Synthesis of 5-amino-4-hetaryl-2,3-dihydro-1h-3-pyrrolones

Abstract

The interest in derivatives of 2-aminopyrrole has arisen in connection with their prospective use as medicines [1][2][3][4][5][6][7][8] and as components of dyes in photography [9][10][11]. The principal methods for the synthesis of these compounds are the condensation of methylene-active nitriles with derivatives of α-aminocarbonyl compounds [12][13][14][15][16][17] or amination of substituted 4-halobutyronitriles [18][19][20][21][22][23][24] or their synthetic equivalents [25][26][27]. Both approaches have been successfully applied to the synthesis of 1-R 1 -2,2-R 2 ,R 3 -5-amino-4-hetaryl-2,3-dihydro-3-pyrrolones [28][29][30][31][32][33][34][35][36][37]. However, they cannot be used for the production of similar derivatives unsubstituted at position 1 since, on the one hand, the N-unsubstituted α-aminocarbonyl compounds quickly dimerize to pyrazine derivatives and, on the other, the use of ammonia in the reaction together with the need for heat and a nonaqueous medium give rise to certain technical difficulties. For this reason we developed a different method for the synthesis of N-unsubstituted 2,3-dihydro-1H-3-pyrrolones 1a-h, and this method is described here.The key compounds in the synthesis of the dihydropyrrolones 1 are 2-hetaryl-3-oxo-4-phthalimidobutyronitriles 2a-e and the corresponding pentanonitriles 2f-h, obtained by acylation of the hetarylacetonitriles 3a-e with the chlorides of N-phthaloylglycine 4a and alanine 4b (see the scheme). It should be noted that acylation of the sodium salts of simple methylene-active compounds with the chlorides [38-41] and esters [17,42,43] of protected α-amino acids was used earlier for construction of the pyrrole ring. However, the acid chlorides often gave the products from bis-C,C-and bis-C,O-acylation [38,40] of complex mixtures [39], while the esters gave the enolates of the corresponding acyl derivatives. During transformation of the latter into the conjugate acids it was not always possible to avoid side processes associated with hydrolysis of the protecting groups [42,43]. We obtained the monoacyl derivatives 2a-h with yields of more than 90% as the only products (Scheme 1).The composition and structure of the nitriles 2a-h were confirmed by the results of elemental analysis (Table 1) and also by data from the IR and 1 H NMR spectra (Table 2). According to the spectral data, compounds 2a-h exist exclusively in the form of NH tautomers with an intramolecular hydrogen bond, as known for the acyl derivatives of hetarylacetonitriles [44]. Thus, the 1 H NMR spectra of the butyronitriles 2a-e

Cyclic α-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones and their spiro derivatives

“…These data were all consistent with the desired structures and agree with the conclusion described in Ref. [12,13].…”

“…Recently, we have introduced a strategy [12,13] for the construction of the 2-amino-3-hetarylpyrrolin-4-one system through an acylation of hetarylacetonitriles with 1-phthalimidoacetic and 1-phthalimidopropanoic acid chlorides in the presence of pyridine in dioxane or DMF. The isolated key intermediates undergo a cyclization reaction (hydrazine hydrate in dioxane) to 2-amino-3-hetarylpyrrolin-4-ones through an intramolecular condensation mechanism.…”