Comprehensive Organic Functional Group Transformations, Volume 2 Elsevier, 2003 Editors-in-Chief: Alan R. Katritzky, Otho Meth-Cohn, and Charles W. Rees Synthesis: Carbon with One Heteroatom Attached by a Single Bond. Part I: Functions Linked by a Single Bond to an sp3 Carbon Atom
2.01 Alkyl Halides, Pages 1-36, Peter L. Spargo 2.02 Alkyl Chalcogenides: Oxygen-based Functional Groups, Pages 37-112, Joseph B. Sweeney 2.03 Alkyl Chalcogenides: Sulfur-based Functional Groups, Pages 113-275, Philip C. Bulman Page, Robin D. Wilkes and Dominic Reynolds 2.04 Alkyl Chalcogenides: Selenium- and Tellurium-based Functional Groups, Pages 277-295, Tadashi Kataoka and Mitsuhiro Yoshimatsu 2.05 Alkylnitrogen Compounds: Amines and their Salts, Pages 297-332, C. M. Marson and A. D. Hobson 2.06 Alkylnitrogen Compounds: Compounds with N---Halogen, N---O, N---S, N---Se and N---Te Functional Groups, Pages 333-370, W. Russell Bowman and Robert J. Marmon 2.07 Alkylnitrogen Compounds: Compounds with N---N, N---P, N---As, N---Sb, N---Bi, N---Si, N---Ge, N---B and N---Metal Functional Groups, Pages 371-423, Patrick R. Huddleston and Ian G. C. Coutts 2.08 Alkylphosphorus Compounds, Pages 425-477, John C. Tebby, Daniel G. Genov and John W. Wheeler 2.09 Alkylarsenic, -antimony, and -bismuth Compounds, Pages 479-512, Mei-Xiang Wang 2.10 Alkylboron and -silicon Compounds, Pages 513-547, Martin Wills and Ernest W. Colvin by kmno4
2.11 Alkyl Metals, Pages 549-603, Steven V. Ley and Cyrille Kouklovsky
Part II: Functions Linked by a Single Bond to an sp2 Carbon Atom
2.12 Vinyl and Aryl Halides, Pages 605-633, Christopher J. Urch 2.13 Alkenyl and Aryl Chalcogenides: Oxygen-based Functional Groups, Pages 635-703, Charles K. -F. Chiu 2.14 Vinyl and Aryl Chalcogenides: Sulfur-, Selenium- and Tellurium-based Functional Groups, Pages 705-736, Paul C. Taylor 2.15 Vinyl- and Arylnitrogen Compounds, Pages 737-817, Gilles Sauvé and Vanga S. Rao 2.16 Vinyl- and Arylphosphorus Derivatives, Pages 819-870, Toru Minami and Kentaro Okuma 2.17 Vinyl- and Arylarsenic, -antimony and -bismuth Compounds, Pages 871-897, Roger W. Read 2.18 Vinyl- and Arylsilicon, -germanium, and Boron Compounds, Pages 899-950, Làszlò Hevesi 2.19 Vinyl- and Arylmetals, Pages 951-995, Ei-Ichi Negishi and Daniele Choueiry 2.20 Stabilized Substituted Ions and Radicals Bearing One Heteroatom (R1R2C−X, R1R2C+X, R1R2C·X), Pages 997-1010, Stephen D. Lindell
Part III: Functions Linked by a Single Bond to an sp Carbon Atom
2.21 Alkynyl Halides and Chalcogenides, Pages 1011-1038, Peter J. Stang and Viktor V. Zhdankin 2.22 Alkynylnitrogen and -phosphorus Compounds, Pages 1039-1074, Kevin I. Booker-Milburn 2.23 Alkynylarsenic, -antimony, -bismuth, -boron, -silicon, -germanium and -metal Compounds, Pages 1075-1102, William Kitching and Klaus Kwetkat 2.24 References to Volume 2, Pages 1103-1295
by kmno4
2.01 Alkyl Halides PETER L. SPARGO Pfizer Central Research, Sandwich, UK
1[90[0 GENERAL METHODS FOR ALKYL HALIDES 1
1[90[0[0 Alkyl Halides from Alkanes 1 1[90[0[1 Alkyl Halides from Alkenes 2
1[90[0[1[0 Alkyl halides by hydrohalo`enation of alkenes 3 1[90[0[1[1 Alkyl halides by halo`enÐhalo`en addition to alkenes 4
1[90[0[2 Alkyl Halides from Alkyl Halides 4 1[90[0[3 Alkyl Halides from Alcohols and their Derivatives 4
1[90[0[3[0 Alkyl halides directly from alcohols 5 1[90[0[3[1 Alkyl halides from alcohols via sulfonates 8 1[90[0[3[2 Alkyl halides from ethers 09 1[90[0[3[3 Rearran`ement of cyclopropyl carbinols 00
1[90[0[4 Alkyl Halides from Amines and their Derivatives 00 1[90[0[5 Alkyl Halides by Halodecarboxylation of Carboxylic Acids and their Derivatives 01 1[90[0[6 Alkyl Halides by Haloalkylation of Arenes 02 1[90[0[7 Alkyl Halides by Miscellaneous Methods 03
1[90[1 ALKYL FLUORIDES] RF 04
1[90[1[0 Alkyl Fluorides from Alkanes 04 1[90[1[1 Alkyl Fluorides from Alkenes 06
1[90[1[1[0 Alkyl ~uorides by hydro~uorination of alkenes 06 1[90[1[1[1 Alkyl ~uorides by ~uorineÐhalo`en addition to alkenes "F0F\ F0Cl\ F0Br\ F0I# 06
1[90[1[2 Alkyl Fluorides from Alkyl Halides 07 1[90[1[3 Alkyl Fluorides from Alcohols and their Derivatives 08 1[90[1[4 Alkyl Fluorides from Amines and their Derivatives 19 1[90[1[5 Alkyl Fluorides by Fluorodecarboxylation of Carboxylic Acids and their Derivatives 19 1[90[1[6 Alkyl Fluorides by Fluoroalkylation of Aromatic Rin`s 19
1[90[2 ALKYL CHLORIDES] RCl 19
1[90[2[0 Alkyl Chlorides from Alkanes 19 1[90[2[1 Alkyl Chlorides from Alkenes 12
1[90[2[1[0 Alkyl chlorides by hydrochlorination of alkenes 12 1[90[2[1[1 Alkyl chlorides by chlorineÐhalo`en addition to alkenes "Cl0Cl\ Cl0Br\ Cl0I# 12
1[90[2[2 Alkyl Chlorides from Alkyl Halides 14 1[90[2[3 Alkyl Chlorides from Alcohols and their Derivatives 14 1[90[2[4 Alkyl Chlorides from Amines and their Derivatives 16 1[90[2[5 Alkyl Chlorides by Chlorodecarboxylation of Carboxylic Acids and their Derivatives 16 1[90[2[6 Alkyl Chlorides by Chloroalkylation of Arenes 16
1[90[3 ALKYL BROMIDES] RBr 16
1[90[3[0 Alkyl Bromides from Alkanes 16 1[90[3[1 Alkyl Bromides from Alkenes 18
1[90[3[1[0 Alkyl bromides by hydrobromination of alkenes 18 1[90[3[1[1 Alkyl bromides by bromineÐhalo`en addition to alkenes "Br0Br\ Br0I# 29
1[90[3[2 Alkyl Bromides from Alkyl Halides 20 1[90[3[3 Alkyl Bromides from Alcohols and their Derivatives 20 1[90[3[4 Alkyl Bromides from Amines and their Derivatives 22 1[90[3[5 Alkyl Bromides by Bromodecarboxylation of Carboxylic Acids and their Derivatives 22 1[90[3[6 Alkyl Bromides by Bromoalkylation of Arenes 22
1[90[4 ALKYL IODIDES] RI 22
0
1 Alkyl Halides
1[90[4[0 Alkyl Iodides from Alkanes 22 1[90[4[1 Alkyl Iodides from Alkenes 23
1[90[4[1[0 Alkyl iodides by hydroiodination of alkenes 23 1[90[4[1[1 Alkyl iodides by iodineÐiodine addition to alkenes 24
1[90[4[2 Alkyl Iodides from Alkyl Halides 24 1[90[4[3 Alkyl Iodides from Alcohols and their Derivatives 24 1[90[4[4 Alkyl Iodides from Amines and their Derivatives 25 1[90[4[5 Alkyl Iodides by Iododecarboxylation of Carboxylic Acids and their Derivatives 25 1[90[4[6 Alkyl Iodides by Iodoalkylation of Arenes 25
1[90[0 GENERAL METHODS FOR ALKYL HALIDES
The chemistry and preparation of halogen!containing compounds have been reviewed in Houben! Weyl ð59HOU"4:3#0\ 51HOU"4:2#0\ in Comprehensive Or`anic Chemistry ð68COC"0#382\ and in an excellent review by Hudlicky and Hudlicky in The Chemistry of Functional Groups series ðB!72MI 190!90[ The latter review includes some useful {Halogenation Tables| "reproduced from an earlier publication ð67OPP070 which correlate starting materials\ halogenating agents and products in such a way that the reader can quickly identify generally useful methods\ as well as the compatibility of functional groups with halogenating agents[ A review in Comprehensive Or`anic Synthesis ð80COS"5#192 provides an account of nucleophilic halogenation methods\ while the synthesis and reactivity of a!halogenated ketones\ aldehydes and imines is the subject of an update volume of the Patai series ðB!77MI 190!90[ Many classical methods for the synthesis of alkyl halides are still widely used\ and the Houben!Weyl volumes ð59HOU"4:3#0\ 51HOU"4:2#0\ despite their age\ provide detailed procedures and numerous tables from which much useful information may be gleaned[ Literature procedures up to and including 0876 have been clearly tabulated in easily accessible form in Larock|s Comprehensive Or`anic Transformations ðB!78MI 190!90[ In addition\ an annual review of the synthesis of organic halides can be found in the new journal Contemporary Or`anic Synthesis ð83MI 190!90[
It would be impossible here to provide a truly comprehensive review of alkyl halide synthesis\ so coverage has been restricted primarily to those methods which would appear to have the greatest general synthetic utility[ Mechanistic details have necessarily been kept to a minimum and are only discussed where they have a direct bearing on regio!\ stereo! or chemoselectivity[ Brief mention of some less well used methods is also made[
Because of the large di}erences in reactivity of ~uorides\ chlorides\ bromides and iodides\ there are very few methods which are generally applicable to all four halogens[ In particular\ the unique properties of ~uorine mean that special methods have had to be developed for this halogen "Section 1[90[1#[ Alkyl chlorides and bromides are synthetically the most widely used alkyl halides and their chemistry is often closely related "Sections 1[90[2 and 1[90[3#[ Although alkyl iodides are often prepared using methods similar to those used to prepare alkyl bromides\ they are much less common synthetic targets or intermediates "Section 1[90[4#[
In this section a range of general synthetic approaches to alkyl halides is described[ Certain transformations are discussed in detail in this section\ while others are expanded in the later sections speci_c to each halogen[ The reader is therefore encouraged to consult the relevant subsection within each of the _ve sections in this chapter for a balanced coverage[
1[90[0[0 Alkyl Halides from Alkanes
Direct halogenation of unactivated alkanes with elemental halogen\ often in the presence of visible or ultraviolet light ðsee reviews B!58MI 190!90\ B!58MI 190!91\ B!62MI 190!91\ B!62MI 190!92\ is generally indiscriminate and therefore not preparatively useful\ except in cases where symmetry dictates that all of the replaceable hydrogens are equivalent "e[g[\ cyclohexane\ ethane#[ There are scattered reports of halogenations of unactivated hydrocarbons with a variety of di}erent reagents ðB!78MI 190!90\ but yields are often low\ and none of the methods appears general[ The most recent work in this area has been by Barton et al[ in the early 0889s\ and their chemistry\ which can be used to prepare chlorides\ bromides and iodides "but not ~uorides#\ is exempli_ed by Equation "0# ð81T8084\ 81TL2302\ 82TL0760\ 82TL4578\ 83T20[ For a short review on this and related chemistry see ð81ACR493[
2General Methods
Fe(III)/pyridine/AcOH (1)
polyhaloalkane = CCl4, CBr4, CBrCl3, CBr2Cl2, etc. M = Li, Na Hal = Cl, Br, I
While the existence of radical intermediates in the processes above has been the source of some dispute ð83TL0316\ 83TL0320\ the radical nature of halogenation at allylic and benzylic sites is universally accepted ðB!61MI 190!90[ The latter reaction is most commonly applied in the synthesis of allylic and benzylic bromides using N!bromosuccinimide "the WohlÐZiegler reaction# "Section 1[90[3[0#[
