A series of reviews by leading specialists in their fields which gives systematic and comprehensive coverage of the progress in major areas of research.

General and Synthetic Methods Volume 5

A Review of the Literature Published During 1980

By G. Pattenden

The Royal Society of Chemistry

Copyright © 1982 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-864-6

Contents

Chapter 1 Saturated and Unsaturated Hydrocarbons By J. M. Clough, 1,
Chapter 2 Aldehydes and Ketones By S. C. Eyley, 59,
Chapter 3 Carboxylic Acids and Derivatives By D. W. Knight, 100,
Chapter 4 Alcohols, Halogeno-compounds, and Ethers By R. C. F. Jones, 148,
Chapter 5 Amines, Nitriles, and Other Nitrogen-containing Functional Groups By G. Kneen, 183,
Chapter 6 Organometallics in Synthesis Part I The Transition Elements By S. v. Ley and R. A. Porter, 208,
Chapter 7 Saturated Carbocyclic Ring Synthesis By A. J. Barker, K. Cooper, and G. Pattenden, 257,
Chapter 8 Saturated Heterocyclic Ring Synthesis By R. C. Brown and A. H. Ingall, 288,
Chapter 9 Strategy and Design in Synthesis By A. P. Johnson, 387,
Author Index, 419,

CHAPTER 1

Saturated and Unsaturated Hydrocarbons

BY J. M. CLOUGH

1 Saturated Hydrocarbons

Many new methods for the preparation of alkanes by reductive removal of functional groups have been reported during the year. Barton and his co-workers have presented a new radical decarboxylation for the conversion of carboxylic acids into hydrocarbons. Following esterification with trans-9-hydroxy-10-phenylthio-(or -10-chloro-)9, 10-dihydrophenanthrene, a primary, secondary, or tertiary carboxylic acid is smoothly reduced under neutral conditions by tri-n-butylstannane and a radical initiator (e.g. Scheme 1). Formation of phenanthrene as by-product provides the driving force for the fragmentation. Another new method for the degradation of carboxylic acids to the corresponding nor-alkanes using the same stannane and radical initiator, but in this case via their phenylselenoesters, has been outlined briefly.

Aldehydes are decarbonylated catalytically using solutions of bis(triphenylphosphine)(tetraphenylphorphyrinato)ruthenium(II) at, or slightly above, room temperature. Decarbonylation of aromatic aldehydes takes place in high yield, but some aliphatic aldehydes give significant amounts of rearranged products.

The nitrile group of 4-cyanopyridine is replaced quantitatively by hydrogen when treated with titanium trichloride in aqueous acetic acid. Under the same conditions, 2-cyanopyridine undergoes reductive decyanation only in poor yield, and 3-cyanopyridine is inert. Highly dispersed potassium on neutral alumina, easily prepared by melting potassium over alumina in an inert atmosphere, effects reductive cleavage of the cyano-group of alkyl nitriles in hexane at room temperature (e.g. Scheme 2). Alternatively, activated tertiary or secondary nitriles can be efficiently decyanated by heating with molten potassium hydroxide. By contrast, aromatic and tertiary cyano-groups of relatively volatile species are transformed into methyl groups by hydrogenolysis in the gas phase over 30% nickel on alumina (52 — 99%). However, nitriles with a -hydrogen atoms undergo predominant decyanation under the reaction conditions, and other functional groups, if present, tend to be removed.

Aryl aldehydes and mono- or di-aryl ketones are conveniently reduced to arylmethanes under neutral conditions by refluxing with a five-fold excess of W-7 Raney nickel in 50% aqueous ethanol. Methoxy-, hydroxy-, carboxy-, methoxycarbonyl, or dimethylamino-groups remain unaffected, though nitro-, cyano-, and halogeno-groups are reduced under the reaction conditions. Saturated ketones, derivatized as toluene-p-sulphonylhydrazones, are reduced to alkanes in high yield within two hours by bis(triphenylphosphine)copper(I) tetrahydroborate in refluxing chloroform. The method gives lower yields with aldehydes, and is not effective for the decarbonylation of aromatic or α,β-unsaturated carbonyl compounds. In a still milder procedure, the same reducing agent reacts with 2,4,6-tri-isopropylhydrazones (trisylhydrazones) to give alkanes in moderate yield at room temperature. Ethylene thioacetals are com- pletely desulphurized to hydrocarbons by four molar equivalents of tri-n-butyltin hydride and catalytic amounts of 2,2′-azobis(isobutyronitrile).

