Metal-Free Hydropyridylation of Thioester-Activated Alkenes via Electroreductive Radical Coupling

Abstract

An electrochemical hydropyridylation of thioesteractivated alkenes with 4-cyanopyridines has been developed. The reactions experience a tandem electroreduction of both substrates on the cathode surface, protonation, and radical cross-coupling process, resulting in a variety of valuable pyridine variants, which contain a tertiary and even a quaternary carbon at the α-position of pyridines, in high yields. The employment of thioesters to the conjugated alkenes enables no requirement of catalyst and high temperature, representing a highly sustainable synthetic method. P yridine-containing compounds play an important role in natural products and drug candidates. 1−3 Hydropyridylation, which is the straightforward incorporation of a pyridyl group onto alkenes, 4,5 has become an appealing strategy, given that the substrates are multitudinous and readily accessible and the produced alkylpyridines feature promising biological utilities. To date, hydrogen/halogen−metal exchange, 6 transition-metal catalysis, 7−9 and radical reaction 10−20 have been developed to accomplish such a significant chemical transformation (Scheme 1a). However, promoter, catalyst, or stoichiometric terminal reductant is indispensable to the reactions, resulting in poor atom economy, which should impede the exploitation of the methods in industry. Furthermore, all methods are limited to constructing a tertiary carbon α to pyridines.

Electrochemical ammonium-cation-assisted pyridylation of inert N-heterocycles via dual-proton-coupled electron transfer

“…Subsequently, the scope of the cyanopyridines was investigated by employing acridine as a benchmark. To our delight, the desired products 3sc and 3sd can be delivered smoothly when 2-fluoroisonicotinonitrile and 3-chloroisonicotinonitrile were executed under current condition, which was difficult to achieve in previous reports ( Xu et al., 2021 ; Zhang et al., 2020 , 2021 ; Lehnherr et al., 2020 ; Wen et al., 2021 ). Besides, a variety of 2-cyanopyridine derivatives can also be compatible with the present protocol and deliver the corresponding products with good yields ( 3se – 3sb ).…”

“…The dual-proton-coupled electron transfer strategy may provide a promising roadmap for this transformation ( Lehnherr et al., 2020 ; Murray et al., 2022 ; Tay et al., 2022 ). Although various elegant pyridylation strategies have been established in recent years by employing photocatalysis and metal or metal-free catalysis ( Huang et al., 2021 ; Kim et al., 2019 ; Novaes et al., 2021 ; Shen et al., 2021 ; Tong et al., 2021 ; Xu et al., 2021 ; Zhang et al., 2017a , 2017b , 2020 , 2021 ; Zhu et al., 2019 ). However, the pyridylation of inert N-heterocyclic derivatives via dual-proton-coupled electron transfer with radical cross-coupling in the absence of metals and external reducing agents under the conditions of electrochemical has not been reported ( Wu et al., 2021 ; Zeng et al., 2021 ; Liu et al., 2018 ; Lu et al., 2022 ; Yuan et al., 2021 ; Chen et al., 2010 ; Zhao et al., 2006 ).…”

“…In recent years, multifarious important pyridine-containing functional molecules have been constructed based on the decyanation of cyanopyridines mediated by electrochemical reduction ( Xu et al., 2021 ; Zhang et al., 2020 , 2021 ; Lehnherr et al., 2020 ; Wen et al., 2021 ). Previously, we have delivered the C3 pyridylation of quinoxalin-2(1H)-ones with readily available cyanopyridines under the electrochemical conditions by employing HFIP as the protonation reagent ( Scheme 1 C) ( Wen et al., 2021 ).…”

Hydropyridylation of α,β-Unsaturated Esters through Electroreduction of 4-Cyanopyridine

“…12 Electroreductive C3 pyridylation of quinoxalin-2(1H)ones was later documented by Yang et al 13 In 2021, Xia and Yang's group described an electroreductive pyridylation of aldehydes and ketones with electron-deficient (hetero)arenes. 14 Very recently, further progress on the electrochemical hydropyridylation of the electron-deficient alkenes was reported by two groups: metal-free hydropyridylation of thioester-activated alkenes by Jiang and Xu's group (Scheme 1d) 15 ketone-activated alkenes through dual proton-coupled electron transfer by Wen and Li's group (Scheme 1e). 16 Among the present approaches to the radical hydropyridylation of the electron-deficient alkenes with cyanopyridines, it is noticed that hydropyridylation of α,β-unsaturated esters is still challenging, especially for the cinnamates, a group of internal alkenes.…”

In Situ Alkyl Radical Recycling-Driven Decoupled Electrophotochemical Deamination

“…Delightfully, the corresponding primary and steric tertiary alkyl radicals were successfully attached in moderate to good yields ( 37 – 40 ). Then, we conducted the alkylation with other heterocycles, such as isoquinoline, phenanthridine, imidazo­[1,2- b ]­pyridazine, pyridine, quinazolin-4­(3 H )-one, quinoxalin-2­(1 H )-one, and benzo­[d]­thiazole derivatives, and moderate to excellent yields were obtained ( 41 – 53 ). Phenanthrolines, one of the frequently employed nitrogen ligands, were modified with our method, delivering privileged skeletons in moderate to excellent yields ( 54 – 56 ).…”