[ Reaction of selenium metal with tri~uoroiodomethane results in the formation of bis"tri~uoromethyl# mono! and diselenide ð47JCS1828Ł[ Similarly\ reaction of silver hepta~uoro! butyrate with selenium metal results in the formation of hepta~uoropropyl mono! and diselenide ð48ZOB831Ł[ Reaction of this diselenide with mercury results in the formation of bis"hepta~uoro! propylseleno#mercury\ which is a versatile alkylseleno transfer agent "Scheme 16# ð52JCS0157Ł[ Treatment of this\ and related mercurials\ with iodine results in near quantitative conversion back to the bis"hepta~uoropropyl# diselenide ð54JCS6400Ł\ whereas combination with 1 equivalents of iodosilane results in good conversion to the corresponding silyl selenide "Scheme 16# ð51JCS1189Ł[ Diselenides also react with manganese pentacarbonyl hydride to yield the corresponding organo! selenium manganese complexes ð54JCS6404Ł[ It has been reported that chlorination of 1\4!dibromo! selenophene results in the formation of 1\4!dibromoselenophene!1\2\3\4!tetrachloride\ although no details of conditions or yield were provided ð25BCJ046Ł[ Diphenyl diselenide reacts under dissolving metal reduction conditions to form an intermediate sodium selenide[ This species can be intercepted with per~uoroalkyl iodides under photolytic conditions to yield per~uoroalkyl selenides in moderate yield "Scheme 16# ð66ZOR1997Ł[ Bis"per~uoroethyl# monoselenide reacts with iodine monochloride to form di~uoro"per~uoroethyl#selenium in quantitative yield ð65JFC"6#150Ł[ Selenocarbonyl di~u! oride is reported to undergo addition with amines to yield an unstable amino di~uoromethyl adduct ð89JOM"275#210Ł[ Tri~uoromethyl selenocarbonyl ~uoride "Se1C"F#CF2#\ produced by thermal 0\1 elimination of trimethyltin ~uoride from trimethylstannylpenta~uoroethylselenane\ is also reported to undergo similar addition reactions ð89JOM"275#210Ł[ Di~uoromethyl selenoethers ArSeCHF1 can be prepared from chlorodi~uoromethane and ArSe− ð74S386Ł[
5[91[0[2[1 Tetracoordinated carbon atoms bearing two halogen and one tellurium function "R0CHal1TeR1# Di~uoromethyl compounds of tellurium were unknown until the mid!0889s[ A general protocol has been reported in which dimethyl telluride is reacted with either a bis"tri~uoromethyl# cadmium or tri~uoromethylzinc bromide in the presence of acetonitrile and boron tri~uoride "Scheme 17# ð83AG"E#212Ł[ The route is reported to be general for all chalcogens\ thus in a similar manner\ methyl "di~uoromethyl# selenide is also formed^ however\ isolated yields were not reported in either case[ Per~uoroalkyl tellurides\ however\ have been prepared by a variety of means ð64JCS"D#377Ł[ One method involves reaction of per~uoroalkyl radicals on a tellurium mirror\ giving low yields of per~uoroalkyl ditelluride ð52AJC611Ł[ A more e.cient method for the preparation of bis~uoroethyl monotelluride is to react tetra~uoroethylene with Te3"AsF5#1 in a Monel reactor "Scheme 17#[ This method is general\ and manipulation of conditions allows formation of varying amounts of the
49
Halo`ens and any other Elements F
F
F
Se
Se, I2, 250 °C, 7 h
F Se
F
+
F Se 5%
10%
F
F
F
F
F
F
OAg
2 SiH3I, 25 °C
H
71%
Ph
Se
Se
Ph
H
H Si
Se
CF3
F
F F
F Se
F3C
ii, Hg, 48 h 99%
Hg(SeC3F7)2
Se
F
i, Se, 280 °C, 2 h
F
F
F3C
87%
O
F3C F
F
Se4(AsF6)2, 14 d, 25 °C
Hg
F
F
F
F
F
Se
C2F5
i, Na, NH3(liq.) ii, C3F7I, hν
Ph 50%
F
Se
CF3 F
+ HgI2
Se
CF3
F
F
Scheme 27
corresponding ditellurides ð64JCS"D#377Ł[ Per~uoroalkyl tellurides have also been prepared from lithium aryl tellurides "obtained by reduction of diaryl ditellurides with LiAlH3# under photo! chemical conditions "Scheme 17# ð68ZOR0450Ł[ Cd(CF3)2, MeCN, BF3, –30 °C
Me2Te
Me
F
Te F
F F
F F
Te4(AsF6)2, 100 °C, 15 atm 87%
F F3C
F
F
F CF3
Te
C3F7I, hν, 30 min
TeLi
Te 44%
C2F5 F
F
Scheme 28
5[91[0[3 Halogen and Mixed Chalcogen Derivatives "R0CHal"OR1#"SR2## Chemistry of these systems is chie~y described by the corresponding oxathiolium salts\ thus excluding their detailed coverage in this section[ The reader is encouraged to consult references describing such systems ð63JHC832Ł[
5[91[1 FUNCTIONS CONTAINING HALOGEN AND A GROUP 04 ELEMENT AND POSSIBLY A CHALCOGEN 5[91[1[0 Halogen and Nitrogen Derivatives] General Considerations Compounds of this general class are somewhat unstable\ with the major contributing isomeric forms being the corresponding haloiminium salts\ for example\ RCHal1NR0R1\ which behaves as
Halo`en and a Group 04 Element
40
RC1N¦R0R1 Hal− ð59AG725Ł[ The degree to which such quaternary salts are formed depends on the overall basicity of the amino "and chalcogen# groups^ thus\ for most compounds of the classes RCHal1NR0R1\ RCHalNR0R1OR2 and RCHalNR0R1SR2 both species must usually be considered whereas\ for compounds of class RCHal"NR0R1#1\ the overriding chemistry is that of the halide salt\ the only exceptions being in cases where "NR0R1#1 1 "NO1#1\ where the electron!withdrawing capacity of the nitro groups diminishes the tendency to ionize[ Several review works discuss this dynamic equilibrium and should be consulted further ðB!65MI 591!90\ B!68MI 591!90\ B!68MI 591!91\ B!68MI 591!92\ B!68MI 591!93\ B!68MI 591!94\ 74HOU"E4#Ł[
5[91[1[0[0 Tetracoordinate carbon atoms bearing two halogens and one nitrogen function Numerous examples exist of compounds in this category[ In many cases\ however\ the chemistry of the product is often described by the corresponding haloiminium salt ð68S130Ł[ All examples described here re~ect cases where product equilibria lie in favour of the covalent species[
"i# From imines Addition of halocarbenes to imines has been successfully used to form 1\1!dihaloaziridines bearing a variety of substituents "Scheme 18# ð48CI"L#0105\ 51JOC2575\ 60JOC2516\ 62ZOR1235\ 63JOC047\ 65JOC2683\ 66ZOR0746\ 67JOC0235\ 68H"01#526Ł[ Methods for formation of the requisite dihalocarbene vary as does the e.ciency of the addition reaction "Scheme 18#[ Addition of ClF to imines takes place at room temperature\ to give N!chloro~uoroalkanes in high yield "Scheme 18# ð64IC0112Ł[ Cl Ph
CHCl3, KOBut, 25 °C, 18 h
N
X
N X = H, 80%; Cl, 68%; OEt, 91%
Ph N
Ph
Cl N
X
Ph Br
HCBr2Cl, KOBut, hexane, 25 °C, 3 h 61%
Ph
Cl
Cl
Cl N
Ph Cl
Ph
Cl
PhHgCCl2F, benzene, 80 °C, 40 h 74%
Cl
N Cl
Ph
Scheme 29
"ii# From amines A variety of halogenation procedures have been applied to tertiary amines\ yielding the cor! responding dihaloaminoalkanes with good conversion[ Yields obtained for di~uoroaminoalkanes using electrochemical ~uorination methods are usually modest\ halogen substitution using sulfur tetra~uoride being a far superior method "Equation "09##[ Perchlorination is also an e}ective route\ giving high yields of a\a!dichloroalkylamines "Scheme 29# ð48CCC3937\ 58LA"629#039\ 66JFC"8#168\ 79JFC"06#54\ 70AG"E#536\ 70ZAAC"363#6Ł[
41
Halo`ens and any other Elements F3C F
CF3 F
F
F3C
98%
F
N
(10)
CF3
Cl
F
Me
N
F
electrochemical
Me
Cl
F
F
ClF, 6 h, 25 °C
N
F
F3C
fluorination 51%
CF3
N
CF3
Cl
F
F
SF4
Cl
N
Cl
F
quantitative
N
Me
F
Me Cl
Cl
N
Cl2
Me
Cl 80%
Me
N Cl
Cl Cl
CCl3 Cl
Scheme 30
"iii# From amides and thioamides Treatment of formamides with chlorinating agents such as thionyl chloride and phosgene often results in formation of dichloroaminoalkanes which exist in equilibrium with the derived chloro! iminium salts "Scheme 20# ð48HCA0542\ 53CB0250\ 68MI 591!91Ł[
+
H
R
R
N
N
Cl– +
COCl2
CHO
H
R
R
N
N
Cl– Cl
H
R = Me, 80%; Ph, 92%
Me
Cl–
Me SOCl2
N
+
Me O
Cl Cl
Me
N 98%
Cl
R N Cl
Cl
Me
R N
Me
Cl
N Cl
Scheme 31
Many such systems of this class have been prepared where electron!withdrawing groups limit the possibility of salt formation[ A wide range of halogenation protocols have been successfully used in these instances\ with a generally high level of conversion to product[ These methods are useful not only for amides but also for thioamides "Scheme 21# ð59JA432\ 51JA3164\ 63JA814\ 64IC0112\ 65ZOR1102\ 67CB810\ 67JOC0616\ 68AG"E#504\ 70JFC"07#82\ 71PJC0258Ł[ Treatment of DMF with carbonyl di~uoride is also reported to give a good "71)# yield of di~uoro"dimethylamino#methane ð51JA3164Ł[
"iv# From acyl halides Treatment of acyl ~uorides with tetra~uorohydrazine under photolytic conditions results in formation of the corresponding N\N!di~uoroaminoalkane "Equation "00##[ One drawback of this radical addition protocol is the requirement that quartz reaction vessels be used ð57JOC2564Ł[
Halo`en and a Group 04 Element CF3
O
Cl CF3
Cl
PCl5, 25 °C, 6 h
CF3
N
F3C
42
O
F N
F15C7
CF3
N
F3C
99%
F
SF4, HF, 150 °C, 18 h
CF3
N
F15C7
78%
CF3
CF3
CF3 O
F N
FCOF, 25 °C, 20 h
Me
F
82%
Me
N
Me
Me
Me N
Me
SF4, KF, 150 °C, 144 h
N Me
90%
F
O O F3C
N
Cl2, CCl4, 20 °C
Et
70%
Cl
Cl
F3C
N
Me
F
Et
Et
Et Scheme 32
O C3F7
N2F4, 40 h, 20 °C, hν
(11)
C3F7NF2
90%
F
"v# From nitriles Chloro~uorination of nitriles is a mild and convenient method for preparation of N\N!dihalo! aminoalkanes[ The reactions have only been reported for nitriles bearing electron!withdrawing groups\ but yields are good to excellent "Scheme 22#[ The intermediate haloimine can be exposed to elemental ~uorine to give N!~uorochloroamines or it can be reacted sequentially with ClF to yield N\N!dichloroamines ð55IC377\ 68JA6539\ 70IC0Ł[ Addition of hydrogen ~uoride to a mixture of HCN and carbonyl ~uoride\ catalyzed by caesium ~uoride\ is reported to yield di~uoromethylcarbamoyl ~uoride\ CHF1NHCOF "69)# ð51JA3164Ł[ Treatment of per~uorinated cycloalkyl nitriles with silver ~uoride at elevated temperature is reported to yield the corresponding per~uorinated cyclo! alkylmethylazo compounds ð73JCS"P0#344Ł[ F
F
R
N
ClF, 0 °C
R
N
ClF, –195 °C
R
Cl
Cl NCl
F F2, –25 °C, 1 h R = CF3, 75%; ClF2C, 70%
F
F
R
N
F
Cl Scheme 33
"vi# From haloiminium salts Treatment of haloiminium salts with hydrogen halides provides a facile route to a!dihaloamines "Equation "01##[ The reactions are typically conducted at or below 9>C in chlorinated solvents\ and
43
Halo`ens and any other Elements
yields of addition products\ which are in equilibrium with their corresponding hydrohalide salts\ are good to excellent ð50CCC2948\ 51CCC1775\ 52CCC1936Ł[ X
+
Me
N
(12)
N
X = Br, 98%; I, 82%; Cl, 77%
Me
Me
X
HX, CHCl3, 0 °C
X–
Me
X
"vii# From haloalkenes and haloalkanes Addition of diethylamine to chlorotri~uoroethene results in the formation of the corresponding diethylaminoalkane in moderate yield "Equation "02## ð70AG"E#536Ł[ The product\ 1!chloro!0\0\1! tri~uorotriethylamine "CTT#\ is a ~uorinating agent ð48JGU1014Ł[ A similar addition reaction has been applied to related secondary amines ð70JFC"07#82Ł[ N!Iodobis"ditri~uoromethyl#amine is reported to add to hexa~uoropropene under photochemical conditions to give "F2C#1NCF1CFICF2 in low yield ð60JCS"C#2722Ł[ ð2¦1Ł Cycloaddition of benzyl azide to hexa~uoropropene gives an intermediate triazoline in 74) yield\ which undergoes thermal decomposition at 149>C to give the corresponding 0!benzyl!1\2\2!tri~uoro!1!"tri~uoromethyl#aziridine "63)# ð55JOC678Ł[ Cyclo! addition of per~uorobutadiene to tri~uoronitrosomethane is reported to give per~uoro!1!methyl! 2\5!dihydro!0\1!oxazine in 59) yield ð54JCS5038\ 55ZOB617\ 56JCS"C#1152Ł[ The azido ester BrCF"N2#CO1Et has been prepared "36)# by reaction of ethyl dibromo~uoroacetate with sodium azide ð75JOC844Ł[ F Cl
F
F
Et2NH 61%
F
Et N
Cl F
(13)
Et
F
CTT
"viii# Routes speci_c to dihalonitroalkanes "a# From nitromethanes[ Di~uoronitromethane reacts with formaldehyde under basic conditions to give 0\0!di~uoro!0!nitroethanol in 77) yield "Scheme 23# ð56ZOB041Ł[ Reactivity of its stabilized anion extends to Michael!type processes\ but only moderate yields of addition products are obtained even for addition to such activated systems as acrylonitrile and ethyl acrylate ð68IZV0800Ł[ Dibromo! nitromethane is reportedly formed when nitromethane is exposed to t!butyl hypobromite ð65JOC0174Ł\ and 0\0!dibromoethane has been prepared from nitroethane by sequential reaction with butyllithium and bromine ð78ZOR1389Ł[ F F
HCHO, K2CO3, H2O
NO2
F
88%
X , NaOEt, K2CO3
F NO2
X = CO2Et, 27%; CN, 13%
F
HO F
NO2
F
X F
NO2
Scheme 34
"b# From haloalkenes[ Fluoroalkenes are reported to react with sodium nitrite in polar aprotic solvents to furnish ~uoronitroalkanes in moderate yield "Scheme 24# ð63IZV1033Ł[ Similar addition reactions can be accomplished using perhaloalkenes and a mixture of concentrated nitric and hydro~uoric acids ð52IZV0835Ł[ 0\1!Dichloro!0\1!di~uoroethylene is converted by nitration followed
Halo`en and a Group 04 Element
44
by reaction with fuming nitric acid into chloro~uoronitrosomethane\ which can then be oxidized to chloro~uoronitromethane ð89MI 591!90Ł[ F
F
F
F3CO
F
F
F
Cl
NaNO2, DMF, 3 d
F
F3CO
50%
F
HNO3 (100%), HF, 20 °C, 7 h
F
F
F
F
Cl
88%
NO2
NO2
F Scheme 35
"c# From nitro alcohols[ 1!Fluoro!1!nitro!0!butanol reacts with aqueous sodium hypobromite to give 0!bromo!0!~uoro!0!nitropropane "Equation "03##[ The reaction is believed to proceed via a transient a!~uoronitronate salt ð69JOC735Ł[ F
NO2 OH
Et
NaOBr, NaOH (aq.), 10 °C, 40 min
F
57%
NO2
Et
(14)
Br
5[91[1[0[1 Tetracoordinate carbon atoms bearing one halogen and two nitrogen functions In all cases in which the nitrogen functions are amino groups\ attempts to prepare compounds of this class results in the formation of the corresponding haloiminium salts[ Examples are widespread\ covering simple amines ð54CB0967\ 62LA39\ 64LA084Ł\ cyclic amines ð50CB1483\ 58RTC178Ł and hydra! zines ð60JOC0044Ł[ One class of compounds within this category which retains stability\ however\ are the halo! diazirines "Scheme 25#[ Typical conditions involve exposure of an acetamidine to bromide saturated DMSO with sodium chlorite] the so!called {Graham conditions| ð54JA3285\ 56JA071\ 57JOC0736\ 70JA5053\ 76TL4790\ 78ACR04Ł or treating N\N!dihaloamidines with base "Scheme 25# ð70JOC4937Ł[ N R
N F3C
H NH2
Cl TRIGLYME, DMSO, 10% NaOH, NaCl, 0 °C
NHCl
NaOCl, NaBr DMSO, LiBr 30%
R = Pri, 49%; MeO, 43%
N N F3C
Br
N N R
tbaf, MeCN 50%
Cl
N N F 3C
F
Scheme 36
"i# Tetracoordinate carbon atoms bearin` one halo`en and two nitro `roups "RCHal"NO1#1# Nearly all compounds in this class have been prepared from the salts of dinitroalkane anions\ reacting with a halogenating agent[ They are grouped according to the nature of the halogenation procedure employed[ "a# Usin` elemental halo`ens[ Typically\ conditions involve formation of the potassium salt of the dinitroalkane\ followed by exposure to the halogen source in situ[ The salts are either prepared by treating the dinitroalkane with the required potassium base or\ in the case of dinitromethane\ via a Ter Meer reaction with chloronitromethane\ itself available by chlorination of nitromethane[ The most commonly used procedure is to pass a ~uorineÐnitrogen mixture into the aqueous solution of the salt at or close to 9>C "Scheme 26# ð57IZV320\ 57IZV1296\ 58IZV0220\ 62IZV0313\ 67JOC2374Ł^ xenon di~uoride is also e}ective as a ~uorinating agent ð76ZOR0546Ł[ Similarly high yields have also
45
Halo`ens and any other Elements
been obtained using the sodium or ammonium salts of dinitroalkanes ð57IZV801Ł and of 1\1! dinitropropane!0\2!diol in which one of the hydroxymethyl groups is cleaved "Scheme 26# ð57JOC2979Ł[ Chlorination of the sodium salts are also reported to give excellent yields of the derived chlorodinitroalkane "Scheme 26# ð58IZV1506\ 76IZV295Ł\ and bromodinitromethane has been prepared by reaction of the sodium salt of dinitromethane with bromine[ ICl has been used to form the corresponding iododinitroalkanes ð66IZV1947Ł[ NO2
NO2
F2, H2O, 0–5 °C
K+
–
NO2
R
F
NO2
R
R = H, 65%; CH2CH2CN, 60%; CH2C(NO2)2, 81%; p-C6H4NO2, 62%; m-diC6H3NO2, 92% NO2 NO2
O2N
76%
NO2
NO2
NO2
NO2
HO
F NO2
84%
Na+
–
NO2
NaOH, H2O, F2, 2.5 h, 0–5 °C
NO2 NO2
F
82%
OH
+ NH4F
NO2
NaOH, H2O, F2, 2 h, 0–5 °C
NO2
HO O2N
F O2N
90%
I
NO2
R
F2, N2, H2O, 1 h, 2–3 °C
NH4+
–
NO2
ICl, CCl4, 10–15 °C
K+
–
NO2
NO2
Cl2, 0–5 °C 99%
Cl
NO2
Scheme 37
"b# Usin` perchloryl ~uoride[ Most work in this category has been conducted using potassium salts of the dinitroalkanes\ providing a generally high yielding approach to the desired ~uoro! dinitroalkanes "Equation "04## ð57JOC2962\ 69IZV276\ 60IZV0376Ł^ similar results "albeit with inferior yields# are obtained using sodium salts ð61JOC041Ł[ For systems where the corresponding salts of dinitroalkanes are unstable\ use of hexamethylphosphoramide "HMPA# and perchloryl ~uoride is reported to allow e.cient ~uorination within 1 hours "Scheme 27# ð58IZV0077Ł[ Interestingly\ exposure of ClOSO1F to cyano!substituted dinitroalkane salts results in formation of the derived N!chloroimidates "Scheme 27# ð65IZV378Ł[ NO2 –
K+
NO2
FClO3, MeOH, 25 °C
F
NO2
R
R
(15)
NO2
R = Ph, 95%; CH2CH2CO2Me, 88%; CH2NHCOPh, 88%; CH2CH2NHCOMe, 93%; CH2CH=CH2, 69%
"c# Usin` hydro`en halides[ Treatment of sulfonium dinitroylides with hydrogen halides results in rapid formation of the corresponding halodinitroalkane "Equation "05##[ The cleavage method is applicable to a range of electrophilic halogen sources including elemental halogens and hypohalites\ with a dialkyl sul_de being the chief by!product ð66IZV028Ł[ NO2 Me
+
S Me
NO2
excess HX, MeCN
+ Me2S
–
NO2
X = Br, 76%; Cl, 89%
X
NO2
(16)
Halo`en and a Group 04 Element NO2
NO2
O2N
FClO3, HMPA, 2 h, 20 °C 88%
NO2
NO2 –
NC
Na+
ClOSO2F, 16 h, 20 °C
NO2 NO2 F
NO2
F O2N
NO2
Cl
N
O2N
66%
NO2
46
Cl
OSO2F Scheme 38
"d# Functional `roup interconversion of dinitrohaloalkanes[ The ~uorodinitromethanide anion undergoes a variety of additional transformations relevant for this section[ Most importantly\ under basic conditions\ 0\ 1 additions to aldehydes are possible to yield secondary alcohols ð69JOC2077Ł\ as are 0\ 3 additions to conjugated alkenes ð68S200Ł\ giving high yields of addition products in both cases[ Related examples of compounds incorporating this functionality where the dinitrohalo group is left intact include acid!catalyzed dimerization of dinitro~uoroalcohols ð58JOC34Ł\ hydrolysis of ~uorodinitroacetonitrile to yield ~uorodinitroacetamide ð57JOC0146Ł and dehydroxymethylation of 1\1!dinitro!1!~uoroethanol ð58JOC34Ł[
"ii# Tetracoordinate carbon atoms bearin` one halo`en\ one nitro `roup and one other nitro`en function An example of this class is the ester BrC"N2#"NO1#CO1Et\ which was obtained in low yield from ethyl dibromonitroacetate by reaction with sodium azide ð75JOC844Ł[
5[91[1[0[2 Tetracoordinate carbon atoms bearing one halogen\ one nitrogen and one oxygen function Based on the previous discussions concerning the stability of ortho!ester halides attached to basic functionality\ salt formation is predominant[ Probably the best studied example of this class is the Vilsmeier reagent and related systems\ formed when formamides are exposed to chlorinating agents "Scheme 28# ð47CCC341\ 48HCA0548Ł[ The equilibrium lies heavily in favour of salt formation\ explain! ing in this case\ and related examples ð58TL1050\ 60CPB1518Ł\ why members of this class have received scant attention[ Other examples can be found describing intermediate formation of this class of compound\ which quickly undergoes rearrangement to give the halide salt ð57JOC0973\ 69CPB673\ 61TL3106\ 62TL3400\ B!68MI 591!92\ 79IZV1245Ł\ and in some cases to give enamines ð54JOC3292\ 57T3106Ł[ R +
R R
R
R POCl3, CH2Cl2
N
R O
N
N
Cl [PO2Cl2]–
Cl OPOCl2
R +
R
N
OPOCl2
Cl–
Scheme 39
5[91[1[0[3 Tetracoordinate carbon atoms bearing one halogen\ one nitrogen and one sulfur function Compounds of this class in which the nitrogen function is an amino group are nearly always found in the form of the corresponding iminium halide salt ðB!68MI 591!94Ł[ The exceptions are nitrohalosul_des[ 0!Chloro!0!chlorosulfenylnitroalkanes have been reported ð74HOU"E4#Ł and the esters PhS"NO1#CXCO1Et "X Br\ and F# have been prepared by halogenation of the ester PhS! "NO1#CHCO1Et ð75JOC844Ł[
47
Halo`ens and any other Elements
5[91[1[1 Halogen and Phosphorus Derivatives 5[91[1[1[0 Tetracoordinate carbon atoms bearing two halogen and one phosphorus function and one halogen and two phosphorus functions "i# From haloalkenes Addition of phosphine to ~uoro and chloro~uoroalkenes is a general route to compounds of this class[ Generally\ the addition reactions are conducted at elevated temperatures\ often in sealed tubes[ Phenylphosphine has also been employed\ with only slight loss of e.ciency resulting "Scheme 39# ð48JA3790\ 54AFC"3#49Ł[ If the reactions are conducted under photolytic conditions\ however\ yields are often substantially improved\ with 73) for the addition to tetra~uoroethylene reported ð52JCS0972Ł[ F
F
X
F F
F
F F
PH3, 150 °C, 8 h
F F
X = F, 53%; Cl, 54%
PPhH2, 150 °C, 8 h 45%
F P
X
H
F
F
F
P F
H
Ph
H
Scheme 40
"ii# From haloalkanes Thermolysis of carbon tetra~uoride with red phosphorus in the presence of iodine results in the formation of a cyclic bis"phosphine# in moderate yield "Scheme 30# ð51JOC2473Ł[ 1\1\1!Trichloro! acetic amidines and imidates react with trialkyl phosphites to yield 1\1!dichloro!1!"dialkoxyphos! phinyl#acetamidines and acetimidates\ respectively "Scheme 30# in good to high levels of conversion ð68ZOB0914Ł[ If the reactions are prolonged\ a second substitution occurs giving a monohalobis"dialkylphosphinyl# derivative[ Addition of chlorodi~uoromethane to sodium diethylphosphonate results in the formation of diethyl di~uoromethylphosphonate ð48JGU0004Ł[ The mechanism of this reaction appears to involve capture of di~uorocarbene rather than an SN1 type process[ Prompted by research on purine nucleoside phosphorylase inhibitors\ it has been shown that diethylphosphinyldi~uoromethyllithium condenses with ortho!a!bromoxylene to give the corresponding di~uorophosphonate in 32) yield "Scheme 30# ð81BMC396Ł[ Interestingly\ other metal dialkylphosphinyldi~uoroalkane derivatives proved vastly inferior in this reaction[ Diisopropylphosphinyldi~uoromethyllithium was shown to give good yields of the 0\1!addition product to o!tolualdehyde at low temperature "Scheme 30#^ the benzylic alcohol was subsequently converted into the tri~uoro derivative using diethylaminosulfur tri~uoride ð81BMC396Ł[ Diethyl "lithiodi~uoromethyl#phosphonate has also been used to introduce the a\a!di~uorophosphonate moiety into phosphate isosteres ð81TL0728\ 83TL2116Ł[ Though alkyl halides are often poor substrates in such coupling reactions\ Martin has reported conditions for addition to aldehydes\ where the resulting product carbinols are deoxygenated using a Barton!type protocol ð81TL0728Ł[ The process is versatile\ tolerant of latent functionality\ and complements existing methods for the introduction of this important moiety ð70JFC"07#086\ 71TL1212\ 78JOC502\ 78TL6902\ 80TL0908Ł[ Dialkyl "iodo~uoro! methyl#phosphonates\ available from dialkyl "bromodi~uoromethyl#phosphonates\ are reported to undergo reductive dimerization to yield tetra~uoroethyl derivatives using cadmium powder\ re~ux! ing in methylene chloride "Scheme 30# ð83JOC1282Ł[ The corresponding dialkyl "bromo! di~uoromethyl#phosphonates fail to undergo this coupling using cadmium\ but this was _nally e}ected using a nickel derivative[ The nickel approach also facilitated dimerization of a dialkyl "iodotetra~uoroethyl#phosphonate\ giving the coupled product in 37) yield ð83JOC1282Ł[ The addition of diethyl trichloromethylphosphonate to alkenes\ catalyzed by copper chloride\ has been reported ð83TL2426Ł[ Ethyl acrylate thus gives the corresponding dichlorophosphonate in moderate yield "Scheme 30#[
