ARTICLE https://doi.org/10.1038/s41467-019-08669-1 OPEN Photoredox-catalyzed branch-selective pyridylation of alkenes for the expedient synthesis of Triprolidine Shengqing Zhu1, Jian Qin1, Fang Wang1, Huan Li1 & Lingling Chu 1 Alkenylpyridines are important pharmaceutical cores as well as versatile building blocks in organic synthesis. Heck reaction represents one of the most powerful platform for the 1234567890():,; construction of aryl-substituted alkenes, nevertheless, examples for Heck type coupling of alkenes with pyridines, particularly with branched selectivity, remain elusive. Here we report a catalytic, branch-selective pyridylation of alkenes via a sulfinate assisted photoredox catalysis. This reaction proceeds through a sequential radical addition/coupling/elimination, by utilizing readily available sodium sulfinates as reusable radical precursors as well as traceless elimination groups. This versatile protocol allows for the installation of important vinylpyridines with complete branched selectivity under mild conditions. Furthermore, this catalytic manifold is successfully applied to the expedient synthesis of Triprolidine. 1 State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Center for Advanced Low-Dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 201620 Shanghai, China. Correspondence and requests for materials should be addressed to L.C. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:749 | https://doi.org/10.1038/s41467-019-08669-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-08669-1 red III IV = – 66 yridine is recognized as one of the most important het- *Ir(ppy)3 2 {E1/2 [*Ir /Ir ] 1.73 V vs. SCE } and cyano- red = – 67 erocycles in pharmaceuticals, agrochemicals, and bioactive pyridine 3 (E1/2 1.75 V vs. SCE in CH3CN) could be feasible P 1,2 natural products . Alkenylpyridines, an important subunit under specific conditions, generating pyridyl radical anion species 3 IV IV red IV of pyridines, also serve as versatile synthetic building blocks for and the oxidizing Ir 5.WehypothesizedthatIr 5 {E1/2 [Ir / complex pyridines3,4, as well as important ligand scaffolds in the IrIII] =+0.77 V vs. SCE}66,68 could affect the oxidation of sodium 5 fi fi red =+ area of catalysis (Fig. 1a) . As a result, the ef cient and selective methanesul nate 6 (E1/2 0.50 V vs. SCE) (see Supplementary assembly of alkenylpyridines from readily available starting Fig. 2) to form sulfonyl radical 7 and regenerate the ground-state IrIII materials has drawn intensive attentions of chemists6–10. catalyst 1. The electrophilic sulfonyl radical 7 would subsequently Alkenes are one of the most ubiquitous material in organic undergo facile radical addition to alkene to generate the nucleophilic synthesis. The cross-coupling of alkenes and aryl halides in the benzylic radical 9. At this stage, we envisioned that radical–radical presence of palladium catalyst, the Heck reaction11–13,isa coupling between the transient benzylic radical 9 and the persistent powerful protocol for the construction of aryl-substituted alkenes. pyridyl radical anion 4 would forge β-sulfonyl pyridine 1032–46.Due Nevertheless, there are few examples of Heck coupling of alkenes totheacidityofthebenzylicprotonandthegoodleavingabilityof with pyridines, probably due to the potential coordination sulfone, alkyl sulfone 10 would be expected to undergo E1 elimina- between the nitrogen atom and metal catalyst14–19. Alternatively, tion with the assistant of base, furnishing the final branched alke- several examples of Pd-catalyzed cross-coupling of alkenes with nylpyridine product 11,aswellassulfinate 6 that could be recycled. pyridine N-oxides have been reported, while only delivering vinylpyridine derivatives with linear selectivity20–23. To the best Optimization study. Our investigation into this photoredox of our knowledge, catalytic alkene–pyridine couplings with cascade protocol began with exposure of 1-(tert-butyl)-4-vinyl- branch selectivity, the control of which remains a big challenge in – benzene 12 and 4-cyanopyridine 3 to a 90 W blue light-emitting Heck couplings24 26, is unknown. diode (LED) in the presence of catalytic amounts of Ir(ppy) (5 Recently, radical-based chemistry provides an alternative platform 3 mol%) and readily available MeSO Na (30 mol%) (Table 1). In to address this challenge. Particularly, the groups of MacMillan, Jui, 2 – the presence of a stoichiometric amount of 1,8-diazabicyclo[5.4.0] and others27 46 have successfully demonstrated that visible light undec-7-ene (DBU) as base; pleasingly, we found that the bran- photocatalyzed cross-couplings of pyridines to access to alkylated ched vinylpyridine product could be obtained