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 9

A Review of the Literature Published in 1984

By G. Pattenden

The Royal Society of Chemistry

Copyright © 1987 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-904-9

Contents

Chapter 1 Saturated and Unsaturated Hydrocarbons By C.R.A. Godfrey, 1,
Chapter 2 Aldehydes and Ketones By S.C. Eyley, 71,
Chapter 3 Carboxylic Acids and Derivatives By D.W. Knight, 130,
Chapter 4 Alcohols, Halogeno-compounds, and Ethers By L.M. Harwood, 233,
Chapter 5 Amines, Nitriles, and Other Nitrogen-containing Functional Groups By S.G. Lister, 284,
Chapter 6 Organometallics in Synthesis, 398,
Chapter 7 Saturated Carbocyclic Ring Synthesis By T.V. Lee, 490,
Chapter 8 Saturated Heterocyclic Ring Synthesis By K. Cooper and P.J. Whittle, 536,
Chapter 9 Highlights in Total Synthesis of Natural Products By K.E.B. Parkes and G. Pattenden, 633,
Reviews on General and Synthetic Methods Compiled by G. Pattenden and G.M. Robertson, 679,
Author Index, 688,

CHAPTER 1

Saturated and Unsaturated Hydrocarbons

BY C. R. A. GODFREY

1 Saturated Hydrocarbons

A number of new methods for the preparation of alkanes via reductive removal of functional groups were reported during 1984. All-cis-[5.5.5.5]fenestrane (2), a hydrocarbon containing a four-co-ordinate carbon atom with planoid configuration, has been synthesized by Keese and Luyten. The final step in the synthesis involves an unusual reductive decarboxylation of the lactone (1) on heating to 310 °c under hydrogen in the presence of excess palladium on carbon (Scheme 1). The radical chain decarboxylation of N-hydroxypyridine-2-thione esters reported previously has now been applied to N-protected α-amino-acids and peptides. Under the mild reaction conditions developed for this transformation, indolic, hydroxylic, and phenolic side-chain functions do not require protection (Scheme 2). Furthermore, removal of side-chain carboxy-groups of glutamic and aspartic acid residues appears to be less facile than the α-amino-acid decarboxylation.

Guttierrez and Summerhays have reported on the use of tri-n-butyltin hydride for the selective cleavage of unsymmetrical dialkyl sulphides to the corresponding alkanes and tri-n-butylstannyl alkyl sulphide. A mild, selective procedure for the reductive deselenization of selenides with nickel boride has also been described by Back. The reagent, which is readily prepared by treatment of nickel chloride hexahydrate with sodium borohydride, selectively reduces vinyl and alkyl selenides to the corresponding hydrocarbons, even in the presence of alkenes and sulphides (Scheme 3).

An improved method for the deoxygenation of tertiary alcohols based on the radical chemistry of thiohydroxamic O-esters has been developed by Barton and Crich (Scheme 4). The itermediate mixed oxalate ester (3), formed in situ, undergoes smooth decomposition at 80 °C in the presence of an excess of t-butyl thiol and traces of base to afford the deoxygenated product (4) in 90% yield. The key step in the novel 1-6 oxygen transposition sequence illustrated in Scheme 5 is the selective reduction of the cyclic carbonate (7) to the alcohol (8) using NaBH3CN-[Pd(PPh3)4]-THF. Attempted reduction (LiAlH4-AlCl3) of the intermediate hydroxy-ketone (5) directly to the homoallylic alcohol (8) fails, giving instead the cis-diol (6) with high selectivity.

Khalifa and Rieker have shown that the 3,5-di-t-butyl-1-phenyl-4-oxo-cyclohexa-2, 5-dienyl N-protecting group can be removed electrochemically. Under the reaction conditions, the N-benzyloxycarbonyl group is stable. ortho-Selective dehalogenation of halogenobenzoic acids can be effected with bis(pentafluorophenyl) ytterbium in THF at -78 °C. The reagent is prepared in situ from bis(pentafluorophenyl) mercury and elemental ytterbium. Iida and his co-workers have reported that the use of acetic acid as solvent, both for the preparation and reductive cleavage of steroidal ketone tosylhydrazones, significantly improves yields and reduces unwanted side reactions.