Alkane activation by an electron!withdrawing group greatly widens the scope of reagents and reaction conditions for halogenation\ since ionic mechanisms may then operate[ Aldehydes and ketones "often in an enol form such as silyl enol ether or an enol acetate# can be halogenated in the a!position with a variety of reagents\ including elemental ~uorine\ chlorine\ bromine and iodine "Scheme 0#[ The most di.cult of these is ~uorination\ but a range of useful procedures have been devised to overcome this problem "Section 1[90[1[0#[
O
R1
R2
O
R1
R2
OR3
R1
R2
Scheme 1
As a general rule\ clean monohalogenation "with minimal dihalogenated by!product formation# is more easily achieved under acidic rather than basic conditions\ although there are nevertheless many examples of the latter[ For unsymmetrical ketones\ halogenation under acidic conditions generally occurs at the more substituted a!carbon\ because the reaction proceeds under thermo! dynamic control through the more stable enol tautomer[
Halide ions can also be used to a!halogenate carbonyl compounds and their enol derivatives in the presence of a suitable oxidant such as lead tetraacetate ð71S0910\ benzoyl peroxide\ hydrogen peroxide or mcpba ð65CPB719[ a!Chloro!\ bromo! and iodocarbonyl compounds have all been prepared using these methods[ For a detailed review of the preparation of a!halo aldehydes\ ketones and imines\ see ðB!77MI 190!90[ Ketals have been brominated and occasionally chlorinated "but apparently not ~uorinated or iodinated# at the b!carbon\ probably via transient enolic intermediates "Section 1[90[3[0#[ Carboxylic esters\ amides and acids are also straightforwardly a!halogenated\ as are nitriles ð37JA054[ Thionyl chloride converts acid chlorides to a!chloro!\ a!bromo! or a!iodoacid chlorides when combined with NCS\ NBS or iodine respectively ð64JOC2319[ A surprisingly little! used alternative approach to a!haloketones exploits the reactivity of the active methylene group in b!ketoesters or malonates by halogenation with NBS\ NCS\ SO1Cl1 or Br1\ followed by hydrolysis and decarboxylation "Scheme 1# ð72TL052\ 76S077 or deacetylation ð38JA2096\ 61TL3956\ 76TL4494[ A related method for preparing a!~uoroketones has also been described ð78CL466[
Scheme 2
1[90[0[1 Alkyl Halides from Alkenes
A wide variety of 1!functionalised alkyl halides can be prepared by addition of Hal0Y "YO\ N\ S\ Se\ etc[# to alkenes ð82S0066[ In accordance with the {rule of latest placement| applied to the organisation of this publication\ most of these are covered in later chapters[ In this chapter the discussion focuses on the addition of halogenÐhydrogen and halogenÐhalogen only[
3 Alkyl Halides
1[90[0[1[0 Alkyl halides by hydrohalogenation of alkenes
The direct addition of HHal "HalF\ Cl\ Br\ I# to alkenes is not a particularly widely used synthetic approach to alkyl halides\ and there are a number of reasons for this[ Among these is the fact that mixtures of regioisomers and rearranged products are often obtained "see reviews ð39CRV240\ 51CRV488 and hydrobromination ð52OR"02#049\ B!66MI 190!90\ 80COS"3#158#[ Commonly\ the reaction proceeds through an ionic mechanism via the more stable of the two possible carbocation intermediates to give the Markovnikov product as indicated in Scheme 2 for a terminal alkene[
Scheme 3
HH
A general method for Markovnikov addition of HHal "HalCl\ Br\ I# to alkenes using phase! transfer catalysis has been reported ð79JOC2416 and a polymer!supported phase transfer catalyst can be conveniently used for this purpose ð77IJC"B#0018[ It has also been shown that Markovnikov hydrohalogenation can be facilitated by performing the reaction in the presence of an inorganic support such as silica or alumina[ Furthermore\ under these latter conditions there is no need to use HHal itself\ since it can be generated in situ from species such as SOCl1\ "COCl#1\ TMS!Cl\ TMS!Br\ TMS!I or PI2 ð89JA6322\ 82JA2960[ Hydrohalogenation of alkenes bearing an electron! withdrawing group gives the b!halogenated product exclusively\ as expected on electronic grounds[ Anti!Markovnikov addition to alkenes is often observed in hydrobromination with HBr\ and suggests a free!radical or four!centre addition mechanism[ Indeed\ if Markovnikov addition of HBr is required\ it is often necessary to take precautions to exclude peroxides or to add free radical inhibitors ð39CRV240[
Anti!Markovnikov addition of HCl\ HBr or HI is generally achieved via hydrometallation\ usually hydroboration ð70JCR"S#265\ 70JOC1471\ 70JOC2002\ 72HCA0907 or hydroalumination ð65JOM"011#C14\ 67CL722\ followed by treatment with an electrophilic halogen source "Scheme 3#[
Scheme 4
M = B, Al, Zr, Si L = Ligand (including carbon-bonded ligands)
Hal = Cl, Br, I
HH
The halogenolysis of organoboranes has been brie~y reviewed ð74OR"22#0\ 80COS"6#482\ as has its applications to the incorporation of radioactive halogen isotopes ð73ACR104[ BCl2 and BBr2 are recent additions to the list of reagents suitable for this purpose ð82S862[ Hydrosilylation followed by treatment with Cl1\ Br1\ I1\ NBS or copper"II# chloride or bromide also gives access to the anti! Markovnikov products ð67JA189\ 67TL0798\ 71OM244\ 71OM258[ In addition\ it has been shown that hydrozirconation of a substituted alkene leads to migration such that\ on quenching with NCS\ NBS\ iodine\ bromine or iodobenzene dichloride\ the terminal primary alkyl halide is obtained "Scheme 4\ ð63JA7004^ see also ð65AG"E#222\ 70JOC0710#[
i, Cp2Zr(H)Cl, PhH ii, I2, CCl4
91% I
Scheme 5
4General Methods
1[90[0[1[1 Alkyl halides by halogenÐhalogen addition to alkenes
The addition of two halogens "X0X or X0Y# across a double bond is a commonly used strategy in synthetic organic chemistry\ and can be achieved in a number of ways[ In most cases\ the addition proceeds by the ionic mechanism depicted in Scheme 5\ giving the product of Markovnikov addition[ Although the reaction is believed to proceed via the cyclic halonium ion "0#\ the fact that there is a preference for Markovnikov addition suggests the transient intermediacy of a species such as "1#[ The regioselectivity is frequently not as high as is usually observed in hydrohalogenation ð61RCR639\ B!65MI 190!90\ B!66MI 190!90\ 70RCR040\ B!78MI 190!91\ 80COS"3#218[ For the purposes of this pres! entation\ this chemistry has been divided up according to the net addition products obtained\ i[e[\ Section 1[90[1[1[1\ F0F\ F0Cl\ F0Br\ F0I^ Section 1[90[2[1[1\ Cl0Cl\ Cl0Br\ Cl0I^ Section 1[90[3[1[1\ Br0Br\ Br0I^ Section 1[90[4[1[1\ I0I[
R2
R4
R3R1
R2
1[90[0[2 Alkyl Halides from Alkyl Halides
Nucleophilic interconversion of halides "Equation "1## is an equilibrium process\ and despite the wide range of C0Hal bond energies "C0F×C0Cl×C0Br×C0I#\ methods exist for the preparation of almost any alkyl halide from almost any other[ It is therefore quite surprising that there are almost no general methods which are genuinely applicable to all halides; For the purposes of clarity\ therefore\ each product halide is considered separately in Sections 1[90[1[2 "~uorides#\ 1[90[2[2 "chlorides#\ 1[90[3[2 "bromides# and 1[90[4[2 "iodides#[ The reader should be aware that this necessarily results in a fair degree of overlap between these sections[
RHal1 RHal2 MHal2
(2)
1[90[0[3 Alkyl Halides from Alcohols and their Derivatives
Alcohols and their derivatives are by far the most widely used precursors to alkyl halides\ and a vast array of procedures for this transformation can be found in the literature[ Hydroxide ion is a poor leaving group and cannot be directly displaced with halide ion[ However\ activation "either in situ or in discrete steps# by protonation\ sulfonation\ or by formation of an oxyphosphonium intermediate\ allows easy access to all four halides[ If a stable carbocation can be formed on loss of the oxygen!containing functionality\ the reaction may proceed in an SN0 fashion with no stereocontrol "Scheme 6#[
OH
(retention) (inversion)
Scheme 7
More commonly\ the reaction proceeds via an SN1 mechanism with inversion of con_guration at carbon "vide infra#[ In situ product epimerisation by SN1 halide exchange can sometimes be a problem with the more nucleophilic halides\ iodide and bromide\ but is rarely seen with chloride[
5 Alkyl Halides
The conversion of alcohols to alkyl halides has been discussed in sections of wider reviews ð59HOU"4:3#0\ 51HOU"4:2#0\ B!60MI 190!90\ 79T0890\ B!72MI 190!90\ 80COS"5#192\ and extensive tabulations of reagents covering the literature up to 0876 can be found in Larock|s compilation of references ðB!78MI 190!90[ The use of oxyphosphonium intermediates for this transformation has been thoroughly reviewed ð72OR"18#0\ as has the synthesis of optically active alkyl halides from opti! cally active alcohols ð58S001\ although the latter was at a time when meaningful and reliable methods for measuring enantiomeric purity were not available[
Space restrictions mean that priority has been given to the more widely applied procedures\ together with those which\ at the time of writing\ have yet to be covered in review publications[
1[90[0[3[0 Alkyl halides directly from alcohols
Alcohols can be converted to alkyl halides by treatment with hydrogen halide HX under a variety of conditions[ The reaction is rapid for alcohols which form a stable carbocation on protonation and loss of water "e[g[\ tertiary or benzylic#\ but side reactions such as elimination to alkenes or rearrangement of the carbon skeleton to a more stable carbocation are quite common[ Not surpris! ingly\ the stereochemical integrity of the carbon centre is often lost under these conditions "Scheme 6#[
The high reactivity and corrosiveness of hydrogen ~uoride means that it is rarely used in this context[ Much more useful "at least for secondary and tertiary alkyl ~uorides# is a combination of HF with organic bases ð62S675\ 80T4218\ particularly Olah|s pyridine poly"hydrogen ~uoride# reagent "PPHF#\ either in solution or in a poly"vinylpyridine#!polymer!supported form "PVPHF# ð89SL156\ 82S582[ Indeed\ by incorporating NaCl\ NH3Br or KI in the reaction mixture\ it is possible to use Olah|s reagent to prepare the corresponding alkyl chlorides\ bromides and iodides from an extremely wide range of alcohols\ including neopentyl systems ð63S542\ 68JOC2761[ This is one of the few procedures useful for the preparation of all four halogens from alcohols[
