Reduction in Organic Synthesis 9783031376856, 9783031376863, 9789380618326

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V. K. Ahluwalia

Reduction in Organic Synthesis

Reduction in Organic Synthesis

V. K. Ahluwalia

Reduction in Organic Synthesis

V. K. Ahluwalia Department of Chemistry University of Delhi Delhi, India

ISBN 978-3-031-37685-6 ISBN 978-3-031-37686-3 (eBook) https://doi.org/10.1007/978-3-031-37686-3 Jointly published with Ane Books Pvt. Ltd. The print edition is not for sale in South Asia (India, Pakistan, Sri Lanka, Bangladesh, Nepal and Bhutan) and Africa. Customers from South Asia and Africa can please order the print book from: ANE Books Pvt. Ltd. ISBN of the Co-Publisher’s edition: 978-93-8061-832-6 1st edition: © Author 2016 © The Author(s) 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publishers, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publishers nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publishers remain neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Reduction of organic compounds plays an important role in synthetic organic chemistry. A large number of organic synthesis involve reduction at some stage. The purpose of this book is to present a comprehensive account of different types of reducing agents and their applications. Reduction of special types of organic compounds like hydrocarbons, alcohols, phenols, aldehydes, ketones, carboxylic acids and their derivatives, nitro compounds and nitriles is described. The mechanism of the reactions involving reduction is also given in most of the cases. Photochemical reductions and enzymatic or microbial reductions have also been described. Most of the reductions require solvents which are volatile organic solvents and are harmful to the environment. In view of this, some reductions under benign conditions have also been described. This book will be useful to undergraduate, postgraduate students and all research workers involved in organic synthesis. I express my special thanks to Mr. Sunil Saxena of Ane Books Pvt. Ltd. for the help in the publication of this book. Books’ names of various authors are listed in the suggested readings at the end of this book. I am also grateful to Dr. Uma Shankar Das for the help rendered. V.K. Ahluwalia

v

Contents

1. Introduction 2. Different Types of Reducing Agents 2.1 Catalytic Hydrogenation 2.1.1 Heterogeneous Catalytic Hydrogenation

1–2 3–54 3 3

Platinum

3

Palladium

4

Rhodium

4

Nickel

4

Miscellaneous heterogeneous catalysts

5

Adkins catalysts

5

Copper chromite

5

Zinc chromite

5

2.1.2 Homogeneous Catalytic Hydrogenation

5

2.1.3 Asymmetric Homogeneous Catalytic Hydrogenations

9

2.2 Hydride-Transfer Reagents

10

2.2.1 Aluminium Alkoxides

10

2.2.2 Lithium Aluminium Hydride

11

2.2.3 Sodium Borohydride

14

2.2.4 Di-isobutylaluminium Hydride (DIBAL)

16

2.2.5 Sodium Cyanoborohydride

18

2.2.6 Trialkylborohydrides

20

2.2.7 Borane and Dialkylboranes

21

2.3 Dissolving Metal Reductions

25

2.3.1 Electrolytic Reduction

25 vii

viii

Reduction in Organic Synthesis

2.3.2 Reduction with Sodium 2.3.2.1 Sodium-alcohol 2.3.2.2 Sodium-liquid Ammonia 2.3.2.3 Sodium Amalgam 2.3.2.4 Sodium and Xylene 2.3.2.5 Salts of Sodium 2.3.3 Reductions with Magnesium 2.3.4 Reductions with Aluminium 2.3.5 Reductions with Zinc 2.3.6 Reductions with Iron 2.3.7 Reductions with Tin and Its Compounds 2.4 Non-metallic Reducing Agents 2.4.1 Reductions with Hydrogen Iodide 2.4.2 Reductions with Hydrogen Sulfide 2.4.3 Reductions with Sulphur Dioxide 2.4.4 Reductions with Dimethly Sulfide 2.4.5 Reductions with Hydrazine 2.4.6 Reductions with Diimide 2.4.7 Reductions with Silanes 2.4.8 Reductions with Formic Acid 2.5. Photochemical Reductions 2.6. Enzymatic or Microbial Reductions 3. Reduction of Specific Types of Organic Compounds 3.1 Reduction of Hydrocarbons 3.1.1 Reduction of Alkanes and Cycloalkanes 3.1.2 Reduction of Alkenes and Cycloalkenes (A) Reduction of Alkenes (B) Reduction of Cycloalkenes 3.1.3 Reduction of Dienes 3.1.4 Reduction of Alkynes and Cycloalkynes 3.1.5 Reduction of Aromatic Compounds 3.1.6 Reduction of Condensed Aromatic Hydrocarbons 3.1.7 Reduction of Heterocyclic Compounds

27 27 28 30 30 31 33 34 35 37 37 38 38 39 39 39 40 41 42 43 44 46 55–114 55 55 56 56 60 61 63 65 67 70

Contents

ix

3.2 Reduction of Alcohols and Phenols

72

3.3 Reduction of Aldehydes

75

3.4 Reduction of Ketones

81

3.5 Reduction of Carboxylic Acids and Its Derivatives

89

3.6 Reduction of Nitro Compounds

101

3.7 Reduction of Nitriles

103

4. Hydrogenolysis 4.1 4.2 4.3 4.4 4.5

Hydrogenolysis of C–X Bond Hydrogenolysis of C–O Bond Reductive Cleavage of a Carbon Oxygen Double Bond Reductive Cleavage Carbon-Nitrogen Bond Reductive Cleavage of Carbon-Sulphur Bonds

5. Enzymatic or Microbial Reduction

115–122 115 116 118 119 120 123–126

5.1 Reduction of β-Ketoesters

123

5.2 Reduction of Ketones and Aldehydes

124

6. Some Reductions under Benign Conditions

127–136

6.1 Introduction

127

6.2 Reduction of Carbon-Carbon Double Bonds

127

6.3 Reduction of Carbon-Carbon Triple Bonds

129

6.4 Reduction of Carbonyl Compounds

130

6.5 Reduction of Esters

134

6.6 Reduction of Aromatic Rings

134

Suggested Readings Index

137–138 139–142

CHAPTER

1

Introduction

Like oxidation, reduction also plays an important role in synthetic organic chemistry. There are only a few organic synthesis which do not involve reduction at some stage. A convenient definition of reduction is the addition of hydrogen (as in the case of reduction of alkenes to alkanes) or addition of electrons to an organic substrate (as in the reduction of 2-butanone to 2-butanol (CH3CH2COCH3 –

gain 2e ⎯⎯⎯ → CH3CH2CHOH CH3).

An important concept to decide whether a particular reaction is reduction that means the conversion of an atom from a higher oxidation state to a lower one. A number of rules were formulated.1 A simplified procedure for determining the oxidation number was subsequently given.2, 3 These rules were used for determination of oxidation numbers of only those atoms, which are commonly encountered like H, O, C, N and halogens. The following convention for assigning the oxidation number is used. Oxidation number for hydrogen is –1; oxidation number for carbon (bonded to the same atom) is 0; oxidation number for carbon bonded to a hetero atom (oxygen or halogen) is +1. The oxidation number of only those atoms that are changed in the reduction are examined. If the sum of oxidation numbers of various atoms in the substrate and the product is compared, the change in oxidation number can be calculated. From this change we can find out whether a particular reaction is oxidation or reduction. Thus, in the reduction of propanal to propanol, the oxidation state of carbon in CHO changes from +1 to –1 for the C in CH2OH. –

CH3CH2CHO

gain of 2e

+1

© The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3_1

CH3CH2CH2OH –1

1

2

Reduction in Organic Synthesis

In the above example, in propanal, the carbon atom of the aldehyde group has an oxidation number +1 (C is 0, H is –1, O is +1 and O from second bond to the carbonyl is +1). However, in case of the product, propyl alcohol, the oxidation number of C in CH2OH is –1 (C is 0, H is – 1, H is –1 and O is +1). We find that the change in oxidation number is +1 → –1, for a net gain of 2 electrons. So this is a reduction reaction. The product obtained in a reduction depends on the nature of the substrate, the nature of the reducing agent and the reaction conditions. The method depends on the selectivity and the stereochemistry of the desired product. Reductions can be effected either chemically or by catalytic hydrogenations. Each method has its advantage. Complete reduction of an unsaturated compound can be achieved without any difficulty. However, the objective is often selective reduction of one group is a molecule in the presence of other unsaturated groups. Both catalytic and chemical method are of considerable use.

REFERENCES 1. S. Solorevchik and H. Kvakauer, J. Chem. Ed., 1966, 43, 532. 2. J. B. Henderickson, D.J. Cram and G.S. Harmmond, Organic Chemistry, 3rd, Ed., McGraw-Hill, New York, 1970. 3. S.H. Pine, Organic Chemistry, 5th Ed., McGraw-Hill, New York, 1987.

CHAPTER

2

Different Types of Reducing Agents

Following are given different types of reducing agents. As already stated, the method of choice depends on the selectivity required and also on the stereochemistry of the desired product.

2.1 CATALYTIC HYDROGENATION Of the numerous methods available for reduction of organic compounds, catalytic hydrogenation is one of the most convenient. Catalytic hydrogenation is of two types: • Heterogeneous catalytic hydrogenation • Homogeneous catalytic hydrogenation 2.1.1 Heterogeneous Catalytic Hydrogenation In this procedure, hydrogenation is effected simply by stiring the substrate with the catalyst in a suitable solvent in an atmosphere of hydrogen. At the end of the reaction, the catalyst is filtered off and the product isolated from the filtrate. Some of the widely used catalysts for heterogeneous catalytic hydrogenations are platinum, palladium, rhodium, ruthenium and nickel. Platinum: Earlier platinum was used in colloidal form or platinum sponge. Now platinum is used in the form of platinum oxide (PtO2) (Adam’s Catalyst)1,2. It is made by fusing chloroplatinic and sodium nitrite, and is the most powerful catalyst. It is required in very small amount (1–3%) and is suitable for almost all hydrogenations (e.g., alkynes and alkenes to alkanes). Another form of very active elemental platinum is obtained by the reduction of chloroplatinic acid with sodium borohydride in ethanolic solution. Such catalyst hydrogented 1-octene much faster than platinum oxide.3

© The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3_2

3

4

Reduction in Organic Synthesis

Palladium: The palladium is used for catalytic hydrogenation in the form of palladium oxide (PdO) (prepared4,5 by fusion of palladium chloride and sodium nitrate at 570 – 600°C), elemental palladium (obtained3,6 by reduction of palladium chloride with sodium borohydride; it is useful6 for the reduction of unsaturated aldehydes to saturated aldehydes) and supported palladium catalysts. Thus, palladium on barium sulphate, deactivated with sulphur and quinoline7 is useful for the well known Rosenmund reduction8, which involves reduction of acid chloride, RCOCl to aldehydes, RCHO. Palladium on calcium carbonate deactivated by lead acetate (Lindlar’s catalyst) is useful9 for the partial hydrogenation of acetylenes to cis-alkenes. Palladium catalysts can be used in acidic or basic media. These are especially useful for hydrogenolysis as in the cleavage of benzyl-type bonds (Scheme 2.1). RCH2OCOOR¢

H2/Pd

RCH3 + HOCOOR¢ HOR¢ + CO2

Scheme 2.1

Rhodium: Rhodium, usually 5% on carbon or alumina is suitable especially for hydrogenation of aromatic systems10. For this purpose, a mixture of rhodium oxide and platinum oxide is also used. Unsaturated aldehydes containing vinylic halogens can be reduced at the double bond without hydrogenolysis of the halogen11. Some of the rhodium complexes are used in homogeneous catalytic hydrogenation (See section 2.1.2). Ruthenium catalysts12 and rhenium heptoxide13 are especially used in the reduction of free carboxylic acids to alcohols. Nickel: Nickel catalysts are widely used in laboratory and also in industry. A typical example of use of nickel in industry is the catalytic hydrogenation of unsaturated fats and oils to obtain saturated fats and oil (used as artificial ghee). A supported form of nickel is nickel on Kieselguhr or infusorial earth. It is obtained by the precipitation of nickel carbonate from a solution of nickel nitrate by sodium carbonate in the presence of infusorial earth and subsequent reduction of the precipitate with hydrogen at 450°C after drying (110 – 120°C). Such catalysts are used at 100 – 200°C and in presence of hydrogen at 100 – 250 atm14. A well known useful nickel catalyst is Raney-nickel, which is prepared from nickel aluminium alloy. Depending on the reaction conditions, Raney nickel of varied activity can be prepared. It is categorised15 by the symbols W1-W8. Raney-nickel W6 (which contains 10–11% aluminium) is the most active form16. Raney-nickel preparations are pyrophoric in the dry state. Raney-nickel can be used for the reduction of any function. Even the difficult reducible acids and esters, are reduced15 to alcohols. A special advantage is that Raney-nickel is not

Different Types of Reducing Agents

5

poisoned by sulphur and can be used for desulphurization of sulphur containing compounds17. Thus, thiol ester can be reduced to aldehydes (Scheme 2.2). S R — C — O Et

H Raney-nickel Et OH

R—C

O

Scheme 2.2

Raney-nickel is also used for hydrogenolysis. A typical example is given below (Scheme 2.3).

Scheme 2.3

Some other nickel catalysts are obtained by the reduction of nickel salts, e.g., nickel acetate with two mol of sodium borohydride18. Such catalysts are designated P-1 or P-2 and can be prepared in situ; this catalyst contains a high percentage of nickel boride and are non-pyrophoric, it can be used for hydrogenations at room temperature and atmospheric pressure. These, particularily nickel P-2 is used for partial hydrogenation of acetylenes to cis-alkenes14,15. Nickel precipitated by adding aluminium or zinc dust to aqueous solution of nickel chloride is called Urushibara catalyst; it resembles Raney-nickel in its activity19. Another active non-pyrophoric catalyst known as Nic catalyst is prepared by the reduction of nickel acetate by sodium hydride in THF at 45°C in presence of tert-amyl alcohol (which acts as an activator). This catalyst is used for partial reduction of acetylenes to cis-alkenes20. Miscellaneous heterogeneous catalysts Adkins catalysts: These catalysts are based on oxides of copper, zinc and chromium, and are specifically useful for reduction of carbon-oxygen bonds. Copper chromite: It is prepared21 by the thermal decomposition of ammonium chromate and copper nitrate; the activity is increased if barium nitrate is added before thermal decomposition22. Zinc chromite (similarly prepared) is useful for the reduction of unsaturated acids and esters to unsaturated alcohols23. These catalysts are specifically useful for reduction of carbonyl and carboxyl containing compounds to alcohols. 2.1.2 Homogeneous Catalytic Hydrogenations All catalysts so far described are used in heterogeneous catalytic hydrogenation. Although useful, these have some disadvantages. They show lack of selectivity

6

Reduction in Organic Synthesis

when more than one unsaturated centre is present. They may also cause doublebond migration and in reactions with deuterium, they may bring about allylic interchanges with deuterium. Also, some of the functional group suffer easy hydrogenolysis; this in fact, leads to complications. The stereochemistry of reduction is difficult to predict, since it depends on chemisorption and not on reaction molecules. Some of these problems associated with heterogeneous catalytic hydrogenations have been overcome by the introduction of homogeneous catalytic used hydrogenations24. In this procedure, the catalysts are soluble in organic solvents. A large number of soluble catalysts have been developed and used. The most effective are found to be those of rhodium and ruthenium complexes. The rhodium complex, tris (triphenyl phosphine) chlororhodium, also known as Wilkinson’s catalyst is prepared by the reaction of rhodium chloride with excess of triphenylphosphine in boiling ethanol (Scheme 2.4). RhCl3.3HO + (C6H5)3P Rhodium chloride

boiling C2H5OH

Triphenyl phosphine (excess)

[(C6H5)3P]3RhCl Wilkinson's catalyst

Scheme 2.4

It is a very effecient catalyst for the homogeneous hydrogenation of non-conjugated alkenes and alkynes at ordinary temperature and pressure in benzene solvent. In the procedure adopted, functional groups, such as oxo, cyano, nitro, chloro, azo remain uneffected. Mono- and disubstituted double bonds are reduced rapidly, permitting the partial hydrogenation of compounds, containing different kinds of double bonds25. Two such examples of partial reduction are given below (Scheme 2.5).

Scheme 2.5

Different Types of Reducing Agents

7

The selectivity of reduction by Wilkinson’s catalyst is also shown by the reduction of ω-nitrostyrene to phenylnitroethane (Scheme 2.6). C6H5CH

CHNO2

w-nitrostyrene

H2[(C6H5)3P]3RhCl C6H6

C6H5CH2CH2NO2 Phenylnitroethane

Scheme 2.6

In case of Wilkinson’s catalyst, the hydrogenation takes place by cis-addition to the double bond. Also, the catalyst does not bring about hydrogenolysis and thus, permits selective hydrogenation of carbon-carbon double bond (without hydrogenolysis of other susceptible groups in the molecule). Thus, benzyl cinnamate is converted smoothly into the dihydro compound and allyl phenyl sulphide is reduced to phenyl propyl sulphide in 93% yield (Scheme 2.7). C6H5CH

CHCO2CH2C6H5

Benzyl cinnamate

CH2

CHCH2 — S — C6H5

Allyl phenyl sulphide

H2[(C2H5)3P]3RhCl C6H6

H2[(C6H5)3P]3RhCl C6H6

C6H5CH2CH2CO2CH2C6H5 Dihydro benzylcinnamate

CH3CH2CH2SC6H5 Phenyl propyl sulphide 93%

Scheme 2.7

Since Wilkinson’s catalyst has strong affinity for carbon monoxide, it decarbonylates aldehydes. Thus, cinnamaldehyde is converted into styrene (65% yield) and benzoyl chloride gives chlorobenzene in 90% yield (Scheme 2.8). C6H5CH

CHCHO

Cinnamaldehyde

C6H5COCl Benzoyl chloride

[(C6H5)3P]3RhCl C6H6

[(C6H5)3P]3RhCl C6H6

C6H5CH

CH2

styrene (65%)

C6H5Cl Chlorobenzene (90%)

Scheme 2.8

Thus, olefinic compounds containing aldehyde group cannot be hydrogenated by this catalyst. The ruthnium complex, [(C 6 H 5) 3P] 3RuClH, is formed in situ from [(C 6H 5) 3P] 3 RuCl 2 and molecular hydrogen in presence of a base like triethylamine. This catalyst is more efficient and is specific for the hydrogenation of monosubstituted alkenes, RCH = CH2. Terminal alkynes also react with this catalyst. However, disubstituted alkynes are converted into Z-alkenes. Thus, stearolic acid on reduction gave oleic acid (Scheme 2.9).

8

Reduction in Organic Synthesis

Scheme 2.9

Hydrogenation with the ruthenium complex, [(C6H5)3P]3 RuCl H is believed to be a two step process as shown below (Scheme 2.10). H [(C6H5)3P]3 Ru

RCH

R

H

CH2

[(C6H5)3P]3 Ru

Cl

CH Cl

[(C6H5)3P]3 Ru — CH CH3 Cl

H2

CH2

R CH2CH3 + [(C6H5)3P]3 Ru

H Cl

R

Scheme 2.10

The high selectivity for the reduction of terminal double bond is due to steric hinderance caused by the bulky P(C6H5)3 group to the formation of metal-alkyl intermediate with other types of alkenes. Another useful homogeneous hydrogenation catalyst is an iridium complex26 [Ir(Cod)Py(PCy3)]PF3, where Cod is 1,5-cyclooctadiene and Cy is cyclohexyl. This catalyst is uneffected by sulphur (in the molecule) and reduces tri and tetra-substituted double bonds besides the mono and di-substituted ones. A special feature of this catalyst is the high degree of stereocontrol in the hydrogenation of cyclic, allylic and homoallylic alcohols. Some examples27, 28 are given in Scheme 2.11. CH3

CH3 H

H OH allylic alcohol

CH3

100%

OH

O

CH3

O Homoallylic alcohol

OH

H

H

OH

Different Types of Reducing Agents

CH3

OH

9

CH3

O

O

OH

H

Homo allylic alcohol

Scheme 2.11

One of the most important iridium complex is Vaska’s catalyst29, [(PPh3)2 IrCO]+Cl–. It also reacts with hydrogen converting the square planar catalyst (A) to the octahedral (B). In this case, reduction is believed to involve in the replacement of triphenylphosphene ligand with hydrogen or an alkene in a rervesible process30 (Scheme 2.12). Ph3P

CO

H2

Ph3P

Ir Cl

H

H

Ir PPh3

Cl

(A)

CO

PPh3

(B)

Scheme 2.12

2.1.3 Asymmetric Homogeneous Catalytic Hydrogenations Homogeneous catalytic hydrogenations have been used to effect asymmetric hydrogenations31-34. The catalyst used for this purpose includes some rhodium complexes containing as ligands chiral phosphines or amides. Thus, trichlorotriphenylpyrididyl rhodium on treatment with dimethyl formamide gave a complex, [Py2.dmf.RhCl2(BH4)], which is used for the hydrogenation of alkenes. In a similar way, by using asymmetric ligands related to dimethyl formamide catalysts obtained can bring about asymmetric hydrogenations. Thus, methyl 3-phenyl-2-butenoate on hydrogenation at a rhodium complex formed in (+) or (–) -1-phenylethyl formamide gave (+)-or (–)-methyl 3-phenylbutanoate in better than 50 per cent optical yield (Scheme 2.13).

Scheme 2.13

Hydrogenation of α-acetylammoacrylic acids using rhodium (I) complexes containing chiral phosphine (C), or the cyclo-octadiene complex [Rh(1,5-cyclo-

10

Reduction in Organic Synthesis

octadiene)Cl] 2 yielded high optical yields of α-amino acids. Thus, α-acetylaminocinnamic acid gave N-acetylphenylalanine in 95 per cent yield and 85 per cent optical purity by using the laevorotatory form of the ligand (C). In a similar way, atropic acid yielded (S)-hydratropic acid (64 per cent optical purity)35, 36 (Scheme 2.14).

Scheme 2.14

2.2 HYDRIDE-TRANSFER REAGENTS Reductions, which proceed by transfer of hydride ions are very common in organic chemistry. Some of the important hydride-transfer reagents are given below: 2.2.1 Aluminium Alkoxides The most important aluminium alkoxide is aluminium isopropoxide, which has long been used under the name of the Meerwein-Pondorff-Verley reduction37. The reaction is carried out by heating the components together in solution in isopropanol. The product is obtained by using an excess of the reagent or by distilling off the acetone as it is formed.The reduction proceeds by transfer of hydride ion from isopropoxide to the carbonyl compound via a six membered transition state. Carbonyl compounds are reduced to the corresponding alcohols in high yield (Scheme 2.15).

Different Types of Reducing Agents

i

Al(OPr)2 R1 R2

O

O

C

+

C H

11

i

CH3

R1

CH3

R2

O

Al(OPr)2

O + C

C H

CH3 CH3

H3O+ OH

R1 R2

C

H

Scheme 2.15

The advantage of using aluminium isopropoxide is that carbon-carbon double bonds and many other unsaturated groups are uneffected, thus permitting only the selective reduction of carbonyl groups. Certain other metallic alkoxides can also be used, but aluminium alkoxide is particularly effective, since it is soluble in both alcohols and hydrocarbons, and being a weak base, there is little tendency of the formation of wasteful condensation reactions of the carbonyl compounds. 2.2.2 Lithium Aluminium Hydride It is commercially available. However, it can be prepared by the reaction of lithium hydride (LiH) with aluminium trichloride (AlCl3) in (tetra hydro furan). 4LiH + AlCl3

THF

LiAlH4 + 3LiCl

It reacts violently with water or protic solvents resulting in the liberation of hydrogen. So the reductions are usually carried out in dry ether, tetrahydrofuran or dioxane. It is one of the most important and useful reagent for the reduction of aldehydes, ketones, carboxylic acids, esters, acid chlorides, anhydrides, epoxides, nitriles and nitro compounds. In case of lithium aluminium hydride (LiAl H4), all the four hydrogen atoms may be used for reduction, being transferred in a stepwise manner as shown below in the reduction of a ketone (Scheme 2.16). H –

H — Al — H H

CH3

CH3 C

H—C

O

CH3

– O Al H3

CH3COCH3

CH3

–

H2 Al [–OCH(CH3)2]2

CH3COCH3

–

H Al [OCH(CH3)2]3 CH3

CH3COCH3

–

Al [OCH(CH3)2]4

H3O+

4H— C CH3

Scheme 2.16

OH

12

Reduction in Organic Synthesis

As seen, the anion of lithium aluminium hydride (–H-AlH3) is a nucleophilic reagent and attacks polarised carbonyl group by transfer of hydride ion to the more positive atom. It does not usually reduce isolated carbon-carbon double or triple bonds. In case of lithium aluminium hydride, each successive transfer of hydride ion takes place more slowly than the one before. This has been exploited for the preparation of modified reagents which are less reactive and more selective than lithium aluminium hydride. More selective reagents can be obtained by modification of lithium aluminium hydride by treatment with alcohols or with aluminium chloride. A typical modified reagent is lithium hydridotri-t-butoxyaluminate, which is readily prepared by the action of stoichiometric amount of t-butyl alcohol on lithium aluminium hydride (Scheme 2.17). Li AlH4 + 3(CH3)3C — OH Lithium Aluminium hydride

tert. butyl alcohol

Li AlH(OC4H9t)3 + 3H2 Lithium hydridotri-tbutoxy aluminate

Scheme 2.17

Similarly reagents are obtained in the same way from other alcohols by the replacement of only one or two of the hydrogen atoms of the hydride by alkoxy groups, yielding a range of reagents of graded activities38. Lithium hydrotri-t-butoxyaluminate is a much milder reducing agent compared to lithium aluminium hydride. Thus, carbonyl compounds (aldehydes and ketones) are reduced normally to the corresponding alcohols, carboxylic esters, epoxides react only and slowly, whereas, halides, nitriles and nitro groups are not effected. Thus, aldehydes and ketones can be selectively reduced in the presence of these groups. Two of the typical examples are given below (Scheme 2.18).

