Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C–H Carboxylation: Parallel, One-Pot Amide Couplings and Machine-Learning-Guided Substrate Scope Design

• DOI: 10.1021/jacs.2c10557
• Publication Date: 2022-12-09T18:50:35Z
• Authors: Stephanie Felten; Cyndi Qixin He; Mark Weisel; Michael Shevlin; Marion H. Emmert
• Keywords: Carboxylation; Azole; Amide

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. demonstrates significant expansion of the accessible chemical space azole-2-amides, compared previously known methodologies. Key described reactivity is use silyl triflate reagents, which serve as reaction mediators deprotonation stabilizers (otherwise unstable) azole carboxylic acid intermediates. A diverse substrate scope designed via machine-learning-guided analysis broad utility sequence. Density theory calculations provide detailed insights into role triflates mechanism. Transferrable applications protocol are successfully established: (i) low pressure (CO2 balloon) option for synthesizing acids without need high-pressure equipment; (ii) 13CO2 synthesis labeled compounds; (iii) isocyanates alternative electrophiles amidation; (iv) developed chemistry 24 × 12 parallel workflow with 90% library success rate. Fundamentally, reported expands heterocycle functionalization from late-stage toward its synthesis. It provides general densely functionalized building blocks their one-pot diversification.