Inorganic acid halides such as SOCl1\ POCl2\ PCl4 and PBr2 can often be used to overcome some of the side reactions associated with the use of hydrogen halides[ Discussion of chloride synthesis using phosphorus chlorides and SOCl1 can be found in Section 1[90[2[3\ while bromide and iodide synthesis using phosphorus halides is covered in Sections 1[90[3[3 and 1[90[4[3[ While these reagents are of fairly wide applicability\ they are still quite aggressive\ and a wide range of alternative phosphorus!based reagent systems has been developed ð72OR"18#0[ Many of these are applicable to more than one halogen\ and are discussed in this section[
Triphenylphosphine and diethyl azodicarboxylate "dead# can be used to activate alcohols towards nucleophilic attack of halide ion\ as outlined in Equation "2# and Scheme 7[ This is a Mitsunobu! like procedure ð70S0\ 81OR"31#224[ Using zinc"II# halide as halide source\ chlorides\ bromides and iodides can be prepared with clean inversion of con_guration ð73JOC2916\ 89SC2928\ while the use of LiF can also give access to ~uorides ð74SC552[ A mild variation of this procedure\ suitable for use with sensitive substrates\ uses amine hydrohalide salts such as pyridine hydrochloride and hydrobromide instead of metal halides ð74G282[ Alternatives to dead include the more stable diisopropyl azodicarboxylate "diad# ð89SC2928 and the cyclic diazodicarboxylate "2#\ which is used in combination with PPh2 and MeI or MeBr ð73BCJ1564[ A driving force in all of these reactions\ and related reactions described below\ is the formation of the strong phosphorusÐoxygen double bond[
OH
Hal = Cl, Br, I
Adducts of triphenylphosphine with elemental halogen\ Ph2PHal1\ either commercially available or prepared in situ\ can be used to convert alcohols cleanly with inversion to ~uorides ð57CPB0998\ chlorides\ bromides and iodides "Equation "3## ð53JA853[
OH
Hal = F, Cl, Br, I
While Ph2PBr1 usually gives the best results ð54JOC1524\ 62OSC"4#138\ 73JOC320\ 81SC1834\ it has been found that the addition of imidazole to Ph2PCl1 ð73S057 or Ph2PI1 ð68CC867\ 89SC0362 or\ alternatively\ the use of triiodoimidazole instead of iodine ð68CC867\ 79JCS"P0#1755\ 71JCS"P0#570\ all lead to signi_cantly improved yields[ Other phosphines such as Bu2P ð71AJC406\ Ph1PCH1CH1PPh1
ð76TL656 or a triaryl phosphite "ArO#2P ð81CL0494 have proved advantageous in certain cir! cumstances[ The use of a polymer!supported triphenylphosphine dibromide ð73JCS"P0#084 greatly facilitates the reaction workup\ since the phosphine oxide by!product is simply removed by _ltration[ Alternatively\ placing a dimethylamino group on one of the phenyl rings of triphenylphosphine enables removal of the phosphine oxide by!product by an aqueous acid wash ð77JOC5015[ Another practical modi_cation is the replacement of PPh2 with Ph1PCl\ which enables the phosphorus! containing by!product to be removed by an aqueous base wash ð77JOC5015[ In a logical extrap! olation of this approach\ PhPCl3 has been introduced as a new reagent for alkyl chloride synthesis from alcohols ð89JOC2304[
The combination of triphenylphosphine and carbon tetrahalide has proved to be a very powerful but mild method\ particularly for the preparation of alkyl chlorides\ once again with inversion of con_guration "Equation "4## ð62CC009\ 65CB2335\ 73S057\ 77OSC"5#523\ 80TL2866[ For reviews on this chemistry see ð64AG"E#790\ B!68MI 190!90\ 72OR"18#0[ This reagent system is particularly useful for the conversion of allylic alcohols to halides without allylic rearrangement ð61JOC0355[ As with the Ph2PHal1 method described above\ the use of a polymer!supported triphenylphosphine gives easier workups ð64CC511\ 64JOC0558\ 73JCS"P0#084\ 74CC226\ as does the use of a phosphine carrying a water!soluble pyridyl side chain ð76JOC3888[ Another alternative phosphine is tris"dimethyl! amino#phosphine\ "Me1N#2P\ which generates the water!soluble "but carcinogenic# by!product hexa! methylphosphoramide "HMPA# ð57CC0249\ 64BSF596[ CBr3 is commonly used in combination with PPh2 ð66LA795\ 76CS366\ 82JOC3271 or other phosphines ð75JOC678\ 75TL0596\ and is particularly useful for allylic\ benzylic and saturated primary alkyl systems[ CI3ÐPPh2 is less commonly used ð67CAR"50#400\ 80TL2866[
OH
Other related halide sources for triphenylphosphine!mediated conversions of alcohols to alkyl halides include a range of polyhalogenoalkanes\ such as C1Cl5\ C1Br5\ BrCCl1CCl1Br and ICH1CH1I ð72S028\ ethyl trichloroacetate and ethyl tribromoacetate ð78JOU531\ trichloroacetonitrile "which even works on neopentyl alcohols# ð78JOU476\ and hexachloroacetone\ which is most e}ective in
7 Alkyl Halides
converting allylic alcohols to allylic chlorides without rearrangement ð66TL1888\ 68JOC248\ 70JOC713\ 73JOC320[ Some of these reagents give higher!boiling by!products\ enabling low!boiling product halides to be distilled from the reaction mixture without contamination with the haloform CHHal2 by!product obtained when carbon tetrahalide is used as halogen source[ The introduction in 0882 of triphosgene as an easily handled solid form of phosgene has rekindled interest in phosgene chemistry\ and when combined with triphenylphosphine it has been shown to give excellent yields of alkyl chlorides from a wide range of alcohols ð82SC600[
Related to the above methods is the triphenylphosphine:N!halosuccinimide combination "Equa! tion "5##\ which is particularly good for selecting primary over secondary alcohols "although sec! ondary chlorides\ bromides and iodides can nevertheless all be prepared this way ð62TL2826#[ It is also particularly useful for the preparation of bromides in sensitive systems "e[g[\ ð75JOC1526\ 82OPP138[
OH
Hal = Cl, Br, I
Triphenyl phosphite P"OPh#2 has been used in combination with Cl1\ Br1 and I1 ð43JCS1170\ with NCS\ NBS and NIS ð62TL2826\ and with benzyl chloride and bromide ð42JCS1113\ but is most commonly used in combination with methyl iodide for the preparation of alkyl iodides[ The latter reagent system\ using the so!called triphenyl phosphiteÐmethiodide reagent\ "PhO#2PMeI\ converts a wide range of primary "including neopentyl#\ secondary\ tertiary\ allylic and benzylic alcohols to iodides "Equation "6## ð42JCS1113\ 77OSC"5#729\ 82TL1646[ It is particularly widely used in carbohydrate and nucleoside chemistry ð69JOC1208[
OH
(7)
An interesting and perhaps surprisingly little!used method of phosphorus activation of alcohols entails the preparation of the nicely crystalline azaphospholane intermediates "3#[ Treatment of "3# with SO1Cl1\ Br1 or MeI yields chlorides\ bromides and iodides\ respectively ð71TL3300[
N P
N
Ph
Ph
RO
(4)
Moving away from phosphorus!based activation\ a method applicable to all four halogens uses the haloenamines "4# derived from dialkylisobutyrylamides "Equation "7##[ Using these reagents\ primary\ secondary\ allylic and propargylic alcohols are converted to alkyl halides in high yields with inversion of con_guration under neutral conditions at room temperature ð78TL2966[ "See also ð59JA898 for related work[# Vilsmeier salts "generalised as formula "5## are widely used to activate alcohols towards halide displacement\ and this approach has been applied to the synthesis of chlorides\ bromides and iodides[ A range of di}erent haloiminium salts has been used for the same transformation ð79S635\ as well as the benzothiazolium salts "6# ð65CL508 and benzoxazolium salts "7# ð66CL272[ The latter works on alicyclic alcohols for which the former fails[ Other procedures useful for the preparation of alkyl chlorides\ bromides and iodides "including optically active ones#\ involve activation of the alcohol with tri~uoroacetic anhydride ð76S400\ or with carbodiimides ð61AG"E#118\ 76TL3334[ Meanwhile\ chlorides\ bromides and iodides can all be readily prepared from xanthates "8# ð65JCS"P0#1001[
OH
8General Methods
(6) (7) (8) (9)
1[90[0[3[1 Alkyl halides from alcohols via sulfonates
Activation of an alcohol towards nucleophilic displacement with halide ion can be achieved by converting it to a sulfonate ester\ commonly tosylate "p!toluenesulfonate#\ mesylate "methane! sulfonate# or tri~ate "tri~uoromethanesulfonate# "Scheme 8#[ These are readily prepared and are often stable enough to be isolated and puri_ed[ In the case of allylic or benzylic alcohols\ the intermediate sulfonate may react further under the reaction conditions to generate the alkyl chloride directly ð73TL1184\ 76TL612[
OH
Scheme 9
Treatment of sulfonate esters of primary and secondary alcohols with alkali metal halides or tetrabutylammonium halides gives high yields of the corresponding alkyl halides\ generally with inversion of con_guration ð64S329[ Indeed\ a comparison of the stereochemical course of sub! stitution of homochiral 1!octyltosylate with all four halides has been made[ Good inversion was observed in all except the iodide case\ where it is believed that the product racemises by reversible SN1 iodides substitution ð64JOC0403[ In the early literature\ sulfonate displacement was almost exclusively applied to the formation of iodides by displacement of tosylates with sodium iodide\ but many other halide sources have been successfully used since then\ including KF ð63CC768\ 76S819\ 82TL182 tetra!n!butylammonium ~uoride "tbaf# ð76JOC547\ 76LA506\ Et2N = 1HF ð89TL5416\ CsF ð83TL0740\ tris"diethylamino#sulfonium "trimethylsilyl#di~uoride "tas!f# ð76CJC301\ LiCl ð75JOC4180\ NaBr ð52OSC"3#642\ KBr ð63CC768 and pyridinium halides ð41M0287[ Resin!bound quaternary ammonium ~uoride and chloride sources ð68JCS"P0#1137\ 82CCC891 have also been applied to sulfonate displacement reactions[ Even neopentyl tosylates can be converted to chlorides\ bro! mides and iodides without rearrangement\ provided the correct solvent is used "often HMPA# ð61JA3073[ Other generally applicable procedures include the use of calcium"II# halides in DMSO\ which have been shown to be an e}ective way of converting allylic and benzylic mesylates to chlorides\ bromides and iodides ð82JOC161[ Magnesium"II# bromide and iodide can also be used ð62CC710\ 65BSF058\ and are particularly good for bridgehead sulfonates ð64AG"E#713\ 80S242 as are halides of aluminum"III# ð78TL3444\ iron"III# and titanium"IV# ð64AG"E#713[ In these cases\ an SN1 mechanism is of course impossible\ and a bridgehead carbocation is the presumed intermediate[
