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 12

A Review of the Literature Published in 1987

By G. Pattenden

The Royal Society of Chemistry

Copyright © 1990 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-934-6

Contents

Chapter 1 Saturated and Unsaturated Hydrocarbons By By N. Simpkins, 1,
Chapter 2 Aldehydes and Ketones By K.E.B. Parkes, 37,
Chapter 3 Carboxylic Acids and Derivatives By D.W Knight, 91,
Chapter 4 Alcohols, Halogeno-compounds, and Ethers By C.J. Urch, 203,
Chapter 5 Amines, Nitriles, and Other Nitrogen-containing Functional Groups By G.M. Robertson, 249,
Chapter 6 Organometallics in Synthesis By T.N. Danks, S.E. Thomas, and T Gallagher, 293,
Chapter 7 Saturated Carbocyclic Ring Synthesis By T.V. Lee, 407,
Chapter 8 Saturated Heterocyclic Ring Synthesis By K. Cooper and P.J. Whittle, 423,
Chapter 9 Highlights in Total Synthesis of Natural Products By C.W. Ellwood, D.C. Harrowven, and G. Pattenden, 486,
Reviews on General and Synthetic Methods Compiled by K. Carr, D.J. Coveney, and G. Pattenden, 518,
Author Index, 527,

CHAPTER 1

Saturated and Unsaturated Hydrocarbons

BY N. SIMPKINS

A number of cyclic and bicyclic hydrocarbons can be formed by cyclisation of suitable unsaturated alkyllithiums (Scheme 1). The in situ formation of the initial alkyllithium is carried out at -78°C using tBuLi. Quenching at low temperature provides simple non-cyclised products, whereas warming to room temperature (and in some cases addition of TMEDA) effects cyclisation. Benzylic alcohols are reduced to the corresponding hydrocarbons by means of the familiar Me3SiCl – NaI combination in CH3CN. The method gives very good yields, and tolerates other functionality. The combination of Mo(CO)6 and phenylsilane comprises a powerful reagent for conjugate reduction of Michael acceptors, including ketones, esters and amides, usually in near-quantitative yield.

Hydrogenation of organic compounds can be carried out effectively using soluble polyethylene-bound Wilkinson’s catalyst, and using a new biphasic reduction system. Electrocatalytic hydrogenation, using specially prepared cathodes, is also an effective method for reducing carbon-carbon double bonds. Other functionality can also be reduced by the system, such as aromatic aldehydes and nitro compounds.

2 Olefinic Hydrocarbons

Deoxygenation of epoxides to the corresponding olef ins can be effected by treatment with SmI2. The reaction requires the use of HMPA and/or other additives for high yields in reasonable reaction times, especially for non-terminal epoxides. A report has detailed the use of titanium on graphite as a highly effective reagent for McMurry coupling of carbonyl compounds to give alkenes.

Methylenation of enolisable carbonyl substrates is a common problem in synthesis, due to the basicity of the reagents employed. The combination of CeCl3 with the Peterson reagent Me3SiCH2Li offers one solution to this problem (Scheme 2). The combined Li/Ce reagent proved superior to Li reagents, Mg reagents or combined Mg/Ce reagents in all cases.

An interesting study of the elimination of stabilised phosphorus ylide adducts brings into question the reversibility of the addition step as an explanation for (E)-olefin selectivity in such Wittig reactions. A variety of α-ydroxy ketones undergo accelerated Wittig reactions with stabilised phosphoranes to give trisubstituted alkenes with good (E)-selectivity, e.g. Scheme 3.

As indicated in Scheme 4, the boron-Wittig reaction of aromatic aldehydes can be effected to give either (E) or (Z) products. The initial erythro boron adduct with the aldehyde is thought to undergo selective syn (TFAA), or anti (HF) elimination, to account for the overall stereoselectivity.