Halo`en and a Group 04 Element
48
I F CF4
P(red), I2, 220 °C, 8 h
F
28%
F
F
P
F F
P
F
F
I NH Cl
NH2
Cl
P
RO
R = Et, 84%; Prn, 62%
NH (RO)3P, CH2Cl2, 50 °C, 1.5 h
RO
R = Et, 70%; Prn, 85%
RO
OMe
Cl
Cl NH
Cl
F
P Cl
O
NH
P
OEt P OEt O
F Li
F P O
CHO
F
O
OPri OPri
F
MeO MeO
EtO EtO
O
P
P
Br
F
F
F
F
Zn, NiCl2(PPh3)2 Et4NI, MeCN, 45 °C
EtO EtO
Cl Cl
P Cl
59%
Scheme 41
F
O
OPri OPri
F P
F
O
OEt OEt
F
P
P
OMe OMe
F
F
O
O
F
F F
F
P
P F
OEt OEt , CuCl
F
O
P
48% O
O
MeO
47 %
Zn, NiCl2(PPh3)2 Et4NI, MeCN, 45 °C
O
F
MeO
F
EtO
EtO EtO
Br
F
OH
69%
F
O
P
Cd, CH2Cl2
I
OEt OEt
F
, THF, –78 °C
O
F
F P
80%
EtO
NH2 Cl
43%
Br
P
OMe
Cl
F
Li
EtO
NH
EtO EtO P EtO O
62%
Cl
Cl
O
EtO
(EtO)3P, CH2Cl2, 85%, 2 h
NH2
Cl
NH2
Cl
Cl
Cl
NH
O
RO
(RO)3P, CH2Cl2, 50 °C, 1.5 h
F F
O
F O P
EtO Cl Cl
Cl
O
OEt OEt
OEt OEt
59
Halo`ens and any other Elements
5[91[1[2 Halogen and Arsenic Derivatives 5[91[1[2[0 Tetracoordinate carbon atoms bearing two halogens and one arsenic function Dimethylarsine is reported to add to hexa~uoropropene to give the corresponding dimethylarsenic derivative "Scheme 31# ð54AFC"3#49Ł[ Unfortunately\ no details either of yield or of conditions for this process were reported[ Another report describes the reaction of tetramethyldiarsine "{cacodyl|# with hexa~uoropropene to produce a ~uorodiarsine in 07) yield "Scheme 31# ð53CJC0012Ł[ Me Me
F
F
F
Me2AsH
As
CF3
F
F
F
Me F
Me2AsAsMe2
CF3
As
Me
18%
F3C
F As
Me
F Me
Scheme 42
5[91[2 FUNCTIONS CONTAINING HALOGEN AND A METALLOID AND POSSIBLY A CHALCOGEN AND:OR GROUP 04 ELEMENT 5[91[2[0 Halogen and Silicon Derivatives A variety of a\a!dihaloalkylsilanes are known but few general methods for their preparation exist ð53CB0562Ł[ The following examples cover speci_c cases where conditions have been examined and optimized[
"i# Dichlorocarbene additions Addition of dichlorocarbene "generated from phenyl"bromodichloromethyl#mercury# to a variety of silanes has been reported\ giving good yields of a dichloromethyl silanes "Scheme 32#[ Competition experiments have been carried out in order to determine the kinetics and the precise mechanism of this electrophilic addition process ð56JA0427\ 57JA1833\ 82T7376Ł[ Me Si Me
Cl
PhHgCCl2Br, PhH, 80 °C
Si
58%
Me
Me
Cl Me
Me
Si H
Si
PhHgCCl2Br, PhH, 80 °C
Cl
68%
Me Si R
Me
H Me
Cl
R 34–67%
Me Cl
Si
PhHgCCl2Br, PhH, 80 °C
Cl
Scheme 43
"ii# Other additions to silanes Low temperature metal halogen exchange of bis"trimethylsilyl#dichloromethane followed by protonation has been used to prepare bis"trimethylsilyl#chloromethane "Scheme 33# ð60JOM"18#278\ 89T2748Ł[ Bromination of alkynylsilanes has also been reported\ the major isolated addition product being the tetrabromosilane in nearly quantitative yield "Scheme 33# ð56IZV582Ł[ An alternative
50
Halo`en and a Metalloid
approach to dihalosilanes is cleavage of a bis"trichloromethylsilyl#dichloromethane using hydro! chloric acid "Scheme 33#\ with the a\a!dichloromethylsilane being formed in 76) yield ð53CB0004Ł[ Another report describes alkyl Grignard addition to trichlorosilyldichloromethane\ which yields using methylmagnesium bromide\ trimethylsilyldichloromethane "50)# ð55CB682Ł[ Photochemical addition of silyl radicals to per~uorinated alkenes has also been employed\ UV irradiation of silane in the presence of tetra~uoroethylene giving a 50) yield of 0\0\1\1 tetra~uoroethylsilane in 07 h ð54JCS1090Ł[ Similarly\ photochemical addition of the chlorosilyl radical derived from methyl! dichlorosilane to tetra~uoroethylene results in a 87) yield of the a\a!di~uorosilane adduct ð57ZOB1702Ł[ Lithiation of 0\5!dibromodeca~uorohexane\ followed by addition of trimethylsilyl chloride\ results in formation of 0\5!bis"trimethylsilyl#deca~uorohexane in 55) yield ð58JOM"05#22Ł[ BunLi. –110 °C
Cl
CH2Cl2 + 2 TMS-Cl
TMS
64%
Me Me Si Me
Cl
i, BunLi, –110 °C
Cl TMS
ii, EtOH, –65 °C 73%
Br2, 50 °C, then 80 °C, 12 h
Me
97%
Me
Me
TMS
TMS
Br
Si
Br
Br
Br
HCl
Cl2CHSiCl3 + SiCl4
Cl2(SiCl3 )2 87%
Cl
NCS, CCl4
TMS
SMe OMe
TMS
SMe
TMS
60%
SMe Cl
Cl2, CCl4, Et3N 69%
TMS
OMe
Scheme 44
Preparation of systems containing a metalloid\ halogen and chalcogen have also been reported[ Chlorination of "methylthiomethyl#trimethylsilane has been accomplished\ giving ðchloro! "methylthio#methylŁtrimethylsilane in 59) yield "Scheme 33# ð78T526Ł[ Additionally\ ðmethoxy"methylthio#methylŁtrimethylsilane "itself prepared from ðchloro"methylthio#methylŁ trimethylsilane by addition of sodium methoxide# has been converted to ðchloro"methoxy# methylŁtrimethylsilane "Scheme 33# in 58) yield\ using traditional chlorination conditions ð78T526Ł[ 5[91[2[1 Halogen and Boron Derivatives Compounds of this class are extremely unstable\ which accounts in part for their general lack of utility in synthesis[ The general mechanism for the decomposition of a!bromoalkylboranes "formed from trialkylboranes and bromine# appears to involve HBr!induced cleavage which may proceed via a radical pathway\ rather than by simple rupture of the C0B bond ð69JA6101Ł[ Treatment of a\a!dihaloalkylboranes with nucleophiles such as water also induces rearrangement\ providing a route\ after oxidation\ to secondary alcohols ð60JA1685Ł[ An a\a!dichloroalkylborane was prepared by Seyferth by dichlorocarbene insertion into a trialkylborane "Scheme 34#^ however\ spontaneous rearrangement occurred with subsequent elimination from the chloroborane species ð55JA0723Ł[ It is reported that the stability of the intermediate a\a!dichloroalkylborane is a function of the borane R group\ and that triarylboranes "R Ph# yield the more stable adducts[
R3B
70 °C, 40 min
R=
Prn,
R
PhHgCCl2Br
Bun,
R
R
B
R
Cl
Cl
Ph Scheme 45
Cl
B
R
Cl
R
51
Halo`ens and any other Elements
5[91[2[2 Halogen and Germanium Derivatives Trichlorogermane has been shown to undergo addition to chlorinated alkenes\ and this constitutes an excellent route to a\a!dichloroalkylgermanes "Scheme 35# ð59DOK"020#87Ł[ Photochemical chlori! nation of alkylgermanium compounds has also been reported\ giving moderate yields of the a\a! dichloro species "Scheme 35# ð56ZOB0939Ł[ Bis"per~uoroalkyl#mercury compounds have been shown to react with germanium tetrahalides to produce per~uorogermanium alkyls in good yield "Scheme 35# ð67JA0611Ł[ The trihalo"per~uoroalkyl#germanium compounds produced are versatile synthetic intermediates\ since they react with dialkylcadmium reagents to give alkyl "per~uoro! alkyl#germaniums ð67JA0611Ł[ Bis"triethylgermyl#mercury undergoes exchange with bis"halo! alkyl#mercury compounds\ to yield mixed haloalkyl "triethylgermyl#mercurials ð61JOM"23#188Ł[ These mixed mercurials react with caesium ~uoride to produce haloalkyl germaniums in good yield "Scheme 35# ð61JOM"23#188Ł[ Bis"trialkylgermyl#mercury reacts with bis"haloalkyl#mercury compounds to produce a variety of mixed haloalkyl germanium species ð61IZV74Ł[ The intermediate is presumably a mixed "triethylgermyl#mercury species\ and the isolated yields are good to excellent ð61IZV74Ł[ Cl
Cl
Cl
Cl
F3C
Cl HGeCl3, 80 °C, 2 h 48%
GeCl3
Cl Cl
Cl2, hν
GeCl3
58%
GeCl3
F3C Cl
CsF, THF, 5 min
Et
75%
Et
Et3GeHgC2F5
Et
75%
Et
Et3GeHgCFClCF3
(C2F5)2Hg
GeBr4, 195 °C
Br
45%
Br
Ge
(C2F5)2Hg
I
53%
I
CF3 F
Et Ge
CF3
Cl
F
Br Ge F
GeI4, 135 °C
Cl
Et
F CsF, THF, 5 min
Cl
CF3 F
I Ge F
CF3 F
Scheme 46
5[91[3 FUNCTIONS CONTAINING HALOGEN AND A METAL AND POSSIBLY A GROUP 04 ELEMENT\ A CHALCOGEN OR A METALLOID 5[91[3[0 Halogen and Lithium Derivatives Under the general heading of {lithium carbenoids|\ haloalkyllithium compounds have enjoyed widespread use due to their unusual reactivity and their ability to deliver the versatile halomethylene functional group to suitable acceptors[ A critical aspect of these species is the role of solvent used in their preparation\ THF being the solvent of choice\ owing to its ability to stabilize the carbenoid species[ However\ the increased viscosity of THF at the low temperatures typically employed to generate carbenoids sometimes poses problems\ and often ether or petroleum ethers are used as co! solvents[ Typical conditions involve treating a dilute solution of either a dihaloalkane or a tri! haloalkene at −099>C with an alkyllithium reagent in THF "Scheme 36# ð54JA3036\ 54TL858\ 82T7376Ł[ Since the carbenoids are typically thermally unstable "decomposing completely above −54>C#\ in
52
Halo`en and a Metal
situ reaction with a suitable electrophile is usually carried out\ otherwise intramolecular carbenoid insertions may take place[ Examples of lithiodi~uoroalkanes are common\ available either by metallation of di~uoroiodoalkanes at low temperature ð74TL4132Ł or by metallation of di~uoro! alkanes with lithium amide bases at elevated temperature ð66JOC454Ł[ Terminal lithioper~uoro! alkanes often undergo spontaneous elimination of LiF to yield per~uorinated alkenes ð74TL4132Ł[ The alkoxycarbenoid ClCH1CH1OCHClLi has been generated and used to cyclopropanate cyclo! hexene ð58OS"38#75\ 61JA014Ł[ I
LDA, –78 °C, THF, 30 min
CH2I2
Li
I BuLi, THF, –100 °C
PhCCl3
Cl
Ph
Li
Cl Scheme 47
5[91[3[1 Halogen and Magnesium Derivatives Transmetallation reactions between Grignard reagents and perhalogenated systems is a versatile route to compounds of this class[ Thus phenylmagnesium bromide reacts with 0!iodohepta~uoro! propane at low temperature to produce hepta~uoropropylmagnesium bromide in good yield "Sch! eme 37# ð46JA2240Ł[ Such Grignard reagents are useful for addition of perhaloalkyl functionality to carbonyl compounds ð77BCJ2210Ł[ Other examples of this transmetallation protocol demonstrate its synthetic utility "Scheme 37# including formation of bis"bromomagnesium# compounds ð64JFC"4#364Ł[ F
F
PhMgBr, –78 °C, Et2O
I
F3C F
F
F
F MgBr
F3C
F
F I
F
F
2 RMgBr, –70 °C, Et2O
F
BrMg
F
+ PhI
F
F
I F
F
MgBr
F
F
F
F
Scheme 48
5[91[3[2 Halogen and Copper Derivatives Reaction of copper metal with terminally iodo!substituted per~uoroalkanes at elevated tem! peratures results in formation of a per~uorinated alkylcopper"I# species\ together with copper"I# iodide "Equation "06## ð76JFC"26#060Ł[ Chain polymerization of these species has been reported on thermolysis in DMF ð77DIS"B#1862Ł[ F F3C
I
F
2 Cu, DMSO, 110 °C
F
F3C
Cu
+ CuI
(17)
F
5[91[3[3 Halogen and Silver Derivatives Addition of silver tri~uoroacetate to chlorotri~uoroethene in the presence of metal ~uorides results in the formation of an organosilver compound bearing an a\a!dihalo alkyl group "Equation
53
Halo`ens and any other Elements
"07## ð62JOM"46#312Ł[ Caesium ~uoride is reported to promote this reaction more e.ciently than other alkali metals[ F
F
F
Cl
CF3CO2Ag, MF
Cl
Ag
(18)
F
F3C
5[91[3[4 Halogen and Zinc Derivatives Zinc metal reacts with alkyl iodides\ chlorides and bromides to give the corresponding halozinc reagents "Scheme 38# ð42JCS2596\ 46JA3048\ 73JFC"15#324\ 77JOM"228#06Ł[ Yields of organozinc reagent are heavily dependent on both concentration and temperature of reaction and\ where ethers are not employed as solvents\ solvated products are formed\ for example\ with DMF[ F
F
F3C
I
F
F3C
Cl
F
F3C
75%
F Cl
F
Zn, dioxane
ZnI
F Cl
Zn, DMF
Cl
F3C
F
ZnCl(DMF)2 Cl
Scheme 49
5[91[3[5 Halogen and Cadmium Derivatives Cadmium metal will insert between the carbonÐbromine or carbonÐiodine bond in mixed per! haloalkanes to yield a variety of organocadmium reagents "Scheme 49# ð77JFC"28#314\ 77JFC"30#074Ł[ Alternatively\ transmetallation from dialkylcadmium reagents to dihaloiodoalkanes can be employed to form perhalodialkylcadmium reagents of this class[ F F
2 F5C2I
F
Cd, DMF, 50 °C
X
X = Br, 75%; I, 91%
Me2Cd, MeCN
F F3C
Cd-X
F F
F Cd
F
+ 2 MeI
CF3
Scheme 50
5[91[3[6 Halogen and Mercury Derivatives Mercuric ~uoride will add to haloalkenes quite readily at elevated temperatures to yield per! halodialkylmercury compounds "Scheme 40# ð59JOC094\ 50JCS2714Ł[ Strict regiocontrol in the addition reactions to mixed haloalkenes is usually observed[ It has been reported that per~uoro! propen!1!ol\ the meta!stable enol form of penta~uoroacetone\ reacts with mercury tri~uoroacetate
54
Halo`en and a Metal
to yield tri~uoroacetoxymercuricper~uoroacetone "Scheme 40# ð64DOK"110#0220\ 65ZOR0266Ł[ Care must be taken when handling this species\ as it is reported to undergo rapid hydration to form the corresponding hydrate[ F
F
F
F
F
Cl
HgF2, HF, ∆
Cl
Cl
69%
F3C
F
HgF2, 100 °C
F
56%
F
CF3
(CF3CO2)2Hg, Et2O
F
OH
20 °C, 12 h 79%
F
Hg
F3C
F
F
Cl
CF3 Cl
Cl
Hg
CF3
CF3CO2HgCF2COCF3
Scheme 51
5[91[3[7 Halogen and Tin Derivatives Reaction of dialkyltin hydrides with tetra~uoroethylene is reported to give the 0 ] 1 adducts "Scheme 41# ð54AFC"3#49Ł[ Another route to these compounds is via insertion to iodoper~uoro! alkanes using either tin"II# chloride or tin"II# ~uoride "Scheme 41#[ The resulting organotin com! pounds retain the halogen atoms originally attached in this rapid reaction ð70CL0226Ł[ Reaction of trimethyltin hydride with trialkyl"tri~uoromethyl#stannanes results in reduction to the cor! responding di~uoroalkyltin species "Scheme 41# ð69IC0571Ł[ Bis"per~uoroalkyl#cadmium com! pounds are reported to undergo transmetallation with Me2SnOCOCF2 to yield the corresponding per~uoro organotin derivatives "Scheme 41# ð74JFC"16#298Ł[ Tetrakis"tri~uoromethyl#germanium is reported to react with trimethyltin hydride to produce\ in addition to tris"tri~uoromethyl#germane\ trimethyl"di~uoromethyl#tin in low yield ð83JOM"354#042Ł[ F
F
F
F
Bu2SnH2
F
F
F3C(CF2)5I
SnCl2 (or SnF2), DMF, 25 °C
Me3SnCF3
Me3SnH, 150 °C
F F
F
Sn F Bu Bu F
F
F3C(CF2)5SnCl2I
Me3SnCHF2
63%
(C2F5)2Cd
Me3SnOCOCF3, 70 °C
Me3SnC2F5
64%
Scheme 52
5[91[3[8 Halogen and Lead Derivatives Addition of tetramethyllead to iodopenta~uoroethane at elevated temperature results in for! mation of penta~uoroethyltrimethyllead in moderate yield "Scheme 42# ð59JA5117Ł[ In an analogous manner to the corresponding organotin compounds\ bisper~uoroalkyl cadmium species undergo
55
Halo`ens and any other Elements
transmetallation with Me2PbOCOCF2 to yield per~uoro organolead derivatives "Scheme 42# ð74JFC"16#298Ł[ CF3CF2I
Me4Pb, 150 °C
Me3PbCF2CF3
28%
(C2F5)2Cd
Me3PbOCOCF3, 70 °C
Me3PbC2F5
91%
Scheme 53
Copyright
#
1995, Elsevier Ltd. All R ights Reserved
Comprehensive Organic Functional Group Transformations
6.03 Functions Containing Three Chalcogens (and No Halogens) GLYNN MITCHELL ZENECA Agrochemicals, Bracknell, UK 5[92[0 INTRODUCTION
57
5[92[1 FUNCTIONS BEARING THREE OXYGEN ATOMS 5[92[1[0 Methods for the Preparation of Carboxylic Ortho!esters and Related Compounds 5[92[1[0[0 Ortho!esters from 0\0\0!trihaloalkanes\ a\a!dihalo ethers and a!haloacetals 5[92[1[0[1 Ortho!esters from imidate ester salts 5[92[1[0[2 Ortho!esters from carboxylic acids and derivatives 5[92[1[0[3 Ortho!esters from dioxocarbenium salts 5[92[1[0[4 Ortho!esters from 0\0!dialkoxyalkenes\ 0\0!dihaloalkenes and 0!alkoxyalkynes 5[92[1[0[5 Ortho!esters from 0\0!dialkoxycyclopropanes and related compounds 5[92[1[0[6 Ortho!esters from acetals 5[92[1[0[7 Ortho!esters from ortho!carbonate esters and trialkoxyacetonitriles 5[92[1[1 Preparation of Carboxylic Ortho!Esters from Other Ortho!Esters 5[92[1[1[0 Trans!esteri_cation reactions 5[92[1[1[1 Modi_cation of R0 and R1 of R0C"OR1#2 5[92[2 FUNCTIONS BEARING THREE SULFUR ATOMS 5[92[2[0 Methods for the Preparation of Trithio!ortho!esters and Related Compounds 5[92[2[0[0 Trithio!ortho!esters from RC"X0#"X1#X2 5[92[2[0[1 Trithio!ortho!esters from thioimidate ester salts 5[92[2[0[2 Trithio!ortho!esters from carboxylic acids and derivatives 5[92[2[0[3 Trithio!ortho!esters from dithio! and trithiocarbenium salts 5[92[2[0[4 Trithio!ortho!esters from dithioacetals 5[92[2[0[5 Trithio!ortho!formates from trithiocarbonates 5[92[2[0[6 Trithio!ortho!formates from tetrathio!ortho!carbonates 5[92[2[1 Preparation of Trithio!ortho!esters from other Trithio!ortho!esters 5[92[2[1[0 Hi`her trithio!ortho!esters from trithioformate esters 5[92[2[1[1 Trans!esteri_cation of trithio!ortho!esters 5[92[2[1[2 Modi_cation of R0 and R1 of R0C"SR1#2 5[92[2[2 Methods for the Preparation of Oxidised Derivatives of Trithio!ortho!esters 5[92[2[2[0 Oxidised trithio!ortho!esters containin` at least one sulfoxide `roup 5[92[2[2[1 Oxidised trithio!ortho!esters containin` at least one sulfone `roup 5[92[2[2[2 Oxidised trithio!ortho!esters containin` at least one sulfonate `roup 5[92[3 FUNCTIONS BEARING THREE SELENIUM ATOMS 5[92[3[0 Methods for the Preparation of Triseleno!ortho!esters 5[92[3[0[0 Triseleno!ortho!esters from RC"X0#"X1#X2 5[92[3[0[1 Triseleno!ortho!esters from carboxylic acids 5[92[3[0[2 Triseleno!ortho!esters from triselenocarbenium salts 5[92[3[0[3 Triseleno!ortho!esters from diselenoacetals and related compounds 5[92[3[0[4 Triseleno!ortho!formates from tetraseleno!ortho!carbonates 5[92[3[0[5 Hi`her triseleno!ortho!esters from triseleno!ortho!formate esters
57 57 57 58 60 62 63 65 66 66 67 67 79 70 70 70 72 73 74 74 76 76 77 77 77 78 89 89 89 80 80 81 81 81 82 82 82 83
5[92[4 MIXED CHALCOGEN FUNCTIONS INCLUDING OXYGEN
84
5[92[4[0 Methods for the Preparation of Functions R0C"OR1#"OR2#SR3 5[92[4[0[0 From R0C"X0#"X1#X2
84 84
56
57
Three Chalco`ens 5[92[4[0[1 From monothiocarboxylic esters 5[92[4[0[2 From dioxo! and oxothiocarbenium salts 5[92[4[0[3 From monothioacetals and related compounds 5[92[4[0[4 From 1!alkoxythiophenes 5[92[4[1 Methods for the Preparation of Functions R0C"OR1#"SR2#SR3 5[92[4[1[0 From R0C"X0#"X1#X2 5[92[4[1[1 From dithiocarbenium salts 5[92[4[1[2 From mono! and dithioacetals and related compounds 5[92[4[1[3 Miscellaneous methods 5[92[4[2 Methods for the Preparation of Functions R0C"OR1#"OR2#SeR3 5[92[4[2[0 From 1!alkoxyselenophenes 5[92[4[3 Methods for the Preparation of Functions R0C"OR1#"SeR2#SeR3 5[92[4[3[0 From R0C"X0#"X1#X2 5[92[4[4 Methods for the Preparation of Functions R0C"OR1#"SR2#SeR3 5[92[4[4[0 From monothioacetals and related compounds
5[92[5 MIXED SULFUR AND SELENIUM FUNCTIONS
85 85 86 86 86 86 87 87 88 099 099 099 099 099 099 090
5[92[5[0 Methods for the Preparation of Functions R0C"SR1#"SR2#SeR3 5[92[5[0[0 From R0C"X0#"X1#X2 5[92[5[0[1 From selenodithiocarbenium salts 5[92[5[0[2 From dithioacetals 5[92[5[1 Methods for the Preparation of Functions R0C"SR1#"SeR2#SeR3 5[92[5[1[0 From diseleno!ortho!esters
090 090 090 091 091 091
5[92[0 INTRODUCTION The scope of this chapter is intended to cover the synthesis of compounds bearing the C"X#"Y#Z group in which each of X\ Y and Z are independently linked through O\ S\ Se and Te atoms[ However\ at the time of writing no such compounds containing Te had been reported in the literature\ so the discussion is limited to O\ S and Se containing compounds[
5[92[1 FUNCTIONS BEARING THREE OXYGEN ATOMS Carboxylic ortho!esters contain a carbon atom bearing three alkoxy or aryloxy groups[ Closely related to these are the corresponding acyloxy esters "bearing at least one RCOO group#\ peroxy esters "bearing at least one ROO group# and aminoxy esters "bearing at least one R0R1NO group#[ Ortho!esters which contain one or more hydroxy groups are generally unstable and decompose to carboxylic esters and alcohols\ though a few examples are known in which ortho!hydrogen esters are stabilised by electronic and:or ring strain e}ects ð15BSB301\ 54T1948\ 79JOC1985Ł[ Methods for the preparation of ortho!esters and related compounds have been reviewed by Post ðB!32MI 592!90Ł\ DeWolfe ðB!69MI 592!90\ 63S042Ł\ Sandler and Karo ðB!75MI 592!90Ł and Simchen ð74HOU"E4#2Ł[ Other reviews concentrate on the reactions of ortho!esters ðB!58MI 592!90\ 75UK0792Ł\ and on their use in polymerisation reactions ð74MI 592!90Ł[
5[92[1[0 Methods for the Preparation of Carboxylic Ortho!esters and Related Compounds 5[92[1[0[0 Ortho!esters from 0\0\0!trihaloalkanes\ a\a!dihalo ethers and a!haloacetals Williamson and Kay reported the _rst synthesis of triethyl and tripentyl ortho!formates by reaction of the appropriate sodium alkoxide with chloroform "Equation "0## ð0743LA"81#235\ 0743PRS024Ł[ This procedure has since been used to prepare a number of simple trialkyl ortho!formates ð0768CB004\ 21JA1853\ 22JA2740\ 53RTC008Ł[ The reaction is carried out either by adding chloroform to the alkoxide\ or by adding sodium metal to a mixture of the alcohol and chloroform^ a typical procedure is described in Or`anic Syntheses for the preparation of triethyl ortho!formate ð40OSC"0#147Ł[ Yields are generally low "29Ð34)#\ irrespective of the method used[ CHCl3
NaOR
OR (1)
RO OR
58
Three Oxy`ens
The use of ~uorodichloromethane or di~uorochloromethane in place of chloroform has been reported to give higher yields of ortho!formates ð46JA4382\ 59JA0287Ł[ Carbon tetrachloride and dichlorodi~uoromethane have also been shown to give ortho!formates on reaction with sodium alkoxides ð10JCS0111\ 47USP1742420Ł\ these reactions proceeding via the corresponding haloforms which are generated in situ under the alkaline conditions[ Triaryl ortho!formates are not obtained in appreciable amounts from the reaction of activated phenols with chloroform since the preferred pathway is that of the ReimerÐTiemann reaction^ less activated phenols do give ortho!formates\ but yields are generally poor ð0771CB1574\ 13JA1989\ 44JA5533Ł[ The Williamson synthesis has been extended to the preparation of certain higher ortho!esters^ trialkyl ortho!benzoates "0# ð31JA1414\ 49JA0550Ł and heterocyclic analogues\ for example "1# ð79LA0105Ł\ and trialkyl and triaryl ortho!esters of perhalogenated!acrylates "2# ð56CB1835\ 60ZOR1050Ł and !crotonates "3# ð59IZV120Ł have all been prepared from the appropriate trichloro! methyl compounds[ However\ the general utility of the method for the synthesis of ortho!esters from trihalomethyl compounds bearing a!hydrogen atoms is limited\ since these substrates may also undergo competing elimination reactions under the strongly basic reaction conditions ðB!69MI 592! 90\ 63S042Ł[ Ar
OR OR OR
Cl
N N (MeO)3C
S
C(OMe)3 Cl
(2)
(1)
F
OR
Cl OR
F
Cl
OR
Cl
OR
F (4)
(3)
OR
OR
A variation of the Williamson synthesis was reported by Hill et al[ ð54JOC300Ł\ who obtained ortho!formates "4\ R H# and ortho!benzoates "4\ R Ph# derived from ~uorinated alcohols\ which do not undergo the base promoted reaction\ by the iron"III# chloride catalysed reaction of the alcohol with chloroform and a\a\a!trichlorotoluene respectively "Equation "1##[ Cl Cl Cl
R
Rf
OH
, FeCl3 cat.