Scheme 2.18

Different Types of Reducing Agents

13

Reduction of tertiary amides with the less active LiAlH (OC2H5)2 (the trit-butoxy compound is ineffective in this case) gives the aldehyde-ammonia, which on hydrolysis gives the corresponding aldehyde (Scheme 2.19). CH2

1. Li AlH(OC2H5)2

CH(CH2)8CON(CH3)2

2. hydrolysis

CH2

CH(CH2)8CHO 85%

Scheme 2.19

Useful modification of the properties of lithium aluminium hydride can be achieved by the addition of aluminium chloride in various proportions. The effect of the addition of aluminium chloride is to reduce the reducing power of lithium aluminium hydride. By this procedure, reagents which are more specific for particular reactions38 are produced (Scheme 2.20). 3LiAlH4 + AlCl3

3LiCl + 4AlH4

LiAlH4 + AlCl3

LiCl + 2AlH2Cl

LiAlH4 + 3AlCl3

LiCl + 4AlHCl2

Scheme 2.20

The modified reagent [LiAlH4 – AlCl3(1:1)] reduces ester to alcohol without affecting the halogen (Scheme 2.21). Br CH2 CH2CO2CH3

LiAlH4–AlCl3 (1 : 1) ether

methyl 3-bromopropionate

Li AlH4

BrCH2CH2CH2OH 3–Bromopropanol

CH3CH2CH2OH Propanol

Scheme 2.21

This reagent [LiAlH4-AlCl3 (1 : 1)] does not affect the nitro group and so p-nitro benzaldehyde is converted into p-nitrobenzylalcohol in 75% yield. Normally, aldehydes and ketones are reduced to alcohols (there is no advantage in these cases in the use of mixed hydrides). However, in case of diaryl ketones and aryl alkyl ketones, the carbonyl group is reduced to methylene group in high yield; this procedure offers a useful alternative to the Clemmensen reduction or Huang-minlon method for reduction of this type of ketones. Another interesting application of mixed lithium aluminium hydridealuminium chloride (3:1) reagent is the conversion of α, β-unsaturated carbonyl compounds to unsaturated alcohols, which are difficult to perpare with lithium aluminium hydride (Scheme 2.22). C6H5 — CH

CHCO2C2H5

3LiAlH4–AlCl3

Scheme 2.22

C6H5CH

CHCH2OH

90%

14

Reduction in Organic Synthesis

In the above case, the effective reagent is believed to be aluminium hydride formed in situ from lithium aluminium hydride and aluminium chloride. Complex aluminium hydrides have been prepared by the reaction of lithium aluminium hydride with appropriate salts of other metals. These include sodium aluminium hydride (NaAlH4) and magnesium aluminium hydride (Mg(AlH4)2]. 2.2.3 Sodium Borohydride Like lithium aluminium hydride, sodium borohydride is also commercially available. However, it can be prepared by the reaction of sodium hydride with trimethyl borate or with sodium fluoroborate and hydrogen (Scheme 2.23).

Scheme 2.23

Sodium borohydride is a very selective reducing agent and reduces aldehyde and ketones to alcohols. Groups like halogens, cyano, amido and alkoxycarbonyl are uneffected. Like LiAlH4, sodium borohydride also does not usually reduce isolated carbon-carbon double or triple bonds. It is also inert towards lactones, epoxides and carboxylic acids. It is insoluble in ether, but soluble in alcohol and water. So it is used in hydroxylic solvents like alcohol, isopropanol etc. Sodium borohydride reacts in a similar manner as LAH. It also delivers hydride ion (H+) as the powerful nucleophile to the carbonyl carbon. The alkoxide ion thus formed in the first step can help to stabilise the electron deficient BF3 molecule. All the steps involved in the reduction of carbonyl compounds are shown in Scheme 2.24.

Different Types of Reducing Agents

R

R R

15

C

O + NaBH4

R

C

– O + BH3

H

R R

C

–+ O — B Na

H

3

R C

R

O

R

R

C

– + O — BH3 Na

H

4

H2O

R 4R

C H

OH Scheme 2.24

As already stated, since sodium borohydride is insoluble in organic solvents, therefore it is normally possible to carry out reduction of those compounds which are insoluble in organic solvents. However, it is now possible to transfer40 the borohydride anion from an aqueous basic solution of sodium or potassium borohydride in benzene by using phase transfer catalysts. Thus, 2-octanone on reduction with aqueous sodium borohydride in benzene solution using trimethylammonium chloride (as PTC) gives 2-octanol in 80% yield. The crown ethers, (e.g., dibenzo-18-crown-6) also catalysed sodium borohydride reduction of a number of ketones in boiling tolune (5 hr). Using this procedure41, acetophenone, cyclohexanone and 2-heptanone were reduced in 49%, 50% and 41% yields, respectively. Sodium borohydride-aluminium chloride complex42 is a more powerful reducing agent and converts nitriles to primary amines and amides to amines. Sodium borohydride-borontrifluoride complex43 reduces lactones to cyclic ethers. In the above case, the actual reducing agent is diborane (B2H6), which is formed by the reaction of sodium borohydride and aluminium chloride or boron trifluoride. The reaction of sodium borohydride with cuprous chloride gives copper hydride which is highly selective reducing agent for the preparation of aldehydes from acyl chlorides44. Following complex boron hydrides have been prepared by the reaction of sodium borohydride with appropriate salts of other metals38a (Scheme 2.25). Lithium borohydride, LiBH4 Potassium borohydride, KBH4 Calcium borohydride, Ca(BH4)2 Tetrabutylammonium borohydride Bu4NBH4 Scheme 2.25

16

Reduction in Organic Synthesis

Table 2.1 gives the products obtained by the reduction of various functional groups with LiAlH4 and NaBH4. Table 2.1. Reductions with LiAlH4 and NaBH4 Substrate —COOH —COOC2H5

LiAlH4

NaBH4

—CH2OH —CH2OH

C=O

— —

CHOH

CHOH

—CHO O

—CH2OH

—CH2OH

—C—Cl

—CH2OH

—

—CH—C—

—CH 2—C—

—CH 2—C—

O —NO2 Aliphatic ArNO2

CH2Br

—NH2

OH

ArNHNHAr or ArN==N Ar CH3

CH—Br

CH2

C=NOH

CH—NH2

OH

—

— — — CHNH2

O — C — NHR

—CH2NHR

—CH2NHR

—C≡N

—CH2NH2

—CH2NH2

—CH = CH—

—

—

2.2.4 Di-isobutylaluminium Hydride (DIBAL) This is a derivative of aluminium hydride and is commercially available as a solution in toluene or hexane. It is named as Diisobutylalane (alane is aluminium hydride) and is represented as (Scheme 2.26).

Scheme 2.26

It is prepared45 by refluxing triisobutylaluminium in heptane. It is a versatile reducing agent. At ordinary temperature, esters and ketones are reduced to alcohols, nitriles to amines and epoxides are cleaved to alcohols.

Different Types of Reducing Agents

17

Its best utility is in the preparation of aldehydes. Thus, at low temperatures esters and lactones are reduced directely to aldehydes and nitriles, whereas amides give aldimines, which are readily converted into aldehydes by hydrolysis (Scheme 2.27).

Scheme 2.27

DIBAL is also useful for the reduction of disubstituted alkynes to cis-alkenes and for the selective 1,2-reduction of α,β-unsaturated carbonyl compounds to allylic alcohols Thus, enedione was reduced to cis, cis-diene (Scheme 2.28).

Scheme 2.28

DIBAL along with methyl copper (MeCu) is used for selective 1,4 reduction of conjugated esters; in this case, the usual reduction of the ester group to

18

Reduction in Organic Synthesis

CH2OH is suppressed. Thus, the conjugated ester (A) is converted into (B) in 63% yield46 (Scheme 2.29). H

H

Me

Me

DIBAL, MeCu HMPA

H

MeO2C

H

MeO2C

(B)

(A)

Scheme 2.29

2.2.5 Sodium Cyanoborohydride A number of reagents derived from sodium borohydride by the replacement of one or more hydrogen atoms by other group permit selective reduction. One such useful reagent is sodium cyanoborohydride, NaBH3CN. It is obtained47 by the reaction of NaBH4 with HCN (Scheme 2.30). THF

NaBH4 + HCN

NaBH3CN + H2

Scheme 2.30

It is a remarkably stable reagent that does not decompose in acid solution (about pH 3). It is soluble in THF, methanol, water, HMPA, DMF and sulfolane and is unreactive; this makes it very selective48. Sodium cyanoborohydride readily reduces iodides, bromides and tosylates to the hydrocarbon in excellent yields (when HMPA is used as the solvent49) even when other functional groups like ester or ketone are present50 (Scheme 2.31). Me Me O

I

H

O

H

NaBH3CN, HMPA 70°, 1 hr

H

O

Me Me O

H

O

H H

O

Scheme 2.31

Even alcohols are reduced (–OH→H) if zinc bromide (ZnBr2) is added to the reagent.51

Different Types of Reducing Agents

19

In the above reaction, the presence of epoxide ring does not change the course of reduction. O C6H5 CH—CH—CH2Br 3–Bromo–1,2 epoxy –1–phenyl propane

NaBH3CN HMPA

O C6H5 CH—CH—CH3 1,2–Epoxy–1–phenyl propane (63%)

Aldehydes and ketones are reduced in acidic media52 as illustrated by the following example (Scheme 2.32). H N

CO2ET O

H NaBH3CN pH 4

N

CO2ET OH

Scheme 2.32

The conversion of carbonyl compounds into the corresponding hydrocarbon is known by the reduction of the derived toluene-p-sulphonyl-(tosyl) hydrozones with sodium borohydride53. Much better yields are obtained by using-sodium cyanoborohydride in acidic dimethyl formamide (Scheme 2.33).

Scheme 2.33

The above reduction is very selective and the formation of alkenes and other unwanted products are avoided. This reaction is specific for aliphatic and alicylic carbonyl compounds; however aromatic compounds are uneffected. For the above reaction the tosylhydrazones are prepared in situ. With α, β-unsaturated carbonyl compounds, reduction of the tosylhydrazone is accompanied by migration of the double bond to the carbon atom which originally carried the oxygen (Scheme 2.34).

Scheme 2.34

Similar migration of the double bond is observed in case of β-ionone (Scheme 2.35).

Scheme 2.35

20

Reduction in Organic Synthesis

2.2.6 Trialkylborohydrides The lithium trialkylborohydrides A, B and C (shown below) are much more powerful reducing agents than lithium borohydride itself (Scheme 2.36).

Scheme 2.36

The alkyl borohydrides reduce aldehydes, ketones and esters to the corresponding alcohols. However, their reactions show special features which is of value in synthesis39. In case of lithium triethyl borohydride (A), due to the inductive effect of the ethyl group and also due to their effect in reducing solvation of the anion, it is a very powerful nucleophile and is an excellent reagent for the reductive fission of primary and secondary alkyl bromides and tosylates; in this respect, it (A) is far superior to lithium aluminium hydride. Aryl halides are not affected, thus allowing selective reduction in a molecule containing both aryl and alkyl halide groups. Thus, cycloheptyl bromide and cyclopentyl tosylate on reaction with lithium triethyl borohydride (A) gave cycloheptane and cyclopentane, respectively in quantitative yield. The deuterated reagent, Li(C 2H5)3BD (easily prepared by hydrogen exchange in D2O at pH 3 ) is useful for introducing deuterium into an alkane with stereochemical inversion at the site of substitution (Scheme 2.37).

Scheme 2.37

This reagent (A) smoothly reduces the epoxides to the alcohols in high yield, by attack at the less substituted carbon. There is no rearrangement even in highly hindered epoxides.

Different Types of Reducing Agents

21

Stereoselective reduction of ketones has been achieved with lithium tri-sbutyl borohydride (B). Thus, in case of 4-methyl or 4-tertiarybutyl cyclohexanone, the reagent (B) attacks predominantly from the equatorial side to give axial alcohol (cis-4-methylcyclohexanol or cis-4-tertiary butylcyclohexanol) in about 93–95% yield. The reagent (B) is prepared in situ from LiAlH(OCH3)3 and tri-s-butylborane and the reaction process smoothly at 0° in THF (Scheme 2.38). O

2.5

99

R

NaBH4 R–CH3 or tert. butyl

O

1

1

R Li(S-C4H9)3BH

Scheme 2.38

2.2.7 Borane and Dialkylboranes Borane, BH3, exists as the gaseous dimer diborane, B2H6. It can be prepared by the reaction of boron trifluoride etherate with sodium borohydride in diglyme solution (diglyme is the dimethyl ether of diethylene glycol) (Scheme 2.39). 3NaBH4 + 4BF3

3NaBF4 + 2B2H6 Scheme 2.39

However, it is commercially available in tetrahydrofuran, which contains the borane-tetrahydrofuran complex, BF3⋅THF. Diborane is a powerful reducing agent and attacks a number of unsaturated groups. The reaction takes place at room temperature and the products are isolated in high yield after hydrolysis (protonolysis) of the intermediate boron compound39,54. One example is given below (Scheme 2.40). C4H9CH

CH2

BH3•THF

(C4H9CH2CH2)2B not isolated

1–Hexene

reflux Propionic acid

C4H9CH2CH3 n-Hexane

Scheme 2.40

22

Reduction in Organic Synthesis

Table 2.2 shows the reactions and products obtained with diborane. Table 2.2. Reduction of Functional Groups with Diborane Reactant

Product

R—CO2H

R—CH2OH

R—CH = CH2

RCH2CH3

R—C ≡ CR′

R—CH = CH—R′

O

C

CHOH

—C ≡ N

—CH2NH2

—CONR2

—CH2NR2

R—CO

O

R—CH2OH

R—CO C

C

CH

C—OH

O

—CO2R

—CH2OH + ROH

Since borane reacts rapidly with water, the reactions must be conducted under anhydrous conditions i.e., nitrogen atmosphere (since borane and lower alkyl boranes may ignite in air). The reduction of carbonyl compound with diborane takes place by the addition of the electron-deficient borane to the oxygen atom followed by irrervessible transfer of hydride ion from boron to carbon. The final step is the protonolysis to give alcohol (Scheme 2.41). C

O + BH3

C

+

–

O — BH3

— C — OBH2 H

CH3COOH

— C — OH H

Scheme 2.41

Remarkably, carboxylic acids are reduced to primary alcohols with borane. In fact the carboxylic acids can be reduced even in presence of other unsaturated groups. Thus, p-nitrobenzoic acid is reduced to p-nitrobenzyl alcohol in 79% yield. A special feature of diborane is the reduction of epoxides, which yields less substituted carbonyl in major amount in contrast to reduction with complex hydrides. The reaction of epoxides is catalysed by small amounts of sodium or lithium borohydride (Scheme 2.42).

Different Types of Reducing Agents

23

Scheme 2.42

Reduction of 1-alkylcycloalkene epoxide with diborane in presence of small amount of lithium borohydride gives the cis 2-alkylcyclo alkanol as the major amount (Scheme 2.43).

Scheme 2.43

A number of borane complexes have been used in place of borane. These are: (i) ammonia-borane and t-butylamine—borane complexes. These reagents reduce55 aldehyde and ketones to alcohols. (ii) Borane pyridine complex—It is a cheap and readily available alternative to sodium cyanoborohydride for the reductive amination56 of carbonyl compound, and (iii) Catecholborane—It is another versatile reducing agent57 with milder action than borane. In case a molecule contains both the carboxyl group and ester group, borane reduces carboxyl to CH2OH, the ester group is not affected. On the other hand, lithium borohydride reduces the ester group to CH2OH without affecting the COOH group. This difference in reactivities of borane and lithium borohydride leads the synthesis of (R)- and (S)- mevalonolactone58 from the same starting material as shown below (scheme 2.44).

Scheme 2.44

24

Reduction in Organic Synthesis

Two other reducing agents, which are more selective and milder than borane are disiamylborane and thexylborane. These are obtained as shown below (Scheme 2.45).

Scheme 2.45

Both the above reagents convert aldehydes and ketones to alcohols. However, in case of ketone the reactivity widely varies with their structure. Acid chlorides, acid anhydrides and esters do not react and epoxides are reduced slowly. Carboxylic acids are not reduced. Two useful reactions of disiamylborane [(C5H11)2BH] are the reductions of lactones to hydroxyaldehydes and of dimethylamides to aldehydes (Scheme 2.46).

Scheme 2.46

Disiamylborane reduces carbon-carbon triple bonds to Z alkenes (Scheme 2.47).

Different Types of Reducing Agents

25

Scheme 2.47

Another boron reagent, 9-borabicyclo [3, 3, 1] nonane (9 BBN)59 is highly selective for the reduction of α,β-unsaturated carbonyl compounds to allylic alcohol in the presence of other functional groups like nitro and ester groups which react slowly under the reaction conditions (Scheme 2.48). BH BH3

1,5-Cyclo octadiene

BH 9-Borabicyclo [3,3,1]nonane (9-BBN)

Scheme 2.48

2.3 DISSOLVING METAL REDUCTIONS We know that reductions involve gain of electrons by an organic substrate. A number of metals and metal salts can transfer electrons to an organic substrate, reducing them with simultaneous oxidation of the metal. Electron transfer in an electrolytic cell also accomplishes the same objective. 2.3.1 Electrolytic Reduction In electrolytic reduction (electroreduction), the most important factor is the nature of the metal used as cathode. Metals of low overvoltage like platinum (0.005–0.09 V), palladium, nickel and iron give results as in the case of catalytic hydrogenations60. Cathodes made of high overvoltage as in the case of copper (0.23 V), cadmium (0.48 V), lead (0.64 V), zinc (0.70 V) or mercury (0.78 V) give results similar to those obtained by reductions by dissolving metals.

26

Reduction in Organic Synthesis

The nature of electrolyte is also an important factor in electroreduction. Most of the electroreductions are carried out in dilute sulphuric acid. However, some are done in alkaline electrolyte, such as alkali hydroxides, alkoxides or solutions of salts like tetramethylammonium chloride in methanol61 or lithium chloride in alkyl amines62,63. The nature of the reduction products depends on whether the electrolytic cell is divided (by a diaphragm separating the anode and cathode spaces) or undivided62. As an example, in the electrolysis of acetone, an electron is transferred to the carbonyl generating a radical atom (A); this exists in two canonical forms, the carbon radical (A) and the carbanion form (B). The two forms can undergo radical coupling to form a dimeric species (Pincalol coupling) or it can remove a proton from an acidic solvent (such as ethanol) to form the reduced product (Scheme 2.49). O

Acetone

O

O

Carbon radical (A)

Carbanion form (B)

e–

H+ O O

O H

Coupling product

Reduced product

Scheme 2.49

Following are given the substrates (in the form of functional group) and the product formed on electroreduction. Table 2.3. Electroreduction of some substrates Substrates C

Products

C

CH — CH

alkene

H

—C ≡ C— alkyne

C H

C

C

+ H

H

C

Different Types of Reducing Agents

Substrates

Products

N H

N R—C—X

R—C—H

X

H

ArNO2 ⊕

27

ArNHOH –

ArNR3 X

Ar

R2NNO2

R2NNH2

RCH=CHCHO

RCH2CH2CH2OH

ArCHO

ArCH3

RCH=CHCOR′

RCH2CH2COR′

ArCOOH

ArCH3

RCONR′R′′

RCHO

RCSNH2

RCHO + RCH2NH2

2.3.2 Reduction with Sodium Sodium has been used for reduction in the following forms: • sodium-alcohol • sodium-liquid ammonia • sodium-amalgam • sodium-xylene • salts of sodium 2.3.2.1 Sodium-alcohol One of the earliest method of reducing ketones to alcohol is with sodium and alcohol. For example, cycloheptanone on reduction with sodium and alcohol gives cycloheptanol (Scheme 2.50). O Cycloheptanone

1. Na—isoPrOH Xylene, reflux 2. H3O+

Scheme 2.50

OH Cycloheptanol 80–90%

28

Reduction in Organic Synthesis

The reduction with sodium and alcohol is believed to proceed as follows (Scheme 2.51). O

–

Na

C

O

O

C

C –

C2H5OH

O C H

–

O Na

OH

C

C5H5OH

H

C H

Scheme 2.51

This reaction is known as Bouveault-Blanc reaction64. A special feature of the sodium alcohol method is that with cyclic ketones it gives alcohols in most cases (although not always) the thermodynamically more stable alcohol either exclusively or in major amount (Scheme 2.52).

Scheme 2.52

Sodium-alcohol is also used for the reduction at aldehydes, esters, oximes of aldehydes and cyanides as shown below (Scheme 2.53). RCHO

Na, C2H5OH Reflux

RCH2OH

O R — C — OR′ C6H13CN

Na, EtOH

Na, C2H5OH

RCH2OH + R′ OH C5H13CH2NH 2 (65–70%)

Scheme 2.53

2.3.2.2 Sodium-liquid Ammonia Sodium (or lithium) and liquid ammonia reduce aromatic rings to give mainly unconjugated dihydroderivatives. This reduction is known as Birch reduction65 (Scheme 2.54).

Different Types of Reducing Agents

29

Scheme 2.54

During the reduction, the alkali metal donates an electron to an aromatic compound forming a radical anion (1) which being basic, abstracts a proton from protic solvent to give a radical (2) which in turn picks up another electron to give an anion (3). It is quenched again by the proton source (alcohol) to give unconjugated dihydro compound (4) (Scheme 2.55). H

H

H ROH

e–

H

– (1)

ROH

e–

H (2)

H

H

H

–

H

(3)

H

H

H (4)

Scheme 2.55

Isolated carbon-carbon double bonds are not normally reduced by metal (Na, Li)—ammonia reagents alone, but in presence of alcohols, terminal double bond may be reduced. However, conjugated dienes are easily reduced to the 1,4-dihydro derivative in the absence of added proton donors. Thus, isoprene is reduced to 2-methyl-2-butene. In this case, the protons required to complete the reduction are supplied by ammonia (Scheme 2.56).

Scheme 2.56

Sodium-ammonia does not normally reduce carbon-carbon double bond. However, partial reduction of carbon-carbon triple bond is convenienty affected by this reagent. The reduction is completely stereospecific and the only product from a disubstituted acetylene is the corresponding E-alkene. This method complements the formation of Z-alkenes by catalytic hydrogenation of acetylenes (Scheme 2.57).

