Abstract
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 aminoethyl 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.
Highlights
The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups
A key difficulty to overcome when developing the proposed alkene aminopyridylation lies in the regioselectivity of the two competing sites (C2 vs. C4) on the pyridinium salts
The generation of N-centered radicals from Naminopyridinium salts proved highly efficient in photocatalytic systems[56,57,58,59], fragmentation of the prefunctionalized Nradical precursor by single electron transfer (SET) reduction results in an inevitable loss of pyridine as chemical waste[56,57,58,59,60,61,62,63,64,65,66,67]
Summary
To conceptually understand the catalytic mechanism and identify the features governing the regiocontrol in this reaction, we carried out quantum chemical calculations based on density functional theory (DFT) In these calculations, the prototype reactant 2a, N-(methyltosyl)aminopyridinium, is employed to form the product 3b. Homolytic cleavage of the N–N bond liberates pyridine and produces the activated Ncentered radical A This reaction is calculated to have a step barrier of 7.8 kcal/mol and is irreversible with a driving force of 28.3 kcal/mol. These two MOs give a 2-orbital-1electron interaction and the radical acts as a nucleophile towards the pyridinium substrate. The final product is formed by N–N bond cleavage to extrude the aminyl radical, which can a SET
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