R
62–80%
OCH2Rf OCH2Rf OCH2Rf (5)
(2)
Nucleophilic displacement of the halogen atoms of a\a!dihalo ethers and a!haloacetals with alkoxides also gives ortho!esters[ In these cases\ mixed ortho!esters "5#\ in which R1 and R2 are di}erent\ may be obtained "Scheme 0# ð24CB1040\ 47JPR59\ 50CB427Ł[ The cyclic diacyloxy ester "6# was obtained from a\a!dichlorophthalide and 2!hydroxybutanoic acid "Equation "2## ð43LA"476#115Ł[ R1
OR2 Cl Cl
OR2 OR3 OR3 (6) Scheme 1
NaOR3
R1
NaOR2
OR3 OR3 Cl
R1
a\a!Dihalo ethers and a!haloacetals may form as intermediates in the reactions between activated 0\0!dihaloalkenes and alkoxides which yield ortho!esters^ these are discussed in Section 5[92[1[0[4[ O O
OH CO2H , PhNMe , 20 °C 2
O Cl
45%
Cl
O O
(3)
O O
(7)
5[92[1[0[1 Ortho!esters from imidate ester salts Imidate ester salts are transformed into ortho!esters by reaction with alcohols "Equation "3##[ The reaction is normally carried out using imidate ester hydrochloride salts\ which are prepared by the
69
Three Chalco`ens
hydrogen chloride promoted addition of alcohols to nitriles\ and the two!step sequence "nitrile to ortho!ester# is named after Pinner\ who _rst described the preparation of a series of trialkyl ortho! formates using this procedure ð0772CB241\ 0772CB0532Ł[ The method is widely applicable to the synthesis of ortho!formic and higher aliphatic ortho!esters^ yields are generally in the 59Ð79) range\ but are lower "29) or less# for aliphatic ortho!esters bearing two substituents a! and:or b! to the ester function ð31JA0714\ 40JA1122Ł[ Ortho!benzoate esters may be prepared from benzimidate ester hydrochlorides\ but reported yields are low ð63S042Ł[ The procedure is normally used for the preparation of trialkyl ortho!esters "7# in which R1 and R2 are the same\ but is also suitable for the synthesis of mixed ortho!esters in which R1 and R2 are di}erent ð0772CB241\ 0772CB0532\ 22MI 592!90Ł[ OR2 R1
R3OH
OR2 OR3 OR3 (8)
R1
+
NH2 X–
(4)
The simplest procedure for the alcoholysis of an imidate ester is to allow a solution of the imidate ester hydrochloride in an excess of the alcohol to stand at room temperature ð17JA405\ 24JA1379Ł[ However\ reaction times can be long\ and yields are often low[ Improved procedures include heating the imidate ester salt with an excess of the alcohol in diethyl ether ð31JA0714\ 35JA0811Ł\ or petroleum ether ð42JA2876\ 47JA2804Ł[ It is important to maintain strictly anhydrous conditions during these alcoholysis reactions\ since the ortho!ester products are extremely prone to acid!catalysed hydrolysis[ High temperatures also need to be avoided\ as imidate ester hydrochlorides decompose to alkyl chlorides and the corresponding carboxamide at elevated temperatures ð40JA1122Ł[ Ortho!esters may be prepared from nitriles without isolation of the intermediate imidate ester salt[ Erickson synthesised a number of trialkyl ortho!formates in moderate yields "up to 45)# by a one!step process which involved the introduction of hydrogen chloride into a large excess of both hydrogen cyanide and the alcohol ð44JOC0462Ł[ Later workers found that better yields were obtained if the acidity of the reaction medium was reduced to pH 1Ð5 after initial formation of the formimidate ester hydrochloride ð65JAP"K#65097901\ 79JAP"K#7972616\ 73MIP410261Ł[ Other methods for the preparation of ortho!esters which proceed via imidate ester salts have been described[ A variation of the Pinner method involves the alcoholysis of O!methyl imidate salts "8^ Equation "4##\ which are prepared from amides and dimethyl sulfate ð79LA0566Ł[ Ethanolysis of imidoyl chloride salts "09\ R Et\ Ph# produced triethyl ortho!propionate and triethyl ortho! benzoate in yields of 51) and 34) respectively\ via the corresponding O!ethylimidate ester salts ð52CB1560Ł[ Reaction of formamide with benzoyl chloride or ethyl chloroformate in the presence of alcohols gave trialkyl ortho!formates in yields of 39Ð49) "Scheme 1# ð57LA"605#196Ł\ and mixed ortho!esters\ "00# for example\ were similarly obtained by treatment of formamide with benzoyl chloride in the presence of a mixture of a simple alcohol and a diol ð70MI 592!90Ł[ OR2 R1 MeOSO3–
N+
R3OH
R1
OR3 OR3 OR3
(5)
(9)
Cl R N+
Cl–
O EtO O
(10)
O H NH2
R1COCl
O COR1 H
(11)
R2OH
+
NH2 Cl–
OR2 H
+
NH2 Cl– Scheme 2
R2OH
H
OR2 OR2 OR2
60
Three Oxy`ens 5[92[1[0[2 Ortho!esters from carboxylic acids and derivatives "i# From carboxylic acids and esters
Tricyclic ortho!esters are obtained from the reaction of carboxylic acids with 1!alkyl!1!hydroxy! methyl!0\2!dihydroxypropanes "Equation "5## ð46MI 592!90\ 54NEP5301525Ł[ The method works best for carboxylic acids bearing electron withdrawing substituents\ and the reactions are forced to completion by azeotropic removal of water using benzene or xylene[ Ortho!esters derived from diols or simple alcohols are not generally available by this method[ OH HO
O R1
R2 HO
OH
O O
R1
H+
(6)
R2
O
Aliphatic carboxylic esters of 2!methyl!2!hydroxymethyloxetane have been shown to rearrange smoothly to bridged tricyclic ortho!esters in high yield on exposure to boron tri~uoride etherate at temperatures of 9>C or less "Scheme 2# ð72TL4460\ 89JCS"P0#264Ł[ The reaction is postulated to proceed via cyclisation of the zwitterionic species "01#[ O
O
R
BF3•OEt2
O
R
+
66–91%
O – F3B
O
O
R
O O O
(12) Scheme 3
Formate esters react with epoxides in the presence of a catalytic amount of boron tri~uoride to give cyclic ortho!formate esters "Equation "6## ð44AG263Ł[ Acetate esters do not react with epoxides under these conditions[ O H
O
O R2
OR1
R2
R1 O
BF3
(7) O
Ethanolysis of the acetoxy p!toluenesulfonate "02# under basic conditions produced the cyclic ortho!ester "03# ð32JA502Ł[ This product is formed by addition of ethoxide to the intermediate dioxocarbenium ion "04#\ which is itself formed by neighbouring group displacement of tolu! enesulfonate by the acetoxy group "Scheme 3#[ The ortho!ester "05# was formed similarly "Equation "7## ð52PCS263Ł[ Acyloxy ortho!esters were formed by a similar mechanism when acetoxyacyl chlor! ides were treated with alcohols in the presence of triethylamine "Equation "8## ð62JA3905Ł^ the use of alkyl hydroperoxides in place of alcohols produced the analogous peroxy acyloxy ortho!esters in high yields "69Ð099)# ð56AG"E#838Ł[ This method of ortho!ester synthesis has received considerable attention in the _eld of carbohydrate chemistry for the conversion of 0!halo!1!acyloxy carbohydrate derivatives "both furanose and pyranose forms# into the corresponding ortho!esters[ Triethylamine ð89LA388Ł\ 1\5!lutidine ð54CJC0807Ł\ 1\3\5!collidine ð45CB203Ł and silver"I# salts ð60CAR"08#028Ł have been used to catalyse the reactions of 0!halo!1!acyloxy carbohydrate derivatives with alcohols\ and amide acetals ð79MI 592!90Ł and alkoxystannanes ð65CAR"40#C02Ł have been used as alternative sources of the alkoxy group[ The exo!form of the ortho!ester product normally predominates\ and is often formed exclusively[ A representative example is illustrated in Equation "09# ð89LA388Ł[ OTs O
EtOH, KOAc
O
O
+
O
O
(13)
(15) Scheme 4
51%
O (14)
OEt
61
Three Chalco`ens
OTs
O
EtOH, KOAc
(8)
OEt 71%
OAc
O (16)
O
O
O
O Cl
ROH, Et3N
O
42–84%
(9)
O O
OR
Br
O
O
EtOH, Me3N, C6H6
AcO
OAc
37%
(10)
OEt
O
AcO OAc
OAc
Aliphatic O!trimethylsilyl ortho!esters "07\ R alkyl# were obtained from hydroxy esters "06# by deprotonation using a strong base "n!butyllithium or lithium diisopropylamide# followed by reaction with chlorotrimethylsilane "Equation "00## ð80SL059Ł[ This method is not suitable for the preparation of ortho!esters from a!branched carboxylic esters[ O R O
OH Ph Ph Ph
Ph i, BunLi or LiN(Pri)2 ii, TMS-Cl 82–94%
TMS-O R
(17)
O
Ph
O
(11)
Ph
(18)
"ii# From lactones Several examples of the direct formation of ortho!esters from lactones and diols have been reported[ Le Mahieu and Kierstead ð69TL4000Ł described the acid catalysed preparation of the steroid ortho!esters "08\ R H\ Br# from the corresponding lactones and 0\1!dihydroxyethane "Equation "01##\ and Tamaru et al[ ð79BCJ2576Ł prepared the carbohydrate ortho!esters "19#\ "10# and "11# similarly from 1\2\3\5!tetra!O!benzylgluconolactone and the appropriate diol in yields of 66)\ 62) and 32) respectively[ A variation of this method\ which is reported to give higher yields of ortho!esters\ involves the trimethylsilyl tri~uoromethanesulfonate catalysed reaction between lactones and bis!O!trimethylsilyl!0\1!diols[ Yoshimura et al[ ð70CL264Ł prepared the ortho!esters "19#\ "10# and "11# from 1\2\3\5!tetra!O!benzylgluconolactone and the corresponding bis!O!tri! methylsilyl!0\1!diols in yields of 80)\ 78)\ and 53) respectively[ The ortho!ester "12# was obtained in 73) yield from 2\3!dihydrocoumarin and 0\1!bis!O!trimethylsilyloxyethane ð78AJC0124Ł[ HO HO
H H O
O
H
R
HO
H
H
OH , H+, C6H6 56–72%
(12) H
O O
O
H
H
R (19)
Lactones undergo Lewis acid catalysed reaction with epoxides in a similar manner to formate esters to give spirocyclic ortho!esters "Equation "02##[ Lewis acids commonly used are boron tri! ~uoride\ tin"IV# chloride and antimony pentachloride[ The reaction is general\ and has been used to prepare a number of ortho!esters[ Thus\ butyrolactone reacts with 0\1!epoxyethane\ 0\1! epoxypropane\ 0\ 1!epoxy!2!phenoxypropane\ 0\ 1!epoxy!2!"3!methoxyphenoxy#propane\ 0\ 1!epoxy!
62
Three Oxy`ens O
BnO
O O
BnO
O
BnO
O O
OBn BnO
OBn
OBn OBn (21)
(20)
O
O
BnO
O
BnO
O
OBn
O
OBn (22)
O
(23)
0!phenylethane and 0\1!epoxycyclohexane to give the ortho!esters "13\ R H\ Me\ CH1OPh\ CH1OC5H3OMe!p\ Ph# and "14# respectively ð48LA"512#072\ 59GEP0973622\ 71MI 592!90Ł[ O
O
R
O
O
O
Lewis acid
R
O
(13)
O
O O
R
O
O (24)
O (25)
"iii# From dithiocarboxylic esters Dithiocarboxylic esters react with dialkoxystannanes at temperatures of 59Ð84>C to a}ord ortho! esters "Equation "03## ð65CL780Ł[ The method has been used to prepare aliphatic ortho!esters and substituted ortho!benzoate esters\ and reported yields "generally 59) or greater# are favourable compared to some other methods[ S R1 SMe
Bun2Sn(OR2)2, 60–95 °C 45–98%
R1
OR2 OR2 OR2
(14)
5[92[1[0[3 Ortho!esters from dioxocarbenium salts Meerwein et al[ ð45CB1959Ł demonstrated that the O!alkyllactonium tetra~uoroborate salts "15\ R Me\ Et# react with alkoxides to form the cyclic ortho!esters "16\ R Me\ Et# in high yields "Equation "04##[ Ortho!esters derived from the O!ethyl tetra~uoroborate salts of coumarin and 2\3! dihydrocoumarin have been prepared similarly ð54HOU"5#250Ł[ Alkoxides have also been added to dioxolenium tetra~uoroborates "17\ R0 Me\ Ph# and to 1!phenylbenzo!0\2!dioxolium tetra~uo! roborate to give the cyclic ortho!esters "18^ Equation "05## ð59LA"521#27Ł and "29^ Equation "06## ð54AG"E#762Ł respectively[ Several further examples of the addition of alcohols to dioxolenium and dioxenium salts have been described ð56CC02\ 56JOC1529\ 56T3070Ł[
63
Three Chalco`ens +
O
BF4–
NaOR
OR
69–85%
OR OR (27)
(26) O +
O
BF4–
O
NaOR2
R1
+
BF4–
OR2
(16)
O
R1 (29)
(28)
O
(15)
O
NaOR
Ph
O
O
OR
O
Ph
(17)
(30)
5[92[1[0[4 Ortho!esters from 0\0!dialkoxyalkenes\ 0\0!dihaloalkenes and 0!alkoxyalkynes Alcohols and phenols add to 0\0!dialkoxyalkenes "ketene acetals# to give high yields of ortho! esters "Equation "07## ð25JA418Ł[ The reaction is catalysed by acids ð47JA0136Ł\ though ortho!esters are also formed under neutral and basic conditions ð26JA1155\ 31JA0852Ł[ This method is particularly useful for the preparation of hindered ortho!esters\ for example trimethyl ortho!diphenylacetate ð40JA2796Ł\ trimethyl ortho!dimethoxyacetate ð55CB0781Ł and triphenyl ortho!acetate ð34JA549Ł\ which are di.cult to prepare by other methods[ The procedure is also suitable for the synthesis of mixed ortho!esters "20# in which R2 and R3 are di}erent ð25JA418\ 31JA1414\ 53JOC1662Ł^ use of benzaldoximes in place of alcohols or phenols gives rise to aminoxy ortho!ester derivatives "20\ R3 NCHAr# ð50JOC1191Ł[ R1
OR3
R2
OR3
R4OH
R1
OR3 OR3 OR4
R2
(18)
(31)
Activated 0\0!dihaloalkenes undergo reaction with sodium alkoxides\ giving rise to ortho!ester products[ Thus\ ortho!ester "21\ R Me^ X H# was isolated in 68) yield from the reaction between 0\0!dichloro!1!nitroethene with sodium methoxide "Equation "08## ð67BSB582Ł\ "21\ R Et^ X Cl# was obtained in 23) yield from 0\0\1!trichloro!1!nitroethene and sodium ethoxide ð67ZOR1118Ł\ and "22# was prepared from per~uoropropene and sodium methoxide "Equation "19## ð62USP2634119Ł[ It is not known whether these reactions proceed by an additionÐelimination mechanism via a 0\0!dialkoxyalkene intermediate\ or whether they proceed by an additionÐsub! stitution mechanism via a\a!dihaloether and a!haloacetal intermediates[ X
Cl Cl
O2N
NaOR, ROH, 0 °C 34–79%
X O2N
OR OR OR
(19)
OMe OMe OMe
(20)
(32)
F
F
F3C
F
NaOMe, MeOH, 55 °C, 5 h
F F3C (33)
In a reaction related to the addition of alcohols to 0\0!dialkoxyalkenes\ mixed ortho!acetate esters have been prepared by the Lewis acid catalysed addition of alcohols and phenols to 0!ethoxyethyne "Equation "10## ð64RTC198Ł[ Zinc chloride is the preferred catalyst for the reaction with alcohols\ whereas mercury"II# acetate is preferred for phenols[ Triethyl ortho!acetate has also been obtained by treatment of 0!ethoxyethyne with ethanolic sodium ethoxide ð42MI 592!90Ł[ Addition of oximes to 0!ethoxyethyne a}orded the mixed ortho!ester derivatives "23\ R NCR0R1# ð59RTC777Ł[
64
Three Oxy`ens OEt OR (Ar) OR (Ar) (34)
ROH, ZnCl2 or ArOH, Hg(OAc)2
OEt 35–79%
(21)
Tris"b!alkoxyalkyl# ortho!acetates have been obtained by treatment of 0\0!dichloroethene with the appropriate sodium alkoxide ð53JOC1662Ł[ It has been proposed that these reactions proceed through a series of elimination and addition steps via a 0!alkoxyalkyne intermediate "Scheme 4#[ Cl
NaOR
OR
NaOR
Cl
Cl
OR OR OR
NaOR
NaOR
OR 41–57%
Cl Scheme 5
0\0!Dialkoxyalkenes undergo zinc chloride promoted reactions with epoxides to give cyclic ortho! esters "Equation "11## ð68TL1814Ł[ The epoxide generally undergoes attack at the least hindered position\ unless attack at the more substituted position is favoured on electronic grounds[
R1
R1
O
OR2
R3
OR2 R3
ZnCl2 40–60%
OR2
O
(22)
OR2
Triethyl ortho!cinnamate esters have been prepared by addition of ethanol to diethoxyethen! ylidinetriphenylphosphorane "24#\ followed by a Wittig reaction of the resulting phosphorane with aromatic aldehydes ð75S286Ł "Scheme 5#[ A related method for the preparation of a series of unsaturated cyclic ortho!esters "25# involves the addition of an enolised 0\1!diketone to phosphorane "24#\ followed by intramolecular Wittig cyclisation of the intermediate ketophosphorane "Scheme 6# ð72CB0352\ 72CB2371\ 77T4984Ł[ +
–
OEt
Ph3P
OEt (35)
EtOH
+
Ph3P
90%
–
OEt
ArCHO
OEt OEt
42–67%
OEt OEt Ar
OEt
Scheme 6
O
R1
R2
–
(35)
R3
R1 OH
+
O
R1
PPh3 OEt
R2
O R3
46–71%
OEt
OEt
R2 O R3
OEt
(36) Scheme 7
The preparation of cyclic ortho!esters by thermal ð3¦1Ł cycloaddition reactions of 0\0! dialkoxyalkenes and a\b!unsaturated carbonyl compounds was _rst described by McElvain et al[ "Equation "12## ð43JA4625Ł[ Many further examples of ortho!esters "26# have since been prepared by reaction of 0\0!dimethoxyethene\ 0\0!dimethoxy!0!propene\ 0\0!dimethoxy!1!methyl!0!propene\ 0\0\1!trimethoxyethene\ 0\0\1\1!tetramethoxyethene and 1!chloro!0\0!dimethoxyethene with a range of substituted a\b!unsaturated carbonyl compounds ð44JA4590\ 60CC272\ 61CC752\ 70RTC02Ł[ 0\0!Dial! koxyalkenes also undergo ð1¦1Ł cycloaddition reactions with electron de_cient carbonyl compounds\ such as acyl cyanides and aldehydes\ giving rise to the cyclic ortho!esters "27# "Equation "13## ð65JCS"P0#0937\ 66JOC2017Ł[ It has been shown that ð1¦1Ł cycloadducts are the products of the low temperature reaction between 0\0!dialkoxyalkenes and a\b!unsaturated carbonyl compounds\ and that this process is reversible at higher temperature\ when formation of the ð3¦1Ł cycloadducts is favoured on thermodynamic grounds ð70RTC02Ł[
65
Three Chalco`ens R5 R6 R7
R3
R5 R4
R2
heat
R4 R1O
O
OR1
R6
R3 R2
R7
OR1 OR1
O
(23)
(37) O
R2
R3 R1O
OR1
R4
R4
R5
R3 R2
R5
(24)
25–90%
O
OR1 OR1 (38)
A number of _ve!membered ring ortho!esters have been prepared by ð2¦1Ł cycloaddition reac! tions of 0\2!dipoles to 0\0!dialkoxyalkenes[ Some examples are given in Equations "14# ð75JMC442Ł\ "15# ð48G0400Ł and "16# ð55G264Ł[
Ph
Ph
OMe
MeCOCHN2, Cu(acac)3, C6H6, 85 °C, 30 min
OMe 65%
OMe
OMe
Ph
OMe
O But
OMe
N O
(26)
OMe
p-ClC6H4
N+ Ph 125 °C, 16 h 84%
OEt
Ph
O–
Cl
OEt
OMe
ButCNO, 80 °C 30%
(25)
Ph
OEt
N O
(27)
OEt
5[92[1[0[5 Ortho!esters from 0\0!dialkoxycyclopropanes and related compounds Alcohols add to 0\0!dialkoxycyclopropanes which bear an electron withdrawing group "EWG# "carboxylic ester or sulfone# at the 1!position to give ortho!esters "Equation "17## ð62JOC0250\ 74S651Ł[ Mixed ortho!esters "28#\ in which R0 and R3 are di}erent\ have been prepared by this method\ which is analogous to the addition of alcohols to 0\0!dialkoxyalkenes[ Examples of ortho!esters prepared using this procedure are listed in Table 0[ OR1
EWG
OR1 OR1
R4OH, heat
OR1 65–78%
R2
OR4
EWG R2
R3
(28)
R3 (39)
Ring opening of 0\0!dialkoxy!1\1!dichlorocyclopropanes with potassium t!butoxide is accompanied by elimination to produce alkynyl ortho!esters "Equation "18## ð48JA1468Ł[ Addition of alcohols to 0\0!dimethoxycyclopropene produces the unsaturated ortho!esters "39\ R Me\ Et\ Prn\ Pri\ But^ Equation "29## ð66JOC568Ł[ OR1
R2
OR1 Cl
Cl
KOBut
R2
OR1 OR1 OBut
(29)
66
Three Oxy`ens Table 0 Ortho!esters "28# prepared from 0\0!dialkoxypropanes[ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * Yield R0 R1 R2 R3 EWG ")# Ref[ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * Me H H Me CO1Et 62 74S651 69 74S651 Et H H Et CO1Et 61 74S651 Me Me H Me CO1Et Et Me H Et CO1Et 65 74S651 67 74S651 Me Et H Me CO1Et Me Ph H Me CO1Et 56 74S651 55 74S651 Me Me Me Me CO1Et Me Me Me Me SO1Ph 54 62JOC0250 60 62JOC0250 Et Me Me Et SO1Ph Et Me Me Me SO1Ph 62JOC0250 ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ *
OMe
OMe OMe
ROH
OMe
(30)
OR (40)
Alcohols also add to 1\1!dialkoxyaziridines and 1\1!dialkoxy!1H!azirines to give a!amino!and a! imino!ortho!esters "30^ Equation "20## ð58TL1112\ 62JMC867Ł and "31^ Equation "21## ð56JA4613Ł respectively[ These compounds are di.cult to prepare by other methods[ OR1 OR1
OR1
R2
OR1
R1OH
R2
N H
(31)
NH2 (41) OR1
R2
OR1
PriOH
OR1 N
OR1 OR1
R2
OPri
(32)
NH (42)
5[92[1[0[6 Ortho!esters from acetals Some acetals undergo electrochemical oxidation in the presence of methanol to give ortho!esters in reasonable yields "Equation "22##[ The reaction has been shown to be successful for 1!alkyl! 0\2!dioxolanes ð67S172Ł\ 1!alkyl! and 1!aryl!0\2!benzodioxoles ð74S20Ł and dimethyl acetals of benzaldehydes ð75T442Ł[ Dimethyl acetals of simple aliphatic aldehydes gave lower yields of ortho! esters\ and the reaction failed completely for the corresponding diethyl acetals ð67S172Ł[ Table 1 lists some representative examples of ortho!esters "32# prepared by this method[ OR2 R1
–2e–(anode), MeOH
R1 OR2
OR2 OR3 OMe (43)
(33)
5[92[1[0[7 Ortho!esters from ortho!carbonate esters and trialkoxyacetonitriles Trialkyl ortho!benzoates have been reported to be formed in up to 66) yield by treatment of the appropriate tetraalkyl ortho!carbonate ester with phenylmagnesium bromide "Equation "23## ð94CB450\ B!32MI 592!90Ł\ and similar syntheses of triethyl ortho!phenylpropiolate ð00BSF0297Ł and triethyl ortho!2!butynoate ð69AG"E#345Ł have been described[ However\ the reaction is not always successful\ and other workers have isolated only ketals and ethers from reactions of ortho!carbonate esters with Grignard reagents ð31JA0714\ 38MI 592!90Ł[ No systematic survey of this method has been
67
Three Chalco`ens Table 1 Examples of ortho!esters "32# prepared by electro! chemical oxidation of acetals[ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * Yield R1 R2 ")# Ref[ R0 ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * H 0"CH1#10 33 67S172 H 0C5H30 38 74S20 53 67S172 Me 0"CH1#10 Me 0C5H30 41 74S20 Pri 0"CH1#10 43 67S172 i 0C5H30 50 74S20 Pr But 0"CH1#10 10 67S172 0C5H30 58 74S20 But 49 74S20 Ph 0C5H30 Ph Me Me 89 75T442 3!ClC5H3 0C5H30 37 74S20 3!ClC5H3 Me Me 73 75T442 0C5H30 33 74S20 3!MeOC5H3 3!MeOC5H3 Me Me 73 75T442 ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ *
carried out\ though DeWolfe ð63S042Ł has suggested that the Grignard reagent needs to bear an electron withdrawing organic moiety for the reaction to work successfully[ RO
OR OR OR
PhMgBr
Ph 77%
OR OR OR
(34)
More recently\ it was reported that trialkyl ortho!benzoate esters are obtained from the reactions of Grignard reagents with trialkoxyacetonitriles "Equation "24## ð70S279Ł[ Trimethyl ortho!benzoate\ trimethyl 1!methyl!ortho!benzoate and triethyl 1!5!di~uoro!ortho!benzoate were prepared in yields of 73)\ 53) and 19) respectively[ Triethyl ortho!phenylpropiolate was prepared in 53) yield from phenylethynyl magnesium bromide and triethoxyacetonitrile using this method ð70S279Ł[ NC
