Volume 1 Synthesis: Carbon with No Attached Heteroatoms
Part I: Tetracoordinated Carbon with No Attached Heteroatoms 1.01 One or More CH Bond(s) Formed by Substitution: Reduction of C---Halogen and C---Chalcogen Bonds, Pages 1-26, Alan G. Sutherland 1.02 One or More CH Bond(s) Formed by Substitution: Reduction of Carbon– Nitrogen, –Phosphorus, –Arsenic, –Antimony, –Bismuth, –Carbon, –Silicon, – Germanium, –Boron, and –Metal Bonds, Pages 27-70, Joshua Howarth 1.03 Two or More CH Bond(s) Formed by Addition to CC Multiple Bonds, Pages 71-103, Keith Jones 1.04 One or More CC Bond(s) Formed by Substitution: Substitution of Halogen, Pages 105-169, Gavin L. Edwards 1.05 One or More CC Bond(s) Formed by Substitution: Substitution of Chalcogen, Pages 171-247, Timothy N. Birkinshaw 1.06 One or More CC Bond(s) Formed by Substitution: Substitution of Carbon– Nitrogen, –Phosphorus, –Arsenic, –Antimony, –Boron, –Silicon, –Germanium and –Metal Functions, Pages 249-292, Philip C. Bulman Page, Heather L. McFarland and Andrea P. Millar 1.08 One or More CC Bond(s) Formed by Addition: Addition of Carbon Radicals and Electrocyclic Additions to CC Multiple Bonds, Pages 319-375, Andrew J. Clark and Paul C. Taylor
1.09 One or More CH and/or CC Bond(s) Formed by Rearrangement, Pages 377-423, Iain Coldham
Part II: Tricoordinated Carbon with No Attached Heteroatoms
1.10 One or More =CH Bond(s) Formed by Substitution or Addition, Pages 425-460,
Martin A. Hayes 1.11 One or More =CC Bond(s) Formed by Substitution or Addition, Pages 461-500, Patrick G. Steel by kmno4 1.12 One or More C=C Bond(s) Formed by Addition, Pages 501-551, Andrew C. Regan 1.13 One or More C=C Bond(s) by Elimination of Hydrogen, Carbon, Halogen or Oxygen Functions, Pages 553-587, Jonathan M. Percy 1.14 One or More C=C Bond(s) by Elimination of S, Se, Te, N, P, As, Sb, Bi, Si, Ge, B or Metal Functions, Pages 589-671, Anita R. Maguire
1.15 One or More C=C Bond(s) Formed by Condensation: Condensation of Nonheteroatom Linked Functions, Halides, Chalcogen or Nitrogen Functions, Pages 673-717, Christopher M. Rayner 1.16 One or More C=C Bond(s) Formed by Condensation: Condensation of P, As, Sb, Bi, Si or Metal Functions, Pages 719-770, Ian Gosney and Douglas Lloyd 1.17 One or More C=C Bond(s) by Pericyclic Processes, Pages 771-791, Hamish McNab 1.18 One or More =CH, =CC, and/or C=C Bonds Formed by Rearrangement, Pages 793-842, Patrick J. Murphy 1.19 Tricoordinate Anions, Cations, and Radicals, Pages 843-951, Julian O. Williams and Michael J. Kelly Part III: Dicoordinate and Monocoordinate Carbon with No Attached Heteroatoms
1.20 Allenes and Cumulenes, Pages 953-995, Christian Bruneau and Pierre H. Dixneuf 1.21 Alkynes, Pages 997-1085, Mark Furber 1.22 Ions, Radicals, Carbenes and Other Monocoordinated Systems, Pages 1087- 1145, Julia M. Dickinson 1.23 References to Volume 1, Pages 1147-1316
by kmno4
Comprehensive Organic
University of Florida, Gainesville, FL, USA
Otto Meth-Cohn University of Sunderland, UK
Charles W. Rees, FRS Imperial College of Science, Technology and Medicine, London, UK
Volume Editors
Volume 1. Synthesis: Carbon with No Attached Heteroatoms Stanley M. Roberts, University of Exeter, UK
Volume 2. Synthesis: Carbon with One Heteroatom Attached by a Single Bond Steven V. Ley, FRS, University of Cambridge, UK
Volume 3. Synthesis: Carbon with One Heteroatom Attached by a Multiple Bond Gerald Pattenden, FRS, The University of Nottingham, UK
Volume 4. Synthesis: Carbon with Two Heteroatoms, Each Attached by a Single Bond Gordon W. Kirby, University of Glasgow, UK
Volume 5. Synthesis: Carbon with Two Attached Heteroatoms with at Least One Carbon-to-Heteroatom Multiple Link
Christopher J. Moody, Loughborough University of Technology, UK
Volume 6. Synthesis: Carbon with Three or Four Attached Heteroatoms Thomas L. Gilchrist, University of Liverpool, UK
Preface Some years ago the three of us met in a London club reviewing an ongoing publishing venture in
Organic Synthesis. The conversation drifted to a consideration of volumes on the synthesis of key functional groups. No doubt the good wine helped since we actually broached the idea of a work on the synthesis of all functional groups. Would it be useful? Definitely. Would it be feasible? How would it be organized? Where do you start? We recognized that functionality was based on the coordination and heteroatom attachment of a carbon atom. But putting together a complete framework seemed particularly daunting. Two of us became very interested in the fascinating bouquet of the Muscat de Beaumes de Venise.
At our next dinner together Alan announced that he had solved the problems posed last time— problems that Charles and I hoped he had forgotten! He brought out a remarkable matrix analysis of all functional groups, analysed rigorously and logically. Even unknown functions were covered. Although we were all very impressed, the practicalities of the idea still seemed daunting. Those who know Alan's terrier instincts will appreciate that he would not give up such a challenge so easily. Our twice yearly club get-togethers, occasionally with friends from Pergamon, refined our thinking. Alan's cosmic vision was tempered by Charles's intuitive realism and fully supported by the publishers.
Another major problem remained: how to reduce our thinking into a practical handbook for authors—a dismaying task for three busy chemists. We settled on a seven-volume work and the indomitable ARK produced a rough breakdown to fit such a format. Putting flesh on these bones became feasible during a fortuitous three-month break between jobs by myself, and the largest handbook ever assembled by Pergamon (120 pages) was written and page allocations agreed—even for little or unknown functional groups. Sample chapters were commissioned and finally proved very encouraging, despite our first chosen topic uncovering virtually no known examples!
Contracts were defined and agreed, volume editors approached, and potential authors considered during a pleasant preconference stay in Grasmere. Following the sale of Pergamon to Elsevier Science Ltd there was a lull in the project but soon Comprehensive Organic Functional Group Transformations was back on track, and everyone adhered to a very businesslike timetable.
OTTO METH-COHN CHARLES W. REES Sunderland London
ALAN R. KATRITZKY Florida
Introduction OBJECTIVES, SCOPE, AND COVERAGE
Comprehensive Organic Functional Group Transformations (COFGT) aims to present the vast subject of organic synthesis in terms of the introduction and interconversion of functional groups. All organic structures can be considered as skeletal frameworks of carbon atoms to which functional groups are attached3; it is the latter which are mainly responsible for chemical reactivity and which are highlighted in COFGT. All known functional groups fit a logical and comprehensive pattern and this forms the basis for the detailed list of contents. The format of the present work was designed with the intention to cover systematically all the possible arrangements of atoms around a carbon, including those which are quite unfamiliar. The work also considers the possibility of as yet unknown functional groups which may be constructed in the future and prove to be important; thus COFGT also indicates what is not known and so points the way to new research areas.
The philosophy of the present work has been to rationalize this enormous subject within as logical and formal a framework as possible, in a scholarly and critical fashion. COFGT is designed to provide the first point of entry to the literature for synthetic organic chemists, together with an unrivalled source for anyone interested in less common, obscure, or unknown functional groups.
All functional groups are viewed as being carbon based (even if the group contains no carbon). Thus, a nitro compound is considered from the standpoint of the immediately attached carbon atom, whether di- (sp), tri- (sp2), or tetracoordinated(.s/?3). The work is organized on the basis of formation or rupture of bonds to a carbon atom and it is the nature of the carbon atom left after the transformation that determines the classification of the overall sequence. Several key criteria have been used to organize the work and to minimize overlap. These are, in order of priority:
1. the number of attached heteroatoms; 2. the coordination of the carbon atom involved in the functional group; 3. the nature of the immediately attached heteroatom(s); and 4. the Latest Placement Principle.
These four key principles have been used to determine the content of each volume, and to develop the detailed chapter breakdown within each volume.
Thus, according to the number of attached heteroatoms: Volume 1 deals with synthetic reactions which result in the alteration of bonding at carbon atoms
which are left with no attached heteroatoms. Volume 2 deals with syntheses which result in carbon atoms attached to one heteroatom by a
single bond. Volume 3 deals with syntheses which result in carbon atoms attached to one heteroatom by a
double or by a triple bond. Volume 4 deals with syntheses which result in carbon atoms attached to two heteroatoms, each
by a single bond. Volume 5 deals with syntheses which result in carbon atoms attached to two heteroatoms by one
single and one double bond, or by two double bonds, or by one single and one triple bond. Volume 6 deals with syntheses which result in carbon atoms attached to three or four heteroatoms. Volume 7 comprises the author and subject indexes. Certain key principles apply to all the volumes because all functional groups are viewed as carbon
based (e.g. a nitro group is either alkyl-, vinyl-, aryl-, or alkynyl-); these are:
(a) Volumes are subdivided according to the coordination of the carbon atom which is the product of the reaction, i.e., tetra- coming before tri- before di- before monocoordinated carbon functions.
"The major exception to this lies in heterocyclic compounds, where the cyclic heteroatoms are more logically considered as part of the framework. The subject of heterocycles has been treated elsewhere in the companion work Comprehensive Heterocyclic Chemistry published in 1984 with a second edition to be published in 1996.
Introduction
In Volumes 1 and 6, reactions producing four-coordinated carbon are considered first, followed by three- and then two-coordinated carbon. The other volumes contain a more limited range of coordination types (Volumes 2 and 4 only four-coordinated, Volumes 3 and 5 only two- or three- coordinated). Each type of coordination is allocated a separate section in each volume.
(b) Attached heteroatoms are discussed in the following order of priority:
Halogens—F, Cl, Br, I Chalcogens—O, S, Se, Te Nitrogen—N Other group 15 elements—P, As, Sb, Bi Metalloids—B, Si, Ge Main group metals—Sn, Pb, Al, Ga, In, Tl, Be, Mg, Ca, Sr, Ba, Li, Na, K, Rb, Cs Transition metals—Cu, Ag, Au, Zn, Cd, Hg, Ti, Zr, Hf, Cr, Mo, W, Mn, Fe, Co, Ni, Pd,
Pt, and others.
