3 t(L DISSOLVING METAL REDUCTIONS OF ALCOHOL DERIVATIVES A thesis presented by PANAYIOTIS ALEXANDROU PROI<OPIOU in partial fulfilment of the requirements for the degree DOCTOR OF PHILOSOPHY HOF! ANN (1976/1978) AND WHIFFEN LABORATORIES (1978/1979) CHEMISTRY DEPARTMENT IMPERIAL COLLEGE LONDON S',!7 2AY , MARCH, 1980, ACKNOWLEDGEMENTS I wish to record eu sincere aratitnde to Professor Sir Derek Barton, FRS for tile privilege of working with him on this project and alt the encouragement and assistance he /Las given me. 1r25 dynamic enthusiasm and depth of insight have been a constant source of inspiration. I also thank Dr. /:.G.I.1. Barrett for his cosupervis- ion, friendship and for reading the manuscript; DrS. R. Bielski and D. PapaioannOu for advice, assistance and f1nendship in the early stages of this project; My wife for her patience and understanding; and, finally, my colleagues in the Hofmann Laboratory, who have made my stay at Imperial College a most memorable and pleasant one. March, 1980. LIST CF CONTENTS page Acknowledgements Abstract 1 CHAPTER 1 2 Some General Methods for the Deoxygenation of Alcohols CHAPTER 2 23 Carbon-heteroatom Sigma Bond Cleavages CHAPTER 3 47 Results and Discussion 82 CHAPTER 4 Experimental 157 References Publications 175 1. ABSTRACT Literature methods for the deoxygenation of alcohols and their derivatives are reviewed. The mechanisms describing the dissolving metal reduction of carbon-heteroatom bonds are classified. The majority of reductions were found to occur via a one-electron process. Reduction of sterically hindered alkyl carboxylic esters using lithium in ettylamine, potassium/18-crown-6/t-butylamine or potassium/ l8-crown-G-/l,2-dimethoxyethane gave predominantly the corresponding alkanes rather than the parent alcohols. The deoxygenation is shown to proceed via alkyl oxygen cleavage of the derived radical anion giving alkane and carboxylate anion provided that the medium is nucleo- phile-free. Reduction of dialkyl carbonates gave alkanes, but not as efficient- ly as esters. Carbamates deoxygenate even less readily, whereas carbo- hydrate esters not at all. Dithiocarbonates and dialkylthiocarbamates of primary and secondary alcohols have been deoxygenated in high yield, thus, complementing the selective ester reduction. 2. CHAPTER 1 SOME GENERAL METHODS FOR THE DEOXYGENATION OF ALCOHOLS 1.1 INTRODUCTION A useful transformation, frequently encountered in organic synthesis, is the replacement of a hydroxyl function by a hydrogen atom. The selective removal of a hydroxyl function (deoxygenation) in carbohydrates, and especially aminoglycoside antibiotics is of current interest. The deoxygenated aminoglycosides often have improved activities against resistant bacteria. In this chapter the various methods for deoxygenating alcohols.that have appeared in the literature are summarised. In theory, there are two ways of deoxygenating an alcohol; either directly on the free alcohol or indirectly via a derivative. In practice, however, there are very few cases where the first method can be applied. These cases are special since they are applicable to allylic and benzylic alcohols only. Most deoxygenations rely on the indirect method. The various derivatives that are used vary from simple halides to complex esters, and the reducing' agents vary from alkali metals to complex hydrides. 1.2 DIRECT DEOXYGENATION This method involves the reduction of allylic or benzylic alcohols by alkali metals in ammonia or alkylamines. Thus, reduction of 1-tetralol 1 (1) with lithium in ammonia gave tetralin (2) in quantitative yield. Reduction of ergosta--3,22-diene-35,I113-diol (3) with lithium in ethylamine 2 gave ergosta-8, 22-diene-3;;-ol (4). 3. OH Li /NH 3 TIIF NH Cl (1) (2) Li/EtNI12 60% HO (3) HO 4. 1.3 INDIRECT DEOXYGENATION 1.3.1 Deoxygenation via Aldehydes and Ketones One of the oldest methods, applicable to primary and secondary alcohols only was their oxidation to the aldehyde or ketone respectively with subsequent Wolff-Kishner or Clemmensen reduction to the hydrocarbon. Other methods for reduction of derivatives of oxo-compounds have been developed and reviewed elsewhere.3 1.3.2 Deoxygenation via Halides The reduction of a halide to a hydrocarbon is a facile process, and since the conversion of an alcohol to a halide is a simple transformation, the deoxygenation of alcohols via halides has been used extensively by organic chemists. A halide can be reduced by dissolving metal reduction, .hydride reduction, hydrogenolysis or photolysis in a hydrogen atom donor solvent. In deoxygenations using dissolving metals the metal could be any- alkali or alkaline earth in ammonia or alkylamine, or a transition metal with a suitable proton source. Examples are listed below: the zinc dust, acetic