N-Acylbenzotriazole as Proficient Substrate for an Easy Access of Urea, Acyl urea, Carbamates and Thiocarbamates via Curtius Rearrangement Using DPPA as Azide Donor

A diverse range of urea, N-acyl urea, and thiocarbamates has been synthesized in good to excellent yields by reacting N-acylbenzotriazoles individually with amines or amides or thiols or phenols in presence of diphenylphosphorylazide (DPPA) as a suitable azide donor in anhydrous toluene at 110 oC for 3-4 hours. In this route, DPPA is found to be a well alternative of trimethylsilylazide and NaN3 for the azide donor in Curtius degradation. The high reaction yields, one-pot and metal-free condition, straight-forward nature, easy to handling, use of readily available reagents, and in many cases avoid of the column chromatography are the notable features of the devised protocol.

Scalable synthesis of (1-cyclopropyl)cyclopropylamine hydrochloride

1-Cyclopropylcyclopropanecarboxylic acid (2), which is accessible on a large scale (900 mmol) from 1-bromo-1-cyclopropylcyclopropane (1) in 64% yield (89% on a 12.4 mmol scale), has been subjected to a Curtius degradation employing the Weinstock protocol to furnish the N-Boc-protected (1-cyclopropyl)cyclopropylamine 3 (76%). Deprotection of 3 with hydrogen chloride in diethyl ether gave the (1-cyclopropyl)cyclopropylamine hydrochloride (4·HCl) in 87% yield.

Potential GABAB Receptor Antagonists. VII. The Synthesis of 2-(4-Chlorophenyl)-3-nitropropan-1-amine and Related Analogs of Baclofen

3-Nitro-2-phenylpropan-1-amine and 2-(4-chloropenyl)-3-nitropropan-1-amine have been synthesized by the addition of nitrous acid to the corresponding trifluoroacetylaminomethylstyrenes followed by reduction of the double bond with sodium borohydride. A more general and efficient route involves the Michael addition of nitroalkane anions to methyl cinnamates followed by Curtius degradation of the corresponding acids. 2-(4-Chlorophenyl)-3-nitropropan-1-amine is a specific agonist of GABA and the GABAB receptor, with about half the activity of racemic baclofen at the isolated guinea pig ileum. Methylation or dimethylation at C3 decreases activity markedly.

SYNTHESIS OF PYRAZOLONES FROM α-KETO AND α-CYANO ESTERS

1,4-Dimethyl-3-amino-5-pyrazolone and 4-methyl- and 4-ethyl-3-amino-1-phenyl-5-pyrazolones were synthesized from α-keto esters and methyl- and phenylhydrazines. The hydrazones first obtained were transformed into pyrazolones having a carbethoxy group in position 3, which was converted into an amino group by a Curtius degradation. 2,4-Dimethyl-3-amino-5-pyrazolone was obtained directly from methylhydrazine and ethyl α-cyanopropionate. A series of 3-imino-2-methyl-5-pyrazolones monosubstituted in position 4 with pentyl, hexyl, heptyl, and octyl groups and another series disubstituted in position 4 with butyl, hexyl, and heptyl groups were also prepared from the corresponding mono- and disubstituted cyanoacetates and methylhydrazine.The ultraviolet absorption spectra were determined in neutral and acid medium.

SYNTHESIS OF α-AMINO ACIDS FROM ETHYL CYANOACETATE

Monosubstituted cyanoacetic esters, obtained by condensation of 1-bromo-3(s)-phenoxypropanes (s = o-Cl, o-Br, o-I, o-, m-, and p-NO2) or 1-bromo-2(s)-phenoxyethanes (s = o-Cl, o-Br, o-I, and m-NO2) with ethyl cyanoacetate by means of potassium carbonate, were transformed through a Curtius degradation into cyanoacetisocyanates. These compounds by hydrolysis in acid or alkaline medium gave α-amino acids. However, hydrolysis of the corresponding carbobenzyloxy- or carbethoxyaminonitriles afforded better yields. The carbobenzyloxyaminonitriles were more readily hydrolyzed in aqueous hydrochloric acid than the carbethoxyaminonitriles. Moreover, the mild action of dry hydrochloric acid on the carbobenzyloxy derivatives yielded the α-amino acids readily whereas similar treatment of the carbethoxy derivatives gave the carbethoxyamino acids.

STUDY OF 4-MONO- AND 4,4-DISUBSTITUTED-3-IMINO-2-BENZOYL-5-PYRAZOLONES

4-Mono- and 4,4-disubstituted-3-imino-2-benzoyl-5-pyrazolones have been prepared from the corresponding ethyl mono- or disubstituted cyanoacetates and N-benzoylhydrazine. The presence of the imino group in 4,4-disubstituted-3-imino-2-benzoyl-5-pyrazolones was ascertained by the hydrolysis of 4,4-dibenzyl-3-imino-2-benzoyl-5-pyrazolone into 4,4-dibenzyl-3-oxo-2-benzoyl-5-pyrazolone. In order to prove that the benzoyl group in these pyrazolones was not in Position 1, the synthesis of 4-benzyl-3-amino-1-benzoyl-5-pyrazolone was attempted from 4-benzyl-3-carbethoxy-1-benzoyl-5-pyrazolone through a Curtius degradation of the 3-carbethoxy substituent into a 3-amino group. It was found that the 1-benzoyl group was hydrolyzed at the same time as the 3-carbethoxyamino substituent. The ultraviolet absorption spectra of all these compounds are reported and discussed briefly.