Iodine‐Promoted One‐pot Synthesis of Highly Substituted 4‐Aminopyrroles and Bis‐4‐aminopyrrole from Aryl Methyl Ketones, Arylamines, and Enamines

Abstract

An iodine-promoted one-pot synthesis of functionally diverse and highly substituted 4-aminopyrroles directly from aryl methyl ketones, arylamines, and enamines was developed. The reaction involves in-situ oxidation of aryl methyl ketone to glyoxal, subsequent imine formation by aniline, followed by nucleophilic addition of enamine, and cyclization to afford highly substituted 4-aminopyrroles. This reaction involved the formation of two CÀN bonds and one CÀC bond by a formal [1 + 1 + 3] annulation approach. The present method provides an interesting framework of two 4aminopyrrole units directly attached to a biphenyl core by the reaction of 4,4'-diacyl biphenyl, amine, and enamine groups. This Hantzsch-type one-pot reaction provides diverse 4-aminopyrroles, which could be useful in medicinal/material chemistry.

p‐Toluenesulfonic acid catalyzed, isocyanide‐free, Groebke–Blackburn–Bienayme (GBB) type multicomponent synthesis of 3‐anilino‐imdazo[1,2‐a]pyridines

“…Considering the above facts, development of isocyanide‐free strategy toward the 3‐aminoimdazo[1,2‐a]pyridine scaffold by taking the advantage of recently developed synthesis of 4‐aminopyrroles [16] by Jalani et al from methyl ketones, anilines, and enamines, wherein the in‐situ generated glyoxal (directly from ketones by Kornblum oxidation) upon reaction with anilines provide electron‐deficient keto‐imine, which served as an electrophile is attacked by enamines and thereby facilitates the cyclization to provide 4‐aminopyrroles, which tempted our interest to address the issue associated with GBB reaction. We envisioned that the reaction of aryl glyoxals with anilines would provide an imio‐ketone, which subsequently on reaction with 2‐aminopyridine could facilitate dehydrative cyclization to provide the desired 3‐anilinoimidazo[1,2‐a]pyridines in a one‐pot multicomponent manner wherein three C–N bond forms sequentially.…”

“…Considering our earlier experimental conditions [16], we began our study with the model reaction between phenyl glyoxal hydrate (100 mg) and p ‐toluidine (0.9 eq.) in ethanol (5 mL) at 55°C with p ‐toluenesulfonic acid ( p ‐TSA; 20 mol%).…”

Recent Advances for the Synthesis of N‐Unsubstituted Pyrroles

“…Choi et al [39] . developed an iodine‐promoted one‐pot synthesis of multisubstituted 4‐aminopyrroles 115 from aryl methyl ketones 113 , arylamines 114 , and enamines 78 via the formation of two C−N bonds and one C−C bond by a formal [1+1+3] annulation approach.…”

“…[37] Sahoo and colleagues [38] developed the first example of an XPhos-gold-catalyzed regioselective cycloisomerization cascade including sulfonyl/sufinyl migrations in alkyne-tethered ynamides 111. This strategy for the synthesis of unconventional 4sulfinylated pyrroles 112 from N-propargyl-tethered ynamides 111 involves [1,3]-sulfonyl migration from the nitrogen to the β-carbon of ynamides, followed by umpolung 5-endo-dig Choi et al [39] developed an iodine-promoted one-pot synthesis of multisubstituted 4-aminopyrroles 115 from aryl methyl ketones 113, arylamines 114, and enamines 78 via the formation of two CÀ N bonds and one CÀ C bond by a formal [1 + 1 + 3] annulation approach. This method involves the oxidation in-situ of aryl methyl ketone to glyoxal B, the subsequent formation of imine C with aniline 114, followed by the nucleophilic addition of enamine, and cyclization to give tetrasubstituted 4-amino-NH-pyrroles 115 (Scheme 40).…”

α-Keto Acids: Acylating Agents in Organic Synthesis

“…Enaminones are an important class of compounds with a wide applicability as synthetic intermediates to construct heterocyclic cores. − In 2017, Deng, Jiang, and co-workers reported a new way to access enaminones 204 by a Cu­(I)-catalyzed C sp3 –H bond functionalization of oxime acetate derivatives 117 with α-keto acids 1 . The protocol is carried out by mixing the oxime acetate 117 and the α-keto acid 1 (1.2 equiv) in the presence of CuI (10 mol %) as a catalyst and molecular sieves (4 Å MS) in DMF as the solvent at 90 °C for 6 h. Applying this method, 28 enaminones 204 could be prepared in moderate to very good yields, starting from differently substituted substrates 1 and 117 .…”