Metal-Free N–H/C–H Carbonylation by Phenyl Isocyanate: Divergent Synthesis of Six-Membered N-Heterocycles

Abstract

We disclose a method using phenyl isocyanate to synthesize carbonyl-containing N-heterocycles. The metal-free novel approach for both N–H and C–H carbonylation processes was successfully refined, delivering a range of synthetically valuable derivatives of quinazoline-2,4­(1H,3H)-dione, 2H-benzo­[e] [1,2,4] thiadiazin-3­(4H)-one 1,1-dioxide, and pyrrolo­[1,2-a] quinoxalin-4­(5H)-one. The protocol features broad substrates with diverse reactions suitable for excellent yields, mild conditions, and good functional group compatibility. Moreover, the applicability of the reaction was characterized by gram-scale synthesis and synthetic transformations for drug molecules.

PhNCO-enabled synthesis of secondary amides from N-(2-aminophenyl)benzamides

“…The results indicate that the facile transamidation step of C may be involved in obtaining 3a . Drawing upon the experimental outcomes mentioned above and the pertinent literature report, 34 we have put forth a plausible mechanism for this methodology (Scheme 4). Initially, a nucleophilic addition takes place in compound 1 with phenyl iso cyanate 2 to form intermediate A and this is followed by intramolecular addition to the carbonyl group of B, and the key process of oxidation occurred by the elimination of aniline leading to C. Finally, the crucial intermediate 1-benzoyl-1,3-dihydro-2 H -benzoimidazol-2-one, C, engages in an effective transamidation with aniline, which transforms into the target product 3a along with the release of 5a .…”

“…30 Inspired by these reports and building on our ongoing research interest in the chemoselective cleavage of C-N bonds in amides, [31][32][33] our recent work reported an N-H/C-H carbonylation reaction using phenyl isocyanate to facilitate the versatile synthesis of diverse Nheterocycles (Scheme 1b). 34 Herein, we envisage a succinct oxidative method for the synthesis of secondary amides (3) employing N-(2-aminophenyl)benzamide (1) and phenyl isocyanate (2). This protocol also offers an advantage in generating waste that converts into carbonylated by-products (5), resulting in the creation of useful and medicinally important Nheterocycles.…”

Iodine-Promoted Oxidative Cyclization of Acylated and Alkylated Derivatives from Epoxides toward the Synthesis of Aza Heterocycles

“…Recently, our group reported a technique using DMSO that serves as the −CH 2 and −CH synthon to produce quinazoline derivatives (Figure c) . As a continuation of our efforts toward the construction of N -heterocycles, we herein developed a fast and efficient method for producing biologically active diverse N -heterocycles such as 2-benzoylquinazolin-4­(3 H )-one and phenyl­(pyrrolo­[1,2- a ] quinoxalin-4-yl) methanone derivatives using epoxides as acyl precursors (Figure d). In addition, the same approach could also be used to successfully synthesize a range of novel 1-methyl-dihydroquinazolin-4­(1 H )-ones in batch, and the use of continuous flow reaction conditions allowed the reduction of the reaction time, made it operationally safe, and improved the reaction yields over the batch technique .…”

One-Pot Synthesis of Core Structure of Shewanelline C Using an Azidoindoline

“…The reported synthetic methods to quinazoline-2,4-diones necessarily require “nitrogen reagents”, such as amines (Scheme B-a), isocyanates (Scheme B-b), isocyanides (Scheme B-c), and urea (Scheme B-d) for the differentiation of two nitrogen atoms. The scope of these protocols depends on the availability of “nitrogen reagents” as the essential substrates.…”