Abstract
A transition‐metal‐free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4‐quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro‐type reduction followed by an Evans–Tishchenko reaction. When isoquinolines featuring a proton at the 4‐position are used, a tandem methylation‐hydroxymethylation occurs, leading to the formation of 2 new C−C bonds in one pot.
Highlights
A transition-metal-free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4-quaternary centers from the corresponding isoquinolines
A multitude of different reaction systems have been reported to achieve arene reductions using catalytic Rh, Ir, and Pd, along with systems utilizing organic reducing agents.[3,4,5,6,7]. Most of these approaches only form CÀH bonds and do not form any CÀC bonds,[8] precluding the ability to prepare saturated azacycles bearing quaternary centers
We have recently reported an Ir-catalyzed interrupted transfer hydrogenation reaction that results in the reduction of pyridines and quinolines along with the simultaneous installation of a CH2OH group in the 3-position of the heterocycle.[9]
Summary
A transition-metal-free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4-quaternary centers from the corresponding isoquinolines. When a C4-unsubstituted isoquinolinium salt was used in this methodology, the isolated product featured a quaternary center bearing a methyl group in addition to the CH2OH group, (cf entry 2 b, Scheme 2).
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