J. Xu, J. Hua, M. Bian et al.
Tetrahedron Letters 67 (2021) 152876
of residence time and continuously collected products, which
could be easily operated and effectively applied to industrial
amplification [15]. Herein, we reported a method for synthesizing
pentafluorophenoxy ketone via DBH/DMSO mediated oxidative
coupling of pentafluorophenol with alkenes at room temperature
in continuous flow reactor. As shown in Fig.1. This continuous flow
reactor system consists of two syringe pumps, one T-piece
micromixers and one microreactors. The volume of the syringe
and microreactors are 10 mL and 1.96 mL. The molar ratio and
the reaction time are controlled by changing the flow rate of the
syringe. The temperature is controlled by an oil bath.
In our initial studies, styrene 1a and Pentafluorophenol 2a were
chosen as a model substrate for application in the microfluidic
reactor. The product 3a could be formed under the system of
DBH/DMSO. Encouraged by this result, the reaction conditions
have been explored and the results were summarized in Table 1.
Initially, different bases were screened, including DBU, Et3N,
DMAP, which showed that Et3N was found to be the favourable
choice (Table 1, entries 1–3). Then the DBH (0.5 equiv.) and the
Pentafluorophenol 2a (1 equiv.) were exhibited the better effect
with 81% yield of pentafluorophenoxy ketone 3a (Table 1, entry
4). Furthermore, the temperature was also tested. When the
reaction temperature was raised to 40 ℃ and 60 ℃, the yields of
3a were decreased (Table 1, entries 8–9). In order to improve the
yield of the product 3a, the residence time in the reactor was
screened. But the yield of 3a was reduced regardless of decreasing
or improving the flow rate. (Table 1, entries 10–11). The yield was
slightly decreased with the extension of the reaction time due to a
smaller average speed in a microfluidic reactor and leads to weaker
mass transfer in the continuous flow system.
Optimizations of reaction condition for the microfluidic synthe-
sis of pentafluorophenoxy ketone from styrenes and pentafluo-
rophenol have been obtained. Then the optimizations in batch
were also screened to compare with microfluidic reactor (support-
ing information). The best yield of 3a reached to 64% in batch
(Table 1, entry 12), which was weaker than that in microfluidic
reactor. And the reaction time prolonged to 12 h in batch, which
was much longer than 10 min. Comparative results indicated that
the microfluidic reactor could enhance the reaction efficiency by
providing efficient mixing between the reactants, which was
weaker in batch.
Having established the optimal reaction conditions in hand, we
investigated the substrate scope of this transformation. As shown
in Table 2, a variety of styrene derivatives including both elec-
tron-donating groups (Me, MeO, AcO, t-Bu, Ph) and halogenated
groups (F, Cl, Br, CF3) were chosen to certificate the general
applicability of the current procedure, and all substrates reacted
successfully for the synthesis of the corresponding products in
good yields (Table 2. 3b-3q). Generally, the positions of
substitution patterns (para-, meta-, and ortho-) have no apparent
influence for this reaction (Table 2, 3b-3d, 3i-3j, 3k-3m, 3n-3o).
It is noteworthy that the yield (3b-3h) of the substrate containing
electron-donating groups is similar to electron-withdrawing
groups (3i-3p). However, the strong electron-withdrawing groups
(NO2) substituted styrene failed to gain product (Table 2, 3r). In
addition, heteroarenes including indene and 2-Vinylnaphthalene
were also applicable for these conditions. The corresponding prod-
ucts 3s and 3t were obtained in 52% and 61% yield (Table 2, 3s, 3t).
But the reactions both failed when the styrene was replaced by ali-
phatic alkenes or a, b-unsaturated carbonyl. (Table 2, 3u, 3v).
Fig. 1. A continuous flow reactor system.
Table 1
Optimization of reaction conditions in continuous-flow reactor.[a,b]
Entry
base
DBH (eq)
2a (eq)
T (℃)
RT (min)
Yield[b] (%)
1
2
3
4
5
6
7
8
DBU
Et3N
DMAP
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
1
1
1
1
1
1
1
1
0.5
2
1
1
rt
rt
rt
rt
rt
rt
rt
40
60
rt
rt
rt
10
10
10
10
10
10
10
10
10
5
33
63
20
81
42
35
65
60
46
51
63
64
0.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
9
10c
11d
12e
1
1
1
15
–
a Reaction conditions: Solution A: 1.5 mmol 1a in 5 mL DMSO, flow rate 0.098 mL/min; Solution B: 0.75 mmol DBH, 0.75 mmol Et3N and 1.5 mmol 2a in 5 mL DMSO, flow rate
0.098 mL/min, unless otherwise noted.
b
Isolated yields.
c
Solution A: 3 mmol 1a in 5 mL DMSO, flow rate 0.196 mL/min; Solution B: 1.5 mmol DBH, 1.5 mmol Et3N and 3 mmol 2a in 5 mL DMSO, flow rate 0.196 mL/min.
Solution A: 0.75 mmol 1a in 5 mL DMSO, flow rate 0.049 mL/min; Solution B: 0.38 mmol DBH, 0.38 mmol Et3N and 1.5 mmol 2a in 5 mL DMSO, flow rate 0.098 mL/min.
The reaction is in a batch instead of a continuous-flow reactor.
d
e
2