OR OR OR
ArMgX
Ar 20–84%
OR OR OR
(35)
5[92[1[1 Preparation of Carboxylic Ortho!Esters from Other Ortho!Esters 5[92[1[1[0 Trans!esteri_cation reactions Ortho!formate esters undergo exchange reactions on treatment with alcohols "Scheme 7#[ The reaction\ which is acid catalysed\ can be forced to completion by distilling out R0OH "preferably methanol or ethanol# as it is formed\ and a number of trialkyl ortho!formates derived from higher alcohols\ including functionalised alcohols such as 1!chloroethanol and 0!chloro!1!propanol\ have been prepared by this method ð41JA443\ 44JA2790\ 69CB528Ł[ The reaction is subject to steric constraints\ proceeding readily with primary alcohols and less readily with secondary alcohols[ Trans!esteri_cation with tertiary alcohols does not proceed to completion^ treatment of triethyl ortho!formate with t!butanol gave a mixture of t!butyldiethyl and di!t!butylethyl ortho!formates ð52PIA"A#34Ł[ Relatively little has been published on the trans!esteri_cation reactions of higher ortho! esters\ though work that has been reported suggests that these proceed in much the same way as for ortho!formate esters ð49DOK"69#120\ 45ACS0995\ 69CB528Ł[ OR1 R1O OR1
R2OH
OR1 R2O
R2OH
OR1
OR2 R2 O OR1
R2OH
OR2 R2O OR2
Scheme 8
The preparation of mixed ortho!esters by exchange reactions of trialkyl ortho!esters with simple alcohols is not usually feasible since equilibration reactions lead to all possible ortho!ester products
68
Three Oxy`ens
ð22JA2740Ł[ Among the few reported exceptions to this general trend are the reactions of ortho!esters with phenol^ treatment of triethyl ortho!formate and triethyl ortho!acetate with one equivalent of phenol produced good yields of the diethylphenyl ortho!esters "33\ R H\ Me#\ and reaction of triethyl ortho!formate with two equivalents of phenol gave a reasonable yield of the ethyldiphenyl ortho!ester "34^ Scheme 8# ð45ACS0995\ 69CB532Ł[ A recently reported trans!esteri_cation route to mixed ortho!esters\ which is potentially general\ involves the magnesium chloride catalysed exchange reaction with alcohols "Equation "25## ð77TL1912Ł[ Mixed ortho!esters have also been obtained from the O!acyl derivative "35# ð58RTC786Ł\ which was itself prepared by treatment of triethyl ortho! formate with one equivalent of acetic formic anhydride "Scheme 09# ð55RTC682Ł[ In contrast to their reactions with alcohols\ ortho!esters react cleanly with peroxides to form monoperoxy ortho!ester derivatives in high yield ð47CB0831Ł[ OPh
OEt OEt OEt
2 equiv. PhOH, heat
EtO
R (R = H) 51%
OPh (45)
1 equiv. PhOH, heat
R 67–92%
Scheme 9
R1
OEt
OEt OEt OEt
R2OH, MgCl2, CH2Cl2
OR2 OEt OEt
R1
56–96%
OEt
HCO2COMe
EtO 62%
(36)
OEt
ROH, Et3N
RO
AcO OEt
OEt OEt OPh (44)
OEt
48–86%
OEt
(46) Scheme 10
Trans!esteri_cation of simple trialkyl ortho!esters with aliphatic 0\1! and 0\2!diols proceeds cleanly to give mixed cyclic ortho!esters in high yields "Equation "26##[ The reaction is catalysed by acids such as sulfuric acid ð47CB549Ł\ p!toluenesulfonic acid ð69JA473Ł and benzoic acid ð62JA167Ł[ Trans! esteri_cation reactions of trialkyl ortho!benzoates with benzene!0\1!diol proceed in the absence of a catalyst ð54AG"E#762Ł[ Treatment of trialkyl ortho!esters with b!hydroxycarboxylic acids yields cyclic acyloxy ortho!esters "36# ð58TL0936\ 76HCA0219Ł[ In contrast to the equilibration reactions between simple trialkyl ortho!esters and alcohols\ the cyclic ortho!ester "00# reacts moderately cleanly with alcohols to give the exchanged products "37# in yields of 30Ð47) "Equation "27## ð79JCS"P0#645Ł[
R1
OR2 OR2 OR2
HO
OH
R2O
O
R1
O
(37)
R3 R2O
O
R4
R1
O
R4 O
(47)
O OEt O (11)
ROH, H+
O
41–58%
O (48)
OR
(38)
Trialkyl ortho!esters react with conformationally ~exible triols such as glycerol\ 0\2!dihydroxy!1! hydroxymethyl!1!methylpropane and 0\1\3!trihydroxybutane to give good yields of the cor! responding tricyclic ortho!esters "38#\ "49# and "40# respectively ð79MM141\ 79CC196\ 77JA3033Ł\ and exchange with all cis!0\2\4!trihydroxycyclohexane gives high yields of polycyclic ortho!esters "41#
79
Three Chalco`ens
ð42CB689\ 43CB194Ł[ Trans!esteri_cation with conformationally restricted triols normally gives prod! ucts arising from exchange of only two of the alkoxy groups of the ortho!ester[ For example\ exchange with 1\2\4!trihydroxy nucleoside analogues generally leads to exclusive formation of the ortho!ester derived from the 1\2!dihydroxy unit of the triol "Equation "28## ð53CI"L#470\ 56CCC2953\ 74S397Ł[ The trans!esteri_cation method has been used for the preparation of many cyclic\ bicyclic and tricyclic ortho!esters from dihydroxy! and trihydroxy!carbohydrate\ nucleoside and steroid derivatives ðB!69MI 592!90\ 66USP3910348\ 77EUP159868Ł[ R
O R
O
O O
R
O
R
O
(49)
(50)
HO
Het
O O
O O (51)
(52)
O
HOH2C
O
HOH2C
O
O
Het
R1C(OR2)3
(39) O
O
R1
OR2
OH
Ortho!esters have also been prepared by the alcoholysis of amide acetals ð70JOC775Ł and trithio! ortho!esters ð37JA1157\ 79JOC639Ł[
5[92[1[1[1 Modi_cation of R0 and R1 of R0C"OR1#2 Ortho!esters bearing a!hydrogen atoms react with one equivalent of bromine to give a!bromo ortho!esters "42# in up to 79) yield ð26JA0162\ 31JA1414\ 35JA0811Ł^ use of two equivalents of bromine gives a\a!dibromo ortho!esters ð31JA0852Ł[ Dehydrobromination of a!bromo ortho!esters\ "e[g[\ "43##\ to unsaturated ortho!esters\ "e[g[\ "44##\ has been achieved\ but yields are low "08Ð21)# ð62S196\ 74JAP"K#59197872Ł[ Reaction of triethyl ortho!acetate with tri~uoromethylselenenyl chloride gave triethyl a!"tri~uoromethylselenenyl#ortho!acetate\ which was converted to the bis"tri~uoro! methylselenenyl# derivative by deprotonation with sodium hydride\ followed by treatment with a further equivalent of tri~uoromethylselenenyl chloride "Scheme 00# ð81CB460Ł[ Trialkyl ortho! acetates have also been shown to react with perhalogenated aldehydes and ketones\ producing the adducts "45\ R0 H\ CF2\ CClF1^ R1 Me\ Et^ X F\ Cl# in yields of 74Ð83) "Equation "39## ð66ZOR832Ł[
Br R1
OEt OEt OEt
OR3 OR3
Br
OR3 R2 (53)
O O O
O
(54)
(55)
87%
OEt OEt OEt Scheme 11
F X
OR2 OR2 OR2
F3CSeCl, Et2O, –20 °C
F O R1
O O
F3CSe
85–94%
NaH, F3CSeCl
F3CSe
Et2O, –20 °C 97%
F3CSe
F2XC
OH
OR2 OR2
OEt OEt OEt
(40)
OR2
R1 (56)
Dehydrohalogenation of tris"b!chloroalkyl# ortho!esters yielded trialkenyl ortho!esters "Equation
70
Three Sulfurs
"30## ð69CB528Ł[ Ozonolysis of tris"1!propenyl# ortho!formate gave tri!O!acetyl ortho!formate "Equa! tion "31## ð69CB528Ł[ Cl
R2 Cl
R2 R2
O R1
R2
O
KOBut
O
R1
O
O
(41)
O
R2
R2 Cl
O
O3, –78 °C
O
OAc (42)
AcO
60%
O
OAc
5[92[2 FUNCTIONS BEARING THREE SULFUR ATOMS Trithio!ortho!esters contain a carbon atom bearing three alkanethio or arenethio groups[ Related to these are the analogous acylthio esters "containing at least one RCOS group#\ hydrogen esters "containing at least one HS group# and oxidised derivatives bearing sulfoxide\ sulfone and sulfonyl groups[ Methods for the preparation of trithio!ortho!esters and related compounds have been reviewed by Post ðB!32MI 592!90Ł\ DeWolfe ðB!69MI 592!90Ł and Simchen ð74HOU"E4#2Ł[
5[92[2[0 Methods for the Preparation of Trithio!ortho!esters and Related Compounds 5[92[2[0[0 Trithio!ortho!esters from RC"X0#"X1#X2 "i# From 0\0\0!trihaloalkanes and a\a!dihalo ethers Gabriel reported the _rst synthesis of triethyl trithio!ortho!formate and triphenyl trithio!ortho! formate by reaction of the appropriate thiolate salt with chloroform "Equation "32## ð0766CB074Ł[ This method has since been used to prepare a range of trialkyl and triaryl trithio!ortho!formate esters ð0767CB1154\ 22RTC326\ 53CR"148#3940Ł^ yields from reactions with arenethiols are usually high "69) or greater#\ but are lower from reactions with aliphatic thiols[ Bromoform and chloro! di~uoromethane also react with sodium arenethiolate salts to give high yields of triaryl trithio! ortho!esters ð45JA368\ 59JA5007Ł[ Carbon tetrachloride reacts with alkanethiolates to give trialkyl trithio!ortho!esters\ the reactions proceeding via formation of chloroform under the alkaline reaction conditions ð22RTC326Ł[ Tris"tri~uoromethyl# trithio!ortho!formate "46# was prepared by reaction of iodoform with Hg"SCF2#1 "Equation "33## ð56JOC1952Ł[ CHCl3
M+ –SR
SR (43)
RS SR
Hg(SCF3)2, 130 °C
CHI3
SCF3 (44)
F3CS SCF3 (57)
Relatively few reports of the preparation of higher trithio!ortho!esters from 0\0\0!trihaloalkanes have appeared[ 1!Trichloromethylbenzimidazole was converted to the trithio!ortho!esters "47\ R Me\ p!ClC5H3# by reaction with the corresponding thiol ð56JCS"C#29Ł\ and the activated tri! ~uoromethyl group of the thiazole "48# underwent reaction with methanethiol to give the trithio!
71
Three Chalco`ens
ortho!ester "59# ð80JHC0902Ł[ A series of a\a\a!trihalotoluenes have been converted to tris "tri~uoromethyl# trithio!ortho!benzoate esters "50# by treatment with AgSCF2 ð58ZOB0644Ł[ N N H (58)
C(SMe)3 O
CF3
SR SR SR
O
N Cl
S
N
N H (59)
Ar
NEt2
Cl
N H (60)
S
NEt2
SCF3 SCF3 SCF3 (61)
Trithio!ortho!formate esters may also be prepared from dichloromethyl alkyl ethers^ treatment with lead"II# alkanethiolates gives trialkyl trithio!ortho!formates ð50CB427Ł\ whereas reaction with arenethiols in the presence of zinc produces triaryl trithio!ortho!formates ð60ZOR0776Ł "Scheme 01#[ SR2 Pb(SR2)2,
SR2
Et2O
SR2 Cl R1O
ArSH, Zn, Et2O, 35 °C
Cl
SAr
66–92%
ArS SAr
Scheme 12
"ii# From a!halodithioacetals and a!acyloxy! and a!alkoxydithioacetals Treatment of chlorobis"methanethio#methane with methanethiol produced trimethyl trithio! ortho!formate\ though reaction with higher alkanethiols was accompanied by disproportionation\ giving rise to mixtures of trithio!ortho!esters ð50LA"537#10Ł[ Cyclic a!chlorodithioacetals "51\ X S\ CH1# reacted with benzenethiol to give high yields of the trithio!ortho!esters "52\ X S\ CH1^ Equation "34## ð65BCJ442Ł[ Reaction of the benzoyloxytrithiane "53# with a range of alkane! and arene!thiols produced the trithio!ortho!esters "54\ R alkyl\ aryl^ Equation "35## ð63BCJ1346\ 64BCJ1385Ł[ The 1!alkoxybenzodithiole "55# reacted similarly with ethanethiol in the presence of acetic acid to give 1!ethylthio!0\2!benzodithiole "Equation "36## ð64S325Ł[ S
S
PhSH, C6H6, RT
X
Cl
X
S S
S S
S (64)
O S (66)
(45)
S (63)
RSH
OCOPh
S
SPh
80–90%
S (62)
(46)
SR S (65)
EtSH, AcOH, 20 C, 5 h
S
84%
S
SEt
(47)
"iii# From carboxylic ortho!esters and related compounds Carboxylic ortho!formate esters undergo exchange reactions with alkanethiols and arenethiols to give trithio!ortho!esters "Equation "37##[ The reaction may be catalysed using hydrogen chloride ð56AG"E#331Ł\ p!toluenesulfonic acid ð44JA498Ł\ zinc chloride ð53T306Ł\ boron tri~uoride etherate ð61CB2179Ł and montmorillonite KSF ð78SC20Ł\ though it will often proceed in the absence of a
72
Three Sulfurs
catalyst ð59IZV0890Ł[ Exchange of trialkyl ortho!formates with ethanedithiol and propanedithiol gave "56# and "57# respectively ð15JCS1152\ 56AG"E#331Ł\ and exchange of triethyl ortho!formate with 1!methyl!1!thiohydroxymethylpropane!0\2!dithiol produced the tricyclic trithio!ortho!ester "58\ R H# ð44JA498Ł[ Little work has been reported on the exchange of higher ortho!esters with thiols\ though triethyl ortho!acetate does undergo reaction with 1!methyl!1!thiohydroxymethylpropane! 0\2!dithiol to give the tricyclic trithio!ortho!ester "58\ R Me# ð44JA498Ł[ OR1
SR2
R2SH
R1O
(48)
R2S
OR1
S S
S
SR2
S
S
S
S
S
S
S
S
S
(67)
S S
R
S (69)
(68)
5[92[2[0[1 Trithio!ortho!esters from thioimidate ester salts Thioimidate ester hydrochloride salts react with alkanethiols and arenethiols to yield the trithio! ortho!esters "69# ð42JA0557\ 51JOC1747Ł[ Although this method is analogous to the widely used Pinner synthesis of ortho!esters\ relatively few reports of the preparation of trithio!ortho!esters using this procedure have appeared[ Some trithio!ortho!esters prepared by this method are listed in Table 2[ SR2 R1
R3SH
R1
+
NH2 Cl–
SR3 SR3 SR3 (70)
(49)
Table 2 Trithio!ortho!esters "69# pre! pared from thioimidate ester hydro! chloride salts[ Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R2 Ref[ R0 ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ * H Ph 42JA0557 C1F4 Me 51JOC1747 Me 51JOC1747 C2F6 C2F6 Et 51JOC1747 ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ *
Other methods for the preparation of trithio!ortho!esters which proceed via thioimidate inter! mediates have been described[ Formamide undergoes an acid catalysed reaction with thiols to give trithio!ortho!esters "Scheme 02# ð96CB0639\ 96LA"242#020Ł\ and the formanilide "60# reacts with phosphorus oxychloride in the presence of thiols to give trithio!ortho!esters in yields of 33Ð58) "Scheme 03# ð59IZV0717Ł[ Acetamide derivatives do not react under similar conditions ð48RTC243Ł[ O
RSH
H NH2
SR
RSH
H NH
SR RS SR
Scheme 13
O H
(71)
H
+
+
N Ph Cl–
N Ph Me
SR
Cl H
N Ph Cl– Me
Me Scheme 14
SR 44–69%
RS SR
73
Three Chalco`ens
5[92[2[0[2 Trithio!ortho!esters from carboxylic acids and derivatives "i# From acyl chlorides and anhydrides A general method for the preparation of trithio!ortho!esters involves the treatment of acyl chlorides with thiols in the presence of zinc chloride or aluminium trichloride "Equation "49##[ This procedure has been used to prepare a range of trithio!ortho!esters derived from aliphatic ð48RTC243Ł and aromatic ð42JA0557\ 79JOC639\ 75TL3750Ł acyl chlorides^ yields are usually greater than 39)[ A limitation of the method is that acyl chlorides containing one or more a!hydrogen atoms give poor yields of trithio!ortho!esters due to competing elimination reactions\ though this problem can be overcome to some extent by using an excess of the thiol reagent ð48RTC243Ł[ Reaction of acetic anhydride with 2!methylbenzenethiol in the presence of boron tri~uoride has been reported to give tris"2!methylphenyl# trithio!ortho!actetate in 29) yield ð42JA0557Ł[ O
SR2 SR2 SR2
R2SH, ZnCl2 or AlCl3, heat
R1
R1 Cl
(50)
"ii# From carboxylic esters and thioesters In 0896\ Holmberg ð96CB0639\ 96LA"242#020Ł discovered that formate esters undergo an acid pro! moted reaction with alkanethiols and arenethiols to give trithio!ortho!esters "Equation "40##[ A range of trialkyl and triaryl trithio!ortho!formates have been prepared using this method ð96CB0639\ 96LA"242#020\ 37JCS576\ 51RTC0998Ł[ These reactions simply involve saturating a mixture of the ester and thiol with hydrogen chloride\ and allowing the mixture to stand^ yields are normally greater than 49)[ Triaryl ortho!formates have also been obtained from the reactions of arenethiomagnesium bromides with ethyl formate ð51ZOB634Ł[ O
SR2
R2SH, HCl
H
(51)
R2S OR1
SR2
The Holmberg method is not suitable for the preparation of trithio!ortho!esters from higher carboxylic esters[ In a modi_cation of the reaction\ triethyl trithio!ortho!acetate has been obtained in low yield from the zinc chloride catalysed reaction of ethanethiol with ethyl acetate ð48RTC243Ł[ More recently\ the synthesis of trialkyl trithio!ortho!benzoate esters by the aluminum trichloride catalysed reaction of methyl benzoates with alkanethiotrimethylsilanes has been reported "Equation "41## ð79JOC639\ 75TL3750Ł[ O Ar
RS-TMS, AlCl3
Ar
OMe
SR SR SR
(52)
Thiocarboxylic esters "61\ R0 H\ alkyl\ aryl# undergo acid or Lewis acid catalysed reactions with thiols to give trithio!ortho!esters ð34USP1278042\ 42JA0557\ 64JOC852Ł[ Mixed trithio!ortho!esters "62#\ in which R1 and R2 are di}erent\ may be prepared by this method "Equation "42## ð34USP1278042\ 42JA0557Ł[ O R1
R3SH
R1 SR2 (72)
HCl or ZnCl2 or BF3
SR2 SR3 SR3 (73)
(53)
"iii# From carboxylic acids Formic acid reacts with alkanethiols and arenethiols to give trithio!ortho!formate esters ð00CB2124\ Higher carboxylic acids do not generally undergo this reaction^ exceptions are the reactions of tri~uoroacetic acid with ethane!0\1!dithiol and propane!0\2!dithiol\ which give the 01CB1831Ł[
74
Three Sulfurs
cyclic bistrithio!ortho!esters "63# and "64# respectively ð56CC0978\ 57JOC1493Ł[ Reaction of formic acid with hydrogen sul_de and acetic anhydride in the presence of zinc chloride a}orded tris "acetylthio#methane "65^ Equation "43## in 39) yield ð65CS011Ł[ This compound may also be prepared by treatment of formic acid with thioacetic acid and acetic anhydride in the presence of zinc chloride ð65CS011Ł[ S
CF3 S S
S
CF3 S
CF3 S
S
S
S
S
S
CF3
S
(75)
(74)
SAc
H2S, (MeCO)2O, ZnCl2, MeCO2H, 20–50 °C, 2 h
HCO2H
(54)
AcS
40%
SAc (76)
5[92[2[0[3 Trithio!ortho!esters from dithio! and trithiocarbenium salts Trithio!ortho!esters and related compounds are obtained from the addition of thiols and other sulfur nucleophiles to dithiocarbenium salts[ Reaction of the dithiolium tetra~uoroborate salt "66# with sodium benzenethiolate produced the 1!phenylthio!0\2!dithiole "67^ Equation "44##\ and reaction with N\N!dialkyldithiocarbamate salts gave 1!dithiocarbamoyldithioles "68# ð58CPB0820Ł[ Treatment of the dithiolium perchlorate salt "79# with one equivalent of potassium ethyl xanthate yielded the analogous ethoxythiocarbonythio derivative "70#\ whereas the use of an excess of potassium ethyl xanthate produced the sul_de "71#\ the reaction being thought to proceed via further reaction of "70# with the xanthate "Scheme 04# ð66JOC0432Ł[ S Ph
+
SCSNR1R2
S
Ph
EtOCS2K
S
Ph S
EtO S
S
Ph S
S ClO4–
Ph
S (80)
S– SCSOEt
(55)
SPh
S (78)
S +
(79)
(81)
Ph
66%
S (77)
S Ph
S
NaSPh, EtOH, 78 °C, 1 h
BF4–
SCSOEt S (81)
Ph S
(80)
S
–EtOCSSCSOEt
S–
S
Ph
S S (82) Scheme 15
1!Methanethio!0\2!dithiolium salts may be reduced to 1!methanethio!0\2!dithioles using sodium borohydride[ The dithiole "73# was prepared in 67) yield from the salt "72# by this method "Equation "45## ð81JOC0585Ł[ MeSe
S +
MeSe
SMe BF4–
MeSe
S
MeSe
S
NaBH4, MeCN, 20 °C, 1 h
S (83)
SMe
(56)
(84)
5[92[2[0[4 Trithio!ortho!esters from dithioacetals Dithioacetals may be converted into trithio!ortho!esters by deprotonation with a strong base\ followed by reaction of the metallated species "74# with a disul_de "Scheme 05#[ The reaction was
75
Three Chalco`ens
_rst described by Frohling and Arens ð51RTC0998Ł\ who prepared triethyl trithio!ortho!benzoate in 65) yield from benzaldehyde diethyl dithioacetal using sodium amide and diethyl disul_de "Equa! tion "46##[ A procedure for the preparation of trithio!ortho!ester "75# from the cyclic dithioacetal "76# using n!butyl lithium and dimethyl disul_de is given in Or`anic Syntheses ð66OS"45#7Ł\ and this method has also been used for the preparation of a range of benzoic\ cinnamic and aliphatic trithio! ortho!esters ð61JOC1646Ł[ However\ the reaction may not be general for the preparation of aliphatic trithio!ortho!esters*trithioacetates and trithiopropionates could not be prepared from the cor! responding dithioacetals using sodium amide and dialkyl disul_des\ presumably because of com! peting elimination reactions ð51RTC0998Ł[ The preparation of trithio!ortho!formate esters by this method appears to be dependent on the nature of the substituents on sulfur\ and on the base used[ Seebach et al[ prepared the mixed trithio!ortho!formate ester "77# in 84) yield from bis"ben! zenethio#methane using n!butyllithium and dimethyl disul_de "Equation "47## ð61CB2179Ł\ whereas Frohling and Arens obtained only tetraethyl tetrathio!ortho!carbonate from the reaction of the bis"ethanethio#methane with sodium amide and diethyl disul_de "Scheme 06# ð51RTC0998Ł[ Doubly 02 C!labelled trimethyl trithio!ortho!formate has been prepared by a related method\ in which the lithiated dithioacetal "78# is treated sequentially with elemental sulfur followed by 02C!labelled methyl iodide "Scheme 07# ð73HCA0969Ł[ SR2
SR2
M+B–
R1
R1
–
SR2
R3SSR3
M+
SR2 SR2 SR3
R1
SR2 (85) Scheme 16
SEt
i, NaNH2
Ph
Ph ii, EtSSEt 76%
SEt
MeS
S
SEt SEt SEt
(57)
S
Ph
Ph S
S
(86)
(87)
SPh
SPh
i, BunLi
(58)
MeS SPh
SEt
NaNH2, EtSSEt
ii, MeSSMe 95%
SEt EtS
SEt
SPh (88)
NaNH2, EtSSEt
EtS
SEt
SEt SEt SEt
Scheme 17
SMe Li+
–
i, BunLi
H
*
SMe (89)
ii, 1/8 S8
*
SMe SMe S– Li+
Scheme 18
Me*I
H 58%
*
SMe SMe * SMe
76
Three Sulfurs
Trithio!ortho!formates have been prepared by reaction of N!p!toluenesulfonylsul_limines "89# derived from dithioacetals of formaldehyde with alkanethiols and arenethiols under alkaline con! ditions "Equation "48## ð65S440Ł[ Mixed trithio!ortho!esters are available by this method[ SR1
SR2
R3SH, KOH
R2
S
(59)
R1S
61–82%
SR3
TosN (90)
5[92[2[0[5 Trithio!ortho!formates from trithiocarbonates Addition of phenyllithium to diphenyl trithiocarbonate at −67>C yields the triphenyl! thiomethylide anion "80^ Equation "59##[ This anion\ when prepared by a di}erent method\ has been quenched with deuterated water to give the deuterated triphenyl trithio!ortho!formate "81# ð61CB376Ł[ Similar addition of methyllithium to the dithiolone "82#\ followed by quenching with acetic acid\ yielded the 1!methanethio!0\2!dithiole "83^ Scheme 08# ð76TL3042Ł[ The use of lithiated trithio!ortho!formates for the preparation of higher trithio!ortho!esters is discussed in Section 5[92[2[1[0[ PhS
