Cross Dehydrogenative Coupling Reactions by Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 107

5.3.1 Asymmetric Alkynylation of Prochiral C(sp 3 )-H Bonds
Traditional strategies for building chiral C1-substituted tetra-
hydroisoquinolines include (1) catalytic asymmetric transfer hydrogenation
of C1-substituted dihydroisoquinolines or acyclic imines or iminium inter-
mediates, 18 such as Pictet-Spengler reaction, Bischler-Napieralski reaction
and Pomeranz-Frisch cyclization, (2) catalytic asymmetric addition reactions
to the C ¼ N bonds of isoquinoline scaffolds, 19 and (3) catalytic asymmetric
intramolecular allylic-amination reactions. 20 Although these methods give
target products with desired enantioselectivity, harsh conditions and complex
operations limit their applications. Quite recently, Li et al. first reported
their asymmetric CDC reaction between tetrahydroisoquinolines and terminal
alkynes, providing an ecient method to build up chiral C1-alkyne tetra-
hydroisoquinolines. 21 In 2012, an organocatalysis/copper-catalyzed asym-
metric CDC reaction of tertiary amines with olefins was reported by Wang et al.
to access diverse optically active C1-alkene tetrahydroisoquinolines. 22 At the
same time, Chi et al. described an enantioselective CDC reaction of aldehydes
and tertiary amines, which allowed optically active b-amino alcohols that
contain tetrahydroisoquinoline units to be synthesized. 23
Inspired by Li's work, a faster and more ecient synthetic method was in-
vestigated to determine the possibility of finishing the asymmetric CDC reaction
under ball milling conditions. 24 By adding Pybox-1 to the reaction mixture dis-
cussed in Section 5.2.2, the desired product with acceptable enantioselectivity
was obtained in 40 min. Several copper catalysts and chiral ligands (Scheme 5.5)
were tested; the system of copper balls and Pybox-1 was the optimum one.
A series of a-alkynylamine derivatives were prepared in good yields with
moderate to good enantioselectivity in a short time (Table 5.5). Strong
substitution effects were observed. Electro-donating groups on tetra-
hydroisoquinolines gave relatively higher enantioselectivities but

lower

O O

O O

PPh 2
PPh 2

N

N N

N N

Ph Ph

Ph

Ph

PyBox-1 DiBox-1 BINAP

O O

O O

OH
OH

N

N N

N N

PyBox-2 DiBox-2 BINOL

Scheme 5.5 Chiral ligands tested for the reaction.
Reproduced from ref. 24, Copyright (2013), with permission from Elsevier.