Fluorosulfonates ROSO1F can be converted to chlorides\ bromides and iodides by treatment with the corresponding tetrabutylammonium halide ð75JOC2106\ while ~uorides\ chlorides\ bromides and iodides can all be obtained from secondary mesylates by treatment with potassium halide under phase transfer conditions ð64CC849\ 64S329[ Imidazolyl sulfonates ROSO1Im have been shown to be less prone to hydrolysis than tri~ates\ and give less elimination and lower reaction temperatures than do conventional sulfonates on substitution with ~uoride\ chloride or iodide ð70TL2468[
Less commonly used sulfonates are the aminoalkanesulfonates "known as {betylates|# "09# which give chlorides\ bromides or iodides with inversion in a so!called substrateÐreagent ion pair "SRIP# reaction "Equation "8## ð68TL2504[
O
(9)
1[90[0[3[2 Alkyl halides from ethers
The conditions required to cleave alkyl ethers to alkyl halides are generally quite vigorous and this approach is therefore of limited synthetic use[ Treatment of an ether with halide ion under Bronsted or Lewis acidic conditions can result in cleavage to 0 mole of alcohol and 0 mole of alkyl halide "Equation "09##[ Except for the cases R1aryl "when cleavage of the alkylÐoxygen bond always occurs# and R0Me "in which cleavage usually occurs to give the methyl halide#\ ether cleavage is usually nonselective\ giving mixtures of both possible alcohols and alkyl halides[ By using an excess of hydrogen halide\ the alcohol produced is also converted to alkyl halide\ and this procedure therefore often _nds use when applied to symmetrical and:or cyclic ethers\ particularly tetrahydrofurans\ tetrahydropyrans and epoxides[ The reaction is most commonly used to prepare bromides and iodides[ Chlorides can also be thus prepared\ but there are few reports of alkyl ~uoride preparation by ether cleavage ð57BCJ0613 other than ~uorohydrin formation by epoxide opening[ Diethylammonium sulfur tri~uoride\ Et1NSF2 "DAST#\ has been used to make 0\1!di~uorides from epoxides but in low yield ð76JFC"25#262[
(10)R1OR2 R1Hal + R2OH HHal
Hal = F, Cl, Br, I
Ether cleavage "particularly for the formation of iodides# has been reviewed ð72S138\ as has cleavage of alkylaryl ethers ð77S638[ Examples of alternative reagents for the conversion of ethers to alkyl halides can be found in Sections 1[90[2[3 "chlorides#\ 1[90[3[3 "bromides# and 1[90[4[3 "iodides#[ Note that the conversion of cyclic ethers "including epoxides ð83S114# to a\v!halohydrins is covered in later chapters\ as are ring openings of lactones to v!haloacids[
Tetrahydropyranyl "and sometimes tetrahydrofuranyl# ethers are easily converted directly to alkyl bromides on treatment with bromine and PPh2 "Equation "00## ð64JOC1309\ 65SC10\ 68RTC260 or a related bisphosphine\ the latter also allowing access to iodides ð76TL656[ The use of PPh2:CBr3
gives inversion with low levels of elimination by!products\ even in tertiary systems ð78TL446[
ORO
Ph3PBr2 RBr (11)
In the early 0889s\ alkali metal halides were shown to convert tetrahydropyranyl ethers into alkyl bromides and iodides under Lewis acid catalysis\ predominantly with retention of con_guration ð80TL0970[ An SNi mechanism involving a tight ion pair "00# has been proposed to explain the stereoselectivity[
OO M
X R
X = Br, I
Silyl ethers are converted directly to alkyl ~uorides using either phenylphosphorus tetra~uoride\ PhPF3 "Equation "01## ð61TL736\ 63T2682\ 67TL3496\ 68JOC2395\ 70JFC"06#016 or sulfonyl ~uorides "e[g[\ TsF# in the presence of tetraalkylammonium ~uorides "e[g[\ TBAF# ð74TL3196[
(12) PhPF4
R1FR1OSiR2 3
Conversion of silyl ethers to bromides can be achieved via alkoxyphosphonium intermediates using Bu2PFBr ð71S215\ or more generally Ph2PBr1 ð75JOC3830 or PPh2:CBr3 in the presence of acetone ð76TL0586\ the latter two proceeding with inversion and being applicable to primary\ secondary\ benzylic\ allylic\ cyclic and acyclic t!butyldimethylsilyl "TBDMS# ethers[ Boron tri! bromide has also been shown to convert benzylic\ allylic\ primary\ secondary and tertiary TBDMS
00General Methods
ethers to bromides\ but in this case\ up to 60) retention of con_guration was observed at secondary centres ð77JOC2000[ Alkyl iodides are formed on treatment of silyl ethers with TMS!Cl:NaI ð68S268[
1[90[0[3[3 Rearrangement of cyclopropyl carbinols
Homoallylic halides can be prepared by treatment of cyclopropyl carbinols with halides under a variety of conditions "Equation "02##[ Suitable reagents include HCl ð40JA1498\ HBr or HI ð68S26\ MgCl1\ MgBr1 or MgI1 ð64CC292\ 79JOC1455 with or without the corresponding zinc"II# halide\ and trimethylsilyl chloride\ which\ on its own\ gives chlorides but can give other halides when combined with the appropriate lithium ð75TL0896 or zinc ð89OPP104 halide[ The only reported procedure for ~uoride preparation from cyclopropyl carbinols uses Olah|s pyridine poly"hydrogen ~uoride# "PPHF# reagent in combination with KHF1 ð76TL552\ 78BCJ1913[
(13) HHal or
R OH
R Hal
1[90[0[4 Alkyl Halides from Amines and their Derivatives
There are very few general methods for this transformation\ since direct nucleophilic displacement of an amine with halide ion is not possible[ However\ the desired transformation can be achieved by converting the amine to a better leaving group\ for example the bis"tri~ate# RNTf1\ before reacting with halide ion "Scheme 09# ð67JOC1180[
RNH2 RNTf2 RI i, TfCl, base
ii, TfCl, base
Scheme 10
An interesting and powerful way of turning an amine nitrogen into a leaving group is by conversion into a pyridinium salt\ as depicted in a generalised manner in Scheme 00[ This chemistry has been used to prepare ~uorides ð68CC127\ 79JCS"P0#1890\ chlorides ð68JCS"P0#325\ 68S326\ bromides ð68JCS"P0#325\ 79JCS"P0#0789 and iodides ð66S523\ 68JCS"P0#322\ and even works in neopentyl systems without rearrangement of the carbon skeleton ð72IJC"B#310[ For reviews of this type of chemistry see ð79T568\ 73AG"E#319 and for a related procedure see ð79S742[
RNH2 RHal Hal–OR1
Scheme 11
Another well!known way of converting an amine to a leaving group is by diazotisation[ While unactivated primary amines can indeed be converted to alkyl chlorides by treatment with NOCl ð67JOC3019\ there are few reports of applications of this chemistry\ presumably because simple alkyl chlorides are more easily accessed by other routes[ In contrast\ diazotisation of a!amino acids has proved to be a good method for preparing a range of a!halocarboxylic acids[ Treatment of a!amino acids with NaNO1 in the presence of Olah|s reagent\ pyridine poly"hydrogen ~uoride# "PPHF#\ results in conversion into a!~uorocarboxylic acids ð63S541\ 68JOC2761\ 70HCA1417\ 71TL0438[ When carried out in the presence of excess KCl or KBr\ the corresonding a!chloro! and a!bromo! carboxylic acids are formed ð72HCA0917[ It has been shown that essentially complete retention of
01 Alkyl Halides
con_guration can be obtained in a related preparation of a!chlorocarboxylic acids ð76OS"55#040[ A double!inversion mechanism via an a!lactone "01# can account for this observation "Scheme 01#[
R OH
Scheme 12
(12)
Diazoketones are good substrates for conversion to a!haloketones by treatment with aqueous HCl ð44OSC"2#008\ or HBr ð42JOC757\ 64LA0141\ and a simple and general procedure for the preparation of chlorides\ bromides and iodides has been reported ð80CE640 "Equation "03##[ a!Fluoroketones can also be prepared using this chemistry ð63S785\ 65HCA0916[
O
R
N2
O
R
Hal
52–100% (14)
Hal = F, Cl, Br, I
Hydrazines have been used as precursors to alkyl halides by treatment with NBS or NIS or iodine "Equation "04## ð56JCS"C#141[ More recently\ a method for converting tosylhydrazines to alkyl halides under basic conditions has been described "Equation "05## ð81JOC2661[ Further methods apparently unique to particular halogens are described in Sections 1[90[2[4 "chlorides#\ 1[90[3[4 "bromides# and 1[90[4[4 "iodides#[
NHNH2
CHCl3 70–100%
70–95%
R Hal
1[90[0[5 Alkyl Halides by Halodecarboxylation of Carboxylic Acids and their Derivatives
Halodecarboxylation has been brie~y reviewed ð80COS"6#612 and is one of the best methods for preparing bridgehead tertiary alkanes[ The _rst reported halodecarboxylation procedure was the classical Hunsdiecker reaction\ which has been the subject of several early reviews ð36CRV270\ 45CRV108\ 46OR"8#221[ In this process\ silver carboxylates react with chlorine\ bromine or iodine to give the corresponding acyl hypohalite "02# which undergoes thermal cleavage to give the alkyl halide "Scheme 02#[ This method su}ers from the practical drawbacks of expense and the need to isolate the silver salt dry[ Various modi_cations of the Hunsdiecker reaction have been reported\ including the widely used CristolÐFirth modi_cation using mercuric oxide ð50JOC179\ 54JOC304\ 61JOC553\ 62OSC"4#015\ 68JOC2394\ 76JA6129[ More recent modi_cations include the use of thallium salts ð70JCS"P0#1597\ or lead tetraacetate in combination with LiCl or NCS\ LiBr or iodine[ The latter method has been reviewed ð61OR"08#168 and is most frequently applied in the preparation
02General Methods
of secondary and tertiary alkyl chlorides ð62S382\ sometimes on quite large laboratory scale ð89SC0900[
O
Scheme 13
An alternative which avoids the use of heavy metals is the radical halodecarboxylation of thiohydroxamate "{Barton|# esters "03# in the presence of the halogen donors CCl3\ BrCCl2 or CHI2
for alkyl chlorides\ bromides and iodides\ respectively "Equation "06##[ This transformation can be achieved thermally ð72TL3868\ photochemically ð78TL1350\ 78TL5856\ and ultrasonically ð78JOC5090 and has been applied to a wide range of primary\ secondary and tertiary carboxylic acids[
(17)
O
60–95%
Alternative radical precursors for related photochemical chlorodecarboxylation include hyd! roxyphthalimide esters "04# ð78CC0525 and benzophenone oxime esters "05# ð77TL5176[ Radical iododecarboxylation can be achieved by direct photolysis of primary\ secondary and tertiary car! boxylic acids in the presence of t!butyl hypoiodite\ ButOI ð54JCS1327\ 79JOC3115 or PhI"OAc#1 and iodine ð75JOC391\ 76CC564[