30

Reduction in Organic Synthesis

C 3 H7 C

C 2 H5 C

C(CH2)7OH

C(CH2)3CO2Na

1. Na/NH3

C3H7

2. NH4Cl

H

1. Na/NH3

C2H5

2. NH4Cl

H

H C

C (CH2)7OH H

C

C (CH2)3COONa

Scheme 2.57

Reduction of 4-t-Butylcyclohexanone with lithium and propanol in liquid ammonia gives exclusively the more stable trans-4-t-butylcyclohexanol. 2.3.2.3 Sodium Amalgam It is easily prepared66 in concentration of 2–4% by dissolving sodium in mercury. Reductions with sodium amalgam are very mild, only easily reducible groups and conjugated double bonds are affected. One such example66 is given below: (Scheme 2.58) C6H5 CH

CHCOOH

Cinnamic acid

1. Na/Hg 2. H+

C6H5CH2CH2COOH 73–80% Hydrocinnamic acid

Scheme 2.58

Sodium amalgam has been widely used for reduction of aldonic acids to aldoses. However, the use of sodium amalgam has dwindled due to the availability of sodium borohydride. 2.3.2.4 Sodium and Xylene Diesters on heating with sodium in xylene (or toluene) give α-hydroxylketones called cyclic acyloins67 (Scheme 2.59). COOEt (CH2)n

1. Na, toluene, D 2. CH3COOH

C

O

(CH2)n CH — OH

COOEt

Cyclic acyloin n = 10–20 or more

Diester

Scheme 2.59

Different Types of Reducing Agents

31

The mechanism of the reaction is given below (Scheme 2.60) :

Scheme 2.60

Improved yields are often obtained68 by carrying out the reaction in the presence of chlorotrimethyl silane. 2.3.2.5 Salts of Sodium Following are given some of the salts of sodium, which are used for reduction purposes: Sodium Metabisulphite It is used for the reduction of diazonium salts to the corresponding hydrazines (Scheme 2.61). +

C 6H 5 N

–

NCl

NaHSO3

Scheme 2.61

C6H5NHNH2

32

Reduction in Organic Synthesis

The mechanism of the reduction is given below (Scheme 2.62). –

+

+

2–

Na + SO3H

Na HSO3

SO3 + H O

O

+

–

C 6H 5 — N

–

N + O—S—O

C 6H 5 — N

N—S

O

O– 2–

SO3

O

O –

2H

C6H5 — N — NH — S — O O

O

S

+

C 6H 5 — N — N –

SO3

O

S

O

O –

O– 2–

–2SO3

C6H5NH NH2 Phenylhydrazine

Scheme 2.62

Sodium metabisulphite is also used for the partial reduction of geminal polyhalides67a as shown in the following example (Scheme 2.63).

Scheme 2.63

Sodium Dithionite (Na2S2O4) It is used for the reduction of p-benzoquinone to hydroquinone (Scheme 2.64). O

O

Na2SO4

HO

p-Benzoquinone

OH Hydroquinone

Scheme 2.64

Different Types of Reducing Agents

33

Sodium dithionite is also used for the reduction of azo dyes and pyridine derivatives. Sodium Hydrogen Sulphide It is used for the selective reduction of one nitro group in polynitro compounds. Thus, m-dinitrobenzene on reduction with sodium hydrogen sulphide gives m-nitroaniline (Scheme 2.65). NO2

NH2 + 6NaSH

4

H 2O

+ 3 Na2S2O3

4

NO2

NO2

m–Dinitrobenzene

m-Nitroaniline Scheme 2.65

2.3.3 Reductions with Magnesium The most important reaction of magnesium is the reduction of ketones to pinacols, carried out by magnesium amalgam (which is prepared69 in situ by adding a solution of mercuric chloride in the ketone to magnesium turnings submerged in benzene). The reduction of acetone to pinacol69 follows the course shown below (Scheme 2.66). CH3 C CH3

O

Mg–Hg

CH3

C6H6 reflux

CH3

–

–

C—O

1 Mg2+ 2

CH3

–

C—O CH3

Acetone

(CH3)2C — OH

H2O

– (CH3)2 — C — O – (CH3)2 — C — O

(CH3)2C — OH Pinacol Scheme 2.66

The reaction of magnesium amalgam with titanium tetrachloride gives a very effective reagent70, which converts cyclohexanone into the unsymmetrical pinacol in 93 per cent yield (Scheme 2.67).

Scheme 2.67

34

Reduction in Organic Synthesis

Another application of magnesium is the conversion of alkyl bromides, iodides into hydrocarbon71,72 (halogen is replaced by H) via the formation of Grignard reagent followed by treatment with water or dilute acids (Scheme 2.68). R—X

Mg dry ether

R — MgX

H+

RH

Scheme 2.68

The above reduction can also be carried out by the action of iso propylalcohol and magnesium activated by iodine73. It is well known that grignard reagents react with carbonyl compounds (aldehydes and Ketones) to give the corresponding alcohols. This procedure may be regarded as reduction of carbonyl compounds. 2.3.4 Reductions with Aluminium Aluminium amalgam74,75 is a convenient reducing agent. It reduces ketones to pinacols76 (Scheme 2.69). OH OH C6H5COCH3

Al–Hg

CH3 — C — C — CH3

Acetophenone

C6H5 C6H5 2, 3-Diphenyl-2, 3-butandiol 56%

Scheme 2.69

Besides the above, aluminium amalgam reduces cumulative double bonds, halogen compounds, nitro compounds, azo compounds, azides, oximes and quinones. Aluminium isopropoxide is known to reduce aldehydes and ketones (in presence of excess of isopropyl alcohol) to alcohol. The reduced product is obtained from the reaction mixture by acidification and acetone is generated from isopropyl alcohol. This is called Meerwein-Ponndorf-Verley reduction7779 (Scheme 2.70).

Scheme 2.70

Different Types of Reducing Agents

35

The mechanism of M-P-V reduction is as given below (Scheme 2.71).

Scheme 2.71

2.3.5 Reductions with Zinc Zinc is most abundently used for reductions. It is available in the form of zinc dust and in granular form (called mossy zinc). Since zinc dust is invariably covered with a thin layer of zinc oxide (which deactivates its surfaces), it is activated by keeping in contact with 0.5 – 2% hydrochloric acid, followed by washing with water, alcohol, acetone and ether80. Activation can also be carried out in situ by its addition to small amount of zinc chloride81 or zinc bromide82 in alcohol or ether. Another way of activation is by its conversion to zinccopper couple by stirring with a dilute copper sulphate pentahydrate in water83. Mossy zinc is activated by conversion into zinc amalgam84. This type of activation is necessary for Clemmensens reduction which is used for the reduction of carbonyl group into methyl or methylene group (Scheme 2.72).

36

Reduction in Organic Synthesis

C6H5COCH3

Zinc amalgam/HCl

Acetophenone

C6H5CH2CH3 79% Ethyl benzene

Scheme 2.72

The mechanism86 of Clemmensen’s reduction is as given below (Scheme 2.73).

Scheme 2.73

Depending on the reduction product to be obtained, the reductions with zinc can be carried out in aqueous as well as anhydrous medium and at different pH of the medium. Thus, reduction of aromatic nitro compounds in alkali hydroxide or aqueous ammonia gives hydrazo compounds, reduction in aqueous ammonium chloride gives hydroxylamines and reduction in acidic medium gives amines (Scheme 2.74). Zn dust NaOH

C6H5 — NO2

Zn dust aq. NH4Cl Zn/HCl

C6H5NH NHC6H5 Hydrazo benzene

C6H5NHOH N-Phenyl hydroxylamine

C6H5NH2 Aniline

Scheme 2.74

Zinc is sometime used for the reduction of double bonds conjugated to strongly polar group and alkynes to trans alkenes. It is excellent for the replacement of halogens by hydrogen. Zinc-acetic acid is used for the reductive coupling of ketones (Scheme 2.75).

Different Types of Reducing Agents

2C6H5COC6H5 Benzophenone

Zn CH3COOH

37

C6H5 C6H5 C6H5—C——C—C6H5 OH

OH

Benzopinacol

Scheme 2.75

2.3.6 Reductions with Iron It has basically been87 used for the reduction of aromatic nitro compounds (Scheme 2.76). 4RNO2 + 9Fe + 4H2O

4RNH2 + Fe3O4

Scheme 2.76

Another important application87 in the partial reduction of m-dinitrobenzene to m-nitroaniline (Scheme 2.77). NO2

NO2

Iron filing, H2O FeCl3, NaCl

NH2

NO2 m-Dinitro benzene

m-Nitoraniline

Scheme 2.77

Iron is also used for reduction of aldehydes88, replacement of halogens89, 90 and deoxygenation of amine oxides.91 2.3.7 Reductions with Tin and Its Compounds Tin is very sparingly used as a reducing metal in organic synthesis. It was used for the reduction of acyloins to ketones92, of quinones93 and of aromatic nitro compounds.94 Stannous chloride and hydrochloric acid are used to convert nitriles into cyanides. The reaction is known as Stephen reaction95 (Scheme 2.78). C6H5C

N

1. HCl, SnCl2 2. hydrolysis

C6H5CHO

Scheme 2.78

The mechanism of the reaction is as follows (Scheme 2.79). RCN

SnCl2 HCl

+

[R — C NH]Cl – aldimme salt

[H]

RCH H2O

RCHO

Scheme 2.79

+

–

NH2Cl

38

Reduction in Organic Synthesis

Stannous chloride also converts secondary amides into aldehydes via the formation of chloroimine (which is formed from amides by treatment with PCl5). This reaction is known as Son-Muller reaction and is closely related to Stephen reaction (Scheme 2.80). CONHC6H5 PCl5

Ar — C

CH3

N — C6H5

SnCl2

Cl Chloroimine

Ar — CH

N — C6H5

CHO

H2O

CH3 70% Scheme 2.80

Stannous chloride and hydrochloric acid are also used for the reduction of azo compounds and nitroso compounds (Scheme 2.81). RN

NR¢ + 2SnCl2 + 4HCl

RNH2 + R¢NH2 + 2SnCl4 H2N — NC2H5

ON—NC2H5 SnCl2/HCl

Scheme 2.81

2.4 NON-METALLIC REDUCING AGENTS A number of non-metallic reagents have been used for reducing various functional group. Following is given a brief account of some of the common non-metallic reducing agents. 2.4.1 Reduction with Hydrogen Iodide Hydrogen iodide is available as gas, but is used mainly in the form of its aqueous solution. Azeotropic hydrogen iodide boils at 127° (density 1.70) and contains 57% of hydrogen iodide. At higher temperature, hydrogen iodide dissociates into iodine and hydrogen, which effects reductions. The reductions are generally carried out by allowing iodine to react with phosphorous to form phosphorous acid and hydrogen iodide. In this way, addition of phosphorous to the reaction

Different Types of Reducing Agents

39

mixture, hydrogen iodide is recycled and the reducing efficiency of hydroiodic acid is enhanced96. An example is the reduction of benzoin to deoxybenzoin97. (Scheme 2.81). O

OH

Ph — C — C — Ph H Benzoin

O Red Phosphorus + iodine CS2, pyridine or HI, CH 3COOH reflux 2hr

Ph — C — CH 2 —Ph 90% Deoxybenzoin

Scheme 2.81

Hydriodic acid is used for the reduction of alcohols, some phenols, some ketones, quinones, halogen derivatives, sulphonyl chlorides, diazo ketones, azides and even carbon-carbon double bonds. In α-bromothiophene, the halogen is replaced by hydrogen with hydrogen bromide in acetic acid provided phenol is added to react with the evolved bromine. 2.4.2 Reductions with Hydrogen Sulphide It is the oldest reducing agent applied in organic chemistry. It is usually used in basic solution in pyridine, piperidine and most frequently is aqueus ammonia98, where it acts as ammonium sulphide or hydrosulphide. An example is the reduction of benzil to benzoin (Scheme 2.82).

Scheme 2.82

2.4.3 Reductions with Sulphur Dioxide Sulphur dioxide is mainly used in reduction of quinones to hydroquinones. In practice, sulphur dioxide is generated from sodium sulphite in acidic solution. 2.4.4 Reductions with Dimethyl Sulphide It reduces hydroperoxides to alcohols and ozonides to aldehydes while being converted to dimethyl sulphoxide101.

40

Reduction in Organic Synthesis

2.4.5 Reductions with Hydrazine Hydrazine is available in the form of its hydrate (NH2 ⋅ NH2 ⋅ H2O). It is mostly used for the reduction of aldehydes and ketones to the corresponding hydrocarbon. This reaction is known as Wolff Kishner reaction102. The reaction is generally carried out by heating the hydrazones of aldehydes and ketones with base like sodium or potassium hydroxide (Scheme 2.83).

Scheme 2.83

A number of modifications have been introduced for this procedure, including the isolation of the hydrozone and using an alkoxide base103. The most important change in this reaction is the Huang-Minlon modification, which uses refluxing diethylene glycol as the solvent and has been shown to be much more efficient for this transformation104. The mechanism of Wolff Kishner reduction is given below (scheme 2.84). R R′ R R′

C

–

CH

R

NH2NH2

O

R′

–N2

R R′

BH+

R R′

H C

N—N H

CH — N

N—H

:B

R

– BH+

R′

H+

R R′

C

–

–

N — NH

C—N

NH

–

CH2 + :B Scheme 2.84

Hindered ketones can be effectively reduced105 by hydrazine hydrochloride (N2H4⋅ HCl). Hydrazine is also used to convert as alkyl phthalimide to an alkyl amine. This is known as Ing-Manske procedure106 (Scheme 2.85).

Scheme 2.85

In the above procedure, the group O = C — NR — C = O is replaced by O = C — NHNH — C = O unit.

Different Types of Reducing Agents

41

Conversion of carbonyl group to methylene group can also be achieved by decomposition of semicarbazones. Another important reduction in which hydrazine is indirectly used is the McFadyen-Steven reduction of a carboxylic acid107, 108 to aldehydes. In this method, the acid is converted into its benzenesulfonyl or p-toleuene sulphonyl hydrazide which is decomposed by sodium carbonate at 160°. 2.4.6 Reductions with Diimide Diimide (HN = NH) is a transitory species and is generated in situ by the reaction of acids with potassium azodicarboxylate109, thermolysis of anthracene-9, 10-diimine110, decomposition of p-toluene sulfonyl hydrazine111 or by the oxidation of hydrazine with oxygen in presence of copper sulphate 112 (Scheme 2.86).

Scheme 2.86

Diimide gives primarily cis reduction of alkenes113 and reduces symmetrical π bonds faster than polarised π bonds114 (Scheme 2.87). C—C C HN

C +

NH

H

H N

N

C—C H N

+

H N

Scheme 2.87

Least conjugated alkenes are reduced in preference to conjugated alkenes and epoxides as shown by the following example115 (Scheme 2.88).

Scheme 2.88

42

Reduction in Organic Synthesis

It was shown116, 116a that the course of the diimide reduction can be altered by the addition of cupric acetate. This new reagent is highly selective for the reduction of conjugated alkenes, with specificity for the less substituted double bond of the diene as shown in the following example (Scheme 2.89).

Scheme 2.89

The selectivity of diimide is demostrated by the reduction of diallyl disulphide and azobenzene (Scheme 2.90). (CH2

CH CH2)2S2

Diallyl disulphide

C6H5N

NC6H5

Azobenzene

tosyl hydrazide boiling glycol

azodicarboxylic acid boiling methanol

(CH3

CH2CH2)2S2

Dipropyl disulphide (93–100%)

C6H5NH NHC6H5 Hydrazobenzene (100%)

Scheme 2.90

2.4.7 Reductions with Silanes Silicon hydride is useful for the reduction of carbonyls and alkenes. Thus, methylcyclohyxene on reduction with triethylsilane and trifluoroacetic acid gives methylcyclohexane in 72% yield (Scheme 2.91). CH3

CH3 Et3SiH, 20° CF3CO2H, 1hr

Methyl cyclohexene

Methyl cyclohexane 72%

Scheme 2.91

119

However, 1-pentene is not reduced. This reagent is used for the reduction117of conjugated carbonyls as shown below (Scheme 2.92). O

O Ph2SiH2 , ZnCl2 Pd(PPh3)4 CHCl3 96%

Scheme 2.92

Different Types of Reducing Agents

43

Triethylsilane and trifluoroacetic acid reduce 116a cyclohexanone to cyclohexanol in 74% yield. The reduction is selective as in the reduction of conjugated aldehyde to allylic alcohol120 (Scheme 2.93).

Scheme 2.93

Silanes reduce α-bromoketones to bromohydrin121 (Scheme 2.94). O

OH (EtO)2SiHMe

Ph

KF

Ph

Br

Br 70%

Scheme 2.94

Silanes have also been used for asymmetric reduction using a chiral additive (A). Thus acetophenone on reduction122 gives (R) phenethyl alcohol in 99% yield and 84.2% e.e. (Scheme 2.95). O Ph

Me

N

+

Ph

Acetophenone

Me

HO

1. H2SiPh2

N H

Ph

2. H2O

(A)

H Me

(R)-Phenethyl alcohol 99% yield 84.2% ee

Scheme 2.95

Another example of asymmetric reduction by H2SiPh2 in presence of rhodium catalyst is given below123 (Scheme 2.96). Me

Ph O

1. H2SiPh2, [Rh(COD)Cl]2 2. H3O+

Ph

Me HO

H

91% yield 52.7% ee, R.

Scheme 2.96

2.4.8 Reductions with Formic acid Formic acid has been used for a number of specific reductions. For example, triphenylcarbinol on heating with formic acid yields triphenyl methane (Scheme 2.97).

44

Reduction in Organic Synthesis

HCO2H

Ph3COH

D

Triphenyl carbinol

Ph3CH

Triphenyl methane

Scheme 2.97

Formic acid is also useful for the stereo selective reduction of enamines125-127. This is illustrated by the reduction of 3-(–)-erythro-2-(2N-methyl) pyrrolidiniminium butanoic acid as shown below (Scheme 2.98).

Scheme 2.98

A mixture of formic acid and ethyl magnesium bromide converts decanal to decanol128 in 70% yield (Scheme 2.99). n — C9H19 — CHO n-Decanal

1. HCO2H, 2EtMgBr 2. H2O

n — C9H19 — CH2OH n-Decanol 70%

Scheme 2.99

The above reduction can also be effected by using sodium formate in N-methyl-2-pyrrolidine as solvent129. Ammonium formate in the presence of palladium on carbon was also used to reduce an azide to primary alcohol130. This reagent also reduces aliphatic nitro compounds to an amine131.

2.5 PHOTOCHEMICAL REDUCTIONS Photochemical reductions are mostly carried out in case of ketones. In fact, the photoreduction of benzophenone leading to the formation of benzopinacol is one of the most thoroughly investigated photochemical reduction. Thus, irradiation of a solution of benzophenone in isopropyl alcohol with light of wavelength 345 nm gives benzopinacol. Various steps in the photochemical reduction of benzophenone are given in Scheme 2.100.

Different Types of Reducing Agents

45

Scheme 2.100

Photolysis of 2, 4, 6-tri isopropyl benzophenone (1) in presence of secbutylamine gave132 only the alcohol (2). However, in the absence of sec butyl amine the product obtained was benzocyclobutane (3) (Scheme 2.101).

Scheme 2.101

It is found that photoreduction is often less stereoselective than other chemical reductions. Thus, catalytic reduction of (4) with metal hydride or other catalytic reduction gave exclusively the endo alcohol (5). However, reduction with dissolving metal gave133 47% of the exo isomer (6). However, photoreduction of (4) gave a 54% yield of a 4 :1 mixture of (5) and (6)133 (Scheme 2.102).

Scheme 2.102

46

Reduction in Organic Synthesis

Another useful application of photoreduction is the reduction of halides. Thus, the bromide in (6) is reductively cyclised to give (7) in 85% yield134 (Scheme 2.103). O

N—H

O

O

hn NEt3

Br

N—H

O

dioxane 2 hr

O

O

(6) O

N—H

O (7)

O

Scheme 2.103

An interesting photoreduction of ∆1, 9-octahydroquinoline (8) led to a 98% yield of trans-octahydroquinoline (9); the reaction proceeds via the formation of a stable radical (Scheme 2.104). H

H hn, 4hr

OH

2 hr

N D1,9–Octahydro quinoline (8)

N

OH

H

N H

H

Trans-octahydro quinoline (9)

Scheme 2.104

2.6 ENZYMATIC OR MICROBIAL REDUCTIONS Enzymes are readily available and are an important tool in organic synthesis. Enzymatic reductions are highly stereoselective and straight forward. Prelug studied the reduction of ketones with a number of enzymatic systems. He found that the reduction of ketones with Curvularia fulcata gave sterochemical induction based on identifying large (L) and small (S) groups around the carbon. This method is called Prelug’s rule136. According to this rule, if the steric difference between large (L) and small (S) groups attached to carbonyl group is large enough, the enzyme attacks from the less hindered face (over S) to give the corresponding alcohol as shown in (Scheme 2.105).

Different Types of Reducing Agents

O enzyme

C S

L

47

H

HO C

S

L

Scheme 2.105

Two of the most common enzyme systems available are yeast alcohol dehydrogenase (YAD) and horse liver alcohol dehydrogenase (HLADH). The selectivity observed in these enzymes is determined by non-bonded interactions of the substrate and enzyme in the hydrogen transfer transition state136. Baker’s yeast (Saccharomyces cerevisiae) selectively reduces β-ketoesters and β-diketones. Thus, reduction of ethyl acetoacetate with Baker’s yeast gave the (S)-alcohol. On the other hand ethyl β-ketovalerate gave the (R)-alcohol137 (Scheme 2.106). O CO2Et

Baker's yeast

Ethyl acetoacetate

O CO2Et

OH CO2Et (S)–alcohol

Baker's yeast

OH CO2Et (R)–alcohol

b-Ketovalerate

Scheme 2.106

Reduction of β-ketoester (A) with Baker’s yeast gave the (S)-alcohol (B) in 71% yield (Scheme 2.107). OH

O CO2Et

CO2Et

Baker's yeast

S (A)

S (B) (S)–alcohol 71%

b-Ketoester

Scheme 2.107

The selectivity of these reactions is in consistent with the S selectivity predicted by Prelug’s rule138. In a similar way, 1, 3-diketones on reduction with Baker’s yeast gave the β-ketoalcohol. Thus, 2, 4-hexanedione on reduction gave (S)-5-hydroxy-3hexanone in quantitative yield (> 95% ee, S)139.

48

Reduction in Organic Synthesis

Besides Bakers yeast, other organisms have also been used to reduce β-ketoesters. It was shown that reduction of ethyl acetoacetate with Geotrichum candidum140 gave S alcohol in 96%, 7 : 93 R : S. Similar reduction with Aspergillus niger gave 98% of a 75 : 25 mixture favouring R-alcohol (Scheme 2.108).

Scheme 2.108

The enzyme Beauveria sulfurescens reduces conjugated carboxyls. Thus trans-crotonaldehyde is reduced in 2-buten-1-ol in 80% yield141. However, reduction of 2-methyl-2-pentenal gave a mixture of 31% of the conjugated alcohol and 69% of the completely reduced alcohol (2-methyl-1-pentanol)141 (Scheme 2.109). CH CH3

CHO

B. Sulfurescens

CH

CH3

2-Buten-1-ol 80%

trans-Croton aldehyde

CHO

CH CH2OH CH

B. Sulfurescens

CH2OH +

2-Methyl-2-pentenal

2-Methyl-2penten-1-ol 31%

CH2OH 2-Methyl -1-pentanol 69%

Scheme 2.109

Thermoanaerobium brockii has also been used for the reduction of carbonyl group. It has been shown that small ketones, such as 2-butanone are reduced by T. brockii to give R alcohol (2-butanol, 12% yield and 48% ee, R), but large ketones, such as 2-hexanone are reduced to S alcohol (85% yield and 96% ee, S)142. Thus, the enantioselectivety of the reduction and the selectivity depend on the size and nature of the groups around the carbonyl (Scheme 2.110). See also Scheme 5.7. O 2-Butanone

O 2-Hexanone

OH

T. brockii

2-Butanol (12% yield, 48% ee, R)

OH T. brockii 2-Hexanol (85% yield, and 96% ee, S)

Scheme 2.110

Different Types of Reducing Agents

49

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52

Reduction in Organic Synthesis

92. P.H. Carter, J.G. Craig, R.E. Lack and M. Moyle, Org. Syn Coll. Vol., 1973, 5, 339. 93. J.P. Schaefer, J. Org. Chem., 1960, 25, 2027. 94. W.W. Hartman, J.B. Dickey and J.G. Stampfli, Org. Syn. Coll. Vol., 1943, 2, 175. 95. H. Stephen, J. Chem. Soc., 1925, 127, 1874; T. Stephen and H. stephen, J. Chem. Soc., 1965, 4695; L.N. Ferguson, Chem. Revs., 1945, 38, 243. 96. R.N. Renaud and J.C. Stephens, Can. J. Chem., 1974, 52, 1229. 97. T. –L. Ho and C.M. Wong, Synthesis, 1975, 161. 98. W.W. Harlman and H.L. Silloway, Org. Syn. Coll. Vol., 1955, 3, 82. 99. R. Meyer, G. Hiller, M. Nitzschke and J. Jenizsch, Angew. Chem., 1963, 75, 1011. 100. J.W. Dodgson, J. Chem. Soc., 1914, 2435. 101. J.J. Pappas, W.P. Keaveney, E. Gancher and M. Berger, Tetrahedron Lett., 1966, 4273. 102. L. Wolff, Ann., 1912, 398, 86; N. Kishner, J. Russ. Chem. Soc., 1911, 43, 1911 (CA, 1912, 6, 347). 103. M.F. Grudnon, H.B. Henbest and M.D. Scott, J. Chem. Soc., 1963, 1855; R.R. Sobti and S. Dev., Tetrahedron, 1970, 26, 649. 104. Huang-Minlon, J. Am. Chem. Soc., 1946, 68, 2486; 1949, 71, 3301. 105. M. Nagata and H. Itazaki, Chem. Ind., 1964, 1194. 106. H.R. Ing and R.H.F. Manske, J. Chem. Soc., 1926, 2348. 107. J.S. Mc Fadyen and T.S. Stevens, J. Chem. Soc., 1936, 584. 108. E. Mosettig, Organic Reactions, 1954, 8, 232. 109. J.W. Hamersma and E.I. Synder, J. Org. Chem., 1965, 30, 3985. 110. E.J. Corey and W.L. Mock, J. Am. Chem. Soc., 1962, 84, 685. 111. E.E. van Tamelen and R.S. Dewey, J. Am. Chem Soc., 1961, 83, 3729. 112. M. Ohno and M. Okamoto, Org. Syn. Coll. Vol., 1973, 5, 281. 113. S. Hünig, H. –R. Müller and W. Their, Tetrahedran lett, 1961, 353; E.E. van Tamelen and R.J. Timmons, J. Am. Chem. Soc., 1962, 84, 1067. 114. E.E. van Tamelen, R.S. Dewey, M.F. Lease and W.H. Pirkel, J. Am. Chem. Soc., 1961, 83, 4302. 115. E.J. Corey and J.P. Dittami, J. Am. Chem. Soc., 1985, 107, 256. 116. E.J. Corey, W.L. Mock and D.J. Paslo, Tetrahedron Lett., 1961, 347; E.J. Corey and A.G.J. Hortmann, J. Am. Chem Soc., 1965, 87, 5736. 116 (a) E.J. Corey and H. Yamamoto, J. Am. Chem. Soc., 1970, 92, 6636. 117. V.Z. Sharf, L. Kh. Freidlin, I.S. Shekoyan and V.N. Kurtii, Bull, Akad. USSR Chem., 1977, 26, 995. 118. I. Ojima and T. Kogure, Organometallics, 1982, 1, 1390. 119. E. Keinan and N. Greenspoon, Tetrahedron Lett., 1985, 26, 1353. 120. J. Boyer, R.J.P. Corriu, R. Perz and C. Réyé, J. Chem. Soc., Chem. Commun, 1981, 121.

