Comprehensive Organic Functional Group Transformations, Volume 4 Elsevier, 2003 Editors-in-Chief: Alan R. Katritzky, Otho Meth-Cohn, and Charles W. Rees Synthesis: Carbon with Two Heteroatoms, Each Attached by a Single Bond Part I: Tetracoordinated Carbon Functions Bearing Two Heteroatoms, R2CXX′
4.01 Dihalo Alkanes, R C(Hal)2 2, Pages 1-40, Robert A. Hill 4.02 Functions Incorporating a Halogen and a Chalcogen, Pages 41-93, Niall W. A. Geraghty 4.03 Functions Incorporating a Halogen and Another Heteroatom Group Othe Than a Chalcogen, Pages 95-157, Alex C. Campbell and David R. Jaap 4.04 Functions Bearing Two Oxygens, R C(OR )1
2 2
2, Pages 159-214, David T. Macpherson and Harshad K. Rami 4.05 Functions Incorporating Oxygen and Another Chalcogen, Pages 215-241, Richard H. Wightman 4.06 Functions Incorporating Two Chalcogens Other Than Oxygen, Pages 243-291, Yannick Vallée and Andrew Bulpin 4.07 Functions Incorporating a Chalcogen and a Group 15 Element, Pages 293-349, Christopher D. Gabbutt and John D. Hepworth 4.08 Functions Incorporating a Chalcogen and a Silicon, Germanium, Boron or Metal, Pages 351-402, Max J. Gough and John Steele 4.09 Functions Bearing Two Nitrogens, Pages 403-449, Derek R. Buckle and Ivan L. Pinto 4.10 Functions Containing a Nitrogen and Another Group 15 Element, Pages 451-504, Frances Heaney by kmno4 4.11 Functions Incorporating a Nitrogen and a Silicon, Germanium, Boron or Metal,
Pages 505-541, John Steele and Max J. Gough 4.12 Functions Containing One Phosphorus and Either Another Phosphorus or As, Sb, Bi, Si, Ge, B or a Metal, Pages 543-589, R. Alan Aitken 4.13 Functions Containing at Least One As, Sb or Bi with or without a Metalloid (Si or Ge) or a Metal, Pages 591-600, William M. Horspool 4.14 Functions Containing at Least One Metalloid (Si, Ge or B) Together with Another Metalloid or Metal, Pages 601-665, Christopher G. Barber 4.15 Functions Containing Two Atoms of the Same Metallic Element, Pages 667-703, William J. Kerr and Peter L. Pauson 4.16 Functions Containing Two Atoms of Different Metallic Elements, Pages 705-727, William J. Kerr and Peter L. Pauson
Part II: Tricoordinated Carbon Functions Bearing Two Heteroatoms, R2C=CXX′
4.17 Functions Incorporating Two Halogens or a Halogen and a Chalcogen, Pages 729-788, Peter D. Kennewell, Robert Westwood and Nicholas J. Westwood 4.18 Functions Incorporating a Halogen or Another Group other than a Halogen or a Chalcogen, Pages 789-822, David I. Smith 4.19 Functions Bearing Two Chalcogens, Pages 823-877, Gary N. Sheldrake 4.20 Functions Containing a Chalcogen and Any Group Other Than a Halogen or a Chalcogen, Pages 879-965, Peter D. Kennewell, Robert Westwood and Nicholas J. Westwood 4.21 Functions Containing at Least One Nitrogen and No Halogen or Chalcogen, Pages 967-1020, Graham L. Patrick 4.22 Functions Containing at Least One Phosphorus, Arsenic, Antimony or Bismuth and No Halogen, Chalcogen or Nitrogen, Pages 1021-1042, John M. Berge 4.23 Functions Containing at Least One Metalloid (Si, Ge or B) and No Halogen, Chalcogen or Group 15 Element; also Functions Containing Two Metals, Pages 1043-1070, Richard A. B. Webster
Part III: Tri- and Dicoordinated Ions, Radicals and Carbenes Bearing Two Heteroatoms (RC+X1X2, RC−X1X2, RC·X1X2, :CX1X2)
4.24 Tri- and Dicoordinated Ions, Radicals and Carbenes Bearing Two Heteroatoms (RC+X1X2, RC−X1X2, RC · X1X2, :CX1X2), Pages 1071-1083, William M. Horspool 4.25 References to Volume 4, Pages 1085-1229
by kmno4
ROBERT A. HILL University of Glasgow, UK
3[90[0 GENERAL METHODS 1
3[90[1 DIFLUORO ALKANES*R1CF1 1
3[90[1[0 Di~uoro Alkanes from Alkanes 1 3[90[1[1 Di~uoro Alkanes from Dihalo Alkanes 2 3[90[1[2 Di~uoro Alkanes from Trihalo Alkanes 4 3[90[1[3 Di~uoro Alkanes from Alkenes 4 3[90[1[4 Di~uoro Alkanes from Alkynes 5 3[90[1[5 Di~uoro Alkanes from Di~uorocarbene 6 3[90[1[6 Di~uoro Alkanes from Aldehydes and Ketones 7 3[90[1[7 Di~uoro Alkanes from Imines 09
3[90[2 DICHLORO ALKANES*R1CCl1 00
3[90[2[0 Dichloro Alkanes from Alkanes 00 3[90[2[1 Dichloro Alkanes from Dihalo Alkanes 02 3[90[2[2 Dichloro Alkanes from Trihalo Alkanes 02 3[90[2[3 Dichloro Alkanes from Alkenes 03 3[90[2[4 Dichloro Alkanes from Alkynes 04 3[90[2[5 Dichloro Alkanes from Dichlorocarbene 05 3[90[2[6 Dichloro Alkanes from Aldehydes and Ketones 07 3[90[2[7 Dichloro Alkanes from Imines 08
3[90[3 DIBROMO ALKANES*R1CBr1 08
3[90[3[0 Dibromo Alkanes from Alkanes 08 3[90[3[1 Dibromo Alkanes from Dihalo Alkanes 11 3[90[3[2 Dibromo Alkanes from Trihalo Alkanes 12 3[90[3[3 Dibromo Alkanes from Alkenes 12 3[90[3[4 Dibromo Alkanes from Alkynes 13 3[90[3[5 Dibromo Alkanes from Dibromocarbene 13 3[90[3[6 Dibromo Alkanes from Aldehydes and Ketones 14 3[90[3[7 Dibromo Alkanes from Imines 16 3[90[3[8 Dibromo Alkanes from Carboxylic Acids 16
3[90[4 DIIODO ALKANES*R1CI1 17
3[90[4[0 Diiodo Alkanes from Alkanes 17 3[90[4[1 Diiodo Alkanes from Halo Alkanes 17 3[90[4[2 Diiodo Alkanes from Alkynes 18 3[90[4[3 Diiodo Alkanes from Diiodocarbene 18 3[90[4[4 Diiodo Alkanes from Imines 18
3[90[5 FLUOROHALO ALKANES*R1CFHal 29
3[90[5[0 Chloro~uoro Alkanes*R1CClF 29 3[90[5[0[0 Chloro~uoro alkanes from halo alkanes 29 3[90[5[0[1 Chloro~uoro alkanes from halo alkenes 29 3[90[5[0[2 Chloro~uoro alkanes from chloro~uorocarbene 21 3[90[5[0[3 Chloro~uoro alkanes from imines 21 3[90[5[0[4 Chloro~uoro alkanes from carboxylic acids 22
3[90[5[1 Bromo~uoro Alkanes*R1CBrF 22 3[90[5[1[0 Bromo~uoro alkanes from halo alkanes 22 3[90[5[1[1 Bromo~uoro alkanes from halo alkenes 23
0
1 Dihalo Alkanes
3[90[5[1[2 Bromo~uoro alkanes from bromo~uorocarbene 24 3[90[5[1[3 Bromo~uoro alkanes from carboxylic acids 24
3[90[5[2 Fluoroiodo Alkanes*R1CFI 25 3[90[5[2[0 Fluoroiodo alkanes from halo alkanes 25 3[90[5[2[1 Fluoroiodo alkanes from halo alkenes 25 3[90[5[2[2 Fluoroiodo alkanes from ~uoroiodocarbene 25 3[90[5[2[3 Fluoroiodo alkanes from carboxylic acids 26
3[90[6 CHLOROHALO ALKANES*R1CCl Hal"not F# 26
3[90[6[0 Bromochloro Alkanes*R1CBrCl 26 3[90[6[0[0 Bromochloro alkanes from halo alkanes 26 3[90[6[0[1 Bromochloro alkanes from halo alkenes 27 3[90[6[0[2 Bromochloro alkanes from bromochlorocarbene 27 3[90[6[0[3 Bromochloro alkanes from ketones 27 3[90[6[0[4 Bromochloro alkanes from carboxylic acids 27
3[90[6[1 Chloroiodo alkanes*R1CClI 28 3[90[6[1[0 Chloroiodo alkanes from halo alkanes 28 3[90[6[1[1 Chloroiodo alkanes from halo alkenes 28 3[90[6[1[2 Chloroiodo alkanes from ketones 39 3[90[6[1[3 Chloroiodo alkanes from carboxylic acids 39
3[90[7 BROMOIODO ALKANES*R1CBrI 39
3[90[0 GENERAL METHODS
There are many general methods for the preparation of `em!di~uoro\ `em!dichloro and `em! dibromo alkanes[ These are given in detail in the following sections[ Direct halogenation of alkanes is of limited use as there is generally little control of the site of halogenation[ The method can be useful\ however\ when there is some control such as halogenation of benzylic positions or a to a carbonyl group[ Replacement of one halogen for another can be useful for diiodo and mixed `em! dihalo alkanes\ but it is often very di.cult to control the degree of exchange[ One of the major problems in the generation of `em!dihalo alkanes by this method is the possibility of elimination of hydrogen halide under the reaction conditions[ This is a particular problem for dihalo alkanes where one of the halides is bromine or iodine[
Addition of hydrogen halides or halogens to halo alkenes has been used extensively for the production of dihalo alkanes[ Radical addition of hydrogen halides often leads to 0\1!dihalo compounds and care must be taken to reduce the possibility of radical formation[ Other problems of direction of addition occur when interhalogen compounds are added across halo alkenes^ mixtures of products are often obtained[
Dihalocarbenes have been used extensively in addition reactions to double bonds to form dihalocyclopropane derivatives[ There are many methods for the generation of carbenes or e}ecting a carbene transfer\ particularly for di~uoro!\ dichloro! and dibromocarbene[ The other dihalocarbenes have been studied less extensively[
The conversion of an aldehyde or ketone into a dihalo alkane works well with ~uoro and chloro alkanes\ but bromo and iodo alkanes are easily hydrolysed back to the aldehyde and ketone[ Many preparations of dibromo and diiodo alkanes result in carbonyl compounds as side products[
3[90[1 DIFLUORO ALKANES*R1CF1
The preparation of `em!di~uoro alkanes is included in a general review by Henne on the synthesis of aliphatic ~uorine compounds ð33OR"1#38[
3[90[1[0 Di~uoro Alkanes from Alkanes
Direct ~uorination of saturated compounds has been used since 0899 to replace hydrogen by ~uorine ð33OR"1#38[ However\ the reaction is not easy to control^ most organic compounds react violently with ~uorine[ The reaction of elemental carbon with ~uorine has been reported to give a mixture of products from which per~uoropropane\ per~uorobutane and per~uoropentane have been isolated ð26JA0396[ This method is clearly not of general application[ More!controlled ~uo! rination of ethane using ~uorine diluted with nitrogen yielded partially ~uorinated ethanes from