O
(15) (16)
There are very few reported methods for ~uorodecarboxylation[ The earliest involved the treat! ment of sodium or potassium carboxylates with elemental ~uorine\ but generally gave low yields ð58JOC1335[ More synthetically useful is the application of xenon di~uoride\ which can be used to prepare primary\ tertiary and benzylic ~uorides from carboxylic acids in generally good yields ð72JOC3047\ 75CJC027[
1[90[0[6 Alkyl Halides by Haloalkylation of Arenes
Treatment of an aromatic hydrocarbon with an aldehyde and hydrohalic acid HHal e}ects the transformation outlined in Equation "07#\ and has been reviewed ð31OR"0#52\ B!53MI 190!90\ 66RCR780[ Although this reaction has been mostly the preserve of hydrochloric acid and formaldehyde "in its various forms\ e[g[\ paraformaldehyde or trioxane#\ bromomethylation and iodomethylation ð39JA2987 are nevertheless possible\ as are chloroethylation\ chloropropylation and chloro! butylation ð31OR"0#52[ Although further catalysis is often not needed\ rate enhancements can be achieved using zinc chloride\ acetic acid\ phosphoric acid ð44OSC"2#084 or sulfuric acid[ In accord! ance with the ionic mechanism\ electron!rich aromatics react better than electron!poor ones[ For less!activated aromatic rings\ chloromethyl methyl ether\ ClCH1OMe\ has been shown to be useful ð69BCJ2188\ while methoxyacetyl chloride\ MeOCH1COCl\ ð72TL0822 and 0!chloro!3!"chloro! methoxy#butane ð63S459\ 65JOC0516 provide useful and mechanistically intriguing alternative
03 Alkyl Halides
ArH RCHO
1[90[0[7 Alkyl Halides by Miscellaneous Methods
The reduction of vinyl halides to alkyl halides is rarely used synthetically because of problems with over!reduction[ Modest yields can nevertheless be achieved using diimide generated in situ "Equation "08## ð54JOC2874[ More spectacular is the enantioselective yeast reduction shown in Equation "19# ð78JOC3878[
(19)Ph Br
Ph Br
66%
R CO2Me
>98% ee
Another reductive approach to alkyl halides is the partial reduction of geminal dihalo compounds\ and is applied almost exclusively to cyclopropyl systems as illustrated in Equation "10#[ A number of di}erent reagents and conditions for this transformation have been reported ð63JOC1299\ 72BCJ0770\ 72CL0766\ 73BCJ292\ 82JOC5418[
HalHal
R1
Hal
(21)
Reductive halogenation of carbonyl compounds "including acids\ aldehydes\ ketones and even ketals# can be achieved under a variety of conditions\ using boranes and silanes as in situ reducing agents "Scheme 03# ð73TL0092\ 74T3546\ 75CJC1231\ 78CC202\ 78TL4552\ 89JOC1816\ 81T7218[
R IRCO2H
60–66%
R1 R2
DIGLYME, benzene
75–82%
Scheme 14
Alkyl halides can be derived from halogen atom transfer reactions such as that shown in Equation "11# ð83TL1652[ For related chemistry\ including cyclisations\ see ð79BCJ669\ 74PAC0716\ 76TL1366\ 80COS"6#482\ 80COS"3#668\ 80SL548\ 81TL102[
EtO2C I
EtO2C R
I (22)
04Alkyl Fluorides
Finally\ a range of homologation procedures for alkyl halides has been reported and can be found in Larock|s survey ðB!78MI 190!90[ A recent example is shown in Equation "12# ð89TL826[
(23)I I
98%
1[90[1 ALKYL FLUORIDES] RF
The high dissociation energy of the C0F bond "×349kJmol−0# makes the use of alkyl ~uorides as synthetic intermediates very rare[ It also means that methods for the formation of C0F bonds are generally quite di}erent from those used for the preparation of other carbonÐhalogen bonds[ Considerable e}orts have been made to facilitate the incorporation of ~uorine into organic molecules because organo~uorine compounds often exhibit interesting biological\ chemical and physical properties[ The number of reviews and monographs relating speci_cally to ~uorine!containing compounds far outweighs those relating to the other halogens\ and the reader is directed to some reviews in this area for more detailed treatments than can be a}orded here ð63OR"10#014\ 67IJ60\ 67T2\ 70AG"E#536\ 74C023\ 75JFC"22#116\ 75JFC"22#266\ 76CSR270\ 76T2012\ B!78MI 190!92\ 89TA550\ 80RCR749\ 80RCR0949\ 81CRV494[ The use of elemental ~uorine in organic synthesis has been reviewed ð74C294\ 75CRV"75#886\ 77ACR296\ as has the use of combinations of hydrogen ~uoride with organic bases ð80T4218[
1[90[1[0 Alkyl Fluorides from Alkanes
Direct replacement of unactivated aliphatic hydrogen with ~uorine using elemental ~uorine is usually nonselective\ often resulting in poly~uorination and fragmentation owing to the high heat of reaction[ Notable exceptions include the use of elemental ~uorine in the regioselective ~uo! rinations of adamantane "Equation "13## ð65JA2923\ 77JOC1792 and branched alkanes ð76JOC3817 at the more substituted positions[ These reactions are believed to be electrophilic in nature ð76JOC1658[
(24)
90%
F
Notwithstanding these successes\ the high electronegativity of ~uorine makes its use as an elec! trophilic reagent somewhat challenging[ One way to overcome this is to incorporate an excellent leaving group adjacent to ~uorine\ such as in CF2OF\ which has been successfully applied to the ~uorination of rigid systems such as adamantanes and steroids ð69JA6383\ 69PAC174\ 65JA2923\ 65JA2925\ 79NJC128[ Olah|s reagent\ pyridine poly"hydrogen ~uoride# "PPHF#\ can 0!~uorinate adamantane in the presence of NOBF3 ð72JOC2245\ while other reagents used for ~uorination at tertiary carbon centres include ClF2 ð76JOC687\ BrF2 ð78JOU0724 and XeF1 ð75BCJ0548[
A class of reagents developed in the early 0889s is that of the {Select~uor| reagents ð81CC484\ 82JOC1680\ 83CC232\ exempli_ed by F!TEDA!BF3 "06#\ a stable solid which has been shown to convert aryl!alkyl substituted alcohols directly to vicinal ~uorohydrins "Equation "14## ð83CC038[ Benzylic ~uorination has been reported using CsSO3F ð80JOC6236 and HF:PbO1 ð66JFC"09#264\ 68JOC0141[
OH
TEDA = triethylenediamine
By far the most widely used synthetic ~uorinations occur at positions a to a carbonyl group\ usually after the carbonyl has _rst been converted into an enol ether\ enol silane\ enol ester or
05 Alkyl Halides
enamine "Equation "15## "reviews ð74T0000\ B!77MI 190!90[ For example\ enol silanes "including those derived from carboxylic acids\ esters\ amides and b!dicarbonyl compounds# can be converted to a!~uorocarbonyl compounds by treatment with ~uorine ð75TL1604\ 76JOC3296\ 89JOC2312\ tri~uoro! methyl hypo~uorite\ CF2OF ð79JA3734\ XeF1 or PhIF1 ð71TL0054\ or N!~uoropyridinium tri~ate ð75TL3354\ 89OS"58#018[ Although FClO2 can be used\ it is not recommended because of its explosive nature ð64JOM"80#C19[ Enol esters are ~uorinated by a range of ~uoroxy compounds ð61CC011\ as well as by XeF1 ð71JOC462\ 77JOC4042\ 78T5992\ CsSO3F ð78T5992\ per~uoroacyl hypo~uorites ð68CC368\ 74JOC2587 or electrochemically with HF:Et2N ð72TL892\ 75BSF844\ 76TL1248[
OR3
R1
R2
O
R1
R2
R3 = alkyl, acyl, silyl
Direct a!~uorination of ketones or b!dicarbonyl compounds with AcOF has been reported ð72JOC613\ 74S554\ and can also be achieved electrochemically ð78T3320[ A range of N!~uoro! sulfonamide derivatives "07#Ð"11# have been shown to ~uorinate enolate anions and derivatives ð73JA341\ 78HCA0137\ 80CC068\ 80JOC3814\ 80SL076\ 80TL0520\ 80TL0668\ while N!~uoropyridinium salts "12# have also been exploited in some depth ð75TL3354\ 80JOC4851[ Indeed\ by changing the sub! stituents on the pyridinium ring of "12#\ the reactivity of the N!~uoro group can be {tuned| to _t a range of substrates\ including enolates and other enol derivatives ð89JA7452[
S N F
X–
(23)
The previously mentioned {Select~uor| reagents such as "06# have been successfully reacted with enol acetates\ enol silanes and enamines[ They are an extension of previously reported N! ~uoroquinuclidinium reagents "13# ð77JCS"P0#1794\ 77JFC"30#186[
N
F +
X–
(24)
Enantioselective a!~uorination of carbonyl compounds is possible using a homochiral N!~uoro! sultam "Equation "16# in which HMDShexamethyldisilazide# ð77TL5976\ but the 64) enanti! omeric excess thus obtained has yet to be improved upon ð82TL2860[ Higher levels of asymmetric induction have been achieved using the achiral ~uorinating agent "08# on a substrate with a covalently bound chiral auxiliary "Equation "17## ð81H"22#094\ 81JCS"P0#110\ 81TL0042[
06Alkyl Fluorides
ii,
40%
ii,
1[90[1[1 Alkyl Fluorides from Alkenes
1[90[1[1[0 Alkyl ~uorides by hydro~uorination of alkenes
All recorded additions of hydrogen ~uoride to alkenes occur in a Markovnikov sense\ i[e[\ the proton attacks the more electronegative "generally less!substituted# end of the double bond "Equa! tion "18##[ The practical di.culties of handling highly corrosive anhydrous hydrogen ~uoride\ and the fact that it tends to cause alkene polymerisation\ means that this reaction is better carried out with the commercially available pyridine poly"hydrogen ~uoride# "PPHF# "Olah|s reagent# ð62S668\ 68JOC2761\ 75JFC"22#266[ This has been further developed into an easily handled solid polymer! bound form\ poly"3!vinylpyridinium# poly"hydrogen ~uoride# "PVPHF# ð89SL156\ 82S582[ One other hydro~uorination procedure of note is the combination of HF with melamine ð72CL0024\ which\ with the use of co!solvents such as pentane or CCl3\ gives simple workups and is reusable ð73CL0130[
(29)R R
F HF–amine
1[90[1[1[1 Alkyl ~uorides by ~uorineÐhalogen addition to alkenes "F0F\ F0Cl\ F0Br\ F0I#
The high reactivity of elemental ~uorine makes its use in synthesis somewhat problematic ð74C294\ 75CRV"75#886\ 77ACR296[ In contrast to the other halogens\ which generally add in a trans "or anti# fashion "Scheme 5#\ ~uorine adds in a stereospeci_cally syn fashion\ suggesting either a four!centre transition state "14# or the rapid collapse of a tight ion pair "15# ð75JOC2596\ 83CPB348[
F F
R4 R3R1
F F– +
(25) (26)
A number of papers discuss the use of xenon di~uoride for the di~uorination of phenyl!substituted alkenes ð65JOC3991\ 66JOC0448\ 67IJ60\ 82JCS"P0#1740 and simpli_ed benchtop procedures for handling XeF1 have been described ð66TL252[ One of the many electrophilic ~uorinating agents developed since the 0879s is the {Select~uor| reagent "06# which\ when combined with pyridine poly"hydrogen ~uoride# "PPHF# allows phenyl!substituted alkenes to be vicinally di~uorinated ð82JOC1680[ Other
07 Alkyl Halides
methods for alkene ~uorination are known ð76JOC808\ B!78MI 190!90 but space restrictions preclude further discussion of these[
