2
and it is a rapidly growing field of research.7 In particular, flow
chemistry technology has been successfully applied for the
preparation of fine chemicals, natural products, and
pharmaceutical building blocks.8
Table 1. Optimization of the flow reaction system conditions
for the synthesis of 2,2,2-trichloroacetophenone
In a conventional batch reactor, reaction times are long and
the product yields are typically low. In addition, it is difficult to
scale up due to the difficulty in conducting experiments while
maintaining same temperature in all regions of the batch reactor.
Conversely, flow chemistry has advantages such as easy control
of heat and mass transfer, controlled mixing, and high surface to
reactor volume ratio.9 When reaction conditions are optimized in
a flow system, several reactors can be placed in series to produce
products without scale up. In a batch reactor, it is difficult to
control rapid exothermic reactions. However, the high surface to
reactor volume ratio in flow systems allows for efficient heat
transfer and the effective removal of heat generated from the
reaction. Owing to the numerous advantages of flow chemistry,
higher yields and selectivity can be obtained when compared to
conventional batch reactors in organic syntheses.10
Residence
Time
(min)
Temp
(°C)
Yield
(%)c
Entry
Solvent Conditiona
BPRb
1
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
I
X
X
X
X
O
O
O
X
X
X
X
X
X
X
25
25
50
60
80
70
70
25
40
10
5
120
240
120
20
20
20
40
20
20
20
20
10
5
22
25
I
3
I
-
4
II
72
To optimize the conditions in flow reaction systems, two
reservoirs were prepared and connected to the flow channel.
Phenylpropiolic acid was dissolved in a mixture of water and
CH3CN and transferred to reservoir A. Trichloroisocyanuric acid
was slowly added to the CH3CN solvent and transferred to
reservoir B. As shown in Table 1, first, we used a low
concentration of TCCA in CH3CN and allowed it to flow at 25
°C. When the mixture was flowed for 120 min,
trichloroacetophenone was formed in 22% yield (entry 1). The
yield of the product was similar even with a longer residence
time. However, the flow clogged at 50 °C (entry 3) and to solve
this issue, acoustic radiation was introduced using a sonicator
(entry 6 and 7). Another potential solution was to use three-fold
higher TCCA concentration than phenylpropiolic acid
concentration (entries 4 and 5). With higher concentrations, a
72% product yield was obtained at 60 °C (entry 4), but the yield
decreased to 54% at 80 °C (entry 5). With much higher
concentration, the desired product was formed in 71% yield when
the residence time was 20 min (entry 6). Clogging issues were
apparent when the reaction was flowed for 40 min (entry 7). As
an alternative method to solve the clogging issue, we used DMF
as the reaction solvent. The concentration of the reactant was
kept 0.3M and the reaction was flowed without a back-pressure
regulator. This system provided the product in 71% yield at 25
°C and in 59% yield at 40 °C (entries 8 and 9). When the reaction
temperature was decreased to 10 °C and 5 °C, the product yield
was increased to 79% and 84%, respectively (entries 10 and 11).
When the residence time was reduced to 10 and 5 min, the
product yields were 86% and 91%, respectively (entries 12 and
13). However, the product yield decreased to 69% at 0 °C (entry
14). It should be noted that this flow reaction system provided the
desired product in better yields than the corresponding batch
reaction system. No benzoic acid by-products were found in the
reaction mixture and trichloroacetophenone was generated in 5
min
5
II
53
6
III
III
IV
IV
IV
IV
IV
IV
IV
71
7
-
8
71
9
DMF
59
10
11
12
13
14
DMF
79
DMF
84
DMF
5
86
91(90)d
DMF
5
DMF
0
5
69
aCondition I: Reservoir A = 1a (4.25 mmol) / H2O (68.0 mmol) / CH3CN
(15.0 mL), Reservoir B = TCCA (4.25 mmol) / CH3CN (15.0 mL),
Condition II: Reservoir A = 1a (4.25 mmol) / H2O (68.0 mmol) / CH3CN
(15.0 mL), Reservoir B = TCCA (12.75 mmol) / CH3CN (15.0 mL),
Condition III: Reservoir A = 1a (8.50 mmol) / H2O (136.0 mmol) /
CH3CN (15.0 mL), Reservoir B = TCCA (12.75 mmol) / CH3CN (15.0
mL). The reaction mixture was treated with a sonicator. Condition IV:
Reservoir A = 1a (4.25 mmol) / H2O (68.0 mmol) / DMF (15.0 mL),
Reservoir B = TCCA (4.25 mmol) / DMF (15.0 mL) bBPR = back pressure
regulator,
X = no BPR, O =
with BPR. cDetermined by gas
chromatography with an internal standard. dIsolated yield.
With the optimized flow conditions, the resultant substituted
aryl propiolic acids were evaluated, as shown in Scheme 1. Halo-
substituted aryl propiolic acids 1b, 1c, and 1d gave
corresponding 2,2,2-trichloroacetophenone derivatives 2b, 2c,
and 2d in 88%, 89%, and 90% yields, respectively. Aryl
propiolic acids containing electron-withdrawing groups such as
cyano and ketone groups provided the desired product in good
yields. 1-Naphthylpropiolic acid and (1,1’-biphenyl)-4-
Scheme 1. Synthesis of 2,2,2-trichloroacetophenone
derivatives using a flow reaction system. Reaction condition:
Reservoir A = 1 (4.25 mmol) / H2O (68.0 mmol) / DMF (15.0
mL), Reservoir B = TCCA (4.25 mmol) / CH3CN (15.0 mL)
aIsolated yield. bYield from the batch reaction. Reaction
condition : 1 (2.0 mmol), TCCA (2.2 mmol) and H2O (32.0
mmol), were reacted in CH3CN (5.0 mL) at 25 oC for 12 h.
ylpropiolic acid afforded the
corresponding 2,2,2-
trichloroacetophenone derivatives 2g and 2h in 75% and 78%
yields, respectively. p-Tolylpropiolic acid gave 2l in 88% yield.
This flow system provided higher yields than the batch system in
all cases and the desired products were formed in 5 min