Palladium catalysed cross-coupling reactions provide a powerful means of synthesising alkenes, as indicated by the examples in Scheme 5. Thus, the use of manganese compounds adds to the ranks of coupling partners which can be used for enol phosphonates or triflates. Trisubstituted systems, e.g. (2), are available by coupling of vinylalanes such as (1), which are themsel ves readily available from acetylenes. 14 The formation of the substituted vinyl silane (3) contrasts with previous palladium-catalysed couplings of CH2 CHSiMe3 with aryl iodides, in which aryl-desilylated products were obtained. The N-nitroso-N-arylacetamide acts as a source of ArPdOAc. More ambitious processes along the same lines allow sequential introduction of two groups. Thus, both 1,1- and 1,2-disubstituted ethenes can be prepared, as indicated in Scheme 6. Both methods are one-pot procedures and have the advantage of using readily available starting materials.

Piers has further extended the chemistry of bis-stannylesters such as (4). A series of metallation-alkylation reactions allowed these compounds to be efficiently converted into differential ly tetra substituted alkenes (Scheme 7; see also Scheme 54). The sequence is highly stereoselective, either isomer of (4) giving the same product in the first step. Surprisingly, direct metallation of (5), as a protected derivative, was not efficient, hence the need to convert to the corresponding iodide. What amounts to an intramolecular version of this chemistry has been used by Negishi et al. in another solution to the exocyclic alkene problem, e.g. Scheme 8.

The use of a new alkylidenation reagent derived from a 1,1-dibromoalkane, zinc and TiCl4 allows conversion of esters and lactones to the corresponding vinyl ethers(Scheme 9). Both chemical yields, and Z/E selectivity are, on the whole, very good, and the method looks operationally quite simple. Vinyl ethers derived from lactones suffered partial hydrolysis to hydroxyketones as indicated in the Scheme; some isomerisation of a cis double bond incorporated into one starting substrate was also observed. A study of the Heck arylation of vinyl ethers describes factors responsible for regiocontrol in the reaction. Vinylic chlorides are available from alkenes by reaction with PhSeCl3, followed by hydrolytic selenoxide elimination (Scheme 10). In many examples regiochemical problems arise, the most useful application of the method being the preparation of 2-chloro-1-alkenes (7) by oxidation of the selenide (6) to the dichloroselenide using SO2Cl2, followed by elimination. The reaction of 1,1-dichloro-l-alkenes with Grignard or organozinc reagents in the presence of [PdCl2 (dppb)] allows replacement of just one chlorine group with high stereoselectivity, e.g. Scheme 11. In each case a new group is introduced trans to the existing substituent, to give the vinyl chloride in good yield. By changing the catalyst to [PdCl2(PPh3)2] the second chlorine could also be substituted, resulting in a very elegant route to trisubstituted alkenes.

Vinyl sulphides and selenides have been prepared by free radical addition to suitable unsaturated starting materials(Scheme 12). The addition of PhSeH to allenes was found to require the presence of oxygen, and presumably takes place via attack of PhSe at the central carbon atom. The use of Et3B allows addition of thiols to acetylenes, although with very poor stereoselectivity. Analogous reactions of acetylenes with Ph3GeH, and with R3SnH, have been reported by the same group of workers.

A variety of vinyl sulphoximines can be prepared by a simple two-step sequence involving dehydration of β-hydroxyalkyl sulphoximines (Scheme 13). Alternative dehydration conditions could also be used to furnish the corresponding N-formyl or N-acetyl derivatives. Optically pure (E) – or (Z) – vinyl sulphoxides can be obtained straightforwardly from the corresponding chiral acetylenic sulphoxide. Back et al. have described further details of the reactions of β-(phenylseleno)vinyl sulphones leading to substituted vinyl sulphones. Stereoselective access to either (E) or (Z)-vinyl sulphones can be achieved via iodosulphonisation of alkenes or acetylenes respectively (Scheme 14). Thus Cope elimination of (8) gives the (E)-product, as does a related selenoxide syn-elimination. The corresponding (Z)-isomer is obtained using a very high-yielding hydrogenolysis reaction. Additional chemistry concerning isomerisation of these vinyl sulphones to allyl sulphones is also described in the same report.

