Copper-catalyzed C-N Bond Cleavage: Synthesis of N-sulfonylformamidines from N-(2-pyridinylmethyl)benzenesulfonamides

Abstract

Abstract: A broad range of N-sulfonyformamidines, widely used intermediates for drugs, were synthesized in moderate to excellent yields from 2-Pyridinemethanamine as N-source via Copper-catalyzed C-N cleavage. Firstly, N-(2-pyridinylmethyl)benzenesulfonamides were smoothly synthesized via 2-pyridinemethanamine and sulfonyl chlorides, then reacted with N,N-dimethylformamide dimethyl acetal to obtain the corresponding N-Sulfonylformamidines analogs, during which pyridin-2-ylmethyl and sulfonyl groups were essential for the C-N bond cleavage. The current work presents a valuable complementarity to the synthesis of N-sulfonyformamidines as 2-pyridinemethanamine can provide the N source and sulfonyl chloride,s which could be original materials. Background: N-sulfonylamidines have gained considerable attention from schools and industries because of their unique bioactivity. Since Pinner’s strategy, expanding the synthesis methods of N-sulfonylamidines has been the goal of many organic chemists over the past decades. Besides the crash reaction conditions and the participation of undesirable reagents, the production of N-sulfonylamidines commonly required unstable ammonia and azides as the source of nitrogen that hindered the further development and application of N-sulfonylamidine derivatives. Objective: The study aims to find a stable N source to replace NaN3 or NH3 to synthesize N-sulfonylamidines from sulfonyl chlorides. Methods: Firstly, N-(2-pyridinylmethyl)benzenesulfonamides were smoothly synthesized via 2-pyridinemethanamine and sulfonyl chlorides. Then the reaction conditions of N-(2-pyridinylmethyl) benzenesulfonamides and N,N-dimethylformamide dimethyl acetal (DMF-DMA) were screened and optimized. The reaction was processed in glycol at 80 ℃ for 8 hours with the addition of 5 mol% Cu(OAc)2·H2O as a catalyst. Results: Taking advantage of pyridin-2-ylmethyl, a scope of N-Sulfonylformamidines were synthesized from those N-(2-pyridinylmethyl)benzenesulfonamides under copper-catalyzed C-N bond cleavage. Conclusion: This ready synthetic method will be more of a promising inspiration for bioactive compound synthesis and drug development than for an innovative approach to synthesizing N-sulfonylformamidines.