2Di~uoro Alkanes
which CHF1CHF1 and CHF1CH1F could be isolated ð39JA0060[ Electrochemical ~uorination of ethane with a solution in hydrogen ~uoride is a more controllable method but again mixtures were obtained\ however\ CH2CHF1 could be obtained in usable amounts ð55BCJ108[ Cobalt tri~uoride is a useful reagent for the per~uorination of unsaturated compounds[ For example\ cyclopentane can be per~uorinated "Equation "0##\ however the substitution of the last few hydrogens in a compound requires higher temperatures ð40JA3130[ Per~uorocyclohexane has been prepared from benzene with ~uorine and a catalyst "Equation "1## ð49JCS1578[ Gold was found to be the best catalyst[ Per~uorocyclohexane has also been made from methyl benzoate by the action of potassium tetra~uorocobaltate at high temperatures "Equation "2## ð62JFC"2#218[ Active methylene compounds have been reported to be ~uorinated e.ciently with two equivalents of sodium ethoxide in ethanol followed by perchloryl ~uoride "Equations "3#Ð"5## ð47JA5422^ however\ a later report suggests that the reaction is quite complex ð55JOC805[
F
F
FF
F
F
3[90[1[1 Di~uoro Alkanes from Dihalo Alkanes
The substitution of halide in dihalo alkanes using metal ~uorides is of general use for the preparation of di~uoro alkanes as the corresponding dichloro and dibromo alkanes are generally more accessible[ The ease of substitution is I×Br×Cl^ the substitution of chlorine frequently requires very high temperatures[ Potassium ~uoride will displace the chlorine in the relatively reactive a!keto alkyl chlorides "for example Equation "6## ð75JA6628\ whereas the chlorine of N\N! diethylchloro~uoroacetamide can only be displaced at high temperatures "Equation "7## ð66CCC1426[ Substitution of unreactive chlorines such as in dichloromethane requires harsher conditions\ for example a melt of potassium hydrogen di~uoride\ KHF1 "Equation "8## ð55AG"E#203[ KHF1 has also been used to prepare 0\0!di~uoroacetone from 0\0!dichloroacetone "Equation "09## ð60JCS"C#168[ Mercuric ~uoride has been extensively used for the preparation of ~uoro alkanes by displacement ð33OR"1#38[ Bromine is substituted at low temperature with good yields "Equation "00## whereas chlorine requires high temperatures and results in low yields "Equation "01## ð25JA778[
3 Dihalo Alkanes
10%
Dibromo alkanes are generally smoothly substituted by mercuric ~uoride "Equation "02## but 2\2!dibromobutan!1!one gives side reactions including the production of diacetyl "Equation "03## ð66JOC2416[ Silver ~uoride has been used in these reactions^ however\ it is di.cult to prepare in anhydrous form and it forms insoluble\ complex silver halides ð33OR"1#38[ Antimony tri~uoride with a catalytic amount of bromine converts dichloro"diphenyl#methane into di~uoro! "diphenyl#methane in high yield "Equation "04## ð27JA753[ Antimony penta~uoride is very e}ective at substituting alkyl bromides "Equation "05## and alkyl chlorides "Equation "06## but it does not exchange vinyl halides ð55JA1370[ A mixture of antimony tri~uoride\ antimony pentachloride and hydrogen chloride has been used to convert 1\1!dichlorobutane into 1\1!di~uorobutane "Equation "07## but many side reactions occurred ð68JFC"02#214
(13) HgF2
89%Ph
(16)
4Di~uoro Alkanes
3[90[1[2 Di~uoro Alkanes from Trihalo Alkanes
Reduction of the bromodi~uoromethyl group with sodium borohydride in DMSO seems an attractive method of preparation of compounds containing the di~uoromethyl group as long as the starting material is readily available as "Equation "08## ð80JOC3211[
Br
3[90[1[3 Di~uoro Alkanes from Alkenes
Addition of an acid to a 0\0!di~uoro alkene will lead to a di~uoromethyl group[ The high electronegativity of ~uorine ensures that hydrogen adds to the carbon bearing the ~uorines[ Thus hydrogen bromide "Equation "19## and hydrogen iodide "Equation "10## add e.ciently to 0\0! di~uoroethene ð45JCS50[ Methanol will add across tetra~uoroethene in the presence of a catalytic amount of sodium methoxide "Equation "11## ð40JA0218[ The addition to the electron!de_cient tetra~uoroethene is initially by nucleophilic attack[ Cyanide will add to chlorotri~uoroethene to give\ after acid hydrolysis\ 2!chloro!1\1\2!tri~uoropropanoic acid "Equation "12## ð59OSC"4#128[ Tetra~uoroethene can be alkylated using aluminum trichloride as a catalyst\ for example\ dichloro! ~uoromethane can be e}ectively added across the double bond as "Equation "13## ð60CCC0756[
(20) HBr
81%
Cl
F
Cl
F
CO2HF
58%
The ð1¦1 adducts of ~uoro alkenes can be prepared at high temperatures\ probably involving a radical mechanism[ Tetra~uoroethene can be dimerised at 599>C to give per~uorobutane "Equation "14##^ temperatures above 599>C give various side reactions including polymerisation ð42JCS1972[ Mixed cycloaddition reactions such as tetra~uoroethene with ethene as in "Equation "15##\ with butadiene "Equation "16## and with acrylonitrile "Equation "17## are possible\ as they occur much more readily than the dimerisation of tetra~uoroethene ð38JA389[ Tetra~uoroethene will also add to acetylene to give 2\2\3\3!tetra~uorocyclobutene "Equation "18## ð50JA271[ A variety of other ~uorinated ethenes will cyclodimerise "Equations "29# and "20## at lower temperatures than tetra! ~uoroethene ð36JA168[ Intramolecular ð1¦1 cycloaddition of 0\0!di~uorobutadiene takes place under UV irradiation "Equation "21## ð76JOC0761[
5 Dihalo Alkanes
40%
F
F
F
F
84%
F
F
F
3[90[1[4 Di~uoro Alkanes from Alkynes
The addition of two equivalents of hydrogen ~uoride across a triple bond is a general method of preparing di~uoro alkanes "Equation "22## ð36JA170[ Fluorination of alkynes by ~uorine in meth! anol leads to the formation of a `em!di~uoro dimethyl acetal "Equation "23## ð75JA6628[
(33)Cl Cl
F F
3[90[1[5 Di~uoro Alkanes from Di~uorocarbene
The generation of di~uorocarbene has been extensively reviewed ð52OR"02#44\ B!58MI 390!90\ B!60MI 390!90\ 66FCR008\ B!74MI 390!90[ Di~uorocarbene transfer is most commonly achieved by decompo! sition of a tri~uoromethylÐmetal complex[ Pyrolysis of trimethyltri~uoromethyl tin generates per~uorocyclopropane "Equation "24##\ formed by di~uorocarbene dimerisation to tetra! ~uoroethene\ which undergoes a di~uorocarbene addition ð59JA0777[ Pyrolysis of potassium tri~uoromethyl~uoroborate also gives per~uorocyclopropane together with per~uorocyclobutane "Equation "25## ð59JA4187[ The complex of bis"tri~uoromethyl#cadmium and DIGLYME reacts with acetyl chloride to produce acetyl ~uoride and di~uorocarbene\ which can be trapped with 1\2!dimethylbut!1!ene in high yield "Equation "26## ð70JA1884[ Metallic lead and dibromo! di~uoromethane have been used to produce di~uorocarbene and its capture by several alkenes studied ð70ZN"B#0264[ Tetrabutylammonium bromide was added to form a complex with the PbBr1
produced in the reaction[ Excellent yields were achieved with 1\2!dimethylbut!1!ene "Equation "27## but the yields decrease with less substituted alkenes "Equations "28# and "39##[
Me3SnCF3 150 °C, 20 h
F
F
FF
F
70%
(38)
55%
Ph
Bromodi~uoromethylphosphonium salts\ prepared in situ\ are good sources of di~uorocarbene[ Treatment with caesium ~uoride formed di~uorocarbene\ which added to 1\2!dimethylbut!1!ene "Equation "30## ð62JA7356\ whereas potassium ~uoride was used likewise with butadiene "Equation "31## ð71JA1383[ Di~uorotris"tri~uoromethyl#phosphorane has been used to transfer di~uoro! carbene to a variety of halogenated alkenes "Equation "32## ð69JCS"C#067[
(41)
79%
(42)
Cl (43) (CF3)3PF2, 120 °C, 24 h
One of the most useful reagents for generating di~uorocarbene is phenyltri~uoromethylmercury ð61ACR54^ an example of its use is the addition of di~uorocarbene to benzobarrelene "Equation "33## ð68TL0802[ One of the earliest methods used to generate di~uorocarbene was pyrolysis of the sodium chlorodi~uoroacetate ð59PCS70\ 53TL0350^ it has been used to add to a double bond "Equa! tion "34## ð62TL0208[ The hindered base\ sodium bis"trimethylsilyl#amide\ has been used to generate di~uorocarbene from chlorodi~uoromethane[ The di~uorocarbene reacted with a malonate anion to give an addition product "Equation "35## ð74TL1334[
(44) PhHgCF3
F F
CO2Et
Ph
F (46)
3[90[1[6 Di~uoro Alkanes from Aldehydes and Ketones
Sulfur tetra~uoride was the _rst reagent used to convert aldehydes and ketones into `em!di~uoro alkanes[ Two excellent reviews cover the use of sulfur tetra~uoride ð63OR"10#0\ 74OR"23#208^ a few examples will be given here to highlight the advantages and disadvantages[ Aldehydes and ketones with a!hydrogen atoms need to be treated at low temperatures for long periods to prevent decompo! sition as shown in Equations "36# and "37# ð60JOC707[ Aromatic aldehydes "Equation "38## ð60T834 and higher temperatures\ generally 049Ð199>C\ give much higher yields[ Formaldehyde "in the form of paraformaldehyde# at a high temperature "049>C# gave only a modest yield "Equation "49## ð59JA432[