Several examples of asymmetric hydrogenation have appeared during the year. Evans and Morissey have observed dramatic hydroxyl-directed stereochemical control of high-pressure (640 p.s.i.) hydrogenation in both cyclic and acyclic systems when the cationic rhodium complex [Rh(NBD)(DIPHOS-4)]BF4 is used as catalyst. As the examples in Scheme 6 show, excellent selectivity can be achieved even in extremely hindered cases such as in the reduction of the allylic alcohol (9). Homogeneous catalytic hydrogenation of the 3-methylenecyclohexanol (10) in the presence of the complex (11) is highly stereoselective, giving predominantly trans-3-methylcyclohexanol. Reduction of 2-methylenecyclohexanol and 2-methlenecyclohexanemethanol, however, under the same conditions, exhibits poor selectivity. Imamoto and his co-workers have successfully reduced a wide range of unsaturated substrates, including alkynes and alkenes, using the intermetallic hydride LaNi5H6 under nitrogen at atmospheric pressure. The hydride is readily prepared by hydrogenation of LiNi5, which unlike many conventional hydrogenation catalysts is unaffected by substrates containing an amino-group, halogen atom, or thiophene ring. Sodium hypophosphite in the presence of palladium on charcoal has also been examined as a convenient alternative to catalytic low-pressure hydrogenation.

Finally, Baldwin et al. have introduced the use of trityl- and diphenyl-4-pyridylmethyl hydrazones (12) for reductive C-C bond formation from aldehydes and ketones (Scheme 7). Thus, hemolytic decomposition of the intermediate azo-compounds (13) and (14) in the presence of a suitable radical trap, such as ethanethiol, leads to the smooth formation of the corresponding alkanes. Furthermore, on treatment with phosphorus trichloride, the ad ducts (14) are converted into unsymmetrical tri- and tetra-substituted alkenes in moderate yield (24-60%).

2 Olefinic Hydrocarbons

Molecules containing highly strained olefinic bonds continue to be of great theoretical interest. Lenoir and his co-workers, for example, have studied the conformational behaviour of (E)-3, 4-diethyl-2,2,5,5-tetramethylhex-3-ene (15), available in good yield by reductive dimerization of t-butyl ethyl ketone using known methodology (Scheme 8). In an extension of earlier work , Tobe’s research group has synthesized a series of bicyclo[n.2.1] bridgehead alkenes of type (16; n=4-6) substituted at the opposite bridgehead position with an acetxy-group. Interestingly, vapour-phase pyrolysis of the alkene (16; n=6) at 400 °c leads via elimination of acetic acid to the novel bicyclo [6.2.1] bridgehead diene (17) in 50% yield. Filipino

The use of low-valent titanium and tungsten for the formation of carbon-carbon bonds is now well established. However, the outcome of the reaction is often unpredictable, depending largely on which method is used for the preparation of the reagent. Reduced tungsten species effective in the reductive dimerization of aromatic carbonyl compounds have now been generated by controlled electroreduction of WCl6 at a platinum electrode. Aliphatic substrates, however, give disappointing results.

General methods for the asymmetric olefination of carbonyl compounds have been scarce in the literature until very recently. Now Hanessian and co-workers have developed the use of chiral bicyclic phosphanamides such as (18) and (19) for this purpose. On deprotonation, these reagents react in a highly diastereofacial manner with substituted cyclohexanones to produce optically enriched (alkylcyclohexylidene)ethanes. Some representative examples of this important development are illustrated in Scheme 9. Mild conditions for the Horner-Wadsworth-Emmons reaction have been described which are applicable to both base-sensitive aldehydes and phosphonates. The successful olefination of aldehyde (20) with the easily epimerizable phosphonate (21) is particularly noteworthy since standard conditions (sodium hydride or potassium t-butoxide) lead predominantly to self-condensation of the aldehyde (Scheme 10).