PhSLi, THF, –78 °C
Li+
S PhS
D
S
S
MeLi, THF, –60 °C
S
S –
S
(60)
SPh SPh SPh (92)
S S
SPh SPh SPh (91) –
S
S
AcOH
SMe Li+
S
S
S
S
SMe 75%
(93)
(94) Scheme 19
Diphenyl trithiocarbonate undergoes cycloaddition reactions with diaryldiazomethanes to pro! duce the cyclic trithio!ortho!ester derivatives "84^ Equation "50## ð54CB2292Ł[ PhS
Ar2CN2
S PhS
S Ar
SPh Ar
(61)
SPh (95)
5[92[2[0[6 Trithio!ortho!formates from tetrathio!ortho!carbonates Seebach ð56AG"E#331Ł reported the preparation of the trithio!ortho!formate "86# by treatment of the tetrathio!ortho!carbonate "85# with n!butyllithium at −67>C\ followed by quenching the reaction with water "Scheme 19#[ The reaction proceeds via the lithiated trithio!ortho!formate ester "87#[ Similar treatment of tetraphenyl tetrathio!ortho!carbonate with n!butyllithium gave the tri!
77
Three Chalco`ens
phenylthiomethylide anion "80#\ which has been used to prepare the deuterated trithio!ortho!formate "81# ð61CB376Ł[ The use of lithiated trithio!ortho!formates for the preparation of higher trithio! ortho!esters is discussed in Section 5[92[2[1[0[ S S
SMe
S
BunLi, THF, –78 °C
–
SMe
(96)
SMe 70%
Li+
S
S
H2O
SMe
S
(98) Scheme 20
(97)
5[92[2[1 Preparation of Trithio!ortho!esters from other Trithio!ortho!esters 5[92[2[1[0 Higher trithio!ortho!esters from trithioformate esters In 0851\ Hine et al[ ð51JA0640Ł reported the generation of the potassium trithio!ortho!formate salt "88# by deprotonation of trimethyl trithio!ortho!formate with potassium amide\ and the reaction of this with methyl iodide to produce trimethyl trithio!ortho!acetate in 64) yield "Scheme 10#[ Seebach et al[ ð56AG"E#331\ 61CB376\ 61CB2179Ł later described the generation of several lithiated trithio!ortho! formate esters from the appropriate trithio!ortho!formate with n!butyllithium at −67>C\ and the subsequent reactions of these with a range of electrophiles to yield higher trithio!ortho!esters[ This has since developed into a general method for the homologation of trithio!ortho!formates[ Thus\ lithiated trithio!ortho!formates react with alkyl halides to give aliphatic trithio!ortho!esters ð56AG"E#331\ 61CB376\ 61CB2179\ 65CL32\ 71TL2396Ł\ with aldehydes and ketones to give a!hydroxy! trithio!ortho!esters ð56AG"E#331\ 61CB376\ 65CL32\ 70TL3998Ł\ with epoxides to give b!hydroxy trithio! ortho!esters ð56AG"E#331\ 61CB376Ł\ with cyclic a\b!unsaturated ketones to give g!ketotrithio!ortho! esters ð64CC105\ 78TL4370Ł\ with carbon dioxide to give trithiomono!ortho!oxalates ð56M0932Ł\ with carbon disul_de to give trithiomono!ortho!dithiooxalates ð77T1952Ł\ with chloroformate esters to give trithiomono!ortho!oxalate esters ð56AG"E#331\ 61CB376Ł and with iodine to give coupled hexa! thiodi!ortho!oxalates ð61CB2781Ł "Scheme 11#[ An example of the acylation of a lithiated trithio! ortho!formate by reaction with a lactone has been reported "Equation "51##\ but this reaction is not general ð80CJC304Ł[ Since lithiated trithio!ortho!esters may also be obtained from trithiocarbonates "Section 5[92[2[0[5# and tetrathio!ortho!carbonates "Section 5[92[2[0[6#\ these compounds should also be regarded as precursors of higher trithio!ortho!esters[ SMe MeS
KNH2, NH3
SMe
MeI
SMe
75%
–
K+ MeS
SMe
SMe SMe SMe
(99) Scheme 21
S
S Li+
MeS
O
–
O
S
OH O
(62)
S SMe
Triethyl trithio!ortho!heptanoate has been prepared by a radical homologation procedure\ involv! ing treatment of triethyl trithio!ortho!formate with 0!hexene in the presence of t!butyl hydroperoxide "Equation "52## ð77MI 592!90Ł[ SEt
1-hexene, ButO2H, 130 °C
SEt
76%
EtS
SEt SEt
(63)
SEt
5[92[2[1[1 Trans!esteri_cation of trithio!ortho!esters In contrast to the chemistry of ortho!esters\ relatively little work has been published on the preparation of trithio!ortho!esters by trans!esteri_cation reactions of other trithio!ortho!esters with
78
Three Sulfurs SR1 SR2 SR3
R4
SR1 SR2 SR3
HO R4 R5
OH SR1 SR2 SR3
R4
R4X
O
R4COR5
O
R4 O
SR2 R1S
BunLi, THF, –78 °C
Li+ –
SR3
SR1 SR2 SR3
SR1 SR2 SR3
CO2
O CS2
HO
R4OCOCl
SR1 SR2 SR3
I2
SR1 SR2 SR3
S R1S 2 RS R 3S
SR1 SR2 SR3
SR1 SR2 SR3
O R4O
HS
Scheme 22
thiols[ Mixed trithio!ortho!esters undergo rapid acid catalysed disproportionation reactions to yield mixtures of trithio!ortho!esters "Scheme 12# ð50LA"537#10Ł[ The dithiolane "099# and dithiane "090# have been prepared by heating triethyl trithio!ortho!formate with the appropriate dithiol in the presence of zinc chloride ð77URP0310633Ł[ R1
SR2 SR3 SR3
H+
R1
SR2 SR2 + SR2 Scheme 23
R1
SR2 SR2 SR3
+
R1
SR3 SR3 SR3
S
S
SEt
SEt S (100)
S (101)
5[92[2[1[2 Modi_cation of R0 and R1 of R0C"SR1#2 Treatment of triaryl trithio!ortho!acetates with deuterated tri~uoroacetic acid in deutero! chloroform results in a rapid proton exchange reaction to give the deuterated trithio!ortho!acetates "091^ Equation "53## ð64JOC852Ł[ However\ attempts to homologate triaryl trithio!ortho!acetates by reaction with electrophilic acylating agents have not been successful ð64JOC852Ł[ SAr SAr SAr
CF3CO2D, CDCl3, RT, 5 min
D3C ca. 100%
SAr SAr SAr (102)
(64)
Deacetylation of tris"acetylthio#methane using methanolic hydrogen chloride produced meth! anetrithiol "092^ Equation "54## in 49) yield ð65CS011Ł[ This product is stable at −29>C\ although
89
Three Chalco`ens
it polymerises slowly at 19>C[ The hydrolysis proceeds via di! and monoacetyl trithiomethane intermediates\ which can be detected in the 0H NMR spectrum of the reaction mixture[ SAc
SH
2% HCl in MeOH, 6 h
AcS
(65)
HS SAc
50%
SH (103)
5[92[2[2 Methods for the Preparation of Oxidised Derivatives of Trithio!ortho!esters 5[92[2[2[0 Oxidised trithio!ortho!esters containing at least one sulfoxide group Triaryl trithio!ortho!formate esters are oxidised to the triaryl sulfoxide derivatives in high yields on treatment with peroxyacetic acid "Equation "55## ð53CR"148#3940Ł[ The sulfoxide "093# has been prepared by oxidation of the corresponding sul_de with peroxybenzoic acid "Equation "56## ð37RTC773Ł[ SAr
SOAr
MeCO3H, Et2O
ArS
(66)
ArOS SAr
SO2Me MeS
>90%
PhCO3H
SOAr
SO2Me (67)
MeOS
SO2Me
SO2Me (104)
5[92[2[2[1 Oxidised trithio!ortho!esters containing at least one sulfone group Treatment of the sulfone "094# with two equivalents of N!ethanethiophthalimide in the presence of potassium t!butoxide produced the sulfonyldithio!ortho!ester derivative "095# in high yield "Equa! tion "57## ð71CC0072Ł[ Bis"sulfonyl#methanes "096# react with alkyl thioalkyl sulfones and alkane! sulfonyl or arenesulfonyl chlorides in the presence of sodium ethoxide to give disulfonylthiomethanes "097# ð22JCS295Ł and trisulfonylmethanes "098# ð30CB0556Ł respectively "Scheme 13#[ These oxidised trithio!ortho!formate derivatives produce the analogous trithio!ortho!acetate derivatives on treat! ment with methyl iodide in aqueous alkali "Equation "58## ð0781CB236\ 0781CB250Ł[ O 2 equiv.
O Ph
N SEt, KOBut, DMSO O
SO2Me
O Ph
87%
(105)
SO2R1 R3S
R3SSO2R4, NaOEt, EtOH
SO2R2 (108)
SO2R1
R3SO2Cl, NaOEt, EtOH
SO2R2 (107) Scheme 24
SO2R2 R1SO2 SOnR3
MeI, aq. NaOH
SO2Me SEt SEt (106)
(68)
SO2R2 R1SO
2
SO2R3 (109)
SO2R1 SO2R2 SOnR3
(69)
80
Three Seleniums
Trisulfones "009# are the products normally obtained from the oxidation of trialkyl and triaryl trithio!ortho!formates using acidic permanganate ð0781CB236\ 22RTC326Ł\ though Laves ð0789CB0303Ł has reported that controlled oxidation of triphenyl trithio!ortho!formate using this reagent produces the disulfone "000#[ Yields from these permanganate oxidations are often low due to the competing formation of disulfonylmethanes and sulfonic acids ð96CB0639\ 22RTC326Ł[ Trialkyl trisulfones have been obtained from the oxidation of trialkyl trithio!ortho!formates with peroxyacetic and mon! operoxyphthalic acids ð35RTC42\ 42LA"470#022\ 56USP2222996Ł[ The tricyclic trisulfones "001\ R H\ Me# and triaryl sulfones "002# were prepared by oxidation of the corresponding trithio!ortho!esters using hydrogen peroxide in acetic acid ð44JA498\ 53CR"148#3940Ł[ Oxidation of disulfones "003\ R H\ Me# with alkaline permanganate or hydrogen peroxide produced the corresponding trisulfones in high yields "Equation "69## ð0781CB236\ 20JCS1526\ 35RTC42Ł[ SO2
SO2Ph
SO2R
R
PhS
RO2S
SO2Ph (111)
SO2R (110)
R1
SO2R2 SO2R2 SR3 (114)
SO2Ar ArO2S
SO2 SO2 (112)
KMnO4 / HO– or H2O2
SO2Ar (113)
SO2R2 SO2R2 SO2R3
R1
(70)
The disulfonylthiomethane "005# was obtained in 83) yield from the sodium ethanethiolate reduction of the disulfonyldithiomethane "004^ Equation "60## ð71CC0072Ł[ EtS
SO2Et SO2Et SEt (115)
NaSEt, THF 94%
SO2Et (71)
EtS SO2Et (116)
5[92[2[2[2 Oxidised trithio!ortho!esters containing at least one sulfonate group Methanetrisulfonic acid "006# has been prepared by various methods\ including sulfonation of methanedisulfonic acid and oxidation of thiol methanetrisulfonic acid^ these have been reviewed by Backer ð29RTC0096Ł and summarised by DeWolfe ðB!69MI 592!90Ł[ The trimethyl and triethyl esters "008\ R Me\ Et# were obtained by treatment of the silver"I# salt "007# with methyl iodide and ethyl iodide respectively "Equation "61## ð38AK"0#120\ 49ACS286Ł[ SO3H HO3S SO3H (117)
SO3– –O S 3
3Ag+ SO3–
(118)
RI, C6H6
SO3R (72)
RO3S SO3R (119)
5[92[3 FUNCTIONS BEARING THREE SELENIUM ATOMS Triseleno!ortho!esters contain a carbon atom bearing three alkaneseleno or areneseleno groups[ Methods for the preparation of triseleno!ortho!esters have been reviewed brie~y by Krief and Hevesi ð73MI 592!90Ł[
81
Three Chalco`ens
5[92[3[0 Methods for the Preparation of Triseleno!ortho!esters 5[92[3[0[0 Triseleno!ortho!esters from RC"X0#"X1#X2 "i# From 0\0\0!trihaloalkanes Triseleno!ortho!formates "019\ R Me\ Ph# have been obtained from the treatment of bromoform with the appropriate sodium selenolate "Equation "62## ð73HCA0969\ 73S328Ł[ The sodium selenolates were prepared by reduction of diselenides in situ^ sodium methaneselenolate was prepared by the sodium:liquid ammonia reduction of dimethyl diselenide ð73HCA0969Ł\ and sodium benzene! selenolate was prepared by reduction of diphenyl diselenide using hydrazine ð73S328Ł[ Seebach ð73HCA0969Ł prepared 02C!labelled trimethyl triseleno!ortho!formate from 02C!labelled bromoform using this method[ CHBr3
NaSeR
SeR (73)
RSe SeR (120)
"ii# From a\a!dihalo ethers A range of alkane! and areneselenolates were shown to undergo a zinc promoted reaction with dichloromethyl methyl ether to give trialkyl and triaryl triseleno!ortho!formate esters in yields of 39Ð35) "Equation "63## ð60ZOR362Ł[ Cl OMe
RSeH, Zn, Et2O
SeR (74)
RSe
40–46%
Cl
SeR
"iii# From ortho!esters Trans!esteri_cation of ortho!formate esters with methane! or benzeneselenol in the presence of boron tri~uoride etherate produced the triseleno!ortho!formates "010\ R1 Me# and "010\ R1 Ph# in yields of 70) and 53) respectively "Equation "64## ð73JA2673\ 61CB400Ł[ Trimethyl ortho!acetate and methaneselenol gave trimethyl triseleno!ortho!acetate in 55) yield under these conditions ð68JOM"0660#Ł[ Ortho!esters have also been shown to undergo exchange reactions with boron tri! selenides to give triseleno!ortho!esters "Equation "65##\ though these reactions are subject to steric limitations[ Thus\ boron tris"benzeneselenide# and triethyl ortho!formate gave triphenyl triseleno! ortho!formate in 65) yield\ boron tris"methaneselenide# and trimethyl ortho!acetate produced trimethyl triseleno!ortho!acetate in 28) yield\ whereas the reaction between boron tris! "benzeneselenide# and trimethyl ortho!acetate proceeded only very slowly\ a}ording little of the triseleno!ortho!ester product ð68JOC0772\ 68JOC3168Ł[ R1O OR1
R2SeH, BF3•OEt2
SeR2 (75)
R2Se
R 1O
SeR2 (121)
R1
OR2 OR2 OR2
B(SeR3)3, cat. TFA, CHCl3
R1
SeR3 SeR3 SeR3
(76)
5[92[3[0[1 Triseleno!ortho!esters from carboxylic acids 02
C!Labelled triphenyl triseleno!ortho!formate has been prepared in 37) yield by the acid catalysed reaction of 02C!labelled formic acid with benzeneselenol "Equation "66## ð73HCA0969Ł[
82
Three Seleniums
The preparation of triseleno!ortho!esters from other carboxylic acid derivatives has not been reported[ PhSeH, HCl, 0 °C, 1 h
HC*O2H
(77)
HC*(SePh)3
then RT, 30 d 48%
5[92[3[0[2 Triseleno!ortho!esters from triselenocarbenium salts In a manner analogous to the reduction of trithiocarbenium salts discussed in Section 5[92[2[0[3\ 1!alkaneseleno!0\2!diselenoles may be prepared by sodium borohydride reduction of the cor! responding triselenocarbenium salts[ 1!Methaneseleno!0\2!diselenole "011\ R Me# was prepared from the corresponding triselenocarbenium iodide in a yield of greater than 79) using this method "Equation "67## ð64TL0148Ł\ and the 1!ethaneseleno derivative "011\ R Et# was similarly prepared from the analogous tetra~uoroborate salt ð75ZC027Ł[ Se +
Se
NaBH4
SeR X–
Se (78)
SeR Se (122)
5[92[3[0[3 Triseleno!ortho!esters from diselenoacetals and related compounds A few derivatives of triseleno!ortho!esters have been prepared by the direct electrophilic selenation of diselenoacetals and related compounds[ Reaction of a\a!bis"benzeneseleno#acetaldehyde with morpholinobenzeneselenamide produced the triseleno!ortho!ester "012^ Equation "68## ð71TL0446\ 74BSF0108Ł\ and reaction of the selenated enamine "013# with the same reagent gave the addition product "014# ð74BSF0108Ł[ Treatment of acetone with red selenium under basic conditions produced the cyclic selenium salt "015# ð81CC0428Ł[ This reaction proceeds through the diselenoacetal!like intermediates "016# and "017#\ and involves three electrophilic a!selenation steps "Scheme 14#^ it is therefore a counterpart of the haloform reaction[ PhSeN
PhSe CHO PhSe
O
PhSe PhSe CHO PhSe (123)
(79)
O PhSe PhSe PhSe
PhSe PhSe
N
N N O
O (124)
(125)
5[92[3[0[4 Triseleno!ortho!formates from tetraseleno!ortho!carbonates Seebach ð58AG"E#349Ł showed that the lithium triselenomethylide "018# is generated by treatment of tetraphenyl tetraseleno!ortho!carbonate with n!butyllithium at −67>C "Equation "79##\ and that this reacts with deuterated water to give the deuterated triseleno!ortho!formate "029#[ The use of lithiated triseleno!ortho!formates\ for example "018#\ for the preparation of higher triseleno!ortho! esters is discussed in the next section[
83
Three Chalco`ens O O
Se– Se
Red Se, K2CO3, (Ph3P)2NCl, RT, 16 h 26%
Se
Se (126)
Se Se
O
O O
Se
Sex Sex Se
Sey (127) Scheme 25
PhSe
N+(PPh3)2
SePh SePh SePh
BunLi, THF, –78 °C
Se (128)
Li+
–
Se Se
SePh SePh SePh
(80)
(129)
D
SePh SePh SePh (130)
5[92[3[0[5 Higher triseleno!ortho!esters from triseleno!ortho!formate esters Metallated triseleno!ortho!formates "020# are generated on treatment of triseleno!ortho!formate esters with strong bases^ the lithiated triseleno!ortho!formate "020\ R Ph# is obtained from tri! phenyl triseleno!ortho!formate and lithium di!s!butylamide at −67>C ð58AG"E#349Ł\ and "020\ R Me# is generated from trimethyl triseleno!ortho!formate and n!butyllithium at −67>C ð68JOM"0660#Ł[ These lithiated triseleno!ortho!formates react with a range of electrophiles to yield higher triseleno!ortho!esters[ Thus\ lithiated triseleno!ortho!formates react with] alkyl halides to give aliphatic triseleno!ortho!esters ð58AG"E#349\ 68JOM"066#0\ 71TL2396Ł^ aldehydes to give a!hyd! roxytriseleno!ortho!esters ð58AG"E#349\ 70TL3998Ł\ and epoxides to give b!hydroxytriseleno!ortho! esters ð67TL2860Ł "Scheme 15#[ Tris"tri~uoromethyl# triseleno!ortho!formate yielded the cor! responding triseleno!ortho!acetate "021# on metallation with potassium di!i!propylamide\ followed by treatment with methyl iodide "Equation "70## ð73T3852Ł[ Since metallated triseleno!ortho!formates may also be obtained from tetraseleno!ortho!carbonates "Section 5[92[3[0[4#\ these should also be regarded as precursors of higher triseleno!ortho!esters[ SeR1 SeR1 SeR1
R2 R2X
SeR1 R1Se SeR1
Li+ –B, THF, –78 °C
Li+
–
SeR1 SeR1 SeR1
(131)
R2CHO
SeR1 SeR1
R2
SeR1
O
OH
R2
SeR1
R2 OH Scheme 26
SeR1 SeR1
84
Mixed Includin` Oxy`en SeCF3
SeCF3 SeCF3 SeCF3 (132)
i, K+ –N(Pri)2
F3CSe
ii, MeI
SeCF3
(81)
5[92[4 MIXED CHALCOGEN FUNCTIONS INCLUDING OXYGEN Mono! and dithio!ortho!esters are derivatives of carboxylic ortho!esters in which one and two of the oxygen substituents respectively are replaced with sulfur substituents[ Similarly\ mono! and diseleno!ortho!esters are mixed oxygen and selenium functions containing one and two selenium substituents respectively[ Monoselenomonothio!ortho!esters bear one oxygen\ one sulfur and one selenium substituent[ Oxidised derivatives of several mixed functions containing sulfur are known[ Methods for the preparation of mixed oxygen and sulfur functions have been reviewed by Simchen ð74HOU"E4#2Ł[
5[92[4[0 Methods for the Preparation of Functions R0C"OR1#"OR2#SR3 5[92[4[0[0 From R0C"X0#"X1#X2 Triphenyl monothio!ortho!formate has been prepared in 31) yield by reaction of chloro! diphenoxymethane with benzenethiol in the presence of pyridine "Equation "71## ð51CB0748Ł[ OPh
PhSH, pyridine
Cl
OPh
42%
OPh
(82)
PhS OPh
Monothio!ortho!esters have been prepared from the reactions of ortho!ester derivatives with thiols[ Ortho!esters react with one equivalent of n!butanethiol in the presence of aluminum tri! chloride to give monothio!ortho!esters "Equation "72##^ yields are reasonable "54Ð79)# for mono! thio!ortho!formates and !acetates\ but are lower "ca[ 24)# for thio!ortho!benzoates ð57CR"C#0495Ł[ This reaction will also proceed in the absence of a catalyst^ monothio!ortho!formates are obtained in high yields ð58BSF214Ł\ though yields are low for monothio!ortho!acetates and !ortho!benzoates\ which are obtained as mixtures with dithio!ortho!esters ð69MI 592!91Ł[ Treatment of the O!acyl ortho! formate ester "35# with a range of thiols in the presence of triethylamine produced the monothio! ortho!esters "022# in yields of 34Ð64) "Equation "73## ð58RTC786Ł[ The acid catalysed trans!esteri! _cation of ortho!esters with 1!hydroxybenzenethiol produced the cyclic monothio!ortho!esters "023# in good yields "69Ð66)# "Equation "74## ð64S559Ł[ Cyclic monothio!ortho!ester derivatives have also been obtained from the exchange reactions of ortho!esters with 1!hydroxyethanethiol ð66MI 592!90Ł and 1!thiohydroxyacetic acid ð67IZV357Ł[ OR2 OR2 OR2
R1
OEt AcO
1 equiv. BunSH, AlCl3, heat
RSH, Et3N, RT, 20 min 45–75%
OEt (46)
OR2 SBu OR2
R1
(83)
OEt (84)
RS OEt (133)
SH
R1
OR2 OR2 OR2
OH ,H2SO4, 100 °C, 15 min 70–77%
S
OR2 (85)
O (134)
R1
85
Three Chalco`ens
5[92[4[0[1 From monothiocarboxylic esters Monothio!ortho!benzoate esters have been prepared in yields of 55) or more by reaction of a monothiobenzoate ester with a sodium alkoxide\ followed by alkylation of the thiolate intermediate with an alkyl iodide "Scheme 16# ð78S573Ł[ However\ this procedure is not suitable for the preparation of monothio!ortho!esters from simple aliphatic monothio esters\ which may undergo deprotonation under the reaction conditions ð78S573Ł[ Treatment of the hydroxy monothioesters "024\ n 9\ 0# with sodium hydride gave the cyclic thiolate intermediates "025\ n 9\ 0#\ which were methylated in situ to yield monothio!ortho!esters "026\ n 9\ 0# in overall yields of 24Ð67) "Scheme 17# ð75JA5572Ł[ Unlike the reaction of simple monothio!ortho!esters with alkoxides\ this procedure is applicable to the preparation of cyclic monothio!ortho!acetate esters as well as monothio!ortho! benzoates[ S Ar
NaOR1, R1OH or THF
S– OR1 OR1
Ar
OR1
R 2I
Ar
SR2 OR1 OR1
Scheme 27
S
O
S–
NaH, MeCN, 0 °C
R
( )n
( )n O
R
OH
(135)
Me3O+BF4– or MeI 35–78%
O
(136) Scheme 28
MeS
O
R
O
( )n (137)
5[92[4[0[2 From dioxo! and oxothiocarbenium salts Monothio!ortho!esters are obtained from the treatment of dioxocarbenium salts with thiols[ This reaction is analogous to the preparation of ortho!esters from dioxocarbenium salts and alcohols described in Section 5[92[1[0[3[ Reaction of the dimethyl dioxocarbenium salt "027# with meth! anethiol in the presence of triethylamine produced the monothio!ortho!ester "028^ Equation "75## ð76JOC1546Ł\ and the cyclic dioxocarbenium tetra~uoroborate salts "039\ R Me\ Ph^ n 9\ 0# gave monothio!ortho!esters "030\ R Me\ Ph^ n 9\ 0# on treatment with lithium methanethiolate "Equation "76## ð75JA5572Ł[ Alternatively\ the salts "039# could be converted to monothio!ortho! esters "030# by treatment with sodium sul_de\ followed by methylation of the thiolate intermediate with trimethyloxonium tetra~uoroborate or methyl iodide ð75JA5572Ł[ The stable monothio!ortho! hydrogen ester "032# was obtained by treatment of the bicyclic dioxocarbenium tetra~uoroborate "031# with sodium hydrosul_de "Equation "77## ð79JA6468Ł[ OMe MeO
BF4–
+
MeSH, Et3N
SMe OMe OMe
MeO
OMe (138)
(139) O
R
(86)
( )n
+
BF4–
LiSMe
MeS
( )n R
O (140)
O
NaSH
O
+
BF4– (142)
O
(87)
O (141)
(88) O
SH
O
(143)
Monothio!ortho!esters may also be prepared from oxothiocarbenium salts by addition of alk! oxides[ Reaction of 1!ethoxythiolenium tetra~uoroborate with sodium ethoxide gave 1\1!diethoxy!
