Direct Dearomatization of Pyridines via an Energy-Transfer-Catalyzed Intramolecular [4+2] Cycloaddition

Abstract

The catalytic dearomatization of pyridines, accessing medicinally relevant N-heterocycles, is of high interest. Currently direct, dearomative strategies rely generally on reduction or nucleophilic addition, thus limiting the architecture of the dearomatized products to a six-membered ring. We herein introduce a catalytic, dearomative cycloaddition reaction with pyridines using photoinduced energy transfer catalysis, thereby advancing dearomatization methodology and increasing the topology of pyridine dearomatization products. This unprecedented method features high yields, broad substrate scope (44 examples), excellent functional group tolerance, and facile scalability. Furthermore, a recyclable and sustainable polymer immobilized photocatalyst was employed. Computational and experimental investigations support a mechanism in which a cinnamyl moiety is promoted to its corresponding excited triplet state through visible-light-mediated energy transfer catalysis, followed by a regioselective and dearomative [4+2] cycloaddition to pyridines. This work demonstrates the contribution of visible light catalysis toward enabling thermally challenging organic transformations.

Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization

“…Notably, as with other arenophile-mediated dearomatizations, this transformation effectively functionalizes one formal double bond in the aromatic system, leaving the other two available for further manipulation. By treating benzene as a surrogate for the fictitious cyclohexa-1,3,5-triene, this approach enables the synthesis of hexafunctionalized cyclohexane derivatives in only two or three steps; this stratagem is used nicely in rapid, enantioselective syntheses of the potent antineoplastic isocarbostyril alkaloids (+)-7-deoxypancratistatin ( 54), (+)-lycoricidine ( 55), (+)-pancratistatin (56), and (+)-narciclasine (57). 29,30 ent-Kaurenoids The Diels-Alder reaction of cyclohexa-1,3-dienes has proven to be one of the most effective and general methods to build the carbogenic bicyclo[2.…”

“…55 Moreover, photocatalytic para-cycloaddition between pyridines and tethered olefins, proceeding through a triplet excited-state of the alkene moiety, gave unique isoquinuclidinebased polycycles (e.g., 114 / 115). 56 Dearomative cycloadditions based on the arenophile MTAD (50) were also used for expansion of arenes to oxepines (e.g., 116 / 117). 57 Such heteroatom insertions and shapeshifting reactions are rare; however, their development will continue to enrich the dearomative molecular editing toolbox.…”

Dearomative [4 + 2] Cycloaddition of Pyridine via Energy-Transfer Catalysis

“…In particular, the collective oscillation of con-duction electrons triggered by incident light in plasmonic nanoparticles has attracted much interest. 1,2 This phenome-non, referred to as localized surface plasmon resonance (LSPR), indeed increases the electromagnetic field intensities around illuminated nanoparticles. This nanosource of energy can be harvested in many ways by neighboring functional nanostructures.…”

Dearomative Cycloadditions Utilizing an Organic Photosensitizer: An Alternative to Iridium Catalysis

“…3,4,7 This catalyst, which has also been shown to be effective in other catalytic energy transfer processes, benefits from a long-lived excited triplet state and a high triplet energy. 1,8,9 Despite these desirable traits, iridium catalysis has several significant drawbacks that limit its widespread use. On the economic side, iridium has the distinction of being the rarest of the rare earth metals and has a correspondingly high price that can make the cost of the catalyst prohibitively expensive.…”