Nitriles P 0350Sodium Borohydride as the Only Reagent for the Efficient Reductive Alkylation of Malononitrile with Ketones and Aldehydes. -Primary and secondary substituted malononitriles are efficiently prepared via one-pot condensation between malononitrile and carbonyl compounds followed by NaBH4 reduction. -(DUNHAM, J. C.; RICHARDSON, A. D.; SAMMELSON*, R. E.; Synthesis 2006, 4, 680-686; Dep. Chem., Ball State Univ., Muncie, IN 47306, USA; Eng.) -Mais 25-078

Density functional theory (DFT) and G3-type (G3(MP2)-RAD) composite calculations were performed on a series of substituted 3-phenylpropyl radicals, to determine the relative importance of fragmentation and cyclization reactions in the chemistry of such species. Our studies indicate that cyclization is generally the more important of these reactions, with exceptions where fragmentation yields highly stabilized benzylic species. The energetic barriers for the cyclization reactions (enthalpies of activation) were found to be determined largely by the stability of the reactant radical and to a lesser but significant extent, by steric factors. Polarity effects in the transition state (modeled by SOMO-LUMO gaps of the products) appear to be less important. The data obtained indicated that the addition of benzyl radical to alkenes may be considered to be irreversible, but calculations for α-substituted styrenic systems indicate that reversibility of addition may become a factor in dilute polymerizing solutions for select systems.

An efficient and convenient method for the synthesis of primary and secondary monosubstituted malononitriles has been developed. In this method, sodium borohydride in isopropanol has a catalytic effect on the initial condensation between malononitrile and aldehydes or ketones at 0°C. The sodium borohydride also simultaneously acts as a reagent and reduces the unsaturated intermediate formed in situ by the condensation. This simple reductive alkylation method effectively consumes all malononitrile and selectively produces only monosubstituted malononitriles. Unsymmetrically disubstituted malononitriles are prepared via alkylation of these monosubstituted derivatives.Control over the synthesis of monosubstituted malononitriles has been a challenging problem in organic chemistry. The most general and direct route to monosubstituted malononitriles is the alkylation of malononitrile, but this method generally produces various amounts of disubstituted malononitriles from over-alkylation when malononitrile is the limiting agent. Indeed, symmetrically disubstituted malononitriles can be efficiently prepared in this manner. 1 Keeping the alkylating agent to a minimum causes the product to be contaminated with significant amounts of unreacted malononitrile, which must be separated from the desired monosubstituted malononitrile. 2 Secondary alkyl substituents are relatively difficult to obtain via alkylation with longer reaction times required and lower yields obtained. 2cMore selective methods for the synthesis of monosubstituted malononitriles followed a two-reaction sequence. The first step is a Knoevenagel condensation between malononitrile and a ketone or aldehyde. 3 The intermediate dicyanoalkene is reduced in a second step to afford the desired monosubstituted malononitrile. 4 The Knoevenagel condensations with malononitrile were carried out with alumina, 3a AlPO 4 /Al 2 O 3 , 3b or amino acids. 3c Various reducing agents included the Hantzsch 1,4-dihydropyridine ester, 4a a polymer-supported NAD(P)H model, 4b indium, 4c or indium(III) chloride/sodium borohydride reagent system. 4d Current work from this laboratory found a one-pot-two-step synthesis that produced secondary monosubstituted malononitriles in good to excellent yields (Scheme 1). 5 In this synthesis, alumina is used for the condensation, sodium borohydride in ethanol for the reduction. The Hantzsch 1,4-dihydropyridine ester was very recently utilized in the one-pot reductive benzylations of malononitrile under solvent-free mechanical milling conditions to give excellent yields for deactivated benzaldehydes. 6 Scheme 1The present investigation began with the hypothesis that lower yields from some of the one-pot syntheses could be attributed to the high concentration of intermediate dicyanoalkene (B) on the alumina in the presence of excess ketone before the ethanol and sodium borohydride were added. If the borohydride could be added while the condensation was taking place, intermediate B would remain at a low concentration and be reduced to A as it formed...