Non-enolizable aldehydes

Non-enolizable aldehydes are transformed into N-trimethylsilylaldimines on treatment with lithium hexamethyldisilazide (22) such imines provide valuable routes to N-unsubstituted / -lactams ... 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

The A-trimethylsilylimines 68 (R = t-Bu, Ph, 2-MeCgH4 or 2-BrC6H4), which are prepared by the reaction of non-enolizable aldehydes with lithium bis(trimethylsilyl)amide, followed by trimethylsilyl chloride, undergo pinacolic coupling induced by NbCLt 2THF to yield the vicinal diamines 69 as mixtures of dl- and meso-isomers, in which the former predominate. Another method for the preparation of 1,2-diamines is by the combined action of the niobium tetrachloride/tetrahydrofuran complex and tributyltin hydride on cyanides RCN (R = /-Hu. Ph, cyclopentyl or pcnt-4-en-l-yl) (equation 32)82. 

Carbanions, generated by the reaction of benzylsilanes with tetra-n-butylammo-nium fluoride react with non-enolizable aldehydes to produce the alcohol [67], When a stoichiometric amount of the ammonium fluoride is used, the methylarene corresponding to the benzylsilane is frequently a by-product and arises from formation of the hydrogen difluoride salt during the reaction. When only catalytic amounts of the ammonium fluoride initiate the reaction, the formation of the methylarene is suppressed. In a similar type of reaction (although the mechanism is not known) between aldehydes and ketones, allyl bromide, and tin in the presence of trimethylsilyl chloride the yield of the but-l-en-4-ol is raised significantly by the addition of tetra-n-butylammonium bromide, particularly in the reactions with... 

Finally, addition of the carbanions derived from 83 to non-enolizable aldehydes is a facile process. Aryl and tertiary alkyl aldehydes gave trimethylsilyl allyl ethers 85 by a [1,4]-Brook isomerization (equation 30). The stereochemistry of the intermediate alkoxides 84 dramatically influences the reaction conditions required . 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

This redox disproportionation of non-enolizable aldehydes to carboxylic acids and alcohols is conducted in concentrated base. 

The carbonyl skeleton of lily aldehyde can be assembled by a mixed aldol condensation between propanal and the non-enolizable aldehyde, 4-tert-butylbenzaldehyde ... 

Gas-phase transfers of hydride from methoxide to C02, CS2 and S02 have been observed by the flowing afterglow technique (Bierbaum et al., 1984) and by Fourier transform ion cyclotron resonance spectroscopy (FT-ICR) (Sheldon et al., 1985). With aldehydes and ketones, the normal gas-phase reaction with methoxide is enolate formation, but FT-ICR methods have been used to demonstrate reduction of non-enolizable aldehydes including benzaldehyde, pivalaldehyde, and 1-adamantylaldehyde. 

The carbanions derived from (2-(benzotriazol-l-yl)-2-substituted-ethyl)trimethylsilanes having an acidic /J-proton 242 reacted with non-enolizable aldehydes to afford the corresponding (l-arylalkenyl)siloxymethanes 243 via the 1,4-silyl migration with the elimination of benztriazol-l-yl group (equation 154)385,386. Compounds 242 serve as the synthetic equivalents of a-X-substituted alkenyllithiums. 

Enols or enolates from anhydrides are not used very often in aldol reactions other than in one important application, usually known as the Perkin reaction. An acid anhydride, such as acetic anhydride, is combined with a non-enolizable aldehyde and a weak base, usually the salt of the acid. This base is used so that nucleophilic attack on the anhydride does no hami, simply regenerating the anhydride. q... 

The Cannizzaro reactionof non-enolizable aldehydes is another example of a hydride transfer reaction. It is carried out under alkaline conditions and involves not only the addition of a hydroxide ion to one aldehyde but the stabilization of the resultant acid as the anion (Scheme 3.41). Methanal (formaldehyde), which gives methanoic acid (formic acid), a relatively strong carboxylic acid, makes a good hydrogen donor in a cross-Cannizzaro reaction. 

A useful variation of this reaction involves lithium enolates derived from esters. - They react with imines derived from non-enolizable aldehydes to form -lactams (equations 44 and 45). ... 

Recently, Sisko and Weinreb have developed a new, in situ procedure for effecting A -sulfonyl imine Diels-Alder reactions. The method consists of treating an aldehyde with an A -sulfinyl sulfon-amide/boron trifluoride etherate in the presence of a diene (Scheme 3). Under these conditions the IV-sul-finyl sulfonamide reacts with the aldehyde to produce an /V-sulfonyl imine. This reaction, developed by Kresze, has been used previously for preparing imines from simple, non-enolizable aldehydes (c/. 1,2), but had not been applied to more complex aldehydes. As can be seen from the scheme, the cycload-... 

Upon treating certain (but not all) aromatic aldehydes or glyoxals (a-keto aldehydes) with cyanide ion (CN ), benzoins (a-hydroxy-ketones or acyloins) are produced in a reaction called the benzoin condensation. The reverse process is called the retro-benzoin condensation, and it is frequently used for the preparation of ketones. The condensation involves the addition of one molecule of aldehyde to the C=0 group of another. One of the aldehydes serves as the donor and the other serves as the acceptor. Some aldehydes can only be donors (e.g. p-dimethylaminobenzaldehyde) or acceptors, so they are not able to self-condense, while other aldehydes (benzaldehyde) can perform both functions and are capable of self-condensation. Certain thiazolium salts can also catalyze the reaction in the presence of a mild base. This version of the benzoin condensation is more synthetically useful than the original procedure because it works with enolizable and non-enolizable aldehydes and asymmetric catalysts may be used. Aliphatic aldehydes can also be used and mixtures of aliphatic and aromatic aldehydes give mixed benzoins. Recently, it was also shown that thiazolium-ion based organic ionic liquids (Oils) promote the benzoin condensation in the presence of small amounts of triethylamine. The stereoselective synthesis of benzoins has been achieved using chiral thiazolium salts as catalysts. 

Me3C H 2so 1 n + C02 — 1 0 Non-enolizable aldehydes react with silylated ketene acetals by thermal ... 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

The foregoing discussion has focused upon condensations of non-enolizable aldehydes and ketones to afford green processes and products. That approach was extended to include a one step multicomponent preparation of N-mono-substituted or N,N-disubstituted aniline derivatives (Scheme 6.2). The... 

More recently, Georg et al. [23] have found that N -trimethylsilyl imines 11 of aromatic non-enolizable aldehydes and ketones, prepared by the methodology of Hart [24], can be converted to the corresponding IST-sulfonyl imines using aryl or alkyl sulfonyl chlorides (Scheme 5). Unfortunately, the procedure is not applicable to forming N-sulfonyl imines from enolizable aldehydes and ketones. 

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