Organic Letters
Letter
a
Scheme 1. Chemosynthetic Strategies for Synthesis of α-
Table 1. Optimization of reaction conditions.
b
b
entry TBAI (mol %) CH CN/H O conv (%)
yields of 2a (%)
3
2
1
2
3
4
5
6
7
8
9
8
9
1
1
1
1
1
1
30
30
30
30
30
50
30
30
30
30
30
30
30
30
30
30
30
CH CN
68
100
100
100
89
100
71
64
43
87
93
81
7
31
61
77(73)
3
15/1
20/1
25/1
30/1
20/1
c
68
57
78
29
22
9
66
65
49
0
d
e
f
g
h
20/1
20/1
20/1
20/1
20/1
20/1
20/1
20/1
i
0
1
2
3
4
5
j
k
l
0
10
3
0
0
0
68
m
n
100
a
Reaction conditions: styrene (0.2 mmol), Fe@NPC-800 (10 mol %
of Fe), TBHP (5 equiv,70 wt % in water), TBAI (30 mol %),
b
CH CN/H O (2 mL, v/v), 90 °C, 12 h. Determined by NMR.
3
2
c
d
e
Isolated yield. THF/H O (2 mL, v/v = 20/1). MeOH/H O (2
mL, v/v = 20/1). DMF/H O (2 mL, v/v = 20/1). 8 h. 80 °C. 4
equiv of TBHP (70 wt % in water). Without Fe@NPC-800.
2
2
f
g
h
i
2
j
k
l
m
Without TBHP. Fe(NO ) instead of Fe@NPC-800. NPC-800
3
3
n
instead of Fe@NPC-800. Styrene (2 mmol), Fe@NPC-800 (10 mol
of Fe), TBHP (5 equiv,70 wt % in water), TBAI (30 mol %),
CH CN/H O (20 mL, v/v), 90 °C, 24 h.
%
3
2
that the proportion of H O has an effect on selectivity to the
2
desired product 2a (Table 1, entries 3−5). The maximum
Styrenes with electron-donating (Me, OMe, PhthN) and
-withdrawing groups (CN, CF , CO R) were both suitable for
selectivity to 2a was achieved in a CH CN/H O (v/v = 20/1)
3
2
3
2
mixture as the solvent (Table 1, entry 3). Other organic
solvents such as THF, MeOH, and DMF were used to replace
CH CN under the optimal ratio (organic solvent/H O = 20/
the reaction (1e, 1f, 1h, 2i, 1k, 1m−1p),; the corresponding α-
keto acids (2e, 2f, 2h, 2i, 2k, 2m−2p) were afforded in 70−
85% yields. The reaction was not sensitive to the steric effect;
those styrenes with bulky substituents, such as 1-methyl-2-
vinylbenzene (1g) and 2,4-dimethoxy-1-vinylbenzene (1j),
afforded their respective product (2g, 2j) in 71% and 73%
yield, respectively. In particular, the phenol (2l) as an easily
oxidized group was also tolerated under this condition. Other
aromatic rings or heterocycles substituted alkenes, such as 2-
vinylnaphthalene (1q), 2-vinylthiophene (1r), 2-vinylfuran
(1s), and 1-tosyl-2-vinyl-1H-pyrrole (1t) were also applicable
to afford their corresponding α-keto acid (2q−2t) in 67% to
82% yields. Moreover, aliphatic alkenes, such as allylbenzene
(1u) and vinylcyclohexane (1v), also showed moderate
reactivity for this oxidative process, and the corresponding
aliphatic α-keto acid (2u, 2v) were obtained in 51% and 63%
yields, respectively, highlighting the generality of the method-
ology. Of note, the product of α-keto acid 2u could be
isomerized into more stable enol isomer.
3
2
1
); the results show that the CH CN/H O mixture is the best
3 2
reaction medium (Table 1, entries 7−9). To further improve
reaction efficiency, the amount of TBAI was increased from 30
to 50 mol %, and a negligible impact on the reaction was
observed (Table 1, entry 6). As a follow-up optimization, other
reaction factors such as reaction time, reaction temperature,
and the equivalent of oxidant were extensively inspected.
Lower conversion of 1a was detected under lower temper-
atures, shorter reaction times, or less amount of oxidant (Table
1
, entry 7−9). In addition, the reaction either in the absence of
catalyst or oxidant, or using Fe salts or NPC-800 without the
introduction of iron as catalyst under otherwise equal
conditions led to no conversion, indicating the indispensable
of catalyst and oxidant for the success of this transformation.
Remarkably, a scale-up reaction (ca. 2 mmol) was also feasible
with a longer reaction time (24 h) under the optimized
conditions (Table 1, entry 15).
The stability and reusability are of great importance for the
heterogeneous catalyst. Thus, we investigated the recyclability
of the catalyst Fe@NPC-800 for the benchmark reaction under
the optimized conditions. As shown in Figure 1, the catalyst
exhibited good stability and can be reused at least six times
without significant loss in both reactivity and selectivity,
strongly indicating its robust stability.
With the optimized conditions in hand, we then explored
the scope of alkenes to α-keto acids. As depicted in Table 2, all
substrates tested afforded their corresponding desired α-keto
acids in moderate to good yields. The halogen substituted
styrenes (1b−1d) could be smoothly converted into
corresponding α-keto acids (2b−2d) in 72−80% yields.
5
918
Org. Lett. 2021, 23, 5917−5921