86
Mixed Includin` Oxy`en
thiolane "Equation "78## ð45CB1959Ł\ and the 1!alkyl! and 1!aryl!1!alkoxy!0\2!benzoxathioles "034# were prepared by treatment of the oxathiolium salts "033# with alcohols in the presence of sodium hydrogen carbonate "Equation "89## ð68S112Ł[ OEt
NaOEt +
S
OEt
S
(89)
OEt
BF4–
S +
O (144)
S
R2OH, NaHCO3, MeCN, 0–5 °C, 10 min
R1 BF4–
R1 (90)
78–97%
O (145)
OR2
5[92[4[0[3 From monothioacetals and related compounds The cyclic monothio!ortho!formate "036# has been prepared in 23) yield by methanolysis of the N!p!toluenesulfonylsul_limine "035^ Equation "80## ð74JOC546Ł[ The alkaline reaction conditions help prevent the product from undergoing disproportionation reactions[ This procedure is analogous to the preparation of trithio!ortho!esters discussed in Section 5[92[2[0[4[ NTos S
S
MeOH, KOH
(91)
OMe 34%
O (146)
O (147)
5[92[4[0[4 From 1!alkoxythiophenes Terrier et al[ demonstrated that the highly electron de_cient 1\3!dinitro!4!methoxythiophene undergoes addition of methanol on treatment with potassium methoxide to produce the stable salt "037#\ which was isolated as a purple solid in virtually quantitative yield "Equation "81## ð64JOC1800Ł[ NO2
NO2 KOMe, MeOH, RT, 15 min
O2N
S
ca. 100%
OMe
–
O2N
S
(92)
OMe K+ OMe
(148)
5[92[4[1 Methods for the Preparation of Functions R0C"OR1#"SR2#SR3 5[92[4[1[0 From R0C"X0#"X1#X2 Cyclic dithio!ortho!esters have been obtained from the reactions of a\a!dichloro ethers with dithiolates[ Treatment of dichloromethyl methyl ether with disodium ethane!0\1!dithiolate "gen! erated from ethanedithiol and sodium# gave 1!methoxy!0\2!dithiolane in 57) yield\ and dilithium propane!0\2!dithiolate "generated from propane!0\2!dithiol and n!butyllithium# reacted with di! chloromethyl methyl ether to produce 1!methoxy!0\2!dithiane in 34) yield "Scheme 18# ð61HCA64Ł[
S
HS(CH2)2SH, Na, MeCN
OMe S
Cl OMe
68%
Cl Scheme 29
HS(CH2)3SH, BunLi, THF
S
45%
S
OMe
87
Three Chalco`ens
Dithio!ortho!esters have also been obtained from exchange reactions of ortho!esters with n! butanethiol ð58BSF214Ł\ though these are normally isolated as side!products from the preparation of monothio!ortho!esters by this method "see Section 5[92[4[0[0# ð69MI 592!91Ł[
5[92[4[1[1 From dithiocarbenium salts Okuyama et al[ ð76JOC1546Ł prepared the dithio!ortho!ester "049# by addition of sodium methoxide to the dithiocarbenium perchlorate "038^ Equation "82##[ This procedure is analogous to the prep! aration of trithio!ortho!esters by the addition of thiols to dithiocarbenium salts discussed in Section 5[92[2[0[3[ SMe ClO4– SMe
MeO
NaOMe, MeOH, MeCN
SMe SMe OMe
MeO
+
(149)
(93)
(150)
5[92[4[1[2 From mono! and dithioacetals and related compounds Dithio!ortho!ester derivatives may be prepared by the reaction of metallated monothioacetals with disul_des[ Deprotonation of 0\2!oxathiane by treatment with n!butyllithium at −67>C\ followed by reaction with dimethyl disul_de produced 1!methanethio!0\2!oxathiane in 71) yield "Scheme 29# ð70TL1994\ 74JOC546Ł[ In a similar manner\ lithiation of a series of sulfonyl oxiranes "040# followed by treatment with diphenyl disul_de gave the oxidised dithio!ortho!ester derivatives "041# in yields of 34Ð89) "Scheme 20# ð80JCS"P0#2980Ł[ S
S
i, BunLi, THF, –100 °C
ii, MeSSMe
S
82%
O
Li+
–
SMe
O
O
Scheme 30
O
R1
SO2Ph
i, BunLi, THF, –100 °C
O
R1
SO2Ph –
R2
R2
ii, PhSSPh
O
R1
Li+
SO2Ph R2
(151)
SPh (152)
Scheme 31
Lithiation of the unsaturated dithioacetal "042# followed by reaction with benzophenone produced the bicyclic dithio!ortho!ester "043# in 87) yield "Scheme 21# ð58S06Ł[ This reaction proceeds via cyclisation of the intermediate ketene dithioacetal "044#[ Selenocyclisation of the related hydroxy ketenedithioacetal "045# gave the spirobicyclic dithio!ortho!ester "046^ Equation "83## ð79JOC1125Ł[
S S
S
i, BunLi
S S
ii, Ph2CO
98%
Li+ –O
Ph
S
Ph
Ph (153)
(155) Scheme 32
Ph
O
(154)
88
Mixed Includin` Oxy`en S
SePh PhSeCl, Et3N, THF, –78 °C
S HO
S
64%
S
Ph (156)
(94) O
Ph
(157)
Some dithioacetals undergo direct oxygenation on treatment with organic peroxides[ Reaction of trithiane with t!butyl peroxybenzoate in the presence of copper"I# chloride gave the benz! oyloxytrithiane "53# and dibenzoyloxytrithiane "047^ Equation "84##^ the yield of "53# was at an optimum "69Ð79) based on recovered trithiane# when 9[6 equivalents of t!butyl peroxybenzoate were used\ and "047# was obtained as the major product when 2[9 equivalents of t!butyl per! oxybenzoate were used ð63BCJ0385Ł[ 1!Benzoyloxydithiane has been generated by an analogous method\ though this product was too unstable to isolate and characterise ð63BCJ0385Ł[ S S
S
S
PhCO3But, CuCl, C6H6, heat
S
S
+
OCOPh
OCOPh
S S
S
(95)
PhOCO (64)
(158)
Cyclic dithio!ortho!formates have been prepared by reaction of N!p!toluenesulfonylsul_limines "89# derived from dithioacetals of formaldehyde with alcohols under alkaline conditions "Equation "85## ð65S440Ł[ SR1
SR1
R3OH, KOH
(96)
R 3O
SR2
56–93%
SR2
TosN (90)
5[92[4[1[3 Miscellaneous methods Generation of benzyne in the presence of carbon disul_de and methanol gave 1!methoxy!0\2! benzodithiole in 67) yield "Scheme 22# ð63CC055Ł[ The reaction proceeds via addition of methanol to the carbene "048#\ which is formed by the cycloaddition of carbon disul_de to benzyne[ A modi_cation of this reaction involves the generation of benzyne by diazotisation of anthranilic acid using an alkyl nitrite^ in this case\ the alkoxy group of the alkyl nitrite is the source of the 1! substituent of the product benzodithiole "Equation "86## ð64S27Ł[ N N
Pb(OAc)4
S
CS2
MeOH
: S
N NH2
S OMe S
(159) Scheme 33
CO2H
RONO, CS2
NH2
S OR
(97)
S
A series of cyclic oxidised derivatives of dithio!ortho!esters "050# has been prepared by the lithium t!butyl peroxide oxidation of alkenes "059^ "Equation "87## ð80JCS"P0#2980Ł[ SO2Ar R1
SR2 (160)
O
LiO2But, THF, –78 °C to –18 °C
SO2Ar R1
SR2 (161)
(98)
099
Three Chalco`ens
5[92[4[2 Methods for the Preparation of Functions R0C"OR1#"OR2#SeR3 5[92[4[2[0 From 1!alkoxyselenophenes In an analogous reaction to that described in Section 5[92[4[0[4\ addition of potassium methoxide to 1\3!dinitro!4!methoxyselenophene produced the stable salt "051#\ which was isolated as a purple solid in virtually quantitative yield "Equation "88## ð64JOC1800Ł[ NO2
NO2 KOMe, MeOH, RT, 15 min
O2N
OMe
Se
–
ca. 100%
O2N
OMe K+
(99)
Se OMe (162)
5[92[4[3 Methods for the Preparation of Functions R0C"OR1#"SeR2#SeR3 5[92[4[3[0 From R0C"X0#"X1#X2 Dihalomethyl methyl ethers react with selenolates to give diseleno!ortho!esters[ Treatment of dichloromethyl methyl ether with sodium benzeneselenolate "generated by the sodium borohydride reduction of diphenyl diselenide# gave the diseleno!ortho!formate ester "052# in 67) yield "Equation "099## ð68JA5527Ł[ Other dichloromethyl alkyl and aryl ethers gave diseleno!ortho!formates "053\ R alkyl\ aryl# in yields of 31Ð65) on treatment with sodium areneselenolates "generated from the selenophenol and metallic sodium# "Equation "090## ð75ZOR096Ł[ Dichloromethyl ethers also react with areneselenomagnesium halides to give diseleno!ortho!formates\ though yields are usually lower than those obtained from reaction with the corresponding sodium selenolates ð75ZOR096Ł[ Reaction of dibromomethyl methyl ether with dilithium benzene!0\1!diselenolate gave 1!methoxy!0\2!di! selenole in 27) yield "Scheme 23# ð77HCA0131Ł[ Cl
NaSePh
OMe 78%
Cl
Cl
PhSe
2 Se, THF/Et2O, –60 °C
Se– Li+
(101)
OR PhSe (164)
42–76%
Cl
(100)
OMe PhSe (163)
ArSeH/Na, MeO(CH2)2OMe
OR
Li
PhSe
Br2CHOMe
Se
38%
Se
OMe Se– Li+ Scheme 34
Li
The cyclic diseleno!ortho!esters "055\ R H\ Me# have been generated from the boron tri~uoride etherate catalysed exchange reactions between triethyl ortho!formate and the 0\2!diselenolates "054\ R H\ Me^ "Equation "091##[ However\ these products were not isolated and characterised\ but were used in situ for the preparation of diselenothio!ortho!esters "see Section 5[92[5[1[0# ð78H"17#278Ł[ Se– Li+
Se
HC(OEt)3, BF3•OEt2
OEt R
Se–
Li+
(165)
R
(102)
Se (166)
5[92[4[4 Methods for the Preparation of Functions R0C"OR1#"SR2#SeR3 5[92[4[4[0 From monothioacetals and related compounds Monoselenomonothio!ortho!ester derivatives have been prepared from the reactions of lithiated monothioacetals with diselenides[ Lithiation of 0\2!oxathiane with n!butyllithium followed by reac!
090
Mixed Sulfur And Selenium
tion with dimethyl diselenide produced 1!methaneseleno!0\2!oxathiane in 49) yield "Scheme 24# ð70TL1994\ 74JOC546Ł[ In a similar manner\ lithiation of the sulfonyl oxiranes "040# followed by treatment with diphenyl diselenide gave the oxidised selenothio!ortho!ester derivatives "056# in yields of 14Ð81) "Scheme 25# ð80JCS"P0#2980Ł[ S
S
i, BunLi, THF, –78 °C
O
ii, MeSeSeMe
S
50%
O
Li+
–
SeMe
O Scheme 35
O
R1
i, BunLi, THF, –100 °C
SO2Ph
O
R1
–
R2
R2
SO2Ph
ii, PhSeSePh
Li+
25–92%
(151)
O
R1
SO2Ph R2
SePh (167)
Scheme 36
5[92[5 MIXED SULFUR AND SELENIUM FUNCTIONS Monoselenodithio! and diselenomonothio!ortho!esters are mixed sulfur and selenium functions which bear one and two selenium substituents respectively[
5[92[5[0 Methods for the Preparation of Functions R0C"SR1#"SR2#SeR3 5[92[5[0[0 From R0C"X0#"X1#X2 1!Chloro!0\2!dithianes react with areneselenolates to give 1!areneseleno!0\2!dithianes[ Thus\ di! thianes "058\ R0 H^ R1 H\ Me\ OMe\ F\ Cl\ NMe1\ CF2# were prepared from 1!chloro!0\2! dithiane and the appropriate sodium areneselenolates "prepared by reduction of the corresponding diaryl diselenide using either sodium borohydride or metallic sodium and ultrasound# ð77JOC2655Ł[ Similar reaction of the 1!chloro!3\5!dimethyl!0\2!dithiane "057\ R0 Me# with sodium "p!methoxy! benzene#selenolate gave the selenodithio!ortho!ester "058\ R0 Me^ R1 OMe#\ which was obtained as a ca[ 4 ] 0 mixture of diastereoisomers "Equation "092## ð77JOC4557Ł[ R1
Na+ –Se
S
R2, C6H6
R1 S
Cl
Se
S R1
R2
(103)
S R1
(168)
(169)
5[92[5[0[1 From selenodithiocarbenium salts 1!Methanethio!0\2!selenothiolium salts are reduced to 1!methanethio!0\2!selenothioles by sodium borohydride[ Reduction of the ~uorosulfonate salt "069# gave the 1!methanethio!0\2!selenothiole "060# in 69) yield "Equation "093## ð79H"03#160Ł\ and similar treatment of the iodide salts "061\ R H\ Me# produced the analogous selenothioles "062\ R H\ Me# ð64TL0148Ł[
091
Three Chalco`ens Se Ph
Se
NaBH4, EtOH
SMe FSO3–
+
SMe
70%
S
Ph
(170)
(171) Se
Se SMe I–
+
R
(104)
S
SMe
S
S
R
(173)
(172)
5[92[5[0[2 From dithioacetals Selenodithio!ortho!esters may be prepared by the selenation of lithiated dithioacetals[ Deprot! onation of 0\2!dithiane using n!butyllithium followed by reaction with p!nitrobenzeneselenyl cyanide produced the 1!seleno!0\2!dithiane "063# in 12) yield "Scheme 26# ð77JOC2655Ł[ However\ treatment of lithiated 0\2!dithiane with the diaryl diselenides "064\ R OMe\ CF2# gave only very low yields of the selenated compounds "065\ R OMe\ CF2# ð75CJC621Ł[ S
O2N
S
BunLi, THF, –20 °C
–
S
Li+
SeCN
S Se
23%
S
NO2
S (174)
Scheme 37 S
R
Se Se
Se
R
R
S (176)
(175)
5[92[5[1 Methods for the Preparation of Functions R0C"SR1#"SeR2#SeR3 5[92[5[1[0 From diseleno!ortho!esters Pinto et al[ ð78H"17#278Ł reported the preparation of the diselenothio!ortho!esters "066\ R H\ Me# from the corresponding O!ethyl diseleno!ortho!esters by treatment with benzenethiol[ The starting diseleno!ortho!esters were generated by the boron tri~uoride etherate catalysed reaction between dilithium diselenides and triethyl ortho!formate "see Section 5[92[4[3[0#\ and were used in situ[ Se OEt R
Copyright
#
Se
1995, Elsevier Ltd. All R ights Reserved
Se
PhSH
SPh R
(105)
Se (177)
Comprehensive Organic Functional Group Transformations
6.04 Functions Containing a Chalcogen and Any Other Heteroatoms Other Than a Halogen MARTIN J. RICE ZENECA Agrochemicals, Bracknell, UK 5[93[0 FUNCTIONS CONTAINING CHALCOGEN AND A GROUP 04 ELEMENT 5[93[0[0 Functions Bearin` Chalco`en and Nitro`en 5[93[0[0[0 Functions bearin` oxy`en and nitro`en 5[93[0[0[1 Functions bearin` sulfur and nitro`en 5[93[0[0[2 Functions bearin` selenium and nitro`en 5[93[0[1 Functions Bearin` Chalco`en and P\ As\ Sb or Bi 5[93[0[1[0 Functions bearin` oxy`en and P\ As\ Sb or Bi 5[93[0[1[1 Functions bearin` sulfur and P\ As\ Sb or Bi 5[93[0[1[2 Functions bearin` selenium and P\ As\ Sb or Bi 5[93[1 FUNCTIONS CONTAINING CHALCOGEN AND A METALLOID AND POSSIBLY A GROUP 04 ELEMENT
093 093 093 000 004 005 005 008 012
013 013 013 013 015 029 029 029 021
5[93[1[0 Functions Bearin` Chalco`en and Boron 5[93[1[1 Functions Bearin` Chalco`en and Silicon 5[93[1[1[0 Functions bearin` oxy`en and silicon 5[93[1[1[1 Functions bearin` sulfur and silicon 5[93[1[1[2 Functions bearin` selenium and silicon 5[93[1[2 Functions Bearin` Chalco`en and Germanium 5[93[1[2[0 Functions bearin` oxy`en and `ermanium 5[93[1[2[1 Functions bearin` sulfur and `ermanium 5[93[2 FUNCTIONS CONTAINING CHALCOGEN AND A METAL AND POSSIBLY A GROUP 04 ELEMENT OR A METALLOID 5[93[2[0 Functions Bearin` Oxy`en and a Metal 5[93[2[0[0 Functions bearin` two oxy`ens and a metal 5[93[2[0[1 Functions bearin` oxy`en\ silicon and a metal 5[93[2[0[2 Functions bearin` oxy`en and two metals 5[93[2[1 Functions Bearin` Sulfur and a Metal 5[93[2[1[0 Functions bearin` sulfur\ oxy`en and a metal 5[93[2[1[1 Functions bearin` two sulfurs and a metal 5[93[2[1[2 Functions bearin` sulfur\ boron and a metal 5[93[2[1[3 Functions bearin` sulfur\ silicon and a metal 5[93[2[1[4 Functions bearin` sulfur and two metals 5[93[2[2 Functions Bearin` Selenium and a Metal 5[93[2[2[0 Functions bearin` selenium\ sulfur and a metal 5[93[2[2[1 Functions bearin` two seleniums and a metal
092
022 022 022 022 022 022 022 023 024 024 024 024 024 024
093
Chalco`en and Any Other Heteroatoms 025 025
5[93[2[2[2 Functions bearin` selenium\ phosphorus and a metal 5[93[2[2[3 Functions bearin` selenium\ silicon and a metal
5[93[0 FUNCTIONS CONTAINING CHALCOGEN AND A GROUP 04 ELEMENT The compounds in this class have been the subject of several reviews ð58ZC190\ B!69MI 593!90\ 60S05\ 66UK574\ B!68MI 593!90\ 68T0564\ 74HOU"E4#2Ł[
5[93[0[0 Functions Bearing Chalcogen and Nitrogen Functional groups bearing chalcogen and nitrogen are available by modi_cation of precursors which contain sp2! or sp1!carbon atoms\ via cycloadditions or by other miscellaneous methods[ This general order is adhered to throughout this section[
5[93[0[0[0 Functions bearing oxygen and nitrogen "i# Functions bearin` two oxy`en and one nitro`en substituent The functional group containing two ether type oxygens and one amine type nitrogen singly bonded to a carbon is most commonly referred to as an amide acetal[ In the majority of cases\ all the heteroatoms are substituted further[ Exceptions are the cyclols which have one unsubstituted oxygen atom[ "a# From sp2!carbon compounds[ Amide acetals can be accessed by transacetalation of other amide acetals ð50LA"530#0\ 52AG185\ 53CCC534\ 54HCA0635\ 57CB30Ł with alcohols[ Typically\ the starting material is N\N!dimethylformamide dimethyl acetal "0#[ The uncatalysed reaction is driven to completion by the removal of generated methanol by distillation[ The use of sterically hindered alcohols can\ however\ lower the reaction yields signi_cantly[ Cyclic amide acetals "1# are available from diols "Scheme 0# ð50LA"530#0\ 53CCC534\ 57CB30Ł[ Transamidation can be achieved with high boiling amines such as morpholine and piperidine ð50LA"530#0\ 55USP2128408Ł[ Simultaneous trans! acetalation and transamidation has also been reported ð53CCC534Ł[ OR
ROH
Me2N
OMe
OR
Me2N HO
OMe
OH
(1)
O Me2N O
Scheme 1
(2)
Cyclols "3# are relatively rare in the literature\ existing as equilibrium mixtures with the cor! responding ring!opened hydroxyamides "2#\ and more commonly they have been proposed as transient reaction intermediates "Equation "0## ð59CRV43\ 52CCC1939\ 52TL328\ 53JOC1658\ 53TL36\ 55UKZ193\ 57TL1602Ł[ O!Alkylation ð51TL690\ 52T0550\ 52T0564\ 54T2426Ł generates fully substituted amide acetals[ O
HO
O (1)
HO
NH (3)
R
R
NH (4)
Symmetrical amide acetals "4# are obtained from ortho!esters with a variety of nitrogen nucleo! philes such as sulfonamides "Equation "1## ð50JOC3204\ 54AJC0856\ 79JOC3927\ 71JCS"P0#1760\ 77JHC896Ł\ ureas ð42JA560\ 52HCA1295Ł\ imidazoles ð79JOC3927Ł and di~uoroamine ð56JA605Ł[
094
Chalco`en and Group 04 OR2 OR2 OR2
R1
R3R4NH
R1
OR2 NR3R4 OR2 (5)
(2)
Under Lewis acid catalysis\ isocyanates will react to give N!carboxy compounds "5# "Equation "2## ð51AG"E#481\ 55GEP0045679Ł[ Cyanide can be displaced from "a!alkoxy!a!alkylamino#acetonitriles "6# ð61CB0239Ł or\ in addition to one of the alkylamino groups\ from a\a!bis"dialkylamino# acetonitriles "7# by alkoxides ð38LA"451#118\ 61CB0239Ł[ Both halogens in a\a!di~uorotrialkylamines "8# have been replaced by alcohols ð52USP2981526\ 53USP2010973\ 54USP2103301\ 72TL0924Ł[ Chloro! diaryloxymethanes have been used to generate diaryloxymethyltriethylammonium chlorides "09# with triethylamine ð47JPR"6#69Ł[ Such reactive compounds give amide acetals on further reaction with amines ð61S21\ 61S307\ 62S312\ 64S161Ł[ OR1
OR1
R2NCO, BF3
R1O
R1O
OR1
NR12
F
NMe2
NC
NMe2 (8)
(7)
OAr NR22
R1
NC OR2
(3) NR2CO2R1 (6)
Cl–
Et3N+
F
OAr (10)
(9)
"b# From sp1!carbon compounds[ The halogen in N\N!dialkyliminium chlorides "00# can be dis! placed on treatment with alkoxides to yield amide acetals "01# "Equation "3## ðB!69MI 593!90\ 61TL3106\ B!68MI 593!90Ł[ In a similar manner\ alkoxide can be displaced from alkoxyiminium salts "02# ð50LA"530#0\ 57PAC408\ B!69MI 593!90\ B!68MI 593!90Ł and thiolate from alkylthioiminium salts "03# ð56BCJ1530Ł[ Lactam acetals are also accessible by this methodology ð52USP2981526\ B!68MI 593!90Ł[ In addition\ pyridine has been demonstrated to react with the oxonium salt "04# to give the pyridinium species "05# ð60S201Ł[ The adduct "06# is formed by capture of the N!acyloxazolium salt with methoxide ð64JCS"P0#0291Ł[ Cl H
