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Comprehensive Organic Functional Group Transformations, Volume 2 (Synthesis: Carbon with One Heteroatom Attached by a Single Bond) PDF

1286 Pages·2003·12.48 MB·English
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Preview Comprehensive Organic Functional Group Transformations, Volume 2 (Synthesis: Carbon with One Heteroatom Attached by a Single Bond)

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. 3 Part I: Functions Linked by a Single Bond to an sp 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 2 Part II: Functions Linked by a Single Bond to an sp 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 1 2 − 1 2 + 1 2 · (R R C X, R R C X, R R C 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‘en�halo‘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 ~uorine�halo‘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 chlorine�halo‘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 bromine�halo‘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 iodine�iodine 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 �59HOU"4:3#0\ 51HOU"4:2#0�\ in Comprehensive Or‘anic Chemistry �68COC"0#382�\ and in an excellent review by Hudlicky and Hudlicky in The Chemistry of Functional Groups series �B!72MI 190!90�[ The latter review includes some useful {Halogenation Tables| "reproduced from an earlier publication �67OPP070� 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 �80COS"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 �B!77MI 190!90�[ Many classical methods for the synthesis of alkyl halides are still widely used\ and the Houben!Weyl volumes �59HOU"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 �B!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 �83MI 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 �see 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 �B!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# �81T8084\ 81TL2302\ 82TL0760\ 82TL4578\ 83T20�[ For a short review on this and related chemistry see �81ACR493�[ General Methods 2 Hal polyhaloalkane/H2O2 or MHal/TBHP (1) Fe(III)/pyridine/AcOH 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 �83TL0316\ 83TL0320�\ the radical nature of halogenation at allylic and benzylic sites is universally accepted �B!61MI 190!90�[ The latter reaction is most commonly applied in the synthesis of allylic and benzylic bromides using N!bromosuccinimide "the Wohl�Ziegler 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#[ 3 O O OR + + 'Hal ' Hal 'Hal ' 1 1 1 R R R 2 2 2 R R R 3 R = alkyl, acyl, silyl 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 �71S0910�\ benzoyl peroxide\ hydrogen peroxide or mcpba �65CPB719�[ 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 �B!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 �37JA054�[ Thionyl chloride converts acid chlorides to a!chloro!\ a!bromo! or a!iodoacid chlorides when combined with NCS\ NBS or iodine respectively �64JOC2319�[ 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# �72TL052\ 76S077� or deacetylation �38JA2096\ 61TL3956\ 76TL4494�[ A related method for preparing a!~uoroketones has also been described �78CL466�[ SO2Cl2 O O O CH2Cl2, RT CO2Me 50% H2SO4, ∆ CO2Me R R R 81–98% 78–85% Cl Cl 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 "Y�O\ N\ S\ Se\ etc[# to alkenes �82S0066�[ 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 halogen�hydrogen and halogen�halogen only[ 3 Alkyl Halides 1[90[0[1[0 Alkyl halides by hydrohalogenation of alkenes The direct addition of HHal "Hal�F\ 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 �39CRV240\ 51CRV488� and hydrobromination �52OR"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[ Hal + Hal– 'Markovnikov' H H+ R H product R Major R H H Minor – Hal 'Anti-Markovnikov' H+ + Hal R R product Scheme 3 A general method for Markovnikov addition of HHal "Hal�Cl\ Br\ I# to alkenes using phase! transfer catalysis has been reported �79JOC2416� and a polymer!supported phase transfer catalyst can be conveniently used for this purpose �77IJC"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 �89JA6322\ 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 �39CRV240�[ Anti!Markovnikov addition of HCl\ HBr or HI is generally achieved via hydrometallation\ usually hydroboration �70JCR"S#265\ 70JOC1471\ 70JOC2002\ 72HCA0907� or hydroalumination �65JOM"011#C14\ 67CL722�\ followed by treatment with an electrophilic halogen source "Scheme 3#[ H H 'LnMH' MLn 'Hal+' Hal R R R M = B, Al, Zr, Si L = Ligand (including carbon-bonded ligands) Hal = Cl, Br, I Scheme 4 The halogenolysis of organoboranes has been brie~y reviewed �74OR"22#0\ 80COS"6#482�\ as has its applications to the incorporation of radioactive halogen isotopes �73ACR104�[ BCl2 and BBr2 are recent additions to the list of reagents suitable for this purpose �82S862�[ Hydrosilylation followed by treatment with Cl1\ Br1\ I1\ NBS or copper"II# chloride or bromide also gives access to the anti! Markovnikov products �67JA189\ 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\ �63JA7004�^ see also �65AG"E#222\ 70JOC0710�#[ i, Cp2Zr(H)Cl, PhH ii, I2, CCl4 I 91% Scheme 5 General Methods 4 1[90[0[1[1 Alkyl halides by halogen�halogen 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 �61RCR639\ 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[ R1 R3 δ+ δ– X + X 3 X R3 X Y 1 3 + R R4 R R R2 R4 R2 R4 R1 R2 R4 R1 R2 Y – Y (1) (2) X, Y = halogens Scheme 6 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[ 2 MHal 1 2 RHal RHal (2) 1 2 Hal , Hal = F, Cl, Br, I M = metal, R4N 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 +OH2 Hal R3 H+ –H2O + R3 R1 R3 R3 R1 R3 + R2 R1 R2 R1 R2 SN1 R2 R1 R2 Hal (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 �59HOU"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 �B!78MI 190!90�[ The use of oxyphosphonium intermediates for this transformation has been thoroughly reviewed �72OR"18#0�\ as has the synthesis of optically active alkyl halides from opti! cally active alcohols �58S001�\ 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 �62S675\ 80T4218�\ particularly Olah|s pyridine poly"hydrogen ~uoride# reagent "PPHF#\ either in solution or in a poly"vinylpyridine#!polymer!supported form "PVPHF# �89SL156\ 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 �63S542\ 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 �72OR"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 �70S0\ 81OR"31#224�[ Using zinc"II# halide as halide source\ chlorides\ bromides and iodides can be prepared with clean inversion of con_guration �73JOC2916\ 89SC2928�\ while the use of LiF can also give access to ~uorides �74SC552�[ 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 �74G282�[ Alternatives to dead include the more stable diisopropyl azodicarboxylate "diad# �89SC2928� and the cyclic diazodicarboxylate "2#\ which is used in combination with PPh2 and MeI or MeBr �73BCJ1564�[ A driving force in all of these reactions\ and related reactions described below\ is the formation of the strong phosphorus�oxygen double bond[ OH Hal EtO2CN=NCO2Et (dead) (3) 1 2 1 2 R R PPh 3, ZnHal2, THF R R 66–92% Hal = Cl, Br, I O N NMe N O (3) General Methods 6 OH + EtO2C EtO2C H PPh3 – R1 R2 OPPh3 EtO2CN=NCO2Et N NCO2Et + N N Ph3P + R1 R2 CO2Et ZnHal2 (SN2) Hal EtO2C Zn )2 + N N + O PPh3 1 2 R R H CO 2Et Scheme 8 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 �57CPB0998�\ chlorides\ bromides and iodides "Equation "3## �53JA853�[ OH Hal Ph3PHal2 (4) 1 2 1 2 R R R R Hal = F, Cl, Br, I While Ph2PBr1 usually gives the best results �54JOC1524\ 62OSC"4#138\ 73JOC320\ 81SC1834�\ it has been found that the addition of imidazole to Ph2PCl1 �73S057� or Ph2PI1 �68CC867\ 89SC0362� or\ alternatively\ the use of triiodoimidazole instead of iodine �68CC867\ 79JCS"P0#1755\ 71JCS"P0#570�\ all lead to signi_cantly improved yields[ Other phosphines such as Bu2P �71AJC406�\ Ph1PCH1CH1PPh1 �76TL656� or a triaryl phosphite "ArO#2P �81CL0494� have proved advantageous in certain cir! cumstances[ The use of a polymer!supported triphenylphosphine dibromide �73JCS"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 �77JOC5015�[ 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 �77JOC5015�[ In a logical extrap! olation of this approach\ PhPCl3 has been introduced as a new reagent for alkyl chloride synthesis from alcohols �89JOC2304�[ 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## �62CC009\ 65CB2335\ 73S057\ 77OSC"5#523\ 80TL2866�[ For reviews on this chemistry see �64AG"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 �61JOC0355�[ As with the Ph2PHal1 method described above\ the use of a polymer!supported triphenylphosphine gives easier workups �64CC511\ 64JOC0558\ 73JCS"P0#084\ 74CC226�\ as does the use of a phosphine carrying a water!soluble pyridyl side chain �76JOC3888�[ Another alternative phosphine is tris"dimethyl! amino#phosphine\ "Me1N#2P\ which generates the water!soluble "but carcinogenic# by!product hexa! methylphosphoramide "HMPA# �57CC0249\ 64BSF596�[ CBr3 is commonly used in combination with PPh2 �66LA795\ 76CS366\ 82JOC3271� or other phosphines �75JOC678\ 75TL0596�\ and is particularly useful for allylic\ benzylic and saturated primary alkyl systems[ CI3�PPh2 is less commonly used �67CAR"50#400\ 80TL2866�[ OH Hal Ph3P (5) 1 2 1 2 R R CHal4 R R Hal = Cl, Br, I 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 �72S028�\ ethyl trichloroacetate and ethyl tribromoacetate �78JOU531�\ trichloroacetonitrile "which even works on neopentyl alcohols# �78JOU476�\ and hexachloroacetone\ which is most e}ective in – 7 Alkyl Halides converting allylic alcohols to allylic chlorides without rearrangement �66TL1888\ 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 �82SC600�[ 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 �62TL2826�#[ It is also particularly useful for the preparation of bromides in sensitive systems "e[g[\ �75JOC1526\ 82OPP138�[ OH Hal Ph3P (6) 1 2 1 2 R R N-halosuccinimide R R Hal = Cl, Br, I Triphenyl phosphite P"OPh#2 has been used in combination with Cl1\ Br1 and I1 �43JCS1170�\ with NCS\ NBS and NIS �62TL2826�\ and with benzyl chloride and bromide �42JCS1113�\ 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 phosphite�methiodide reagent\ "PhO#2PMeI\ converts a wide range of primary "including neopentyl#\ secondary\ tertiary\ allylic and benzylic alcohols to iodides "Equation "6## �42JCS1113\ 77OSC"5#729\ 82TL1646�[ It is particularly widely used in carbohydrate and nucleoside chemistry �69JOC1208�[ OH + – I (PhO)3PMe I (7) 1 2 1 2 R R R R 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 �71TL3300�[ Ph N RO P N Ph (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 �78TL2966�[ "See also �59JA898� 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 �79S635�\ as well as the benzothiazolium salts "6# �65CL508� and benzoxazolium salts "7# �66CL272�[ 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 �76S400�\ or with carbodiimides �61AG"E#118\ 76TL3334�[ Meanwhile\ chlorides\ bromides and iodides can all be readily prepared from xanthates "8# �65JCS"P0#1001�[ 3 NR 2 (5) OH Hal Hal (8) R1 R2 CH2Cl2, RT R1 R2 53–99% Hal = F, Cl, Br, I 3 i R = Me, Pr

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