Angewandte
Chemie
Herein, we present a transition-metal-free Cs2CO3-cata-
lyzed direct a-hydroxylation of carbonyl compounds with O2
for the synthesis of tertiary a-hydroxycarbonyl compounds at
room temperature (Scheme 2c). The significance of the
present finding is fourfold: 1) The reaction shows broad
generality: various carbonyl compounds, including ketones,
esters, amides, aldehydes, and b-dicarbonyl compounds, could
be efficiently converted into the desired tertiary a-hydroxy-
carbonyl compounds. Bioactive compounds and drugs could
be modified by this procedure. 2) Molecular oxygen is
employed as a reagent and the sole oxidant, thus making
this method very environmentally friendly. 3) Simple and
readily available Cs2CO3 emerges as an efficient catalyst,
rather than a transition-metal catalyst, which is often
expensive and is required to be completely removed from
products, especially in the synthesis of pharmaceutical com-
pounds. 4) The Cs2CO3/P(OEt)3/O2 system is inexpensive,
mild, and readily handled with high catalytic efficiency and
safety.
with just a catalytic amount of Cs2CO3 (Table 1, entry 3). The
Pd, Cu, Fe, Ru, Ir, Ni, and Ag content in the Cs2CO3, P(OEt)3,
and DMSO used was less than d = 0.1 ppm in each case
(ICPMS analysis; see the Supporting Information), which
indicated that this hydroxylation reaction is promoted by
Cs2CO3 itself rather than catalyzed by trace metal impurities.
Reactions in the presence of other bases as potential catalysts,
such as K2CO3, Na2CO3, CsOAc, and CsNO3, did not proceed
(Table 1, entries 4–7; see also the Supporting Information).
Product 2a was observed in trace amounts when CsOH was
employed (Table 1, entry 8). The yield decreased slightly
when PPh3 was used instead of P(OEt)3 (Table 1, entry 9); in
contrast, the reaction did not proceed in the presence of
Na2S2O3 (entry 10). The use of other solvents, such as DMF,
NMP, and toluene, led to the formation of 2a in very low
yields (see the Supporting Information). Notably, a reaction
in the absence of Cs2CO3 did not proceed, and only a trace
amount of 2a was formed without P(OEt)3 (Table 1,
entries 11 and 12). This transformation also proceeded well
in air, but the yield of 2a was slightly lower (Table 1,
entry 13). In contrast, the reaction did not occur under
argon (Table 1, entry 14).
À
Recently, copper-catalyzed aerobic oxidative C H func-
tionalization reactions have been significantly improved.[11,12]
Inspired by these results, we initially investigated the copper-
catalyzed aerobic oxidation of 2-methyl-1-phenylpropan-1-
one (1a) under O2 in the presence of Cs2CO3 as a base at room
temperature. To our delight, the expected hydroxylation
product 2a was obtained; however, the yield was very low
(Table 1, entry 1). The efficiency of the reaction was signifi-
cantly improved by the addition of inexpensive and readily
available P(OEt)3 (Table 1, entry 2). We were surprised to
find that the hydroxylation reaction also took place efficiently
The above results indicate that Cs2CO3 is a competent
catalyst for the a-hydroxylation of carbonyl compounds. The
scope of the transformation was then investigated under the
standard conditions (Table 1, entry 3; Scheme 3). Hydroxy
and fluoride groups were compatible with this protocol
(products 2b,c). Naphthyl and heteroaryl substrates could
also participate in the reaction (products 2d–f), and a variety
3
À
of tertiary C(sp ) H bonds at the a-position of ketones could
be hydroxylated in excellent yields (products 2g–p). The
Table 1: Screening of different parameters.[a]
Entry
Catalyst
Base
Additive
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13[c]
14[d]
15[e]
CuBr2
CuBr2
Cs2CO3
Cs2CO3
–
5
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
PPh3
Na2S2O3
P(OEt)3
–
P(OEt)3
P(OEt)3
P(OEt)3
91 (87)
91 (87)
0
0
0
Cs2CO3
K2CO3
Na2CO3
CsOAc
CsNO3
CsOH
Cs2CO3
Cs2CO3
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
–
–
–
–
–
–
–
–
–
–
–
–
0
trace
78 (74)
trace
0
trace
76 (73)
0
79 (75)
[a] Reaction conditions: 1a (0.5 mmol), catalyst (0.1 mmol), base
(1.0 mmol), additive (1.0 mmol), DMSO (2 mL); the mixture was stirred
at room temperature under O2 (1 atm) for 24 h. [b] The yield was
determined by GC with biphenyl as an internal standard. The value in
parentheses is the yield of the isolated product. [c] The reaction was
carried out in air (1 atm) for 48 h. [d] The reaction was carried out under
Ar (1 atm). [e] The reaction was carried out in the dark. DMSO=di-
methyl sulfoxide.
Scheme 3. Cs2CO3-initiated a-hydroxylation of ketones with O2. For the
standard reaction conditions, see Table 1, entry 3. Yields shown are for
the isolated products. [a] Reaction time: 72 h. [b] The reaction was
carried out with 1.0 equiv of Cs2CO3. [c] The yield was determined by
1H NMR spectroscopy.
Angew. Chem. Int. Ed. 2014, 53, 548 –552
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
549