Higher coordination of heteroatoms is treated after lower. Thus, in sections dealing with iodo compounds, monocoordinate (e.g. iodides) are discussed before dicoordinate (e.g. iodoxyls) and tricoordinate functions.
(c) The Latest Placement Principle (or Last Position Principle) is used to avoid undue overlap in the work. Thus, the carbon attached to the heteroatom is discussed at the last possible position in the above prioritizing of heteroatoms. Examples of its application are noted later. On this basis, for example, when both C—C and C—H bonds are formed the reaction will appear in the latest chapter (i.e. Chapters 1.04—1.10 rather than in the earlier Chapters 1.01-1.03), and when both C—C and C = C bonds are formed, this will be found in the later Chapter 1.17. The Latest Placement Principle is particularly important in determining where to find electrocyclic reactions in Volume 1. If C—H, =C—C, and C = C bonds are all formed in a reaction, then the latest appropriate chapter will deal with the reaction. Only if a change in heterofunction occurs is the reaction left to a later volume.
Exceptions to the above principles are rare. However the reactions of heteroarenes are mentioned along with those of arenes. If on reduction no change in the heterofunction occurs (e.g. in going from thiophene to tetrahydrothiophene or from pyridine to 2,3,4,5-tetrahydropyridine) the reaction is found in Volume 1. However, when the function changes (e.g. pyridine to piperidine), the conversion is considered in Volume 2. Conversion of methyl phenyl sulfone into methyl cyclohexyl sulfone appears in Volume 2, whereas the formation of cyclohexyl methyl ketone is treated in Volume 1, since the coordination of the carbon atom to the heteroatoms is changed in the first but not in the second hydrogenation.
Some further exceptions to the rigorous ordering of the work have been made for the purpose of easy reference. Thus, in Volume 1, a special chapter on ions, radicals, and carbenes is added: this chapter is limited to the treatment of species capable of more than a transitory existence. Throughout the work aspects of the Latest Placement Principle are occasionally ignored for reasons of clarity. Thus metal ligands that are incidental to the chemistry under discussion are not considered when prioritizing. Also, references to aromatic substituents, some of which involve a heteroatom (e.g. pyridyl, thienyl, etc.) but are incidental to the chemistry being described, are not viewed as changing the priority.
Within each section, we have endeavored to explain the influence of important secondary effects such as inclusion in a ring, degree of strain, degree of substitution, various types of activation, influence of stereochemistry, and so on, on the transformation under consideration. General syn- thetic methods are treated before specific methods.
Transient intermediates, as such, do not fall within the scope of this work. Although there is clearly no sharp division, we have attempted to restrict coverage of radicals, etc., to more stable, longer lived species. It is the aim of this work to consider all organic functional groups provided that the molecules which incorporate them, though they may be unstable, can have a finite lifetime and chemistry. The whole work deals with the generation and transformation of functional groups, not of molecules such as CO2, COS, CS2, CICN, etc. Such simple carbon derivatives are not treated unless a further carbon is attached (e.g. R N = C = O ) .
VOLUME 1 SYNTHESIS: CARBON WITH NO ATTACHED HETEROATOMS
Volume 1 deals solely with the formation of nonheteroatom functional groups and as such is different in style to the remaining volumes.
Introduction
In addition to the general principles, Volume 1 is further organized as follows:
1. By the type of bond formed (i.e. C—H before C—C). 2. By the type of reaction involved (i.e. substitution, then addition, then rearrangement). With
C = C bond formation the order is addition, elimination, condensation, then electrocyclic and other methods. One rearrangement chapter only is devoted to each of the Parts I and II.
3. In Parts II and III the treatment of formation of ions, radicals, and carbenes is added at the end of the section dealing solely with those species with a significant rather than a transient lifetime.
In Volume 1, the heteroatom sequence is a secondary feature since only remote heteroatom functions are involved in the products: but the standard order pertains in reactants that contain heteroatoms (see, e.g. Chapters 1.01 and 1.02).
All the major structural influences that are treated throughout this work apply equally (or perhaps more importantly) in Volume 1. Thus the effects of conjugation, remote substituents, rings, stereochemistry, strain, kinetic or thermodynamic factors, solvation, primary, secondary and tertiary nature, etc., are mentioned whenever relevant.
VOLUME 2 SYNTHESIS: CARBON WITH ONE HETEROATOM ATTACHED BY A SINGLE BOND
Volume 2 is arranged in three parts: I, II and III, dealing respectively with sp3, sp2, and sp carbon linked to the heteroatom. In each chapter we have endeavored to explain important effects due to such features as the primary, secondary, tertiary nature, ring effects, strain activation, effect of beta, gamma, and more remote functionality, stereochemical effects, and so on. Methods that are common to a larger group are dealt with at their first appearance and suitably cross-referenced.
Volumes 2-6 all deal with the synthesis of functions involving at least one heteroatom. To avoid major overlap we have applied the Latest Placement Principle; that is, the chemistry is discussed at the last possible position based on the prioritization of the carbon attached to the heteroatom. Thus the compound CH3ONH2 is treated under "Alkyl Chalcogenides" in the subsection "Functions Based on the RON-Unit" (i.e. 2.02.6). However, CH3ONHCH3 appears under "Alkyl Nitrogen Compounds" (2.06.2.3) since the Latest Placement Principle prevails. Also, dialkyl ethers appear in Part I of Volume 2 (Functions Linked by a Single Bond to an sp2" Carbon Atom), while alkyl aryl ethers appear in Part II of Volume 2 (Functions Linked by a Single Bond to an sp2 Carbon Atom). Exceptions to the rule are:
(a) When a fully unsaturated heterocyclic substituent (e.g. thienyl, pyridyl, etc.) is used as an example Of an aryl group, the ring heteroatom(s) is (are) not taken into account (e.g. 2-methoxy- pyridine should strictly appear in Volume 6, but is covered in Volume 2 along with 3- and 4-methoxypyridine).
(b) Carbon-based metal ligands that are incidental to the synthesis under discussion (e.g. carbonyls, cyclopentadienyls, etc.) are not taken into consideration.
VOLUME 3 SYNTHESIS: CARBON WITH ONE HETEROATOM ATTACHED BY A MULTIPLE BOND
Volume 3 follows the logical development indicated in Volume 2. Thus, according to the Last Placement Principle, the imines, RCH=N—R, appear in Volume 3 rather than in Volume 2 (where functions singly bonded to carbon are treated). Furthermore, acetophenone, PhCOCH3, is treated under cc,/J-unsaturated ketones (3.05) rather than saturated ketones (3.04). Chloronitroacrylonitriles would appear under the section "a,/?-Vinylic Nitriles with Nitrogen-based Substituents" (3.19.2.7), not under the related earlier section dealing with halo-substituents (3.19.2.3).
VOLUME 4 SYNTHESIS: CARBON WITH TWO HETEROATOMS, EACH ATTACHED BY A SINGLE BOND
Volume 4 is in three parts. Part I deals with tetracoordinated carbon bearing two heteroatoms, Part II with tricoordinated carbon bearing two heteroatoms, and Part III (a brief chapter) with stabilized radicals, ions, and the like bearing two heteroatoms. The material is arranged according
Introduction
to the Latest Placement Principle: thus, the synthesis of CHBr2CHI2 would appear in the section dealing with diiodo, not dibromo functions (i.e. in 4.01.5, not 4.01.4), and the synthesis of CF3CH- BrCl is discussed in Volume 6 (carbons bearing three heteroatoms), rather than in Volume 4.
VOLUME 5 SYNTHESIS: CARBON WITH TWO ATTACHED HETEROATOMS WITH AT LEAST ONE CARBON-TO-HETEROATOM MULTIPLE BOND
Volume 5 is in three parts. Part I deals with functions with one doubly bonded and one singly bonded heteroatom, Part II with functions containing two doubly bonded heteroatoms and Part III with one triply bonded and one singly bonded heteroatom. Part I constitutes the bulk of Volume 5.
The arrangement of the chemistry in each part follows the same logical sequence. The multiply bonded heteroatom is focused on first and then the other heteroatom in a secondary classification, both following the priority rules already described. Each section excludes the coverage of the previous sections. Thus, all carbonyl derivatives will appear in Chapters 5.01-5.10 but not in Chapters 5.11, et seq.
According to the Latest Placement Principle structure RC(O)OC(S)R is discussed in the chapter dealing with carbons bearing a doubly bonded sulfur and singly bonded oxygen (5.12.3), not in that dealing with doubly and singly bonded oxygen (5.04.1). Another effect of the Latest Placement Principle is that the amides RCONMePh are discussed under Af-arylalkanoamides (5.06.2.4), rather than 7V-alkylalkanoamides (5.06.2.2). Again, exceptions are made to the latest placement rules for: (a) hetaryl rings used as examples of aryl substituents which are not viewed as functional groups. Thus, 2-methylimidazole is not considered as an example of an amidine function and 2-methoxy- pyridine is not an example of a doubly bonded nitrogen, singly bonded oxygen function; (b) metal ligands that are incidental to the organic chemistry under discussion are not viewed as functions in priority considerations.
VOLUME 6 SYNTHESIS: CARBON WITH THREE OR FOUR ATTACHED HETEROATOMS
Volume 6 is in four parts. Part I deals with tetracoordinate carbons bearing three heteroatoms. Part II covers tetracoordinate compounds bearing four heteroatoms, i.e. substituted methanes, and Part III deals with tricoordinate systems bearing three heteroatoms, i.e. where one heteroatom is attached by a double bond. Part IV is brief and deals with stabilized radicals and ions. Not surprisingly, the coverage of Volume 6 is very large—and also shows that many gaps in the development of organic chemistry still exist.
The organization within the three sections not only follows the same broad logic developed in the previous volumes, but also has a structure unique to the multiheteroatom volume. According to the Latest Placement Principle CF3C(NR2)3 appears in the section dealing with carbons bearing three nitrogens (6.05.1.1), not that dealing with carbons bearing three halogens (6.01.2), while (CF3CH2O)2CO appears in Part III, not in Part I.
In the chapter dealing with iminocarbonyl functions in Part III, the substituents on nitrogen are discussed in each appropriate subsection in the order outlined above. Thus, the R N = group would be first considered with R = H, then alkyl, alkenyl, aryl and hetaryl, alkynyl and then heteroatom substituents in the usual order.
In each relevant section, we have endeavored to explain the influence of important secondary effects on the synthesis such as structure (primary, secondary, etc.), ring effects, strain, activation, stereochemistry, remote substituent effects, etc.
The arrangement of the chemistry in each of Parts I—III follows a similar pattern. Thus, each section commences with functions containing at least one halogen. This section deals with all combinations of halogen with other heteroatoms in the described order. The next section deals with functions containing at least one chalcogen in combination with any other heteroatoms except halogens. Subsequent sections each exclude the previous title heteroatom functions.
