Synthesis of aryl α-keto-acids via the Cu-catalyzed conversion of aryl nitroaldol products

Article abstract of DOI:10.1016/S0040-4039(99)02179-6

Cu(II) salts efficiently catalyze the conversion of a variety of aryl nitroaldol products to afford the corresponding aryl α-keto-acids in high yields using 30% aq. AcOH:MeOH (1:1) as the solvent. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02179-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 959–961
Synthesis of aryl α-keto-acids via the Cu-catalyzed conversion of
aryl nitroaldol products
Milind D. Nikalje, Iliyas Sayyed Ali, Gajanan K. Dewkar and A. Sudalai
∗
Process Development Division, National Chemical Laboratory, Pune, India
Received 13 September 1999; revised 19 November 1999; accepted 24 November 1999
Abstract
Cu(II) salts efficiently catalyze the conversion of a variety of aryl nitroaldol products to afford the corresponding
aryl α-keto-acids in high yields using 30% aq. AcOH:MeOH (1:1) as the solvent. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: nitroaldol; conversion; catalyst; keto-acid.
We wish to report a new catalytic method for the synthesis of α-keto-acids in a single step from a
1
variety of aryl nitroaldol products, prepared from Henry reactions. Several synthetic procedures have
been reviewed in the literature for the synthesis of α-keto-acids which involve multiple steps or use
2
costly or hazardous reagents. The use of stoichiometric anhydrous CuSO has been reported for the
4
3
conversion of 1-alkyl-2-nitrocyclohexanols to nitroketones via a retro-Henry reaction. We here report
that catalytic Cu-salts in 30% aq. AcOH:MeOH (1:1) can be useful for the conversion of aryl nitroaldol
products into aryl α-keto-acids (Scheme 1). Table 1 shows a comparative study of the use of Cu-salts and
other oxidizing reagents for the conversion of aryl nitroaldol products to α-keto-acids.
The results of Cu(II)-salt catalyzed conversion of aryl nitroaldol products to the corresponding α-
†
keto-acids is summarized in Table 2. The catalytic activity of CuSO ·5H O was found to be low when
4
2
compared to Cu(OAc) ·H O towards the reaction. It was observed that, for aryl nitroaldol products
2
2
∗
Corresponding author. E-mail: sudalai@dalton.ncl.res.in (A. Sudalai)
Typical experimental procedure: A mixture of 1-(4-chlorophenyl)-2-nitroethanol (0.5 g; 2.48 mmol), Cu(OAc)2·H
†
2
O (0.05
g, 10 mol%) and 30% aq. AcOH:MeOH (1:1, 10 ml) was heated under reflux at 90°C (bath temperature) for 3 h. After 1 h,
progress of the reaction could be seen by the formation of a solid product precipitating from the reaction mixture (also monitored
by TLC, 15% EtOAc in pet-ether). The reaction mixture was then poured into water and extracted with EtOAc (25 ml×3) and
2 4
dried over anhydrous Na SO . Removal of solvent under reduced pressure gave the crude α-keto-acid (0.45 g) which was
1
−
purified by column chromatography (7% EtOAc in pet-ether). Yield: 93%; m.p. 92–94°C; IR (cm ): 3045, 2924, 1775, 1702,
1
13
1
674, 1576, 1592, 1490, 1206, 1102, 968, 942; H NMR (200 MHz, CDCl
NMR (50.3 MHz, CDCl ): δ 129.62, 130.59, 135.19, 141.05, 165.02, 191.13; MS: m/z (% rel. intensity): M , 184(1), 183(10),
66(1), 148(20), 136(67), 125(15), 101(100), 89(21), 75(50) 63(3), 57(1). Anal. C ClO : requires: C, 52.06, H, 2.73, Cl,
9.21%; found: C, 51.99, H, 2.70, Cl, 19.01%.
3
): δ (7.37, d J=8 Hz, 2H), (7.85, d J=8 Hz, 2H). C
+
3
1
1
8
H
5
3
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02179-6
tetl 16107

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Table 1
Reactions of 1-(4-chlorophenyl)-2-nitroethanol (1d) with various catalystsa
Scheme 1.
Scheme 2.
bearing electron-withdrawing groups such as NO and CN, the rate of reaction is slower than for
2
substrates with electron-donating groups. It is remarkable that in the case of substrates with NO and
2
quinoline moieties (entries 1j–k), the reaction stops at the keto-aldehyde stage without undergoing
further oxidation to the corresponding acid. Under similar conditions aliphatic analogues (3a–c) undergo
reaction to produce nitroalkyl ethers (4a–c) instead of undergoing conversion to α-keto-acids (Scheme
2
).
1
Analysis of the reaction mixture hourly using H NMR spectroscopy indicated that the reaction
mixture contained both the α-keto-aldehyde and the α-keto-acid. As time progressed, the yield of α-
keto-acid increased with a concurrent decrease of α-keto-aldehyde.
In conclusion, the results described herein demonstrate the novelty of Cu-salts as efficient catalysts
for the conversion of aryl nitroaldol products to the corresponding α-keto-acids in high yields. For
aliphatic analogues, nucleophilic displacement with MeOH leads to the formation of nitroalkyl ethers
in moderate yields instead of the conversion to α-keto-acids. It may be noted that α-keto-acids are of
biological interest as intermediates in amino acid metabolism, as participants in the citric acid cycle and
4
as intermediates in other biological reactions.

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Table 2
a
Cu(II)-catalyzed conversion of aryl nitroaldol products to α-keto-acids
Acknowledgements
M.D.N. thanks CSIR for SRF. We thank Dr. S. Devotta (Head, PD-Division) for his constant encoura-
gement to carry out the above work.
References
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