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. 2023 Jan 11;145(1):47-52.
doi: 10.1021/jacs.2c12466. Epub 2022 Dec 27.

Photochemical Organocatalytic Functionalization of Pyridines via Pyridinyl Radicals

Emilien Le Saux  1   2 , Eleni Georgiou  1   2 , Igor A Dmitriev  1   2 , Will C Hartley  1 , Paolo Melchiorre  3
Affiliations

Photochemical Organocatalytic Functionalization of Pyridines via Pyridinyl Radicals

Emilien Le Saux et al. J Am Chem Soc. .

Abstract

We report a photochemical method for the functionalization of pyridines with radicals derived from allylic C-H bonds. Overall, two substrates undergo C-H functionalization to form a new C(sp2)-C(sp3) bond. The chemistry harnesses the unique reactivity of pyridinyl radicals, generated upon single-electron reduction of pyridinium ions, which undergo effective coupling with allylic radicals. This novel mechanism enables distinct positional selectivity for pyridine functionalization that diverges from classical Minisci chemistry. Crucial was the identification of a dithiophosphoric acid that masters three catalytic tasks, sequentially acting as a Brønsted acid for pyridine protonation, a single electron transfer (SET) reductant for pyridinium ion reduction, and a hydrogen atom abstractor for the activation of allylic C(sp3)-H bonds. The resulting pyridinyl and allylic radicals then couple with high regioselectivity.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Radical pathways for the functionalization of pyridines: (a) Minisci reaction; (b) C4 functionalization via (path i) ipso substitution or (path ii) a Minisci process using blocking groups at the pyridine’s nitrogen; (c) The new reactivity promoted by pyridinyl radicals II generated upon SET reduction of pyridinium ions I.
Figure 2
Figure 2
(a) Proposed mechanism of the direct functionalization of pyridine 1a via the formation of pyridinyl radical II. (b) Optimization studies: reactions were performed on a 0.2 mmol scale at 35 °C for 16 h under illumination by a 365 nm EvoluChem LED spotlight using 10 equiv of 2a. Yields and regioisomeric ratios were determined by 1H NMR analysis of the crude mixtures. Numbers in parentheses refer to yields of isolated 3a. (c) Cyclic voltammetry studies (scan rate = 100 mV·s–1). (d) Calculated spin density and NBO analysis of pyridinyl radical II (uB3LYP/6-31G+(d) level of theory). (e) Stern–Volmer quenching studies of the excited anion of catalyst A2 (using A2·Et3N as the source of A2–) with increasing amounts of pyridinium·TFA salt I ([A2–] = 5 mM; [I] = 0.125 to 0.625 mM; excitation wavelength = 350 nm). (f) EPR spectrum of pyridinyl radical II measured after 15 min of irradiation of a 5:1 mixture of 1a and A2 at 77 K. Collidine refers to 2,4,6-collidine (50 mol %); n.d. denotes not detected; Ir-PC = [Ir(dtbbpy)(ppy)2]PF6; TFA = trifluoroacetic acid. aThe reaction was performed on a 1 mmol scale.
Figure 3
Figure 3
Photochemical organocatalytic allylation of pyridines and derivatives: (a) scope of pyridines 1; (b) scope of allylic substrates 2. Reactions were performed on a 0.2 mmol scale using 10 equiv of 2. Yields refer to isolated products 3 after purification. Products 3 were obtained as single regioisomers (>20:1 r.r.), unless otherwise stated. When more than one regioisomer was observed, the minor site of functionalization is highlighted by a gray circle. In these cases, the regioisomeric ratio (r.r.) of the crude mixture is specified, and the r.r. after isolation is reported in parentheses. When applicable, d.r. was ∼1:1. aYield determined by 1H NMR analysis. b The conditions described in Figure 2b, entry 5 were used. Boc = tert-butoxycarbonyl.
Figure 4
Figure 4
Probing the formation of pyridinyl radical II.
See this image and copyright information in PMC

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