Selenium is smoothly extruded from dibenzyl selenides at 600°C to give high yields of bibenzyl and elemental selenium. Unsymmetrically substituted dibenzyl selenides give mixtures of the three possible bibenzyls, suggesting that the reaction proceeds via free benzyl radicals.

A direct deoxygenation of alcohols that are capable of forming relatively stable carbanions has been reported. The alcohol reacts with potassium to form its alkoxide, which is treated with pentacarbonyliron; acidic work-up furnishes the alkane (43 — 90%) together with dimerized and dehydrated products in some cases.

A much improved method for the replacement of phenolic hydroxy-groups by hydrogen has been reported. 2-Phenyltetrazolyl ethers [e.g. (1)], easily pre- pared from phenols, are now shown to be cleaved reductively by catalytic transfer hydrogenation within two hours at room temperature in a two-phase solvent system (e.g. Scheme 3).

Alper and his co-workers have reported two new methods for the desulphurization of aliphatic, aromatic, and benzylic thiols. In one method thiols are treated with hexacarbonylmolybdenum, either in acetic acid or following pre-adsorption on silica. An alternative and milder procedure uses anhydrous ferrous chloride and sodium triethylhydroborate in THF at –78°C. The 2-benzothiazolylthio-group, useful for stabilizing carbanions, is conveniently removed by electroreduction at a carbon electrode in a cathode cell (e.g. Scheme 4).

Brown and his co-workers have compared representative simple and complex metal hydrides in order to assess their capabilities for the hydrogenolysis of alkyl halides. Of the reducing agents studied, lithium triethylborohydride is the most powerful, and is the reagent of choice for the hydrogenolysis of alkyl iodides, bromides, and chlorides. Weaker reagents offer the possibility of selective hydrogenolysis. β-Hydroxy-bromides and -iodides, protected as their tetrahydropyranyl ethers, are dehalogenated in practically quantitative yields by chromium(II)-catalysed electrochemical reduction. The method can be used to prepare deoxy- from halogenodeoxy-nucleosides. The use of chlorotrimethyl-silane and sodium iodide in acetonitrile constitutes a new mild and simple method for the dehalogenation of a-halogeno-ketones in high yields. 2′,3′,5′-Tri-O-acetyl-6-bromotoyocamycin (2) is reductively debrominated in 60% yield by a mixture of N,O-bis(trimethylsilyl)acetamide (BSA), potassium fluoride, and dicyclohexyl-18-crown-6 in refluxing acetonitrile. Other brominated purine and purine-like nucleosides are debrominated in the same way.

It has been shown that the nature of the solvent can dramatically change the chemoselectivity of reduction by a complex metal hydride. Thus lithium aluminium hydride in diethyl ether rapidly and selectively reduces alkyl tosylates to the corresponding alkanes in the presence of alkyl iodides and bromides without concurrent attack on the halogen; in diglyme the selectivity is reversed.

Di-isobutylaluminium hydride is an effective reagent for removing tosyl groups from tetrahydrobenzo[b]thiophens and other thiophen-containing species which are sensitive to methods described previously.

Hydrodethallation of alkylthallium(III) compounds using N-benzyl-1,4-dihydronicotinamide (BNAH) gives high yields of alkanes via an unusual homolysis of the thallium-carbon bond. On irradiation with light, BNAH also allows aliphatic nitro-groups of compounds containing cyano-, carboalkoxy-, and keto-groups in the a -position to be replaced by hydrogen (e.g. Scheme 5). The reaction appears to proceed by an electron-transfer chain mechanism.

A radical-induced reductive deamination procedure, previously used on aminoglycosides, has been successfully applied to amino-acid esters (e.g. Scheme 6).

