Imidazoles

Varvounis, George; Gkalpinos, Vasileios K.; Theodorakopoulou, P.; Tsemperlidou, E.

doi:10.1016/b978-0-12-818655-8.00140-2

Cited by 3 publications

(1 citation statement)

References 682 publications

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“…As shown in Scheme , 11 of the 12 employed amine building blocks were successfully reacted, with 53 being the only amine showing no formation of the desired product. Notably, the mild reaction sequence allows access to Weinreb amides by employing 47 as the coupling partner; the obtained amide product can serve as a valuable building block for further late-stage diversification …”

Section: Resultsmentioning

confidence: 99%

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

Felten

Weisel

et al. 2022

J. Am. Chem. Soc.

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

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Section: Resultsmentioning

confidence: 99%