(47)
39%
70%
F
CHO
F
49% H2C O FF
Hindered ketones require an acid catalyst^ hydrogen ~uoride\ boron tri~uoride\ arsenic tri~uoride and titanium tetra~uoride have been used[ Hydrogen ~uoride is conveniently produced in situ by the hydrolysis of sulfur tetra~uoride[ This reagent has been used extensively in the production of ~uoro steroids "Equation "40## ð60JOC464[ Large!ring ketones give particularly low yields "Equation "41## ð60JOC707[ A tosyloxy group has been introduced adjacent to the carbonyl group to increase the latter|s reactivity\ but the yields are disappointingly low "Equation "42## ð61JA1919[ One way round this problem is to convert the ketone "or aldehyde# into a 0\2!dithiolane derivative followed by treatment with the hydrogen ~uorideÐpyridine complex and 0\2!dibromo!4\4!dimethylhydantoin "DBH#[ This gives high yields of di~uoro alkanes as in Equations "43# and "44# ð75JOC2497[
(51)
85%
23%
FF
One of the problems with sulfur tetra~uoride as a reagent is that it is a gas[ Liquid ~uorinating reagents have been developed to overcome this problem[ Phenyl sulfur tri~uoride\ PhSF2\ ð62OSC"4#848 has been used to convert cyclooctanone into 0\0!di~uorooctane in 8) yield "Equation "45## ð58JA0275[ This same transformation has been reported with sulfur tetra~uoride to give only 0[5) yield ð60JOC707[ Phenyl sulfur tri~uoride has been used to convert other ketones "Equation "46## ð60JOC707 and aldehydes "Equation "47## ð62OSC"4#289 into the corresponding di~uoro compounds[
09 Dihalo Alkanes
F
F
Diethylaminosulfur tri~uoride "DAST# and related amino~uorosulfuranes have become very useful ~uorinating agents ð77OR"24#402[ They also have the advantage of being liquids[ DAST is about equivalent to SF3 for the preparation of geminal di~uorides from aldehydes and ketones\ however DAST has the advantage of not reacting with carboxylic acids and esters[ N\N!Dialkyl! aminosulfur tri~uorides have been used to prepare a wide range of geminal di~uoro compounds in good yield ð77OR"24#402[ Aromatic and aliphatic aldehydes and ketones are converted into the corresponding di~uoro derivatives in good!to!excellent yields in the presence of several other functional groups apart from hydroxy groups ð62S676[
Two other reagents that have seen limited use for the conversion of aldehydes and ketones into `em!di~uoro derivatives are selenium tetra~uoride and molybdenum hexa~uoride[ Molybdenum hexa~uoride has been used in dichloromethane with boron tri~uoride as catalyst at room tem! perature and gives moderate!to!good yields ð60T2854[ Selenium tetra~uoride is also used under mild conditions and gives excellent yields of `em!di~uoro products "Table 0# ð63JA814[
Table 0 Yields of `em!di~uoro compounds prepared from ketones and aldehydes with selenium tetra~uoride\ SeF3[
R0COR1:R0CF1R1
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R0 R1 Yield
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me Me 67 Et Me 79 Et Et 64 "CH1#4 "CH1#4 69 Ph Me 64 Ph Ph 89 Ph H 69 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
3[90[1[7 Di~uoro Alkanes from Imines
Diazo alkanes can be converted into `em!di~uoro alkanes in excellent yield using ~uorine dis! solved in Freon!00 at −69>C "Equations "48#Ð"51## ð70JOC2806[ An interesting method for the preparation of `em!di~uoro alkanes with adjacent amino groups is by the treatment of azirines with the hydrogen ~uorideÐpyridine complex "Equations "52# and "53## ð79JOC4222[
(59) F2, Freon-11, –70 °C
71%Ph Ph
88%
79%
43%
N
67%
N
Ph
3[90[2[0 Dichloro Alkanes from Alkanes
Direct chlorination of alkanes generally gives a mixture of chlorinated products[ For example\ direct chlorination of methane at 374Ð409>C gives a mixture of products from which dichloro! methane can be isolated\ although better yields can be obtained by chlorination of methyl chloride at 239Ð249>C in the presence of a catalyst ð67KO575[ Direct chlorination is only of synthetic use if the rest of the molecule either has no hydrogens or is an unreactive aromatic system[ Direct chlorination of pivalic acid yields 2\2!dichloro!1\1!dimethylpropanoic acid under irradiation con! ditions "Equation "54## ð53T0456[ Chlorination of aromatic methyl groups to give dichloromethyl groups can be achieved relatively easily as the replacement of the last hydrogen is much harder^ examples include the chlorination of methylbenzoyl chlorides "Equation "55## ð11JCS1191\ ~uoro! toluenes "Equation "56## ð33JIC001 and hexamethylbenzene "Equation "57## ð76JOC2602[ Toluene when treated with sulfuryl chloride in the presence of dibenzoyl peroxide gives an excellent yield of dichloromethylbenzene "Equation "58## ð28JA1031[
Cl2, hν But CO2H
Cl Cl
90%
a\a!Dichlorination of aldehydes is relatively straightforward using acid catalysis[ Propanal has been chlorinated using chlorine in hydrochloric acid in good yield "Equation "69## ð51JOC161[ The chlorination of a series of aldehydes has been reported with chlorine in DMF and HCl "Table 1# ð74T3946[ Ketones with only one a!methylene group can also be a\a!dichlorinated without too many problems "Equation "60## ð44JA2167[ Several phenyl ketones have been a\a!dichlorinated in excellent yield with chlorine in DMF at 099>C "Table 2# ð68SC464[ Sulfuryl chloride has also been used to a\a!dichlorinate phenyl ketones ð66JOC2416[ Caprolactam can be a\a!dichlorinated with chlorine and phosphorus pentachloride "Equation "61## ð47JA5122[
(70) Cl2, HCl (aq.)
Cl
Cl
Table 1 Yields of 1\1!dichloro aldehydes from aldehydes with Cl1:DMF:HCl[
RCH1CHO:RCCl1CHO
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R Yield
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me 72 Et 65 Prn 73 Pri 72 Bun 70 n!C4H00 35 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
(71) Cl2
O O
Cl
Cl
Table 2 Yields for the a\a!dichlorination of phenyl ketones with Cl1 in DMF at 099>C for
29Ð34 min[
Ph COCH1R:PhCOCCl1R
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R Yield
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me 76 Et 83 Prn 85 But 85 Ph 75 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
(72) Cl2, PCl5
Cl
Cl
Tri~uoromethanesulfonyl chloride is a mild chlorinating agent when used with an equivalent of triethylamine or 0\4!diazabicycloð4[3[9undec!4!ene "dbu#[ Dimethyl malonate and ethyl aceto! acetate have been dichlorinated under these conditions "Equations "62# and "63## ð68TL2532 and b! dicarbonyl compounds containing double bonds have been similarly dichlorinated without a}ecting the double bonds ð77JA4422[ Ketones with two a!methylene groups cause more problems and
02Dichloro Alkanes
mixtures of products are normally obtained[ The best reagent for a\a!dichlorination in this case appears to be sulfuryl chloride "Table 3#[
(73)MeO2C CO2Me MeO2C CO2Me
CO2Et CO2Et
Cl Cl
O O
Table 3 Yields for the a\a!dichlorination of ketones with sul! furyl chloride\ SO1Cl1[
R0COCH1R1:R0COCCl1R1
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me H 50 53JOC0845 Me Me 37 53JOC0845 Me Me 79 66JOC2416 Et Me 47 53JOC0845 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
3[90[2[1 Dichloro Alkanes from Dihalo Alkanes
The benzylic proton of dichloromethylbenzene can be removed with butyllithium and the resulting carbanion alkylated with methyl iodide to give 0\0!dichlorophenylethane "Equation "64## ð54JA3036[ A similar reaction occurs with allyl dichloride^ the carbanion can be treated with carbon dioxide to give 1\1!dichlorobut!2!enoic acid "Equation "65## or with ketones to give a\a!dichloro alcohols "Equation "66## ð66JA4206[
(75)Ph
Cl
91%
3[90[2[2 Dichloro Alkanes from Trihalo Alkanes
The reduction of trichloromethyl compounds to the corresponding dichloromethyl derivatives has been achieved with a wide variety of reagents[ Tin and hydrochloric acid have been used to reduce trichloro!a!picoline to its dichloro analogue "Equation "67## ð40JCS0034[ Tin"II# chloride has also been used for this transformation ð69JOC497[ General reagents for the conversion of trichloromethyl groups into dichloromethyl groups include diethyl phosphite ð72BCJ0770\ tributyltin hydride ð57ACR188 and a hydrogen donor such as triethylsilane or isopropanol together with a transition metal complex\ for example Fe"CO#4 ð72S662[ Electrochemical reduction is also e}ective ð64TL886[ Trichloroacetic acid can be reduced to dichloroacetic acid by a metal such as zinc\ cadmium\ iron or copper[ Copper has been reported to give an 79) yield of dichloroacetic acid
03 Dihalo Alkanes
ð20JA0483[ Chloral hydrate can be converted into the calcium salt of dichloroacetic acid with calcium carbonate and a cyanide catalyst "Equation "68## ð32OSC"1#070[
