Oxidative sp³ C–H Functionalization of Methyl Substituted Aza‐Aromatics: An Easy Access to N‐Fused Polyheterocycles

Abstract

An efficient metal‐free, one‐pot strategy has been developed for the synthesis of diverse N‐fused polyheterocycles such as pyrido‐/thiazolo‐/benzthiazolo‐imidazo[4,5‐c]quinolines and indolo‐/pyrrolo‐[1,2‐a]quinoxalines mediated by I2/DMSO in the presence of 10 mol‐% TBHP. This protocol involves a cascade sequence of oxidative imination/cyclization/aromatization reactions through sp3 C–H functionalization of methyl‐substituted aza‐aromatics with a variety of arylamine conjugated heterocycles by means of modified Pictet–Spengler type cyclization. The advantage of the present method includes environmentally benign, atom economy, and mild reaction conditions resulting in various N‐fused polyheterocycles.

Molybdenum‐Catalyzed One‐Pot Multi‐Step Synthesis of N‐Polyheterocycles from Nitroarenes and Glycols

“…Another approximation consists in the reaction of the corresponding bromide with an aldehyde and an external nitrogen source under copper‐catalysis [21] . In addition, the reaction of anilines with benzylamines [22] or 2‐methyl aza‐arenes [23] catalyzed by molecular iodine also led to the formation of imidazo[4,5‐ c ]quinolines. At this point, we envisaged that the reduction of nitroaromatic compounds 1 a , b with different glycols 2 under Mo‐catalysis and subsequent cyclization of the intermediate imine could afford the corresponding imidazo[4,5‐ c ]quinolines 3 and 5 , which incorporate the waste carbonyl byproduct of the first step into their structures.…”

“…[20] Another approximation consists in the reaction of the corresponding bromide with an aldehyde and an external nitrogen source under copper-catalysis. [21] In addition, the reaction of anilines with benzylamines [22] or 2-methyl azaarenes [23] catalyzed by molecular iodine also led to the formation of imidazo [4,5-c] With this goal in mind, and based on the conditions we had previously reported for the synthesis of pyrrolo and indoloquinoxalines, [10,11d] we found that the treatment of nitroarene 1 a with glycol 2 a (2.2 equiv) in the presence of p-TsOH (0.5 equiv), a catalytic amount of dioxomolybdenum(VI) complex (MoO 2 Cl 2 (dmf) 2 ) and N,N-dimethylacetamide (DMA) as solvent, under microwave heating led to the formation of pyridoimidazoquinoline 3 a (see Table S1), isolated in 70 % yield (Table 1, entry 1). Next, a variety of functionalized glycols 2 were evaluated.…”

Iodine and DMSO as Surrogate of Hazardous Metal and Non‐Metal Reagents in Organic Synthesis

“…In 2019, Sridevi and co-workers developed a strategy to synthesize biologically active molecules, such as pyrido-/thiazolo-/benzthiazoloimidazo[4,5c]quinolones, by the CÀ H activation and functionalization of methyl aza-aromatics (Scheme 33 (e)). [324] This involved the use of 1.5 equivalents of iodine and 10 mol% TBHP as the cooxidant, and the absence of either iodine or DMSO resulted in no reaction. In 2022, Jinkala and group used the same parent scaffold and synthesized the target molecules using phenylacetic acid as the model substrates and 1.5 equivalents of iodine in DMSO as the solvent (Scheme 33 (f)).…”

“…Derivatives of imidazoquinolines have been prepared under the influences of various reagents such as p ‐TsOH (Scheme 33 (a)), [320] the copper‐catalyst supported by a ligand (Scheme 33 (b)), [321] catalytic cyanuric chloride (Scheme 33 (c)), [322] and catalytic FeCl 3 (Scheme 33 (d)), [323] using indazoles as the starting scaffold. In 2019, Sridevi and co‐workers developed a strategy to synthesize biologically active molecules, such as pyrido‐/thiazolo‐/benzthiazoloimidazo[4,5‐c]quinolones, by the C−H activation and functionalization of methyl aza ‐aromatics (Scheme 33 (e)) [324] . This involved the use of 1.5 equivalents of iodine and 10 mol% TBHP as the co‐oxidant, and the absence of either iodine or DMSO resulted in no reaction.…”

Recent advances in iodine–DMSO mediated C(sp3)–H functionalization of methyl-azaarenes via Kornblum oxidation

“…Sridevi and Reddy et al reported an iodine–DMSO mediated synthesis of nitrogen-containing poly-heterocycles 130 and 131 in the presence of 10 mol% TBHP from methyl azaarenes 20 and various arylamines 128 and 129 respectively (Scheme 31). 51 Several methyl azaarenes such as 2/4-methylquinolines and 2/4-methylpyridines were found suitable for this protocol. The method is efficient in terms of the yield of the product.…”