A detailed paper describes the preparation and reactions of alkenes having vicinal silyl and stannyl substituents. Two new methods for the preparation of vinyl silanes are illustrated in Scheme 15. The direct silylation of vinyl iodides such as (9) using the Me3SiSiMe3/TASF/Pdo system gives good yields, and also works, although less efficiently, with aryl iodides. The reaction also tolerates ester and nitrile functional groups. The other procedure produces (E)-vinylsilanes exclusively, presumably via gem dichromium species.

Methods for the incorporation of single fluorine atoms or of perfluorinated alkyl groups into unsaturated systems continue to be of interest. Three recent examples of this type of chemistry are shown in Scheme 16. The production of (10) in 63% yield illustrates the efficiency and flexibility of the first process, in which the four substituents ending up on the alkene each come from different fragments. The phosphonate (11) is cleanly produced in stereoselective fashion by cuprate-induced reduction of the corresponding enol derivative (12). Lastly, Scheme 16 indicates how α-fluorothioethers can be oxidised to the corresponding sulphoxides, and pyrolysed to give simple vinyl fluorides.

The electrochemical oxidation of ethyl silanes has now been extended to silyl dienes. The major products are oxygenated, unsaturated acetals resulting from 1,4-oxidation( Scheme 17).

Allylic azides are produced in good yield by reaction of the corresponding allyl silanes with a cocktail of iodosylbenzene, Me3SiN3 and BF3.OEt2. Unsaturated nitriles are amongst the products available using a new hydrocyanation procedure( Scheme 18). The method has the prime advantage of using isocyanides (trimethylsilylcyanide is in equilibrium in solution with the isocyanide) in place of HCN, which has obvious attractions.

Several new methods for the synthesis of allylsilanes have appeared this year, along with improvements and modifications of previous methods. Scheme 19 highlights some of these developments.

Two research groups have described the advantages of using CeCl3 in combination with Me3SiCH2M (M = Li or Mg) for reaction with acid derivatives (13) (X = OR or Cl). Whilst reagents derived from CeCl3 and Me3SiCH2Li work very well with acid chlorides, better results are obtained with esters by using the CeCl3/Me3SiCH2MgCl combination. 42 The versatile species (15) is produced by electrophile-initiated migration of an alkyl group from boron to carbon. Subsequent protonolysis gives the allylsilane, whereas H2O2/NaOH work-up gives a β-silylketone. A rather more laborious route to simple allylsilanes uses the unusual synthon (16). Combination of (16) with a Grignard gives (17) which on treatment with methanesulphonyl chloride undergoes Reich-type elimination to give the final product. No alternative elimination (to give allyl selenides) is observed, and the products are obtained solely as (E)-isomers.

Two new methods for the synthesis of allyl stannanes both rely on the introduction of tin into a preformed allylic functional group (Scheme 20). In both methods the tin group ends up at the least substituted end of the allylic system, with mixtures of stereoisomers resulting where possible. Allylic sulphides also act as electrophilic partners in a new Mo(CO)6 – mediated reaction with certain carbon nucleophiles such as malonate or enolates of β-ketoesters (Scheme 21). In addition to substitution, reductive desulfenylation was also observed in some cases. Similar allylic substitution using soft carbon nucleophiles is possible using novel π-allyl palladium complexes incorporating a phosphonate group (Scheme 22). Since the starting materials e.g. (18) are easily available from α,β-unsaturated aldehydes the method offers a useful entry into functionalised phosphonates. Alternatively, amino-substituted phosphonates can also be prepared by substituting a secondary amine for the carbon nucleophile.

