Reaction for the Synthesis of Benzimidazol-2-ones, Imidazo[5,4-b]-, and Imidazo[4,5-c]pyridin-2-ones via the Rearrangement of Quinoxalin-2-ones and Their Aza Analogues When Exposed to Enamines

Abstract

A synthetically useful protocol has been developed for the preparation of highly functionalized N-pyrrolylbenzimidazol-2-ones. The reaction of variously substituted 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with commercially available enamines in acetic acid results in a rapid rearrangement and formation of N-pyrrolylbenzimidazol-2-ones in modest to excellent yields. The key step of the rearrangement involves the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with enamines. In this case, the atom of carbon which is displaced from the pyrazine ring of quinoxalin-2(1H)-one becomes the fourth carbon atom of the newly formed pyrrole ring. The method is applicable for the aza analogues of quinoxalin-2(1H)-ones.

Acid-Catalyzed Multicomponent Rearrangements via 2-((Quinoxalin-3(4H)-on-2-yl)(aryl)methylene)malononitriles, Generated In Situ, for Divergent Synthesis of Pyrroles with Different Substitution Patterns

“…In contrast to the rearrangements of 3-aroyl-quinoxalin-2­(1 H )-ones that occur with commercially available enamines and enamines generated in situ from ammonium acetate and the corresponding methylaryl­(hetaryl)­ketones, rearrangements of 3-aroyl-quinoxalin-2­(1 H )-ones considered in this work, proceeding under the action of enamines generated in situ from malononitrile and secondary amines or primary alcohols, allow us to introduce pharmaceutically significant piperazine, piperidine, morpholine, pyrrolidine ring systems, and diethylamine and alkoxyl groups into the rearrangement products in a one-pot process, which is an undeniable advantage of the described method over other methods of synthesis of polysubstituted pyrroles.…”

“…In our previous work, the reactions of 3-aroylquinoxalin-2­(1 H )-ones and their 5- and 7-aza-analogues, namely, 3-benzoylpyrido-[3,2- b ]­pyrazin-2­(1 H )-one and 3-benzoylpyrido­[3,4- b ]-pyrazin-2­(1 H )-one, with enamines in acetic acid, were found to give variously substituted 1-[pyrrol-4­(and 5)-yl]-benzimidazol-2­(3 H )-ones through the quinoxalinone–benzimidazolone rearrangement. In these examples, commercially available enamines were used, namely, methyl- and ethyl-3-aminocrotonates (a) and enamines generated in situ in the reactions of variously substituted acetophenone derivatives with ammonium acetate (b) . Assuming that the enamine triatomic moiety is an integral part of amidines and imino esters and can be easily generated by the interaction of amines with nitriles with an active methylene group, in this paper, we present the results of studies of reactions proceeding in a multicomponent system containing aroylquinoxalinones, malononitrile, and various nucleophilic reagents (amines and alcohols) in the presence of acetic acid (c) (Scheme ).…”

“…To test our hypothesis, we investigated the reaction with 3-benzoylquinoxalin-2-one 1a , malononitrile 2 , and piperidine 3a as the model substrates. Based on previous studies, , a dual solvent system consisting of AcOH and MeOH was chosen. To optimize the process, we initially carried out the reaction in boiling MeOH as in the previous case in the presence of acetic acid with various ratios of reagents, solvents, and different reaction times.…”

Mechanistic Insights for Acid‐catalyzed Rearrangement of Quinoxalin‐2‐one with Diamine and Enamine

“…In 2000, we discovered the acid‐catalyzed rearrangement of 3‐aroylquinoxalin‐2‐ones into 2‐(benzimidazol‐2‐yl)quinoxalines when exposed to 1,2‐benzenediamines [8] . In the last two decades, we have published a series of works on the rearrangement of quinoxalin‐2‐ones via the proposed spiro‐quinoxalinone [9] intermediates ( A ) into 2‐hetarylbenzimidazoles [9a–h] ( B , Type I) as well as 1‐hetarylbenzimidazolones in cases of enamine nucleophiles ( C , Type II, Scheme 1), [9i–k] thus opening a simple way to access various 2‐hetarylbenzimidazoles and 1‐hetarylbenzimidazolones according to the S N (ANRORC) mechanism (i. e., via sequential steps of addition of nucleophile, ring‐opening and ring‐closing) [10] . It was shown that the type of rearrangement may depend on the fact if tautomerizable hydrogen is available or not in the spiro‐forming ring within A .…”

“…In this theoretical work, extensive DFT calculations at the PW6B95‐D3+COSMO‐RS//TPSS‐D3+COSMO level in acetic acid solution (see below for computational details) are performed to explore the detailed free‐energy paths for two typical rearrangements of 3‐benzoylquinoxalin‐2‐one ( 1 Q ) with 1,2‐benzendiamine ( 1 a ) [8] and methyl 3‐amonocrotonate ( 1 b ), [9i] which selectively leads to 2‐(benzimidazol‐2‐yl)quinoxaline (Type I) and two N ‐pyrrolyl‐substituted benzimidazol‐2‐ones (Type II), respectively. It is shown that while the former reaction is initiated by a site‐selective N⋅⋅⋅C condensation at the protonated benzoyl group of 1 Q , the latter can be initiated by two C⋅⋅⋅C nucleophilic additions at both protonated benzoyl and imine sites of 1 Q that eventually leads to two isomeric products.…”