Fast, solvent-free asymmetric alkynylation of prochiral sp3 C–H bonds in a ball mill for the preparation of optically active tetrahydroisoquinoline derivatives

Solvent-free asymmetric cross-dehydrogenative-coupling (CDC) reaction between the sp3 C–H bond of prochiral CH2 and terminal alkynes was first studied under High-Speed Ball-Milling conditions. A series of optical active 1-alkynyl tetrahydroisoquinoline derivatives were achieved by using recoverable copper balls together with PyBox chiral ligand in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). All coupling products were obtained in good yields at short reaction time with enantiomeric excesses up to 79%.