Cyanoacetate cyanoester

A somewhat more complex side chain is incorporated by alkylation of the carbanion of the substituted cyanoacetate, 148, with 2-chloroethylmethyl sulfide. Condensation of the resulting cyanoester (149) with thiourea followed by hydrolysis of the resulting imine (150) affords methitural (151)... 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

A Michael addition of ethyl cyanoacetate followed by protection of the cyclohexanone carbonyl group of the major cis isomer 18 as a cyclic acetal led to cyanoester 19. Hydroxymethylation with formaldehyde and subsequent protection of the hydroxy group as a MOM-ether provided the substituted cyclohexane derivative 20 as a mixture of diastereoisomers. 

Intramolecular Addition Reactions. Early studies by Julia and his co-workers on the cyclization of hexenyl (eq 11) and hep-tenyl radicals played a key role in the development of radical synthetic methodology, and many of the earher studies were conducted with peroxides as initiators. Cyclization of stabilized radicals such an malonates and cyanoesters are reversible, and the course of ring closure can be controlled by the appropriate choice of precursors and reaction conditions. Thus the cyanoacetate in eq 12 with 2 equiv of DTBP gives the products shown, whereas under kinetic conditions, using the tin hydride method, a different product distribution is obtained (eq 13). 

Finally, the third method for synthesizing (478), developed by Johnson et al.[577,578], also starts from the Mannich base (496). Its condensation with cyanoacetic ester led to the cyanoke toes ter (493), which, by the Stobbe reaction with dimethyl succinate,formed compound (492). On hydrogenation of the double bond and angular methylation, this was converted into the cyanoester (489) which, in a similar manner to the preceding case, gave the intermediate (478) on treatment with methanolic hydrogen chloride. 

Total syntheses of this group also include the synthesis of 11-oxo-steroids described in the patent literature [1066] (Scheme 118). The starting material used was the cyanoester (413) formed by the condensation of acetoacetic and cyanoacetic esters. The successive addition of hydrogen cyanide and acrylonitrile, hydrolysis, decarboxylation, and esterification of the product led to the tetraester (414). Dieckmann condensation, hydrolysis, decarboxylation, and esterification gave the monocyclic... 

---