A number of new methods of reducing carbon–carbon multiple bonds to single bonds have been reported during the year. The following are of particular interest.

Olefins are hydroaluminated by tri-isobutylalane at or below room tem- perature under the catalytic influence of Cl2ZrCp2; protonolysis then furnishes the corresponding alkanes in almost quantitative yield (e.g. Scheme 7). The reaction tolerates certain functional groups (hydroxy, phenylthio, bromo) which can interfere with other hydroalumination procedures. In a closely related study it has been shown that the carbon-carbon double bond of allylic alcohols and ethers can be reduced via hydroalumination with lithium aluminium hydride and catalytic amounts of zirconium tetrachloride or Cl2ZrCp2. Deoxygenation is not a problem under these conditions. A related catalyst, Cl2TiCp2, permits the selective reduction of carbon-carbon multiple bonds by a variety of complex metal hydrides. Terminal olefinic and internal acetylenic bonds are reduced rapidly and in high yield to single and to Z-double bonds respectively, whereas terminal acetylenes and internal olefins are essentially inert. A mixture of vanadium trichloride and activated lithium hydride selctively reduces terminal olefins in the presence of internal olefins and both internal and terminal acetylenes, but carbonyl groups are also reduced.

Magnesium and methanol, a reducing system described as early as 1929, has now been shown to reduce the carbon–carbon double bond of α,β-unsaturated amides in the presence of other olefins (e.g. Scheme 8). The double bond may be mono-, di-, tri-, or tetra-substituted with alkyl or aryl groups, and nitrogen is also optionally substituted. Paquette and his co-workers have extended the use of the copper hydride reagent prepared from cuprous bromide, Vitride, and s-butanol in THF to the reduction of the double bond of α,β-unsaturated nitrites.

Benzeneselenol, already widely used to reduce a variety of functional groups, has now been shown to efficiently reduce the olefinic bond of many β-aryl-α,β-unsaturated carbonyl compounds under the influence of light. α,β-Unsaturated ketones are reduced to saturated ketones in high yield by a substantial excess of lithium in triethylamine when the reduction is carried out at –78°C in the presence of t-butanol as a proton source. The carbon–carbon double bonds of conjugated ene-1,4-diketones are selectively reduced by sodium iodide and hydrochloric acid in acetone; reaction times are short (one minute) and yields are quantitative. Butenedioic acids or their esters, or α,beta]-unsaturated monocarbonyl compounds, are not reduced. Doubly activated olefins of the type Ph2C=CXY, where X and Y are electron-withdrawing substituents, react in THF at –78°C with lithium amides having a hydrogen atom at the α-carbon (e.g. LDA) to give the corresponding diphenylethanes. Singly activated or non-activated olefins are not reduced under these conditions.

The recently characterized ruthenium complex (Ph3P)2(Ph2PC6H4) RuH2-K+·C10H8·(Et2O) in THF catalyses the hydrogenation of polynuclear aromatics, predominantly to their tetrahydroderivatives, at 100°C and 620 kPa gauge of hydrogen.

A Dutch research group has described elegant syntheses of the two enantiomers of the chiral alkane butylethylmethylpropylmethane with high and known optical purities. The chemistry involves a variety of masked alkyl groups which are ultimately reduced to n-alkyl chains. In line with theoretical predictions, the compounds show only weak optical activity due to the almost equal polarizability of different normal alkyl groups.

The three stereoisomers of 17,21-dimethylheptatriacontane (3), the sex recognition pheromone of the tsetse fly, have been synthesized in pure forms.

Hindered cuprates, conjectured to be of the type (4), which cannot be formed by normal methods, can be prepared from the bromomagnesium or lithium salts of tosylhydrazones of secondary or tertiary aldehydes by reaction with suitable mixtures of alkyl-lithiums and cuprous iodide. Alkylation of the cuprates furnishes high yields of branched alkanes (e.g. Scheme 9). Tosylhydrazones of primary or aromatic aldehydes give very low yields of hydrocarbons, or none at all.

