Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.
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http://dx.doi.org/10.1021/jacs.3c05822 | DOI Listing |
Nat Commun
August 2024
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Building C(sp)-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp)-H and C(sp)-O bonds are commonly used to strategically disassemble and construct bioactive compounds, respectively. However, the direct cross coupling of these two chemical bonds to form C(sp)-C(sp) bonds is rarely explored in existing literature.
View Article and Find Full Text PDFChem
May 2024
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
Site-selective functionalization of the heterobenzylic C(sp)-H bonds of pyridines and related heteroaromatic compounds presents challenges associated with the basic nitrogen atom and the variable reactivity among different positions on the heteroaromatic ring. Methods for functionalization of 2- and 4-alkylpyridines are increasingly available through polar pathways that leverage resonance stabilization of charge build-up at these positions. In contrast, functionalization of 3-alkylpyridines is largely inaccessible.
View Article and Find Full Text PDFOrg Biomol Chem
June 2024
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta, T2N 1N4, Canada.
Benzylic C-H bonds can be converted into numerous functional groups, often by mechanisms that involve hydrogen atom transfer as the key bond breaking step. The abstracting species is most often an electrophilic radical, which makes these reactions best suited to electron-rich C-H bonds to achieve appropriate polarity matching. Thus, electron deficient systems such as pyridine and pyrimidine are relatively unreactive, and therefore underrepresented in substrate scopes.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
July 2024
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Methods enabling the broad diversification of C(sp)-H bonds from a common intermediate are especially valuable in chemical synthesis. Herein, we report a site-selective (N-phenyltetrazole)thiolation of aliphatic and (hetero)benzylic C(sp)-H bonds using a commercially available disulfide to access N-phenyltetrazole thioethers. The thioether products are readily elaborated in diverse fragment couplings for C-C, C-O, or C-N construction.
View Article and Find Full Text PDFAcc Chem Res
December 2023
Department of Chemistry, University of Wisconsin─Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
ConspectusCross-coupling methods are the most widely used synthetic methods in medicinal chemistry. Existing reactions are dominated by methods such as amide coupling and arylation reactions that form bonds to sp-hybridized carbon atoms and contribute to the formation of "flat" molecules. Evidence that three-dimensional structures often have improved physicochemical properties for pharmaceutical applications has contributed to growing demand for cross-coupling methods with sp-hybridized reaction partners.
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