Cross Dehydrogenative Coupling Reactions by Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 103

Table 5.2 (Continued)

MeO

N

MeO

7m

65%, 50 min
a Reactions were carried out with 1 (1.0 mmol), 6 (1.1 mmol), DDQ (1.0 mmol), silica gel (0.5 g)
and two copper balls (d ¼ 8.0 mm) at 30 Hz, 20-50 min. Isolated yields based on 1.

substrates. As with terminal alkynes, the coupling between indoles and
tetrahydroquinolines also needs the participation of metal catalyst. Fortu-
nately, the reaction could also be eciently promoted by copper balls and a
slight excess of the tetrahydroisoquinoline was conducive to the conversion.
Various indoles were tested to afford desired products in moderate to good
yields (Table 5.3).
Under the milling conditions, the electronic character of the substituents
on different positions of indole did not show a significant influence on the
yield. In contrast, using 6,7-dimethoxy-2-phenyl-tetrahydroisoquinoline (1d)
as pro-electrophile leads to a relatively lower yield.
Compared with traditional solvent-free reaction under heating conditions,
the mechanical activated solvent-free conditions proved to be advantageous
due to a short reaction time and recoverable catalyst (Table 5.3; see in
parentheses).

5.2.4 Milling Parameters
5.2.4.1 Milling Frequency (v) and Milling Time (t)
The milling frequency v was proven to be one of the most important par-
ameters to be considered as it influences yield, selectivity or similar properties
during ball milling. Besides v, the consideration of milling time t is almost as
important. Commonly, an increase of t leads to higher yields in ball milling
promoted organic reactions. 16 However, in some cases a decrease in yield and
enantioselectivity was attributed to the prolonged time of reaction. Even
though some studies have paid attention to the combined effects of v and t,
this issue is still of specific interest due to its unpredictability.
Evaluation of the process parameters (t & v) in the case of C(sp 3 )-C(sp 3 )
coupling reaction was conducted by using tetrahydroisoquinoline 1a and
nitromethane 2a as substrates. The results showed that the main influence
on the yields come from the milling frequency v, while milling time t has
little effect (Figure 5.1). When the reaction was performed at lower fre-
quencies, such as 20 Hz, a few substrates were still present in the crude
product, probably due to the diminished amount of energy per impact.
Furthermore, ball milling with pauses also resulted in lower conversion.