acid and hydrogen chloride reduction of n-hexadccyl iodide gave n-hexadecane in 85; yield. l Hydrogen chloride limited this method to non-acid sensitive compounds, for example simple alkyl halides. Alkyl iodides prepared from toluene-4-sulphonates or methanesulphonates can be reduced with zinc dust in 1,2-dimethoxyethane, dimethylformamide, dirnethyl- sulphoxide or hexamethylplrosphoramide, all in one-pot without isolating 3 the intermediate iodide. '6 This method is selective for iodides in presence of olefins, ketones,m-hydroxyketones,cd -unsaturated ketones, 5. tertiary_ hydroxyl, epoxides and nitriles. It is limited, however, to primary or non-hindered secondary sulphonates where simple SN2 dis- placement can occur without complications. The reduction of 33-chloro- androst-5-en-17-one (5) with lithium in ammonia gave 175-hy,lroxyandrost- 7 5-ene (6). Titanocene dichloride (7) with excess finely divided magne- 8 sium metal in water is reported to reduce halides to hydrocarbons. NaI/7n HMPA/1050 48% A c0 A c 0 6. 0 Li/NH3 r Cl (5) OH (6) II 0 ?- + nClOH21Cl + Mg anClOH22 (7) 7. Lithium aluminium hydride for many years has been known to reduce halides 9 to hydrocarbons in excellent yields. Many other functional groups, however, are simultaneously reduced. The powerful lithium triethylboro- hydride10 is known to reduce hindered halides to hydrocarbons in high yields, for example neopentyl bromide to neopentane in 96', yield. Sodium cyanoborohydridei1 and tetrabutylammonium cyanoborohydride12 in hexamethyl- phosphoramide are excellent selective reductants for primary iodides. A useful reagent for the selective reduction of tertiary, benzylic or allylic halides in the presence of primary and secondary alkyl and aryl halides is B-n-butyl-9-borabicyclo [.3.3.J nonane n-butyl-lithium ate complex (8). Potassium copper (I) hydride can reduce halides as well as other functional groups13 whereas lithium copper hydride is slightly more selec- tive and can reduce halides in the presence of esters. 14 Another powerful non-selective halide reducing agent is triethyl- silane used in the presence of aluminium chloride.lo Reductions of halides in excellent yields can be achieved with tributylstannane. This method has been reviewed.'16 17 Iodides were cleanly reduced to hydrocarbons with hydrogen on nickel or palladium on carbon.18 For example, 3-deoxy-3-iodo-1,2:5,6-di-O-iso- propylidene-a-D-glucofuranose (9) was reduced to 3-deoxy-1,2:5,6-di-0-iso- prop lidene —Y-D-glucofuranose (10).17 Other functional groups like benzyl ethers can be simultaneously hydrogenolysed. Carbohydrate iodides have been photolysed giving dcoxysufiars, e.g. 6-deoxy-G-iodo-1,2:3,4-di-O-isopropylidene-u-D-galactopyranose (11) has been photolysed giving G-deoxy-1,2:3,4-di-0-isopropylidene-o.-D-galacto- 19 pyranose (12). Photolytic methods, however, are not attractive for large scale preparations. 8. Li B u ~B / Bu (8) (9) (10) hy/;,fe01i NaOii/pyrex 97 (12) 9. 1.3.3 Deoxygenation via Sulphonate Esters .Sulphonate esters can easily be prepared from alcohols and sulphonyl chlorides or anhydrides, and their deoxygenation has been achieved by dissolving metal, metal hydride, electrolytic and photolytic methods. Trifluoromethanesulphonates have recently been reduced with sodium in ammonia, e.g. methyl 4,6-0-cyclohexylidene-2-deoxy-2-methoxycarbonyl- amino-3-0-trifluoromethanesulphonyl-a-D-glucopyranoside (13) gave methyl 4,6-0-cyclohexylidene-2,3-dideoxy-2-methoxycarbonylamino-a-D-glucopyrano- side (14).`0 The synthetic utility of this method is limited to cases where the a-substituents are not easily eliminated. Alkyl alkanesulphon- 21 ates are known to deoxygenate with sodium-naphthalene in tetrahydrofuran or with potssium in hexamethylphosphorictriamide.22 Arylsulphonates such 23,24 as toluene-4-sulphonates are less effective than alkyl analogues. Toluene-4-sulphonate esters of primary and'sometimes secondary alco- hols are deoxygenated when treated with lithium aluminium hydride. An example is the reduction of phenyl 6-0-benzoyl-2,3-di-0-benzyl-3-0-(toluene- 4-sulphonyl)-(3-D-glucopyranoside (15) to phenyl 2,3-di-0-benzyl-3-deoxy- 25 (3-D-glucopyranoside (16). Other procedures involve the copper hydride reagent of Masamune,14 and the powerful lithium triethylborohydride which is reported to be superior to LiA1Ii 1, LiI311,1, LiAl(OR) 311, Ali;3 or 13113 and deoxygenates even sterically hindered secondary sulphonate esters. An electrolytic method has recently been reported27 to selectively deoxygenate methanesulphonates in the presence of olefins, aromatic func- tions, esters, nitriles, epoxides and hydroxyls in yields ranging from GO to 90'7,. For example, the epoxymesylate (17) was reduced to the epoxide (18) in 87; yield. 10. Trifluoromethanesulphonates