Methylenation of acidic ketones can be effected under mild conditions using the organotitanium reagents (22) and (23). Yields are generally high even with ketones such as (24) and (25) which normally respond badly to conventional methods. α, α-Disubstituted ketones, however, are converted under these conditions into the corresponding titanium enolates, presumably for steric reasons. Hernandez and Larsen have further extend ed their earlier work on the chemistry of α-silyl esters to include the synthesis of both tri- and tetra-substituted oefins (Scheme 11). Although operationally simple , the reaction appears to be quite sensitive to steric factors and is therefore of limited scope.

Several conceptually similar methods for the construction of olefins based on the chemistry of acyl sulphones have been published. Hendrickson and co-workers, for example, have exploited the use of the reagent (26) which is readily prepared by acylation of the anion of dimethyl sulphone (Scheme 12). Although the sequential alkylation of this compound proceeds with complete regiocontrol, the stereoselectivity is poor, and as a consequence mixtures of isomeric products are obtained. The decomposition of appropriately substituted phenylaziridine hydrazones at 140-160 °c leads to the formation of trisubstituted olefins in good yield. The reaction works well even for sterically hindered substrates such as (27 ), thus allowing transformations not possible using Shapiro or Bamford-Stevens methodology (Scheme 13).

The conversion of a carboxylic acid into the corresponding nor-olefin is possible via photolysis of the derived α-diazomethyl ketone in the presence of imidazole (Scheme 14). This procedure has now been applied with some success to the degradation of bile acid side-chains.

The direct deoxygenation of epoxides to alkenes remains a synthetically important transformation. Martin and Ganem have suggested that the development of mild methods compatible with complex functionalized systems might lead to the use of the epoxide blocking group. To this end , they have shown that rhodium(II) carboxylate salts catalyse the deoxygenation of epoxides by dimethyl diazomalonate (Scheme 15). The reaction proceeds smoothly under mild, neutral conditions without either alkene isomerization or cyclopropanation, but, with certain aldehydes, competing carbonyl insertion is observed. Recent results suggest that the previously reported conversion of epoxides into iodohydrins on treatment with the triphenylphosphine-iodine complex is in fact sensitive to the degree of substitution of the epoxide ring. Indeed, in the case of a variety of trisubstituted steroidal epoxides, deoxygenation to the corresponding olefin takes place preferentially and in high yield (Scheme 16).

A mild synthesis of olefins from vicinal diols, applicable to the field of ribonucleotides, has been described by Robins et al. The reagent [(C5H5)2TiCl2] is an effective catalyst in the stereoselective reduction of vicinal dibromides with zinc in THF. The actual reducing species are thought to be [(C5H5)2TiCl]2 and [(C5H5)2TiCl]2ZnCl2.

The stereospecific syntheses of both the major and minor sex pheromones (28) and (29) of the Douglas fir tussock moth (Orgyia pseudotsugata), carried out by Itoh and co-workers, illustrate the potential of the silicon-directed Beckmann fragmentation for stereocontrolled olefin synthesis (Scheme 17). γ-Stannyl alcohols also undergo selective fragmentation on reaction with lead tetra-acetate in refluxing benzene to afford excellent yields of either (E)- or (Z)-keto-olefins according to the stereochemistry of the staring mat rials. Noteworthy examples illustrating this point are outlined in Scheme 18. Similar 1,4-fragmentation has also been observed on treatment of γ-stannyl alcohols with iodosylbenzene, boron trifluoride etherate, and DCC.

A new catalyst for the (Z)-selective semihydrogenation of alkynes has been developed by Brunet and Caubere. Disubstituted acetylenes undergo palladium-catalysed coupling with aryl iodides in the presence of both formic acid and a tertiary amine to afford trisubstituted olefins in high yield (Scheme 19). Regio-selectivity for unsymmetrically substituted substrates, however, is poor and mixtures of olefinic products are obtained.

General methods for the deoxygenation of carbonyl compounds to olefins are clearly important in synthesis. A versatile two-step conversion reported this year involves the palladium-catalysed reduction of enol triflates using trialkylammonium formate. Although the reduction step is quite efficient, overall yields are often depenent on the efficiency of the initial formation of the triflate, as demonstrated in Scheme 20. The controlled generation and cyclization of vinyl-lithium species containing primary chloride groups has been used as a means of preparing a variety of alkylidene-cycloalkanes (Scheme 21). The high regioselectivity observed in these sequences for the Shapiro reaction is well precedented.

