Reaction with malononitrile amides

Amides of 4-amino-5-benzoylisoxazole-3-carboxylic acid could give both iso-xazolo[4,5-Z>]pyridines and isoxazolo[4,3-Z>]pyridines, but only isoxazolo[4,3-ft] pyrimidines 60 were obtained (80LA1623, 94FA529). The reaction of the same amides with malononitrile affords isoxazolo[4,5-Z>]pyridines 61 (80LA1623) (Scheme 26). 

Reaction of 6-methyl- or 6-styryl-2-phenyl-4-thioxopyrimidinc-5-carbonitrilc 3 with arylidene-malononitriles 4 in pyridine or with paraformaldehyde and malononitrile in dimethylform-amide/piperidine solution affords the 5-amino-2-phenyl-4-thioxo-3,4-dihydroquinazoline-6-carbonitriles 5 in moderate yields. 

As base. Many reactions that are promoted by a base can be effected with KF/AljO, for example, in deprotonating malononitrile for Michael reaction, in N-pyridylation of indole which is based on the S,.jAr mechanism, and in the preparation of a-heterosubstituted Weinreb amides from 7V-methoxy-A(-methyl chloroacetamide. ... 

A new approach to the synthesis of the fused 1,2,3-thiadiazolo ring systems, for example (81) and (82), has been studied by Dehaen and coworkers. Displacement of 5-halo-l,2,3-thiadiazoles (77) with sodium salts of malononitrile has led to the formation of the intermediate (78) which upon treatment with alkali gave the pyrano fused system (81) via the intermediate carboxylate anion (79). Alternatively, reaction of (78) with methylamine or with hydrazine furnished the fused pyridinone (82) via the amide (80) <97JCR(S)396>. 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

The scope of Pd-catalyzed a-arylation of enolates has been further expanded so as to include amides,malononitrile, a-cyanoesters, ° a-cyanophosphates, and a-cyanosulfones. " The metal countercations in these reactions are mostly alkali metals, such as Li, Na, K, and Cs. Some representative examples of these reactions are shown in Scheme 13. The Pd-catalyzed reaction of 2-methyl-l-propenyl chloride with NaCH(COOMe)2 in the presence of 2 mol% of Me2Pd(dcypb), where dcypb is Cy2P(CH2)3PCy2, led to 2-methylallylationf i (Scheme 14). 

Enantioselective hydrolysis of nitriles into amides or acids has primarily been catalyzed by various Rhodococus and Pseudomonas species (Fig. 10.33). Prochiral compounds were also hydrolyzed to give the corresponding acid in high yield and ee (Fig. 10.33(d), (e) and (g)). - In the reaction of substituted malononitrile with Rhodococcus rhodochrous, the first hydrolysis step leading to diamide proceeded without enantiodiscrimination, but further hydrolysis of the diamide proceeded with high enantioselectivity, affording the (Placid in 92% yield and 96% ee (Fig. 10.33(g)). 

Compared to a maximal bioconversion yield of 50% in racemic resolutions, asymmetric syntheses have a theoretical yield of 100%. Such an ideal yield was nearly reached with another R. rhodochrous ATCC 21197, which transformed disubstituted malononitriles such as butylmethylmalononitrile to the corresponding (7 )-amide carboxylic acid with high enantiomeric excesses and yields [80]. The reaction proceeded via a fast, nonstereospecific hydration of the starting dinitrile followed by a slow, enantioselective hydrolysis of the diamide intermediate by the amidase (Fig. 27). 

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