Carbonyl compounds cyanomethylation

Whether the dianion of azohenzene is able to deprotonate MeCN (pK 31.3) has been discussed [62, 64, 68]. However, on a preparative scale generation of CH2CN takes place at the potential of the second reduction of azohenzene, and reactions initiated by cyanomethylation of benzamide [108], carbonyl compounds (or their Schiff bases) or Q , 8-unsaturated nitriles either present in situ [69, 109] or added subsequently [110-112] have been studied. A mixture of products is normally obtained. 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

However, efficient generation of CH2CN takes place at the second reduction potential of azobenzene using MeCN as solvent, which has been used in preparative-scale reactions initiated by cyanomethylation of benzamide [19] carbonyl compounds and a, )6-unsatured nitriles either present in situ [18,20] or added subsequently [21-23]. However, product mixtures are often complex, and although the products indicate the range of acid-base reactions possible, and the reacivity of the species generated, the electrochemical method offers little preparative advantage for these conversions. 

Reduction of aromatic carbonyl compounds in dry MeCN may lead to significant amounts of cyanomethylation products rather than the expected pinacols [58]. This is explained by the deprotonation of MeCN (p.Sra31.3) by the dimer dianions formed by initial dimerization of the carbonyl radical anions and subsequent attack of CH CN on unreacted substrate. 

Cyanomethylation. Carbonyl compounds and imines are subject to cyanomethylation by Me3SiCH2CN with tris(2,4,6-trimethoxyphenyl)phosphine as catalyst. ... 

A novel approach presents the previously inaccessible regioselective formation of substituted pyrido[2,3-b]indolizine-10-carbonitriles, via a cascade transformation of a,p-unsaturated carbonyl compounds with a dimer of l-(cyanomethyl) pyridinium chloride, in ethanol/water in the presence of sodium acetate [41]. 

Further examples of nucleophihc attack by phosphorus at sihcon appear to be involved in the cyanomethylation and trifluoromethylation reactions of carbonyl compounds and imines using trimethylsilylacetonitrile and trifluoromethyltrimethylsilane, respectively, in the presence of tris(2,4,6-trimethoxyphenyl)phosphine. ... 

Cyanomethylation. Efficient catalytic cyanomethylation reactions of carbonyl compounds with TMSCH2CN have been reported in the presence of catalytic copper complex (CuF-3PPh3-2EtOH) and a stoichiometric amount of (EtO)3SiF. The reaction is followed by a desilylation step, yielding the... 

NHC (162) has also been applied as an efficient catalyst for cyanomethylation of carbonyl compounds. In that way, a series of j0-hydroxynitriles have been prepared in... 

These are usually prepared by the following methods (a) the Willgerodt reaction on the corresponding methyl ketone,82,98,337,485, 557 (6) hydrolysis of the corresponding cyanomethyl compound,77,337, 485,499,517,521,568 cyclization reactions (Section IV, C) (for 3-acetic acids only),143,209,310,311,313,351 or (d) the Arndt-Eistert reaction on the corresponding carbonyl chloride, which may lead directly to the acetic acid 689 or its amide.337, 568... 

Two different carbon functional groups can be introduced simultaneously into 1,2-positions of aromatic skeletons based on a novel insertion reaction of arynes (101) into a carbonyl-cyanomethyl a-bond of a-cyanocarbonyl compounds (102) to produce 1,2-disubstituted aromatics (103).134... 

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