Cross Dehydrogenative Coupling Reactions by Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 109

Table 5.5 (Continued)

OMe

OMe

N

∗

OMe

N ∗

N N

∗

∗

O OMe O OMe

F

7o 7p 7q 7r

72%, 62% ee,
40 min

60%, 79% ee,
50 min
a Reactions were carried out with 1 (1.0 mmol), 6 (1.1 mmol), DDQ (1.0 mmol), Pybox-1
(10 mol%), silica gel (0.5 g) and two copper balls (d ¼ 12.0 mm) at 30 Hz for 10 min followed by
a 5 min pause until the finish of reaction. Isolated yields based on 1.
b Enantiomeric excess determined by HPLC analysis using a chiral stationary phase.

71%, 52% ee,
40 min

65%, 34% ee,
40 min

yields. Noticeably, higher ee's were obtained by using propiolates as pro-
nucleophiles, while aliphatic alkynes give moderate yield with low
stereoselectivity.
As in previous work, 6,7-dimethoxytetrahydroisoquinolines still show
low activity in this asymmetric CDC reaction, which requires further
activation. By adding a catalytic amount of Cu(OTf) 2 to the system, an
improvement in yields was observed, but the enantioselectivity remained low
(Table 5.6).

5.3.2 Effects on Enantioselectivity
It is widely accepted that high temperatures disfavor asymmetric reactions.
Under ball milling conditions, higher frequency usually leads to a higher
reaction temperature, which may cause a decrease in enantioselectivity. As
an uncommon technique, it is hard to control the change of temperature
during the ball milling procedure. To avoid overheating, the strategy
of intermittent milling 16a,17a,b was taken to cool down the reaction. The
effect of frequency on reaction enantioselectivity was then investigated in
detail.
Interestingly, high frequency gave the best result after 30 min, while lower
frequencies required prolonged reaction time and gave lower enantioselec-
tivity (Table 5.7, entries 1-4). Noticeably, when the reaction was performed
without a pause at 30 Hz, lower enantioselectivity was obtained after 30 min,
while the yield was improved to 75% (Table 5.7, entry 5).
Further research was conducted to explain the phenomenon. Owing to the
good conductivity of heat of the stainless steel vial, the inside temperature
was probably similar to the outside temperature. After the reaction was
completed, the outside temperature was measured (about 25-27 1C at 30 Hz;
23-26 1C at 25 Hz; 22-24 1C at 20 Hz, o 20 1C at 15 Hz). Since an intermittent