VOLUME 7 INDEXES
Subject Indexes are included in each of Volumes 1-6 and Cumulative Subject and Author Indexes appear in Volume 7. Most entries in the Subject Index consist of two or three lines: the first line is the entry itself (e.g. Lactones) and the second line is descriptive of that entry (e.g. reduction); in many cases more detail is given (e.g. with 9-BBN).
Introduction
REFERENCES
The references are handled by the system previously used successfully in Comprehensive Hetero- cyclic Chemistry. In this system reference numbers appear neither in the text, nor as footnotes, nor at the end of chapters. Instead, each time a reference is cited in the text there appears (in parentheses) a two-letter code assigned to the journal being cited, which is preceded by the year (tens and units only for twentieth-century references) and followed by the page number. For example: "It was shown <8OTL1327> that . . .". In this phrase, "80" refers to 1980, "TL" to Tetrahedron Letters, and "1327" to the page number. For those journals which are published in parts, or which have more than one volume number per year, the appropriate part of the volume is indicated, e.g. as in <73JCS(P2)1594> or <78JOM(l62)6ll>, where the first example refers to / . Chem. Soc, Perkin Trans 2, 1973, page 1594, and the second to J. Organomet. Chem., 1978, volume 162, page 611.
This reference system is adopted because it is far more useful to the reader than the conventional "superscript number" system. It enables readers to go directly to the literature reference cited, without first having to consult the bibliography at the end of each chapter.
References to the last century quote the year in full. Books have a prefix "B-" and if they are commonly quoted (e.g. Organic Reactions) they will have a code. Otherwise, as with uncommon journals, they are given a miscellaneous code (MI) and numbered arbitrarily abbl, abb2, etc., where abb refers to the volume and chapter number and 1, 2, etc., are assigned sequentially. Patents are assigned appropriate three-letter codes.
The references are given in full at the end of each volume. They include Chemical Abstract references when these are likely to help; in particular, they are given for all patents, and for less accessible sources such as journals in languages other than English, French, or German, company reports, obscure books, and theses.
Notes on the Reference Style within this Work
The original print version of Comprehensive Organic Functional Group Transformations gathered references for each volume into a section at the end of that volume. In this online version, references cited in the text of each chapter may be found in the ‘‘References’’ section at the end of the Chapter HTML, but are not featured in the PDF files since they were not part of the original printed chapters. The entire reference section for each volume may be accessed in both HTML and PDF format via the ‘‘Table of Contents’’ tab and at the end of each volume.
1.01 One or More CH Bond(s) Formed by Substitution: Reduction of C0Halogen and C 0Chalcogen Bonds ALAN G. SUTHERLAND University of North London, UK
0[90[0 REDUCTION OF C0HALOGEN BONDS TO CH 0
0[90[0[0 General Methods 0 0[90[0[1 Reduction of Fluoroalkanes 5 0[90[0[2 Reduction of Chloroalkanes 5 0[90[0[3 Reduction of Bromoalkanes 7 0[90[0[4 Reduction of Iodoalkanes 09 0[90[0[5 Reduction of Hypervalent Haloalkanes 00
0[90[1 REDUCTION OF C0OXYGEN BONDS TO CH 00
0[90[1[0 General Methods 00 0[90[1[1 Reduction of C0OX Bonds 01
0[90[1[1[0 Reduction of C0OH bonds 01 0[90[1[1[1 Reduction of C0O0C bonds 02 0[90[1[1[2 Reduction of C0O0heteroatom bonds 06
0[90[1[2 Reduction of C1O Bonds to CH1 07 0[90[1[2[0 Reduction of aldehydes 07 0[90[1[2[1 Reduction of ketones 07
0[90[1[3 Reduction of "C1O#X to CH2 19 0[90[1[4 Reduction of C"OX#n Systems 10
0[90[2 REDUCTION OF C0SULFUR\ C0SELENIUM AND C0TELLURIUM BONDS TO CH 10
0[90[2[0 General Methods 10 0[90[2[1 Reduction of C0SX Bonds 10 0[90[2[2 Reduction of C1S to CH1 13 0[90[2[3 Reduction of C"1S#X to CH2 13 0[90[2[4 Reduction of C"SX#n Systems 13 0[90[2[5 Reduction of C0Se Systems 14 0[90[2[6 Reduction of C0Te Systems 14
0[90[0 REDUCTION OF C0HALOGEN BONDS TO CH
0[90[0[0 General Methods
A large majority of the methods available for the reduction of alkyl halides to the corresponding alkanes\ often referred to as the process of hydrogenolysis in earlier works\ can be loosely grouped
0
1 Reduction of C0Halo`en and C0Chalco`en Bonds
into four categories] catalytic hydrogenation\ low!valent metal reduction\ metal hydride nucleophilic displacement and radical substitution[
Generally\ the observed reactivity is in the order I×Br×Cl××F for all four categories\ matching the order of bond strengths "C0I 42 kcal mol−0\ C0Br 56 kcal mol−0\ C0Cl 70 kcal mol−0\ C0F 098 kcal mol−0#[ Benzylic and\ to a lesser extent\ allylic halides also tend to be more reactive than similar alkyl halides[ The order of reactivity between primary\ secondary and tertiary alkyl halides tends to be dependent on the reagent in use[ a!Halo carbonyl compounds are par! ticularly prone to reduction by these methods\ especially in the case of low!valent metal reductions ð72OR052\ although competing carbonyl group reductions may occur with some procedures[
Until the late!0869s the _rst three categories appeared more commonly\ as re~ected in a con! temporary review ð79S314\ but radical reduction procedures have dominated since[
Catalytic hydrogenation methods have been reviewed ðB!74MI 090!90[ Practical di.culties can be encountered in utilising these procedures\ owing to catalyst poisoning by the hydrogen halide evolved\ particularly in the reduction of alkyl ~uorides ð79S314[
Palladium!on!carbon is employed most regularly as the catalyst in these reductions[ Early reports ð35JA150 suggested that only activated systems such as ethyl bromoacetate or benzyl chloride could be reduced while\ for example\ primary alkyl bromides were inert\ even under high hydrogen pressure[ However\ many examples have been reported since which demonstrate a wider reactivity\ concomitant with high chemoselectivity "Scheme 0# ð68T774\ 73CAR"029#014[ Isolated examples of reductions of benzylic ~uorides ð52JA0598 and even a secondary alkyl ~uoride "Scheme 0# ð60LA"637#012 have been reported[
O
Br
AcO
AcO
OCH2Ph
Br
O
AcO
AcO
OCH2Ph
O
F
AcO
O
AcO
O
OH
HO
HO
OMe
F
O
HO
HO
OMe
H2
a!Haloketones are readily dehalogenated with no competing carbonyl reduction ð47JOC0827\ 67JA0675\ while the possibility of utilising transfer hydrogenation has also been highlighted ð74JOC2397[
Raney!nickel has been shown to catalyse the reduction of a series of alkyl bromides and iodides in addition to tertiary and benzylic chlorides ð48CB0699\ while the range can be extended to primary alkyl ~uorides under more forcing conditions "Scheme 0# ð59JCS187[ Platinum oxide has been reported to catalyse the reduction of a benzylic ~uoride under relatively mild conditions ð54CJC0578[
As indicated above\ low!valent metal!based procedures appear to be the method of choice for the reduction of a!halocarbonyl compounds ð72OR052[ The metal employed most commonly in this context is zinc\ although the use of iron pentacarbonyl ð68JOC530 and of samarium"II# iodide ð75JOC0024 has been exempli_ed[
The zinc reductions are generally performed in the presence of a proton source\ typically acetic acid ð61JOC1252 or ammonium chloride ð67BCJ1634\ 67JA0654\ and give high yields for chloro! ð68JA3992\ 74JOC2846\ bromo! ð67JA0675 and iodocompounds "Scheme 1# ð54LA"570#085[ The
2C0Halo`en Bonds to CH
chemoselectivity of these processes is high\ notably alkenes which are reduced preferentially or competitively in catalytic hydrogenation procedures remain intact ð67JA0675[
Zn
N
O
MeO
O
Alkyl halides which are not adjacent to a carbonyl group can also be reduced by low!valent metals[ Here\ lithium or sodium are generally used in conjunction with an alcohol acting as proton source[ This procedure is often used to reduce polycyclic alkyl halides "Scheme 2# ð75JA0154\ 76JA6129\ 89S538[
Scheme 3
O O
Alkyl ~uorides are not reduced by the above procedures[ However\ potassium has been reported to e}ect a high yielding reduction of a range of ~uorinated steroids in the presence of an excess of crown ether ð70TL1472[
Despite the obvious analogy of generating a Grignard reagent from an alkyl halide\ followed by reacting with a proton source\ there has been little use of magnesium in the context of a direct reduction ð52PCS108[ Samarium"II# iodide causes the reduction of primary iodides and bromides\ but primary chlorides are unreactive\ and both benzylic and allylic systems undergo Wurtz coupling ð79JA1582[
The utility of a wide range of metal hydrides in the reduction of carbonÐhalogen bonds has been compared ð79JOC738[ Lithium aluminium hydride has long been known to reduce primary or secondary alkyl iodides and bromides and also benzylic chlorides ð38JA0564[ Benzylic ~uorides have also been shown to be prone to reduction ð52JA0598\ particularly in the presence of an ortho or para electron!donating group ð60CC354\ while primary ~uorides may be reduced after the addition of aluminium chloride ð53CJC461\ 53JOC1769[ More recently\ the simple expedient of employing a clear solution of lithium aluminium hydride in THF\ rather than the more typical slurry\ has been shown to markedly improve the reduction process such that secondary alkyl
3 Reduction of C0Halo`en and C0Chalco`en Bonds
chlorides are reduced readily at room temperature ð71JOC165[ Alternatively\ DIGLYME has been shown to be an excellent solvent for these reactions ð79JOC1449[ The reduction can also be promoted by the addition of nickel"II# chloride or cobalt"II# chloride ð67JOC0152[ The main drawback to the use of lithium aluminium hydride in this context is the poor chemoselectivity obtained\ particularly through the competing reduction of carbonyl groups "Scheme 3# ð38JA0564\ 53CJC461\ 60CC354\ 60LA"637#012\ 76TL2772[
120 °C, 84%
Scheme 4
Sodium borohydride has been shown to reduce alkyl chlorides\ bromides and iodides but not ~uorides[ Initially\ two!phase solvent systems were utilised ð55JA0362\ but polar aprotic solvents such as DMSO ð58JOC2812\ sulfolane ð60JOC0457 and hexamethylphosphoramide "HMPA# ð67JOC1148 are now used almost exclusively\ although the use of phase transfer catalysis has been recommended ð70JOC2898[ There is evidence to suggest that these reactions proceed via an eliminationÐalkene hydroboration mechanism ð69CC227[ Tertiary alkyl chlorides\ which often prove resistant to reduction by other methods\ are converted cleanly\ although elevated temperatures are required ð60JOC0457[ More activated systems are converted at room temperature "Scheme 3# ð75JOC2491[
Sodium borohydride shows greater chemoselectivity than lithium aluminium hydride in that esters remain intact ð67JOC1148[ Under similar conditions\ sodium cyanoborohydride has been shown to reduce alkyl bromides in the presence of ketones\ aldehydes and benzylic epoxides ð66JOC71[
Zinc borohydride o}ers unusual reactivity\ reducing only tertiary and benzylic halides "Scheme 3# ð72AG"E#451[
Lithium triethylborohydride reduces primary alkyl ~uorides ð72ACS"B#030 and both primary and secondary alkyl iodides\ bromides and chlorides[ Tertiary bromides undergo elimination ð72JOC2974[
Radical reduction processes have been dominated by the use of organostannanes\ principally tributyltin hydride ð76S554\ although organosilanes have attracted more recent attention ð81ACR077[ Primary\ secondary and tertiary alkyl chlorides\ bromides and iodides are all reduced^ however\ alkyl ~uorides do not react[
The popularity of the tributyltin hydride!mediated reduction arises from the high chemoselectivity of the reaction[ Thus\ acetals ð65CB2487\ benzyl ethers\ esters ð73CAR"029#014\ lactones ð81TL5562\ lactams ð68TL3520\ 80JCS"P0#545\ carbamates ð73CAR"029#092\ ketones ð72AJC1132\ a!acyloxy!
