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

Abstract

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.

Carboxylic Acid Salts as Dual‐Function Reagents for Carboxylation and Carbon Isotope Labeling

“…Idealized methods that carboxylate C−H bonds are available, but they generally require high temperatures and/or transition metal catalysts [3] . The groups of Kondo [4] and Nolan [5] have developed promising methods for base‐promoted C−H carboxylation of arenes, [6, 7, 8] however, these protocols suffer from several drawbacks (Scheme 1A, i and ii). For example, the route described by the Kondo group requires high temperatures (generally 100–150 °C) and excess reagents (3.0 equivs of LiO t Bu/CsF/18‐crown‐6) [4] .…”

“…Nolan and co‐workers reported a room temperature carboxylation, however, a non‐commercially available gold catalyst and pressurized CO 2 (1.5 atm) were needed [5] . During the submission of this manuscript, scientists at Merck & Co., Inc. again demonstrated the importance of this type of C−H carboxylation, but high pressure CO 2 (24 atm) and specialized equipment were used (Scheme 1A, iii) [6] . Pressurized vessels or excess CO 2 are routine throughout carboxylation chemistry.…”

“…[5] During the submission of this manuscript, scientists at Merck & Co., Inc. again demonstrated the importance of this type of CÀ H carboxylation, but high pressure CO 2 (24 atm) and specialized equipment were used (Scheme 1A, iii). [6] Pressurized vessels or excess CO 2 are routine throughout carboxylation chemistry. This presents significant problems when using these methods for isotope labeling as considerably more expensive gases are needed (e.g.…”

Data Science-Enabled Palladium-Catalyzed Enantioselective Aryl-Carbonylation of Sulfonimidamides

“…Herein, we set out to develop this reaction (Figure D) by applying a data science-guided reaction optimization and scope exploration. Our recently reported virtual library of calculated bisphosphine ligand descriptors enabled the effective sampling of catalyst chemical space with the aim of shortening optimization timelines and increasing the possibility of locating a global optimum. − Data science techniques were also employed for substrate scope selection in order to maximize chemical space exploration, thus assessing the generality of this method. , …”

Enabling Deoxygenative C(sp2)-C(sp3) Cross-Coupling for Parallel Medicinal Chemistry

“…In PMC, the diversity of synthesized compounds is directly linked to the chemical space of building blocks being utilized. − Therefore, in considering a synthetic method for library synthesis, the availability and chemical diversity of its reagent pool becomes imperative. − We conducted cheminformatic analysis on common alkyl precursors for C­(sp 2 )-C­(sp 3 ) coupling reported in literature including boronates, trifluoroborate salts, alkyl halides (from which organozinc reagents may be derived), carboxylic acids and alcohols (Figure A). , Specifically, t-distributed stochastic neighbor embedding (t-SNE) dimensionality reduction of the first 50 principal components using 512-bit Morgan fingerprint descriptors was employed to quantify structural similarities and visualize the commercially accessible chemical space for each sp 3 building block. − As shown in Figure A, alkyl boronates, including potassium trifluoroborate salts, are commercially available in limited numbers and represent limited chemical diversity. A significant number of alkyl halide building blocks are commercially available, but there are significant gaps in their chemical space coverage.…”