Selective One-Pot Multicomponent Synthesis of N-Substituted 2,3,5-Functionalized 3-Cyanopyrroles via the Reaction between α-Hydroxyketones, Oxoacetonitriles, and Primary Amines

Abstract

A one-step, three-component reaction between α-hydroxyketones, oxoacetonitriles, and primary amines gives N-substituted 2,3,5-functionalized 3-cyanopyrroles with complete selectivity in up to 90% isolated yields. The reaction worked on a wide substrate scope under mild reaction conditions (AcOH as a catalyst, EtOH, 70 °C, 3 h). The reaction proceeded with very high atom efficiency as water is the only molecule lost during the reaction. The practicality of the reaction was demonstrated on a large gram scale. The structures of the 3-cyanopyrroles were confirmed by single-crystal X-ray diffraction and NMR; this work provides a general and practical entry to pyrrole scaffolds suitably decorated for the synthesis of various bioactive pyrroles in a concise manner.

Cu‐Catalyzed Synthesis of Coumarin‐1,2,3‐Triazole Hybrids connected with Quinoline or Pyridine Framework**

“…As we have mentioned earlier, 1,2,3‐triazole hybrids of coumarin or quinoline present anticancer, anti‐inflammatory, and antioxidant activities [13b,c,d,14a,d,f,21d,g] As a consequence we subjected the synthesized compounds to preliminary in vitro examination. The antioxidant and anti‐inflammatory activity were performed through their ability to inhibit soybean lipoxygenase (LOX).…”

A Concise Synthesis of Pyrrole-Based Drug Candidates from α-Hydroxyketones, 3-Oxobutanenitrile, and Anilines

“…BM521 2b and BM533 2c can be obtained in a similar fashion from pyrroles 16 and 17, respectively. α-Hydroxyketones 3 and 11 – 13 were synthesized from the corresponding substituted phenacyl bromide using sodium formate (General Procedure 1, experimental section and [ 13 ]).…”

“…Previously, we reported the selective synthesis of N -substituted 2,3,5-functionalized 3-cyanopyrroles via a one-step, three-component reaction between α-hydroxyketones, oxoacetonitriles, and primary amines [ 13 ]. The mild reaction conditions (AcOH as a catalyst, EtOH, 70 °C, 3 h), applicability on a large scale, and high atom efficiency (water is the only molecule lost during the reaction) warranted the application of this synthesis to important pyrrole-based lead drug candidates [ 13 ].…”

“…Previously, we reported the selective synthesis of N -substituted 2,3,5-functionalized 3-cyanopyrroles via a one-step, three-component reaction between α-hydroxyketones, oxoacetonitriles, and primary amines [ 13 ]. The mild reaction conditions (AcOH as a catalyst, EtOH, 70 °C, 3 h), applicability on a large scale, and high atom efficiency (water is the only molecule lost during the reaction) warranted the application of this synthesis to important pyrrole-based lead drug candidates [ 13 ]. In this work, we report the synthesis of a key pyrrole framework and develop it further for the synthesis of several pyrrole lead drug candidates, including COX-2 selective inhibitor, antituberculosis lead candidates BM212 2a , BM521 2b , and BM533 2c , and several analogues.…”