FluorineÐhalogen addition "halogenCl\ Br\ I# is achievable in a very large number of ways and has been reviewed ð61RCR639\ 73RCR0067[ In essentially all cases\ the addition proceeds in a trans "anti# fashion as indicated in Scheme 04\ and Markovnikov regioselectivity is usually observed[
R2
Scheme 15
The most widely used active halogen sources are N!chloro!\ N!bromo! and N!iodosuccinimide\ N!bromoacetamide ð62OSC"4#025\ 67S106\ and dibromodimethylhydantoin "dbh#\ although mixtures of elemental ~uorine with iodine or bromine have also been used ð79TL3432\ 74JOC2231[ The ~uoride source is commonly hydrogen ~uoride\ usually in combination with organic bases such as indicated in Table 0 ð80T4218[ One of these\ pyridine poly"hydrogen ~uoride# "PPHF# ð62S679 has been prepared in a more convenient poly"vinylpyridine# polymer!supported form "PVPHF# which would appear to o}er practical advantages ð82S582[ Alternatively\ a mild\ and as yet little exploited way of generating in situ HF for bromo! or iodo~uorination of alkenes involves reaction with Ishikawa|s reagent "16# "hexa~uoropropeneÐdiethylaniline complex\ sometimes referred to as FPA# in the presence of water "Equation "29## ð80BCJ1485[
Table 0 Halo~uorination of alkenes using amineÐHF adducts[
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ NCS NBS NIS DBH
Et2N CF3
Alternative reagent combinations not referred to in Table 0 or discussed above include bis"py! ridine#iodine tetra~uoroborate\ IPy1BF3 ð74AG"E#208\ 80JOC1123\ and its collidine analogue ð76S440\ XeF1:Br1 ð67IJ60\ BrF2:Br1 ð76JOU129\ AgF:I1 ð82JCS"P0#0684\ BF2:ROBr "or BF2:ROCl# ð72JOC2084\ AgFÐCaF1:I1 "or AgFÐCaF1:DBH# ð77CL0766\ Pb"OAc#3:CuCl1:HF ð89JOU0673\ SiF3:DBH ð78CC0770 and Bu3PH1F2:"NIS or NBS or DBH# ð82CL562[
1[90[1[2 Alkyl Fluorides from Alkyl Halides
Nucleophilic halogen exchange is one of the most widely used approaches to alkyl ~uorides\ and a very large number of procedures for the conversion of alkyl chlorides\ bromides and iodides to alkyl ~uorides "Equation "20## have been reported[ The reader is therefore referred to the relevant sections in Houben!Weyl ð51HOU"4:2#0\ Larock ðB!78MI 190!90 and Or`anic Reactions ð33OR"1#38\ 63OR"10#014 for more comprehensive listings of references than can be a}orded here[
RHal RF F–
08Alkyl Fluorides
Calcium ~uoride is a useful support for halide displacement with potassium ð75CC680\ 75CC682\ caesium ð75CC680 or silver ð77CL0766 ~uorides[ Although copper ~uoride ð76CL0564 and lead ~uoride ð81CL0050 also have some utility\ displacement of alkyl chlorides and bromides with ~uoride is most commonly achieved with potassium ~uoride in anhydrous polar solvents such as glycols ð46JA1200\ 52OSC"3#414\ 63CCC1505\ 75JCR"S#299\ acetonitrile ð70CL650\ 75CC682\ formamide ð75TL0388\ 78BSF145 or sulfolane ð75CC680[ Anhydrous conditions are usually essential for the success of the reaction\ since water hydrogen bonds to the ~uoride ion\ decreasing its nucleophilicity[ Formation of solubilised {naked ~uoride| ion from potassium ~uoride can be enhanced by {spray! drying| the KF ð70CL650\ by using crown ethers ð63JA1149\ 71JCS"P0#74\ by way of a CuF1Ðbipyridine complex ð74CL122\ or by phase!transfer catalysis ð63S317\ 75TL0388\ 77SC0550\ 78BSF145[ Even bridge! head halides can be substituted with ~uoride using XeF1 ð81JOC1749 or amineÐHF adducts ð72S602\ although an SN1 mechanism is clearly impossible in these cases[
Polymer!bound tetraalkylammonium ~uorides can also displace chlorides\ bromides and iodides ð65S361\ 68JCS"P0#1137\ 78JOC4279[ Indeed\ the stoichiometric use of organic!soluble quaternary ammonium or quaternary phosphonium ~uorides or hydrogen ~uorides has become increasingly popular\ examples of reagents including Bu2MePF ð68TL242\ Bu3NF ð73JOC2105\ Bu3NHF1
ð76TL3622\ Ph3PHF1 ð74CC561\ Bu3PF = nHF "n9\0\1# ð80CL0074 and polymer!supported HF1 −
or H1F2 − ion ð78JOC4279[
One of the drawbacks of ~uoride ion is its basicity\ which can lead to elimination rather than substitution with some secondary "particularly cyclic# and tertiary alkyl halides[ This has been overcome by the use of amineÐHF adducts ð79JFC"04#312\ 89TL5416 or Cu1O:HF mixtures ð74CL0582\ which work particularly well on cyclic or tertiary systems ð76CL0564[
1[90[1[3 Alkyl Fluorides from Alcohols and their Derivatives
Procedures for the conversion of alcohols to alkyl ~uorides are quite specialised and\ with the exceptions described in Section 1[90[0[3\ cannot be applied to the other halides[ Sulfur tetra~uoride can be used for this transformation ð63OR"10#0\ 74OR"23#208\ but its gaseous and corrosive nature makes it unattractive[ Although selenium tetra~uoride o}ers some advantages ð63JA814\ both SF3
and SeF3 have been superseded by a more convenient liquid reagent\ diethylaminosulfur tri~uoride\ Et1NSF2 "DAST# "review ð77OR"24#402#\ which readily converts primary\ secondary\ tertiary\ allylic and benzylic alcohols to alkyl ~uorides "Scheme 05# ð64JOC463\ 77OSC"5#724[ Rearrangements and eliminations sometimes occur with DAST\ suggesting an SN0 mechanism\ but there are many examples which proceed with complete inversion of con_guration\ suggesting an SN1 mechanism ð77T1764[ Retention has sometimes been observed as a result of neighbouring group participation ð68TL0712\ 80CPB0977[ DAST has been extensively applied in sugar chemistry ð77JCS"P0#438\ and a modi_ed form of DAST\ 3!morpholinosulfur tri~uoride\ has been reported to give high yields in reactions with cyclohexanols provided the solvent is chosen carefully ð78JFC"32#394[
ROH + F3SNEt2 ROSF2NEt2 RF F–
(DAST)
Scheme 16
Prior to the discovery of DAST\ the most popular reagent for converting alcohols to ~uorides was the less reactive ~uoroalkylamine reagent "sometimes referred to as FAR#\ 1!chloro!0\0\1! tri~uorotriethylamine "{Yarovenko|s reagent|# "17# ð48JGU1014\ giving ~uorides generally with inversion of con_guration "Equation "21##[ A polymer!supported version of Yarovenko|s reagent has been reported ð70JFC"06#82\ and Ishikawa|s reagent "16# has also been used for this purpose ð68BCJ2266\ 89JOC4180[ Alcohols can also be converted to alkyl ~uorides with a related per~uoro! alkene:Et2N reagent combination ð70BCJ0040[
OH
(28) (Yarovenko's reagent)
19 Alkyl Halides
Less well!used reagents for the ~uorodehydroxylation of alcohols include the phenyl~uoro! phosphoranes PhmPF"4−m# "m0\1\2# ð57CPB0673\ which\ with the exception of PhPF3 ð62CPB756\ require elevated temperatures[ Finally\ primary alcohols have been shown to be selectively converted to ~uorides by treatment with tosyl ~uoride and tbaf in the presence of molecular sieves ð74TL3196[
Ethers are rarely used as direct precursors to alkyl ~uorides "although see Section 1[90[0[3[2#[
1[90[1[4 Alkyl Fluorides from Amines and their Derivatives
See Section 1[90[0[4[
1[90[1[5 Alkyl Fluorides by Fluorodecarboxylation of Carboxylic Acids and their Derivatives
See Section 1[90[0[5[
1[90[1[6 Alkyl Fluorides by Fluoroalkylation of Aromatic Rings
Fluoroalkylation of aromatic rings has not been reported[
1[90[2 ALKYL CHLORIDES] RCl
Chlorine is the cheapest and most readily available of all the halogens[ Alkyl chlorides are not as reactive as bromides "or iodides# and are therefore not quite so widely used as synthetic intermediates[ Nevertheless\ methods for their preparation abound[
1[90[2[0 Alkyl Chlorides from Alkanes
The direct chlorination of unactivated alkanes using Barton|s {Gif| GoAgg!type systems has been discussed brie~y in Section 1[90[0[0\ and is complemented by a high!yielding 0!chlorination of adamantane using ButCl:AlCl2 ð78SC0586[ N!Chloroamines chlorinate alkanes\ often quite regio! selectively\ under strongly acidic conditions in the presence of a radical initiator such as iron"II# or light\ in reactions that are closely related to the classical Ho}manÐLo/erÐFreytag reaction ð69CRV528\ 60JA327\ 65AG"E#295\ 68JOC2617 "Scheme 06#[
Scheme 17
CO2H CO2H
80%
Somewhat less vigorous conditions for alkane chlorination involve the use of iodobenzene dichlor! ide\ PhICl1 ð68CL850\ which has been elegantly applied to the regioselective photochlorination of steroids\ under the direction of a covalently bound template "Equation "22## ð66JA894\ 80COS"6#32\ 82TL0096[
10Alkyl Chlorides
100% (33)
Photochlorination of alkanes with Cl1 ð69S6\ 89ACR108\ 81LA448\ and chlorination with sulfuryl chloride "SO1Cl1# in the presence of a radical initiator such as dibenzoyl peroxide are well docu! mented ðB!63MI 190!90[
SO1Cl1 can also be used for benzylic chlorination using benzoyl peroxide as radical initiator[ Palladium catalysis has been shown to reduce the levels of dichlorinated by!product ð67CL112\ and milder radical conditions using a tetraalkylammonium tetrachloroiodate\ BnMe2NICl3\ have been described ð77TL4672[ While Cl1 can give allylic or benzylic chlorination under certain conditions ð77T5414\ 81TL384\ allylic chlorination quite often requires reagents such as ButOCl ð79TL670 or HOCl ð79TL330\ 70TL4908\ which is conveniently generated in situ from Ca"OCl#1 and acetic acid ð89JOC2779[ Unlike the corresponding bromination reaction with N!bromosuccinimide\ allylic halogenation with N!chlorosuccinimide usually requires extra catalysis[ Using PhSeCl or PhSeSePh or TsNSO as catalysts\ allylic chlorination can be controlled to give the rearranged or unrearranged product "Equation "23## ð68JOC3193\ 68JOC3197[
R3
R1
R2
R4
R5
R3
R1
R2
Cl
(34)
Other procedures which have found limited use in the chlorination of allylic and benzylic systems include the use of chlorine oxide\ Cl1O ð73CL766\ a Vilsmeier!type reagent in the presence of peroxide ð80SL366\ and electrochemical methods using sodium chloride as halogen source ð70TL1180\ 70TL2082[ In many cases\ the reaction is believed to proceed by way of an ene!type mechanism depicted in a generalised manner in Equation "24#[
R
Cl R Cl + HX (35)
a!Chlorination of enolisable carbonyl compounds is quite readily achieved\ often without the need to convert the carbonyl to an enol silane or similar derivative ðB!77MI 190!90[ The classical methods which have been applied to ketones\ aldehydes\ esters and particularly carboxylic acids involve the treatment of the carbonyl compound with Cl1 under various oxidative conditions "Equation "25## ð44OSC"2#077\ 64JOC1859\ 66CI"L#427\ 68BCJ144\ 72JOC0253\ 74SC866\ 77OSC"5#89 or SO1Cl1 ð52OSC"3#051\ 70JOC3375\ B!77MI 190!90\ 89S484[
