Cyanide, reaction with aldehydes

In 1987 Kunz [32] reported the use of 2,3,4,6-tetra-0-pivaloyl-/ -D-galactopyrano-sylamine 27 as chiral auxiliary in the preparation of a-aminoacid derivatives via the Strecker reaction with aldehydes and trimethylsilyl cyanide. One year later he reported [33, 34] the use of the same chiral auxiliary in the Ugi reaction, where trimethylsilyl cyanide was replaced by an isocyamde and a carboxylic acid (Scheme 1.12). 

In contrast, a similar reaction with aldehydes at lower temperatures (-78 °C) might not involve such a preformahon of the aluminum cyanide [90]. The reaction had a strong preference for aromahc aldehydes over aliphatic aldehydes in the presence of Me2AlCl (Scheme 6.67). 

A further method of pteridine synthesis from pyrimidine-4,5-diamine involves their reaction with aldehydes and hydrogen cyanide to give 5-(a-cyanoalkylamino)pyrimidines as intermediates which undergo cyclization to yield dihydropteridines which are subsequently oxidized to give the pteridines.118 In some cases the oxidation occurs spontaneously under the conditions of the cyclization. 

You met nucleophilic addition to a carbonyl group on pp. 115 and 121, where we showed you how cyanide reacts with aldehydes to give an alcohol. As a reminder, here is the reaction again, this time with a ketone, with its mechanism. 

Tetrabutylammonium cyanide Reactions with tetraalkylammonium salts Benzoins from aldehydes... 

In 1977 Davis, Temai et al. introduced an interesting variation to the synthesis. In their efforts to form substituted 2,5-diaryl oxazoles, a simple modification of the Fischer oxazole synthesis rendered a good yielding process. Acyl cyanide replaces cyanohydrins, which reacts with aldehyde to form 2,5-diaryl-4-chloro- (or bromo-) oxazoles. An example for such variation is the synthesis of the chloro-oxazoles 14. Benzoyl cyanide (12) reacts with aldehyde 13a at 0 C in the presence of HCl, and the mixture is stirred overnight to give 14a in a 75% yield. Similarly, benzoyl cyanide reacts with aldehyde 13b to give 14b in a 65% yield. 4-Bromo-oxazoles can also be formed using such variation. An example is the synthesis of 16 by the reaction of p-nitrobenzoyl cyanide (15) with benzaldehyde in the presence of HBr the 4-bromo adduct is formed in a 68% yield. 

Cyanosilylation. The Lewis acid-catalyzed reaction of t-butyldimethylsilyl cyanide (TBDMSCN) with aldehydes andke-tones affords the corresponding silylated cyanohydrins in good yield (eq 1). These have a greater stability than the silylated cyanohydrins obtained by using cyanotrimethylsUane The... 

The resurgence of interest in NHC as catalysts in the last 6 years led several chemists to reinvestigate external oxidants for the azolium-catalyzed esterification of aldehydes. Using cyanide, which shares many similarities to azolium salts in its reactions with aldehyde, Corey had shown in 1968 that the combination of an aldehyde and sodium cyanide in the presence of Mn02 and an alcohol led to esters. Scheldt executed this work with triazolium carbene as a promoter, leading to similar results (Scheme 14.9). Other oxidants including TEMPO radicals (2,2,6,6-tetramethylpiperidine 1-oxyl) and azobenzene" were also found suitable for NHC-catalyzed oxidative esterifications. 

With this as background let us now examine how the principles of nucleophilic addition apply to the characteristic reactions of aldehydes and ketones We 11 begin with the addition of hydrogen cyanide... 

Aldehydes by reaction with ammonia and cyanide ion (the Strecker synthesis)... 

In summary, the Bucherer-Bergs reaction converts aldehydes or ketones to the corresponding hydantoins. It is often carried out by treating the carbonyl compounds with potassium cyanide and ammonium carbonate in 50% aqueous ethanol. The resulting hydantoins, often of pharmacological importance, may also serve as the intermediates for amino acid synthesis. 

Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins, RCH(OH)C=N. Studies carried out in the early 1900s by Arthur Eapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CN. Alternatively, a small amount of KCN can be added to HCN to catalyze the reaction. Addition of CN- takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN-. 

In contrast, transmetalation of the lithium enolate at —40 C by treatment with one equivalent of copper cyanide generated a species 10b (M = Cu ) that reacted with acetaldehyde to selectively provide a 25 75 mixture of diastereomers 11 and 12 (R = CH3) which are separable by chromatography on alumina. Other diastereomers were not observed. Similar transmetalation of 10a (M = Li0) with excess diethylaluminum chloride, followed by reaction with acetaldehyde, produced a mixture of the same two diastereomers, but with a reversed ratio (80 20). Similar results were obtained upon aldol additions to other aldehydes (see the following table)49. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile... 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

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