An efficient synthesis of aryl α-keto esters

Article abstract of DOI:10.1016/j.tetlet.2005.03.199

A new one-pot approach for the synthesis of aryl α-keto ester based on the diazo transfer and oxidation of diazo group is developed.

Full text of DOI:10.1016/j.tetlet.2005.03.199

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3927–3929
An efficient synthesis of aryl a-keto esters
Ming Ma, Changkun Li, Lingling Peng, Fang Xie, Xiu Zhang and Jianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
Received 8 November 2004; revised 4 March 2005; accepted 9 March 2005
Available online 12 April 2005
Abstract—A new one-pot approach for the synthesis of aryl a-keto ester based on the diazo transfer and oxidation of diazo group is
developed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
a-Keto acids and esters have been important com-
pounds as natural products and as the building blocks
in organic synthesis. Over the past decades, various
methods have been reported for the synthesis of such
compounds. The most commonly applied synthesis of
a-keto ester is the reaction of Grignard reagent to oxalyl
chloride,1 ethyl a-oxo-1H-imidazole-1-acetate2 or
diethyl oxalate.3 The drawbacks of these approaches
are the strict anhydrous reaction condition, the func-
tional group tolerance in the preparation of Grignard
reagent, and in some cases the low yield of the reaction.
A different but interesting approach is the oxidation of
alkynyl derivatives.4 For example, Wu et al. reported a
two-step (bromination and permangnate oxidation)
reaction sequence that converts terminal alkynes to
a-keto esters.4b Ruchirauat et al. have recently reported
a novel synthesis of aryl a-keto esters based on the rear-
rangement of aryl cyanohydrin carbonate esters.5
range of substrates. For example, in NolteÕs system of
N-hydroxyphthalimide/CoII/O2 the benzylic oxidation
works poorly for the arylacetic esters with electron with-
drawing substituent in the para position and any substi-
tuent in the ortho position.7b One successful direct
oxidation of arylacetic esters has been reported by
Choudary et al., in which case the oxidant is tert-butyl-
hydroperoxide (TBHP) and the catalyst is vanadium
pillared montmorillonite.7d Under this condition, wide
range of arylacetates with different substituents were
smoothly transformed to the corresponding arylglyox-
ylic esters, with only one exception in which no oxida-
tion occurs when the aryl group was o-nitrophenyl. The
drawback of this approach is that the reaction has to
be carried out at 70 ꢁC for a prolonged time (20–96 h).
Here, we report a one-pot conversion of aryl acetic
esters to aryl a-keto ester through diazo transfer,
followed by oxidation with dimethyldioxirane generated
in situ from acetone and Oxoneꢂ (Scheme 1).
The approaches through introduction of a keto group to
a carbonyl group have also been applied to the synthesis
of a-keto acid derivatives. For example, Wasserman
et al. developed a method through the formation and
singlet oxygen oxidation of enamino carbonyl inter-
mediates.6 On the other hand, direct oxidation of aryl
acetic esters with hydrogen peroxide or molecular oxy-
gen in the presence of transition metal catalyst has
recently been reported.7 Since aryl acetic esters are
readily available starting materials, the direct oxidation
approach has the advantages over other methods. How-
ever, this approach is sometimes limited to a narrow
O
OMe
[O]
OMe
Ar
Ar
O
O
1
3
N2
ArSO2N3
Base
[O]
OMe
Ar
O
2
*
Corresponding author. Tel.: +8610 6275 7248; fax: +8610 6275
1708; e-mail: wangjb@pku.edu.cn
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.199

