C. Liu et al. / Tetrahedron Letters 56 (2015) 5973–5976
5975
Table 3
Library synthesis in continuous-flow system
OH
R2
O
continuous-flow
R1
R1
R2
Entrya
Substrates
Product no.
Yieldb (%)
R1
R2
1
2
3
4
5
6
7
8
9
Ph
o-CH
o-ClPh
o-BrPh
o-IPh
o-OHPh
m-NO
m-CH
m-ClPh
m-BrPh
p-NO
p-CH
p-ClPh
p-BrPh
p-FPh
p-CF
p-OMePh
p-NH
Ph
p-CH
p-ClPh
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
9
98
96
95
97
97
97
93
97
97
96
93
96
96
96
95
94
98
90
98
99
97
96
94
94
97
95
96
96
97
98
93
3
Ph
10
11
12
13
14
15
16
17
1
18
3
19
20
21
5
2
Ph
Ph
3
10
11
12
13
14
15
16
17
18
19
20
2
Ph
Ph
3
3
Ph
H
H
2
Ph
6
4
CH
CH
CH
CH
CH
H
CH
H
CH
H
3
3
3
3
3
3
Ph
22
23
24
25
26
27
28
29
30
31
32
33
Figure 3. Optimization of flow rate and residence time in continuous-flow system.
a, study of flow rate; b, study of residence time; c, coil reactors with various
21
22
23
(
p-BrPh
p-FPh
volumes, ID = 0.5 mm).
24
25
26
27
28
29
2-Furan
2-Furan
2-Thiophene
2-Thiophene
3-Pyridine
3-Pyridine
Ph
3
3
3
were realized. Higher yields of product 2, 3, and 4 were obtained.
More interestingly, 97% of 5 and 88% of 6 were produced, while
the reactions were inhibited in batch conditions. This proved that
continuous-flow could improve the functional-group compatibility
of the oxidation. Unfortunately, oxidation of aliphatic alcohols was
unsuccessful in continuous-flow system, which is due to the low
reactivity. Oxidation of 4-nitrobenzyl alcohol was found at 40%
decreasing in yield (Table 2, entry 1). However, the oxidation
was found in excellent selectivity in continuous-flow system
compared with batch reaction (Fig. 2). Although a yield of 72% of
aldehyde was produced in batch, there was also over oxidation
to acid observed. While, only aldehyde was formed in continu-
ous-flow system, which is probably due to the continuous feature
in continuous-flow system.
CH
Ph
H
30
31
2,6-Dichloro-Ph
OH
3
2
34
98
a
Reaction conditions: store solution A: 0.667 M of alcohol in dioxane, flow rate
0.327 ml/min; store solution B: 1.333 M of hydrogen peroxide, 2 mol % of sodium
bromide, and 1 mol % of sulfuric acid in dioxane, flow rate 0.327 ml/min, 70 °C,
unless otherwise noted.
b
Yield of isolated product.
4
-Nitrobenzyl alcohol was chosen to optimize the reaction con-
donating or electron-withdrawing substituents in benzylic
alcohols as regards reaction conversion (Table 3, entries 1–23).
Meanwhile, steric hindrance, which could affect oxidation process
dramatically, could also be overcome, since both 1° benzylic alco-
hols (Table 3, entries 1–18 and 31) and 2° benzylic alcohols
(Table 3, entries 19–23, 30 and 32) were oxidized at almost quan-
titative conversion. Oxidation of hetero aryl alcohols, such as
furan-, was addressed efficiently (Table 3, entries 24–29), which,
ditions of continuous-flow system. Flow rate and residence time
were investigated (see Fig. 3). In a fixed coil reactor with a total
volume of 0.785 mL, residence time was adjusted from 0.6 min to
.6 min, corresponding to flow rate from 1.308 mL/min to
.496 mL/min. Better conversions were observed with longer resi-
dence time, initially. A yield of 32% was obtained at 1.2 min.
However, the reaction yield was reduced by extending the
residence time after 1.2 min. This is a common phenomenon in
continuous-flow system, since a longer residence time brings a
smaller average velocity in a fixed reactor, which leads to weaker
mass transfer. Therefore, volume of the reactor was increased by
extending length of the coil reactor to improve the residence time
at the modified flow rate. Eventually, a yield of over 90% was
obtained at a residence time of 3 min by increasing volume of
the reactor to 1.962 mL. Constant yields were obtained after
1
0
À
+
again, indicated that the H O /Br /H oxidation system was practi-
2
2
cal. Oxidation of benzylic alcohols with sensitive groups, which
could react with hypobromite, was also performed successfully
(Table 3, entries 6, 17 and 18).
In a typical oxidation pathway, 1° hydroxyl groups were pre-
ferred rather than 2° hydroxyl group. Generally, oxidation of 2°
benzylic alcohols containing 1° hydroxyl group demands compli-
cated protection and de-protection process of 1° hydroxyl group.
Since reactions of both 1° and 2° benzylic alcohols showed similar
results in this novel process, selectivity of oxidation of 1° and 2°
benzylic alcohols was investigated.
A diol 35 containing both 1° and 2° hydroxyl groups was oxi-
dized directly (Scheme 1). Interestingly, the product 36 was
formed in a yield of 82% with a little 37 detected, which suggested
that reactivity of 2° hydroxyl group was better than 1° hydroxyl
3
min at a total flow rate of 0.654 mL/min. (Two source solutions
were infused into the coil reactor at 0.327 mL/min, respectively.)
With the optimized reaction conditions in continuous-flow
system, a library of aldehydes and ketones was synthesized from
various alcohols (Table 3).
Generally, all the reactions were successful with high yields.
There was no obvious effect observed from either electron-