Different Types of Reducing Agents

53

121. R.G. Saloman, N.D. Sachinvala, S.R. Raychaudhuri and D.B. Miller, J. Am. Chem. Soc., 1984, 106, 221. 122. H. Brunner, G. Riepl and H. Weitzer, Angew. Chem. Int. Ed., Engl. 1983, 22, 331. 123. H. Brunner, R. Becker and G. Riepl, Organometallics 1984, 3, 1354. 124. H. Kaufmann and P. Pannwitz., Ber., 1912, 45, 766; A. Kovache, Ann. Chem., 1918, 10, 184. 125. J.V. Paukstelis and M.E. Kuehne. In Enamines : Synthesis, Structure and Reactions; A.G. Cook Ed., Marul Dekker, New York, 1969, p. 169-210, 313-468. 126. R. Lukieš and J. Jizba, Chem. Listy, 1953, 47, 1366, Chem. Abstr., 1955, 49, 323 g; Collect. Czech. Chem. Commun, 1954, 19, 941, 930; N. J. Leonard, and R.R. Sauers, J. Am. Chem. Soc., 1957, 79, 6210.
ervinka, Collect. Czech. Chem. Commun., 1959, 24, 1880. 127. O. C 128. J. H. Babler and B. J. Invergo, Tetrahedron Lett., 1981, 22, 621. 129. J.H. Babler and S.J. Sarussi, J. Org. Chem., 1981, 46, 3367. 130. T. Gartiser, C. Selve and J.J. Delpeuch, Tetrahedron Lett., 1983, 24, 1609. 131. S. Ram and R.E. Ehrenkaufer, Tetrahedron Lett., 1984, 25, 3415. 132. Y. Ito, N. Kawatsuki and T. Matsuura, Tetrahedron Lett., 1984, 25, 2801. 133. T. Mamose, O. Muraoka and K. Masuda, Chem. Pharm. Bull., 1984, 32, 3730. 134. T. Tiner Harding and P. Mariano, J. Org. Chem., 1982, 47, 482. 135. J.M. Hornback, G.S. Proehl and I.J. Starner, J. Org. Chem., 1975, 40, 1077. 136. V. Prelog, Pure Appl. Chem., 1964, 9, 119. 137. B. Zhou, A.S. Gopalan, F. Van Middlesworth, W.–R. Shieh and C.J.J. Sih, J. Am. Chem. Soc., 1983, 105, 5925. 138. R.W. Hofmann, W. Helbig and W. Ladner, Tetrahedron Lett., 1982, 23, 3479; M. Hirama, M. Shimizu and M. Iwashita, J. Chem. Soc. Chem. Commun, 1983, 599. 139. J. Bolte, J.G. Gourcy and H. Veschambre, Tetrahedron Lett., 1986, 27, 565. 140. R. Bernardi, R. Cardillo and D. Ghiringhelli, J. Chem. Soc., Chem. Commun, 1984, 460. 141. M. Desrut, A. Kergomand, M.F. Renard and H. Veschambre, Tetrahedron 1981, 37, 3825; M. Bostmembrun-Desrut, C. Dauphin, A. Kergomard, M.F. Renard and H. Veschambre, Tetrahedron, 1985, 41, 3679. 142. E. Kiehan, E.K. Hafeli, K.K. Seth and R.J. Lamed, J. Am. Chem. Soc., 1986, 108, 162.

CHAPTER

3

Reduction of Specific Types of Organic Compounds 3.1 REDUCTION OF HYDROCARBONS 3.1.1 Reduction of Alkanes and Cycloalkanes Alkanes, being saturated hydrocarbons cannot be reduced any further. However, cycloalkanes give alkanes on catalytic hydrogenation in quantitative yield. Some examples are given below (Scheme 3.1). H2/Ni Cyclopropane

120° H2/Ni

Cyclobutane

220° 12% Pt/C

Cyclopantane

R1

300° H2/Pt or Pd 25°, 1 atm.

R2

R1 = R2 = Me or Ph

CH3CH2CH3 Propane

CH3CH2CH2CH3 n-Butane

CH3CH2CH2CH2CH3 n-Pentane

R1CH2CH2CH2R2 R1 = R2 = Me or Ph

Me Me

CH3 Me3SiH/CF3CO2H

Me

CH3

CH3CH — CH.CH3 2,3-Dimethyl butane 65%

1,1,2-Trimethyl Cyclopropane

Scheme 3.1

© The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3_3

55

56

Reduction in Organic Synthesis

3.1.2 Reduction of Alkenes and Cycloalkenes A. Reduction of Alkenes (a) Catalytic Hydrogenation Heterogeneous Hydrogenation Alkenes are reduced with hydrogen gas in presence of transition metal catalyst (Pt, Pd, Rh) adsorbed on solid support, such as carbon or alumina. The reduction of alkenes results in the reduction of the π bond resulting in the formation of an alkane. The stereospecific reduction of E and Z alkene shows that the addition of hydrogen occurs in a syn fashion (Scheme 3.2).

Scheme 3.2

Some other examples of hydrogenation of alkenes are given below (Scheme 3.3). CH3(CH2)7CH

CH(CH2)7COOH + H2

5% Pd-C

OH Cinnamyl alcohol

CH3(CH2)16COOH Octadecanoic acid

Oleic acid H2/Pd

OH

Raney Ni Et OH

3-Phenyl-1-propanol

Scheme 3.3

The mechanism of heterogeneous catalytic hydrogenation is as follows: The reaction takes place on the surface of the catalyst. As a first step, hydrogen (H2) is dissociatively adsorbed onto the catalyst surface. Subsequently, alkene π bonds are also adsobred onto the metal, forming complexes. This is followed by addition of a hydrogen atom in one of the carbon atoms of the adsorbed species to give an intermediate which is called half hydrogenated state (A). Finally, the addition of a second atom of hydrogen onto the other carbon atom occurs; the reduced product is then dissociated from the catalyst. As one face of the alkene is adsorbed onto the metal and both hydrogen atoms are transferred from the metal to the π-system, the addition of hydrogen is syn (Scheme 3.4).

Reduction of Specific Types of Organic Compounds

R

R

H2

H H

C

R

C

R

H H

R R

57

R R

addition

Catalyst surface

R R

R R H

H

R R

R R

addition

H

(A)

H

Reduced Product Alkane

Scheme 3.4

On the basis of extensive studies, it has been found that highly substituted alkenes are reduced slowly than the less substituted alkene. The following order is followed (Scheme 3.4a). R 2C

CR2

RCH

CR2

RCH

CHR

RCH

CH2

Scheme 3.4a

In the above case, the steric hindrance around the π-bond hinders adsorption onto the metal surface. Homogeneous Hydrogenation A most useful catalyst for the homogeneous hydrogenation of alkenes is Wilkinsons catalyst, [Ph3P]3 RhCl (see also section 2.1.2). The addition of hydrogen to a red solution of Wilkinsons catalyst promotes the formation of a yellow complex (A) by oxidative addition of hydrogen followed by dissociation of the phosphine ligand from the metal. In fact, the yellow complex (A) is the actual reducing agent. It (A) coordinates with the alkene. Subsequent steps in the reduction are as shown below (Scheme 3.5). (Ph 3P) 3RhCl Wilkinsons Catalyst

PPh3 H Rh Cl PPh3

H

H2

Ph3P

H H

Rh

Cl (B)

Butane

H H + Cl — Rh

PPh3 PPh3

PPh3 PPh3 Scheme 3.5

— PPh3

H

Rh Ph3P

Reductive elimination

H

Cl (A)

H Cl H

PPh3

Rh

PPh3 PPh3

58

Reduction in Organic Synthesis

In the above process (Scheme 3.5), the generated species (B) adds on hydrogen to become (A) and in this way the catalytic cycle continues. Wilkinson’s catalyst reduces hindered alkenes more slowly. An advantage is that scrambling of the double bond does not occur during the reduction (Scheme 3.6). OH

OH

(Ph3P)3RhCl H2

80%

Scheme 3.6

The Wilkinson’s catalyst can also reduce allyl phenyl sulphide (Scheme 3.7). SPh Allyl Phenyl Sulphide

(Ph3P)3RhCl H2

SPh Phenyl propylsulphide 93%

Scheme 3.7

Allyl phenyl sulphide normally deactivates heterogeneous transition metal catalyst. In view of this, homogeneous hydrogenation is most suitable for the reduction of alkenes containing sulphur. Some more cases of homogeneous hydrogenations are discussed in section 2.1.2. Alkenes containing nitro group (Scheme 2.6), ester group (Scheme 2.7) can also be reduced using the technique of homogeneous hydrogenation. Stereoselectivity in the Hydrogenation of Alkenes Under normal hydrogenation (homogeneous or heterogeneous) of alkenes, addition of hydrogen occurs to both faces of the alkene to give a racemic product (Scheme 3.8).

Scheme 3.8

However, by using a chiral ligand along with the catalyst, it is possible to get either of the two reduction products (Scheme 3.8). The chiral ligand commonly used (for rhodium or rutherium) is BINAP [(S) or (R) 2, 2′-bis (diphenyl-phosphino)-1, 1′-binaphthyl)] (both the chiral ligands (S) or (R) are commercially available (Scheme 3.9).

Reduction of Specific Types of Organic Compounds

PPh2 PPh2

59

PPh2 PPh2

(S)-(-)BINAP

(R)-(+)-BINAP

Scheme 3.9

It is believed that during hydrogenation, complex formation between the metal (Rh or Ru), BINAP and the alkene takes place. In this case, the BINAP used could be either (S) or (R). The complex on reduction gives only the enantiomer (S or R depending on whether BINAP used is S or R). This procedure is applicable for the stereoselective reduction of only those alkenes which have an electron withdrawing group and a group with chelating carbonyl (OAc, NHAc, etc.) on one of the alkene carbon. One example of stereoselective reduction is given below (Scheme 3.10). COOH Ph

NHCOPh

Rh(I)(S)–BINAP H2

Ph

COOH H NHCOPh 98% ee. S.

Scheme 3.10

In place of rhodium catalyst, ruthenium catalyst can also be used. Ruthenium catalyst reduces a variety of alkenes with high enantioselectivity and are generally used in place of rhodium catalyst. One such example of the synthesis is of the active form of naproxen, which is used as a pain killer (Scheme 3.11). COOH

Ru(OAc)2/H2

COOH

(S)–BIN AP

MeO

MeO

Naproxen 97% ee.s

Scheme 3.11

Allylic alcohols, such as geraniol and nerol are reduced to (R)-citronellol and (S)-citronellol by (OAC)2 Ru BINAP complex in high chemical and optical yield (Scheme 3.12).

60

Reduction in Organic Synthesis

Scheme 3.12

Some other examples of steroselective hydrogenations are discussed in section 2.1.3. (b) Hydroboration/Protonation Alkenes react with borontrifluoride (in THF) to give alkyl borane, which on protonalysis by treatment with propionic acid gives the corresponding alkane. one such examples given in Scheme 2.40. For more details see section 2.2.7. (c) Sodium Amalgam It reduces alkenes to alkanes. For details see section 2.3.2.3. (d) Diimide Alkenes are reduced to alkanes by diimide. For details see section 2.4.6. (e) Silanes Silanes (e.g., triethyl silane) in presence of trifluoroacetic acid reduces alkenes. For details see section 2.4.7. B. Reduction of Cycloalkenes Reduction of cycloalkene is as easy as that of alkenes. Generally, the preferred method of reduction is catalytic hydrogenation. Thus, cyclopentene, cyclohexene and cyclooctene can be catalytically reduced to the corresponding cycloalkanes. In case of 1, 2 dimethyl cyclohexene, the stereochemistry of the product is affected by the catalyst and the pressure of hydrogen4. Thus, hydrogenation of 1, 2-dimethylcyclohexene over platinium oxide gave 81.8 and 95.4 % of cis-1, 2-dimethyl cyclohexane at 1 atm and 500 atm, respectively. However, hydrogenation over Pd/C or Pd/Al2O3 at 1 atm. 73% of trans and 27% of cis 1, 2-dimethylcyclohexane is obtained (Scheme 3.12).

Reduction of Specific Types of Organic Compounds CH3

CH3

CH3

H2

61

+

CH3

CH3

1,2-Dimethyl cyclohexene

CH3

Cis 1,2-Dimethyl cyclohexane

trans-1,2 Dimethyl cyclohexane

Pt O

1atm

81.8%

18.2%

AcOH

4 atm

83.3%

16.7%

25°

500 atm

Pd(C)

1 atm

94.5% 27%

5.5% 73%

AcOH

Scheme 3.12a

In the case of 2, 3-dimethylcyclohexene, the results of hydrogenation are given below (Scheme 3.13). CH3 CH3 2,3-Dimethyl cyclohexene

PtO

1atm

76.6%

23.4%

AcOH 25°

4 atm 500 atm

70.6%

29.4%

69.7%

30.3%

Pd(C) AcOH 25°

1 atm

27 %

73 %

Scheme 3.13

The results obtained by hydrogenation of 2-, 3-and 4-methylcyclohexenes over Raney nickel were found to be even less stereoselective. The composition of the stereoisomers are 27 – 72% cis and 28 – 73% trans5. Trialkylsilanes and trifluoroacetic acid has also been used for the reduction of cycloalkenes. Thus, methylcyclohexene was converted to methylcyclohexane in 67 – 72% of yield on heating for 10 hrs, at 50° with one equivalent of triethylsilane and two to four equivalents of trifluoroacetic acid6, 7. Cycloalkenes can also be hydrogenated with more or less stereospecificity using disodium azodicarboxylate as a source of diimide8. 3.1.3 Reduction of Dienes The behaviour of diens, both open chain and cyclic towards reduction depends on the respective position of the double bonds. If the two double bonds (in dienes) are separated by at least one carbon atom, these behave as independent units and can be partially or completely reduced by catalytic hydrogenation or by diimide. We have known (see page 57, Scheme 3.4a) that mono substituted double bonds are reduced in preference to di-and tri substituted ones. Thus, 2-methyl-1, 5-hexadiene is hydrogenated over nickel boride to give 2-methyl-1-hexene9 (Scheme 3.14).

62

Reduction in Organic Synthesis

CH3 CH2

CH3

C — CH2 — CH2 — CH

CH2

2–Methyl 1,5–hexadiene

Nickel boride H2

CH2

C — CH2 CH2CH2CH3 2–Methyl-1-hexene 95%

Scheme 3.14

In 4-vinylcyclohexene, a monosubstituted double bond, is hydrogenated over P-1 nickel (prepared10 by the reaction of nickel acetate with two moles of sodium borohydride and washing the formed catalyst with alcohol); in this case, the monosubstituted double bond is reduced in preference to the disubstituted double bond in the ring giving 98% 4-ethylcyclohexene (Scheme 3.15)11.

Scheme 3.15

Similarly, the double bond in the side chain of limonene is reduced with one mole of H2, in presence of 5% Pt/C leaving the double bond in the ring intact12 (Scheme 3.16).

Scheme 3.16

Some other examples of reduction of non-conjugated dienes are given in (Scheme 2.5). In systems containing conjugated double bonds (e.g., isoprene), reduction can be affected with sodium/liquid ammonia to give 2-methyl-2-butene (Scheme 3.17)13. CH3 CH2

C — CH

CH3 CH2

Na liq. ammonia

CH2

C — CH

Isoprene

CH2 CH3

CH3

C — CH 2-Methyl-2butene

Scheme 3.17

CH3

Reduction of Specific Types of Organic Compounds

63

Reduction of 1, 3-butadiene with lithium in ether in presence of Nethylaniline gave cis-2-butene in 92% yield14. Similar reduction of cis-cis-1, 3-cyclooctadiene in the presence of N-methylaniline gave cis cyclooctene in 99% yield15(Scheme 3.18). With sodium in liquid ammonia, the yields of reduction products of conjugated dienes was much lower16 (Scheme 3.18).

Scheme 3.18

3.1.4. Reduction of Alkynes and Cycloalkynes A. Alkynes (a) Catalytic Hydrogenation Reduction of alkynes with hydrogen on a metal catalyst (usually Pt, Ru, Ni) gives the corresponding alkanes (Scheme 3.19). R—C

C — R¢

Pt, Ni or Pd H2

Alkyne

R — CH2 — CH2 — R¢ Alkane

Scheme 3.19

Partial reduction of alkynes to alkenes (especially in case of internal alkynes) is more important. The product obtained in cis or trans alkene depending on the reducing agent. Hydrogenation of internal alkynes under mild conditions gives cis-alkenes and yield ranges from 50 – 100% 17-21 using Raney nickel. The most popular catalyst for the reduction of alkynes to cis-alkenes is palladium on calcium carbonate deactivated by lead acetate (Lindlar’s catalyst)22. (b) Hydride Transfer Reagents Reduction of alkynes with lithium aluminium hydride in tetrahydro furan or its mixture with diglyme gave trans alkenes in good yield 22 . Lithium methyldiisobutyl aluminium hydride (prepared in situ from diisobutyl alane

64

Reduction in Organic Synthesis

and methyl lithium) reduce 3-hexyne to pure trans 3-hexene in 88% yield23. Alkynes could also be reduced to cis-alkene by diisobutyl alanane in 90% yield(23, 24) (Scheme 3.20) (alanane is aluminium hydride).

Scheme 3.20

Similar reductions could also be effective with nickel boride (P2-nickel, prepared by the reduction of nickel acetate with sodium boro hydride)25, 27 or by reduction with sodium hydride28. Magnesium hydride (prepared in situ from lithium aluminium hydride and diethyl magnesium) reduced terminal alkynes to 1-alkenes in 78-79 % in presence of cuprous iodide or cuprous tert-butoxide29 and 2-hexyne to pure cis-2-hexene in 80% yield29 (Scheme 3.21). CH3CH2CH2CH2C 1–Hexyne CH3C

CH

MgH/CuI

MgH/CuI

C — CH2CH2 — CH3

2–Hexyne

CH3CH2CH2CH2CH 1–Hexene 78–79% CH3CH

CH2

CHCH2CH2CH3 cis 2-hexene 90%

Scheme 3.21

(c) Dissolving-metals Partial reduction of carbon-carbon triple bond is conveniently effected by sodium in liquid ammonia in presence of ammonium chloride. For details see Scheme 2.57. (d) Hydroboration-protonation Disiamyl borane reduces carbon-carbon triple bond to Z-alkenes. For details see Scheme 2.47. In acetylenes containing double bonds, the triple bond is selectively reduced by palladium deactivated with quinoline or lead acetate or with triethylammonium

Reduction of Specific Types of Organic Compounds

65

formate in presence of palladium30. The 1-Ethnylcyclohexene on hydrogenation over a special nickel catalyst28 (Nic) gave 84% yield of 1-vinylcyclohexene (Scheme 3.22). The catalyst is prepared as given on page 5.

Scheme 3.22

Diacetylenes having an internal and a terminal triple bond can be reduced selectively at the internal triple bond if they are first converted to sodium acetalides and at the terminal bond31 by sodamide (prepared in situ from sodium in liquid ammonia. (B) Cyclo-alkynes Cyclo-alkynes in 14-membered rings on reduction with sodium/liquid ammonia give the corresponding alkenes32, 33. Cycloalkynes with smaller rings do not show clear-cut stereochemistry. It has been found34 that cyclononyne on reduction with sodium in liquid ammonium gave pure trans-cyclononene in 63.5% yield. In fact the stereochemistry of reductions of cyclo-alkynes depends on the size of the ring and reaction conditions32, 33. 3.1.5 Reduction of Aromatic Compounds Reduction of aromatic compounds by catalytic hydrogenation is more difficult than most of the other functional groups, and selective reduction is not easy. Following are given some of the methods used for the reduction of aromatic compounds: (a) Catalytic Hydrogenation Benzene itself can be reduced to cyclohexane with platinum oxide, rhodium and Raney nickel in acetic acid solution (Scheme 3.22 a).

Scheme 3.22a

Derivatives of benzene, such a benzoic acid, phenol or aniline are reduced more easily (Scheme 3.23).

66

Reduction in Organic Synthesis

R

OH CH3

CH3

H2 Raney Ni

CH3

CH3

R = COOH, OH, NH2

Scheme 3.23

(b) Birch Reduction Sodium (or lithium) and liquid ammonia reduce aromatic ring to give mainly unconjugated dihydro derivatives. This reduction is known as Birch reduction. For details including the mechanism see Schemes 2.54 and 2.55. Alkyl benzenes on subjecting to Birch reduction, give 2-alkyl-1, 4-dihydrobenzenes. An interesting reduction is the reduction of methoxy and amino benzene to dihydro compounds, which can be hydrolysed to cyclohexanones. This is a convenient method for preparing substituted cyclohexanones (Scheme 3.24).

Scheme 3.24

Selective reduction of benzene ring in the presence of another reducible group is possible if the other group can be protected or masked. One such example is given in Scheme 3.25.

Reduction of Specific Types of Organic Compounds

67

Scheme 3.25

3.1.6 Reduction of Condensed Aromatic Hydrocarbons Condensed aromatic hydrocarbons are reduced much more easily than those of benzene and its derivatives, both catalytically and by dissolving metals. Thus, naphthalene on reduction gives35-37 tetrahydronaphthalene (tetralin), or cis or trans decalins (decahydronaphthalene). Tetrahydronaphthalene can be converted to cis-decalin by hydrogenation over platinum oxide35 (Scheme 3.26). H2/PtO AcOH, 25°, 120 atm

H

H Reduction

+

+ H

Naphthalene

Tetralin

cis-decalin

H

trans-decalin

80%

—

—

—

71%

21%

H2/Pt

—

75%

25%

H2/Ni, 160–162°

—

22%

78%

H2/Cu Cr2O4, 200° 150–200 him H2/Pt O, AcOH, 25°, 130 atm

Scheme 3.26

Naphthalene is reduced by dissolving metals to give products depending on the reaction conditions. Thus, Naphthalene on heating with sodium to 140 – 145°38 or treating naphthalene with sodium and liquid ammonia at temperatures below –60° gives 1, 4-dihydronaphthalene (1) which slowly rearranges to 1, 2-dihydronaphthalene39 (2); the latter compound (2) (since it has a double bond in conjugation to the remaining benzene ring) is reduced to 1, 2, 3, 4tetrahydronaphthalene (3)39 . In fact, this (3) is also the final product when reduction is carried out with enough sodium in liquid ammonia at –33°39. In the presence of alcohols, sodium and liquid ammonia reduce naphthalene40, 41 and 1, 4-dihydronaphthalene to 1, 4, 5, 8-tetrahydronaphthalene41 (4) (Scheme 3.27).

