Divergent reactivity of sulfinates with pyridinium salts based on one- versus two-electron pathways

Abstract

One of the main goals of modern synthesis is to develop distinct reaction pathways from identical starting materials for the efficient synthesis of diverse compounds. Herein, we disclose the unique divergent reactivity of the combination sets of pyridinium salts and sulfinates to achieve sulfonative pyridylation of alkenes and direct C4-sulfonylation of pyridines by controlling the one- versus two-electron reaction manifolds for the selective formation of each product. Base-catalyzed cross-coupling between sulfinates and N-amidopyridinium salts led to the direct introduction of a sulfonyl group into the C4 position of pyridines. Remarkably, the reactivity of this set of compounds is completely altered upon exposure to visible light: electron donor-acceptor complexes of N-amidopyridinium salts and sulfinates are formed to enable access to sulfonyl radicals. In this catalyst-free radical pathway, both sulfonyl and pyridyl groups could be incorporated into alkenes via a three-component reaction, which provides facile access to a variety of β-pyridyl alkyl sulfones. These two reactions are orthogonal and complementary, achieving a broad substrate scope in a late-stage fashion under mild reaction conditions.

Scheme 1. Divergent reactivity of sulfinates based on one- versus two-electron reaction manifolds.

Fig. 1. (a) UV-Vis absorption spectra of N-amidopyridinium salt (1a), sodium p-toluenesulfinate (2a), and the mixture of 1a and 2a (0.15 M in DMSO). (b) Job's plot for the ratio between 1a and 2a. (c) Two orthogonal resting states (X = NTs(Me)). SET = single-electron transfer. BET = back-electron transfer.

Scheme 2. Control experiments for the three-component reactions. (a) Reaction with mixtures of 1a and 2-phenyl-substituted pyridine. (b) Radical trapping experiments using 1,1-diphenylethene.

Fig. 2. (a) Proposed mechanism for the sulfonative pyridylation of alkenes. (b) Free-energy profile for the site-selective sulfonative pyridylation of alkenes. The blue traces represent the C4-product formation pathway. The red traces represent the C2-product formation pathway.

Fig. 3. Control experiments and the proposed mechanism for the two-component reactions. (a) Reaction with mixtures of 1a and 2-phenyl-substituted pyridine. (b) Proposed mechanism.

Scheme 3. Late-stage modifications of pyridine-based drug derivatives.

Scheme 4. Synthetic utilities of sulfones 4ba, 5c and 5r (see the ESI for details).