(78) Sn, HCl, 100 °C, 1 h
49%N CCl3 N
CaCO3, KCN (cat.) (Cl2HCCO2)2Ca
Trichloromethyl groups undergo metalÐhalogen exchange with butyllithium to give carbanions that can be alkylated "Equation "79## ð79S533[ A similar metalÐhalogen exchange with allyl tri! chloride gives the allyl carbanion intermediate involved in Equations "65# and "66#[ This time it was alkylated with methyl iodide "Equation "70## ð66JOM"030#60[ The allyl radical is an intermediate in the reaction of chloroform or 0\0\0!trichloroethane with allyltributyltin to give 3\3!dichlorobut!0! ene and 3\3!dichloropent!0!ene\ respectively "Equations "71# and "72## ð72BCJ1379[ Zinc has also been used to remove a chlorine from a trichloromethyl group\ the resulting carbanion reacting readily with formaldehyde "Equation "73## ð75HCA770[ Copper"I# catalysis has been used to add a trichloromethyl group across a double bond "Equation "74## ð79HCA0836[
(80)PhCCl3 Ph CHO
81%
76%
76% F3C CO2H
3[90[2[3 Dichloro Alkanes from Alkenes
Addition of chlorine to a chloro alkene is a straightforward method for producing a `em!dihalo alkane "Equations "75# ð37JA1702 and "76# ð40JA3282#[ Nitrogen trichloride is an e}ective reagent for the addition of chlorine to a chloro alkene "Equation "77## ð60JOC2455[ Many other chlorine! containing reagents can be added to chloro alkenes[ These include iodine monochloride\ e}ectively generated from iodine and CuCl1 "Equation "78## ð60JOC2213\ acetyl chloride catalysed by aluminum trichloride "Equation "89## ð89JCS"P0#2206\ chloroform\ also catalysed by aluminum chloride "Equa! tion "80## ð32OSC"1#201 and phosgene\ e}ectively generated from PdCl1 and carbon monoxide "Equation "81## ð53JA3740[
04Dichloro Alkanes
(86) Cl2Cl
Cl Cl
PdCl2, CO Cl
O (92)
The addition of chlorine to an enamine leads to an a\a!dichloro aldehyde "Equation "82## ð62TL3126[ A range of Grignard reagents were added to the chloro enamine "0# to give\ after acid hydrolysis\ dichloromethyl ketones "Table 4# ð63BSF0422[
(93)NEt2
Cl
CHO
Cl NEt2
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me 39 Et 67 Pri 14 n!C4H00 66 Ph 89 Vinyl 14 BuC2C 59 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
3[90[2[4 Dichloro Alkanes from Alkynes
The addition of two molecules of HCl to an alkyne\ in principle\ should give a `em!dichloro alkane^ however\ in practice\ the yields are poor "Equation "84## ð54JA2040\ 56JOC1540[ Chlorination
05 Dihalo Alkanes
of terminal alkynes with chlorine in water or acetic acid gives dichloromethyl ketones "Equation "85##^ however\ again the yields are poor ð28JA0359[ A better method for the preparation of dichloromethyl ketones from terminal alkynes is to use N!chlorosuccinimide in methanol followed by hydrolysis of the intermediate acetal "Table 5# ð54JOC1084[ This method may also be used for symmetrical alkynes "Equation "86##[
(95) ClClHCl
(96)R R
H2O or AcOH
Table 5 Yields for the preparation of dichloromethyl ketones from terminal alkynes[
R R Cl
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R Yield
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me 57 Et 62 Prn 55 Bun 57 Ph 57 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
(97)
O
70%
3[90[2[5 Dichloro Alkanes from Dichlorocarbene
Dichlorocarbene production\ properties and uses have been covered in several reviews ð52OR"02#44\ B!53MI 390!90\ B!60MI 390!90\ B!74MI 390!90[ There are many ways to generate dichlorocarbene e.ciently[ One of the earlier methods was to use chloroform and potassium t!butoxide "Equation "87## ð43JA5051[ The same reaction can be performed in excellent yield "80)# using bromo! trichloromethane and butyllithium to generate the dichlorocarbene ð48JA4997[ Phase!transfer con! ditions have been used extensively to generate dichlorocarbene\ for example chloroform\ 49) aqueous sodium hydroxide and a quaternary ammonium salt such as benzyltriethylammonium chloride "TEBA#[ These conditions have been used for the production of a range of dichloro! cyclopropanes "Equations "88# ð60LA"633#31 and "099# ð89CB472#[ The addition of dichlorocarbene to alkenes that contain base!sensitive groups can be achieved using the thermal decomposition of sodium trichloroacetate\ for example\ for the reaction with cyclohexene "Equation "87## in 54) yield ð48PCS118[ However side reactions tend to occur ð51RTC814[ The best method for base! sensitive compounds appears to be the use of phenyl"bromodichloromethyl#mercury "PhHgCBrCl1# in an inert solvent at 79>C ð54JA3148[ For example 6\6!dichloronorcarane can be prepared from cyclohexene "Equation "87## in 78) yield using this method[ A large range of dichlorocyclopropanes has been produced in high yield from the corresponding alkenes "Equation "090##[ cis!Alkenes and trans!alkenes react with retention of con_guration[
(98) Cl
Ph Ph Ph
(101)CO2Me CO2Me
ClCl PhHgCBrCl2
76%
Dichlorocarbene can also be inserted into CÐH bonds\ particularly when there is an a!oxygen anion "Table 6# ð72JA1660[ The carbene CÐH insertion competes favourably with addition to an alkene except for more highly substituted alkenes "Equation "091##[ Chloroform may be added across the double bond of styrene using copper metal and 0\09!phenanthroline "as a Cu"I# complex# "Equation "092## in high yield[ The reaction is less e.cient with aliphatic alkenes ð72CCC0609[
Table 6 Yields for the insertion of carbenes into the CÐH bonds of alkoxides[
R Cl
(102) OLi
95%
Dichlorocarbene is involved in the ReimerÐTiemann reaction for the production of aromatic aldehydes from phenols with chloroform and aqueous sodium hydroxide ð71OR"17#0[ The inter! mediate dichloromethylated compounds are normally hydrolysed during the reaction\ however if the ortho! and para!positions are blocked the abnormal ReimerÐTiemann product\ a chloro! methylcyclohexadienone\ is formed "Equation "093## ð63T1550[ Chloromethylation of aromatic compounds can be achieved with aluminum trichloride and chloroform "Equation "094## ð80JOC4334[
But But
78%
3[90[2[6 Dichloro Alkanes from Aldehydes and Ketones
Aldehydes and ketones can be readily converted into dichloro alkanes by phosphorus penta! chloride\ which is by far the most widely used reagent for this conversion ð79LA0[ Aliphatic ketones do not normally give the corresponding dichloro alkane in particularly high yield since elimination products are frequently formed "Equation "095## ð23JA1629\ 28JA827[ Aliphatic aldehydes generally give better yields "Equation "096## ð52BSF0757 and if the conditions are carefully controlled\ spectacular yields can be attained "Equation "097## ð58JOC1507[
(106) O ClClPCl5
97%
Aromatic aldehydes can be easily converted in high yield into the corresponding dichloromethyl compound "Equation "098## ð22JCS385^ there are many examples in the literature ð13LA"324#108\ 59JA5004[ a\b!Unsaturated aldehydes are also converted smoothly into the corresponding dichloro! methyl compounds with phosphorus pentachloride "Equation "009## ð68S314[
(109) PCl5
Cl
Cl
(110)CHO
Cl
Cl
PCl5
50%
Ketones that lack a!hydrogens can be converted into the dichloro alkane but particularly high temperatures are needed as in Equations "000# and "001# ð32JA278\ 38JA2328\ 54JOC0130[
(111) Ph CF3
90%
85%
Only a few other reagents have been used for the transformation of aldehydes and ketones into dichloro alkanes[ Thionyl chloride in DMF has been used for this transformation "Equations "002# and "003##[ Ketones require a higher reaction temperature than aldehydes ð67JOC3256[ Oxaloyl chloride has also been used for the preparation of benzal chloride from benzaldehyde ð98CB2855 and antimony pentachloride with a trace of iodine as catalyst has been used in a similar transformation "Equation "004## ð20RTC642[
08Dibromo Alkanes
85%
89%
(116)
3[90[2[7 Dichloro Alkanes from Imines
Diazoketones can be converted into the corresponding dichloromethyl ketones by chlorine "Equa! tion "006##^ however\ the yields tend to be poor ð55ACS142[ In a similar reaction with triphenyl! phosphoranylidenehydrazones\ sterically hindered dichloro alkanes can be produced "Equation "007##\ again with a low yield ð72OMR"10#53[ In an interesting reaction of chlorine on 0\1\2!triazoloð0\4! apyridine\ 1!dichloromethylpyridine is produced in high yield "Equation "008## ð70JCS"P0#67[
N2
67%
Oxidative deamination of a variety of primary amines using copper"II# chloride and isopentyl nitrite gives `em!dichloro compounds in moderate to good yields "Table 7# ð65CC322\ 65JA0516[
3[90[3 DIBROMO ALKANES*R1CBr1
3[90[3[0 Dibromo Alkanes from Alkanes
Bromination of alkanes under radical conditions has been used since the mid 0819s[ Sunlight has been used to produce dibromomethyl aromatic compounds from toluene derivatives "Equation
19 Dihalo Alkanes
Table 7 Yields for the oxidative deamination of primary amines by copper"II# chloride and isopentyl nitrite to give `em!
