ARTICLE https://doi.org/10.1038/s41467-019-12216-3 OPEN Visible light induced alkene aminopyridylation using N-aminopyridinium salts as bifunctional reagents Yonghoon Moon1,2,3, Bohyun Park 1,2,3, Inwon Kim1,2, Gyumin Kang 1,2, Sanghoon Shin1,2, Dahye Kang2,1, Mu-Hyun Baik 2,1 & Sungwoo Hong 2,1 1234567890():,; The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups. Here we report a strategy for the photocatalytic aminopyridylation of alkenes using a variety of N-aminopyridinium salts as both aminating and pyridylating reagents. Using Eosin Y as a photocatalyst, amino and pyridyl groups are simultaneously incorporated into alkenes, affording synthetically useful ami- noethyl pyridine derivatives under mild reaction conditions. Remarkably, the C4-regioselectivity in radical trapping with N-aminopyridinium salt can be controlled by electrostatic interaction between the pyridinium nitrogen and sulfonyl group of β-amino radical. This transformation is characterized by a broad substrate scope, good functional group compatibility, and the utility of this transformation was further demonstrated by late- stage functionalization of complex biorelevant molecules. Combining experiments and DFT calculations on the mechanism of the reaction is investigated to propose a complete mechanism and regioselectivity. 1 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. 2 Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea. 3These authors contributed equally: Yonghoon Moon, Bohyun Park. Correspondence and requests for materials should be addressed to M.-H.B. (email: [email protected]) or to S.H. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:4117 | https://doi.org/10.1038/s41467-019-12216-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12216-3 lkenes are ubiquitous in organic chemistry and the ami- be modestly regioselective (C2 vs. C4) when secondary alkyl Anative difunctionalization of olefins is a convenient radicals were employed. Clearly, a key difficulty to overcome strategy for directly accessing nitrogen-containing mole- when developing the proposed alkene aminopyridylation lies in cules1–11. However, adding hard Lewis basic amino functional- the regioselectivity of the two competing sites (C2 vs. C4) on the ities to carbon–carbon double bonds that are of course soft Lewis pyridinium salts. bases on their own right is fundamentally problematic and The generation of N-centered radicals from N- requires a non-classical strategy because simply using an amino aminopyridinium salts proved highly efficient in photocatalytic group as a nucleophile is not promising. Recently, photoredox systems56–59, although fragmentation of the prefunctionalized N- catalysis12–19 proved to be highly efficient for generating N- radical precursor by single electron transfer (SET) reduction centered radicals20–28 that could be employed to drive anti- results in an inevitable loss of pyridine as chemical waste56–67. Markovnikov-selective alkene carbo-, hydroxyl-, and fluoro- We envisioned that N-aminopyridinium salts may serve as amination/amidation reactions and form synthetically and bio- bifunctional reagents to deliver both the aminyl radical and the logically valuable linear amines29–31. The pyridine moiety is a pyridyl group to an olefin. In this scheme, the aminyl radicals basic structural unit of numerous natural products, pharmaceu- generated from a fragmentation of the N-aminopyridinium salt ticals, agrochemicals, and fine chemicals32–34. Therefore, a react with the alkene to form a new C–N bond and an adjacent β- number of synthetic strategies have been explored to install amino radical. The resultant alkyl radical may then trap pyridyl groups on molecules35–44. Bringing together these two N-aminopyridinium salt to install a pyridyl group, affording valuable but challenging methodological avenues, we questioned synthetically and biologically valuable aminoethyl pyridines whether aminopyridylation of olefins can be achieved using the (Fig. 1d)68,69. Herein, we report an efficient aminopyridylation of power of photoredox catalysis techniques to offer an efficient, alkenes using a variety of N-aminopyridinium salts as bifunc- direct and environmentally benign synthetic route to these tional reagents for simultaneous amination and pyridylation valuable products (Fig. 1a). Moreover, the development of under mild reaction conditions. Moreover, this catalytic platform intermolecular alkene difunctionalization with a bifunctional does not require any oxidant and allows excellent C4 regiocontrol reagent29,30 has great potential for quickly increasing molecular over radical trapping with N-aminopyridinium salts. complexity in a single operation with high levels of atom and step economy. The Minisci-type C–H alkylation of pyridines by directly Results adding alkyl radicals to the C2-position of the pyridine core