Azacycloalkanes: XXXIX. New Syntheses of 1H-Pyrrole-1-carboxylic acid and 1,2-dihydropyrrolo-[1,2-a]pyrazin-3(4H)-one derivatives

Abstract

New procedures have been developed for the synthesis of α-(2-formyl-1H-pyrrol-1-yl)-substituted carboxylic acids, α-(2-R-aminomethyl-1H-pyrrol-1-yl)-substituted carboxylic acids, and 1,2-dihydropyrrolo-[1,2-a]pyrazin-3(4H)-ones on the basis of furfurol and α-amino acids.* For communication XXVIII, see [1].We previously described methods for the synthesis of a series of 1,2-substituted pyrroles [2] and 3,4-dihydropyrrolo[1,2-a]pyrazines [3,4] and showed that some of these compounds exhibit cardiovascular [2] and psychotropic [5] activity. It is also known that the process of preparing food by heating is accompanied by formation of various pyrrole and pyrrolo[1,2-a]pyrazine derivatives from carbohydrates and proteins [6,7], and these compounds are introduced into human organism together with food. Therefore, target-oriented syntheses of such compounds are very important from the viewpoints of both search for new medical agents and elucidation of their biological effect in the nutrition process.In the present communication we report on new methods of synthesis of α-(2-formyl-1H-pyrrol-1-yl)-substituted carboxylic acids III, α-(2-R-aminomethyl-1H-pyrrol-1-yl)-substituted carboxylic acids IV, and pyrrolo[1,2-a]pyrazine derivatives V and VI from 2,5-dimethoxy-2-(dimethoxymethyl)tetrahydrofuran (I) and α-amino acids II. Acetal I is readily prepared from accessible 2-furaldehyde [8]; it reacted with amino acids IIa-IIf to give the corresponding 2-(2-formyl-1H-pyrrol-1-yl)alkanoic acids IIIa-IIIf in high yield (Scheme 1). The optimal reaction conditions implied heating the reactants at a I-to-II molar ratio of 1.1 : 1 in boiling water over a period of 1 h; these conditions ensured 80-90% yield of acids IIIa-IIIf. The amount of water depended on the solubility of the initial amino acid. The results of the reactions with optically active (R)-and (S)-α-alanines and racemic (RS)-α-alanine demonstrated that the proposed procedure can be successfully used for the preparation of individual stereoisomers. Acids IIIb and IIIc were characterized by similar (in absolute value) but opposite in sign specific rotations and similar melting points (mp 131-132°C), while racemic compound IIId melted at 110-112°C. Furthermore, a mixture of equal amounts of the (S)-isomer and (RS)-compound showed depression of the melting point (mp 107-108°C). The above data indicated that no racemization occurred during the synthesis of acids III.In order to elucidate the mechanism of formation of acids III, we examined the reaction of glycine (IIa) with 2-oxopentanedial (A) which was obtained by hydrolysis of acetal I with dilute hydrochloric acid. This reaction afforded only traces of acid IIIa, indicating that the condensation of glycine with tricarbonyl system A involves terminal carbonyl groups in the latter rather than those in the 1,4-positions. Presumably, the reaction of acetal I with amino acids II begins with hydrolysis of the least stable endocyclic ketal moiety in molecule I. Next follows condensation of the amino acid at the ketone carbonyl gr...

Synthesis and selected properties of N-substituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

“…The resulting carboca tion reacts with the amino group of ester 6 followed by the closure of the five membered ring, which is transformed into pyrrole. 12, 13 The developed method for the synthesis of esters 4 has an advantage over the procedures described previously 14- 16 because it has a general character and allows the one pot synthesis of these compounds in good yield.…”

Ribose conversion with amino acids into pyrraline platform chemicals – expeditious synthesis of diverse pyrrole-fused alkaloid compounds

“…chemical for the development of pyrrole-motif natural and articial therapeutic agents by further reactions. [39][40][41][42][43] The rst chemical synthesis of pyrralines 1 by Kato from the reaction of D-glucose and primary amines either at 100 C in H 2 O for 1 h or at 70 C in MeOH for 3 h both with acetic acid just conrmed the formation of pyrralines 1. 44 Monnier reported the synthesis of butyl pyrraline 1 (R ¼ Bu) in only 3.4% yield by the reaction of D-glucose and butylamine in aqueous acetic acid at 100 C for 2 h. 38 We believed that the low yield of pyrraline 1 was ascribed to the unstable imine intermediates under the aqueous acidic condition.…”

“… 38 Pyrraline 1 would be a useful platform chemical for the development of pyrrole-motif natural and artificial therapeutic agents by further reactions. 39–43 …”