dichloro alkanes[
R0CH10NH1:R0CHCl1 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R Yield
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Ph 03 PhCH1 47 PhCH1CH1 23 PhCH1CH1CH1 21 Ph"CH1#4 23 CH2"CH1#7 15 EtO1C"CH1#3 29 HO"CH1#4 28 Cyclohexyl 15 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
"019##^ however\ the yields tend to be low ð15JA0982[ One of the reasons is that\ unless there is a constraint on the number of bromines that can be added to the molecule\ there is generally a mixture of brominated products[ Steric crowding of ortho!substituents results in better yields of dibromomethyl products "Equation "010## ð43OSC"3#796[ Extreme crowding can completely inhibit the production of tribromomethyl products "Equation "011## ð77JCS"P0#850[ A 199 or 299 W sunlamp is found to be best for these benzylic brominations\ the lamp providing both light and heat for the reaction[ The concentration of bromine should be low during the reaction and for highly hindered cases the concentration of the precursor should also be low[
(120)
CN
Br
Br
CN
100%
Bromination a to ketones is generally performed with bromine without irradiation "Equations "012# ð64JCS"P0#140 and "013# ð55JCS"C#422#[ Bromination of ketones with two equivalents of bromine under acid conditions generally gives an a\a?!dibromo derivative "Equation "014## rather than a `em!dibromo derivative^ however\ four equivalents of bromine gives a reasonable yield of the bis"`em!dibromo# derivative "Equation "015## ð51ACS1356[ a\a!Dibromination of aldehydes is generally poor due to the variety of side reactions that occur "Equation "016## ð68LA167[ Bro! mination between b!dicarbonyl groups can be carried out under basic conditions "Equations "017# ð47JA0831 and "018# ð65TL3466#[
(123)
Br Br
10Dibromo Alkanes
(124) CO2H
50%
(126) O
(127)CHO CHO
CHO
CHO
CHO
CHOBr
Br
N!Bromosuccinimide "NBS# is often the reagent of choice for bromination ðB!63MI 390!90[ Bromination of aromatic methyl groups under radical conditions normally leads to a mixture of mono!\ di! and tribrominated products together with products due to radical dimerisation\ although reasonable amounts of dibromomethyl compounds can generally be obtained "Equation "029## ð73JHC0046[ As observed for bromination with bromine\ steric crowding increases the yields of dibromination of methyl groups "Equation "020## ð75JCS"P0#0384[ A range of ketones have been a\a!dibrominated in very good yields by NBS in carbon tetrachloride with a 299 W sunlamp "Table 8# ð66JOC2416[ The yield for the reaction of pentan!2!one is low as the main product is 1\3! dibromopentan!2!one[ Radical initiators\ such as dibenzoyl peroxide and 1\1?!azobisisobutyronitrile "AIBN#\ have been used extensively in NBS reactions "Equations "021# ð43HCA89 and "022# ð51JOC646#[ NBS can also be used under nonradical conditions "Equation "023## ð78JCS"P0#1998[ Bromotrichloromethane in the presence of dbu has been shown to be e}ective at dibrominating active methylene compounds "Equation "024## but diethyl malonate gives monobromination and dimerisation products ð67CL62[
N S
N N
S N
78%
11 Dihalo Alkanes
Table 8 Yields of a\a!dibromo ketones formed with NBS in CCl3 and a 299 W sunlamp[
R0COCH1R1:R0COCBr1R1
(133) NBS, CCl4, dibenzoyl peroxide
65%
Br
Br
Br
Br
Br
Br
N
Br
O
H
Dichloro alkanes can be converted into dibromo alkanes by calcium bromide under phase! transfer conditions with tetrahexylammonium bromide "Equation "025## ð73S23\ boron tribromide "Equation "026## ð55JA1370 or boron tribromide with aluminum tribromide and bromine "Equation "027## ð62JOC042[
(136)ClCl BrBr CaBr2, (n-C6H11)4NBr
78% (138)
Dibromomethyllithium\ prepared from dibromomethane and lithium diisopropylamide "LDA# can be alkylated "Equation "028## ð89JOC4608[ a\a!Dibromo alkyllithium compounds can in general be prepared from the corresponding dibromo alkanes and LDA\ and they can be used in a variety of reactions such as alkylations and reactions with esters to give a\a!dibromo ketones "Equation "039##\ with carbon dioxide to give a\a!dibromo carboxylic acids "Equation "030## ð64BSF0686 and with methyl formate to give a\a!dibromo aldehydes "Equation "031## ð79S533[
12Dibromo Alkanes
73% Ph
3[90[3[2 Dibromo Alkanes from Trihalo Alkanes
Bromoform can be reduced to dibromomethane by sodium arsenite in good yield "Equation "032## ð21OSC"0#246[ Tribromoquinaldine has been reduced to dibromoquinaldine "Equation "033## with tin and hydrobromic acid ð40JCS0034 but also with ethanol in concentrated sulfuric acid producing a 87) yield ð35JOC44[
(143)HCBr3 CH2Br2
Na3AsO3, NaOH
88–90%
3[90[3[3 Dibromo Alkanes from Alkenes
Addition of hydrogen bromide to bromo alkenes under ionic conditions gives good yields of `em! dibromo alkanes "Equation "034## whereas addition of hydrogen bromide to 1!bromobut!1!ene under UV irradiation gives 2\3!dibromobutane ð48JA4826[ The addition of hydrogen bromide to bromo alkenes under radical and ionic conditions has been reviewed ð39CRV240[ Ionic addition of hydrogen bromide can be assisted by a small amount of a Lewis acid catalyst such as FeCl2 "Equation "035## ð44JA2354^ however an excess of FeCl2 causes elimination and halogen exchange reactions ð46JA5169[
(145) Br Br
Br BrBr HBr, FeCl3
Addition of bromine to bromo alkenes also gives `em!dibromo alkanes in good yields "Equation "036## ð24JA0977\ 56BCJ483 and "Equation "037## ð43JA368[ Addition of bromine to dibromo alkenes often requires radical conditions "Equation "038## ð55JA1370[ Bromination of 1\3\5!tribromophenol
13 Dihalo Alkanes
produces a tetrabromocyclohexadienone ð65OS"44#19 which is itself a mild brominating agent "Equation "049##[
(147) Br2Br Br
61–67%
Br Br
(150)
An interesting rearrangement occurs when trans!1\2!dibromobut!1!ene is treated with tri~uoro! peracetic acid and boron tri~uoride giving 2\2!dibromobutan!1!one "Equation "040## ð56JOC1558[
(151) CF3CO3H, CH2Cl2, BF3
3[90[3[4 Dibromo Alkanes from Alkynes
Addition of two equivalents of hydrogen bromide to propyne under ionic conditions gives good yields of 1\1!dibromopropane "Equation "041## ð24JA1352[ However\ under radical conditions the yields are poor and several side reactions occur ð54JA2040[ A variety of other terminal alkynes give good yields in addition reactions with hydrogen bromide "Equations "042# ð25JA0795 and "043# ð96JCS705#[
(152) BrBrHBr
(153) HBr
Br Br
The formation and reaction of dibromocarbene has been extensively reviewed ð52OR"02#44\ B!53MI 390!90\ B!60MI 390!90\ B!74MI 390!90[ The classic production of this carbene using bromoform and potassium t!butoxide ð53JOC1840 gives good yields in addition reactions to a variety of substituted alkenes\ for example Equation "044# ð51JOC637\ 69JA4358\ Equation "045# ð45JA4329\ 72JA2300 and Equation "046# ð45JA4329\ 66OS"45#21[ Phase!transfer conditions using benzyltriethylammonium chloride "TEBA#\ 49) sodium hydroxide solution and bromoform\ have been used to add
14Dibromo Alkanes
dibromocarbene to a variety of alkenes "Equations "047# ð89CB472 "048# ð60LA"633#31 and "059# ð62TL0256# again with good yields[ In many cases the traditional method using potassium t!butoxide gives better yields than the phase!transfer method\ for example with cyclohexa!0\2!diene "Equation "050## KOBut gives 69) yield ð48JA881 whereas phase!transfer conditions give only 49) ð78S077[
(155) Br
BrBr
CO2But
BrBr
PhPh
73%
Br
Phenyl"tribromomethyl#mercury has been reported to produce a range of dibromocarbene addition reactions ð61ACR54 and\ as for the chloro analogue "Section 3[90[2[5#\ it is useful for base! sensitive compounds "Equation "051## ð89CB472[
(162)
CO2But
BrBr
3[90[3[6 Dibromo Alkanes from Aldehydes and Ketones
Compared with the formation of `em!dichloro alkanes from aldehydes and ketones\ there are fewer general methods for the conversion of aldehydes and ketones into `em!dibromo alkanes[ Phosphorus pentabromide has been used to convert benzaldehyde derivatives into the corresponding dibromomethylbenzenes "Equation "052# ð12LA"320#169#[ PBr1Cl2\ formed from phosphorus tri! chloride and bromide in situ is an alternative reagent "Equation "053## ð60JA3361^ see also 72JOC1973[ Phosphorus tribromide has been reported to give a high yield of dibromo alkane "Equation "054## ð73JA7063[ An interesting new reagent\ "PhO#2PBr1\ formed from a 0 ] 0 mixture of triphenyl phosphite and bromine\ seems to have general application for the production of `em!dibromo alkanes from aldehydes "Table 09# ð89S546[
15 Dihalo Alkanes
91%
But
O
But
BrBr
Table 09 Yields for the production of dibromo alkanes from aldehydes and "PhO2#PBr1 in CH1Cl1 at −04>C[
R0CHO:R0CHBr1
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ n!C5H02 69 1!pentyl 45 cyclohexyl 44 But 49 BnOCH1 53 Ph 65 2!chloro!3!nitrophenyl 80 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Boron tribromide was found to convert an aromatic aldehyde into the corresponding dibromo! methylbenzene derivative during the demethylation of a methoxyl group[ The reaction has been shown to be generally applicable "Table 00# ð68SC230[ Ketones\ when converted into their catechol acetal derivatives\ can be converted into the corresponding dihalo alkane in good yield using boron tribromide "Scheme 0# ð75S011[
Table 00 Yields for the preparation of benzal bromides from aldehydes with BBr2[
CHO
O OMe
77%
Scheme 1
16Dibromo Alkanes
An interesting route for the preparation of dibromo ketones from a!diketones utilises the reaction of bromine with the adduct of the a!diketone and triphenyl phosphite "Scheme 1# ð57JOC14[
O
O
Ph
Ph
92%
3[90[3[7 Dibromo Alkanes from Imines
A general method for the preparation of sterically hindered dibromo alkanes from hydrazones "Equation "055## with bromine and triethylamine has been described ð77S436[ They are also available from triphenylphosphoranylidene hydrazones "Equation "056##ð72OMR"10#53[ In a reaction analogous to that with chlorine\ 0\1\2!triazoloð0\4!apyridine when treated with bromine yields 1!dibromo! methylpyridine "Equation "057## ð70JCS"P0#67[ A range of primary amines have been converted into `em!dibromo alkanes "Table 01# ð65JA0516 with copper"II# bromide and isopentyl nitrite[
Br2, Et3N, RT, 16 h
62%But But
65%
(168) Br2, CCl4
Table 01 Yields for the oxidative deamination of primary amines by copper"II# bromide and isopentyl nitrite to give `em!
