Microwave-assisted synthesis of a 3-aminoimidazo[1,2-a]-pyridine/pyrazine library by fluorous multicomponent reactions and subsequent cross-coupling reactions

Microwave irradiation has been widely used as a powerful and easily controllable heating source for organic reactions. Reactions conducted under microwave usually have short reaction times, high yields, and better selectivities.1 The coupling of microwave-assisted reactions with phase-tag-based separations, such as solid-phase2 or fluorous synthesis,3 has great potential to further improve the efficiency of organic synthesis. Fluorous synthesis is a new solution-phase technology that has favorable homogeneous reaction kinetics and solid-phase type separation.4 Perfluoroalkyl groups employed in fluorous synthesis have good physical and chemical properties including high stability at elevated temperature, low ability to absorb microwave, good solubility in many common organic solvents. Limitations associated with solid-phase synthesis such as slower heterogeneous reactions, resin swelling in different solvents, requirement of large excess reagents to complete the reaction, and difficulty to analyze resin-bound intermediates are not concerns in fluorous synthesis. Multicomponent reactions (MCRs) are powerful tools to assemble molecules with high diversity.5 Performing additional reactions after MCRs can increase the molecular complexity and improve drug-like characteristics of the initial products.6 We recently reported the use of perfluorooctylsulfonates as an alternative to halogen atoms and triflate groups for Suzuki and other cross-coupling reactions in the formation C-C, C-S, and C-H bonds.7 In this paper, perfluorooctanesulfonyl benzaldehydes are used for the synthesis of 3-aminoimidazo[1,2-a]pyridine and 3-aminoimidazo[1,2-a]pyrazine derivatives 4. Imidazo[1,2-a]pyridines/pyrazines are biologically interesting compounds which possess antifungal, antibacterial, cytoprotective, cardiac stimulating, and benzodiazepine receptor antagonistic properties.8 The Blackburn and other groups have reported solution-phase syntheses of 4 by 3-component condensation reactions involving 2-aminopyridines/2-aminopyrazines, aldehydes, and isonitriles (Scheme 1A).9 The MCRs completed in 48–72 hours at ambient temperature and purifications were conducted by resin capture and release.9a The Blackburn group also developed a solid-phase synthesis with polymer-supported aldehydes to simplify the purification of condensation products (Scheme 1B).10 We report here a new method that incorporates microwave irradiation and fluorous tagging strategy11 to speed up reaction and separation processes (Scheme 1C). The post-condensation modification was carried out by Pd-catalyzed cross-coupling reactions to cleave the fluorous tag and introduce an additional diversity point (YR4). In the fluorous approach, the perfluoroalkanesulfonyl tag has three functions: as a phenol protecting group for the condensation reaction, as a phase tag for purification of reaction mixture, and as an activating group for the cross-coupling reaction. The final products have four diversity points (R1 to R4) with additional variations of X (= N or CH) and Y (= nothing or S).