4C0Halo`en Bonds to CH
carbonyls ð72LA694\ nucleosides ð72S293\ epoxides ð71JOC4930 and some alkenes ð66CB0712 represent some of the functional groups which are not reduced under the same conditions "Scheme 4#[ Azides\ converted to amines\ are a notable exception here ð70LA0104[ Alkenyl halides\ which contain a carbonÐcarbon multiple bond removed by _ve atoms from the halogen\ undergo radical dehalogenation\ but with concomitant _ve!membered ring formation ð76S554[
N
S
59%
The marked di}erence in rates of radical formation between di}erent halogens and between the same halogen in di}erent environments ðB!72MI 090!90 can also be readily exploited in highly selective dehalogenations "Scheme 4# ð68JOC040\ 73S838[
The di.culties which can be encountered in removing the organotin residues from the product have led to the development of carbonÐhalogen bond reduction procedures which are catalytic in tin ð64JOC1443\ 76JOC362 but\ in common with the use of a water!soluble tin hydride reagent ð89TL1846\ these have yet to be exploited widely[
Tris"trimethylsilyl# hydride reduces a similar range of alkyl halides as tributyltin hydride with similar e.ciency ð77JOC2530\ 80JOC567[ Attempts to use this relatively esoteric reagent in a catalytic process were partially successful ð78TL1622\ but simpler silanes may also prove equally useful in stoichiometric processes ð81JOC1316\ 81JOC2394[ The readily available triethylsilane also exhibits utility in this context when used in conjunction with a thiol {polarity reversal catalyst| ð80JCS"P0#092[
a!Halocarbonyl compounds undergo a further general reaction unique to their class[ Treatment with a nucleophile\ typically iodide\ in the presence of a Bronsted ð79TL2084 or Lewis acid ð60TL026\ 68S48\ 79JOC2420\ 72JOC2556\ 75S469 results in formation of a halogenÐhalogen bond with cleavage of the halogenÐcarbon bond and consequent reduction of the substrate "Scheme 5#[
NaI, H2SO4
THF, H2O
Scheme 6
ii, H2O
0[90[0[1 Reduction of Fluoroalkanes
Fluoroalkanes are the most di.cult class of alkyl halides to reduce by any given procedure[ Indeed\ no examples of successful radical substitution!based methods have been reported[ A recur! rent problem encountered is that other groups tend to be reduced preferentially ðB!65MI 090!90[
Catalytic hydrogenation procedures tend to su}er from the catalyst poisoning e}ect of the ~uoride ion that is liberated in the reaction ð79S314[ Nonetheless these reactions can be performed under su.ciently forcing conditions[ Experiments in the mid 0849s using simple ~uoroalkanes at elevated temperatures in the gas phase indicated that secondary ~uorides are reduced more readily than primary under palladium!on!carbon catalysis ð45JPC0343[ The same catalyst has been shown to reduce more complex secondary ~uorides "Scheme 0# ð60LA"637#012 and benzylic ~uorides ð52JA0598 under less forcing conditions\ while an example exists of the reduction of a primary ~uoride at ambient temperature and elevated pressure "Equation "0## ð81JA630[
O H N
(1)
Raney!nickel has been employed to reduce a primary ~uoride "Scheme 0# ð59JCS187\ while platinum oxide catalysed the reduction of a benzylic ~uoride under mild conditions ð54CJC0578[
Low!valent metal!mediated reductions have seen little use[ Benzylic ~uorides have been shown to be resistant to both zinc and sodium amalgam ð52JA0598\ while elimination reactions compete when magnesium is employed ð52PCS108[ The most successful of these methods is the use of potassium in the presence of 07!crown!5 which was shown to reduce a range of primary\ secondary and tertiary ~uorides in high yield ð70TL1472[
Lithium aluminium hydride can sometimes be used to reduce alkyl ~uorides\ particularly when used in conjunction with aluminium chloride\ but high yields from such reactions are rare ð53CJC461\ 53JOC1769\ 60LA"637#012[ Many benzylic systems are either inert or reduced in low yield ð38JA0656\ 52JA0598 but the presence of an amino! or hydroxy! functional group in the ortho or para position causes high yielding conversions to occur\ possibly via an eliminationÐaddition mechanism ð60CC354[
Sodium borohydride ð70JOC2898 and sodium cyanoborohydride ð66JOC71 are apparently not powerful enough reducing agents to cleave C0F bonds\ but lithium triethylborohydride does reduce primary ~uorides\ although the reduction of secondary or hindered primary systems is slow ð72ACS"B#030[
Electrochemical techniques have been used to reduce a!~uorocarbonyl ð46JA0435\ 57CC823 and benzylic systems ð69CC627[
0[90[0[2 Reduction of Chloroalkanes
Reports of the catalytic hydrogenation of chloroalkanes are relatively rare[ Palladium!on!carbon catalyses the reduction of benzyl chlorides using either a hydrogen atmosphere ð35JA150 or transfer hydrogenation ð74JOC2397[ Primary and secondary chloroalkanes do not undergo hydrogenation in the presence of Raney!nickel\ but this catalyst does mediate the reduction of tertiary and benzylic systems\ as well as geminal and vicinal dichloroalkanes ð48CB0699[
Primary\ secondary and tertiary chloroalkanes can be reduced by a variety of low!valent metals\ typically in the presence of an alcohol proton source[ Examples include lithium with ethanol ð89S538 or t!butanol ð59CI"L#394\ 76JOC3673\ sodium with t!butanol ð57JA6160\ 75JA0154\ potassium ð70TL1472\ magnesium with isopropanol ð52PCS108 and samarium"II# iodide ð79JA1582[ Wurtz coupling can occur with these procedures in the reduction of benzylic and allylic systems ð79JA1582[
a!Chlorocarbonyl compounds are dechlorinated cleanly by zinc in acetic acid[ These reaction conditions are employed most commonly in the reduction of cyclic ketone systems\ for example\ with four! ð61JOC1252\ 72JA1324 and _ve!membered rings "Scheme 1# ð68JA3992\ 74JOC2846\ but are
6C0Halo`en Bonds to CH
also compatible with lactone ð72JOC759\ lactam and carboxylic acid moieties "Scheme 6# ð76TL4228[ The combination of samarium"II# iodide and methanol has been shown to be of use in this context ð75JOC0024[
NCH2Ph
~100%
O
OOHSaccharomyces cerevisiae
100% conversion
Early reports ð38JA0564\ which indicated that lithium aluminium hydride reduced only activated chloroalkanes\ have been countered more recently ð71JOC165 by demonstrations that relatively unreactive systems\ such as secondary chloroalkanes\ can be reduced cleanly at ambient temperature by homogenous solutions of the reagent in THF[ The use of cobalt"II# and nickel"II# chloride has also been shown to promote these reductions ð67JOC0152\ and even a tertiary neopentyl chloride has been reduced ð76TL2772[
Sodium borohydride also reduces chloroalkanes ð55JA0362[ Generally\ these reactions are per! formed in polar aprotic solvents such as DMSO ð58JOC2812\ 75JOC2491\ sulfolane ð60JOC0457 or HMPA ð67JOC1148\ and often at elevated temperatures\ but still tend to o}er greater chemo! selectivity than lithium aluminium hydride "Scheme 6# ð70JOC2898\ 67JOC1148[ Other borohydride systems of use in this context include zinc borohydride "tertiary systems# ð72AG"E#451\ sodium cyanoborohydride ð66JOC71 and lithium triethylborohydride ð71JOC1489\ 72JOC2974[
Primary\ secondary ð65CB2487\ 70LA0104\ 73S838 and tertiary ð79TL176 chloroalkanes are all reduced in high yield by tributyltin hydride by a radical mechanism[ The power of this approach is illustrated by an example where low!valent metal procedures failed and ionic metal hydrides would o}er no chemoselectivity "Scheme 6# ð76JOC296[
A similar range of substrates undergo radical reduction using silyl hydrides[ Tris"trimethyl! silyl#silane has seen most use\ with the reaction being initiated by the use of light\ peroxides ð77JOC2530 or azobisisobutyronitrile "AIBN# "Scheme 6# ð80JOC567[ The use of bis"trimethyl! silyl#methylsilane ð81JOC2394\ triethylsilane in the presence of a thiol catalyst ð80JCS"P0#092 and\ although with lower e.ciency\ tris"alkylthio#silanes ð81JOC1316 have also been demonstrated in this reduction[
a!Chlorocarbonyl compounds can be reduced by iodide ion in the presence of a Lewis acid[ The
7 Reduction of C0Halo`en and C0Chalco`en Bonds
reaction generally proceeds in high yields with both ketones and esters ð75S469\ utilising a range of Lewis acids ð68S48\ 79JOC2420\ 75S469\ unless the system is particularly hindered "Scheme 6# ð60TL026[
A biological reductive dechlorination has also been reported ð81TL6226[ Treatment of ethyl a! chlorobenzoylacetate with bakers| yeast at low concentrations "0 g l−0# results in reduction of both the carbonyl group and the C0Cl bond "Scheme 6#[ At higher concentrations\ the carbonyl group is reduced but the chloro moiety remains intact\ suggesting that the dechlorination is an enzyme! catalysed process and not the result of a fortuitous noncatalysed chlorination of a constituent of the microorganism[
0[90[0[3 Reduction of Bromoalkanes
Although it was suggested initially that only activated "e[g[\ benzylic and a!carbonyl# bromoalkane systems were reduced by hydrogenation over palladium!on!carbon ð35JA150\ it has now been demonstrated that a full range of these compounds can be reduced by this procedure "Scheme 0# ð47JOC0827\ 68TL774\ 73CAR"029#014[ This approach can fail if other functional groups\ that are prone to hydrogenation\ are present ð67JA0675\ 73CAR"029#014[ Allylic bromides may be reduced by such procedures\ but concomitant alkene migration can occur ð44JA4859[
Catalytic hydrogenation can also be performed over Raney!nickel ð48CB0699 or using a homo! genous palladium"9# catalyst in conjunction with transfer hydrogenation techniques ð75JOC623[
There are remarkably few examples of the reduction of simple bromoalkanes using a low!valent metal\ and the procedure appears low yielding ð76JA6129[ Samarium"II# iodide does reduce primary alkyl bromides in high yield\ but allylic and benzylic substrates undergo Wurtz coupling ð79JA1582[
