Synthesis of 4-substituted 3,5-dinitro-1,4-dihydropyridines by the self-condensation of ß-formyl-ß-nitroenamine.

3,5-Dinitro-1,4-dihydropyridines (DNDHPs) are readily constructed by the acid-promoted self-condensation of ß-formyl-ß-nitroenamines. In the DNDHPs, one molecule of the nitroenamine serves as a C3N1 building block and the other serves as a C2 block. This synthetic method does not require any special reagents and conditions. When the reaction is conducted in the presence of electron-rich benzene derivatives, arylation at the 4-position of DNDHP is achieved by trapping the 3,5-dinitropyridinium ion intermediate.

One-step synthesis of differently bis-functionalized isoxazoles by cycloaddition of carbamoylnitrile oxide with ß-keto esters.

A new protocol for synthesizing different functionalized isoxazoles is provided. Carbamoylnitrile oxide generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with 1,3-dicarbonyl compounds in the presence of magnesium acetate that formed magnesium enolate in situ. Although electron-deficient trifluoroacetoacetate did not undergo this cycloaddition under the same conditions, conversion to sodium enolate furnish the corresponding bis-functionalized trifluoromethylisoxazole. The DFT calculations using B3LYP 6-31G+(d,p) also supported the aforementioned reactivity.

Inverse electron-demand 1,3-dipolar cycloaddition of nitrile oxide with common nitriles leading to 3-functionalized 1,2,4-oxadiazoles.

A carbamoyl-substituted nitrile oxide was generated upon treatment of easily available 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with THF (not dried); the reaction proceeded efficiently even in the absence of any special reagents and reaction conditions. The nitrile oxide caused 1,3-dipolar cycloaddition with common aliphatic nitriles or electron-rich aromatic nitriles to afford 3-functionalized 1,2,4-oxadiazoles, which are expected to serve as precursors for the preparation of a variety of functional materials by the chemical transformation of the carbamoyl group. While conventional preparative methods for 1,2,4-oxadiazoles involve the cycloaddition of an electron-rich nitrile oxide with an electron-deficient nitrile or a nitrile activated by a Lewis acid, our method employs the complementary combination of an electron-rich nitrile and an electron-deficient nitrile oxide- the inverse electron-demand 1,3-cycloaddition. The DFT calculations using B3LYP 6-31G* supported the abovementioned inverse reactivity, and also suggested the presence of an accelerating effect by the carbamoyl group as a result of hydrogen bond formation with a dipolarophilic nitrile.

An anomalous hydration/dehydration sequence for the mild generation of a nitrile oxide.

A nitrile oxide containing a carbamoyl group is readily generated upon the treatment of 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with water under mild reaction conditions, even in the absence of special reagents. The obtained nitrile oxide undergoes cycloaddition with dipolarophiles, alkynes and alkenes, to afford the corresponding isoxazol(in)es, which are useful intermediates in the synthesis of polyfunctionalized compounds. A plausible mechanism underlying the formation of the nitrile oxide is proposed, which involves an anomalous hydration/dehydration sequence. DFT calculations were also performed to support this mechanism.

Base induced chemical conversion of 3-carbamoyl-2-isoxazolines.

3-Carbamoyl-2-isoxazolines, prepared by cycloaddition of functionalized nitrile oxide, serve as masked 3-unsubstituted isoxazolines to afford 2-isoxazoline-3-carboxylic acid, beta-cyanoalcohol, alpha,beta-unsaturated nitrile, and alpha,beta-unsaturated amide upon heating in the alkaline solution. The present reaction is also applicable to synthesis of 3,4-difunctionalized isoxazoles and beta-hydroxy-gamma-lactone.

Formylnitroenamines: useful building blocks for nitrated pyridones and aminopyridines with functional groups.

beta-formyl-beta-nitroenamines possess both an electrophilic formyl group and a nucleophilic amino group and, therefore, serve as C3N1 building blocks having a nitro group to afford nitropyridones and aminonitropyridines with a functional group at the 3-position. Upon treatment with malonic acid derivatives or beta-keto esters, nitropyridones were obtained, whereas reactions with functionalized acetonitriles afford aminonitropyridines, via a formal transfer of an alkyl group from the ring nitrogen to the imino group. These procedures provide practical and useful methods for preparation of heterocycles with a nitro group.

Dimerization of acetoacetamide leading to 5-carbamoyl-4,6-dimethyl-2-pyridone.

The dimerization of acetoacetamide easily proceeds at room temperature in a dimethyl sulfoxide solution to afford 5-carbamoyl-4,6-dimethyl-2-pyridone.

A convenient method for synthesizing modified 4-nitrophenols.

[reaction: see text] Beta-nitroenamine having a formyl group behaves as the synthetic equivalent of unstable nitromalonaldehyde upon treatment with ketones under basic conditions and leads to 2,6-disubstituted 4-nitrophenols. The present method is safer than the conventional one using sodium nitromalonaldehyde and enables the preparation of hitherto unknown nitrophenols.

New synthetic equivalent of nitromalonaldehyde treatable in organic media.

beta-Nitroenamines having a formyl group at the beta-position behave as the synthetic equivalent of unstable nitromalonaldehyde, which is a useful synthon for syntheses of versatile nitro compounds. High solubility of the nitroenamines into general organic solvents enables us to conduct reactions in the organic media accompanied by easy experimental manipulations and considerable safety. When nitroenamines are treated with 1,2-bifunctional nucleophiles such as hydrazines, hydroxylamine and glycine ester, nitrated pyrazoles, isoxazole and pyrrole-2-carboxylate were readily prepared. This methodology was also applicable to guanidines and 1,2-diamines, leading to pyrimidines and 1,4-diazepines, respectively.

Synthesis of unnatural 1-methyl-2-quinolone derivatives.

Unnatural 1-methyl-2-quinolone derivatives were synthesized by regioselective C-C bond formation. When 1-methyl-3,6,8-trinitro-2-quinolone (TNQ) was treated with enamines, nucleophilic addition readily occurred at the 4-position, and succeeding hydrolysis of enamine moiety followed by elimination of nitrous acid furnished 4-acylmethyl-1-methyl-6,8-dinitro-2-quinolones. The same products could be prepared by the reaction of TNQ with ketones in the presence of triethylamine. The present reaction enabled the introduction of various kinds of acylmethyl groups substituted with alkyl, aryl or hetaryl groups.