Heterocyclic methylene-active carbonyl compounds, reaction

Dihydro-l,4-benzoxazin-3-ones and -benzothiazin-3-ones are synthesized by the reductive cyclodehydration of 2-nitrophenoxyacetic acids or their thioxy equivalents and as these heterocycles have an active methylene group it is a simple matter to prepare 2-substituted derivatives by condensation reactions with aldehydes and other carbonyl compounds (Scheme 123) (79AP302). 

Nitrogen heterocycles can also b e prepared by silver(I)-catalyzed cyclization reaction. Asao, Yamamoto, and their colleagues have shown synthesis of 1,2-dihydro-isoquinoline derivatives by addition of pronucleophiles to ortho-alkynylaryl ald-imines employing AgOTf as a catalyst [29]. For example, treatment of imine (19) with 2 equiv of nitromethane (20) in the presence of 3 mol% of the catalyst at 80 °C, 1,2-dihydroisoquinoline derivative (21) is produced in 85% yield (Scheme 18.7). Terminal alkynes and carbonyl compounds possessing activated methylene groups are also usable as the pronucleophiles [29]. 2-Alkoxyazetidines are efficiently synthesized by Ag(fod)-catalyzed [2-F2] cycloadditions of imines to (alkoxymethylene)... 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section I.I.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated meAylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

Isocyanides readily undergo cycloaddition reactions, and these are very valuable in the formation of heterocyclic rings. Reaction of j5-nitrostyrene with an alkyl isocyanide gives a hydroxy indole (146). Reaction proceeds even more readily between tosylmethyl isocyanide (147), in which the methylene is activated, and aryldiazonium compounds. With ketenes, isocyanides give imino lactones. However, with r-butylcyanoketene, the reaction follows a different pathway involving the carbonyl bond of the ketene, to yield 148. A [1 + 3] cycloaddition of an isocyanide to a 1,3-dipole has been used to prepare azetidines. The method has been used for synthesis of a number of azetidines . 

Knoevenagel condensation is the addition of a nucleophile from active methylene compound to a carbonyl group followed by dehydration to form a P-conjugated enone. The Knoevenagel condensation between different aldehydes (15), including various aliphatic, aromatic, and heterocyclic aldehydes with active methylene compounds (119) in the presence of nano-ZnO under solvent-free conditions (Scheme 9.37) has been reported (Hosseini-Sarvari et al. 2008). Most of the aldehydes investigated reacted smoothly to afford the corresponding products in excellent yields (90%-98%) in a reaction time of 5 min to 3 h. 

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