(36)
O
R1
R2
O
R1
R2
A more convenient reagent for a!chlorination of carbonyl compounds is benzyltrimethyl! ammonium dichloroiodate\ BnMe2NICl1\ either in solution ð77S434\ 89S101 or in a polymer!bound form ð79CC0167\ while a related polymer!bound tetrachloroiodate has been reported for a similar application ð73T1754[
Direct chlorination of carbonyl compounds can be readily achieved with copper"II# chloride ðB!62MI 190!91\ and the use of this method in malonate chemistry has been discussed in some depth
11 Alkyl Halides
ð82JOC3485[ Chloride ion can also be used to a!chlorinate carbonyl compounds when in the presence of manganese"III# ð76BCJ798\ 82JCS"P0#2060 or manganese"IV# ð89JCR"S#077 species[ In the latter case\ TMS!Cl and MnO1 combine to generate reactive MnCl3 in situ[ A related procedure for a!chlorination of acetals has been described\ which is believed to proceed through an enol ether intermediate ð81T3468[ Also related is a method which combines TMS!Cl with KBrO2 ð81BAU245\ but a method which may _nd wider application makes use of DMSO as the oxidant "Scheme 07# ð75JCR"S#315[ A chlorosulfonium intermediate "18# is postulated as the reactive halogenating species[ Interestingly\ this reaction can be enhanced by bromide ion catalysis ð77SC0960[
O
(29)
(29)
Cl–
Although direct chlorination of ketones with N!chlorosuccinimide has not been described\ the related trichloroisocyanuric acid "29# has been shown to chlorinate ketones in the presence of BF2 =OEt1 ð74SC274[ N!Chlorosuccinimide can\ nevertheless\ be used to chlorinate enol silanes without Lewis acid catalysis ð75TL1452\ 78JCS"P0#0433\ and this chemistry has been applied in asym! metric synthesis using covalently!bound chiral auxiliaries ð74TL4926\ 80SL796[ N!Chlorosuccinimide is one of a few reagents which can be used to a!chlorinate enamines and imines ð66JA5561\ 67ACS"B#"21#535\ 68OPP004\ and is used in an improved method for the a!chlorination of imines "and therefore\ indirectly\ aldehydes# which avoids unwanted dichlorination "Scheme 08# ð81BSB126[
N
N
N
O
Cl
O
Cl
O
Cl
(30)
NBut
R
NBut
R
NBut
R
NBut
R
O–
R1
R2
O
R1
R2
12Alkyl Chlorides
Although amides are not easily a!chlorinated\ ClSO1Ph has been used to quench enolate anions of lactams ð82T2082[ An interesting alternative approach to a!chloroamides is shown in Scheme 19 ð81JA5151\ 81JOC4699[
O
Et3N (2.5 equiv.) 34–80%
Scheme 20
1[90[2[1 Alkyl Chlorides from Alkenes
1[90[2[1[0 Alkyl chlorides by hydrochlorination of alkenes
Many of the general methods for alkene hydrohalogenation have already been discussed in Section 1[90[0[1[0\ and a review of alkene hydrochlorination has been published ð72RCR148[ The addition of HCl to alkenes generally occurs in a Markovnikov sense\ but is very slow\ except in strained\ highly substituted or styryl systems ðe[g[\ 32OSC"1#225[ Synthetically useful reaction rates can only be achieved by using either a phase!transfer catalyst ð79JOC2416\ or a solid inorganic support such as silica or alumina ð89JA6322\ 82JA2960[ The latter approach not only tends to improve the regioselectivity ð80TL2694\ but has the added advantage of working with more convenient halide sources\ such as SOCl1\ "COCl#1 or TMS!Cl\ which are presumed to generate HCl in situ[ Hydrochlorination can give syn or anti addition to alkenes\ depending on the reaction conditions ð62S678\ but the surface!mediated procedure described above gives syn addition stereoselectively ð82JA2960[
If anti!Markovnikov addition of HCl is required\ the most reliable approach is via hydroboration "Scheme 3#[ Although a number of reagents can be used for the conversion of trialkylboranes to alkyl chlorides see ð77JOC4553 for a comparison\ one of the most e}ective would appear to be NCl2 ð77T1674[ "Note\ however\ that nitrogen trichloride is explosive and shock sensitive[# Hydro! alumination\ using LiAlH3 with titanium or zirconium catalysis\ has also been used to good e}ect in preparing alkyl chlorides from alkenes ð65JOM"011#C14\ 66JOM"031#60\ 67CL722[
Finally\ compounds derived from boron trichloride have been found to be e}ective in promoting the conjugate addition of chloride ion to a\b!unsaturated carboxylic acid derivatives\ and this has been realised diastereoselectively "Equation "27## ð83CC624[
ON
OO
CH2Cl2, –78 °C (38)
1[90[2[1[1 Alkyl chlorides by chlorineÐhalogen addition to alkenes "Cl0Cl\ Cl0Br\ Cl0I#
The reaction of elemental chlorine with alkenes is conceptually the most obvious method for chlorineÐchlorine addition\ but it is often a messy reaction giving many by!products[ Furthermore\ the gaseous and noxious nature of Cl1 makes it experimentally unappealing[ Although alternatives such as SOCl1\ PCl4 ð28JA839\ SO1Cl1 ð28JA2321\ 57JCS"C#305\ and NCl2 ð58S024 can be used\ a variety of more attractive alternatives have been reported[ Among these are the tetraalkylammonium chloroiodate salts R3NICl1 and R3NICl3\ which are less reactive than elemental chlorine\ thus giving cleaner reactions[ They can be used in solution ð59JOC19\ 80CE074\ or in a polymer!bound form ð79CC0167\ and give the product of anti addition to the alkene[ Iodobenzene dichloride\ PhICl1 ð55CJC1228\ 57JOC27\ and\ perhaps more conveniently\ copper"II# chloride ð60JOC2213 also give
13 Alkyl Halides
trans dichlorination of alkenes[ In 0883\ hexachloroethane was shown to chlorinate alkenes in the presence of catalytic amounts of RuCl1"PPh2#1\ but the overall stereochemistry of the products was not discussed in detail ð83TL626[
In the 0879s and 0889s\ the use of chloride ion in the presence of manganese"III# species was shown to be very useful in e}ecting trans addition of chlorine to alkenes ð73TL596\ 78JCR"S#097\ 78JCR"S#259\ 80SC378\ 80SL622\ 80TL0720[ The mechanism by which these processes occur is not fully understood\ but this approach is synthetically quite ~exible\ in that di}erent manganese sources "including permanganate\ MnO1\ Mn"OAc#2#\ and di}erent chloride sources "including AcCl\ "COCl#1\ TMS!Cl# can be used[ This methodology allows electron!rich alkenes to be selectively chlorinated in the presence of less!activated double bonds ð80TL0720[
Using DMSO as oxidant\ TMS!Cl can be used to vicinally chlorinate styrenes\ the active electro! philic chlorine source being the chlorosulfonium species "18# ð80G448[ The latter procedure is related to one using DMSO and t!butyl bromide to generate a dimethylsul_deÐbromine adduct\ which\ in the presence of CaCl1\ generates vicinal dichlorides from alkenes ð74G18[ Hydrogen peroxide can also be used as oxidant\ and a convenient phase transfer method using HCl:H1O1 has been described ð66S565[
Cis!addition of chlorine to alkenes is readily achieved using molybdenum pentachloride and antimony pentachloride ð63BCJ581\ 63BCJ2010\ 64JA0488[ An extension of this approach makes use of an octamolybdate species\ "Bu3N#3Mo7P15\ which enables even tetrasubstituted alkenes to be vicinally dichlorinated in acceptable yields using acetyl chloride as halide source ð67TL2316[ Meanwhile\ a one!pot method for achieving overall cis!chlorination via reaction with phenylselenenyl chloride "PhSeCl# has been reported "Scheme 10# ð73TL0086[
R2
Scheme 21
Asymmetric chlorination of methacrylic acid has been achieved with 099) optical purity by prior inclusion of the starting material into a!cyclodextrin "Equation "28##[ Using b!cyclodextrin\ the opposite enantiomer was obtained in 77) optical purity ð72CC836[
CO2H Cl
(–)-enantiomer 100% ee
(39)
Chlorobromination of alkenes can be achieved in a variety of ways\ and all of the reported methods give the expected Markovnikov product "i[e[\ bromine as the positive halogen# resulting from trans "anti# stereochemical addition to the double bond[ The addition can be e}ected with BrCl ð62MI 190!90 or with a mixture of Cl1 and Br1 ð59JOC13[ Other suitable reagent combinations include N!bromoacetamide:HCl ð40JA887\ 41JA3780\ 48JA1080 and MoCl4:Br1 ð63BCJ2010 or SbCl4:Br1 ð63BCJ032[ From the late 0849s\ a report of chlorobromination of a steroidal alkene using phenyltrimethylammonium dichlorobromate "PhMe2NBrCl1# ð48TL13 has been followed more recently with methods using tetrabutylammonium dichlorobromate ð73BCJ1000\ 75BCJ2408[ The regiochemistry of addition with the latter reagent has been shown to be in~uenced more by steric than electronic factors ð75BCJ1436[ Addition of benzyltriethylammonium chloride to a mixture containing dimethylsul_deÐbromine adduct generated in situ also results in net chlorobromination of alkenes ð74G18[
ChlorineÐiodine addition is similarly regio! and stereoselective under a range of conditions[ It is possible to use iodine monochloride ðB!72MI 190!91 either directly ð58T3172\ 66JCS"P0#115\ 76CC0466 or generated in situ from iodine and a wide range of metal halides ð60JOC2213\ including CuCl1 ð60JOC1977\ 60JOC2213\ HgCl1 ð75JCR"S#163\ MoCl4 ð63BCJ2010 and SbCl4 ð79BCJ0289[ The latter is particularly good for deactivated alkenes[ Other reports of chlorineÐiodine addition to alkenes describe the combination of chloride ion with either I1:CuO =HBF3 or the easily!handled solid reagent bis"pyridine#iodine tetra~uoroborate\ IPy1BF3 ð74AG"E#208[ Regio! and stereoselective chloroiodination can also be achieved with iododichloride ion "ICl1−# either as its benzyltrimethyl! ammonium salt ð89BCJ2922 or in a polymer!bound pyridinium salt form ð89T1492[
14Alkyl Chlorides
1[90[2[2 Alkyl Chlorides from Alkyl Halides
Substitution of alkyl halides with chloride ion is not a particularly widely used method for alkyl chloride preparation[ Alkyl ~uoride substitution can be achieved using somewhat vigorous conditions "01M HCl "aq[## ð89TL3862 and is facilitated by phase!transfer catalysis ð81JCS"P0#1298[ Alkyl bromide substitution is more readily achieved\ either under the same conditions\ or more classically using lithium chloride in acetone ð44JCS2062[ Other phase!transfer catalytic procedures for this transformation are known ð66JOC764\ 68JOC0850\ 70TL3398\ 73TL4838\ 75CC0149[ The conversion from alkyl bromides can also be achieved using a polymer!supported chloride source "Amberlyst A15# ð65S361\ or in more extreme cases "e[g[\ adamantyl systems# using tin tetrachloride ð78S503 or silver chlorodi~uoroacetate ð69TL2336[ Both bromides and iodides are converted to chlorides on treatment with antimony pentachloride on graphite ð63TL652\ while primary iodides can be converted to chlorides with PCl4 in POCl2 ð74AJC0768[ Iodobenzene dichloride PhICl1 is useful for bridgehead iodide!to!chloride conversions ð75TL5944\ 78TL680\ while a little!used iodide!to!chloride conversion uses HCl in the presence of HNO2\ which oxidises the liberated iodide ion to I1
