Copper(II)-Mediated Aerobic Synthesis of Imidazo[1,2-a]pyridines via Cascade Aminomethylation/Cycloisomerization of Alkynes

Abstract

A single copper(II)-catalyzed three-component cascade aminomethylation/cycloisomerization of propiolates to form imidazo[1,2-a]pyridines was explored. A straightforward method was developed for the practical synthesis of functionalized imidazo[1,2-a]pyridines from benzaldehydes, 2-aminopyridines, and propiolate derivatives catalyzed by Cu(OAc)2 hydrate in the presence of air. The protocol is marked by excellent yields, functional group tolerance, and, above all, adaptability to synthesize imidazo[1,2-a]pyridine-based drug molecules such as Alpidem.

Metal‐Free Approach to Zolpidem, Alpidem and their Analogues via Amination of Dibromoalkenes Derived from Imidazopyridine and Imidazothiazole

“…data, 193–195 °C); 1 H NMR (400 MHz, CDCl 3 ): δ [ppm] = 2.30 (s, 3H), 2.36 (s, 3H), 2.84 (s, 3H), 2.91 (s, 3H), 4.03 (s, 2H), 7.00 (dd, J = 9.6, 1.5 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 9.6 Hz, 1H), 7.51 (d, J = 8.1, 2H), 7.95 (s, 1H); 13 C NMR (CDCl 3 , 100 MHz): δ [ppm] = 18.4, 21.2, 30.2, 35.8, 37.4, 113.6, 116.5, 121.6, 122.1, 127.4, 128.3, 129.3, 131.8, 137.3, 143.8, 144.1, 168.3. The NMR data are in agreement with those in the literature , , …”

“…Gevorgyan and co‐workers elaborated an efficient one pot copper‐catalyzed three‐component coupling of 2‐aminopyridines, benzaldehydes and acetylenes to synthesize Zolpidem and their analogues . Recently “on air” (without isolation from the atmosphere) modifications of this approach were elaborated . In spite of this approach is shorter than other methods, application of copper catalyst may inflict difficulties aroused from toxicity of traces of copper in the final product and application of such methods is restricted by FDA for industrial processes.…”

Dihydroquinazolinones via A3‐Type Reactions of N‐Carbamoyliminium Ions

“…Several variants of the A 3 coupling have been developed, [16, 17] however, examples where the amine reaction partner has been replaced by other nitrogen nucleophiles are scarce [19–23] . To the best of our knowledge the present results provides the first examples of using urea for the condensation as an amine surrogate in the A 3 reaction.…”

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

“…The intermediate thus obtained was further oxidized by oxygen (air) to the Cu(III) complex 64 , which on reductive elimination gave the final product 62 (Scheme 22). Also, Irina V. Rassokhina and others have employed Cu(OAc) 2 for the synthesis of imidazo[1,2- a ]pyridines under aerobic conditions (Scheme 23) [114]. They have performed aminomethylation and cycloisomerization of propiolates 66 with imines 65 for the first time, using aerobic conditions with a Cu(II) catalyst.…”