4-Ketonitriles

Isoxazoles (478) in the presence of base undergo ring opening to a-ketonitriles (479). When the reaction was carried out in the presence of hydrazines, 5-aminopyrazoles (480) were obtained. The reaction is also a convenient source of imidazoles, For example, when the 1,2-benzisoxazole (481) was treated with phenylhydrazine, decarboxylation initially occurred with subsequent ring closure to (482) (see Chapter 4.16). 

It should be noted that when 3-acylisoxazoles (116) are heated with a base such as sodium ethoxide, the acyl group is eliminated to give a carboxylate salt and a /3-ketonitrile (117). The reaction probably occurs via initial attack at the carbonyl group (46G206). 

Zl -Pyrrolines have been isolated from the hydrogenation products of y-ketonitriles (23-26) and in a large number of reactions during which enamino ketones are formed as intermediates. The preparation of pyrrolines from anhydro-5-hydroxyoxazolinium hydroxides (13, R, R" = Ph, R = Me) is also important (27). By the reaction of 13 with styrene, l-methyl-2,3,5-triphenyl-/l -pyrroline (14) is formed. 

This group of reactions has already been reviewed by Quilico and Barnes. However, the important data recently published make it advisable to reassess the subject. In 1891 Claisen first gave an example of the cleavage of the isoxazole ring he treated 5-phenylisoxazole with dilute sodium hydroxide or sodium ethylate at room temperature,the reaction involving the cleavage of the 0—N bond to yield a y8-ketonitrile (106). 

It is sometimes impossible to isolate the resultant jS-ketonitrile derivatives as such as they are unstable and readily polymerize, e.g. cyano-acetone. They are therefore identified as their corresponding arylhydrazones. The simpler alkyl-w-cyanomethyl ketones are, however, much more stable and their production through the cleavage of 5-alkylisoxazoles has been suggested as a preparative synthetic method. ... 

Decarboxylation of isoxazole-3-carboxylic acids is related to the nucleophilic cleavage of the isoxazole ring as far as the nature of the reaction products is concerned. It occurs at temperatures above 200°C and is accompanied by the cleavage of the nitrogen-oxygen bond of the heterocyclic ring to yield a j8-ketonitrile. It was first reported by Claisen with 5-methyl- and 5-phenyl-isoxazole-3-carboxylic acids (153- 154).Under the reaction conditions, j8-ketonitriles condense... 

The monoimines of the substituted -diketones formed can usually be isolated but sometimes they undergo further reactions. Thus, 5-substituted 3-chloroisoxazoles yield / -ketonitriles, and hydrogenation of 5-acylaminoisoxazoles (174) is a general method of synthesizing 4-hydroxypyrimidines (175). 2 3,214 One should note the increased stability of the isoxazole ring in styrylisoxazoles toward reduction. No hydrogenolysis of the 0—N... 

Ketoesters, synthesis of 608, 615 Ketones - see also a-Cyanoketones, Hydroxyketones, Sulphinylketones synthesis of 811-814 y-Ketonitriles, synthesis of 322 /3-Ketosulphones... 

Natural products, synthesis of 829, 835, 837, 840-842, 948, 958 Nitrile oxides, reactions of 807 Nitriles - see also y-Ketonitriles reactions of 277 synthesis of 815 Nitrilimines, reactions of 277 Nitritosulphonium intermediates 206 Nitrogen compounds, as oxidizing agents 970-972... 

Ketonitriles Preparfx) by Cyanide-Catalyzed CoNJuoArii Addition of Aryl Aldehydes to a,0-UNSATURATED Nitriles... 

Dithioacetal monoxides undergo Michael addition to acrylonitrile. The addition products are easily converted into y-ketonitriles 382 (equation 221). Benzenesulphinyl allylic carbanions 383 derived from the corresponding allylic sulphoxides react selectively at the y-position with a variety of cycloalkenones to give the l,4-adducts " (equation 222). Recently, Nokami and coworkers have synthesized some prostaglandin analogues via a three-component coupling process involving 1,4-addition of phenylsul-phinyl allylic carbanion (equation 223) . ... 

The Cp2TiCl2-catalyzed reductive radical cyclization of the ketonitriles 37 results in the formation of the 2-amino-3-cyano-2-cyclopenten-l-ols 38... 

A choice between mechanisms (b) and (c) was achieved by photolyzing a mixture of a 14N-nitrite in the pregnane series and the 15N-nitrite (29) to half-completion. Rearrangement of the nitroso dimers thus obtained to a mixture of oximes followed by oxidation of the pure oxime from (29) to the ketonitrile and mass spectrometric analysis indicated the N15/N14 ratio to be 1.15 1.00. Analysis of pure unreacted (29) gave a ratio of 1.00 0.00. These results indicate that mechanism (c) is operative in nitrite photolyses. 

In a similar transformation using 4-hydroxycoumarin (2-781) as the 1,3-dicar-bonyl compound the cycloadduct 2-794 was obtained also in good yield. In order to demonstrate the general applicability of this process, a small library using substituted pyruvate was prepared without optimizing the reaction conditions for the single transformations. a-Ketonitrile can also be used, though with a much lower yield. 

Scheme 7.11. Domino ozonolysis/aldol cyclization of unsaturated ketonitriles.

Zhu, D., Ankati, H., Mukheijee, C. et al. (2007) Asymmetric reduction of /3-ketonitriles with a recombinant carbonyl reductase and enzymatic transformation to optically pure /3-hydroxy carboxylic acids. Organic Letters, 9 (13), 2561-2563. 

Another type of synthesis involves cyclization of ketonitrile 107 into fused pyridopyrimidine 108 in the presence of Et3N (Equation 9) <1998CHE1442, 2000T5185>. 

A Knorr-type pyrrole synthesis involving the condensation between a-amino-P-ketoesters and P-ketonitriles provided P-cyanopyrroles <06OPRD899>. The former amine substrates were prepared by reduction of the corresponding a-isonitroso-P-ketoesters with Zn/HOAc. 

Compound 254 can be considered as a masked /3-ketonitrile. Treatment of the latter with hydrazine hydrate led to nucleophilic opening and recyclization to give the triazolopyridine 255 along with 256 which was converted to the [1,2,4] triazolo[4,3-<2 pyridine 257 (Scheme 62) <2004JHC549>. 

Scheme 5 Reductive cyclization of ketonitriles an route to guaiazulene.

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

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