68

Reduction in Organic Synthesis

Scheme 3.27

Lithium in ethylamine converted napthalene to a mixture of 80% 1, 2, 3, 4, 5, 6, 7, 8-octahydronaphthalene (∆9, 10-octalin) (5) and 20% of 1, 2, 3, 4, 5, 6, 7, 1010 octahydronaphthalene42 (6)9. ∆9, 10-Octalin (6) could also be obtained in 68.7% yield by the reduction of tetralin (3) with lithium and ethylene diamine43. Tetralin on reduction with sodium and ammonia yielded 1, 2, 3, 4, 5, 8hexahydronaphthalene44 (7). Reduction of ∆9, 10-octalin (5) with lithium and ethylene diamine gave43 trans-decalin (8). All the above reduction products are shown in Scheme 3.27. Reduction of naphthol forms the subject matter of a separate section. Reduction of anthracene can give completely reduced or partially reduced products depending on the reaction conditions45-48 (Scheme 3.28).

Reduction of Specific Types of Organic Compounds

69

Scheme 3.28

Phenanthrene on reduction gives completely or partially reduced products depending on the reaction conditions49-52 (Scheme 3.29). Na, C5H11OH, 50–80% or Raney Ni/EtOH 110°, 127 atm 9 8

1,2,3,4-Tetrahydrophenanthrene

10 1 2

7 3 6 5 4 Phenanthrene

Cu Cr2O4, C6H12 150°, 136–197 atm Cu Cr2O7/ EtOH 130–150° 150–200 atm

9,10, Dihydrophenanthrene

Raney Ni, C6H11Me 110°, 260 atm 1,2,3,4,9,10-hexahydro phenanthrene Raney NO, C6H11Me 120°, 150–200 atm. or CuCr2O4, EtOH 200–222°, 150–200 atm

1,2,3,4,5,6,7,8octahydrophenanthrene

Raney Ni, C6H11 Me 110°, 260° atm 80–89% Perhydrophenanthrene

Scheme 3.29

70

Reduction in Organic Synthesis

3.1.7 Reduction of Heterocyclic Compounds Furan and its homologues are readily reduced by catalytic hydrogenation using palladium53, nickel54 or Raney nickel55 as catalysts (Scheme 3.30). O Furan

H2/Pd or H2, Raney Ni 25°, 2– 4 atm

O 90–95% Tetrahydrofuran

Scheme 3.30

Benzofuran can be reduced over Raney Ni to 2, 3-dihydrobenzofuran or octahydrobenzofuran depending on the reaction condition56. However, further hydrogenation over copper chromite at 200 – 300°C caused hydrogenolysis to 2-ethylcyclohexanol56 (Scheme 3.31).

Scheme 3.31

In case of thiophene, catalytic hydrogenation is not possible, since noble metal catalysts are poisoned and Raney nickel causes desulphurization. Best catalysts are cobalt polysulphide57, dicobalt octacarbonyl58 and rhenium heptasulphide.59 These catalysts yield tetrahydrothiophene in good yield. Pyrrole and its homologues can be reduced partially or completely. Pyrrole itself is hydrogenated with difficulty60, 61 over platinum, nickel, Raney nickel or copper chromite. Reduction over Raney nickel at 180°C and 200 – 300 atm gives 47% yield of pyrrolidine. Pyrrole homologues and derivatives, are easily hydrogenated particularly if the substituents are attached to nitrogen. Thus, 1-methyl and 1-butyl pyrrole on hydrogenation over platinum oxide gave high yield of the corresponding or N-alkyl pyrrolidines60. The 2, 5-Dimethylpyrole in acetic acid over rhodium at 60°C and 3 atm. yielded 70% of cis-2, 5-dimethylpyrrolidine62. Reduction of pyrrole ring in benzopyrrole can be affected with various catalytic procedures63-66 as described in Scheme 3.32.

Reduction of Specific Types of Organic Compounds

N H

71

N H

Benzopyrrole (Indole)

Dihydroindole

NaBH3CN

86%

BH3.NEt3 BH3, C5H5N, AcOH

80% 86%

Zn, H3PO4, 70–80°

64%

Scheme 3.32

In case of indole, catalytic hydrogenation may selectively reduce the double bond or reduce the aromatic ring as well depending on the reaction conditions67-69 (Scheme 3.33). H2/CuCr2O4

CH3 N H

190°, 250–300 atm

2-Methyl indole

CH3 N H Dihydro 2-methyl indole

H2/Ni

230°, 250–300 atm

CH3 N H 80% Octahydro-2-methyl indole

Scheme 3.33

Dibenzocarbazole (carbazole) can also be reduced partially to dihydro carbazole by sodium in liquid ammonia70 or to tetrahydrocarbazole by sodium in liquid ammonia and ethanol70 or by sodium borohydride.63 Catalytic hydrogenation of carbazole using Raney nickel or copper chromite gives 1, 2, 3, 4-tetrahydrocarbazole, 1, 2, 3, 4, 10, 11, hexahydrocarbazole and dodecahydrocarbazole in good yields.67 Pyridine and its homologues can be completely reduced to hexahydro derivatives or partially to dihydro and tetrahydro pyridines. Thus, catalytic hydrogenation of pyridine with Raney nickel71 (200°, 130 – 300 atm) and RuO272 (95°, 70 – 100 atom) give 80 – 100% yield of poperidine. Total and partial reduction of pyridine and its homologues can be achieved by electro reduction and by reduction with sodium in alcohol73.

72

Reduction in Organic Synthesis

Quinoline and its homologues and derivatives are usually reduced in the pyridine ring. Thus, reduction of quinoline with sodium and alcohol gives 1, 2-dihydro quinoline74. Whereas, 1, 2, 3, 4-tetrahydro quinoline is obtained by catalytic hydrogenation75, 76 and by reduction with diborane65. Various products obtained by reduction of quinoline are given in Scheme 3.34.

Scheme 3.34

As seen, vigorous hydrogenation gave cis-and trans-decahydroquinoline75, 76. For more details see reference73.

3.2 REDUCTION OF ALCOHOLS AND PHENOLS Reduction of saturated alcohols is difficult; it requires drastic conditions. Thus, catalytic hydrogenation over molybdeneum or tungsten sulphides at 310°– 350°and 75 – 120 atmospheric pressure, converts alcohols (1°, 2° or 3°) to the corresponding alkanes in good yield (96%)77. It is reported78 that some alcohols are hydrogenolysed with chloroalanes generated in situ from LiAlH4 and AlCl3; however, alkenes are obtained as byproducts.

Reduction of Specific Types of Organic Compounds

73

A convenient method79 for the replacement of hydroxy group in alcohols by hydrogen is by the reaction of alcohols with dicyclohexyl carbodiimide, followed by catalytic hydrogenation of the formed O-alkoxy-N, N′-dialkyl isourea over palladium-carbon (Scheme 3.35). Alternatively, the alcohols are converted into arene sulfonyl ester, which on treatment with iodide gives the allyl idodide; finally iodine is replaced by hydrogen via catalytic hydrogenation (Scheme 3.35).

Scheme 3.35

Phenolic hydroxyl is difficult to reduce. It is known that distillation of phenols with zinc dust80 or with dry lithium aluminium hydride81 result in hydrogenolysis of the phenolic hydroxyls. Since these required very high temperatures, the methods are only of limited use. As in the case of alcohols, phenols can also be hydrogenated82 by treatment with dicyclohexyl carbodiimide followed by reduction of the formed N, N′-dialkyl isourea with Pd-C (see Scheme 3.35 above). Benzylic alcohols can be converted into hydrocarbons by sodium borohydride 83, by chloroalane 84 and by hydriodic acid 85 in good yield (Scheme 3.36). C6H5CH2OH

NaBH4 or Li Al4-AlCl3 or HI

C6H5CH3 80–85%

Scheme 3.36

Cinnamyl alcohol undergoes easy saturation of the double bond86. However, reduction with H2/PtO2 in presence of HCl and CH3COOH, gives completely saturated hydrocarbon85 (Scheme 3.37). C6H5—CH

CH CH2OH

Cinnamyl alcohol

H2/Pt O2, EtOH or LiAlH4, Et2O, reflux H2/Pt O2 HCl/HOAc

Scheme 3.38

C6H5CH2CH2CH2OH 3-Phenyl propanol

C6H5CH2CH2CH3 1-Phenyl propane

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Reduction in Organic Synthesis

Catalytic hydrogenation of aromatic hydroxy compounds (phenols and alcohols) over PtO2, Rh-PtO2, Ni or Raney nickel gave alicyclic alcohols. Thus, phenol yielded cyclohexanol by hydrogenation over PtO2 at room temperature and 210 atm. in 47% yield87. Better yeilds (88 – 100%) are obtained by heating with hydrogen and nickel at 150° and 200 – 250 atm 88. Reduction of 2-phenylethanol gave 2-cyclohexylethanol in 66 – 75% yield88 (Scheme 3.39). OH

OH

PtO2/Rt 210 atm

Cyclohexanol

Phenol H2/Ni/150° 200–250 atm 188-100 % yield

CH2CH2OH

H2/PtO2/RT

2-Phenyl ethanol

CH2CH2OH

2-cyclohexyl phenol (66–75%)

Scheme 3.39

Phenolic hydroxyl can be replaced by hydrogen by converting it into p-toluenesulphonyl derivative followed by hydrogenolysis by H2/Raney Ni (Scheme 3.40).

Scheme 3.40

Acidic hydroxyl groups can be conveniently removed by tosylation followed by treatment with Zn/HCl. Thus, 3, 7-dimethoxy-4-hydroxy-coumarin, and 3phenyl-7-methoxy-4-hydroxy-coumarin on tosylation gave the corresponding 4-tosyl oxycumarins, which on reductive detosylation with Zn/HCl result in removal of 4-hydroxy group to give the corresponding 3-substituted-7methoxycoumarin89 (Scheme 3.41).

Reduction of Specific Types of Organic Compounds

75

Scheme 3.41

Formic acid has been used90 for the replacement of OH group in tertiary alcohols by hydrogen (Scheme 3.42). (Ph3) COH Triphenyl carbinol

HCOOH D

Ph3CH

Triphenyl methane

Scheme 3.42

3.3 REDUCTION OF ALDEHYDES The reduction of aldehydes is easier than that of aromatic rings, but not so easy as carbon-carbon double bond. The product obtained depends on the nature of the aldehyde and the reducing agent. Reduction of Aldehydes to Primary Alcohols Saturated aliphatic aldehydes can be readily reduced to primary alcohols by catalytic hydrogenation; the catalysts used are Raney nickel, platinum, ruthenium etc. Much higher yields of primary alcohols can be obtained with lithium aluminium hydride 91 , lithium borohydride 92 and with sodium borohydride93. Complex hydrides such as trialkoxyaluminium hydrides94, sodium bis 2-methoxy ethoxyaluminium hydride95 and tetrabutylammonium cyanoborohydride96 can also be used. Some of the reducing agents used for the reduction of saturated aldehydes to alcohols are described in Table 3.1.

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Reduction in Organic Synthesis

Table 3.1: Reduction of Saturated Aliphatic Aldehydes to 1° Alcohol RCHO ⎯⎯→ RCH2OH Aldehydes (R)

Reducing agent

C6H13 C6H13 C3H7 C8H17

LiAlH4/ether, reflux LiBH4, Et2O NaBH4, H2O Bu4NBH3CN HMPA, 25°, 1 hr. NaAlH2(OCH2CH2 OMe)2, C6H6, 30 – 80°

C3H7

% Alcohol obtained

Reference

86 83 83

91 92 93

84

96

97

95

Aldehydes can also be reduced to alcohols by sodium–Ethanol (BouveaultBlanc reduction)97 (Scheme 3.42). RCHO

Na/C2H5OH

RCH2OH

Scheme 3.42

Another convenient method for the above conversion is to react the aldehyde with Grignard reagent98 followed by acid work up (Scheme 3.43).

Scheme 3.43

Formaldehyde98

gives primary alcohols (Scheme 3.44). OMgBr

H HCHO + CH3MgBr

H

C

H+

CH3

CH3CH2OH 1°Alcohol

Scheme 3.44

Reduction of Aldehydes to Alkanes Saturated aliphatic aldehydes on reduction with amalgamated zinc and hydrochloric acid (Clemmensen reduction)99, 100 or by heating with hydrazine and potassium hydroxide (Wolff-Kishner reduction)101, 102 give alkanes (Scheme 3.45). C6H13.CHO n-Heptaldehyde

Zn-Hg/HCl, reflux, 70% NH2NH2/KOH/D yield 54%

Scheme 3.45

C6H13CH3 n-Heptane

Reduction of Specific Types of Organic Compounds

77

Reduction of Unsaturated Aliphatic Aldehydes Unsaturated aliphatic aldehydes can be selectively reduced to unsaturated alcohols by controlled catalytic hydrogenation. Thus, citral on treatment with hydrogen over platinium dioxide in presence of ferrous chloride or sulphate and zinc acetate at room temperature, and 3.5 atm. gives geraniol103 (3, 7dimethyl-2, 6-octadienol); in this case, only the CHO was reduced to CH2OH without affecting the double bond. Another example is the hydrogenation of crotonaldehyde over 5% osmium on charcoal to give crotyl alcohol 104 (Scheme 3.46). H2/PtO2/FeSO4/Zn(OAc)2

CHO

CH2OH

Citral

CH3 — CH

Geraniol

CH — CHO

Crotonaldehyde

5% Os — C/H2 or LiAlH4

CH3 — CH

CH — CH2OH

Crotylalcohol

Scheme 3.46

The reduction of crotanaldehyde to crotylalcohol can also be affected with LiAlH4/Ether (70% yield)91, LiBH4. THF (yield 70%)92, NaBH4/H2O (yield 85%)93. A convenient and dependable procedure to convert α, β-unsaturated aldehydes to α, β-unsaturated alcohols is the Meerwein-Ponndorf Verley reduction105. This method consists in the reduction of aldehyde to the corresponding primary alcohol using aluminium isopropoxoide (Scheme 3.46a).

Scheme 3.46 a.

The presence of double bond in the aldehyde (e.g., in α, β-unsaturated aldehyde) does not affect the course of the reaction. The mechanism of the reaction is given in Scheme 3.47.

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Reduction in Organic Synthesis

Scheme 3.47

In the case of α, β-unsaturated aldehydes (e.g., croton aldehyde, CH3CH = CHCHO), it is possible to reduce both the double bonds and the aldehyde to butyl alcohol (CH3CH2CH2CH2OH) by H2/Raney nickel (125°, 100 atm. 5 hrs. yield 94%)106, H2/Ni (25°, 2 atm. 8 hr.)107 or by electro reduction108. However, croton aldehyde is reduced to butanal (CH3CH2CH2CHO, only the double bond is reduced) by H2/Pd (25°, 2 atm)109 or by H2/10% Pd/C in presence of Et3N or by HCO2H (100°, 8 hr., yield 81%)110. Reduction of Aromatic Aldehydes As in the case of aliphatic aldehydes, the product obtained by reduction of aromatic aldehydes also depends on the nature of the aldehyde and the reducing agent. Reduction of Aromatic Aldehydes to Alcohols Aromatic aldehydes can be readily reduced to primary alcohols (as in the case of saturated aliphatic aldehydes). The catalyst used are H2/Pt, H2/Ni, NaH/ FeCl3, LiAlH4, NaBH (OMe)3, Bu4NBH4 and Al(OCMe2)3|Me2CHOH. Some of the reducing agents used for the reduction of aromatic aldehydes to alcohols are described in the Table 3.2. Table 3.2: Reducing Agents Used for Reduction of Aromatic Aldehydes to Alcohols Ph CHO ⎯⎯→ ArCH2OH Reducing Agent H2/Pl, Et OH, 20°, 2 atm. 5 hr. H2/Ni, EtOH, 25°, 1 atm. 1.5 hr. NaH/FeCl3, THF, 25° 24 hr. NaBH(OMe)3, Et2O, reflux 4 hr.

% Yield

Reference

100 91 85 78

111 112 113 114

Bu4NBH4, CH2Cl2, 0° → 25°, 24 hr.

91

115

Al(OC Me2)3, Me2 CHO H, reflux (Meerwein-ponndorf. verley reduction)

55

105

Reduction of aromatic aldehydes to alcohols was also accomplished by lithium aluminium hidride91, alane106, lithiumborohydride92, and tetrabutylammonium cyanoborohydride96. A convenient method for the

Reduction of Specific Types of Organic Compounds

79

conversion of aromatic aldehydes to the corresponding alcohols is by reacting with formaldehyde (Cannizzaro reaction)117. Asymmetric reduction of deutrated benzaldehyde (C6H5CDO) can be affected by the chiral reagent prepared from (+)-α-pinene and 9-borabicyclo [3.3.1] nonane. The product obtained is benzyl-1-d alcohol in 81.6% yield (95% ee)118 (Scheme 3.48).

Scheme 3.48

Reduction of Aromatic Aldehydes to the Corresponding Toluenes Reduction of aldehyde group to methyl group in aromatic aldehydes can be achieved by catalytic reduction by palladium over nickel119 or nickel88 or copper chromite at 250 – 300° at atmospheric pressure. Besides the above reducing agents, triethylsilane in presence of boron trifluoride120 or trifluoroacetic acid121 also reduce the aldehyde group to a methyl group. Clemmensen reduction100, 121 and Wolff-Kishner reduction102, 122 are also well-known for the reduction of aldehydes to the corresponding methyl compounds in good yield. Similar reduction can be accomplished by the conversion of aldehydes to the corresponding p-toluenesulfonyl hydrazones, followed by reduction with lithium aluminium hydride or sodium borohydride123 (Scheme 3.49).

Scheme 3.49

80

Reduction in Organic Synthesis

Reduction of Unsaturated Aromatic Aldehydes A typical example of unsaturated aromatic aldehyde is cinnamaldehyde. The reduction of double bond in cinnamaldehyde could be achieved by catalytic hydrogenation over palladium prepared by reduction of PdCl2 with sodium borohydride. This catalyst does not reduce the aldehyde group124. Similar reduction could also be affected with sodium borohydride-reduced nickel124. Total reduction of cinnamaldehyde to hydrocinnamyl alcohol could be affected by Raney nickel125. The same result was accomplished by electrolysis108 and refluxing with lithium aluminium hydride in ether86. In cinnamaldehyde, only the aldehyde group could be reduced to alcohol (the product is cinnamyl alcohol) with osmium catalyst104. The same result was obtained by reduction with lithium aluminium hydride at –10° using the inverse technique86 or with alane (prepared in situ from lithium aluminium hydride and aluminium chloride)126, with sodium trimethoxyborohydride114 or with sodium cyanoborohydride127. The above reductions of cinnamaldehyde are shown in Scheme 3.50. H2/Pd (MeOH), 25° 2 atm Or H2/Ni (MeOH), 25° 2 atm

C6H5CH

CH CHO

Cinnamaldehyde

H2/Raney Ni, 25 –30° 1-3 atm, (100% yield) or electro reduction or LiAlH4/Et2O reflux, 30 mm (93%)

C6H5CH2CH2CHO Hydrocinnamaldehyde

C6H5CH2CH2CH2OH Hydrocinnamyl alcohol

H2/5% Os(C) 100°, 53–70 atm (45%) (95%) or LiAlH 4, Et2O, –10° (90%)

or Li AlH4/AlCl3, Et2O (90%)

C6H5CH

CH — CH2OH

Cinnamyl alcohol

or NaBH (OMe)3, Et2O, reflux 4 hr. (79%)

Scheme 3.50

Unsaturated aldehydes could be reduced to unsaturated hydrocarbons (C6H5CH = CHCHO → C6H5CH = CHCH3) only by converting them to the corresponding p-toluene sulphonylhydrazone followed by reduction with sodium cyanoborohydride128 as was done in Scheme 3.49. In case sodium cyanoborohydride is used as the reducing agent, the tosylhydrazone may be prepared in situ, since the catalyst does not reduce the aldehyde prior to conversion to their tosylhydrazone. This is a very simple and convenient method for the reduction of α, β-unsaturated aldheydes which cannot be reduced by Clemmenson reduction or Wolff-Kishner reduction. The mechanism of the reduction is the same as shown in Scheme 3.49; R = C6H5CH = CH–.

Reduction of Specific Types of Organic Compounds

81

3.4 REDUCTION OF KETONES As in the case of aldehydes the products obtained by the reduction of ketones depend on the nature of the substrate and the reducing agent. Reduction of Aliphatic Ketones to Alcohols Catalytic hydrogenation of aliphatic ketones give the corresponding secondary alcohols. Common catalysts used are platinium oxide, rhodium-platinium oxide129 and over platinum, rhodium and ruthenium. Under the above conditions, secondary alcohols were obtained in quantitative yield129. Excellent yields were also obtained by catalytic hydrogenation using normal nickel75. and copper chromite130. A number of hydrides and complex hydrides have also been used for the reduction of aliphatic ketones to secondary alcohols (RCOCH3 → RCHOH CH3). These include lithium aluminium hydride (Et2O reflux, yield 88 – 100%)91, magnesium aluminium hydride131, lithium tris (tert-butoxy) aluminium hydride132, dichloroalane (prepared from lithium aluminium hydride and aluminium chloride)133, lithium borohydride92, lithium triethyl borohydride134, sodium borohydride93, 135 and cyanoborohydride96. Reduction of Aliphatic Ketones to Hydrocarbons Aliphatic ketones are conventiently reduced to hydrocarbons (RCOCH3 → RCH2CH3) by Clemmensen reduction99, 100, Wolff-kishner reduction102 (see Scheme 3.45) and with triethylsilane and boron trifluride.120 Aliphatic ketones can also be reduced to the corresponding hydrocarbons, by first converting them into p-toluenesulphonylhydrazones followed by reduction with sodium borohydride136, sodium cyanoborohydride128 or borane137 (Scheme 3.51). R R′

C

O

R

H2N NH SO2 C7H7

R′

C

N NH SO2 C7H7 NaBH4 or NaBH3 CN or B2H6

R R′

CH2

Scheme 3.51

The mechanism of the above reaction is similar to that shown in Scheme 3.49.

82

Reduction in Organic Synthesis

Most gentle reduction of the ketones to methylene group is by converting the ketone to dithioketals (mercaptoles) by treatment with HS – CH2 – CH2 – SH (1, 2-ethane dithiol) in presence of acid followed by desulphurization of the mercaptoles by refluxing an acetone solution of the thioacetal over Raney nickel (Scheme 3.52)138, 139. This reduction method is known as Mozingo reduction. For the last step, hydrazine can also be used. HSH2C CH2SH

R — C — R¢

R — C — R¢ S S

H+

O

H2 Raney nickel

R CH2 R¢

Scheme 3.52

This method finds use for the reduction of cyclic ketones and also to replace it with CH2 in steroids. Reductive dimerisation of aliphatic ketones give pinacols. Thus, acetone on refluxing with magnesium amalgam in benzene140 yield pinacol in 45% yield (Scheme 3.53). CH3 CH3

CH3 CH3 C

O

Mg—Hg benzene, reflux

H3C — C — C — CH3 OH OH Pinacol (45%)

Acetone

Scheme 3.53

Reduction of Aromatic Ketones to Alcohols Like aliphatic ketones, aromatic and aromatic aliphatic ketones are easily reduced to alcohols. However, in case of aromatic ketones in the formed hydroxy compound, the secondary alcoholic group being adjacent to the benzene ring is easily hydrogenolysed. In view of this, special precautions have to be taken to reduce the keto group to the methylene group particularly during catalytic hydrogenation. It has been found141, 142 that aromatic ketones could be reduced with 50% nickel-aluminium alloy in 10–15% aqueus sodium hydroxide at 20 – 90° giving 65 – 90% yield of the reduced product (Ar COCH3 → Ar CHOH CH3). Reduction of aromatic ketones to secondary alcohols is more dependable by hydrides and complex hydrides like lithium aluminium hydride143, lithium borohydride92, sodium borohydride93, tetrabutylammonium borohydride115 and tetrabutylammonium cyanoborohydride144. Following Table 3.3 gives some of the important reducing agents used for the reduction of aromatic ketones to secondary alcohols.