3928
M. Ma et al. / Tetrahedron Letters 46 (2005) 3927–3929
group generally gave satisfactory results. It is worth-
r.t
1) DBU/CH3CN/
AcHN
while to note that this new approach works well with
the substrates with more than one halogen atom substit-
uents (entries 5 and 6, Table 1). It would be difficult to
prepare this type of a-keto esters with Grignard reagent
approach. This approach is also applicable to the sub-
strate with heteroaromatic ring. For example, the sulfur
of the thiophene ring remained intact in the diazotiza-
tion and oxidation, although in this particular case,
the diazotization and oxidation were preformed sepa-
rately due to the low efficiency in the diazotization step
(excess amount of diazo transfer reagents was required).
O
SO2N3
OMe
OMe
Ar
Ar
2)
O
H O/ NaHCO
2 3
PhH/
O
O
1
3
/OxoneR
Scheme 2.
It has been well documented that the benzylic position
of the aryl acetic esters can be easily diazotized.8 On
the other hand, the diazo group can be easily oxidized
with dimethyldioxirane solution,8,9 which is generated
from Oxoneꢂ. Since the preparation of dimethyldioxi-
rane is troublesome and the yield is low,10 we considered
an oxidation with dimethyldioxirane generated in situ
from acetone and Oxoneꢂ after the diazotization of
the aryl acetate in one-pot. Thus, methyl phenylacetate
1a was treated with p-acetamidobenzene-sulfonyl
azide/DBU in CH3CN at room temperature. After the
diazotization is complete as judged by TLC, a mixture
of Oxoneꢂ/NaHCO3/benzene/H2O/acetone was added
to the reaction mixture at 0 ꢁC. The oxidation was com-
pleted within 25 min as determined by the disappearance
of the yellow color and TLC, to yield the methyl a-oxo
phenylacetate 3a in 83% isolated yield (Scheme 2).
On the other hand, it is worth-noting that one-pot reac-
tion gave low yield for aryl substrates with electron
donating group, such as methoxy group. In this case, a
considerable amount of unreacted starting material of
methyl p-methoxyphenylacetate was recovered. Obvi-
ously, the low efficiency is due to the difficulty in the first
diazotization step.
It was observed that the rates of the diazotization and
the following oxidation were dependent on the substitu-
ent of the phenyl ring. The electron-donating group re-
tards the diazotization but accelerates the oxidation,
while the electron-withdrawing group works in the
opposite way (compare entries 11 and 12 in Table 1).
For the diazotization reaction, this substituent effect is
easily understandable. The initial step of the diazo trans-
fer is the deprotonation of the a-proton by base.12 In the
oxidation step, it is reasonable to propose that the diazo
compounds are oxidized by the in situ generated
The scope of this one-pot reaction sequence is shown by
the data summarized in Table 1.11 The data indicate the
tolerance of the aromatic substituent to the reaction
conditions. The phenyl ring with electron withdrawing
Table 1. Transformation of arylacetates to aryl a-ketoesters11
Entry
1 (Ar=)
RT for diazotization (h)
RT for oxidation (min)
Yield (%)a
1
1a, C6H5–
12
48
24
12
24
12
12
24
14
24
48
2
25
30
60
90
60
20
90
40
25
25
15
120
83
84
2
1b, 1-naphthyl
1c, o-ClC6H4–
1d, m-ClC6H4–
1e, o,p-Cl2C6H3–
1f, m,p-Cl2C6H3–
1g, o-FC6H4–
1h, o-BrC6H4–
1i, p-BrC6H4–
1j, m-MeC6H4–
1k, p-MeOC6H4–
1l, p-O2NC6H4–
3
88
83
4
5
92
81
6
7
81
74
8
9
84
73
13(83)b
48
10
11
12
13
14
1m,
12
12
30
30
86c
S
1n,
99c,d
N
15
1o,
12
30
99c,d
N
a Isolation yields for two steps after column chromatography.
b Number in bracket refers to the starting material 1k recovered.
c The diazo product was isolated and purified before oxidation, and the yield refers to the oxidation step only. The diazotization step gave the diazo
compounds with the isolated yields of 65–98%.
d The oxidation was carried out with a solution of dimethyldioxirane in acetone due to the difficulty in product purification with in situ condition.
Pyridine ring was oxidized to the corresponding N-oxide.