in 69% yield (entry pyridines under mild conditions, by taking advantage of unique 1). The nature of sodium sulfinates was found to have an reactivity of open-shell pyridyl radical species (Fig. 1b). While sig- important effect to the reaction efficiency. Generally, electron- nificant advances, no examples of vinylation of pyridines via pyridyl poor aryl sulfinates, which are better leaving groups, afforded radical species has been reported. Herein, we demonstrate an alter- higher efficiency than electron-rich ones (entries 2–6). And, native protocol, through a sequential radical addition/radical cou- comparable yields were obtained when para-chlorophenyl sulfi- pling/elimination pathway, to access vinylpyridines from readily nate was employed as the co-catalyst (entry 4). Gratifyingly, available alkenes with complete branch selectivity (Fig. 1c). This increasing the photocatalyst loading to 5 mol% provided the reaction takes advantage of a synergistic combination of visible optimal yield of product (entry 7). Control experiments indicated light-induced photoredox catalysis and a catalytic radical precursor, that photocatalyst, sulfinate, and light were all essential to this providing an effective and selective strategy for the synthesis of transformation, as no desired products were observed in the α-vinylpyridines under mild conditions. absence of either photocatalyst, sulfinate, or light (entries 8–10). While conducting the reaction in the absence of DBU afforded Results the expected product in 18% yield, probably due to the basic condition in the presence of MeSO Na (entry 11). Interestingly, a Design plan. We hypothesized that sodium sulfinates would be the 2 trace amount of C2-substituted product 13′, which is assumed to ideal reusable radical precursors, due to the unique properties be formed by the S Ar reaction of cyanopyridine with alkyl of which: (i) sufinates have been recently employed as efficient sul- N radical, was observed under the reaction conditions69. fonyl coupling partners in photoredox catalysis47–62; (ii) it is well known that the alkyl sulfones would be prone to undergo desulfo- nylation under basic conditions63–65.AsdepictedinFig.2,we Substrate scope. With the optimal conditions in hand, we next envisioned that a single-electron reduction between photoexcited explored the generality of this transformation with respect to a Alkenylpyridine motifs b Photocatalyzed alkylation of pyridines via open-shell pyridyl species Privileged pharmaceutical cores N X CN Alkyl Radical e Versatile building blocks –radical coupling Important ligand scaffolds – N N N N Me N Challenging selective synthesis X = CN, Open-shell (MacMillan, Jui, Triprolidine halides pyridyl species and others) c This work: Branch-selective alkene-pyridine coupling via visible-light induced photoredox catalysis N Me CN SO2 CN Ir Base – N MeSO Na – – MeSo2 2 α N N -Vinylpyridines Alkene Pyridine SO2Me Branch selectivity Fig. 1 Design of catalytic and branch-selective alkene–pyridine coupling via photoredox catalysis. a Importance of alkenylpyridines. b Photocatalyzed alkylations of pyridines. c Design of branch-selective alkenylation of pyridines via photoredox catalysis 2 NATURE COMMUNICATIONS | (2019) 10:749 | https://doi.org/10.1038/s41467-019-08669-1 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-08669-1 ARTICLE CN CN – N N 3 4 X N SET Vinylpyridine 11 IV *IrIII (2) Photoredox Ir (5) catalytic O cycle S – Me O 6 SET +Base Ir(ppy)3 (1) SO2Me O S Me O 7 X N 10 – CN– SO2Me X CN X – Alkene 8 9 N 4 Fig. 2 Proposed mechanism. Possible reaction pathway utilizing sulfinate as a promoter Table 1 Optimization of reaction conditionsa diminished yields (products 30–32,53–68% yields). Furthermore, this catalytic protocol was applicable to other aryl and heteroaryl alkenes, in the form of naphthalene, benzofuran, thiophene, and thiazole, furnishing the corresponding products in moderate CN Ir(ppy)3 (5 mol%) yields (products 33–36,56–78% yields). It should be noted that MeSO Na (30 mol%) 2 both cyclic (e.g., 1,2-dihydronaphthalene) and acyclic (e.g., trans- DBU, MeCN/EtOH, 40 °C N β-methylstyrenes and benzyl ether of cinnamyl alcohol) internal N 90 W Blue LED t Bu t Bu alkenes were found to be viable substrates, delivering the corre- Alkene 12 Pyridine 3 α-vinylpyridine 13 sponding alkenylpyridines with exclusive selectivity at the benzylic positions, respectively (products 37–40,69–75% yields). b Entry Ir(ppy)3 RSO2Na (30 mol%) Yield Finally, styrenes derived from drugs or natural products, including oxaprozin, nonivamide, hymecromone, estrone, and 1 1 mol% MeSO2Na 69% 2 1 mol% PhSO Na 52% indomethacin, could be successfully employed to furnish the 2 –