OR2
NaOR2
R12N
+
NR12 (11)
(12)
OR2 H
(4) OR2
SEt
+
NR12 (13)
H
+
NMe2 (14) O N
+
+
EtO
OEt BF4– (15)
OEt
N
N O
O
OEt (16)
O
MeO (17)
Formamide acetals are produced by the reaction of N\N\N?\N?!tetrasubstituted formamidium salts with sodium alkoxides ð59AG845\ 51JOC2553\ 52GEP0035781\ 53CCC534Ł[ Tetrakis"dimethylamino#ethene "07# is converted by methanol into a mixture of amide acetals "08# and "19# ð61T0854Ł[ Hexa! ~uoropropene "10# combines with diethanolamine "11# to generate an azadioxabicycloð2[2[9Łoctane
095
Chalco`en and Any Other Heteroatoms
"12# ð61TL2846Ł[ Similar systems\ such as "14#\ are obtained by the reaction of the sodium salts of dialkanolamines such as "13# with nitriles "Scheme 1# ð62AG"E#885Ł[ Me2N
NMe2
Me2N
OMe
MeOH
NMe2
OMe
(18)
HO
Me2N
(19)
H N
F
F
F
CF3
(20) F3C
F
O
O
Et3N
+
OH
OMe NMe2 OMe
MeO
+
Me2N
N (23)
(21)
(22)
i, Na ii, EtCN
H N
HO
O
OH
O N (25)
(24) Scheme 2
"c# Cycloaddition methods[ The unsubstituted ketene acetal "15# reacts with isocyanates to give barbituric acid acetals "16# ð48MI 593!90\ 51AG"E#220\ 55CB2781Ł while the cyclic analogue "17# generates the b!lactam "18# ð77TL1216Ł[ Similarly\ tetramethoxyethene gives the azetidin!1!one "29# "Scheme 2# ð48MI 593!90\ 53AG"E#279Ł[ Ketene acetals will also react with nitrosobenzene\ with dialkyl azo! dicarboxylates ð60CB762Ł and with ketenimines ð65IZV747Ł to give four!membered ring products "20#\ "21# and "22#[ O
O OEt
EtO
PhNCO
Ph
NHPh
PhNCO
N OEt
OEt
EtO
O
N Ph (27)
(26) O
O
PhNCO
O
O
N
(28)
Ph (29)
MeO
OMe
MeO
OMe
OEt
PhNCO
O
MeO MeO
O
N MeO Ph MeO (30) Scheme 3
MeO MeO
O
N MeO Ph MeO (31)
MeO MeO MeO MeO
CF3 CO2Me N
Ph
F3C
N
N
OEt OEt
CO2Me (32)
(33)
Dichloroketene acetals such as "23# react with sulfamyl chlorides to give four!membered ring products "24# "Equation "4## ð56JA1491\ 61JA5024Ł[ a\b!Unsaturated ketones combine with ynamines ð69CR"C#357Ł and with 0!dialkylamino!0!alkylthioethenes ð56BCJ1530Ł to give bicyclic amide acetals "Scheme 3# ð57TL386Ł[
096
Chalco`en and Group 04 O O
O
EtNHSO2Cl
Cl
(34)
(35)
O
2
(5)
SO2
Cl
Cl
Cl
Et N
O
O
2
R2N
R2N O
MeS
O NR2
Scheme 4
An unsymmetrical bicyclic amide acetal "26# has been obtained by treatment of the dihydrooxazole "25# with benzonitrile oxide ð60AG"E#709Ł[ Dialkoxydihydro!0\1\2!triazoles such as "27# are produced by the reaction of azides with some ketene acetals ð52G831\ 57G570\ 61JHC0976\ 65JHC194Ł[ Cyclo! propanone acetals such as "28# undergo ring expansion with aryl isocyanates to give g!lactam acetals "39# "Scheme 4# ð76JCR"S#251Ł[ Ph N
+
O
Ph
N
N+ O– O
(36)
(37) MeO
MeO PhN
N+
N O
N–
N N
MeO
+
N
MeO
Ph (38)
MeO
O
OMe PhNCO
EtO2C
H
EtO2C
N
Ph
OMe H OMe (40)
H (39) Scheme 5
"d# Miscellaneous reactions yieldin` amide acetals[ The imidate "30# has been oxidized by mcpba to the corresponding oxaziridine ð60TL3408\ 62TL0796Ł[ t!Butyl hypochlorite has been used to oxidise a 3!oxa!b!lactam "31# to the amide acetal ð71H"07#190Ł[ Benzoylhydrazones "32# react with lead tetraacetate to give 1\4!dihydro!0\2\3!oxadiazoles ð56TL2490\ 57CB2740Ł[ Reductive conditions are exempli_ed by the reaction of N\N!dimethylformamide and N\N!dimethylacetamide with 0\2!dibro! moketones and a zinc:copper couple to give amide acetals "33# "Scheme 5# ð61JA2190Ł[ The insertion of ethoxycarbonylnitrene\ generated by photolysis of ethyl azidoformate\ into acetals ð56T34Ł and ketene acetals ð61JHC0976Ł leads to N!carboxy amide acetals such as "34#[ Dichlorocarbene reacts with dialkylamines and sodium alkoxides to give the amide acetals HC"OR0#NR11 resulting from insertion and double halogen displacement ð53GEP0050174\ 58LA"614#04\ 58RTC178Ł while the diazo compound "35# on photolysis undergoes cyclisation to the dihydrooxazole "36# ð63JHC418Ł[ Epoxides add to dihydrooxazoles "37# and 4\5!dihydro!3H!0\2!oxazines to give bicyclic amide acetals such as "38# ð55AG"E#764\ 55AG"E#783\ 55LA"587#063Ł[ The bicyclic amide acetal "49# was obtained by the addition of diketene to the C1N bond of a chiral oxazoline "Scheme 6# ð80TL486Ł[ N!Methylpyrrole undergoes anodic oxidation in methanol to generate the symmetrical product "40# ð55JOC3943Ł[ Under basic conditions\ the diazene oxide "41# reacts with methanol to give the azo compound "42# ð67JOC0348Ł[ Ozonides "43# are formed by the reaction of ozone with indoles
097
Chalco`en and Any Other Heteroatoms MeO
N
mcpba, CH2Cl2
But
MeO
(41) Ph
O
Ph
O
HN
OMe O
LiOMe, ButOCl
N
N
O-TMS
O
O
O
Ph (42)
Ph
Ph
Et Pb(OAc)4
Ph
N Et
O-TMS
O
O
O
But
O
HN
O
Ph
N
N H (43)
Et Et
O
N N O
Ph OAc R5
NMe2
O
O
O R1
R3 R4
Br
Br
Zn–Cu
+ R5CONMe2
R2
R1
R4
R2 R3 (44)
Scheme 6
O
O
N2 Ph MeO
N H O (45) Ph
H N
CO2Et OMe
N
OEt N
MeO
OMe (47) O
N
LiCl
+ Et
O
hν
(46)
O
CO2Et
O
hν
+ N3CO2Et
O
Ph
Ph O
Et (49)
(48) H O
O
N But
O (50) Scheme 7
ð41JA2744Ł[ Compounds of this type have also been obtained by cyclisation of hydroperoxides ð41CB838Ł[ The reaction of some cyclic ortho!esters with TMS azide leads to the formation of displacement products such as "44# "Scheme 7# ð68TL402Ł[ "ii# Functions bearin` one oxy`en and two nitro`en substituents Functions bearing two nitrogens and one oxygen are known commonly as ester aminals[ As with the amide acetals\ they are synthetically accessible from sp2! and sp1!carbon compounds\ by cyclisations\ by cycloadditions and by other miscellaneous methods[
098
Chalco`en and Group 04 Me
Me MeO
hν
N
N
OMe
MeO
OMe (51)
Ph
+
–O
Ph
Et3N, MeOH
N N
N N
OPrn
OPrn MeO (53)
(52) Scheme 8
R
O O
N H (54)
N3
O
O
O
Ar (55)
"a# From sp2!carbon compounds[ Some examples of the formation of ester aminals by dis! placement reactions are shown in Scheme 8[ Treatment of bis"dimethylamino#acetonitrile with sodium ethoxide yields the ester aminal "45# ð61CB0239Ł[ The base induced cyclisation of 0!chloro! 4\4\4!trinitropentan!1!ol "46# occurs with the elimination of nitrite ð54AG316Ł[ All three halogens are displaced in the reaction of chloroform with aziridine and sodium methoxide ð58LA"614#04Ł[ Reaction of triethyl ortho!acetate with the 1!aminobenzenecarboxamide "47# leads to the 1! ethoxyquinazolinone "48# ð89JHC0842Ł[ NMe2
NaOEt
NC
NMe2 EtO
NMe2
NMe2 (56)
C(NO2)3 Cl
NO2
Cl O
OH (57)
CHCl3
+
O N H
NaOH
+
H N
NO2
OMe NaOMe
N
OEt OEt OEt
NH2
N
O AcOH
N N H OEt (59)
(58) Scheme 9
"b# From sp1!carbon compounds[ Electron!de_cient heterocycles undergo a range of related additions of water and alcohols ð73CHEC"2#80Ł[ Some examples of these reactions are shown in Scheme 09[ {Covalent hydration| is exempli_ed by the addition of the elements of water to the tetrazoloquinazoline "59# ð54JOC718\ 56KGS0985Ł[ An intramolecular addition occurs when the dini! tropyridine "50# is treated with base ð57TL548Ł[ Diethylamine reacts with 4!phenyl!0\1\3!dioxazolin! 2!one "51# ð61JPR034Ł[ An analogous reaction occurs when 0\2\3!oxadiazolium salts are treated
009
Chalco`en and Any Other Heteroatoms
with secondary amines leading to tertiary products^ primary amines lead to ring!opened products ð60JCS"C#398Ł[
N N
N N
N
2M HCl
N
HN
N N
(60)
OH
NO2
O 2N
N
NO2
O2N NaOMe
N
O (61)
Ph
O
O
OH
N H O Ph
O
Et2NH
N
Et2N
O
O O N H
O
(62) Scheme 10
In a reaction analogous to that with the oxazoline "37#\ epoxides have been demonstrated to react with dihydroimidazoles and tetrahydropyrimidines to give ester aminals ð69LA"631#017Ł[ "c# Cycloaddition methods[ Reaction of p!nitrophenyl isocyanate with O!alkyllactims such as "52# leads to 3!alkoxy!0\2!diazetin!1!ones "Equation "5## ð62TL0108Ł[ O N
OMe
NCO
N
N
+
(6)
OMe
O2N
NO2
(63)
"d# Miscellaneous reactions yieldin` ester aminals[ Addition of a!tetralone to the bisurea "53# in ethanolic hydrogen chloride a}ords a 1!hydroxyhexahydroquinazoline "54# ð55IZV87Ł[ A 2! "dimethylamino#oxaziridine "55# is formed by photocyclisation of the nitrone "56# ð60JA3964Ł[ The reaction of hydrazoic acid with ethoxypropyne gives bisazide "57# "Scheme 00# ð46RTC838Ł[
OH HN
O H2NCONH
Ar
+ Ar
H2NCONH (64) Ph
(65)
NMe2 hν
Me
N+
O Me2N
N Ph (66)
O–
(67)
OEt
NH
+ HN3
Scheme 11
Et
Me
N3 OEt N3 (68)
000
Chalco`en and Group 04 5[93[0[0[1 Functions bearing sulfur and nitrogen "i# Functions bearin` one sulfur\ one nitro`en and one oxy`en substituent
Functional groups bearing oxygen\ sulfur and nitrogen are nonsymmetrical\ and this reduces the number of synthetic routes available for their preparation compared to their symmetrical analogues[ "a# From sp2!carbon compounds[ Two examples of formation of this functional group by dis! placement are shown in Scheme 01[ Triethyl ortho!formate reacts with 1!thiolbenzamide to give a dihydrobenzothiazine "58# ð58T4884Ł[ Displacement of aniline from the 0\2\3!thiadiazoline "69# by ethanol produces the 4!ethoxy analogue "60# ð65ACS"B#726Ł[ O CONH2
OEt
+
EtO
2-Naphthyl-SO3H
NH
OEt
SH
N
Ph
N
Ph
S (69)
EtOH
N
Ph
S
N S
Ph NHPh (70)
OEt
Ph Ph
OEt (71) Scheme 12
1
"b# From sp !carbon compounds[ The N!alkylbenzothiazolium cation "61# reacts with the 1! hydroxybenzaldehyde "62# to give the spiro compound "63# ð61HCA0671Ł^ there are other examples of intramolecular cyclisation of benzothiazolium cations with phenolic ð58T4884Ł and ketonic functions ð89IJC"B#079Ł in the presence of base\ and related reactions of thiazoles ð73H"11#170Ł[ The dime! thylformamide monothioacetal "64# is prepared by O!methylation of N\N!dimethylformamide with dimethyl sulfate\ and subsequent interception of the iminium cation "65# with sodium ethanethiolate ð60BSF2243Ł[ An alternative approach\ the interception of a thioimidate with an alcohol\ has also been reported ð73H"11#02Ł[ Reaction of 1!"1?!thiolphenyl#dihydroimidazole "66# with phthalolyl chloride gave the spiro thioacetal "67#[ In this reaction it may be the cyclic tautomer "68# of phthaloyl chloride which is the reactive species "Scheme 02# ð77LA488Ł[ "c# Cycloaddition methods[ Benzonitrile oxide can undergo 0\2!dipolar cycloadditions to C1S or to C1N bonds which lead to amide thioacetals[ Two examples of such reactions\ leading to the oxathiazole "79# ð68CB0762Ł and to the fused azetidine "70# ð89TL012\ 80JHC370Ł are shown in Scheme 03[ The reaction of keteneÐsulfur dioxide adduct with the 1!aryldihydrooxazoles "71# gives the cycloadduct "72# ð58JHC618Ł[ The dihydroindole "74# was obtained from the reaction of dichloro! ketene with the indole "73# "Scheme 04# ð78JOC0671Ł[ "d# Miscellaneous reactions yieldin` amide monothioacetals[ 3!Thio!b!lactam "75^ R H# under! goes oxidation with lead tetraacetate ð63JCS"P0#11Ł or with t!butyl perbenzoate in benzene ð68CC374Ł to give O!acylated derivatives "75^ R OCOMe or OCOPh#[ Phenacyl bromide reacts with phenyl! propiolic thioanilide "76# in the presence of acetone to produce a 0\2!oxathiole "77# "Scheme 05# ð64LA847Ł[ "ii# Functions bearin` two sulfur and one nitro`en substituent There are many parallels that can be drawn between the preparation of thioamide acetals and their oxa analogues[ It is likely that many of the principles behind the methods for preparation of the latter could be applied to the former[ "a# From sp2!carbon compounds[ Reaction of amide acetals with thiols provides a route to both acyclic and cyclic thioamide acetals "78# and "89# "Scheme 06# ð58BSF221\ 69BSF1902Ł[ Replacement of the alkoxy function of the dithio!ortho!ester "80# has been demonstrated to give the amide dithioacetal "81# ð79PJC034Ł[ a!Chlorothioacetals such as "82# are converted into amide thioacetals "e[g[ "83## by treatment with amines ð50LA"530#10Ł[ "b# From sp1!carbon compounds[ The reaction of alkoxyiminium cations such as "65# with thiolate salts in excess leads to amide thioacetals HC"SR0#1NR11 ð54IZV1068\ 62CB2614Ł[ Chloroiminium salts react with thiols in a similar way ð59MI 593!90Ł and "alkylthio#iminium cations "84# have also been
001
Chalco`en and Any Other Heteroatoms CHO HO
S
piperidine
+ N+
OMe
MeO S
MeO
N
O Me MeO (74)
NO2
Me (72)
(73) OMe
OMe
EtS–
Me2N
N+
SEt
Me (76)
Me
NO2
(75) N
O
N
+
N H
+
S
PhCH2NEt3Cl–
Cl
SH
N
Na2CO3
O
O
Cl
(77)
(79)
(78)
O Cl Cl O Scheme 13
O Ph
Ph S
Ph
N O
N+ O–
Ph
N
N
O
S
CN (80)
CN
SEt
SEt Ph
O
N+ O–
N
N
N
Ph (81) Scheme 14
i, SO2 ii, ketene
N O2N
O
O2S O2N
N
O
O
(82)
(83) Cl O–
S+ N Me SO2Ph (84)
+
Cl3CCOCl
Zn–Cu
Cl O O
N
SMe
SO2Ph (85) Scheme 15
O
002
Chalco`en and Group 04 Br
Ph
R
Br
SMe
NHPh
O N O
CO2Me
+
Br
Ph
O
Ph
S NHPh
S Ph
(86)
(87)
(88)
Scheme 16
SC7H15
HSC7H15
Me2N SC7H15 (89)
OMe Me2N OMe HS
S
SH
S NMe2 (90)
Scheme 17
Ph Ph
Ph
S
Ph
S
S
O
S SMe
SMe
N
O
Me2N
Cl
SMe
SMe
OMe (91)
(93)
(92)
(94)
intercepted with thiols to give thioamide acetals ð54BCJ1096\ 55BCJ1994\ 72CI"L#194Ł[ 0\2!Thiazolium cations "85# undergo reaction with azide anions and with amines to give the addition products "86^ X N2 or NR1# ð54JCS21\ 65BCJ2456\ 65JPR016\ 79JOC1913\ 70JCS"P0#507Ł[ Reduction of the C1N bond of the iminium salt "87# with sodium borohydride yields the corresponding amide thioacetal ð58CPB0813Ł[ A more unusual example is that provided by the reaction of the tris"alkylthio#borane derivatives "88# with amides "Equation "6## ð55IZV253\ 68ZN"B#888Ł[ Ph S S+
SR2
R1
S N+
S
X–
X +NR3
S
2
(95)
S (97)
(96)
SR3
O
+ R1
(98)
R3S
R1
B
NR22
SR3
SR3 NR22 SR3
(7)
(99)
"c# Cycloaddition methods[ The ð1¦1Ł cycloaddition of ketenes to iminodithiocarbonate esters has been used as a route to b!lactams which incorporate the amide dithioacetal function[ Examples with cyclic ð46CB1359\ 62JHC680Ł and acyclic ð65JOC0001\ 76S889Ł iminodithiocarbonates are shown in Scheme 07[ Dihydrothiazoles also react with the keteneÐsulfur dioxide adduct "in a manner
003
Chalco`en and Any Other Heteroatoms
analogous to that shown for the oxazoline "71## to give products which contain this functionality ð58JHC618Ł[ S
MeS
+ ClCOCH2OMe
SMe S
MeO
Et3N
N
N
O
MeS
MeS MeS
SMe Et3N
+ ClCOCH2ON3
N
N3
N O
CO2But
CO2But Scheme 18
"d# Miscellaneous reactions yieldin` amide thioacetals[ Photo!rearrangement of N!"ethoxy! acetyl#tetrahydro!0\2!thiazine!1!thione gives the thiazolidinone "099# "Equation "7## ð75TL0224Ł[ There are several routes to compounds containing methanesulfonyl functions[ The azo compound "090^ R H# has been obtained by the reaction of bis"methanesulfonyl#methane with benzene! diazonium chloride ð40RTC622Ł and from its analogue "090^ R SMe# by reaction with piperidine ð40RTC781Ł[ Reaction of diazomethane with the oxime "091# gave the N!methoxyaziridine "092# ð49RTC0112Ł[ S
O EtO
N
S
S
S
hν
EtO
(8)
N O (100) OMe
R
N NPh SO2Me SO2Me
N
N SO2Me
SO2Me
MeO2S
(101)
OMe
MeO2S (103)
(102)
"iii# Functions bearin` one sulfur and two nitro`en substituents "a# From sp1!carbon compounds[ Addition to alkylthioiminium salts "093# by sodium azide and subsequent cyclisation gives thiatriazoles "094# ð63JCS"P0#439Ł[ Amines will add in a similar manner to the C1N bond of thiazolium cations such as "095# ð60CPB1111\ 76JOC1904Ł and to 2!methylthio! 0\1\3!dithiazolium cations "096# ð63JCS"P0#439Ł[ Phenylmagnesium bromide adds to both the C1C and the C1N bonds of 4!arylidine!1!phenyliminothiazolidin!3!ones "097# ð53T14Ł[ Treatment of hydrazonyl halides with thioamides leads to 1\1!disubstituted dihydro!0\2\3!thiadiazoles "098# ð65ACS"B#726Ł[
+
N O
Ar
N N
SMe Ph
N
S
N
Ph
Me
+
N
S
O
(104)
(105)
(106)
"b# Cycloaddition methods[ Cycloaddition of cyclopentadiene to thiocarbonylbis"0\1\3!triazole# "009# gives the adduct "000# ð79JOC2602Ł[ Diphenylethyne reacts under photochemical conditions to the C1S bond of "001# to give both four! "002# and six! "003# membered ring adducts "Scheme 08# ð65TL2452\ 79LA762Ł depending on the wavelength employed[ Acid chloride derived ketenes undergo
004
Chalco`en and Group 04 O +
S
S
H N N
H N
Ph
SMe
N (107)
Ph
Ph
Ph
S
NPh
S (108)
Ph
NHPh
(109)
ð1¦1Ł cycloaddition with tetrahydro!1!alkylthiopyrimidines to yield thio substituted b!lactams such as "004# ð73TL0738Ł[ Trichloroacetyl isocyanate reacts with mesoionic thiazoles to give cycloadducts such as "005# ð65ACS"B#726\ 65JOC702Ł[ Amide thioacetals react with aryl isocyanates to furnish the imidazolinediones "006# ð62CB2614\ B!68MI 593!91Ł^ a similar reaction occurs with N!alkyl!0\2\3! thiadiazolium salts ð77LA594Ł[ "c# Photoreduction[ The C1S bond of 0\2!diphenyl!1!thioparabonate "007# undergoes photo! reduction in ethanol ð58BCJ1212Ł[ N
N N
N
N
N
N
N
+
N
S N N
S (110)
N
(111) Ph
Ph Me N
S Me
N
Me
N
O
+
Ph
S
hν
Ph
Me
Ph
N
or
Me
N
S
O
N
Me
O O (112)
O
O (113)
(114)
Scheme 19
PhO MeS CBZ N
N
Ph
Ar
O
O
O
N
S
N
RS
COCCl3
Ar (116)
(115)
O
N
Me2N
O Ph
N O (117)
Ar
O
N
N
Ph
S (118)
5[93[0[0[2 Functions bearing selenium and nitrogen "i# Functions bearin` one selenium\ one oxy`en and one nitro`en substituent The 1!methoxydihydroselenazole "008^ Ar 3!PhC5H3# has been obtained from the corresponding N!methylselenazolium cation by reaction with sodium methoxide ð70ZOB0731Ł[ Similarly\ treatment of a N!alkylbenzoselenazolium cation "019# with a 1!hydroxybenzaldehyde derivative generates a 1!spiro derivative "010# ð60BSF445\ 80CL0762\ 82CL02Ł[ R1 N Me N Ph
Ar
Se OMe (119)
R1 N+ Se (120)
Se O R2O (121)
NO2
005
Chalco`en and Any Other Heteroatoms
"ii# Functions bearin` one selenium\ one sulfur and one nitro`en substituent Selenium substituted b!lactams such as "011# have been obtained by cycloaddition of ketenes to 1!alkylselenothiazolines ð75JAP50047875\ 75JOC3626\ 76NKK0336Ł[ SeMe S
MeO
N O
CO2Me (122)
"iii# Functions bearin` one selenium and two nitro`en substituents Two examples of such compounds are provided by the selenide "012# which was obtained from 0\0!dinitroethane and benzeneselenyl chloride ð71IZV050Ł and by the 0\2\3!selenadiazole "013#\ which is formed by addition of a hydrazonyl chloride to the C1Se bond of a selenamide ð89ZOR0018Ł[ Ph
Ph N
N
NO2 SePh NO2
N
Se
O (124)
(123)