ð58JOU860[
1[90[2[3 Alkyl Chlorides from Alcohols and their Derivatives
A number of methods for the conversion of alcohols to halides "including chlorides# have already been discussed in Section 1[90[0[3[0[ Classical methods using hydrochloric acid often work well on tertiary systems ð30OSC"0#033 where an SN0 mechanism is favoured\ but primary and secondary alcohols react more slowly\ and often need catalysis with ZnCl1 ð30OSC"0#031\ 32JCS525 or phase! transfer catalysts ð63S26\ 76JCS"P0#1046\ 77S757[ Use of HCl in hexamethylphosphoramide "HMPA# gives good yields of alkyl chlorides from primary\ secondary and tertiary alcohols without rearrange! ment ð64CJC2519[ In many cases\ hydrogen chloride causes in elimination\ rearrangement and loss of stereochemical integrity at carbon\ so alternative reagents are frequently used[ Probably the most commonly used inorganic acid chloride for this purpose is thionyl chloride "SOCl1# ð52OSC"3#058\ B!63MI 190!90\ 64JOC023\ which can give chlorides with inversion\ retention or racemisation\ depend! ing on the substrate and conditions ð41JA297\ 42JCS0698\ B!63MI 190!90\ 65JCS"P0#093[ A rarely used alternative to SOCl1 is SeOCl1 "generated in situ from SeO1 and TMS!Cl#\ which is e}ective on primary\ secondary\ tertiary\ allylic and benzylic alcohols ð77JOC2523[ PCl4 usually gives inversion ð35JCS0027\ but tertiary chlorides can be obtained with retention of con_guration provided CaCO2
is present to bu}er the HCl produced ð65AJC022[ PCl4 adsorbed onto a polymer!supported tertiary amine has been applied to alkyl chloride synthesis from alcohols ð72S295[ Although POCl2 is rarely used for this purpose\ Me1NP"O#Cl1 is e}ective in primary systems ð67CL812[ DMF catalyses the decomposition of alkyl chloroformates derived from alcohols as shown in Scheme 11 ð72JOC1514[
R OH R Cl R O Cl
OCOCl2
CH2Cl2
DMF
76–100%
Scheme 22
Further reductions in the levels of rearrangement products can be achieved using reactive Vilsmeier species such as "5# and "20#\ which can be prepared in situ by reaction of amides "usually DMF# with PCl2 ð65S287\ SOCl1 ð65JCS"P0#093\ 65JCS"P0#643\ PCl4 ð63CI"L#553\ 65JCS"P0#643\ POCl2 ð82SC1088 or "COCl#1 ð58JOC1052\ 74JA2174[ Vilsmeier|s salt "20# and the related Viehe|s salt "21# have been shown to be selective for primary over secondary alcohols in their conversion to chlorides ð81TL2018\ 81TL3890[ A range of less common iminium salts have also been reported for alkyl chloride preparation from alcohols ð79S635\ 73CL0062 "see also Section 1[90[0[3[0#[
N
(31) (32)
Allylic and benzylic alcohols are readily chlorinated with either COCl1:pyridine ð80JOC6075\ or a combination of dimethylsul_de and N!chlorosuccinimide "Scheme 12# ð61TL3228\ but note that under the latter conditions saturated alcohols give carbonyl compounds if Et2N is present "Swern!
15 Alkyl Halides
type oxidation#[ Allylic rearrangement can be minimised by converting the alcohol to a phosphate ester before treatment with halide ion "Equation "39## ð73S730[
Scheme 23
SMe2
major minor
Other reagent systems useful for the preparation of allylic and benzylic chlorides from alcohols include TMS!Cl:K1CO2 ð72S203 and the somewhat more vigorous tin tetrachloride ð78S503[ The latter reagent also converts tertiary "including adamantyl# and benzylic alcohols to chlorides[ Milder conditions for tertiary and adamantyl systems use radical methods as illustrated in Scheme 13 ð64JA1170\ 71JOC021\ 76S24[
OH O
Cyanuric chloride ð69JOC2856 and even stoichiometric Pd"PhCN#1Cl1 ð67TL3464 have been reported for alkyl chloride preparations from alcohols\ but these methods are little used[
Cleavage of dialkyl ethers with HCl is of little preparative use\ but the use of surfactants has facilitated the HCl!mediated conversion of arylalkyl ethers to alkyl chlorides\ and of cyclic ethers to a\v!dichlorides "Equation "30## ð78JCR"S#173[ Cyclic ethers can also be converted to a\v!dichlor! ides by treatment with the Vilsmeier reagent derived from thionyl chloride and DMF ð51CB1865[ Acetyl chloride cleaves ethers to alkyl chlorides in the presence of ZnCl1 ð43JCS1708 or SnCl3 ð56JOC20\ 67T0140\ the former being restricted to benzylic systems and the latter being particularly e}ective in bridgehead systems[ BCl2 has also been used to cleave secondary ethers to secondary alkyl chlorides ð52CI"L#598[
O Cl
87% (41)
Finally\ epoxides can be converted directly into 0\1!dichlorides by treatment with SO1Cl1:pyridine ð55CJC1228\ PCl4 ð57CC865\ PPh2:Cl1 ð60T1506\ 65JOC2168\ 77OSC"5#313 or PPh2:CCl3 ð61TL2758\ 72JOC2242[ Inversion occurs at both carbons\ so the stereochemistry of the product is dictated by the stereochemistry of the epoxide "Equation "31##[ An alternative procedure for 0\1!dichloride synthesis from epoxides is depicted in Equation "32# ð66CL0902[
O R1
R2 R4
16Alkyl Bromides
1[90[2[4 Alkyl Chlorides from Amines and their Derivatives
In addition to those methods described in Section 1[90[0[4\ it has been shown that treatment of allylic or benzylic tertiary amines with ethyl chloroformate gives rise to the corresponding allylic or benzylic chlorides "Equation "33## ð60JMC871\ 66CL0914\ 66S675[ By using a!chloroethyl chloro! formate\ substituted piperidines can be converted to saturated primary alkyl chlorides in high yields "Equation "34## ð73JOC1684[ Extension of this procedure to secondary alkyl chloride preparation is problematic\ not so much because of competing piperidine ring cleavage\ but because the secondary alkyl halide produced is prone to HCl elimination under the reaction conditions[ In a procedure sometimes called the von Braun reaction "but see also Section 1[90[3[4#\ benzylic amides are converted to benzylic chlorides by treatment with thionyl chloride "Equation "35## ð51JA658[
R1 NR3R4
MeNO2
(46)
1[90[2[5 Alkyl Chlorides by Chlorodecarboxylation of Carboxylic Acids and their Derivatives
See Section 1[90[0[5[
1[90[2[6 Alkyl Chlorides by Chloroalkylation of Arenes
See Section 1[90[0[6[
1[90[3 ALKYL BROMIDES] RBr
The chemistry of alkyl bromides closely resembles that of alkyl chlorides\ but bromides are far more widely used as synthetic intermediates since they undergo a large range of transformations under relatively mild reaction conditions[
1[90[3[0 Alkyl Bromides from Alkanes
The bromination of unactivated alkanes by free!radical means has been discussed in a review ð69S6[ In addition to the methods of Barton et al[ described in Section 1[90[0[0\ the bromination of symmetrical alkanes can be achieved with elemental bromine in the presence of HgO "forming Br1O in situ# ð61CJC2098[ While elemental bromine itself can halogenate benzylic positions ð52OSC"3#873\ 71BSF"1#216\ 82TL4614\ N!bromosuccinimide "NBS# is far and away the reagent of choice for allylic and benzylic bromination "without bromination of aromatic rings# and this reaction "known as the WohlÐZiegler bromination# has been the subject of a number of reviews ð37CRV160\ 48AG238\ B!63MI 190!91[ The reaction usually "but apparently not always\ ð89TL6498# requires radical initiators such as irradiation ð81BCJ234 or dibenzoyl peroxide ð52OSC"3#097\ 52OSC"3#810\ 62OSC"4#217\ 62OSC"4#714\ 82JOC3271\ and is typically carried out in a nonpolar solvent such as CCl3 from which the succinimide by!product is readily removed by _ltration[ It has been suggested that the reaction involves molecular bromine which is formed at very low concentrations ð63JA4505[ Little used alternatives to NBS include 0\1!dibromotetrachloroethane ð52CI"L#0843 and N!bromosaccharin
17 Alkyl Halides
ð65S625\ 71JOC0477[ A polymer!supported poly"vinylpyridine#ÐBr1 complex has been used for ben! zylic bromination ð75JOC818\ as has CuBr1 in the presence of t!butyl hydroperoxide ð70SC558[ A comparison of photochemical methods of benzylic bromination has been made ð77T5414[
A whole host of di}erent brominating agents have been applied to the a!bromination of various ketones and aldehydes\ as indicated in Larock|s tabulations ðB!78MI 190!90[ In addition to this\ a detailed discussion of the synthesis of a!bromoketones has been published ðB!77MI 190!90[ Not! withstanding the plethora of alternative reagents\ molecular bromine is probably still the most commonly used reagent for this transformation[ Direct bromination of ketones can be achieved with Br1 in acetic acid "e[g[\ Equation "36## ð75JOC2279\ or conc[ HBr"aq[# ð77OSC"5#419\ 77OSC"5#600[ Nonacidic solvents can also be used ð77OSC"5#082\ 77OSC"5#880\ and the addition of trimethylborate has been shown to boost yields in certain circumstances ð76IZV1284[ Even aldehydes can be controllably a!brominated ð62BSF0354[ HBr is of course generated during the reaction\ and this can be scavenged by incorporating an epoxide into the reaction mixture ð66JCS"P0#490[ Other milder reagent systems include pyridinium hydrobromide perbromide "PyHBr2# ð77TL5724\ its 3! dimethylamino analogue ð73SC828\ 1!pyrrolidone hydrotribromide ð74BCJ0488\ 76JOC4513\ PhMe2NBr2 ð77OSC"5#064\ Bu3NBr2 ð76BCJ0048 and some polymer!supported tetraalkylammonium perbromides ð68S53\ 79S032\ 81SC0812[ In the latter case\ even acid!sensitive furyl ketones were successfully brominated "Equation "37## ð81SC0812[ A polymer!supported pyridineÐBr1 complex has also been reported for ketone bromination ð78SC1370[
O
O
O
O
O Br (48)
R = alkyl, aryl
For substrates which contain a double bond or aromatic ring which might be susceptible to electrophilic bromination\ the use of CuBr1 is recommended ð51JOC3826\ 53JOC1914\ 53JOC2348\ B!62MI 190!93\ 64JOC0889\ and this is a particularly useful reagent for the bromination of malonates ð82JOC3485[ Using DMSO as oxidant\ TMS!Br ð75JCR"S#317 or ButBr ð73T1924 can be used to brominate aldehydes and ketones[ In both cases\ a bromosulfonium ion "analogous to the chlorosulfoniu