Reduction of Specific Types of Organic Compounds

83

Table 3.3: Reducing Agents for Reduction of Aromatic Ketones to Alcohols C6H5CO CH3 ⎯⎯→ C6H5CHOH CH3 Reagent

% yield

Reference

92 100 60 100 94 82 75 94

112 125 75 130 106 114 141 145

H2/Ni-NaOH, EtOH 25°, atm. 2.5 hr. H2 Raney-Ni, 25.30°, 1-3 atm. 20 min H2/Ni, EtOH, 175°, 160 atm. 8 hr H2/Cu Cr2O4, 150°, 100 – 150 atm. 30 min Li AlH4/AlCl3, Ether, reflux, 30 min Na BH (OMe)3, Et2O, reflux, 4 hr Ni-Al alloy, 10% aq. NaOH, 10 – 20° Na2S2O4, DMF-N2O, reflux, 4 hr.

Asymmetric Reduction of Aromatic Ketones Reduction of prochiral ketones by any of the reducing agent described above gives a racemic mixture. The problem of synthesing optically pure secondary alcohol is more important. The hydride reducing agent approaches a carbonyl group from the least hindered face gives one of stereoisomer in major amount (Scheme 3.54).

Li AlH4

H

THF

OH

O

Scheme 3.54

Asymmetric reduction of aromatic ketones can be affected by the chiral reducing agent prepared from (+)-α-pinene and 9-borabicyclo [3.3.1] nonane (see Scheme 3.48) to give optically pure secondary alcohol. Chiral reducing agents can also be prepared by treatment of (2S, 3S) and (2R, 3R)-1, 4-bis (diethylamino)-2, 5-butanediol with lithium aluminium hydride146. Advances have been made in recent years to use enantiomerically pure reducing agents to impose stereoselectivity during the reduction of ketones. One of the more useful chiral reducing agent is oxazaborolidine complex (A) prepared from L-proline (Scheme 3.55) by Corey.147 N H

CO2H

N B O

L-Proline

Ph Ph

Me Oxazaborolidine complex (A)

Scheme 3.55

84

Reduction in Organic Synthesis

The oxazaborolidine complex (A) has the ability to accelerate the reduction of ketones by diborane. The complex (A) is used as catalyst in very small amount. The source of ‘hydride’ for the reduction comes from diborane or catechol borane, which is used in stoichiometric amounts. Some examples of the reduction of ketones are given below (Scheme 3.56). OH

O Ph

B2H6

Me

Ph

A(0.1–0.05 eq)

Acetophenone

Me 97% ee

OH

O Me

B2H 6

Me

A(0.1 –0.05 eq)

97% ee

t-Butyl methyl Ketone

Scheme 3.56

Another way of preparing optically active alcohols is based on the reduction of prochiral ketones with the aluminium salt of optically active amyl alcohol (pentyl alcohol). Using this procedure optically active alcohols are obtained in good yield and excellent optical purity148. Alcohols of highest ee can be obtained by biochemical reductions using microorganisms. Thus, reduction of acetophenone with Cryptococcus macerans gave 90% yield of 1-phenyl-(1S) ethan-1-ol149 (Scheme 3.57). OH

O C6H5

C

CH3

Acetophenone

Cryptococcus macerans

C6H5

CH3

1–Phenyl-(1S)-ethan-1-ol 96%

Scheme 3.57

The above conversion (Scheme 3.57) can also be achieved in better yield (73%) by using D. Corota found in carrots139a. Using this procedure a number of ketones (viz p-Cl, p-Br, p-F, p-NO 2 , p-CH 3 , p-OCH 3 and p-OH acetophenones) could be reduced to the corresponding S alcohol with 90 – 98% ee and in 70 – 82 % yield. Similarly, α, β-and γ-acetyl pyridines on reduction with Cryptococcus macerans gave the corresponding (–)-S-1-pyridyl ethanols with 79 – 85% ee150. Enzymatic reduction of 2-butanone with Thermoanaerobium brockii gave the R-alcohol (2-butanol) in 12% yield and 48% ee. However, larger ketones like 2-hexanone on reduction with T. brockii gave the corresponding S-alcohol (85% yield, 96% ee) (Scheme 3.58)151.

Reduction of Specific Types of Organic Compounds

85

Scheme 3.58

Reduction of Aromatic Ketones to Hydrocarbons The carbonyl group adjacent to an aromatic ring is converted to methylene in good yields by hydrogenation over palladium and platinum catalysts in acetic acid and hydrochloric acid at room temperature129, 152, over Raney nickel153 or copper chromite153 at 130°–178°C and 70 – 350 atm. Reduction of carbonyl group to methylene in aromatic ketones can also be achieved by alane (prepared from lithium aluminium hydride and aluminium chloride)116, by sodium borohydride in trifluoroacetic acid154, and by sodium in refluxing ethanol155. Most frequently used methods for reduction of aromatic ketones to hydrocarbons are the well known Clemmensen reduction156, 157, WolffKishner reduction158 or reduction of p-toluenesulphonyl-hydrazones with lithium aluminium hydride123, 158. Reduction of Cyclic Ketones Cyclic ketones can be reduced to secondary alcohol by all reducing agents used for reductions of aliphatic and aromatic ketones. However, in cyclic ketones, stereoselectivity of reduction and stereochemistry of the products is more important (particularly in keto steroids). It is found that catalytic hydrogenation may give either cis isomers (when reduction is carried out over platinium oxide159) or trans isomers, if Raney nickel is used.159 An acidic medium favours alcohols with an axial-hydroxyl; an alkaline medium favours alcohols with an equatorial hydroxyl160. Sodium-alcohol has been used for the reduction of cyclic ketones. Thus, the reduction of 2-methyl cyclohexanone gives the thermodynamically more stable alcohol (trans-2-methylcyclohexanol) either exclusively or in major amount. The Table 3.4 shows the percentage of more stable trans (equatorial) alcohol formed by the reduction of 2-methyl cyclohexanone with different reducing agents.

86

Reduction in Organic Synthesis

Table 3.4: Percentage of Trans-2-methylcyclohexonol by the Reduction of 2-methyl cyclohexanone using different reagents. Reagent

Percentage of Trans-alcohol

Na-alcohol Lithium aluminium hydride Sodium borohydride Aluminium isopropylate Catalyst and hydrogen

99 82 69 42 3–35

In a similar way, 4-t-butylcyclohexanone, an unhindered cyclic ketone gave the more stable trans-4-t-butyl-cyclohexanol almost exclusively on reduction with lithium aluminium hydride or with lithium and propanol in liquid ammonia. The formation of more stable epimer in these reductions has been explained161, 162. However, reduction of hindered 3, 3, 5-trimethylcyclohexanone affords a mixture containing mainly the exo alcohol (A). The latter alcohol (A) is exclusively obtained by reducing with more selective reducing agent, lithium hydridotri-t-butoxyaluminate, Li AlH (O But)3 (Scheme 3.59)163.

Scheme 3.59

With strongly hindered cyclic ketones, the main product is formed by approach of the reagent to the less hindered side of the carbonyl group. Thus, reduction of camphor with lithium aluminium hydride gives mainly the exo

Reduction of Specific Types of Organic Compounds

87

alcohol (isoborneol), whereas norcamphor, in which approach of the hydride anion is now easier from the side of the methylene bridge, leads mainly the endo alcohol (Scheme 3.60).

Scheme 3.60

Reduction of α, β-Unsaturated Ketones to Unsaturated Hydrocarbons Such reductions are rare and are accompanied by a shift of double bond. However, such reductions can be accomplished (as in the case of α, βunsaturated aldehydes-see Scheme 3.49) by treatment of the p-toluenesulphonyl hydrazones of the unsaturated ketones with sodium borohydride136, borane137 or catecholborane164, or by Wolff-Kishner reduction165. Reduction of Quinone Quinones can be easily reduced. Thus, p-benzoquinone and its derivatives are catalytically reduced to hydroquinone under mild conditions. Palladium is the best catalyst (H2/5% Pd-C, 100% yield) for the reduction of p-benzoquinone to hydroquinone166. Lithium aluminium hydride also reduce p-benzoquinone to hydroquinone in 95% yield167 and anthroquinone to anthrahydroquinone in 95% yield 167 . Tetrahydroxy-p-benzoquinone can be reduced to hexahydroxybenzene in 70 – 80% yield168 by stannous chloride. The same reagent reduces 1, 4-naphthoquinone to 1, 4-dihydroxy naphthalene (96% yield)169. Some of the reagents reduce quinones selectively in presence of other reducible groups. Thus, hydrogen sulphide converts 2, 7-dinitrophenanthrene quinone to 9, 10-dihydroxy-2, 7-dinitrophenanthrene in 90% yield170. A convenient procedure for converting p-benzoquinone to hydroquinone is reduction by sodium dithionite (Na2S2O4). Reductive Alkylation of Carbonyl Group Treatment of aldehydes or ketones with ammonia, primary or secondary amines in reducing medium is called reductive alkylation. The reducing agents are hydrogen

88

Reduction in Organic Synthesis

in presence of catalysts, such as platinium, nickel or Raney nickel, or complex borohydrides. The reductive alkylation is represented in Scheme 3.61.

Scheme 3.61

By using proper conditions, particularly the ratio of the carbonyl compound to the amino compound, good yields to the desired amines could be obtained171, 172. Thus, the reaction of benzaldehyde (Scheme 3.62) and acetone (Scheme 3.63) with ammonia and amines is given below: 1NH3,EtOH; Raney Ni, 40 –70°, 90 atm 30mm

Ph CH 2NH2 90% Benzylamine

PhCHO Benzaldehyde

0.5 NH3,EtOH

(PhCH2)2NH 90% Diphenyl amine

EtNH2; Li BH3 CN, MeOH, 25°, 72 hr

PhCH2NHEt 2° amine (80%) Benzylethylamine

Scheme 3.62

Reduction of Specific Types of Organic Compounds

89

Scheme 3.63

Reductive alkylation can also be accomplished by heating the carbonyl compound with 4-5 mol of ammonium formate, formamide or formates or formamides prepared by heating 1° or 2° amines with formic acid at 180 – 190° (Leuckart reaction).171

3.5 REDUCTION OF CARBOXYLIC ACIDS AND ITS DERIVATIVES Depending on the reaction conditions, the carboxyl group in carboxylic acid can be reduced to an aldehyde group or to an alcoholic group. Reduction of Saturated Aliphatic Acids to Aldehydes The reduction of saturated aliphatic acids to aldehydes can be affected by aminoalanes (prepared in situ from alane and two molecules of a secondary amine); the best reagent is prepared by adding 2 mol of N-methyl piperazine to 1 mol of alane in THF at 0–25°. Thus, the following carboxylic acids on reduction with aminoalane gave the corresponding aldehydes in good yield173 (Scheme 3.64). CH3(CH2)4 COOH Hexanoic acids

CH3(CH2)6 COOH Octanoic acid

CH3(CH2)14COOH Palniutic acid

Amino alane reflux, 6 hr. Amino alane reflux, 6 hr.

Amino alane reflux, 6 hr.

CH3(CH2)4 CHO 63% Hexanol

CH3(CH2)6 CHO 69% octanal

CH3(CH2)14 CHO 77%

Scheme 3.64

Another reducing agent, lithium in methyl amine reduces aliphatic acids containing 5–14 carbon atoms to the corresponding aldehydes in 61–84% yields174 (Scheme 3.65).

90

Reduction in Organic Synthesis

R — COOH R

C5 to C14

1. Li/Methyl amine

R — CHO

2. hydrolysis of the intermediate N-methylaldimine

61–84%

Scheme 3.65

The carboxylic acids are also reduced to aldehydes by electrolysis using lead electrodes174. Reduction of Carboxylic Acids to Alcohols Carboxylic acids are reduced to the corresponding alcohols by lithium aluminium hydride in ether solution. Since the carboxylic acid contains an acidic hydrogen, an additional equivalent of lithium aluminium hydride is needed beyond the amount required for reduction. The stoichiometric ratio is 4 mol of acid to 3 mol of lithium aluminium hydride.

4RCOOH + 3LiAlH4 + 2H2O → 4RCH2OH + 3LiAlO2 + 4H2, Thus, trimethylacetic acid is reduced to neopentyl alcohol in 92% yield and stearic acid to 1-octadecanol in 91% yield (Scheme 3.66).

Scheme 3.66

Sebacic acid, a dicarboxylic acid is reduced to 1, 10-decanediol in 91% yield (Scheme 3.67)165. HOOC — (CH2)8COOH

LiAlH4/ether

HOH2C(CH2)8CH2OH 91% 1,10-Decanediol

Sebacic

Scheme 3.67

Reduction of Specific Types of Organic Compounds

91

A new reagent, Vitride [sodium bis (2-methoxyethoxy) aluminium hydride] reduces nonanoic acid to 1-nonanol in refluxing benzene in 92% yield176. The same reagent also converts sodium stearate to 1-octadecanol at 80°C in 90% yield.177 Though sodium borohydride does not reduce the free carboxylic acid, but borane (prepared from NaBH4 and BF3-etherate in THF) converts aliphatic acids to alcohol at 0 – 25°C in 89 – 100% yields178. Lithium aluminium hydride reduces exclusively the carboxyl group even in an unsaturated acid with α, β-conjugated double bonds. One such example is given below (Scheme 3.68)175. CH3CH

CHCH

CHCO2H

LiAlH4/Et2O

Sorbic acid (2,4 Hexa dienoic acid)

CH3CH

CHCH

CHCH2OH

92% Sorbic alcohol (2,4 Hexadien-1-ol)

Scheme 3.69

Some more examples of the reduction of unsaturated carboxylic acids are given below (Scheme 3.70)179.

Scheme 3.70

However, in case, the α, β-conjugated double bond of an acid is conjugated to with an aromatic acid, it (the double bond) is reduced. A more convenient way of reducing acids to primary alcohols involves prior activation of the acid as a mixed anhydride followed by reduction of this reactive intermediate with sodium borohydride (Scheme 3.71)180. most electrophilic

O

O R — COOH + ClCOOEt Carboxylic acid

ethyl chloro acetate

–HCl

OEt R

O

Mixed anhydride NaBH4

CH2 R Scheme 3.71

OH

92

Reduction in Organic Synthesis

In the above procedure (Scheme 3.71), the anhydride is electrophilic and so this two step process is an excellent way of reducing acids. The mixed anhydride shown in Scheme 3.71 is most reactive at the C = O that originally belonged to the carboxylic acid; the other carbonyl is not as electrophilic because of overlap of the C = O π system with electrons on two oxygen atoms. Reduction of Aromatic Carboxylic Acids Like aliphatic carboxylic acids, the aromatic carboxylic acids can also be reduced to aldehydes or alcohols depending on the reducing agent. Bis (N-methylpiperazino) alane in THF reduces benzoic acid and nicotinic acid to the corresponding aldehydes (Scheme 3.71a)173. Ph CO2H

Benzoic acid

COOH N Nicotmic acid

AlH — N

N Me , THF 2

Ph CHO

reflux 3hr.

AlH — N

86% Benzaldehyde

N Me , THF

CHO

2

reflux 3hr.

N 75% Pyridine-3-aldehyde

Scheme 3.71a

Aromatic carboxylic acids can be reduced to the corresponding alcohols by hydrides and complex hydrides, e.g., lithium aluminium hydride, sodium aluminium hydride and sodium bis (2-methoxyethoxy) aluminium hydride and with borane. Unsaturated aromatic carboxylic acids with double bond conjugated with both the carboxylic acid and aromatic ring (as in the case of cinnamic acid, PhCH = CHCOOH), undergo reduction of the double bond by catalytic hydrogenation 174. However, on reduction with Li AlH4-ether, cinnamic acid gives 85% yield of dihydro cinnamyl alcohol (C6H5CH2CH2OH).175 Reduction of Acyl Chlorides Depending on the reagents, the reduction of acyl chlorides can give aldehydes or alcohols. Acyl chlorides are easily reduced to aldehydes by the well known Rosenmund reduction181. The procedure182 involves bubbling of hydrogen through a solution of an acyl chloride in boiling toluene or xylene containing deactivated palladium on barium sulphate. The palladium catalyst is deactivated by sulphur compounds like the so called quinoline-S prepared by boiling quinoline with sulphur.

Reduction of Specific Types of Organic Compounds

93

A variation183 of Rosenmund reaction is heating an acyl chloride at 50°C with an equivalent amount of triethyl silane in the presence of 10% palladium on charcoal. By this process aldehyde are obtained in 45 to 70% yield. A more suitable complex hydride, lithium tris (tert-butoxy) aluminium hydride, which due to its bulkines does not react with formed aldehydes at low temperatures. Best results were obtained by carrying with the reduction with the complex hydride at –75° to –80° for 1 hr.184, 185 Acyl chlorides can also be reduced to aldehydes by another hydride, H

H (PH3P)2 Cu

B H

obtained by treatment of a mixture of cuprous chloride H

and triphenyl phosphine, trimethyl phosphite or triisoproyl phosphite in chloroform with a solution of sodium borohydride in ether; the reduction is carried out in acetone solution at room temperature in 15 – 80 minutes (yield 55 – 85%)186. Lithium hydrotri-t-butoxyaluminate is much milder reducing agent than lithium aluminium hydride itself. It reduces acyl chlorides to aldehydes. Nitriles and nitro group remain uneffected by this reducing agent. One example is given below (Scheme 3.71 b).

Scheme 3.71b

Reduction of α, β-unsaturated acyl chlorides to α, β-unsaturated aldehydes can be affected by treatment with triethyl phosphite and subsequent reduction of the diethyl phosphonate with sodium borohydride at room temperature followed by alkaline hydrolysis187. Reduction of Anhydrides Reduction of anhydrides of monocarboxylic acids can be affected by complex hydrides91, 188, one such example is given in Scheme 3.72. Cyclic anhydrides, e.g., phthalic anhydride on reduction with copper chromite afforded 82.5% yield of lactone189. However, reduction with lithium aluminium hydride in refluxing ether gives diols (phthalylalcohol, o-hydroxy methylbenzyl alcohol in 87% yield91. Similar yields of phthalyl alcohol were obtained by reduction with sodium bis (2-methoxyetoxy) aluminium hydride (Scheme 3.72)176, 199.

94

Reduction in Organic Synthesis

Scheme 3.72

Reduction of Esters Esters can be reduced to aldehydes or alcohols depending on the reducing agents and reaction conditions. Thus, esters are reduced to aldehydes by aluminium hydride and complex hydrides provided the reductions are carried out at low temperature (–78°). Some of the reducing agents and the conditions are given below for the reduction of methyl hexanoate to hexanal (Scheme 3.73). C5H11 CO2Me

C5H11 CHO

Reducing agent/conditions

% yield

Reference

LiAlH4, THF, –78°

49

191

NaAlH4, THF, –60° to –45°, 3hr. AlH (CH2(CH2CHMe)2, PhMe or C6H6, 0.5–1 hr.

85

191

85

192

Na AlH2(CH2CHMe2), Et2O, –70°

72

192

Al H

78

193

N

NMe , THF, reflux, 6 hr, 2

Scheme 3.73

Esters are reduced by sodium and alcohols to form primary alcohols. This reaction, known as Bouveault-Blanc reduction 194 is one of the oldest established methods of reduction used in organic chemistry. During reaction with sodium-alcohol, double bonds remain unaffected. One such example is given below (Scheme 3.74).195

Scheme 3.74

The above reduction can also be accomplished by H2|CuCr2O4 (Scheme 3.74).

Reduction of Specific Types of Organic Compounds

95

Treatment of esters with sodium in aprotic solvents give α-hydroxy ketones called acyloins. Such a reaction is known as acyloin condensation196. In this case, the initially formed radical anion diminishes and ultimately forms α-hydroxyketone, an acylon (Scheme 3.75)197.

Scheme 3.75

The acyloin condensation is especially useful with esters of α, ωdicarboxylic acids of at least six carbons in the chain for cyclic acyloins to be formed in good yield. One such example is given below (Scheme 3.76)198.

Scheme 3.76

Esters can also be reduced to aldehyde by DIBAL-H [Diisobutylalane or Diisobutylaluminium hydride [AlH (CH2CHMe2)2]. A typical example is given below199 (Scheme 3.77).

Scheme 3.77

96

Reduction in Organic Synthesis

The reduction of esters to primary alcohols is best accomplished by a powerful reducing agent like Li Al H4 (or iBu2 AlH4 or Li BH4) (Scheme 3.78).

Scheme 3.78

The above reduction cannot be accomplished by NaBH4. This is because Li+ activates the ester carbonyl to reduction. Na+ is insufficiently lewis acid to do this.189 Reduction of Amides Amides can be reduced to aldehydes, alcohols or amines depending on the reducing agent and the reaction conditions. It is found that tertiary amides can easily be reduced to aldehyde in good yield. Thus N.N. dimethyl benzamide, N-benzoyl derivatives of pyrrole or piperidine can be reduced to benzaldehyde (Scheme 3.79).

Scheme 3.79

There is not a general reducing agent which can reduce amides to aldehyde. The best reagent available is the ATE complex (A), obtained by the addition of BuLi to DIBAL-H (Scheme 3.80)199.

Reduction of Specific Types of Organic Compounds

97

Scheme 3.80

It is however, not possible to reduce primary or secondary amide. A convenient procedure of reducing amides selectively involves the formation of Weinreb amides (which can be prepared from the corresponding acid chloride and NHMeOMe or by the reaction of an ester with Mg3Al and NH Me OMe); these react with either LiAlH4 or DIBAL-H at low temperature to form aldehydes (Scheme 3.81)189.

Scheme 3.81

Reduction of amides to alcohols is only exceptionally used for preparative purposes. A typical example is the conversion of trifluoroacetamide to trifluoroethanol in 76.5% yield by catalytic hydrogenation203 (Scheme 3.82). F F — C — CO NH2 F

PtO/90° 105 atm

F F — C CH2OH F

76.5% Trifluoro ethanol

Trifluoro actamide

Scheme 3.82

98

Reduction in Organic Synthesis

Tertiary amides derived from pyrrole, indole and carbazole were hydrogenolysed to alcohols by refluxing with LiAlH4/ether (Scheme 3.82a ). PhCONMe2 NN-Dimethyl benzamide

Ph CO N N-Benzoyl pyrrole

Ph CO N

2.2 Li BHEt3,THF 25°, 1 hr.

PhCH2OH 90%

1.15 Li AlH4, Et2O reflux, 1 hr.

PhCH2OH

1.15 Li AlH4, Et2O reflux, 1 hr.

PhCH2OH

Reference 203

201

80%

201

92.5%

N-Benzoyl indole

PhCO N

1.15 Li AlH4, Et2O reflux, 1 hr.

PhCH2OH

201

80.4%

N-Benzoyl carbazole

Scheme 3.82a

Amides can be reduced to amines with excess of magnesium aluminium hydride, with aluminium hydride in THF, with sodium borohydride, with borane and with sodium-ammonia (Scheme 3.83).

Scheme 3.83

The mechanism of the reduction of amides to amines by LAlH4 is given in Scheme 3.84.

Reduction of Specific Types of Organic Compounds

99

Scheme 3.84

The conversion of amides to amines (having one carbon less than the amides) can be easily carried by the well known Hofmann bromamide reaction209. It involves the action of sodium hypohalite (usually generated in situ from halogen and sodium hydroxide (Scheme 3.85). CH3CH2COONH2 + Br2 + 4KOH

CH3CH2NH2 + 2KBr + K2CO3 + 2H2O Scheme 3.85

Using the procedure, alkyl, aryl or heterocyclic amines could be prepared. The mechanism of the reaction is given below (Scheme 3.86).

Scheme 3.86

Amides containing nitro group are reduced to diamino compounds. Thus, N, N-dimethyl-p-nitrobenzamide on reduction with lithium aluminium hydride in presence of THF, gave 98% yield of dimethyl-p-aminobenzylamine (Scheme 3.87)210.

100

Reduction in Organic Synthesis CONMe2

CH2NMe2

LiAlH4/THF

O2N

H2N

N, N–Dimethyl-p-nitrobenzamide

98% N, N–Dimethyl-p-amino benzylamine

Scheme 3.87

Reduction of Imides Imides are reduced to lactams (cyclic amides) or amines. Thus, electro reduction of succinimide gives pyrrolidone211. However, it can be reduced by sodium borohydride in water to γ-hydroxybutyramide222 (Scheme 3.88). Electrolytic reduction Pb cathode, 50% H2S4 54 amp.