In common with the chloroalkane analogues described above\ zinc cleanly reduces a!bromo! carbonyl compounds "Scheme 1# ð67BCJ1634\ 67JA0675 and the diastereoselectivity of the protonation step in this reaction has been investigated ð48JA2523\ 48JA2533[ These substrates can also be reduced with samarium"II# iodide in high yield "Scheme 7# ð75JOC0024 and\ in moderate yield\ with iron pentacarbonyl ð68JOC530[
Scheme 8
(TMS)3SiH
( )14 ( )14
Lithium aluminium hydride reduces most bromoalkanes ð38JA0564[ Benzylic and primary systems are the most reactive\ but secondary and tertiary systems can also be reduced\ particularly in the presence of nickel"II# or cobalt"II# chloride ð67JOC0152 or when a homogenous solution of lithium aluminium hydride in THF is used ð71JOC165[ The carbonÐbromine bond can be reduced by lithium aluminium hydride in the presence of other reactive centres when DIGLYME is used as the solvent "Scheme 7# ð79JOC1449[
Sodium borohydride reduces primary and secondary bromoalkanes in high yield and with good chemoselectivity[ These reactions are usually carried out in polar aprotic solvents\ typically DMSO
8C0Halo`en Bonds to CH
ð58JOC2812\ sulfolane or HMPA ð67JOC1148\ although two!phase systems involving an aqueous layer have been used successfully in conjunction with phase transfer catalysis ð70JOC2898[ Zinc borohydride shows complementary activity\ reducing only tertiary and benzylic bromoalkanes\ even in the presence of primary alkyl bromides "Scheme 3# ð72AG"E#451[
Sodium cyanoborohydride in HMPA o}ers very high chemoselectivity[ BromineÐcarbon bonds can be reduced by this system in the presence of a variety of functional groups\ including carboxylic acids and esters\ ketones\ nitriles and epoxides ð66JOC71[
Other metal hydride systems have also been used to reduce bromoalkanes\ for example\ lithium triethylborohydride ð72JOC2974 and potassium hydride ð76JOC3188\ but these reagents have yet to see widespread use[
The most popular method for the reduction of bromoalkanes is the use of tributyltin hydride in a radical substitution procedure[ Essentially\ all classes of bromoalkane can be reduced\ usually in high yield\ with excellent chemoselectivity\ thus sul_des\ b!lactams and benzyl ethers ð68TL3520\ g! lactams ð80JCS"P0#545\ epoxides and lactones "Scheme 4# ð71JOC4930\ alkyl ~uorides\ alkyl chlor! ides\ ketones and enones "Scheme 4# ð68JOC040\ ethers ð61S372\ a!acyloxyketones ð72LA694\ alkenes ð66CB0712\ strained ð72TL0036 and rigid cycloalkanes ð72AJC1132\ carbohydrates ð73CAR"029#014\ 81JA09027 and nucleosides ð72S293 are all una}ected by typical reaction conditions "Scheme 7#[
The main di.culty encountered with these procedures is the removal of tin residues from the product ð76S554[ Attempts to circumvent this by developing methodology which is catalytic in tin "and stoichiometric in sodium borohydride# have achieved some success ð64JOC1443\ 76JOC362 but see little contemporary use[
Silyl hydrides have again been shown to be of use in place of tributyltin hydride[ Tris"trimethyl! silyl#silane has seen the most investigation "Scheme 7# ð77JOC2530\ 80JOC567\ including its use in catalytic amounts ð78TL1622\ but other silanes have also been shown to work well ð80JCS"P0#092\ 81JOC1316\ 81JOC2394[
The carbonÐbromine bond of a!bromoketones can be reduced by treatment with iodide ion in the presence of an acid[ Although sulphuric acid has been used in this context "Scheme 5# ð79TL2084\ the reaction is usually driven by a Lewis acid "Scheme 5# ð60TL026\ 68S48[ When trimethylsilyl chloride is employed\ the silyl enol ether intermediate is usually not isolated\ and is hydrolysed in situ "Scheme 8# ð79JOC2420\ 72JOC2556[
O
Br
O
N Me
Me N
09 Reduction of C0Halo`en and C0Chalco`en Bonds
The dihydrobenzimidazole "0# has been shown to e}ect an unusual\ but high yielding\ reduction of a!bromocarbonyl compounds ð75JOC4399[ The process\ which presumably involves hydride transfer assisted by the nitrogen lone pairs\ is highly chemoselective "Scheme 8#[
0[90[0[4 Reduction of Iodoalkanes
Iodoalkanes undergo facile reduction by all the general methods available[ Perhaps as a conse! quence of this\ with there being little need to develop new methods or re_ne old ones\ there are relatively few investigations of these reductions reported in the literature[
As would therefore be expected from the precedents described above\ iodoalkanes can be reduced by catalytic hydrogenation over palladium ð79S314 or Raney!nickel ð48CB0699[
Samarium"II# iodide is a particularly e.cient low!valent metal reducing agent for simple alkyl iodides ð79JA1582\ while the {classic| combination of zinc in acetic acid cleanly reduces a!iodoketones "Scheme 1# ð54LA"570#085[
Again\ as might be predicted\ lithium aluminium hydride reduces iodoalkanes readily ð38JA0564\ 71JOC165[ The rate of the reaction can be promoted by the use of solvents such as GLYME or DIGLYME ð79JOC1449 or the addition of nickel"II# or cobalt"II# salts ð67JOC0152\ but yields are generally high regardless of the method used[
Similarly\ other metal hydride reagents "such as sodium borohydride ð58JOC2812\ 70JOC2898\ sodium cyanoborohydride ð66JOC71 and lithium triethylborohydride ð72JOC2974# capable of reducing bromoalkanes also work well with iodoalkanes\ while o}ering the possibility of greater chemoselectivity than that available with lithium aluminium hydride[
Chemoselectivity is also the strength of the radical substitution of iodoalkanes using tributyltin hydride\ where high yielding reductions can be performed in the presence of a wide range of other sensitive functional groups "Scheme 09# ð71JFC"19#202\ 73CAR"029#092\ 80JOC5195\ 81TL5562\ 81TL6318[ Methodology for performing these reductions in the presence of catalytic amounts of the reducing agent\ together with an inexpensive coreductant\ is recorded ð64JOC1443[
n-C4F9 OAc
O
Ph
O
As with chloro! and bromoalkanes\ such radical!based reductions can also be performed with a range of silanes in place of tributyltin hydride with no loss in yield or e.ciency ð77JOC2530\ 78TL1622\ 80JCS"P0#092\ 80JOC567\ 81JOC1316\ 81JOC2394[
a!Iodoketones can be reduced by a range of procedures distinct from those described above "Scheme 09#[ Thus treatment of aryl a!iodoketones with iodide in the presence of a Lewis ð60TL026 or Bronsted ð79TL2084 acid has been shown to provide a clean reduction[ A closely related process is the reaction with benzene thiolate or benzene selenolate ion\ which gives high yields for the reduction of both aryl and alkyl ketones ð70JOC1485[ Curiously\ this reaction fails for the cor! responding a!bromoketones\ when thioester formation occurs[ An isolated example of the reduction of an a!iodoketone in the presence of an a!bromoketone moiety using sodium bisul_te has also been reported ð49JA251[
00C0Oxy`en Bonds to CH
0[90[0[5 Reduction of Hypervalent Haloalkanes
There have been few reports of the reduction of a hypervalent haloalkane to the corresponding alkane[ The esoteric nature of this reaction is highlighted by the fact that the only alkanes that have been formed by these processes are all b!dicarbonyl compounds[
When an ethanolic solution of phenyldimedonyliodone is re~uxed\ decomposition occurs to give dimedone as a minor component in a complex mixture of products "Equation "1## ð69BCJ1495[ Cleaner reductions of the same substrate have been performed with either aryl thiols ð67JOC1565 or sodium bisul_te ð66JOU0922 as the reducing agent "Equation "1##\ and the latter method has been shown to be applicable to a wider range of substrates[
O O– O O
i or ii or iii
i, EtOH, reflux, 10% ii, 4-ClC6H4SH, CH2Cl2, 86% iii, NaHSO3, H2O, 90%
(2)
0[90[1[0 General Methods
It is di.cult to identify general methods for the reduction of carbonÐoxygen single bond systems\ particularly due to the dramatic variation in reactivity of the di}erent structures which come into this class[
While benzylic systems can be reduced by catalytic hydrogenation "Scheme 00# ð42OR"6#152\ 71SC872\ 82T7322\ most alcohols "and simple derivatives thereof# are largely inert to direct reduction[ These species are transformed to alkanes by conversion to a more reactive substrate\ usually one of the range of thionoethers or a sulfonate\ then reduction of this intermediate by a radical substitution or nucleophilic displacement procedure\ respectively "Scheme 01# ð64JCS"P0#0463\ 66JOC71[
CO2H CO2H
Scheme 11
Most aldehydes and ketones can be reduced to methyl and methylene compounds\ respectively\ by treatment with hydrazine and base\ the Wol}ÐKischner reduction ð37OR"3#267[ The HuangÐ Minlon modi_cation of this procedure is usually employed ð35JA1376\ and high yields are often obtained "Scheme 02# ð38JA2290\ 76JOC2194[
Benzylic aldehydes and ketones can also be reduced\ via the benzylic alcohol intermediate\ to the corresponding alkane by catalytic hydrogenation[ Again\ high yields can be obtained\ and the procedure is tolerant of many other functional groups "Scheme 03# ð79TL1526\ 71JOC3293[
Aldehydes and ketones can also be deoxygenated by conversion to a dithioacetal derivative\ then treatment with Raney!nickel[ This approach is discussed in Section 0[90[2[4[
01 Reduction of C0Halo`en and C0Chalco`en Bonds
O
O
O
OMeS
0[90[1[1[0 Reduction of C0OH bonds
As indicated above\ the C0O bond of alcohols is not particularly prone to reduction\ and only systems activated through a neighbouring group can be transformed readily[
Catalytic hydrogenation over palladium!on!carbon is an e}ective method for the reduction of benzylic alcohols ð35JA150\ 42OR"6#152\ and it has been demonstrated that transfer hydrogenation is as least as e}ective as the use of a hydrogen atmosphere "Schemes 00 and 04# ð82T7322[ Tertiary alcohols can be hydrogenated under platinum"IV# oxide catalysis in tri~uoroacetic acid "when the intermediacy of an alkene is probable# ð53JOC1214 or in the presence of Raney!nickel ð77JOC321[ Selective reduction of the alcohol in the presence of a primary bromoalkane functional group has been achieved by the latter method[ Allylic alcohols can be converted to alkenes by hydrogenation
