2
Journal of Chemical Research 00(0)
Scheme 2. Initial results for the oxidation of methyl
2-phenylacetate: (a) the reaction of CuI, TBHP and 1a; (b) the
reaction of CuI, TBHP, 1a and pyridine; (c) the reaction of CuI,
TBHP and 1a was treated with pyridine.
With optimized reaction conditions in hand, various
aryl acetates were used to synthesize α-ketoesters (Table
2). Methyl ester 2a, ethyl ester 2b, isobutyl ester 2c and
even esters containing a benzyl group (2d and 2e) were
generated in good yields. Aryl acetates with electron-
donating and electron-withdrawing groups, such as meth-
oxy, methyl, tert-butyl, halogen and carboxylic ester, at
the para positions of the aryl rings afforded the corre-
sponding products with high yields (entries 6–12). meta-
Substituted aryl product 2m and ortho-substituted aryl
product 2n were achieved with low yields perhaps because
of steric hindrance (entries 13 and 14). 1-Naphthyl and
3-thienyl α-ketoesters were also accessible (entries 15
and 16). Furthermore, a large-scale reaction gave 2.3g
(59%) of methyl 2-(4-methoxyphenyl)-2-oxoacetate (2f)
(Scheme 3). Methyl 3-oxo-3-phenylpropanoate (4)21 was
obtained instead of methyl 2-oxo-3-phenylpropanoate
(2q) when methyl 3-phenylpropanoate (1q) was used as
the reactant (Scheme 4).
Scheme 1. Approaches for the synthesis of α-ketoesters
from aryl acetates: : (a) a direct oxidation in a dry solvent;
(b) a multistep process involving enamino carbonyl systems;
(c) a multistep process employing a diazo group; (d) this work.
analysis of the crude reaction mixture indicated that the
desired product, methyl 2-oxo-2-phenylacetate (2a), was
obtained (Scheme 2(a), Figure 1(a)). However, purification
through silica gel column chromatography was unsuccess-
ful, because the side product and 2a had identical Rf values.
1
The H NMR data of the side product were as follows: δ
7.45–7.40 (m, 2H), 7.38–7.34 (m, 3H), 5.38 (s, 1H), 3.76
(s, 3H), 1.28 (s, 9H). Combined with the reaction character-
istics of TBHP10,18,19 and the 1H NMR data of methyl 2-tert-
butoxy-2-phenylacetate,20 we speculated that the side
product was peroxide 3. Minisci’s research demonstrated
that mixed peroxides could be decomposed mainly to car-
bonyl compounds and tert-butanol by pyridine bases.18
When 3.0 equiv. of pyridine, 0.2 equiv. of CuI and 3.0
equiv. of aq TBHP were used to oxidize 1a at 50°C in one
pot, substrate 1a was unexpectedly left intact (Scheme 2(b),
Figure 1(b)). However, when the reaction mixture of CuI,
aq TBHP and 1a was treated with pyridine, peroxide 3 dis-
appeared leaving 1a and 2a in the system (Scheme 2(c),
Figure 1(c)). Through the latter protocol, pure 2a was
achieved in 13% yield (Figure 1(d)).
Based upon the above reaction facts and the relevant
publications,18,19 a possible reaction mechanism is pro-
posed in Scheme 5. Catalysed by CuO, aryl acetate 1 is
converted into peroxide 5 in the presence of TBHP with
part of the peroxide decomposing to give α-ketoester 2.
The remaining peroxide can be changed into α-ketoester 2
by further treatment with pyridine.
In order to improve the yield, different solvents (MeOH,
EtOAc, THF, DMF, DMSO and CH3CN) and other oxi-
dants (H2O2 and cumene hydroperoxide) were introduced
to the reacting system, however, in all these cases, no 2a
was detected. Catalyst screening showed that CuO and
Cu(OAc)2 gave the best yield among CuI, MnO2, FeCl3 and
Fe(acac)3 (Table 1, entries 1–6). CuO was chosen as the
catalyst. Elevating the reaction temperature was beneficial
to obtain a higher yield (Table 1, entries 7–8), and 110°C
was found to be the best. Extending the reaction time to
12h increased the yield slightly to 55% (Table 1, entry 9).
Further prolonging the reaction time to 24h attenuated the
yield (Table 1, entry 10). In view of time-saving, 4.5h was
selected as the reaction time. Loading of aq TBHP and CuO
had only a small effect on the yield (Table 1, entries 11–14).
Therefore, 0.1 equiv. of CuO and 3.0 equiv. of aq TBHP
were chosen for lower consumption.
Conclusion
In conclusion, a practical method to access α-ketoesters
from readily available aryl acetates under reflux conditions
has been developed. In the approach, aq TBHP and CuO are
employed and no additional solvents are required. Besides,
the peroxide side products in the reaction could be decom-
posed to α-ketoesters by pyridine.
Experimental sectiona
Typical procedure for the synthesis of α-
ketoesters
Aryl acetate 1a (2.0mmol, 1.0 equiv.), CuO (0.2mmol, 0.1
equiv.) and aq TBHP (6.0mmol, 3.0 equiv.) were added to a
flask connected to a reflux condenser. The flask was heated