A method for the preparation of alkanes in which alkylazodiphenylmethanols (5) decompose at 35 — 50°C to hydroalkylate olefins has now been examined in detail. The yields, which are only moderate, can be improved by the addition of a hydrogen-atom donor (e.g. phenol). Unsymmetrical olefins are hydroalkylated with the regiochemistry expected for a radical mechanism in which the alkyl radical adds first (Scheme 10).

Antimony pentafluoride, inserted into graphite to form the first stage insertion compound, is a mild and efficient solid superacid catalyst for the isomerization of alkanes to a thermodynamic equilibrium mixture at or below room temperature. Thus an equilibrium mixture of cyclohexane and methylcyclopentane (91:9) was obtained from either of the pure hydrocarbons, and cis-decalin isomerized almost completely to the trans-isomer.

A Russian research group has reported a novel synthesis of hydrocarbons with quaternary centres from olefins, esters, or tertiary hydrocarbons. In the presence of a Lewis acid, an alkyl group migrates from tetra-alkylsilanes, -germanes, or -stannanes to a tertiary carbenium ion generated from the substrate (e.g. Scheme 11). Reetz and his co-workers have also described new methods for the preparation of quaternary hydrocarbons. The key step is the replacement of a tertiary chlorine atom by a methyl group using MeTiCl3 or Me2TiCl2 (each readily prepared from dimethylzinc and titanium tetrachloride in suitable proportions), or using dimethylzinc with catalytic quantities of titanium tetrachloride. This enables, for example, geminal dialkylation of saturated ketones in high yield (e.g. Scheme 12).43 Under carefully controlled conditions the reaction tolerates carbon-carbon double bonds and ester functions.

Later the same group demonstrated that the use of dialkyl- or diaryl-zinc compounds in dichloromethane enables a tertiary chlorine atom to be replaced by groups other than methyl. For example, the reaction of trityl chloride with diphenylzinc constitutes the best current synthesis of tetraphenylmethane (54% isolated yield).

2 Olefinic Hydrocarbons

Intramolecular olefin metathesis has been used for the first time as the ring-closure step in syntheses of macrocyclic lactones (Scheme 13). A mixture of Cp2TiMe2 and WOCl4 or WCl6 is an effective catalytic system for the metathesis of olefins.47 Importantly, the system tolerates carboxylic esters, and this enabled it to be used to effect the key steps in syntheses of civetone and other macrolides. Unsaturated ketones or acetals are not suitable substrates.

The preparation of strained olefins continues to challenge the synthetic chemist. Although the synthesis of tetra-t-butylethylene remains an elusive goal, the related tetrakis(trimethylsilyl)ethylene has now been prepared and characterized.

Lenoir and his co-workers have published further syntheses of sterically crowded olefins. Many hindered ketones, 1-ethyladamantan-2-one (6) for example, can be reductively coupled by variations of the well known method involving low-valent titanium salts, but in cases of extreme hindrance [e.g. (7) and (8)] no coupling occurs and instead the ketone is reduced to the corresponding alcohol or is completely deoxygenated under the reaction conditions. The preparation of hindered olefins by the dehydration of di-t-butylalkylcarbinols is not straightforward, rearrangements taking place in many cases (Scheme 14).

Analytical quantities of highly strained cycloalkenes can be obtained by dehydrohalogenation of halogenocycloalkanes in the vapour phase over potassium-t-butoxide supported on silica; reaction times are in the order of one second (e.g. Scheme 15).

The strained tetrasubstituted olefin (9) has been synthesized; it yields no peroxidic products with singlet oxygen because the ene reaction is prevented by the Bredt’s rule effect, all the α-hydrogen atoms being at bridgeheads. Steric clash causes the olefinic bond of perchlorobi-9-ftuorenylidene (10) to be strongly twisted, but there is no evidence of any biradical character. An unusual bilaterally flanked olefin (11) has been prepared by a double Diels–Alder reaction between 7-methylenenorbornadiene and anthracene. The entombed olefinic bond fails to react with a variety of electrophilic reagents (D2SO4, Br2, O3, BH3·THF, Br2C:) because their normal geometric approach is blocked.

(Continues…)Excerpted from General and Synthetic Methods Volume 5 by G. Pattenden. Copyright © 1982 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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