M. Ma et al. / Tetrahedron Letters 46 (2005) 3927–3929
3929
the reaction can be easily scaled up, which makes it a
prospective method in the organic synthesis.
N
N
O
N
N
O
O O
O
+
Ar
R
Ar
CO2R
O
Acknowledgements
O
The project is generously supported by Natural Science
Foundation of China (Grant Nos. 20225205, 20390050).
, N2
O
O
References and notes
Ar
R
O
1. Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 1996, 52, 13513–13520 and references cited
therein.
Scheme 3.
2. Nimitz, J.; Mosher, H. S. J. Org. Chem. 1981, 46, 211–213.
3. Singh, J.; Kissick, T. P.; Mueller, R. H. Org. Prepr.
Proced. Int. 1989, 21, 501–504.
4. (a) Tatlock, J. H. J. Org. Chem. 1995, 60, 6221–6223; (b)
Li, L.-S.; Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427–
2430.
5. Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.;
Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1019–1021.
6. Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50,
3573–3580.
7. (a) Matsunaka, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 1999, 40, 2165–2168; (b) Wentzel, B. B.;
Donners, M. P. J.; Alsters, P. L.; Feiters, M. C.; Nolte, R.
J. M. Tetrahedron 2000, 56, 7797–7803; (c) Velusamy, S.;
Punniyamurthy, T. Tetrahedron Lett. 2003, 44, 8955–8957;
(d) Choudary, B. M.; Vidya Sagar Reddy, G.; Koteswara
Rao, K. J. Chem. Soc., Chem Commun. 1993, 323–324.
8. (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
catalytic methods for organic synthesis with diazo com-
pounds; Wiley-Interscience: New York, 1998; (b) Ye, T.;
McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160.
9. Ihmels, H.; Maggini, M.; Prato, M.; Scorrano, G. Tetra-
hedron Lett. 1991, 32, 6215–6218.
r.t
1)
DBU/CH3CN/
O
O
AcHN
SO2N3
(
)
4
(
)
4
OMe
OMe
2)
H O/NaHCO
PhH/
O
2
3
O
Ph
O
/OxoneR
80 %
4
5
Scheme 4.
O
/OxoneR
O
N2
OEt
OEt
Ph
Ph
H O
PhH/
2
O
O
NaHCO3
60 %
7
6
Scheme 5.
10. Murray, R. W.; Singh, M. Organic syntheses collected vol.
IX; Wiley: New York, 1998, p. 288–293.
11. General procedure for the one-pot transformation of
arylacetate to aryl a-ketoesters. Methyl phenylacetate 1a
(100 mg, 0.67 mmol) was dissolved in anhydrous MeCN
(5 mL), and to this solution was added DBU (72 mg,
0.48 mmol). After the solution was stirred at room
temperature under N2 for 15 min, p-acetamidobenzene-
sulfonyl azide (92 mg, 0.8 mmol) was added at 0 ꢁC. The
solution was stirred at room temperature for 12 h until the
diazotization was complete as judged by TLC. To the
solution were added benzene (5 mL), acetone (3.5 mL),
H2O (5 mL), NaHCO3 (2.16 g, 25 mmol) and Oxoneꢂ
(4.0 g, 6.5 mmol). The reaction mixture was vigorously
stirred for 25 min until the oxidation was complete as
judged by TLC and by the disappearance of the yellow
color. Water (10 mL) was added and the mixture was
extracted with diethyl ether (3 · 10 mL), and combined
organic layer was dried over anhydrous Na2SO4. Removal
of the solvent gave a crude product, which was purified by
column chromatography to give pure product 3a (90 mg,
83%).
dimethyldioxirane. The oxidation occurs through the
nucleophilic attack of the dimethyldioxirane oxygen by
the negatively polarized carbon to which the diazo
group is attached (Scheme 3).
The in situ oxidation approach can be extended to ali-
phatic esters. For aliphatic esters, because the direct
diazotization is difficult, it is necessary to convert them
to b-ketoesters first.13 Then the same one-pot diazotiza-
tion/oxidation can be applied, as demonstrated by con-
verting b-ketoester 4 to a-oxo ester 5 (Scheme 4).
On the other hand, the in situ oxidation can also be used
to oxidize the diazo group of vinyl diazo carbonyl com-
pound,14 suggesting that a double bond may tolerate the
oxidation condition (Scheme 5).
In conclusion, we have developed a new approach to
aryl a-keto esters in a one-pot manner using readily
available aryl acetate as starting material. The reaction
condition is mild (diazotization at room temperature
and oxidation at 0 ꢁC), the operation is simple, and
12. Regitz, M. Synthesis 1972, 351–373.
13. Taber, D. F.; You, K.; Song, Y. J. Org. Chem. 1995, 60,
1093–1094.
14. Shi, W.; Ma, M.; Wang, J. Chin. Chem. Lett. 2004, 15,
911–914.