Simple homoallylic alcohols are available by coupling of allylic halides with aldehydes using a BiCl3-metallic aluminium combination in aqueous THF. The scope and limitations of the Wenkert coupling of substituted dihydrofurans with Grignard reagents using nickel catalysis have been examined. Providing care is taken on work-up the reaction provides excellent stereoselective access to a variety of homoallylic alcohols (Scheme 23). The reaction gives by-products due to competing reduction, i.e. (19), with Grignard reagents bearing β-hydrogens. Homoallylic fluorides are formed on treating cyclopropylmethanols with a specially modified HF-pyridine reagent. The reaction of allylstannanes with in situ generated immonium salts provides a high-yielding route to various homoallylic amines (Scheme 24). The outcome of this reaction using allylstannanes contrasts to earlier results using allylsilane, in which cyclisation to form N-substituted piperidines occurred.

A novel two-carbon homologation reaction converts amides into enaminones (vinylogous amides) by reaction with lithium triphenylacetylide (Scheme 25). The use of other silyl acetylides (e.g. tBuMe2SiC [equivalent to] CLi) gave only the expected, “normal” product, i.e. the silylylated acetylenic ketone. A simple stereoselective preparation of (Z)-α-fluoro-α,β-unsaturated esters involves reaction of aldehydes with methyl dichlorofluoroacetate (20) using zinc powder (Scheme 26). The starting ester (20) was itself prepared from methyl trichloroacetate by the action of antimony (III) fluoride and bromine. Finally, a full report has appeared describing the palladinum-catalysed decarboxylation-allylation reaction of allylic esters of various a-ketocarboxylic (and other) acids.

3 Conjugated and Non-conjugated Dienes

Two new reports further demonstrate the usefulness of the Peterson olefination in the synthesis of 1,3 dienes (Scheme 27). Although both syntheses involve a series of at least four steps, they each solve problems of regio- and/or stereo-chemistry, and are reasonably efficient.

A number of THP-protected dienyl alcohols were found to undergo smooth nucleophilic substitution reactions with allyllithiums to give conjugated (E,E)-dienes(Scheme 28). Other nucleophiles such as R2NLi, R3SiLi and R3SnLi also effect substitution, although a lower degree of stereoselectivity was obtained in some cases. Another route to variously substituted dienes involves the Ireland Claisen ester enolate rearrangement of propargyl esters, followed by decarboxylation(Scheme 29). Temperatures for the decarboxylation range from 140°C-250°C, and some limitations to the combinations of ester and alkynyl groups useful in the process were noted. α-Lithiation of alkoxy-substituted dienes is possible using sec-butyllithium in THF, as evidenced by quenching with Me3SiCl.

Two unusual, chiral alkoxy dienes can be obtained from a protected arabinose by a Wittig-elimination sequence, e.g. Scheme 30. The diene (21) was shown to undergo Diels-Alder reaction with N-phenylmaleimide. The diene (22) was highlighted previously in connection with Diels-Alder reactions. Further studies now show that the corresponding ammonium salts, e.g. (23), undergo reaction with Grignard reagents to give substituted isoprenylsilanes (Scheme 31). Yields are quite good providing an excess of Grignard (2-8 eq.) is used, the use of Li2CuCl4 as catalyst being preferable to several other cuprous salts tried.

Another process which uses the migration of a group from boron to carbon allows the synthesis of alkyl- and alkylthio-substituted 1,3-dienes(Scheme 32). Two interesting steps occur in the reaction, the first involving migration of an SBu (or secondary alkyl) group as shown, the second being elimination of the β-chloroborane using MeLi. The paper includes some interesting results concerning the relative migratory aptitude of various groups in the first step.

Two methods for the preparation of 1,3-dienes substituted with an SePh group are outlined in Scheme 33. The Wittig preparation using (24) proved troublesome, largely due to the instability of (24). An alternative scheme was also investigated by incorporating the SePh group into the aldehyde rather than the phosphorane. The use of the Grignard (25) allowed efficient preparation of either tin or selenium derivatives, which were then examined as partners for Diels-Alder reactions Another stannyl diene synthesis involves introduction of the tin group by free radical hydrostannylation of an acetylene, followed by a 1,4-elimination to give the product(Scheme 34). Yields overall are moderate, with (Z)-isomers predominating in the final mixture.

(Continues…)Excerpted from General and Synthetic Methods Volume 12 by G. Pattenden. Copyright © 1990 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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