dibromo alkanes[
3[90[3[8 Dibromo Alkanes from Carboxylic Acids
The Hunsdiecker reaction of the silver salt of a!bromo carboxylic acids with bromine has been used to prepare dibromo alkanes "Equation "058## ð42JA0037[ Apart from the reaction of silver salts ð45CRV108\ 46OR"8#221\ there are several other ways to bromodecarboxylate acids\ including the use of lead tetraacetate and lithium bromide ð61OR"08#168 and of thallium"I# salts and bromine ð70JCS"P0#1597[ Silver acrylate\ when treated with bromine\ undergoes addition across the double bond as well as the Hunsdiecker reaction "Equation "069## ð56BCJ483[
17 Dihalo Alkanes
Br
Br2
Other methods of bromodecarboxylation are exempli_ed by treatment of an a!keto acid with bromine and sodium acetate "Equation "060## ð42JA2186 and of cyanoacetic acid with NBS "Equa! tion "061## ð52OSC"3#143 and by the Hofmann degradation of a!bromo amides with sodium hydrox! ide and bromine "Equation "062## ð45JA1153[
Br2, NaOAc
3[90[4[0 Diiodo Alkanes from Alkanes
Iodination of alkanes is restricted to the iodination of active methylene groups[ Malonic acid can be diiodinated with iodine and potassium iodide ð40JIC564 but better yields are obtained with iodine and potassium iodate "see Scheme 2# ð03JA0788\ 47JOC0257[ Heating the diiodomalonic acid causes decarboxylation to give diiodoacetic acid[ Decarboxylation also readily occurs when acetone dicarboxylic acid is treated under the same conditions as Equation "063# ð61ACS0624[
CO2H
CO2H
CO2H
CO2H
I
3[90[4[1 Diiodo Alkanes from Halo Alkanes
There are only a few reports of replacement of dihalides by iodides\ for example dichloromethane when treated with sodium iodide in DMF gives diiodomethane "Equation "064## ð62CI"L#220 and benzal bromide is converted into benzal iodide by sodium iodide in carbon disul_de in the presence of silver nitrate "Equation "065## ð65JCS"P0#305[ An interesting exchange reaction is used in the conversion of 0\0!dichloroethane into 0\0!dibromoethane where ethyl iodide is the iodine source with aluminum trichloride as a catalyst as Equation "066# ð40JA3365[
18Diiodo Alkanes
Ph
Br
Br
Ph
I
I
82%
60%
Cl
Cl
I
I
(177)
Iodoform was reduced to diiodomethane by sodium arsenite "Equation "067## ð21OSC"0#247[
(178)CHI3 I INa3AsO3, NaOH
3[90[4[2 Diiodo Alkanes from Alkynes
Two equivalents of hydrogen iodide add readily to terminal alkynes to give diiodo alkanes "Equations "068# ð54JA2040 and "079# ð96JCS705#[
(179) IIHI
(180) II
CO2HCO2H HI
3[90[4[3 Diiodo Alkanes from Diiodocarbene
The generation of diiodocarbene has received relatively little attention compared to that of other dihalocarbenes\ largely because the adducts with alkenes are too unstable[ However the diiodocyclopropanes can be isolated when formed from potassium t!butoxide and iodoform at low temperatures ð65JCS"P0#43\ 65S202[ Diiodocarbene can also be generated under phase!transfer conditions ð70T0104[
3[90[4[4 Diiodo Alkanes from Imines
The production of diiodoalkanes from imino compounds is the most generally applicable strategy\ even though the yields can be low[ Diazo alkanes react with iodine to give `em!diiodo alkanes in yields in the range 16Ð26) "Equation "070# ð55JOC0746\ 72OMR"10#53#[ Higher yields can be achieved from hydrazones with iodine and triethylamine^ a range of diiodo alkanes has been prepared by this method "Equation "071## ð69AJC878\ 64SC22[
(181)N2 I
I I2
3[90[5[0 Chloro~uoro Alkanes*R1CClF
3[90[5[0[0 Chloro~uoro alkanes from halo alkanes
Chlorination of ~uoro alkanes "Equation "072## is not a good method for the preparation of chloro~uoro alkanes as a mixture of chlorinated by!products is obtained ð60JCS"B#0612[ The best method for the preparation of chloro~uoro alkanes is by exchange of a halogen for ~uorine[ Several reagents are available for this transformation[ Heating dichloromethane with a mixture of sodium and potassium ~uoride at high temperatures is reported to give high yields of chloro~uoromethane "Equation "073## ð75CI"L#389[ The same transformation has been achieved using antimony tri~uoride ð26JA0399[ Antimony tri~uoride has been used to produce a variety of chloro~uoro alkanes "Equa! tion "074## but care must be taken not to replace both `em!chlorines ð55JA1370[
(183)
Cl
SbF3, 90 °C
Silver ~uoride has also been used to e}ect the last reaction in 39) yield ð67HCA1371[ Potassium ~uoride in the polar solvent\ N!methyl!1!pyrrolidone\ has been reported as an e}ective reagent for the preparation of chloro~uoro alkanes "Equation "075## ð52JOC001[ One of the most common reagents for replacement of a halogen by ~uorine is mercury di~uoride "Equations "076# ð66JOC2416 and "077# ð25JA778#[ In a di}erent approach\ iodine has been replaced by chlorine under radical conditions in very high yield "Equation "078## ð67JFC"00#416[
F3C CF3
F3C CF3
FCl (189)
3[90[5[0[1 Chloro~uoro alkanes from halo alkenes
Addition of hydrogen ~uoride to a chloro alkene such as 0!chlorocyclohexene "Equation "089## ð52HCA0707\ 1!chloropropene "Equation "080## ð62JOC1980 and 1\2!dichloropropene "Equation "081## ð35JA385 gives very good yields of chloro~uoro alkanes[
20Fluorohalo Alkanes
Cl FCl ClCl (192)
Addition of ~uorine to chloro alkenes "Equation "082## ð52JOC383\ chlorine to ~uoro alkenes "Equation "083## ð40JA600\ FCl to chloro alkenes "Equation "084## ð65JFC"6#458\ FBr "e}ectively formed from Br1 and AgF# to chloro alkenes "Equation "085## ð62JA071\ BrCl to ~uoro alkenes "Equation "086## ð62JA071 and hydrogen bromide to chloro~uoro alkenes "Equation "087## ð43JCS2636 have all been reported^ however in many cases mixtures of products are obtained due to elimination or halogen exchange reactions ð69JOC3190 or by interhalogen compounds adding to an unsymmetrical alkene both ways round ð62JA071[
F2
66%
Other reagents for the addition of ~uorine to chloro alkenes such as cobalt tri~uoride "Equation "088## ð52JOC383 and sulfur tetra~uoride and lead dioxide "Equation "199## ð53JOC0480 have been reported[
(199) CoF3
43% F
21 Dihalo Alkanes
A useful method for the preparation of chloro~uoro alkanes is by the addition of HX to a suitable chloro~uoro alkene[ The alkene needs to be polarised so that the H of the HX adds to the correct carbon[ This can be achieved by using chlorotri~uoroethene in addition reactions such as the addition of ethanol ð37JA0449\ 41JCS3148\ 52OSC"3#073\ diethylamine ð63CCC1505\ 66CCC1426\ hydrogen cyanide "the nitrile is hydrolysed to a carboxylic acid under the reaction conditions# ð62OSC"4#128\ trichlorosilane ð59JCS3492 and hydrogen ~uoride "using formamide as a hydrogen donor# "Scheme 3# ð50JCS2714\ 73JFC"15#18[ Cyclodimerisation of chlorotri~uoroethene gives a good yield of a 0\1!dichloroper~uorocyclobutane "Equation "190## ð36JA168[
F Cl
46%
O
NH2
76–79%
F
F
F
(201)
3[90[5[0[2 Chloro~uoro alkanes from chloro~uorocarbene
Chloro~uorocarbene ð66FCR008 has been generated by a variety of methods and added to a range of alkenes to form chloro~uorocyclopropanes "Equation "191##[ The methods for the generation of chloro~uorocarbene are listed in Table 02[
(202) CClF
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Rea`ents Ref[ *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ CHFCl1 and KOBut 46JOC629 CHFCl1 and MeLi 60CB0810 CFCl2 and TiCl3\ LiAlH3 89JOC478 "CFCl1#1CO and KOBut 52JOC1383\ 56T1438 PhHgCFCl1 69JOC0186 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
3[90[5[0[3 Chloro~uoro alkanes from imines
Chloro~uoromethyl ketones can be readily prepared from the corresponding diazo ketone using N!chlorosuccinimide and pyridinium poly"hydrogen ~uoride# "Equation "192## ð68JOC2731[
22Fluorohalo Alkanes
R N2
F
(203)
3[90[5[0[4 Chloro~uoro alkanes from carboxylic acids
The Hunsdiecker reaction of silver ~uoroacetate with chlorine gives a good yield of chloro! ~uoromethane "Equation "193## ð41JCS3148[ The Barton generation of a cyclopropyl radical using sodium mercaptopyridine N!oxide\ followed by abstraction of a chlorine atom from carbon tetra! chloride lead to a chloro~uoroalkane in poor yield "Equation "194## ð80JOC1082[
(204)AgO2C F Cl F Cl2
52%
3[90[5[1 Bromo~uoro Alkanes*R1CBrF
3[90[5[1[0 Bromo~uoro alkanes from halo alkanes
Bromination of a benzylic or a!keto mono~uoro alkane leads to a bromo~uoro alkane in good yield[ Benzylic ~uoro alkanes require radical conditions for bromination "Equation "195## ð68T1550\ whereas bromination of a a!keto mono~uoro alkane can be performed with bromine "Equations "196# ð50JCS2341 and "197# ð42JA3980# or NBS "Table 03# ð66JOC2416[ Replacement of one bromine of a dibromo alkane can be achieved with one equivalent of mercury di~uoride "Equations "198# ð25JA778 and "109# ð43JA368#[ The Grignard reagent made from a dibromo~uoro alkane will react with a series of aldehydes and ketones to give a!hydroxy bromo~uoro alkanes "Equation "100## ð73JFC"15#356[
Ph F
95%
45% F
O F
95%
O
CO2Et
(208)
23 Dihalo Alkanes
Table 03 Yields for the synthesis of a\a! bromo~uoro ketones from ~uoro ketones using
N!bromosuccinimide[
R0COCHFR1:R0COCBrFR1
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me Me 84 Ph Me 84 CH1Cl Me 87 Me Ph 86 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Br CO2Me
BrF OH (211)
3[90[5[1[1 Bromo~uoro alkanes from halo alkenes