02C0Oxy`en Bonds to CH
in the presence of the hydridopentacyanocobaltate anion\ although double bond migration can occur and tertiary allylic alcohols are reported not to react ð89TL3090[
Scheme 15
i, TMS-Cl, NaI, MeCN
ii, Zn, AcOH 80%
By analogy with a!halocarbonyl compounds\ it might be expected that the alcohol moiety of the corresponding a!hydroxycarbonyl series should be reduced by the action of low!valent metals[ While this is the case\ it would seem that here the combination of zinc in acetic acid ð43JCS2934 is less popular than samarium"II# iodide ð75JOC0024\ 76JA3313[
The use of lithium in ammoniacal THF containing ammonium chloride has been shown to reduce benzylic alcohols without concomitant Birch reduction ð64JOC2040\ while zinc has been employed in the latter stage of a two!stage\ one!pot process to reduce primary\ secondary and benzylic alcohols through the intermediacy of the corresponding iodoalkane "Scheme 04# ð70S21[
The combination of an acid and a hydride source\ often termed ionic hydrogenation ð63S522\ reduces alcohols where the intermediate carbonium ion is relatively stable "i[e[\ tertiary and benzylic alcohols#[ Initially\ triethylsilane was used as the hydride donor in the presence of tri~uoroacetic acid ð58JOC3\ 60JOC647\ but it has since been demonstrated that the use of sodium borohydride with the same acid is highly e}ective "Scheme 04# ð66S061[ The use of zinc iodide\ rather than a protic acid\ together with sodium cyanoborohydride\ also reduces tertiary and benzylic alcohols ð75JOC2927\ while the combination of diisobutylaluminium hydride "dibal!H# with aluminium bromide reduces benzylic alcohols in high yield\ and has been shown to provide a rare method for a direct\ if low!yielding\ reduction of a secondary alcohol ð81JOC1032[
0[90[1[1[1 Reduction of C0O0C bonds
"i# Reduction of oxiranes
There are\ not unexpectedly\ few examples of the reduction of both carbonÐoxygen bonds of an oxirane "epoxide#[ The use of titanocene has met with some success\ although yields are variable\ being poor for highly substituted epoxides ð63JA4189[ Triethylsilane\ in combination with boron tri~uoride\ also performs this reduction "Scheme 05# ð68TL738\ but rearrangement of the inter! mediate carbonium ion can also occur[
O
Scheme 16
Procedures involving the reduction of only one carbonÐoxygen bond of an oxirane are relatively common\ and usually involve the use of metal hydride reagents[ Here\ the question of the regio! selectivity of the reduction of unsymmetrically substituted epoxides is important[
03 Reduction of C0Halo`en and C0Chalco`en Bonds
In aliphatic substituted systems where one oxirane carbon atom has fewer substituents "i[e[\ 1! alkyl\ 1\1!dialkyl or 1\1\2!trialkyloxiranes#\ reduction with highly nucleophilic metal hydride reagents "such as lithium aluminium hydride ð81JOC0507\ 81T8316\ lithium triethylborohydride ð79JOC0 and dibal!H ð81JOC0507# occurs at the less substituted position "Scheme 06#[ In contrast\ reducing agents with Lewis acid character ð81JOC0507\ or used in the presence of an acid ð70JOC4103\ 81JCS"P0#0770 tend to deliver hydride to the more substituted carbon centre "Scheme 06#[
O OH
~100%
When the more substituted carbon of the oxirane is also benzylic\ selective delivery of hydride to that centre can be achieved by a range of reagents including either borane ð57CC0438 or sodium cyanoborohydride ð70JOC4103 in combination with boron tri~uoride\ and also triisobutylaluminium ð81JOC0507[ Reduction of these compounds at the less substituted carbon atom can still be per! formed using reagents such as lithium aluminium hydride\ but the regioselectivity of this process is not always as clear cut as with the nonbenzylic systems ð81JOC0507\ 57JA1816[
Reductions of 1\2!disubstituted oxiranes tend to give mixtures of products\ even when one substituent is aromatic\ and the geometry of the oxirane can have a dramatic e}ect on the outcome of the reaction "Scheme 06# ð72JOC2980[
Reduction takes place at the allylic carbonÐoxygen bond when oxiranes with vinyl substituents are treated with reagents such as lithium aluminium hydride ð74JA6867\ 76JOC3787 or dibal!H ð71CC0181[
The popularity of the Sharpless asymmetric epoxidation procedure has led to the study of the reduction of glycidols "hydroxymethyloxiranes# as an approach to 0\1! and 0\2!dihydroxylated systems[ When the glycidol alcohol moiety is primary\ selective reductions to give 0\2!diols can be performed using sodium bis"methoxyethoxy#aluminium dihydride "Red!Al# "Scheme 07# ð71CC0181\ 71JOC0267[ Reductions to the 0\1!dihydroxy system are more di.cult\ unless the site of reduction is benzylic ð71TL2486[ The most e}ective systems are dibal!H ð71TL1608\ 71TL2486 and lithium borohydride:titanium tetraisopropoxide "Scheme 07# ð75TL3232[ Glycidols with a secondary alcohol and terminal oxirane can be reduced to the vicinal diol using lithium aluminium hydride ð74JOC4567[
Oxiranes with a carbonÐoxygen bond a to an aromatic ring or carbonyl group can be reduced selectively using low!valent metal techniques[ Samarium"II# iodide ð75JOC1485\ 76TL3326\ lithium and potassium ð75AG"E#542 have all been used with success[
Catalytic hydrogenation methodology can be employed to reduce certain oxiranes\ for example\ those with vinyl ð78JA5179 or carbonyl ð80CC424 substituents[
04C0Oxy`en Bonds to CH
OHO O
"ii# Reduction of other ethers
Ethers share a resistance to reductive cleavage similar to the corresponding alcohols[ Although benzyl ethers are frequently used as alcohol protecting groups in synthesis and are
subsequently cleaved by catalytic hydrogenation\ the alkane product\ toluene\ is of no synthetic interest[ Hydrogenation of cyclic benzylic ethers\ where both alcohol and alkane are part of the required product\ have been reported and work well ð37JA0389[
Allylic ethers can be reduced to the corresponding alkenes by the combination of a homogenous palladium"9# catalyst and lithium triethylborohydride in high yields with little or no double bond migration ð71JOC3279 while g!alkoxy!a\b!unsaturated esters can be reduced to the corresponding fully saturated ester by the action of magnesium in methanol "Equation "2## ð82JCS"P0#8[ Alkyl methyl ethers can also be reduced by low valent metal methods after in situ conversion to the corresponding alkyl iodide ð70S21\ while a!alkoxyketones are reduced cleanly by samarium"II# iodide ð75JOC0024[
Mg, MeOH
"iii# Reduction of esters
The reduction of the alkyl carbonÐoxygen bond of esters can be performed in preference to the reduction at the carbonyl carbon atom in some speci_c situations[
In common with benzyl ethers\ benzyl esters are often used as protecting groups in organic synthesis\ and are subsequently removed by catalytic hydrogenation[ There are\ however\ examples of this reaction with more complex aromatic systems\ where the alkane formed is the required product of the reaction "Schemes 00 and 08# ð72JCS"P0#76\ 71SC872[
O
CO2Me
05 Reduction of C0Halo`en and C0Chalco`en Bonds
The b!acetoxy group of a\b!diacetoxybutanolides can be reduced by catalytic hydrogenation over Raney!nickel in the presence of base "Scheme 08# ð82OS"61#37\ via an alkene[ If platinum"IV# oxide or palladium!on!carbon is used as catalyst then reduction of the a!acetoxy group also occurs ð80TL3852[
a!Acetoxyketones can be reduced using zinc in acetic acid ð44JA3256\ 46JA4439 or samarium"II# iodide ð75JOC0024[ The latter procedure is particularly selective\ notably the reduction can be performed in the presence of a primary iodide[ A vinylogous example of this type of reduction has been performed with magnesium in methanol as the reducing system\ although alkene reduction also occurred under these conditions ð82JCS"P0#8[
Sterically hindered esters are reduced by the action of lithium in ethylamine[ Less hindered systems undergo oxygenÐcarbonyl bond cleavage under these conditions\ but this selectivity can be exploited bene_cially ð70JCS"P0#0490[ The similar conditions of lithium in ammoniacal THF have been employed to reduce benzylic esters selectively in the presence of alkenes ð76JOC3767[
"iv# Reduction of thionoethers
One of the most important methods for the deoxygenation of alcohols is the radical chain reduction of a thionoether derivative\ typically using tributyltin hydride as the reducing agent[ This process\ often termed the BartonÐMcCombie reaction ð64JCS"P0#0463\ has been the subject of extensive reviews ð72T1598\ 76S554\ B!78MI 090!90[
A range of thionoethers has been used in this procedure[ While thioesters were utilised in the original paper in this area ð64JCS"P0#0463\ these intermediates now see little use and S!methyl dithiocarbonate "xanthate# ð64JCS"P0#0463\ 82TL1622\ phenylthiocarbonate ð76JOC2695\ 89SL694 and imidazoylthiocarbonyl ð70JOC3732\ 82TA514 derivatives are employed now[
These reductions are used most commonly in the deoxygenation of secondary\ often cyclic\ alcohols and are high yielding\ notably in the presence of acid or base sensitive functionality "Schemes 01 and 19# ð64JCS"P0#0463\ 76JOC2695\ 82TA514[ The procedure is used only rarely for primary alcohols\ and can be low yielding ð70JOC3732\ 80JCS"P0#092\ although the use of high boiling solvents can be bene_cial ð70S632[ Tertiary alcohols can be deoxygenated cleanly if elimination of the thionoether can be avoided\ and a revised methodology for the synthesis of these intermediates has been reported ð82TL1622[
O N
O O
06C0Oxy`en Bonds to CH
