Michael addition of HCN

Mettler and colleagues reported an alternative synthesis of malonate 16 in the same paper (Griffiths et al., 1991) in which they condensed cyclohexanone with ethyl cyano-acetate instead of diethyl malonate in the Knoevenagel reaction to give ethyl cyano(cyclohexylidene)-acetate (18). In the presence of a catalytic amount of sodium cyanide, the Michael addition of HCN to cyanoacetate 18 proceeded in good yield at room temperature to generate the dicyanoester 19. Intermediate 19 was selectively converted to malonate 16 with pressurized HCI treatment in ethanol (Scheme 16.4). 

Some improvements in the synthesis of thiet 1,1-dioxide have been reported, and 2-phenylthiet 1,1-dioxide, 2-benzylthiet 1,1-dioxide, and 4-methyl-2-phenyl-thiet 1,1-dioxide have been prepared. The Michael addition of HCN to... 

Addition of HCN to unsaturated compounds is often the easiest and most economical method of making organonitnles. An early synthesis of acrylonitrile involved the addition of HCN to acetylene. The addition of HCN to aldehydes and ketones is readily accompHshed with simple base catalysis, as is the addition of HCN to activated olefins (Michael addition). However, the addition of HCN to unactivated olefins and the regioselective addition to dienes is best accompHshed with a transition-metal catalyst, as illustrated by DuPont s adiponitrile process (6—9). 

The addition of hydrogen cyanide (HCN) to carbon-carbon double bonds activated by electron-withdrawing groups in the presence of a base as a catalyst (a variation of the Michael Reaction) has been known for a long time. Nitriles were also obtained by hydrocyanation of branched olefins, such as isobutylene and trimethylethylene, in vapor phase reactions in particular the reactions over alumina (3) and cobalt-on-alumina (4) were reported in the late 1940s and early 1950s. Addition of HCN to conjugated dienes in the presence of cuprous salts (vapor and liquid phase) was reported as early as 1947 (5). 

The addition of HCN to activated alkenes, as in Michael additions (Eq. 1), has been known and commercially practiced for many years. However, due to the potential for competitive addition of water to Michael substrates under conditions of general base catalysis, few examples of these additions are known in aqueous me-... 

The Aldol Cyclization 877 The Conjugate Addition of HCN 879 The Conjugate Addition of an Amine 879 The Michael Addition 880 The Mannich Reaction 882... 

It was observed by Barwald and Jaenicke that no spectral change occurs upon addition of mandelonitrile, benzaldehyde, or HCN to the enzyme [81]. Apparently, binding of substrate and product does not involve the flavin molecule. It was subsequently found that one of the cysteine residues in the enzyme is essential for activity and can be selectively reacted with Michael acceptors. Upon reaction with labeled 3-oxo-3-phenylpropene, followed by reduction (to prevent a retro-Michael reaction) and extensive hydrolysis, l-2-amino-4-thia-DL-7-hydroxy-7-phenylheptanoic acid, the reduced conjugate addition product of cysteine to the inhibitor, was isolated [82] (Scheme 4). 

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