is Reaction discovery and optimization. We tested the viability of well-established, but overalkylation at the C6-position is a com- our proposed approach using vinyl ether 1a and N- mon problem resulting in mixtures of mono- and disubstituted aminopyridinium salt 2a as model reactants under blue LED – products (Fig. 1b)45 52. Recently, the N-alkoxypyridinium salts irradiation, and selected data are enumerated in Table 1. After emerged as easily accessible, versatile, and bench-stable pyridine evaluating different reaction conditions, we were pleased to find surrogates that in principle may offer increased levels of that the use of Ir(ppy) in acetonitrile initiated 1,2-aminopyr- – 3 selectivity and reactivity40 44. For example, Herzon reported a idylation at room temperature to afford the desired product 3a in cobalt-mediated reductive cross-coupling of alkenes with N- 30% yield (entry 1), indicating that the proposed overall process methoxypyridinium salts53,54, and we developed remote C–H involving tandem amination and pyridylation is possible. Nota- pyridylation reactions55 by using N-alkoxypyridinium salts as bly, radical trapping with 2a occurs selectively at the C4 position substrates (Fig. 1c). Unfortunately, these reactions were found to of the pyridine core. Significant turnover was observed with the a Bioactive aminoehtyl heteroarenes b Acid-promoted Minisci-type alkylation of pyridine 4 OH R N + HO 2 H N N Alkyl radical N R R N R MeO H N CF3 Radical pyridylation using N-alkoxypyridinium salts N c CF 3 4 Mefloquine Quinine (FDA-approved (FDA-approved antimalarial drug) antimalarial drug) 2 + N 2° Radical N OR N OH OH N N d This work: alkene aminopyridylation using N-aminopyridinium salts H H Ts N N N PC R N + Cl OMe Blue N TsNR N LED NSC23925 Vacquinol-1 R Ts N N (MDR-reversing agent) (glioblastoma therapy) R Ts C selective Bifunctional reagent 4 Fig. 1 Project background and design plan for photocatalytic aminopyridylation of olefins. a Bioactive aminoethyl heteroarenes. b Minisci-type alkylation of pyridine core. c Radical pyridylation using N-alkoxypyridinium salts. d Aminopyridylation of olefins using N-aminopyridinium salts as bifunctional reagents. PC photocatalyst. Ts toluenesulfonyl 2 NATURE COMMUNICATIONS | (2019) 10:4117 | https://doi.org/10.1038/s41467-019-12216-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12216-3 ARTICLE Table 1 Optimization of Reaction Conditionsa In these calculations, the prototype reactant 2a, N-(methylto- syl)aminopyridinium, is employed to form the product 3b.As illustrated in Fig. 2, the proposed mechanism is fundamentally nBuO Ts different from the previously studied alkylation reactions. The PC N catalytic cycle is initiated by the excitation of the photocatalyst n base BuO + N – PC to PC*, which subsequently transfers a single electron to 2a to BF4 Solvent, N , rt 1a N 2 form the unstable N-pyridine radical 2a*. Homolytic cleavage of Ts blue LED, 3 h – 2a N 3a the N N bond liberates pyridine and produces the activated N- centered radical A. This reaction is calculated to have a step entry photocatalyst base solvent yield barrier of 7.8 kcal/mol and is irreversible with a driving force of [%]b 28.3 kcal/mol. From the N-centered radical A, we considered two 1 Ir(ppy)3 (2 mol%) K3PO4 MeCN 30 plausible reaction pathways invoking the attack of either the 2 Ir(dFCF3ppy)2(bpy)PF6 K3PO4 MeCN 64 alkene 1b or a second equivalent of the pyridinium 2a. (2 mol%) Interestingly, attacking 2a is both kinetically and thermodyna- ∙ 3 Ru(phen)3Cl2 xH2O K3PO4 MeCN 75 mically disfavored and requires a step barrier of 21.3 kcal/mol (2 mol%) associated with the transition state p-A-TS’ to afford the putative 4 Eosin Y (2 mol%) K PO MeCN 57 3 4 intermediate p-B’, found to be 11.6 kcal/mol higher in energy 5 Eosin Y (2 mol%) K2HPO4 MeCN 46 6 Eosin Y (2 mol%) Na CO MeCN 52 than A, as shown in red dotted line in Fig. 2. Our calculations 2 3 fi 7 Eosin Y (2 mol%) K3PO4 DMSO 79 indicate that the N-centered radical A prefers to attack the ole n 8 Q1 (2 mol%) K3PO4 DMSO 79 substrate 1b to give an intermediate B with a barrier of only 8.5 9 Eosin Y (0.5 mol%) K3PO4 DMSO 86 kcal/mol and this step is energetically downhill by 7.3 kcal/mol. It 10 Q1 (0.5 mol%) K3PO4 DMSO 76 is interesting that the N-centered radical A acts as an electrophile c 11 Eosin Y (0.5 mol%) K3PO4 DMSO 0 to attack the electron-rich olefin substrate in this instance, rather 12 Eosin Y (0.5 mol%) − DMSO 75 than behaving like a nucleophile that may have preferred to react aReaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), and base (0.06 mmol) in solvent (0.5 with the electron-poor pyridinium substrate. Although it is easy b 1 mL) under irradiation using blue LEDs at rt for 3 h under N2. Yields were determined by H to recognize electrophilic and nucleophilic reactants in closed- c NMR spectroscopy.