The practical di.culty of removing unwanted tin!containing residues from the reaction product can be avoided by the use of polystyrene!supported tin hydrides ð81SL790[
More recently\ the use of organosilanes to reduce thionoethers to alkanes has seen a rise in popularity matching the analogous usage in the reduction of haloalkanes ð81ACR077[ The most useful of these reagents seem to be tris"trimethylsilyl#silane ð89SL694\ 80JOC567 and diphenylsilane ð89TL3570[ The combination of the latter reagent with the triethylborane:oxygen initiator system and p!~uorophenyl thiocarbonyl substrates seems particularly e}ective "Scheme 19# ð89TL3570[
A number of other silanes have been reported to perform these reductions in high yields but have yet to see widespread use ð81JOC1316\ 81JOC2394[ The least esoteric of these\ triethylsilane\ can be used in the presence of a thiol catalyst ð80JCS"P0#092 or in excess with relatively large amounts of initiator in what has been shown not to be a conventional chain reaction process ð80TL6076\ 82JOC138[
0[90[1[1[2 Reduction of C0O0heteroatom bonds
The reduction of alcohols is often achieved by conversion to a group more prone to nucleophilic displacement\ usually a "p!toluene or benzene# sulfonate\ then treatment with a suitable metal hydride reagent[
Thus highly nucleophilic reagents such as lithium aluminium hydride ð67JOC0152 and lithium triethylborohydride ð72JOC2974 have been used to e}ect e.cient reductions of such esters[ The chemoselectivity of such reactions can be poor ð71AJC0784\ but choice of solvent can be important "Scheme 10# ð79JOC1449[
Br OTs Br
Scheme 21
The use of less reactive reagents such as sodium borohydride ð58JOC2812\ 67JOC1148 or sodium cyanoborohydride ð66JOC71 still allows the reduction of sulfonates\ but with a consequent increase in chemoselectivity "Scheme 10#[
Sulfonates can also be reduced electrochemically ð68TL1046 or\ in the case of primary ð79JA1582 or a!carbonyl ð75JOC0024 systems\ by reaction with samarium"II# iodide in the presence of a proton source[
Sulfates can also be reduced via nucleophilic displacement by a metal hydride reagent\ but only benzylic\ allylic or a!carbonyl systems seem to have su.cient reactivity "Scheme 10# ð58JOC2556\ 75TL3702\ 77JA6427[
Phosphates and phosphoramidates can be reduced by lithium in the presence of ethylamine and t!butanol in a procedure that appears to be e.cient for primary\ secondary and tertiary systems but has few proponents ð61JA4987\ 75JA2724[
The reduction of the carbonÐoxygen bond of relatively activated silyl ethers "allylic\ benzylic and a!carbonyl systems# has been reported in a few speci_c instances ð70S21\ 71JOC3279\ 75JOC0024[ These procedures may be of value in particular circumstances\ but would not be one of the _rst methods of choice if starting from the corresponding alcohol[
07 Reduction of C0Halo`en and C0Chalco`en Bonds
0[90[1[2 Reduction of C1O Bonds to CH1
0[90[1[2[0 Reduction of aldehydes
There is a surprisingly small number of reports of the direct reduction of aldehydes to methyl groups compared to those devoted to the analogous conversion of ketones to methylene moieties\ which may be more a re~ection of the relative synthetic utilities of the procedures than of ease of reaction[
The Clemmensen reduction\ using zinc in the presence of an acid\ illustrates this point[ While the original paper on this procedure reported the reductions of heptanal and benzaldehyde in moderate yield ð02CB0726\ very few aldehyde reductions have appeared subsequently ð31OR"0#044\ 48AG615\ and the reaction is now used almost exclusively for the deoxygenation of ketones ð64OR"11#390[
The Wol}ÐKischner reduction\ in which the carbonyl compound is treated with hydrazine and a base ð37OR"3#267\ has seen rather more use in the reduction of aldehydes than the Clemmensen procedure[ The HuangÐMinlon modi_cation of the reaction\ where "tri! or# diethylene glycol is used as solvent\ and volatile by!products are removed by distillation as the reaction temperature is raised from 079>C to 199>C ð35JA1376\ is now employed generally\ and aryl and aliphatic aldehydes which are tolerant of base and these elevated temperatures can be reduced in high yields "Schemes 02 and 11# ð38JA2290\ 73JA5691[
Scheme 22
HO O
Me2N
72%
The variant of the Wol}ÐKischner reduction in which the tosylhydrazone of the aldehyde is formed\ then converted to the methyl compound by treatment with a metal hydride reagent also works well[ Lithium aluminium hydride is used in the conversion of aromatic aldehydes ð52T0016 but tends to give alkenic by!products with aliphatic systems when sodium borohydride becomes the reagent of choice ð53CI"L#042[ Carbohydrate aldehydes have also been reduced by this approach\ using potassium borohydride\ in moderate yields ð53CI"L#0578[
Benzylic aldehydes can be reduced directly to the corresponding toluene derivative by catalytic hydrogenation ð42OR"6#152[ Systems with electron!donating substituents on the ring tend to react more quickly\ particularly when transfer hydrogenation techniques are used ð77TL2630\ but high yields can be obtained in many cases\ especially when Raney!nickel is employed "Schemes 03 and 11# ð79TL1526[
An aldehyde unit attached to an electron!rich aromatic system can be reduced directly to the methyl group using Red!Al ð58TL0628 or sodium cyanoborohydride in the presence of zinc iodide ð75JOC2927[ An aliphatic aldehyde has been reduced quantitatively by the combination of tri! ethylsilane and boron tri~uoride ð68TL738\ while titanocene has been reported to reduce aliphatic\ but not aromatic\ aldehydes ð63JA4189[
0[90[1[2[1 Reduction of ketones
The Clemmensen reduction\ in which the substrate is reduced by the action of zinc in the presence of an acid\ is one of the longest established methods for ketone deoxygenation ð64OR390[ The
08C0Oxy`en Bonds to CH
reaction does not work well for diketones owing to pinacol coupling\ a process which can also be a signi_cant side reaction\ in an intramolecular sense\ for monoketones ð35JA1376\ and the alkene unit of a\b!unsaturated ketones is reduced in tandem with the carbonyl group ð61BCJ153[ Nonethe! less\ high yields of alkanes can be obtained for this procedure\ particularly when the reaction is carried out under anhydrous conditions "Scheme 12# ð61BCJ153[ A variation in the procedure\ using base rather than acid\ has also shown promise ð76JOC2194[
Scheme 23
H O
Et2O, HCl 42%
The Wol}ÐKischner reduction\ in which the ketone is treated with hydrazine and a base\ is as well established a procedure as the Clemmensen reduction ð37OR"3#267[ It has been demonstrated that\ if the intermediate hydrazone is isolated _rst\ the reaction can be carried out in DMSO at room temperature ð51JA0623[ However\ most practitioners use the procedure at elevated tem! perature "079Ð199>C# with in situ hydrazone formation "termed the HuangÐMinlon modi_cation ð35JA1376#\ and are generally rewarded with high yields "Schemes 02 and 13# ð35JA1376\ 71JOC1489\ 73JA5589\ 76JOC2194[
Scheme 24
HO O
H
82%
Hindered ketones are not reduced by these procedures ð38JA2290 and\ sometimes\ pyrazoline formation can compete with the reduction of a\b!unsaturated ketones ð76JOC2194[
A useful variation of the Wol}ÐKischner procedure involves forming the tosylhydrazone\ and treating this intermediate with a reducing agent such as sodium borohydride ð53CI"L#042\ 76TL3648\ sodium cyanoborohydride ð74JOC1596 or catecholborane ð64JOC0723\ 74JA4621[ These reactions are performed at much lower temperatures than the HuangÐMinlon type procedures and give com! parable yields "Scheme 14# ð64JOC0723\ 76TL3648[
Aromatic ketones can be reduced\ via the benzyl alcohol\ to arylalkanes ð42OR"6#152[ Both Raney!nickel and palladium!on!carbon are e}ective catalysts for this procedure\ and the reactions can be carried out under a hydrogen atmosphere or using transfer hydrogenation techniques ð77TL2630[ These reactions are generally high yielding\ although some functional groups "e[g[\ chloro! or nitroarenes# are reduced preferentially "Schemes 03 and 15# ð47JOC022\ 79TL1526\ 71JOC3293\ 71S839\ 72CJC1304[ Aliphatic ketones are normally reduced to the corresponding alcohol by catalytic hydrogenation but it has been reported that\ under strongly acidic conditions and platinum"IV# oxide catalysis\ conversion to the alkane "without the intermediacy of the alcohol# can occur ð56TL1218[
The combination of sodium borohydride and tri~uoroacetic acid has been shown to reduce a range of diaryl ð67S652 and aryl alkyl ketones "Scheme 16# ð74JOC4340 in high yield\ unless a strong electron withdrawing group is present ð67S652[ This range of ketones can also be reduced e.ciently by the action of hydride reagents in conjunction with Lewis acids\ for example\ lithium
19 Reduction of C0Halo`en and C0Chalco`en Bonds
Scheme 25
EtOH, H2O 91%
aluminum hydride ð47JA1785\ 76TL1826 or sodium borohydride "Scheme 16# ð76S625 with aluminum chloride\ dibal!H with aluminum bromide ð81JOC1032\ sodium cyanoborohydride with zinc iodide ð75JOC2927\ and triethylsilane with boron tri~uoride ð70OS"59#097 have all been used to good e}ect[ This last combination has also been shown to reduce a\b!unsaturated ketones without alkene reduction ð76JOC0873[
N
O
SO2Ph
N
SO2Ph
O
0[90[1[3 Reduction of "C1O#X to CH2
The sole example of the direct hydrogenation of a carboxylic acid derivative to a methyl group by catalytic hydrogenation is the quantitative transformation of benzoic acid to toluene under
10C0Sulfur\ C0Selenium and C0Tellurium Bonds to CH
rhenium"II# oxide catalysis ð52JOC1236[ Aliphatic acids are converted to alcohols under the same conditions[
A series of benzoic acids and esters "with electron!donating substituents on the ring# has been converted to the corresponding toluene derivatives by reduction with Red!Al in re~uxing xylene ð58TL0628[
