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. 2022 Mar 4;24(8):1678-1683.
doi: 10.1021/acs.orglett.2c00267. Epub 2022 Feb 24.

Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of Structurally Diverse Heterobiaryls

Alejandro Cervantes-Reyes  1 , Aaron C Smith  2 , Gary M Chinigo  2 , David C Blakemore  2 , Michal Szostak  1
Affiliations

Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of Structurally Diverse Heterobiaryls

Alejandro Cervantes-Reyes et al. Org Lett. .

Abstract

Heteroaromatic biaryls are core scaffolds found in a plethora of pharmaceuticals; however, their direct synthesis by the Suzuki cross-coupling is limited to heteroaromatic halide starting materials. Here, we report a direct synthesis of diverse nitrogen-containing heteroaromatic biaryls by Pd-catalyzed decarbonylative Suzuki cross-coupling of widely available heterocyclic carboxylic acids with arylboronic acids. The practical and modular nature of this cross-coupling enabled the straightforward preparation of >45 heterobiaryl products using pyridines, pyrimidines, pyrazines, and quinolines in excellent yields. We anticipate that the modular nature of this protocol will find broad application in medicinal chemistry and drug discovery research.

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Figures

Figure 1.
Figure 1.
Analysis of Available Building Blocks at Pfizer. The Pfizer file and the Quick Building Block collection were sorted by heterocycle across the carboxylic acid and halide functional groups and a count was performed. Structures that were available as both functional groups were filtered out to highlight the unique space that each set offers. Blue represents a count of >300 unique building blocks while red represents <20 unique building blocks.
Figure 2.
Figure 2.
Selected Examples of Carboxylic Acid Monomers with Greater Availability.
Figure 3.
Figure 3.
(A) Selected examples of pharmaceuticals containing heteroaromatic biaryls. (B) Decarbonylative cross-coupling reactions of arene carboxylic acids. (C) Present work: heterocyclic carboxylic acids.
Scheme 1.
Scheme 1.. Decarbonylative Cross-Coupling of Pyridine-3-Carboxylic Acid with Various Aryl Boronic Acidsa
aConditions: Pyridine-3-carboxylic acid (1.0 equiv), Ar-B(OH)2 (2 equiv), Piv2O (2.0 equiv), Pd(OAc)2 (10 mol%), L6 (5 mol%), H3BO3 (2 equiv), Et3N (1.75 equiv), dioxane (0.20 M), 160 °C, 15 h.
Scheme 2.
Scheme 2.. Scope of Heterocyclic Carboxylic Acids in the Pd-Catalyzed Suzuki–Miyaura Biaryl Synthesis
aConditions: Carboxylic acid (1.0 equiv), 4-MeO-C6H4B(OH)2 (2 equiv), Piv2O (2.0 equiv), Pd(OAc)2 (10 mol%), L6 (5 mol%), H3BO3 (2 equiv), Et3N (1.75 equiv), dioxane (0.20 M), 160 °C, 15 h.
Scheme 3.
Scheme 3.. Scope of (Hetero)Aryl Boronic Acids in the Pd-Catalyzed Suzuki–Miyaura Biaryl Synthesis
aConditions: HetAr–CO2H (1.0 equiv), Ar–B(OH)2 (2 equiv), Piv2O (2.0 equiv), Pd(OAc)2 (10 mol%), L6 (5 mol%), H3BO3 (2 equiv), Et3N (1.75 equiv), dioxane (0.20 M), 160 °C, 15 h.
Scheme 4.
Scheme 4.
Mechanistic Studies
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