CH2 — CO CH2 — CO

NH

Succinimide

CH2 — CH2 CH2 — CO

NH

60% Pyrrolidone

2NaBH4, H2O

CH2 — CH2OH

25°, 18–20 hrs

CH2 — CONH2 87.5% g -Hydroxybutyramide

Scheme 3.88

N-Aryl substituted succinimide is reduced by borane (generated from sodium borohydride and boron trifluoride etherate) in diglyme to Narylpyrrolidones in 50 – 75% yield.215 Phthalimide on catalytic reduction at 60 – 80° over palladium or barium sulphate in acetic acid containing an equimolar quantity of sulphuric acid or perchloric acid gave phthalimidine266; the same compound was obtained in 75% yield by reduction over nickel at 200° and 200 – 25 atm75 and in 75% yield over copper chromite at 250° and 190 atm203. However, reduction with lithium aluminium hydride reduced both the carbonyl giving isoindoline in 5% yield213; it was also obtained in 72% yield by electro reduction213 (Scheme 3.89).

Scheme 3.89

Reduction of Specific Types of Organic Compounds

101

3.6 REDUCTION OF NITRO COMPOUNDS In general, nitro compounds are reduced to amines. Aliphalic nitro compounds with nitro group on a tertiary carbon are reduced to amines. Thus, 2-nitro-2-methylpropane on reduction with aluminium amalgum214 or iron215 gave tert butylamine in 65 – 75% yield. Also, trans-1, 4-dinitrocyclo hexane could be reduced to trans-1, 4-diamino cyclohexane with retention of configuration206 (Scheme 3.90).

Scheme 3.90

Primary nitro compounds are reduced to aldoximes and secondary nitro compounds are reduced to ketoximes by metal salts. Thus, 1, 5-dinitropentane on reduction with stannous chloride yielded dioxime of glutaric dialdehyde in 55–60% yield217. Similarly, nitro cyclohexane on catalytic reduction or reduction with sodium thiosulphate gave cyclohexanone oxime in 75% yield218 (Scheme 3.91).

Scheme 3.91

The reduction products obtained by the reduction of aromatic nitro compounds depends on the reducing agent used and the reaction condition. Thus, nitrobenzene on reduction under different conditions gives azoxy benzene, azobenzene, hydroazobenzene or N-phenyl hydroxylamine.

102

Reduction in Organic Synthesis

Azoxybenzene is obtained by reduction of nitrobenzene with sodium arsenite219 or reduction with hydrogen in presence of Pd-C in alkaline medium220 (Scheme 3.92). PhNO2

Nitrobenzene

Na3AsO3, reflux or 1.5 H2, Pd/C, KOH, EtOH

+ Ph N

NPh

O–

85% Azoxybenzene

Scheme 3.92

Azobenzene is obtained by the reduction of nitrobenzene with lithium aluminium hydride221 or with zinc in strongly alkaline medium222 (Scheme 3.93).

Scheme 3.93

Hydroazobenzene is obtained by the reduction of nitrobenzene with Zn/ KOH or with H2/KOH/Pd-C/EtOH.220 Hydroazobenzene can also be obtained from azobenzene by reduction with H2/Pd/C, aq. EtOH220 (Scheme 3.93). N-phenylhydroxylamine is obtained by the reduction of nitrobenzene with aluminium-amalgam223, or by H2 Pd C EtOH220 or by Zn, NH4Cl224 (Scheme 3.94). PhNO2 Nitrobenzene

NaHg/Et2O, cooling or 2H2./Pd–C, aq EtOH or Zn, NH4Cl, H2O, 65°

Ph NH OH 60–90% Phenylhydroxylamine

Scheme 3.94

Complete reduction of nitro compounds to amines can be accomplished by catalytic hydrogenation. The catalysts used are platinium oxide, rhodiumplatinum oxide, palladium, Raney nickel or copper chromite. However, the most popular reducing agent for the conversion of aromatic nitro compounds into amines is iron. It is cheap and gives good yields of amines225. Iron is also suitable for the reduction of complex nitro derivatives, since it does not attack many functional groups226. Another suitable reducing agent for the reduction of nitro compounds to amino compounds is sodium hydrosulphite (hyposulphite, dithionite). Thus, 2-chloro-6-nitronaphthaline on reduction with dithionite gives227, 2-amino-6-

Reduction of Specific Types of Organic Compounds

103

chloro naphthalene. As seen, the chloro group remains unaffected (Scheme 3.94a). Cl

Cl

Dithionite (Na 2S2O4) H2O, EtOH, reflux 1hr.

O2N

H2N

2–Chloro-6-Nitro naphthalene

100% 2–Amino–6–chloro naphthalene

Scheme 3.94a

It is possible to reduce selectively one nitro group in polynitro compounds. Thus, 2, 4-dinitro phenol, anisole or amines on selective reduction with HCOOH, Et3N, Pd give228 partial reduction products (Scheme 3.95). X

X NO2

NH2

HCOOH, Et3N/Pd

NO2 X

NO2

OH, OMe, NH2

60–70%

Scheme 3.95

Surprisingly, as seen (Scheme 3.95), it is the sterically less accessible ortho group which is reduced. However, in case of 2, 4-dinitrotoluene, the reduction with the same reagent gives 92% yield of 4-amino-2-nitrotoluene.

3.7 REDUCTION OF NITRILES Nitriles can be reduced to aldehydes or amines depending on the reducing agent and the reaction conditions. Reduction of nitriles to aldehydes is accomplished by the well known Stephen reduction229-231. It involves treatment of a nitrile with anhydrous stannous chloride and gaseous hydrogen chloride in ether or diethylene glycol (Scheme 3.96). R—C

N

SnCl2 HCl

R—C

+

NH Cl –

[H]

R — CH

+ – NH2Cl

H 2O

R — CHO

Scheme 3.96

Stephens reduction is applicable to both aliphatic and aromatic nitriles. A special advantage of this method is that it is applicable to polyfunctional compounds containing reducible groups, such as carbonyl that is reduced by hydrides, but not with stannous chloride232.

104

Reduction in Organic Synthesis

Aromatic aldehydes could be converted to aldehydes in 50 – 95% yield on treatment with 1.3 – 1.7 mol sodium triethoxyaluminium hydride (generated in situ from lithium aluminium hydride and excess of ethylacetate) in THF at 20 – 60° for 0.5 to 3 hrs.233 Aliphatic as well as aromatic nitriles can be reduced to aldehydes with lithium trialkoxyaluminium hydrides234 (generated in situ from lithium aluminium hydride and the appropriate alcohol). Reduction of nitriles could also be accomplished by diisobutylalane in low yields231. Nitriles are reduced to amines by catalytic hydrogenation (using platinium, or palladium at room temperature or Raney Nickel under pressure). Unless suitable precautions are taken, larger amounts of secondary amines may be formed in a side reaction of the amine with the intermediate imine (Scheme 3.97). RC

R CH2 NH2

H2

N

RCH

RCH2N

RCH

NH

H2

imine

NH

1° Amine

R CH2 NH — CH — R

CHR

H2

R CH2 NH2

–NH3

RCH2N

CHR

NH2 R CH2NHCH2R 2° Amine

Scheme 3.97

The side reaction leading to the formation of 2° amines (or even 3- amines) can be suppressed by carrying out hydrogenations in presence of ammonia, which affects the equilibrium of the condensation reaction. Another way of preventing the formation of 2° and 3° amines is to carry out the hydrogenation in acetylating solvents, such as acetic acid or acetic anhydride. Good yields of 1° amines are obtained by hdyrogenation of nitrites over 5% rhodium on alumina in presence of ammonia. Under such conditions, no hydrogenolysis of benzyl residues took place230. Hydrogenation over Raney nickel at room temperature and atmospheric pressure236 also gave higher yields of 1° amine, especially in presence of ammonia. Another reducing agent for the conversion of nitriles to primary amine without producing 2° and 3° amines is lithium aluminium hydride. It is used in equimolar ratio in ether at refluxing temperature. Using this procedure octane nitrile (capronitrile) was reduced to octylamine in 89 – 92% yield237. A modified reagent, lithiumtrimethoxyaluminium hydride also gave higher yields of 1° amines238. In contrast to LiAlH4, borohydrides are not suitable for the reduction of nitriles.

Reduction of Specific Types of Organic Compounds

105

Borane is also used for the reduction of nitriles. Some examples are given below (Scheme 3.98)239.

Scheme 3.98

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Reduction of Specific Types of Organic Compounds

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CHAPTER

4

Hydrogenolysis

The cleavage of a bond between carbon and electronegative element, and replacing them with bonds to hydrogen is known as hydrogenolysis or reductive cleavage.

4.1 HYDROGENOLYSIS OF C–X BOND Halogens can be reductively cleaved by hydrogen and a metal catalyst i.e., hydrogenolysis. The best metal for this is Pd/C and a base (Et3N) is usually added as the H–X byproduct from the cleavage may retard the rate of the reduction. Normally, the case of hydrogenolysis follows the same order as carbonhalogen bond strength, i.e., C—I < C—Br < C—Cl < C—F, with the weakest bond, C—I, being easiest to reduce. Alkyl bromides and especially alkyl halides are reduced faster than chlorides, using Raney nickel in presence of potassium hydroxide1,2 (Scheme 4.1).

Scheme 4.1

Tributylstannane (tributyl tin hydride) is a good reagent for the hdrogenolysis of octyl bromide and octyl iodide to octane3 (Scheme 4.2). C6H13CH2CH2Br Octylbromide

Bu3SnH, DMSO 83°, 18 hr. 72% yield

C6H13CH2CH3 n-Octane

Bu3SnH, DMSO 83°, 18 hr. 82% yield

C6H13CH2CH2I Octyliodide

Scheme 4.2

2-Bromo or 2-iodo octane (see alkyl halides) can be reduced with NaBH4 (Scheme 4.3). C6H13CHBrCH3 2-Bromo octane

NaBH4, DMSO 85°, 18 hr. 72% yield

C6H13CH2CH3 n-Octane

NaBH4, DMSO 85°, 18 hr. 82% yield

C6H13CHICH3 2-Iodo octane

Scheme 4.3 © The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3_4

115

116

Reduction in Organic Synthesis

Alkyl chlorides (with a few exceptions) are not reduced by mild catalytic hydrogenation over platinum, rhodium and nickel even in presence of alkali. However, alkyl chlorides can be reduced (e.g., C8H17Cl → C8H18) with metal hydrides and complex hydrides like lithium aluminium hydride3, lithium copper hydrides5, sodium borohydride4 and especially different tin hydrides (stannanes)6-8. In aromatic series, both benzylic halogens and aromatic halogens can be reduced by catalytic hydrogenation. Benzylic halides, as expected, reacted much faster than aromatic halides. Aromatic aldehydes, known to be reluctant towards reduction by hydrides, undergo a substitution by hydride in excellent yield in dimethoxyethane solution under sonication (Scheme 4.4)9a.

Scheme 4.4

4.2 HYDROGENOLYSIS OF C–O BOND Hydrogenolysis of C–O bond in saturated alcohol requires drastic conditions. This can be achieved by catalytic hydrogenation over molybedenum or tungsten sulphides at 310 – 350°. Thus, 1°, 2° and 3° alcohols are converted into the corresponding alkanes in good yield9. Hydrogenolysis of alcohols can also be affected with chloroalanes (generated in situ from LiAlH4 and AlCl3), but in this case alkenes are obtained as by-products10. A convient method11 for the replacement of hydroxyl group in alcohols and phenols is by the reaction of the hydroxyl group with dicyclocarbodiimide followed by catalytic hydrogenation of the formed o-alkoxy-N, N′-dialkyl isourea over Pd–C. Alternatively, the hydroxyl group is converted into arenesulfonyl ester, which on reaction with an iodide gives the allyl iodide; finally, iodine is replaced by hydrogen by catalytic hydrogenolysis (see Scheme 3.35). Benzylic alcohols can be hydrogenolysed by sodium borohydride12, by chloroalane13 and by hydroiodic acid14 in good yield (Scheme 4.5). C6H5CH2OH

NaBH4, or AlH4AlCl3 or HI

Scheme 4.5

C6H5CH3 80–85%

The α, β-Unsaturated alcohols, like benzyl alcohol undergo saturation of the double bond15. However, reduction with H2|PtO2 in presence of HCl and CH3COOH gives completely saturated hydrocarbon (Scheme 4.6).

Hydrogenolysis

117

Scheme 4.6

Phenolic hydroxyl can be replaced by hydrogen by converting it into p-toluene sulphonyl derivative followed by hydrogenolysis with H2/Raney nickel. The tosyl derivative can also be hydrogenolysed with LiAlH4/THF. Alternatively, the phenolic hydroxyl is converted into benzyloxy group which on reduction with Pd–C16 gives the hydrogenolysis product (Scheme 4.7).

Scheme 4.7

Sonication has been used16a for the hydrogenolysis of the benzyl ether with Raney nickel and hydrogen (Scheme 4.7). By dissolving metal 17 , reduction can also induce hydrogenolysis, particularly for the cleavage of O-benzyl and N-benzyl derivatives and is a useful alternative to catalytic hydrogenation. Acidic hydroxyl group can be conveniently removed by tosylation followed by treatment with Zn|HCl (see Scheme 3.41). In tertiary alcohols, the hydroxyl group can be replaced by hydrogen through formic acid (see Scheme 3.42). A convenient procedure for deoxygenating tertiary alcohol uses hydride transfer from a silane18 (Et3SiH is normally used) in presence of acid (Scheme 4.8). OH

Ph

Et3, SiH, CF3COOH 96%

Ph H+

Ph

+

Et

Ph H

Si

Ph Ph

Et Et

Scheme 4.8

H

118

Reduction in Organic Synthesis

Primary and secondary alcohols can also be deoxygenated by the Barton– Mc Combie reaction18. In this procedure the alcohol is first converted into its Xanthate ester derivative (NaH, CS2, MeI), which is reduced by tributyl tin hydride in hot benzene (Scheme 4.9). S •SN(Bu)3 R

OH

NaH, CS2, MeI

O

R

SMe Xanthate

S — SnBu3 R

O

•

• R

SMe

Bu3, SnH, D [(Bu)3Sn•]

Bu3, SnH

H (Bu3

)Sn• +

R

Scheme 4.9

In the above method (Scheme 4.9), initiations are added to form small amount of Bu5Sn•, though the reaction can proceed without them. This reaction does not work with tertiary alcohols, as in this case, the xanthate ester undergoes a concerted elimination (the Chugaev reaction) at elevated temperature, as shown in Scheme 4.10. H

S

SR

∆

O

Scheme 4.10

4.3 REDUCTIVE CLEAVAGE OF A CARBON OXYGEN DOUBLE BOND The Clemmensons reduction and the Wolff-kishner reduction are well-known methods for the reduction of aldehydes and ketones to methyl and methylene group, respectively (see Schemes 3.45 and 3.51). The original Wolff-kishner reduction involved the reaction of carbonyl group with hydrazine to form a hydrazone, which on heating with potassium hydroxide gave the reduced product. Subsequently, Wolff-kishner reduction was modified and the procedure called the Huang-Milan modification of the Wolff-Kishner reaction. In this procedure, the hydrozone is formed in situ (by the reaction of carboxyl compound with hydrazine) and heated with potassium hydroxide and ethylene glycol at high temperature. Mozingo reduction can also be used for the conversion of carbonyl to methylene. In this reaction, the ketones on treatment with 1, 2-ethane dithol give the corresponding dithioketal (mercaptol), which on reduction with H2/ Raney nickel give the required product (see Scheme 3.52).

Hydrogenolysis

119

A typical example of the cleavage of the carbon-oxygen bond is the cleavage of carbonylbenzyloxy (Cbz group). The carbonylbenzyloxy group is a useful protecting group for amines. This group is stable to hydrolysis and most of the oxidising agents. Thus, the amine on treatment with ClCOOCH2Ph gave the corresponding carbonylbenzoxy product, which is subjected to hydrogenolysis; in this the rupture of a carbon-oxygen bond takes place and this leads to the removal of Cbz group. The hydrogenolysis of the O-Bn bond is followed by decarboxylation of the formed carbamic acid (Scheme 4.11). O H

H

N

H

+ ClCOOCH2Ph

R

OCH2Ph

N R

O H

H

N

–CO2

H

N

R

OH

R Carbamic acid

Scheme 4.11

The keto group is 2-pyridone can be reduced by the Scheme 4.12. H2

POCl3

N

O

2-Pyridone

N

Cl

Pd-c

N Pyridine

2-Chloro pyridine

Scheme 4.12

4.4 REDUCTIVE CLEAVAGE CARBON-NITROGEN BOND Amines that are substituted by benzyl group (CH2Ph) may be broken by reduction with hydrogen and a transition metal catalyst; the benzylic carbonnitrogen bonds are cleaved as shown by dotted line. In fact benzyl group is often used as a protecting group for amines. Generally, 3° amines are easier to protect than the secondary, which in turn are more reactive than primary. A typical sequence of event is shown in Scheme 4.13. NH + ClCH2C6H5

N

Piperidine

Scheme 4.13

Ph

Pd — C H2

N—H

120

Reduction in Organic Synthesis

As an alternative to hydrogenolysis for deprotecting benzyl amines, sodium in liquid ammonia (with a proton source such as t-butanol) is added.

4.5 REDUCTIVE CLEAVAGE OF CARBON-SULPHUR BONDS Carbon-sulphur bonds in sulphides and sulphoxides are easily cleaved with a reactive metal and a suitable proton source. One typical example is given in Scheme 4.14. OH

OH

Li, NH3 THF

PhS

73%

SO2Ar

Li/Hg EtOH 70%

Scheme 4.14

Raney nickel has also been used to completely reduce sulphur containing compounds like sulphides, sulphoxides and sulphones. Sulphides can also be reduced to hydrocarbons by Bu3SnH (Scheme 4.15). SPh

Bu3SnH, AlBN

+ PhSSnBu3

benzene, D 67%

Scheme 4.15

REFERENCE 1. 2. 3. 4. 5. 6. 7. 8. 9.

L. Horner, L. Schläfer and H. Kämmerer, Chem. Ber., 1959, 92, 1700. H. Kämmerer, L. Horner and H. Beck, Chem. Ber., 1958, 91, 1376. S. Krishnamurty and H.C. Brown, J. Org. Chem., 1980, 45, 849. R.O. Hutchins, D. Hake and B. Koharski, Tetrahedron Lett., 1969, 3495. E.C. Ashby, J.–J. Lin and A.B. Goel, J. Org. Chem., 1978, 43, 183. H.G. Kuivila and L.W. Menapace, J. Org. Chem., 1963, 28, 2165. F.D. Greene and N.N. Loury, J. Org. Chem., 1967, 32, 882. H.G. Kuivila, Synthesis, 1970, 499. S. Landa and J. Mostecky’, Coll. Czech. Chem. Common, 1955, 20, 430; 1956, 21, 1177.

Hydrogenolysis

121

9 (a). B.H. Han and P. Boudjouk, Tetrahedron Lett., 1982, 23, 1643. 10. J.J. Brewster, S.F. Osman, H.O. Bayer and H.B. Hopps, J. Org. Chem., 1964, 29, 121. 11. E. Vowinkel and I. Buthe, Chem. Ber., 1947, 107, 1353. 12. G.W. Gribble, R.M. Leese and B. Evans, Synthesis, 1977, 172. 13. J.H. Brewster and H.V. Bayer, J. Org. Chem., 1964, 29, 105, 110. 14. C.S. Marvel, F.D. Hager and E.C. Caudle, Org. Synth. Coll. Vol., 1932, 1, 224. 15. S. Nishimura, T. Onoda and A. Nakamura, Bull. Chem. Soc. Japan, 1960, 33, 1356; F.A. Hochstein and W.G. Brown, J. Am. Chem. Soc., 1948, 70, 3484. 16. C.H. Heathcock and R. Ratcliffe, J. Am. Chem. Soc., 1971, 93, 1746. 16 (a). C.A. Townsend and L.T. Nguyen, J. Am. Chem. Soc., 1981, 103, 4582. 17. C.M. McClosky, Adv. Carbohydrate Chem., 1957, 12 137, E.J. Reist, V.J. Bartuska and L. Goodman, J. Org. Chem., 1964, 29, 3725. 18. T.J. Donohoe, Oxidation and Reduction in Org. Synthesis, Oxford Science Publications, 2000, pp. 78–79.

CHAPTER

5

Enzymatic or Microbial Reduction

Enzymatic reductions are highly stereoselective and straight forward. Enzymes are easily available and are important tool in organic synthesis. Prelog was the first to study the reduction of carbonyl compunds with a number of enzymes. The reduction of ketones with Curvularia fulcatta gave stereochemical induction based on Prelog’s rule1. According to this rule if the stearic difference between Large (L) and Small groups (S) attached to the carbonyl group is large enough, the enzyme attacks from the less hindered face (over S) to give the corresponding alcohol as shown below (Scheme 5.1). O

L

H

HO

enzyme

C

C

S

S

L

Scheme 5.1

Some of the common enzyme systems available are yeast alcohol dehydrogenase (YAD) and horse liver alcohol dehydrogenase (HLADH). The selectivity observed in these enzymes is determined by non-bonded interactions of substrate and enzyme in hydrogen transfer transition state2.

5.1 REDUCTION OF β-KETOESTERS Baker’s yeast (Saccharomyces cerevisiae) is known to reduce β-keto esters to give 71% yield of S-alcohol, which was used in Mori’s synthesis of (S) – (+) sulcatol3 (Scheme 5.2). O

OH CO2Et

Baker's yeast

CO2Et S-Alcohol 68%

Ethyl acetoacetate

Scheme 5.2 © The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3_5

123

124

Reduction in Organic Synthesis

However, reduction of β-ketovalerate gave the R alcohol. It was shown that the selectivity of reduction with small chain esters from S changed to R selectivity with long chain esters (Scheme 5.3). O

CO2Et

CO2Et

Baker's yeast R alcohol

Ethyl b-Ketovalerate

Scheme 5.3

A number of synthetic applications of reduction by Baker’s yeast are available. Thus, the reduction of β-keto ester (A) gives the hydroxy ester (Scheme 5.4). The S selectivity of these reactions is in consistent with the S selectivity predicted by Prelog’s rule6.

5.2 REDUCTION OF KETONES AND ALDEHYDES 1, 3-Diketones are reduced to β-ketoalcohol. Thus, 2, 4-hexanedione was reduced to (S)-5-hydroxy-3-hexanone quantitatively (Scheme 5.4). OH

O

S

O

CO2Et

CO2Et

Baker's yeast

S

(A)

71%

O

Baker's yeast

OH

O

(S)-5-Hydroxy-3-hexanone

2,4-Hexanedione

Scheme 5.4

Simple ketones can also be reduced by Baker’s yeast7. Thus, the ketone moiety in the side chain of B was reduced selectively to the R alcohol with Baker’s yeast (Scheme 5.5). Me

Me

O Baker's yeast

O

Me HO

O (B)

Me H

O

O

(R alcohol)

Scheme 5.5

The above example (Scheme 5.5) is taken from the synthesis of norgestrel8.

Enzymatic or Microbial Reductions

125

It has been found that Baker’s yeast often leads to enantioselective or diastereospecific reductions. Thus, reduction of carbonyl group in the dicarbonyl compound (C) gives (S) alcohol in 40% yield (98% ee)9 (Scheme 5.5a). S

O

O OMe

S

S

K. Corticus

OH H

S

O OMe

(c)

Scheme 5.5a

The reduction of trans-crotonaldehyde, with Beauveria sulphurescens gives 80% yield of 2-buten-1-ol10. However, 2-methyl 2-pentenal gave a mixture of 31% of the conjugated alcohol and 69% the completely reduced product, 2methyl-1-pentanol (Scheme 5.6)10.

Scheme 5.6

Reduction of geranial with Baker’s yeast gave R-citronellol. However, the Z-isomer neral on reduction gives a 6 : 4 R : S-mixture, possibly due to isomerisation of the double bond in neral prior to the delivery of hydrogen11. Carbonyl group can also be reduced by Thermoanaerobium brockii. Thus, 2-butanone on reduction gives the R-alcohol (2-butanol) in 12% yield and 48% ee, R. However, a larger ketones such as 2-hexanone are reduced to the S-alcohol (85% yield, 96% ee, S)12 (Scheme 5.7). OH

O T- brockii

2-Butanol (12% 48% ee R)

2-Butanone

OH

O T- brockii

85%, 96% ee, S 2-Hexanol

2-Hexanone

Scheme 5.7

Thus, the selectivity of reduction depends on the size and nature of the groups around the carbonyl.

126

Reduction in Organic Synthesis

An interesting example of microbial reduction is the reduction of acetophenone to 1-phenyl-(1S)-ethan-1-ol by D. Carota (from Daucus carota root) in 73% yield, 92% ee (Scheme 5.8).