Aliphatic esters and lactones undergo this type of reduction upon treatment with titanocene\ but the reduction stops at the benzylic alcohol stage with aromatic systems ð63JA4189[
The most clearly delineated method for the full reduction of benzoic acids involves the sequential\ one!pot treatment with excess trichlorosilane\ then a tertiary amine\ then hydroxide in aqueous methanol ð69JA2121[ The _rst step is thought to cause anhydride formation[ In the presence of an amine\ the excess silane converts the anhydride to two moles of benzyl silane\ which is cleaved to give the toluene derivative and a silanol[ The reaction is highly chemoselective\ aryl bromides\ and even ester groups remain intact "Scheme 17# ð69JA2121\ 62JOC2559[ The procedure can be extended to the reduction of aryl esters by preliminary treatment with trimethylsilyl iodide and iodine\ forming the trimethylsilyl ester\ followed by the reduction sequence ð68JOC1074[
Br
CO2H
Br
3N
CO2H
MeO2C
94%
MeO2C
3N
0[90[1[4 Reduction of C"OX#n Systems
Many methods are available for the reduction of ortho!esters to acetals\ or of acetals to ethers ðB!73MI 090!90\ B!78MI 090!90[ However\ complete reduction to the alkane oxidation state is rare[
Some simple benzylic acetals have been reduced to the corresponding toluene derivative by catalytic hydrogenation ð42OR"6#152[ Very occasionally this methodology is used to deprotect benzylidene derivatives of carbohydrates ð17CB0649\ 52JOC0284[
0[90[2 REDUCTION OF C0SULFUR\ C0SELENIUM AND C0TELLURIUM BONDS TO CH
0[90[2[0 General Methods
The most general method for reduction to alkanes in this area is by treatment with Raney!nickel ð51CRV236\ 51OR"01#245[ Thiols ð49JCS2999\ sul_des ð81TL4456\ sulfoxides ð75CC0577\ dithioacetals ð49JA3185 and selenium systems ð65TL1532 are all reduced cleanly and chemoselectively by this procedure "Scheme 18#[
Radical chain reactions using stannanes are e.cient for the reduction of selenium and tellurium systems "Scheme 29# ð79JA3327 but generally do not work well for the complete reduction of sulfur analogues[
0[90[2[1 Reduction of C0SX Bonds
Historically\ the most important method for the reduction of alkyl thiols is Raney!nickel ð51CR236\ 51OR245\ which provides excellent chemoselectivity with consequent high yields "Schemes 18 and 20# ð49JCS2999\ 40JCS445[
11 Reduction of C0Halo`en and C0Chalco`en Bonds
SH
OH
HO
HO
OH
SH
OH
HO
HO
OH
S
67%
More recently the use of homogenous transition metal reagents\ such as molybdenum hexa! carbonyl "Scheme 20# ð79CC058\ 74JOC4302\ and catalysts ð78JOC3363 have become popular ð89S78 while stannane!mediated radical reductions have also proved successful ð71JA1935[
In common with thiols\ the desulfurisation of dialkyl or aryl alkyl sul_des is often performed by
12C0Sulfur\ C0Selenium and C0Tellurium Bonds to CH
treatment with Raney!nickel ð51CRV236\ 51OR"01#245[ The mild conditions a}orded by this procedure are particularly useful when the stereochemical integrity of labile chiral centres elsewhere in the molecule is important "Scheme 21# ð81TL4456\ 81TL5256[
S
O
Ph
O
Ph
Scheme 32
Homogenous transition metal catalysts and reagents have also been used in this context ð89S78\ but seem to have a less general reactivity\ with most reported reductions being of relatively activated "i[e[\ benzylic and a!carbonyl# sul_des ð74JOC4302\ 78JOC3363[
Sul_des that are in the a!position of a carbonyl group can be reduced by a range of methods which includes the use of Raney!nickel ð74JOC1478\ but also low!valent metals\ such as samarium"II# iodide and zinc\ in the presence of a proton source "Scheme 21# ð75JOC0024\ 76JOC1206[ Allylic sul_des are also prone to reduction by low!valent metals ð79JOC3986\ or by lithium triethylborohydride in the presence of a palladium"9# catalyst ð71JOC3279[
There are relatively few examples of the desulfurisation of alkyl sulfoxides\ but here again Raney! nickel appears to be the reagent of choice "Schemes 18 and 22# ð40JA0417\ 51OR"01#245\ 75CC0577[ Sulfoxides a to a carbonyl group are reduced conveniently by low!valent metal systems such as aluminium amalgam "Scheme 23# ð70JA1775\ samarium"II# iodide ð75JOC0024 and zinc ð76JOC1206[ Benzylic sulfoxides have been reduced by lithium aluminium hydride in the presence of a homo! genous nickel catalyst ð78JOC3363[
S
O–
Ph
O
R1
R2
O
R1
R2
S
13 Reduction of C0Halo`en and C0Chalco`en Bonds
The reduction of sulfones to alkanes has been reviewed ðB!82MI 090!90[ Most of these reactions have been performed with low!valent metal reducing reagents\ most commonly sodium amalgam "Scheme 23# ð65BSF402\ 65BSF414\ 70S44 "sodium in liquid ammonia has also been employed ð75JOC747#[ More recently\ other low!valent metal reagents\ such as lithium in ethylamine ð81JOC3487\ aluminium amalgam ð73JOC0135 and samarium"II# iodide ð75JOC0024\ 80TL0838\ have been employed and\ of these\ the use of magnesium in ethanol with a catalytic amount of mercury"II# chloride seems particularly e}ective "Scheme 23# ð82TL3430[
Potassium\ dispersed ultrasonically in toluene\ has been used to reduce only one carbonÐsulfur bond of cyclic alkyl sulfones in high yields ð74TL3384\ 80TL2440[ Unsymmetrical systems are reduced at the more substituted position[
Benzylic sulfones can be reduced by dibal!H ð73RTC119 or by lithium aluminium hydride under nickel catalysis ð78JOC3363\ while allylic sulfones have been reduced by lithium triethylborohydride in the presence of a palladium catalyst ð71JOC3279[
Sulfoximines have been reduced by Raney!nickel ð71JOC0082[
0[90[2[2 Reduction of C1S to CH1
There is little evidence to suggest that Raney!nickel is an e}ective agent for the desulfurisation of thioaldehydes or thioketones ð51CRV236[
Biarylthioketones have been reduced by zinc in aqueous acid ð55CB0282\ diphosphorus tetraiodide then sodium bisul_te ð74BCJ1310\ a nicotinamide derivative in the presence of a dimercurated benzene derivative "Scheme 24# ð74JA5010 and the tetrahydridocarbonylferrate anion "Scheme 24# ð64JOC1583[ The last of these methods is the only one shown to be applicable to aliphatic thioketones[
O
S
O
HgO2CCF3
HgO2CCF3
N
CONH2
Ph
HFe(CO)4 –
77%
0[90[2[3 Reduction of C"1S#X to CH2
Toluenes are formed in the reduction of methyl dithiobenzoates by zinc\ but only as minor components of a complex mixture of products in which the corresponding methyl benzyl sul_de predominates "Equation "3## ð55CB0282[
Zn(Hg), HCl, H2O S
58% trace
0[90[2[4 Reduction of C"SX#n Systems
One of the most important methods of deoxygenation of a ketone is by conversion to a dithioacetal derivative\ which is then desulfurised by treatment with Raney!nickel "Schemes 18 and 25# ð38JA1769\ 49JA3185\ 74JOC1596[
14C0Sulfur\ C0Selenium and C0Tellurium Bonds to CH
EtS SEt
Scheme 36
Although the method involves two separate reactions\ certain advantages are presented in com! parison to protocols such as the Wol}ÐKischner and Clemmensen reductions[ Thus enone systems are cleanly reduced without alkene reduction "Scheme 25# ð76JA2914\ 76JOC2235\ and dicarbonyl compounds can be reduced to a monocarbonyl derivative if selective dithioacetal formation can be obtained "e[g[\ an aldehyde can be reduced in the presence of a ketone ð75CC340#[
Dithioacetals in which both sulfur atoms are in the sulfone oxidation state can be reduced to the alkane by treatment with magnesium in methanol "Scheme 26# ð77JOC0712\ 77T5744[
Scheme 37
0[90[2[5 Reduction of C0Se Systems
Although Raney!nickel can be used to reduce selenides and diselenoacetals "Schemes 18 and 27# ð65TL1532\ 70T3986\ these compounds are more commonly reduced "in higher yields# by radical reduction procedures using stannanes "Schemes 18 and 27# ð79JA3327\ 70TL0512\ 70T3986 or silanes ð81JOC1316\ 81JOC2394[
Selenides have also been reduced by lithium in ethylamine ð65TL1532 and nickel boride ð73CC0306[ Allylic systems can be reduced by lithium triethylborohydride under palladium"9# catalysis ð71JOC3279[
0[90[2[6 Reduction of C0Te Systems
Tellurides can be reduced in a radical chain process by triphenylstannane "Schemes 29 and 28# ð79JA3327[ Telluride dichlorides are also reduced under these conditions at faster rates despite the reduction proceeding via the corresponding telluride "Scheme 28# ð79JA3327[
15 Reduction of C0Halo`en and C0Chalco`en Bonds
C10H21
SePh
SePh
O
O
PhSe
O
O
All Rights Reserved# Copyright 1995, Elsevier Ltd. Comprehensive Organic Functional Group Transformations
1.02 One or More CH Bond(s) Formed by Substitution: Reduction of Carbon–Nitrogen, –Phosphorus, –Arsenic, –Antimony, –Bismuth, –Carbon, –Silicon, –Germanium, –Boron, and –Metal Bonds JOSHUA HOWARTH Dublin City University, Republic of Ireland
0[91[0 THE REDUCTION OF CARBONÐNITROGEN BONDS TO CARBONÐHYDROGEN BONDS 17
0[91[0[0 Reduction of CarbonÐNitro`en Sin`le Bonds 17 0[91[0[0[0 Loss of sulfonamide anion 17 0[91[0[0[1 Loss of succinimide 18 0[91[0[0[2 Loss of pyridine derivatives 29 0[91[0[0[3 Loss of amines 21 0[91[0[0[4 Loss of nitro`en `as 24 0[91[0[0[5 Loss of nitro `roups 25 0[91[0[0[6 Loss of cyanide 27
0[91[0[1 Reduction of CarbonÐNitro`en Double Bonds to Methylene and Methyl Groups 27 0[91[0[1[0 Reduction of C1N0NR0R1 systems where R0 is an aryl sulfonyl `roup 28 0[91[0[1[1 Reduction of C1N0NR0R1 systems where R0 or R1 is alkyl\ acyl\ aryl or hydro`en 30 0[91[0[1[2 Reduction of diazo systems 33 0[91[0[1[3 Reduction of N!alkylimine type systems 34
0[91[0[2 Reduction of CarbonÐNitro`en Triple Bonds to the Methyl Group 35 0[91[0[2[0 Reduction usin` palladium catalysts 36 0[91[0[2[1 Reduction usin` oxide supported catalysts 37 0[91[0[2[2 Reduction usin` hydride rea`ents 37
0[91[1 REDUCTION OF CARBONÐPHOSPHORUS\ ÐANTIMONY AND ÐBISMUTH BONDS TO CARBONÐHYDROGEN BONDS 38
0[91[1[0 Reduction of CarbonÐPhosphorus Bonds 38 0[91[1[0[0 CarbonÐphosphorus bond cleava`e to `ive