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.
Keywords: formaldehyde; reductive-functionalization; tandem reaction; tetrahydroisoquinoline; transition-metal-free synthesis.
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.