(1,2-Dialkoxyethylene)iron complexes of type (30) function as specific cis- or trans-vinylene dication equivalents on reaction with a wide range of carbon nucleophiles, including cuprates, enolates, and Grignard reagents (Scheme 22).

As part of a programme d irected towards the synthesis of a toxic alkaloid isolated from the poison dart frog, Ibuka and co-workers have studied the decarboxylative reduction of γ-carbamoyloxy-α, β-unsaturated esters with lithium dialkylcuprates. Application of this methodology to the cyclic carbamate (31) led to the formation of the (E)-alkene (32) which has been previously transformed into (±)-perhydrogephyrotoxin (Scheme 23).

Variants of the Claisen [3,3] sigmatropic rearrangement, in particular Ireland’s modification, continue to play a central role in strategies aimed at the stereocontrolled synthesis of complex molecules. A number of new applications and modifications are worth noting. Reports on 1,4-chirality transfer via Claisen rearrangement of (S)-but-1-en-3-yl propanoate, palladium(II) catalysis, and the chelation-controlled rearrangement of certain allylic glycolate esters have been published. Additionally, the research groups of Kurth and Fujisawa have both carried out independent studies on the [3,3] sigmatropic rearrangement of β-hydroxy-ester dianions and their derived silyl ketene acetals. An excellent example of the application of this reaction in natural product synthesis is provided by Paquette’s synthesis of precapnelladiene (Scheme 24).

Similarly, Knight and his co-workers have developed a stereo-specific route based on this methodology to the perhydroazulenes (33) and (34), potential precursors of the dictyol family of marine natural products. A prerequisite for chiral synthesis via the Claisen rearrangement is that the allylic system be derived from an enantiomerically pure secondary or tertiary alcohol, since primary allylic alcohols can lead only to racemic diastereomeric products. Ireland and Varney have explored the concept of a chiral primary alcohol equivalent, focussing their initial attentions on the propionates derived from the optically active (S)-α-silyl crotyl alcohol (35) and its enantiomer (Scheme 25). Rearrangement occurs successfully with high selectivity to give either of the two products (36) or (37) depending on the reaction conditions, Subsequent modification and removal of the silicon groups via protiodesilylation affords the corresponding monosubstituted olefins (38) and (39), thus completing the process.

Highly substituted allyl vinyl ethers such as (40) unexpectedly undergo both thermal (135 °C) and anionic versions of the Claisen rearrangement with the formation of products containing vicinal quaternary centres (Scheme 26). Wilson and Price have discovered that dianions derived from allylic acetoacetates readily und ergo the related ester enolate Carrol rearrangement at temperatures below 65 °C. In contrast to the corresponding thermal rearrangement, products of [3,3] rearrangement are formed exclusively. Subsequent heating at 77 °C results in decarboxylation (Scheme 27).

Methods for the highly regio- and stereo-selective formation of enolates and their derivatives are important targets in organic synthesis which continue to attract attention. A widely used two-step procedure for the selective formation of kinetically generated silyl enol ethers involves the slow addition of carbonyl compounds to lithium di-isopropylamide (LDA) at -78 °C in THF followed by silylation. Corey and Gross have now shown that when deprotonation is carried out with LDA at -78 °C in the presence of trimethylsilyl chloride, regioselectivity is markedly improved (Scheme 28). The use of the more hindered base lithium t-octyl-t-butylamide (LOBA) is even more effective, and in addition gives excellent control of enolate stereochemistry. A reversal of selectivity (Scheme 29) is observed in the presence of HMPA, however, a result closely paralleled by the work of Turner et al. on the preparation of t-butyldimethylsilyl enol ethers. The use of triethylsilyl perchlorate-Hunig’s base for the synthesis of (Z)-O-silyl ketene acetals works well even in the case of isopropyl α-bromoacetate, a compound which has resisted previously reported methods.

(Continues…)Excerpted from General and Synthetic Methods Volume 9 by G. Pattenden. Copyright © 1987 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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