Herein, we report an iridium-catalyzed directed C−H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating accessible directing group chemical space for the reaction, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of an empirical predictive model to guide future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally reaction miniaturization to a nano molar range highlights the opportunities for more sustainable screening with decreased material consumption.
A key intermediate was obtained as solid through filtration of the reaction mixture of saccharin, chloro(triphenyl)phosphonium chloride, and N,N-diisopropylethylamine (DIPEA) in chloroform. The soluble triphenylphosphine oxide went to filtrate as waste, while the solid was reacted with amines to afford N-sulfonylamidines. In total, 26 N-sulfonylamidine products were obtained in moderate to good overall yields.
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