As with the other classes of `em!dihalo alkanes\ a good way to generate them is by addition to halo alkenes[ The various ways to make bromo~uoro alkanes are exempli_ed by the following reactions] bromination of ~uoro alkenes by bromine either with irradiation "Equations "101# ð40JA600 and "102# ð46JA3069# or under ionic conditions with bromine in the dark "Equation "103## ð65JCS"P0#1238 or with a catalytic amount of sodium iodide "Equation "104## ð68JOC0283^ ~uorination of bromo alkenes\ "Equation "105## with ~uorine or cobalt tri~uoride ð52JOC383^ addition of hydrogen bromide to a ~uoro alkene "Equation "106## ð65JCS"P0#1238 or hydrogen ~uoride "Equation "107## ð64JOM"81#6 or hydrogen chloride "Equation "108## ð68T1550 to a bromo! ~uoro alkene and of BrF "Equation "119## ð50JCS2668 or BrCl "Equation "110## ð62JA071 to a ~uoro alkene[
(212) HBr, hν
100% (213)
(214) Br2
90% F
65%
O
NH2
(218)
48%
30%
3[90[5[1[2 Bromo~uoro alkanes from bromo~uorocarbene
The generation of bromo~uorocarbene has been reviewed ð66FCR008^ see Table 04 for the methods of generation[ The reported yields for the adducts formed with phenyl"dibromo~uoro! methyl#mercury are better than those from other methods "Equation "111## ð62JOM"40#66[
Table 04 Reagents used to generate bromo~uorocarbene[
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Rea`ents Ref[ *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ CHFBr1 and KOBut 58TL0846 CHFBr1\ 49) NaOH and BnEt2NCl 60TL2758\ 72ZOR0514 PhHgCFBr1 62JOM"40#66 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
(222) Br
88%
3[90[5[1[3 Bromo~uoro alkanes from carboxylic acids
The Hunsdiecker reaction ð45CRV108 gives good yields of bromo~uoro alkanes from the cor! responding silver a!~uoro carboxylate and bromine "Equation "112## ð41JCS3148[ The radical formed in the Barton method from an a!~uoro acid chloride will abstract a bromine atom from bromotrichloromethane "Equation "113## ð80JOC1082[
(223)AgO2C F Br F Br2
55%
3[90[5[2[0 Fluoroiodo alkanes from halo alkanes
Exchange of one iodine of a diiodo alkane using mercury di~uoride is possible\ however the yields are low "Equation "114## ð64JOC1685[
(225)I I F I HgF2
20%
3[90[5[2[1 Fluoroiodo alkanes from halo alkenes
Addition of IF to a ~uoro alkene is a useful way to generate a ~uoroiodo alkane[ For example\ IF\ generated by various methods\ has been added across the double bond of hexa~uoropropene "Table 05#[ ICl has also been added to a ~uoro alkene "Equation "115## ð59JCS0287[ The overall addition of an iodo alkene across the double bond of ~uoroethene has been achieved with UV irradiation initiating a radical mechanism "Equation "116## ð45JA48[
Table 05 Reagents for the generation of IF for the addition to hexa~uoropropene[
F3C F
ICl F
26Chlorohalo Alkanes
3[90[5[2[3 Fluoroiodo alkanes from carboxylic acids
The Hunsdiecker reaction ð45CRV108 gives poor yields of iodo~uoro alkanes from the cor! responding silver a!~uoro carboxylate and iodine "Equation "118## ð41JCS3148[ The radical formed in the Barton method from an a!~uoro acid chloride will abstract an iodine atom from trichloro! iodomethane "Equation "129## ð80JOC1082^ however\ the yield is low[
(229)AgO2C F I FI2
3[90[6[0 Bromochloro Alkanes*R1CBrCl
3[90[6[0[0 Bromochloro alkanes from halo alkanes
Replacement of one chlorine in dichloromethane by a bromine with calcium bromide under phase!transfer conditions has been achieved "Equation "120##[ However\ the major product is dibromomethane ð73S23[ Better methods to produce bromochloro alkanes are chlorination of a!bromo carbonyl compounds "Equation "121## ð16LA"342#002\ bromination of a!chloro carbonyl compounds "Equation "122## ð60JCS"C#168 and radical chlorination of benzyl bromides "Equation "123## ð80JOC0552[
(231)Cl Cl Cl Br CaBr2, (n-C6H11)4NBr
32%
(232)NHEt
Br
O
NHEt
Br
O
ClPCl5
(233)Cl
27%
89%
3[90[6[0[1 Bromochloro alkanes from halo alkenes
As with the other mixed `em!dihalo alkanes\ there are a variety of ways to produce bromochloro alkanes by addition to halo alkenes[ Some of the methods are illustrated by the following reactions] addition of hydrogen bromide "Equations "124# ð44JA2354 and "125# ð23JA601# and addition of bromine to a chloro alkene as in Equations "126# ð41JA2784\ 69JA6248\ "127# ð17JCS1014 and "128# ð41JA2784 and chlorine to a bromo alkene "Equations "139# ð68T1550 and "130# ð24JA0977#[
(235)
40%
F
F
Br
F
F
Br
3[90[6[0[2 Bromochloro alkanes from bromochlorocarbene
Bromochlorocarbene has been generated by electroreduction of tetrabromomethane in the pres! ence of chloride^ however\ dichlorocarbene is also produced by this method ð89IZV0791[ The best method for generating bromochlorocarbene for the addition to alkenes is from dibromo! chloromethane and potassium t!butoxide at 14>C for 07 h ð74AG"E#474[
3[90[6[0[3 Bromochloro alkanes from ketones
Bromochloro alkanes can be conveniently synthesised from ketones via oximes and `em!chloro! nitroso compounds in high yield "Table 06# ð65TL832[
3[90[6[0[4 Bromochloro alkanes from carboxylic acids
The Hofmann degradation of a!chloro amides is a useful method for the generation of bromo! chloro alkanes "Equation "131## ð45JA1153[
28Chlorohalo Alkanes
Table 06 Yields for the preparation of `em!bromochloro alkanes from ketones[
R1 R2
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ R0 R1 Yield
")# *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Me Me 64 Me Et 74 Et Et 89 Me But 69 *ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
(242) CONH2Cl BrClBr2, NaOH
3[90[6[1[0 Chloroiodo alkanes from halo alkanes
Replacement of one chlorine of a `em!dichloro alkane by iodine can be e.ciently performed using sodium iodide in DMF as the solvent of choice "Equation "132## ð60BCJ1753\ 62CI"L#220[ The substitution of the bromine of a bromochloro alkane by an iodine has been accomplished with the iodide form of Amberlyst A!15 resin "prepared from the chloride form and methyl iodide# in excellent yield "Equation "133## ð77JOC0220[
(243)Cl Cl I Cl NaI, DMF
83%
3[90[6[1[1 Chloroiodo alkanes from halo alkenes
As with other mixed `em!dihalo alkanes additions to halo alkenes is a useful method of prep! aration of chloroiodo alkanes[ The addition to chloro alkenes of hydrogen iodide is exempli_ed by Equation "134# ð23JA601\ of ICl by Equation "135# ð12JCS465\ 16JCS427 and of IF by Equation "136# ð50JA1272[
(245)Cl Cl
I HI
(246) ICl
3[90[6[1[2 Chloroiodo alkanes from ketones
The reaction of `em!chloronitroso alkanes "prepared from ketones as shown in Table 06# and iodine with UV irradiation has the potential to be a useful route to chloroiodo alkanes "Equation "137# ð65TL832#[
I2, hν
R1 R2
3[90[6[1[3 Chloroiodo alkanes from carboxylic acids
Treatment of a!chloro carboxylic acids with lead tetraacetate and iodine gives a poor yield of iodo decarboxylated products "Equation "138# ð55JOC0746#[
(249) Pb(OAc)4, I2
3[90[7 BROMOIODO ALKANES*R1CBrI
There are only a few methods for the preparation of bromoiodo alkanes[ These include the substitution of one bromine of a `em!dibromo alkane for an iodine "Equation "149## ð60BCJ1753\ 62CI"L#220 and iodo decarboxylation of an a!bromo carboxylic acid "Equation "140## ð55JOC0746[
(250)Br Br I Br NaI, DMF
84%
All Rights Reserved# Copyright 1995, Elsevier Ltd. Comprehensive Organic Functional Group Transformations
4.02 Functions Incorporating a Halogen and a Chalcogen NIALL W. A. GERAGHTY University College Galway, Republic of Ireland
3[91[0 HALOGEN AND OXYGEN DERIVATIVES\ R0 1CHal"OR1# 30
3[91[0[0 a!Halo Alcohols "Geminal Halohydrins#\ R1CHal"OH# 30 3[91[0[1 a!Halo Ethers\ R0
1CHal"OR1# 32 3[91[0[1[0 a!Fluoro ethers\ R0
1CF"OR1# 33 3[91[0[1[1 a!Chloro ethers\ R0
1CCl"OR1# 35 3[91[0[1[2 a!Bromo ethers\ R0
1CBr"OR1# 49 3[91[0[1[3 a!Iodo ethers\ R0
1CI"OR1# 40 3[91[0[2 Other Derivatives of a!Halo Alcohols "Geminal Halohydrins#\ R0
1CHal"OR1# and R1CHal"OX# 40 3[91[0[2[0 a!Haloalkyl esters\ R0
1CHalOCOR1 40 3[91[0[2[1 a!Haloalkyl haloformates "R1CHalOCOHal# and carbonate derivatives
"R0 1CHalOCOOR1# etc[ 47
3[91[1 HALOGEN AND SULFUR DERIVATIVES\ R0 1CHal"SR1#\ etc[ 50
3[91[1[0 Dicoordinate a!Halo Sulfur Derivatives\ R0 1CHal"SR1#\ etc[ 50
3[91[1[0[0 a!Halo sul_des\ R0 1CHal"SR1# 50
3[91[1[0[1 Other dicoordinate a!halo sulfur derivatives\ R1CHal"SX# 60 3[91[1[1 Tricoordinate a!Halo Sulfur Derivatives\ R0
1CHalS"O#R1\ etc[ 62 3[91[1[1[0 a!Halo sulfoxides\ R0
1CHalS"O#R1 62 3[91[1[1[1 Other tricoordinate a!halo sulfur derivatives\ R1CHalS"O#X 67
3[91[1[2 Tetracoordinate a!Halo Sulfur Derivatives\ R0 1CHalS"O#1R
1\ etc[ 68 3[91[1[2[0 a!Halo sulfones\ R0
1CHalS"O#1R 1 68
3[91[1[2[1 Other tetracoordinate a!halo sulfur derivatives\ R1CHalS"O#1X 74
3[91[2 HALOGEN AND SELENIUM AND TELLURIUM DERIVATIVES\ R0 1CHal"SeR1# AND
R0 1CHal"TeR1#\ etc[ 76
3[91[2[0 a!Halo Selenium Derivatives\ R0 1CHal"SeR1#\ etc[ 76
3[91[2[0[0 Dicoordinate a!halo selenium derivatives\ R0 1CHal"SeR1# 76
3[91[2[0[1 Tri! and tetracoordinate a!halo selenium derivatives\ R0 1CHalSe"O#R1\
R0 1CHalSe"O#1R
1\ etc[ 81 3[91[2[1 a!Halo Tellurium Derivatives\ R0
1CHal"TeR1#\ etc[ 82 3[91[2[1[0 Dicoordinate a!halo tellurium derivatives\ R0
1CHal"TeR1# 82 3[91[2[1[1 Tri! and tetracoordinate a!halo tellurium derivatives\ R0
1CHalTe"O#R1 and R0
3[91[0 HALOGEN AND OXYGEN DERIVATIVES\ R0 1CHal"OR1#
3[91[0[0 a!Halo Alcohols "Geminal Halohydrins#\ R1CHal"OH#
a!Halo alcohols in general are unstable relative to mixtures of the appropriate hydrogen halide and aldehyde or ketone "Equation "0##^ despite this\ the simpler a!halo alcohols in particular have been the subject of considerable interest\ much of it theoretical[ The early work in this area has been reviewed ðB!53MI 391!90 and the status of ~uoro! and chloromethanol has been summarised
