Zhihua Peng and colleagues, China University of Petroleum (East China), Qingdao, have developed an efficient C(sp³)–H bond alkylation of tetrahydroisoquinolines (THIQs) or isochroman with alkylzinc reagents (product pictured; X = NR’ or O; R = alkyl). THIQs and isochroman derivatives show a variety of biological activities, which makes these compounds interesting for pharmaceutical chemistry.

The team used phenyliodine bis(trifluoroacetate) (PIFA) as an oxidant to convert THIQs (X = NR’) to iminium cations in dichloroethane (DCE) at 80 °C. These were then reacted with alkylzinc reagents coordinated with MgCl₂ and LiCl at 25 °C to give the desired products. The less reactive isochroman (X = O) can be converted under the same conditions.

The reaction proceeds without a heavy-metal catalyst under mild conditions. It tolerates sensitive functional groups such as cyano groups or boronic acid pinacol esters and can be performed on a gram scale.

• Direct and Efficient C(sp³)–H Bond Alkylation of Tetrahydroisoquinolines and Isochroman with Alkylzinc Reagents,
  Zhihua Peng, Yilei Wang, Zhi Yu, Hao Wu, Shanshan Fu, Linhua Song, Cuiyu Jiang,
  Adv. Synth. Catal. 2019.
  https://doi.org/10.1002/adsc.201900023