5[93[0[1 Functions Bearing Chalcogen and P\ As\ Sb or Bi 5[93[0[1[0 Functions bearing oxygen and P\ As\ Sb or Bi "i# Functions bearin` two oxy`en and one phosphorus substituent Ortho!esters and amide acetals may be converted into phosphorus containing functions by treatment with a phosphorus"III# nucleophile ð75MI 593!90Ł[ A 1!trimethylammonium!0!2!dioxane "014# reacts with isopropyl diphenylphosphinate to give the phosphine oxide "015# "Equation "8## ð77JOC2598Ł[ Similarly\ triethyl phosphite combines with 1!trimethylammonium!0\2!dioxolane a}ording the phosphonate ester ð63JPR802Ł[ Chlorodiphenylphosphine and dichloromethyl! phosphine react with ortho!formate esters to give the phosphine oxides "016# and phosphonate esters "017#\ respectively ð72TL0292\ 78T2676Ł[ Related reactions with hypophosphorous acid ð79AJC176Ł and with diethyl phosphinate ð66TL1876Ł have been reported[ Triethyl phosphite\ in combination with phosphorus trichloride and zinc chloride\ reacts with triethyl ortho!acetate to form the phosphonate diester acetals "018# ð62S436Ł[ The adduct "029# formed from phosphorus trichloride and acetaldehyde reacts with triethyl ortho!formate to give the mixed phosphonate diester acetal "020# ð89CC0022Ł[ O
O N+Me3
+
OPri
Ph2P
PPh2
O (125)
O (126)
O
Me
Ph2P OR (127)
O
OR
OR
P OEt OR (128)
O
O
OEt
EtO P OEt OEt (129)
(9)
006
Chalco`en and Group 04 Cl
O
Cl O (130)
P O MeO
PCl2
OMe
OMe (131)
Dialkyl phosphinates react with the 2!acetylcoumarin to give the hemiacetal "021# ð80PS"46#100Ł[ Hydration of a!phosphono!a!oxo esters "022# proceeds in high yield to give the hydrates "023^ R H#[ Similarly\ alcohols yield the corresponding hemiketals "023^ R alkyl# "Scheme 19#[ The yield is higher for methanol than for t!amyl alcohol as branching leads to steric congestion at the quaternary centre ð78CC135Ł[ 1\1!Dimethylpropylidynylphosphine "024# undergoes a double 0\2! dipolar cycloaddition with 3!chlorobenzonitrile oxide to yield the bicyclic product "025# ð73CC0523Ł[ O
O HOP(OR)2
O
PO(OR)2
O
O
OH (132)
O
O
(Et2O)P
H2O or ROH
CO2Et
(Et2O)P
CO2Et
HO
O (133)
OR
(134) Scheme 20
N
Ar
O But But (135)
P O
Ar N (136) (Ar = 4-ClC6H4)
P
Functions which already contain two oxygens and a phosphorus can be elaborated further at the phosphorus atom by standard methods[ Phosphinite acetals "026# undergo an Arbuzov reaction with alkyl iodides "Equation "09## ð77PS"24#218Ł\ and the trimethylsilyl group of the phosphinites "027# is lost in the Arbuzov reaction with alkyl chloroformates which gives the phosphinates "028# ð75ZOB1316Ł[ Examples of aminoalkylation of phosphorus are also known ð78JCS"P0#0208Ł[ O
OR2
R3I
(R1O)2P
R1O
OR2
OR2 (10)
P R3
OR2
(137) R1O
O
OR2 R1 O
P TMS-O (138)
OR2
OR2
P
R3O2C
OR2
(139)
"ii# Functions bearin` one oxy`en\ one phosphorus and one nitro`en substituent Electrochemical oxidation of the a!acylamino phosphonate "039# in methanol with a carbon anode gives the methoxylated compound "030# "Equation "00## ð78T0580Ł[ In an unexpected reaction\
007
Chalco`en and Any Other Heteroatoms
the phosphonate "031# is generated from the treatment of the tosylate "032# with sodium diethyl! phosphinite ð82HCA1396Ł[ O
O
OMe
MeOH, NaCl
Ph
N H
P(OEt)2
Ph
C anode
N H
O
(140)
P(OEt)2
(11)
O
(141)
O
O N
N (EtO)2P
O
OTs O (143)
O (142)
"iii# Functions bearin` one oxy`en and two phosphorus substituents Double addition of phosphinic acids and phosphites to activated carboxylic acid derivatives such as acid chlorides and anhydrides leads to a\a!diphosphino and a\a!diphosphono alcohols\ respectively ð45JA3349\ 56JCS"C#0436\ 60JOC2732\ 62ZAAC"288#0\ 66TL0954\ 67CC174\ 68S70Ł[ An example of the reaction sequence is shown in Scheme 10[ Carboxylic acids combine with phosphorus trichloride bisphosphonic acids ð61MI 593!90\ 71MI 593!90Ł^ thus\ acetic acid gives MeC"OH#ðPO"OH#1Ł1[ Reaction of chlorodiphenylphosphine with acetic acid and then with acetic anhydride a}ords the bisphosphine oxide "033^ R H# via the intermediate ketone "034# "Scheme 11#[ The acetylated analogue "033^ R Ac# is obtained after prolonged reaction times ð66JCS"P0#0787Ł[ Products analogous to "033^ R H# have also been obtained by hydrolysis of acylphosphine oxides ð67ZN"B#738Ł[ O O Ph
O
(MeO)3P
Cl
Ph
HPO(OMe)2
P(OMe)2
HO
P(OMe)2
Ph
P(OMe)2
O Scheme 21
O
O
O
O
AcOH
Ph2PCl
Ph2PH
O
Ac2O
O
Ph2PH
RO
Ph2P
PPh2 PPh2
O (144)
(145) Scheme 22
The diazophosphonate "035# reacts with cyclohexenol in the presence of rhodium acetate to give the ether "036# "Equation "01## ð81JOC067Ł[ Photochemical oxidation of a!diazophosphonates in methanol leads to the formation of products of an analogous type ð71JOC0173Ł[ Cycloaddition of the silylnitronate "037# to the vinylbis"phosphonate# "038# leads to the formation of the dihy! droisoxazole "049# "Equation "02## ð81PS"58#64Ł[ Oxygen functions can also be introduced by reaction with hydrogen peroxide\ as shown in Scheme 12 ð78JOC3161\ 82JOC3048Ł[ O
O
(MeO)2P
P(OMe)2
OH
O (MeO)2P N2 (146)
O
, Rh2(OAc)4
O
P(OMe)2
(12) (147)
008
Chalco`en and Group 04 Ph O
Ph
TMS-O
N+
+ O–
P(OEt)2 (EtO)2P
P(OEt)2
O (148)
N O
O
(13) P(OEt)2
O (150)
(149)
O
O
P(OH)2
P(OH)2
Na2CO3, H2O2, Na2WO4
P(OH)2
HO
O
HO
O
P(OH)2 O
O
P(OR)2
P(OR)2
H2O2, NaHCO3
P(OR)2
O
O
P(OR)2 O
Scheme 23
"iv# Functions bearin` two oxy`en and one arsenic substituent The cycloaddition of the benzoxarsole "040# to tetrachloro!o!benzoquinone gives a product "041# bearing this array of functional groups "Equation "03## ð72TL4370Ł[
As But O
Cl
Cl
Cl Cl
O
Cl
O
+
Cl
O
(14)
As Cl
O O
(151)
Cl
But (152)
5[93[0[1[1 Functions bearing sulfur and P\ As\ Sb or Bi "i# Functions bearin` one sulfur\ one oxy`en and one phosphorus substituent Removal of an acidic proton from a!oxygen substituted phosphonic acid derivatives gives the opportunity for reaction with electrophilic sulfenylating reagents[ Diethyl a!methoxy phosphonate "042# when treated sequentially with a mixture of n!butyllithium and potassium t!butoxide\ elemental sulfur and iodomethane gives the methylthio product "043# ð65TL366Ł[ The use of n!butyllithium alone gives compounds resulting from transesteri_cation ð68JOC1856Ł[ Similarly\ the a!sily! loxyphosphonate "044# reacts with LDA and diphenyl disul_de a}ording the trisubstituted product "045# ð67TL252Ł[ Activation of the a!carbon atom in a!"alkylthio#phosphonates can be achieved by halogenation[ Treatment of the phosphonate "046# with N!chlorosuccinimide gives the a!chloro derivative "047# which\ in the presence of methanol\ is converted into the a!methoxy compound "048# "Scheme 13# ð74TL2368Ł[ The same substitution can be achieved using electrochemical oxidation in methanol ð76S33Ł\ and a similar halogenationÐsubstitution sequence takes place with sulfoxides analogous to "046# ð67JOC1407Ł[ 1!Lithio!0\2!oxathiane reacts with dimethyl thiophosphonyl chloride to give the substitution product "059# ð74JOC551\ 78JPO238Ł[ The ability of a sulfoxide to activate a neighbouring carbon atom is employed in the Pummerer rearrangement of a!sul_nyl phosphonates such as "050# in the presence of acid anhydrides ð66S070\ 67JOC1407\ 75BCJ2182Ł[ In a reaction analogous to that of the diazo compound "035# the ether "051# is formed from the rhodium catalysed solvolysis of the a! diazophosphonate "052# in 1!propanol "Scheme 14# ð81SL864Ł[ Oxygen substitution can also be achieved by photolysis ð71JOC0173Ł[
019
Chalco`en and Any Other Heteroatoms i, BunLi, ButOK ii, S8 iii, MeI
O (EtO)2P
OMe
O (EtO)2P
SMe (154)
(153) O (EtO)2P
O
i, LDA ii, (PhS)2
Ph
(EtO)2P
O
O
NCS, CCl4
SMe
Ph
O-TMS SPh (156)
O-TMS (155)
(EtO)2P
OMe
(EtO)2P
O
MeOH
SMe
(EtO)2P
OMe (159)
Cl (158)
(157)
SMe
Scheme 24
S
S
S
Me2PSCl, THF
Li
P(OEt)2
O
O (160)
O
O
(EtO)2P
O
Ac2O, MeSO3H
SMe
(EtO)2P
(161)
OAc
O PhO2S
SMe
O Rh2(NHCOCF3)4 PriOH
P(OEt)2
PhO2S
P(OEt)2
OPri (162)
N2 (163) Scheme 25
"ii# Functions bearin` two sulfur and one phosphorus substituent 0\2!Dithianes and 0\2!dithiolanes substituted at the 1!position with leaving groups can react with triphenylphosphine ð66TL774\ 70S42Ł\ to give phosphonium salts such as "053# and "054#[ Similarly\ trialkyl phosphites undergo Arbuzov reactions forming phosphonate diesters such as "055# "Equa! tion "04## ð66TL774\ 67JPR144\ 79S016\ 75MI 593!91Ł[ The alternative approach\ the reaction of 1! lithio!0\2!dithiane with an electrophilic phosphorus species\ chlorodiphenylphosphine ð75T0852\ 80JOC4808Ł or diethyl chlorophosphonate ð67S298Ł\ has also been reported[ Phosphorus substituents can also be introduced by nucleophilic addition\ as with the benzo!0\2!dithiolium salt "056# ð65TL2584\ 89CC369\ 80JCS"P0#046Ł[ Reaction of the dithiocarbonate "057# with trialkyl phosphites generates the phosphonates "058# ð64JOC1466Ł[ S
S
+
PPh3 Cl–
S
S (164)
S Cl S
+
PPh3 BF4– (165)
P(OEt)3, Et3N
S
O P(OEt)2
S (166)
(15)
010
Chalco`en and Group 04 NC
S+
S
–
S
NC
S
O
O
BF4 S (167)
NC
NC
S
P(OR)2
(168)
(169)
Sulfur functionality can be introduced into phosphorus!containing compounds by nucleophilic displacement of chloride by thiols\ in a manner analogous to that in which "047# is formed from "046# ð77SC0500Ł[ More commonly\ sulfur is introduced as an electrophile[ Sulfenylation of phosphorus stabilised carbanions is a useful general method for the formation of compounds containing two sulfurs and phosphorus[ A further sulfur substituent can be introduced into a species containing one sulfur and one phosphorus substituent\ as in sulfenylation of the ylide Ph2P1CHSPh ð89TL3248Ł and of the phosphonate Ph1POCH1SPh ð66JCS"P0#1152\ 79S016Ł[ Alternatively\ both sulfur substituents can be introduced by sequential sulfenylation^ two examples are shown in Scheme 15 ð77S451\ 81SC0248Ł\ and other examples are known ð74JCS"P0#1474Ł[ i, LDA, THF ii, (MeS)2
NPh PPh2
NPh PPh2
i, LDA, THF ii, (MeS)2
(EtO)2P
Al2O3-KF, MeSSO2Me microwave
CO2Et
PPh2 MeS
SMe O
NPh
SMe
O (EtO)2P
CO2Et
MeS
SMe
Scheme 26
S!Methyl "diisopropoxyphosphonyl#dithioformate "069# reacts with carbon nucleophiles on sulfur to give S!alkylated products such as "060# "Equation "05## ð76JCS"P0#070\ 78TL2304Ł[ A similar attack on sulfur occurs with thiols ð81JOC3496Ł[ O
O (PriO)
2P
(PriO)
SMe
SMe O
2P
(EtO)2POCF2Li
S
S
(16)
P(OEt)2
F F (171)
(170)
Trialkylphosphines add to carbon disul_de to give zwitterionic adducts "061#[ These will undergo cycloaddition with acetylenedicarboxylic esters leading to the ylides "062# ð64CC859\ 65BCJ0885\ 68JOC829\ 80JOC0705Ł[ Benzyl thiol reacts with the bisisothiocyanate "063# to give the symmetrical product "064# arising from double cyclisation ð81HAC004Ł[ Similar compounds are obtained by the treatment of compound "065# with acid chlorides with aluminum trichloride catalysis[ The product "066# is a result of a carbon for phosphorus replacement[ Oxidation with hydrogen peroxide gives the phosphine oxide "067# "Scheme 16# ð89JCS"P0#08Ł[ Preformed diethyl a\a!bis"methylthio#phosphonate undergoes lithiation and subsequent 0\1! addition on to a\b!unsaturated aldehydes and ketones to give the alcohols "068# "Equation "06## ð81T7586Ł[ The phosphine sul_de "079# can be methylated with methyl tri~ate to give the S!methyl! phosphonium salt\ which on reaction with HMPA is reduced to the corresponding phosphine ð80TL6218Ł[ R2 O (EtO)2P
SMe Li SMe
+
R1
COR1
O R1
(EtO)2P MeS
OH SMe
(179)
(17)
011
Chalco`en and Any Other Heteroatoms +
PR13
S
+
R2O2C
R13P
R13P + CS2
–
CO2R2
S–
S R2O2C
(172)
Ph
CO2R2 (173)
O N P N
O SCN P NCS
S
SH
S
S
CHCl2 (174)
(175)
RCOCl, AlCl3
P S P S
O
H2O2
P S
P
S
S
(176)
S R (178)
R (177) Scheme 27
S
S
PPh2 S (180)
"iii# Functions bearin` one sulfur\ one phosphorus and one nitro`en substituent This functionality can be produced by reaction of suitably substituted carbanions with elec! trophilic sulfur reagents[ Compounds "070# ð81SC1270Ł and "071# ð74RTC066Ł are examples of compounds formed in this way\ by sulfenylation a! to phosphorus[ The same type of sulfenylation can be achieved starting with a haloalkane and elemental sulfur ð71TL802Ł[ A di}erent method is the addition of a nucleophilic phosphorus reagent to a thioimidate\ as in the conversion of the thioimidate "072# into "073# with sodium diethyl phosphite ð67JCR"S#30Ł[ The same product can be formed by addition of methylmagnesium iodide to the C1N bond of compound "074# "Scheme 17# ð64S674Ł[ O Ph
SMe N H
O (EtO)2P
PPh2 O
SR (182)
(181)
NCO2Et MeS
(EtO)2PO–Na+
O (EtO)2P
O NHCO2Et SMe
(183)
NC
(184)
MeMgI
(EtO)2P NCO2Et MeS (185)
Scheme 28
Diazomethane undergoes cycloaddition with the vinyl sulfone "075# yielding initially the dihy! dropyrazole "076# "Equation "07## ð74CL0988Ł[
012
Chalco`en and Group 04 O
O CH2N2
(EtO)2P
(EtO)2P
N N (18)
Ph MeO2S
SO2Me
Ph
(187)
(186)
"iv# Functions bearin` one sulfur and two phosphorus substituents The sulfenylation of carbanions a! to phosphorus is used to produce this type of compound ð79S016\ 89H"29#744Ł^ an example is the bis"phosphonate# "077# ð79S016Ł[ Trialkyl phosphites react with thiophosgene to give compounds containing this functionality "Scheme 18# ð77PS"39#0Ł[ A related reaction has also been reported ð89TL0040Ł[ O
O
(EtO)2P
P(OEt)2 SPh (188)
O
O P+(OR)3 Cl–
(RO)2P (RO)3P + CSCl2
S
O
(RO)2P
∆
P(OR)2 S
P(OR)2
O Scheme 29
P(OR)2 O
5[93[0[1[2 Functions bearing selenium and P\ As\ Sb or Bi "i# Functions bearin` one selenium\ one sulfur and one phosphorus substituent Selenylation of the anion of the a!sul_nylphosphonate "078# can be accomplished with phenyl! selenyl bromide "Equation "08## ð81TA0404Ł[ Similar selenylations can be achieved using selenium and iodomethane ð70TL2986Ł[ Phenylselenyl chloride also adds to the phosponium ylide Ph2P1 CHSPh ð72CB0844Ł[ Alternatively\ a compound with this functionality is formed by addition of trimethyl phosphite to the heterocyclic cation "089# ð89CC369\ 80JCS"P0#046Ł[ i, BunLi ii, PhSeBr
(EtO)2P O
S
PhSe
(19)
(EtO)2P
S
O
O
O (189) S+ Se (190)
"ii# Functions bearin` two selenium and one phosphorus substituent Reaction of diethyl methylphosphonate with LDA and then with phenylselenyl bromide gives the diselenated product ð81TL4264Ł[ In a similar fashion\ double selenation of the ylide Ph2P1CHMe has been observed ð68CB244Ł[ Trialkyl phosphites add to 0\2!diselenonium cations in a manner
013
Chalco`en and Any Other Heteroatoms
analogous to that with the cation "089# ð77HCA0131\ 81TA0404Ł^ a similar reaction is known with tributylphosphine ð73TL3116Ł[ The a!diazophosphonate "081# undergoes insertion into the diseleno heterocycle "080# in the presence of boron tri~uoride etherate "Equation "19## ð80TL3078Ł[ Se Se
N2
+
Se
BF3•Et2O
P(OMe)2
P(OMe)2
O (192)
(191)
Se
(20)
O
5[93[1 FUNCTIONS CONTAINING CHALCOGEN AND A METALLOID AND POSSIBLY A GROUP 04 ELEMENT 5[93[1[0 Functions Bearing Chalcogen and Boron No compounds in this category have been noted[ It is possible\ however\ that the anion which can be formed from a!phenylthioalkylboronic esters "082# ð67JA0214Ł could react with a range of sulfur\ selenium and phosphorus electrophiles[ R1
O B O
PhS
(193)
5[93[1[1 Functions Bearing Chalcogen and Silicon 5[93[1[1[0 Functions bearing oxygen and silicon "i# Functions bearin` two oxy`en and one silicon substituent Silyl ketals such as "083# are produced from the reaction of alkyl benzoates with TMS!Cl\ magnesium and HMPA ð60JOM"15#072\ 68JOC319Ł[ Silylated hemiketals are also accessible from the TMS!Cl\ magnesium and HMPA reagent combination ð60JOM"15#072Ł[ Acetals with a su.ciently acidic a!hydrogen atom can be deprotonated and silylated using TMS!Cl ð80T2060Ł[ An alternative approach is to form acetals from silyl ketones such as "084# "Scheme 29# ð58CJC3236\ 79TL0246\ 89JA0851Ł[ O
TMS-Cl, Mg, HMPA
OMe
Ph
O Ph
HO
OH
, BF3, Et2O
SiPh3 (195)
Ph
OMe O-TMS TMS (194) O
O
Ph
SiPh3
Scheme 30
Oxidation of compounds containing a vinylsilane moiety provides another route into functions bearing two oxygens and a silicon[ Treatment of a highly strained 0!trimethylsilylcyclopropene derivative "085# with excess mcpba leads to the formation of the epoxide "086# ð75TL4032Ł[ Oxidation of the compound "087# containing two furan rings with singlet oxygen selectively gives the product "088# resulting from cycloaddition to the silylated ring ð89TL6190Ł[ Two other methods starting from vinylsilanes are the rearrangement of the trimethylsilylallene "199# to the dihydrofuran "190# ð71TL298Ł and the addition of dichlorocarbene to 1!trimethylsilyldihydrofuran "191# and sub! sequent reaction with methanol ð73JOM"154#126Ł[ 0!Ethoxy!0!trimethylsilylallene also undergoes
014
Chalco`en and a Metalloid
cycloaddition with enones at the substituted double bond to give products containing this func! tionality "Scheme 20# ð80CB0314Ł[ TMS
mcpba
O TMS
OCHO
TMS
OCHO (197)
(196) 1O 2
O
O
O
O
O TMS
O
TMS (198)
(199) TMS
HO
OMe
•
MeO O
TMS (200)
(201) Cl
Cl TMS
:CCl2
Cl
O
O
(202)
MeOH
OMe O
TMS
TMS
Scheme 31
The disilene "192# and methylfuran!1!carboxylate give a ð1¦1Ł cycloaddition product "193#[ This reaction is particular to the methyl ester\ higher homologues failing to react "Equation "10## ð80OM2355Ł[ Ar
Ar O Si Ar
Ar
+
Si Si Ar
Ar
O
CO2Me
(203)
Si
O
MeO Ar (204)
(21)
Ar
"ii# Functions bearin` one oxy`en\ one phosphorus and one silicon substituent Deprotonation of the a!"trimethylsilyloxy#phosphonate ester "194# with LDA and quenching with TMS!Cl gives the silylated adduct "195# ð70CC858Ł[ Quenching of the lithiated intermediate generated from the a!substituted!a!trimethylsilyloxy phosphonate "196# a}ords some of the alcohol "197# by Wittig rearrangement in addition to recovered starting material ð68TL3364\ 71BCJ113Ł[ The a! diazophosphonamide "198# reacts with aldehydes to yield epoxides "109# "Scheme 21# ð78AG506\ 80NJC282Ł[
"iii# Functions bearin` one oxy`en and two silicon substituents Two silicons can be introduced into a variety of carboxylic acid derivatives by reaction with TMS!Cl and Group 0 or Group 1 metals "Equation "11##[ The addition of HMPA and the use of coordinating solv