Scheme 5.8

REFERENCES 1. V. Prelog, Pure and Applied Chem., 1964, 9, 179. 2. B. Zhou, A.S. Gopalan, F.V. Middlesworth W.H. Shieh and C.J.J. Sih, J. Am. Chem. Soc., 1983, 105, 5925. 3. E.E. van Tamelen, E.E. Deaway, R.S. Lease and W.H. Pickel, J. Am. Chem. Soc., 1961, 83, 4302. 4. B. Zhou, A.S. Gopalan, F. Van Middleworth, W. –R. Shieh and C.J.J. Sih, J. Am. Chem. Soc., 1983, 105, 5925. 5. K. Mori, Tetrahedron, 1981, 37, 1341. 6. M. Hirama, M. Shimizu and M. Iwashita, J. Chem. Soc. Chem. Commun., 1983, 599. 7. J.K. Lieser, Synths. Commun., 1982, 13, 765. 8. W.S. Zhou, D.Z. Huang, Q.C. Dong, Z.P. Zherung, and Z.Q. Wang, Chem. Nat. Prod. Proc. Sino-Am. Symp. 1980, 299; Chem. Abstr., 1983, 98, 198545 w. 9. T. Takarsi, Y. -L. Yang, d. Di Tullio and C.J. Sih, Tetrahedron Lett., 1992, 23, 5489. 10. M. Desert, A. Kergomard, M.F. Renard and H. Veschambre Tetrahedron, 1981, 37, 3825. 11. M. Dost membrum-Desrut, G. Dauphin, A. Kergomard, M.F. Renard, and H. Veschambre, Tetrahedron, 1985, 41, 3679. 12. E. Kinan, E.K. Mafeli, K.K. Seth and R. Lamed. J. Am. Chem. Soc., Chem. Commun., 1980, 1026. 13. J.S. Yadav, S. Nanda, P.T. Reddy and A.B. Raji , J. Org. Chem., 200, 67, 3900.

CHAPTER

6

Some Reductions under Benign Conditions 6.1 INTRODUCTION Most of the reduction requires solvents which are volatile organic solvents and are harmful to the environment. Besides, the catalysts used produce harmful effects. In view of this, it is best to carry out the reductions under benign conditions. Some of these conditions include use of phase transfer catalysts and other benign catalyst. Use of solvents like water, ionic liquids and polythylene glycol are good. Better yields of reduced products are obtained by sonication and microwave irradiation. Besides, these enzymatic reductions are one hundred per cent benign (for detail see Chapter 5).

6.2 REDUCTION OF CARBON-CARBON DOUBLE BONDS The alkenes are known to be reduced to the corresponding alkanes by PtO2/H2, Pd/H2, Raney nickel/H2 or dimide. Sonication plays an important role1 in the reactivity of Pt, Pd and rhodium black. Thus, formic acid and Pd/C are an efficient couple for the hydrogenation2 of a wide range of alkenes at room temperature in presence of low intensity ultrasonic fields (cleanings bath, 50 kH2).

Scheme 6.1

The reduction of carbon-carbon double bonds is possible in water by using water soluble hydrogenation catalysts3. Thus, 2-acetamido acrylates can be reduced with hydrogen at room temperature in water, in the presence of water soluble chiral Rh(I) and Ru(II) complexes with (R)-BINAP (SO3Na) [BI NAP is 2, 2′-bis (diphenylphospheno-1, 1′-binaphthyl) (Scheme 6.2)4.

© The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3_6

127

128

Reduction in Organic Synthesis

Scheme 6.2

The reduction of carbon-carbon double bond of α, β-unsaturated carbonyl compound can be accomplished by Zn-NiCl2 (9 : 1) in Ethanol-H2O (1:1) using sonication (Scheme 6.3). O

O Zn–NiCl2 (9 : 1)/ EtOH-H2O (1:1) rt. 2.5 hr. )))) 97%

Scheme 6.3

In the above reduction (Scheme 6.3), catalytically active nickel is obtained by sonichemical reduction of its salts (e.g., the chloride) with zinc powder. Under these conditions, the excess of metallic zinc is activated and reduces the water present in the medium, producing hydrogen gas6. In this way not only the catalyst, but also the reagents are produced in situ with maximal efficiency and safety. It is interesting to note that the variation of the conditions, especially the pH, allows a modification of this selectivity as shown with carvone (Scheme 6.4). O

Zn–NiCl2 (9:1). EtOH–H2O (1:1) rt. 3hr. ))))

O 96% (+) –Dihydrocarvone

Carvonel

O

Zn–NiCl2 (9:1)/EtOH–H2O (1:1) pH 8, r%, 1.5 hr. ))))

95%

Scheme 6.4

Some Reductions under Benign Conditions

129

Reduction of carbon-carbon double bond can also be affected with H2 and Wilkinsons catalyst using ionic liquids, such as [bmin] [BF4], [bmin] [PF6] and [bmin] [SbF6] as solvent (Scheme 6.4a)6a.

Scheme 6.4a

The product obtained being not miscible with the ionic catalyst solution could be removed from the reaction mixture by simple decantation and the recovered ionic catalyst solvent could be reused several terms without any significant change in catalyst activity and selectivity. The reduction of carbon-carbon double bond is also possible6b using waxy solid, PEG-900 at 155 bar pressure in SC–CO2 at 40°. The RhCl (PPh3)-catalysed hydrogenation of styrene to ethylbenzene in PEG-900 at 155 bar, 55°, in SCCO 2 was conducted in a homogeneous catalyst reaction. The formed ethylbenzene could be extracted into SC-CO2 and the catalyst containing PEG phase was reused6b (Scheme 6.4b).

Scheme 6.4b

Another example of the reduction of α, β-unsaturated carbonyl compound with Zn/NiCl2, (sonication) is given in Scheme 6.5. O

O Zn—NiCl2 1 m NH4OH — NH4Cl ph. 8, 1.5 hr. 30° ))))

95%

Scheme 6.5

6.3 REDUCTION OF CARBON-CARBON TRIPLE BONDS The carbon-carbon triple bonds (alkynes) are known to be reduced by catalytic hydrogenation to alkanes. However, reduction with Pd-CaCO3, which is deactivated by adding lead acetate (Lindlars catalyst) or Pd-BaSO4 deactivated by quinoline gives Z-alkenes.

130

Reduction in Organic Synthesis

It has been shown the disubstituted alkynes (which are electron deficient) can be reduced with water soluble monosulphonated or trisulphonated triphenyl phosphine (Scheme 6.6)8. Ph2 P (m C6H4 — SO3Na) 1.2 eq H2, RT. 5 mm

Ph — C

COMe

Ph H

H

+

Ph

70%

C — COMe Ph2P (m — C6H4 — SO3Na), 0.9 eq

Ph H

H2O RT. 3 mm

H COMe

H 30%

H COMe

Scheme 6.6

As already stated, partial reduction of triple bonds in alkynes to cis-olefins can be accomplished by lindlars catalyst, Pd-CaCO3 poisoned with PbO. This reduction could be conducted in polyethylene glycol-400 (PEG-400). The advantage is that the PEG and the catalyst could be used for a number of times (3–5) without loss of activity or yield.

6.4 REDUCTION OF CARBONYL COMPOUNDS The carbonyl compounds are known to be reduced

C

O — CH2

by the well

known clemmensen reduction. It is found the yield is improved by sonication. Sonication has been used to reduce carbonyl groups. Thus, camphor on sonication with a metal (Li, Na or K) in THF yields a mixture of endo and exo borneol10 in the same ratio as by using metal in liquid ammonia (Scheme 6.7).

Scheme 6.7

The endo product is obtained in 73, 68 or 42% by the use of Li, Na or K as the metal in the above reduction. Carbonyl groups with less negative redox potential, such as quinone or α-diketones can be reduced with zinc in the presence of trimethylchlorosilane11 (scheme 6.8). THF was found to be better than ether in the above transformation.

Some Reductions under Benign Conditions

O

131

OSiMe3 Zn/Me3SiCl/THF 40°, 10–30 mm )))

O

OSiMe3 90%

Scheme 6.8

Ketones can be dimerised to pinacol by sonication with zinc and trimethylchlorosilane in dioxane followed by hydrolysis with tetrabutylammonium fluoride12. By the same procedure, aryl ketones can be reductively coupled in excellent field12. However, the outcome of the reaction depends on the stoichiometry of the reactants (Scheme 6.9)13. O

1. Zn/Me3SiCl/dioxane rt., 2hr. ))))

Ph

HO

OH

2. Bu4NF

Ph Ph 56%

Scheme 6.9

However in the reaction of 2-cyclohexen-1-one with Zn (Cu) in acetone led to unsymmetrical coupling with acetone, which is used as a solvent (Scheme 6.10)14. O

OH

OH

Zn (Cu)/acetone rt. 2 hr. )))) 2-Cyclohexen-1-one

85%

Scheme 6.10

The solid state reduction of carbonyl compounds has been accomplished by mixing them with sodium borohydride and storing the reaction mixture in a dry box for five days. However, the longer reaction time was an disadvantage. It has now been possible to expediously reduce aldehydes and ketones that uses alumina-supported NaBH4. The reaction proceeds in solid state using microwaves15. The process involves simple mixing of the carbonyl compounds with 10% Na BH4 supported on alumina and exposure of the reaction mixture to microwaves in a household MW oven for 0.5–2 min (Scheme 6.11). In the reaction (Scheme 6.11), the reaction rate improves in the presence of moisture and the reaction does not take place in the absence of alumina. The advantage is that the alumina support can be recycled and reused for the subsequent reaction, repeatedly by mixing fresh NaBH4 without any loss of activity. The process has been utilised for the MW-enhanced solid state deutration reactions using sodium borodeutide imprignated with aluminia16.

132

Reduction in Organic Synthesis

OH

O R1

C — R2

Al2O3 — NaBH4

R1

MW

62–93%

R2

R1 Cl, Me, NO2

H

H

MePh

Ph

Ph CH(OH)

p-MeOC6H4

p-MeO C6H4CH(OH)

R1

CH — R2

R2

Me,

Scheme 6.11

A useful characteristic feature of the reaction is the reduction of trans cinnamaldehyde; in this case the olefinic moiety remains intact and only the aldehyde is reduced (Scheme 6.12). C6H5CH

CH CHO

Cinnamaldehyde

Al2O3 — BaBH4 MW 1 min

C6H5CH

CH — CH2OH

90% Cimmamyl alcohol

Scheme 6.12

As already stated, the main problem of reduction of carbonyl compounds with NaBH4 is its insolubility in organic solvents in which the reduction is attempted. The problem has been solved by using tetraalkylammonium borohydrides which are generally obtained in situ by the action of tetraalkyl ammonium halides with sodium borohydride in aquous medium. In general, the compound is reduced in organic solvent (e.g., benzene) with potassium or sodium borohydride, water and the appropriate tetraalkylammonium halide (stirring at room temperature) for 0.5, 0.75 hr17 (Scheme 6.13). C

O

+ R3N Cl / NaOH / NaBH4 organic solvent stirring, 0.5–0.75 hr.

CHOH

Scheme 6.13

Reduction of aldehydes with trialkyborane generally requires temperatures of approximately 150°C. Ionic liquids like [bmin] [BF4] and [emin] [PF6] can be used in trialkylborane for the reduction of aromatic and aliphatic aldehydes with enhanced rate at low temperature18 [even room temperature (Scheme 6.14)]. The reduced products are easily removed from the ionic liquid via extraction and no decrease in reduction yield is found when the ionic liquid is reused.

Some Reductions under Benign Conditions

100° rL

RCHO + R3B

RCH2OH

O — BR2 R H

+ – O BR3

133

OH

R—C—H

R—C—H

H

H

Scheme 6.14

The reduction of ketones and aldehydes can be affected19-21 with PEG and NaBH4 and PEG-NaBH4 complex (Scheme 6.15). RCOR¢ + NaBH4 R R¢

PEG-400/C6H6

RCH(OH)R¢

Ph, C6H5CH2 CH3, Ph

Scheme 6.15

A very convenient method for the reduction of aldehydes to alcohols is by the well known solid-state crossed Cannizzaro reaction. In this procedure, the aldehyde (1 m mol) is heated with Ba(OH)2⋅ 8H2O (2-m mol) under microwave irradiation (Scheme 6.15a)21a. RCHO + (CH2O)n

Ba(OH)28H2O MW 100–110°

RCH2OH + ROOH 80–90%

1–20%

Scheme 6.15a

Aldehydes are very conveniently reduced to alcohol by hydrogen-transfer reaction. In the method developed21b, starting aldehydes or ketones are heated with a low boiling alcohol, which behaves both as reducing agent and the solvent at temperatures around 225° (attainable by specialised constructed microwave ovens). Some examples of reduction of aldehydes and ketones are given in Scheme 6.15 b. CHO

225°/24 hr.

OH

iso PrOH Benzaldehyde

92% Benzyl alcohol

CHO

227°/27 hr. iso PrOH

trans-Cinnamaldehyde

83%

OH

(E) Cinnamyl alcohol

134

Reduction in Organic Synthesis

CHO MeO

225°/29 hr.

OH

iso PrOH

MeO

p-Methoxy benzaldehyde

81%

OH

O 227°/20 hr.

50%

iso PrOH

Cyclohexanone

Cyclohexanol

Scheme 6.15b

6.5 REDUCTION OF ESTERS The reduction of alkyl and aryl esters to the corresponding alcohols is enhanced by NaBH4 in PEG–400. These alkyl and aryl esters are considered inert towards reductions in other organic solvents (Scheme 6.16). R — COOR¢ + NaBH4 R R¢

PEG – 400

R — CH2OH

alkyl, aryl CH3, C2H5

Scheme 6.16

Esters can also be reduced using enzymes (see Schemes 5.2, 5.3 and 5.4)

6.6 REDUCTION OF AROMATIC RINGS Reduction of aromatic rings has been investigated only in few cases. For example, N-protected indole on sonication in presence of lithium and trimethylchlorsilane undergoes a clean reduction to give the dihydro compound (Scheme 6.17). SiMe3 Li/Me3SiCl/THF

N

RT, 16 hr. ))))

N Me3Si

SiMe3

SiMe3

Scheme 6.17

Extension of this process to other aromatic rings, followed by benzophenone oxidation of the dihydro intermediate provides a satisfactory method for ring silation22, 23. Aromatic halides, which are known to be reluctant towards reduction by hydrides, undergo a substitution by hydride with excellent yield in DME solution24 on sonication (Scheme 6.18).

Some Reductions under Benign Conditions X R

LiAlH4/DME/35°C 4.5 hr. ))))

135

R 98%

R X

2 — CH3; 2 — OCH3, 3—Cl Br, I

Scheme 6.18

REFERENCES 1. 2. 3. 4. 5. 6. 6(a).

(b). 7. 8. 8(a). 9. 10. 11. 12. 13. 14. 15. 16. 17.

18.

A.W. Maltsev, Russ. J. Phys. Chem., 1976, 50, 995. J. Jurizak and R. Ostaszewki, Tetrahedron Lett., 1988, 29, 959. K. Kalack and M. Montel, Adv. Organomet. Chem. 1992, 134, 219. K. Wan and M.E. Davis, Tetrahedron Assymetry, 1993, 4, 2461; K. Wan and M.L. Davis, J. Chem. Soc. Chem. Commun., 1993, 1262. C. Petrier and J.L. Luche, Tetrahedron Lett., 1987, 28, 2347. C. Petrier and J.L. Luche, Tetrahedron Lett., 1987, 28, 2351. V.K. Ahluwalia and R.S. Varma, Green Solvents for Organic Synthesis, Narosa Publishing House, 2009, page 7, 19 and the references cited therein. D.J. Heldebrant and P.G. Jessop J. Am. Chem. Soc., 2003, 125, 5600. C. Petrier, I.L. Lavaitte and C. Morat, J. Org. Chem., 1989, 54, 5313. C. Larpent and G. Meignam, Tetrahedron Lett., 1993, 34, 4331. S. Chandrasekhar, Ch. Narsihmulu, G. Chandrasekar and T. Shyam sunder, Tetrahedron Lett., 2004, 45, 24. W.P. Reeves, J.A. Murry, D.W. Willoughby and W.J. Friedrich, Synthetic. communication, 1988, 18, 1961. J.W. Huffman, W., Liao and R.H. Wallace, Tetrahedron Lett., 1987, 28, 3315. P. Boudjouk and J. So, Synth. commun., 1986, 16, 775. J. So, M. Park and P. Boudjouk, J. Org. Chem., 1988, 53, 5871. M. Park, Chungnam Kwahak Yonguchis, 1986, 13, 61; Chem. Abs., 1988, 109, 149601. P. Delair and J.–L. Luchi, J. Chem. Soc., Chem. Commun., 1989, 398. R.S. Varma and R.K. Saini, Tetrahedron Lett., 1997, 38, 4337. W.T. Erb, J.R. Jones and S.–Y. Lu, J. Chem. Res (S), 1999, 728. V.K. Ahluwalia and Renu Aggarwal, Organic Synthesis, Special Techniques, Second Edn., Narosa Publishing House, 2002, page 56 and reference cited therein. G.W. Kobalka and R.R. Malladi, Chem. Commun., 2000, 2191.

136

Reduction in Organic Synthesis

19. 20. 21. 21(a). (b). 22. 23. 24.

J.R. Blantan, Synth., Commun., 1977, 27, 2093. J.R. Blanton, React. Funct. Polym, 1977, 33, 61. B.G. Zupanic and M. Kolaji, Synth. Commun., 1982, 12, 88. R.S. Varma, K.P. Naicker and P.J. Liesen, Tetrahedron Lett., 1998, 39, 8437. C.R. Strauss, Aust. J. Chem., 1999, 52, 83–96 and the references cited therein. A G.M. Barrett, I.A. Dauzonne, I.A. Oneil and A.J. Renaud, J. Org. Chem., 1984, 49, 4409. A.G.M. Barrett and I.A. O’Neil, J. Org. Chem., 1988, 53, 1815. B.H. Han and P. Boudjouk, Tetrahedron Lett., 1982, 23, 1643.

Suggested Readings

1. Reductions in Organic Chemistry. MILO Ś Hudlicky, E John Willyand sons; New York. 2. Oxidation and Reduction in Organic Synthesis, Trimothy J. Donohoe, Oxford Science Publications, UK. 3. Reduction in Organic Synthesis, Michail B. Smith, McGraw Hill International Editions, 1994, Pages 343–505. 4. Reduction in Organic Reaction Mechanism, V. K. Ahluwalia and Rakesh Kumar Parashar, Narosa Publishing House, New Delhi, 2011, Pages 227–265. 5. Reduction in Some Modern-methods of Organic Synthesis, W. Carruthers, Cambridge University, Press, 1886, Pages 411–491. 6. Reductions in Green Solvents for Organic Synthesis, V.K. Ahluwalia and Rajender S. Varma, Narosa Publishing House, New Delhi, Pages 1.43 to 1.44, 8.4 to 8.5 and 8.9 to 8.14. 7. Reductions in Organic Synthesis, Special Techniques, V. K. Ahluwalia and Renu Aggarwal, Narosa Publishing House, New Delhi, 2006, Pages 56–57, 130–132, 167 and 208 and the references cited therein. 8. Reductions in Alternate Energy Processes in Chemical Synthesis, V. K. Ahluwalia and R. S. Verma, Narosa Publishing House, New Delhi, 2008, Pages 4.15 and 9.5–9.7 and the references cited therein. 9. Reductions, Thomas N. Sorrell, Organic Chemistry, Viva Books, 2010, Pages 334–338. 10. Reductions, Francis A. Carey and Richard J. Sundberg, Springer, 2001, Pages 249–314. 11. Marye Anne Fox and James K. Whilesell, Reductions in Organic Chemistry, Jones and Bartlett Publishers, 2004, Pages 507–512.

© The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3

137

Index

A Adkins catalysts 5 Aluminium 34 Aluminium Alkoxides 10 Aluminium amalgam 34 Ammonium formate 44 Asymmetric Homogeneous Catalytic Hydrogenations 9 Asymmetric Reduction of Aromatic Ketones 83

Dialkylboranes 21 Diborane 22 Diimide 41, 60 Dimethyl Sulphide 39 Disiamylborane 24 Dissolving Metal Reductions 25

E Electrolytic Reduction 25 Enzymatic or microbial reductions 46 Enzymatic reductions 123

B Biochemical reductions 84 Birch Reduction 66 Borane 21 Bouveault-Blanc reaction 28 Bouveault-Blanc reduction 94

F Formic acid 43

H Heterogeneous Catalytic Hydrogenation 3

C

Heterogeneous Hydrogenation 56 Homogeneous Catalytic Hydrogenations 5

Calcium borohydride 15 Catalytic Hydrogenation 3, 56, 63, 65 Clemmensen reduction 76, 79, 81 Clemmensens reduction 13, 35, 80, 118 Copper chromite 5

D Di-isobutylaluminium Hydride (DIBAL) 16 © The Author(s) 2023 V. K. Ahluwalia, Reduction in Organic Synthesis, https://doi.org/10.1007/978-3-031-37686-3

Huang-Milan modification of the WolffKishner reaction 118 Huang-Minlon method 13 Huang-Minlon modification 40 Hydrazine 40 Hydride Transfer Reagents 10, 63 Hydroboration 60, 64 Hydrogen iodide 38 Hydrogen Sulphide 39 139

140

Reduction in Organic Synthesis

Hydrogenolysis 115 Hydrogenolysis of C–O Bond 116 Hydrogenolysis of C–X Bond 115

I Ing-Manske procedure 40 Iron 37

L Lindlar’s catalyst 4 Lithium Aluminium Hydride 11 Lithium borohydride 15

M Magnesium 33 Magnesium amalgam 33 McFadyen-Steven reduction of a carboxylic acid 41 Meerwein-Ponndorff-Verley reduction 10, 77, 34 Microbial Reduction 123 Mossy zinc 35 Mozingo reduction 82, 118

N Nickel 4 Non-metallic reducing agents 38

P Palladium 4 Photochemical reductions 44 Platinum 3 Potassium borohydride 15 Prelog’s rule 46

R Raney-nickel 4 Reduction of a, b-unsaturated Ketones to Unsaturat 87

Reduction of Acyl Chlorides 92 Reduction of alcohols 72 Reduction of aldehydes 75 Reduction of Aldehydes to Alkanes 76 Reduction of Aldehydes to Primary Alcohols 75 Reduction of Aliphatic Ketones to Alcohols 81 Reduction of Aliphatic Ketones to Hydrocarbons 81 Reduction of Alkanes and Cycloalkanes 55 Reduction of Alkenes 56 Reduction of Alkenes and Cycloalkenes 56 Reduction of Alkynes and Cycloalkynes 63 Reduction of Amides 96 Reduction of Anhydrides 93 Reduction of Aromatic Aldehydes 78 Reduction of Aromatic Aldehydes to Alcohols 78 Reduction of Aromatic Aldehydes to the Corresponding Toluenes 79 Reduction of Aromatic Carboxylic Acids 92 Reduction of Aromatic Compounds 65 Reduction of Aromatic Ketones to Alcohols 82 Reduction of Aromatic Ketones to Hydrocarbons 85 Reduction of Carbon-carbon triple bonds 129 Reduction of carboxylic acids 89 Reduction of Carboxylic Acids to Alcohols 90 Reduction of Condensed Aromatic Hydrocarbons 67 Reduction of Cyclic Ketones 85 Reduction of Cycloalkenes 60 Reduction of Dienes 61 Reduction of Esters 94 Reduction of Heterocyclic Compounds 70 Reduction of Hydrocarbons 55 Reduction of Imides 100

Index

Reduction of Ketones 81 Reduction of Quinone 87 Reduction of saturated alcohols 72 Reduction of Saturated Aliphatic Acids to Aldehyde 89 Reduction of Unsaturated Aliphatic Aldehydes 77 Reduction of Unsaturated Aromatic Aldehydes 80 Reductions Under Benign Conditions 127 Reductive Alkylation of Carbonyl Group 87 Reductive Cleavage Carbon-nitrogen Bond 119 Reductive Cleavage of a Carbon Oxygen Double Bond 118 Reductive Cleavage of Carbon-Sulphur Bonds 120 Rhodium 4 Rosenmund reduction 4, 92

Sodium Hydrogen Sulphide 33 Sodium Metabisulphite 31 Sodium-alcohol 27 Sodium-liquid Ammonia 28 Stephen reaction 37 Sulphur Dioxide 39

T Tetrabutylammonium borohydride 15 Tin 37 Trialkylborohydrides 20

U Urushibara catalyst 5

V Vaska’s catalyst 9

S Silanes 42, 60 Silicon hydride 42 Sodium Amalgam 30, 60 Sodium and Xylene 30 Sodium Borohydride 14 Sodium Cyanoborohydride 18 Sodium Dithionite 32

141

W Wilkinson’s catalyst 6, 57 Wolff-Kishner reduction 76, 79, 80, 87, 118

Z Zinc 35 Zinc chromite 5