30
31 A Halo`en and a Chalco`en
ð70JOC460[ Some a!~uoro alcohols are relatively stable in ionic form] thus the protonated form of ~uoromethanol has been obtained in HF:SbF4:SOCl1F at −67>C "Scheme 0# ð60JA670\ although it was concluded that the free alcohol is unstable relative to HF and formaldehyde\ and the a! ~uoroalkoxy anion "0# is stable at room temperature as its tris"dimethylamino#sulfonium salt ð74JA3454[
O + HX
(1)
Evidence for the protonated form of chloromethanol has been obtained at −79>C in FSO2H:SbF4:SO1 "Scheme 1#^ attempts to obtain the protonated form of higher homologues failed ð64JA1182[ More recently evidence has been obtained for the photochemical\ gas!phase chlorination of methanol\ under which conditions the chloromethanol formed undergoes a rapid decay to HCl and formaldehyde\ its lifetime being only some minutes ð82JPC0465[
H H
Scheme 2
Substantial NMR evidence con_rms the formation of the a!bromo alcohol "1# by the reaction of HBr with 0\0\0!tri~uoropentane!1\3!dione in dibromodi~uoromethane at temperatures below −12>C "Equation "1##^ the reaction of 0\0\0!tri~uoroacetone with HBr under the same conditions leads to the formation of the a!bromo alcohol "2# ð77JCS"P1#0096[ Similar but somewhat less substantial evidence has also been provided for the formation of a!bromo alcohols in the reactions of acetaldehyde\ 1!methylpropanal and 1\1!dimethylpropanal with HBr in dibromodi~uoromethane ð71JCS"P1#770[ All of these bromo alcohols are unstable at room temperature\ decomposing to a mixture of HBr and aldehyde or ketone[
F3C
OO
F3C
F3C
(3)
IR evidence alone has been adduced to support the formation of the a!bromo alcohol "4# from levoglucosenone "3# "Scheme 2# ð70CAR173\ and no evidence is provided to support the formation of the a!bromocyclopropanol "5# "Equation "2## ð63TL898[ The formation of iodomethanol in the photochemical reaction between ozone and iodomethane\ in an argon matrix at 06 K\ has been reported ð74IC2174\ as has 0H NMR evidence for the formation under basic conditions of the
32Halo`en and Oxy`en
a!iodo alcohols "7# and "8# from the 3\3!diiodo!0\0!dimethyl!0\3!dihydroquinolinium cation "6# "Equation "3## ð63CJC840[
O
+ NaOH
(4)I–
There are\ however\ a few a!halo alcohols which are stable[ The chlorination of the 1!hydroxy! 0\2!diketones "09# and "00# with sulfuryl chloride gives the a!chloro alcohols "01# and "02#\ respec! tively\ which function as masked cyclohexane!0\1\2!triones "Equation "4## ð70CB0840[ a!Halocyclo! butanols "03# are formed in good yield when per~uorocyclobutanone reacts with hydrogen halides "Equation "5## ð50JA3569^ these compounds are stable in the absence of water but revert to a mixture of the ketone and hydrogen halide when heated[ Neither ring strain nor per~uorination alone is su.cient to account for the stability of these materials\ as neither cyclobutanone nor per~uoro! acetone gives isolable a!halo alcohols under these conditions[
OO Cl OH
(12) R = Me, 66% (13) R, R = (CH2)5, 68%
F F
OH
X = F, 75% X = Cl, 73–90% X = Br, 73–90% X = I, 73–90%
(14)
3[91[0[1 a!Halo Ethers\ R0 1CHal"OR1#
The synthetic utility of a!halo ethers "geminal halohydrin ethers# is partly due to their reactivity^ however\ this property in some cases results in limited thermal stability\ a susceptibility to hydrolysis and poor storage properties[ A number of a!halo ethers are lachrymatory[
33 A Halo`en and a Chalco`en
3[91[0[1[0 a!Fluoro ethers\ R0 1CF"OR1#
An early report of the synthesis and properties of a!~uoro ethers concluded that they are inherently unstable\ being very susceptible to hydrolysis\ unless they contain a CF2 or a CF1 group in the b position ð49JA3267[ Although a number of a!~uoro ethers have been characterised which do not possess such a structural feature\ the conclusion does re~ect the situation in general[ Spectroscopic evidence for the formation of bis"~uoromethyl# ether in HF:SO1ClF at −67>C has been obtained ð60JA670\ although its preparation by the reaction of formaldehyde with hydro~uoric acid in a two!phase system has also recently been claimed ð83MIP8211154[ The potentially useful physical properties of per~uoro ethers ð70JCS"P0#0210 has led to considerable interest in their synthesis and\ of those prepared\ a number contain the "RF#1CFORF grouping\ where RF is a per~uoroalkyl group^ the work has also led\ incidentally\ to the isolation of some hydro~uoro ethers whose physical properties\ however\ are less interesting[ The reactions of polypropylene oxide "Equation "6## and paraformaldehyde "Equation "7## with ~uorine lead to the formation of a number of these compounds\ which were isolated by preparative GC of the volatile products in relatively small amounts ð70JCS"P0#0210[ Similar per~uorinated ethers have been obtained by the nucleophilic displacement of ~uorosulfate from per~uoroallyl ~uorosulfate by per~uoroalkoxide anions "Scheme 3# ð70JA4487[ The direct ~uorination of a number of monomeric a!s!alkyl and phenyl ethers also leads to the formation of monomeric a!~uoro ethers\ the products again being isolated by preparative GC "Scheme 4# ð77JOC67[
O
CF3 F3C
F F
Scheme 5
Addition reactions in which one of the addends contains ~uorine have been used to synthesise a! ~uoro ethers[ Thus\ acetyl hypo~uorite undergoes 0\1!addition to the aromatic ring of piperonal and related molecules\ over!reaction being controlled by restricting the conversion to low levels "Equation "8## ð73JOC795[ The Prins addition of formaldehyde to tetra~uoroethene in hydrogen ~uoride gives "05# as the major product\ together with some of the alcohol "06# which is formed from "05# by hydrolysis^ the reaction is believed to involve bis"~uoromethyl# ether "04# as an intermediate "Scheme 5# ð52JOC383[
34Halo`en and Oxy`en
OHC O
Scheme 6
Although the selective introduction of a ~uorine atom into an organic molecule is di.cult\ a number of a!~uoro ethers have been synthesised in this way[ Glycosyl ~uorides\ for example\ which are useful in building ~uorine!containing carbohydrates\ have been prepared from phenyl thioglycosides using DAST "diethylaminosulfur tri~uoride#:NBS or HF =pyridine:NBS "Equation "09## ð73JA3078\ the reactions proceeding with retention of con_guration^ the use of the HF =py! ridine:NBS system is reported to be compatible with most of the functional groups found in carbohydrates ð73JA3078[ Glycosyl ~uorides have also been prepared from substrates which contain a free ð73CL0640 or acetylated ð73CL0636 hydroxyl in the 0!position with HF =pyridine complex "Equation "00##[
O SPh
O OAcO
O F
O OAcO
HF•pyridine
NBS (10)
OHF•pyridine
OBn
BzO
OH
Xenon di~uoride converts benzyl alcohol\ and benzyl alcohols containing electron!withdrawing groups\ into ~uoromethyl aryl ethers "Equation "01## ð82TL3244^ the reaction becomes less con! trolled when electron!donating groups are introduced\ producing a complex mixture from which only 19) of the ~uoromethyl ether could be isolated in the case of a methyl substituent\ and no a!~uoro ether with substituents such as OH\ OR or NHR[ The reaction also failed with diphenyl! methanol and 1!phenyl!1!propanol\ both of which give largely dimeric products[ Selective mono! ~uorination of the ether "07# was achieved using bromine tri~uoride in a synthesis of the partially deuteriated anaesthetic sevo~urane "08# "Equation "02## ð82MI 391!90[
OH
F3C O CD3
BrF3 (13)
The chemistry of ~uorinated epoxides has been reviewed ð60FCR66[ a!Fluoro epoxides have been prepared in the usual way by the reaction of ~uorinated alkenes with sodium hypobromite "Equation "03## ðB!81MI 391!90^ the vanadyl acetylacetonate!catalysed reaction of t!butyl hydroperoxide "tbhp# with 1\2!di~uoroallylic alcohols is reported to proceed with good diastereoselectivity for the "Z# isomer "19# "Equation "04## ð82JFC"52#046[ The development of the chemistry of hexa~uorobenzene has led to the isolation and characterisation of a number of structurally unusual a!~uoro epoxides[
35 A Halo`en and a Chalco`en
Thus\ the diene "10#\ obtained from hexa~uorobenzene\ reacts with tri~uoroperacetic acid to give the epoxide "11#\ which was subsequently converted into hexa~uorobenzene oxide "12# "Scheme 6# ð89JA5604[ The diene "13# was converted into the monoepoxide "14# with tri~uoroperacetic acid\ the stereochemistry of the epoxide being assigned on steric grounds "Equation "05## ð78JOC4419[ Dewar hexa~uorobenzene reacts with bis"~uoroxy#di~uoromethane under photochemical con! ditions to give small amounts of the a!~uoro epoxides "15# and "16#\ the latter rearranging thermally to the a!~uoro acetal "17# "Scheme 7# ð68JOC1702[ Hexa~uorobenzene also reacts photochemically in the vapour phase with oxygen to give a low yield of the unsaturated a!~uoro epoxide "18#\ which undergoes addition reactions with halogens\ and cycloaddition reactions with dienes and 0\2!dipoles\ to give a series of other a!~uoro epoxides "Equation "06## ð79CC047[
F3C CF3
O
3[91[0[1[1 a!Chloro ethers\ R0 1CCl"OR1#
Methods for the synthesis of a!chloro ethers have been reviewed ð44CRV290 and a general account of their synthetic utility is available ð53ZC390[ Many synthetic routes to one of the most potentially
36Halo`en and Oxy`en
useful a!chloro ether