Novel, simple method for the preparation of 7-hydroxy-4-phenylquinoline-2- carboxylic acid

Full text of DOI:10.1007/s10593-010-0515-0

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
NOVEL, SIMPLE METHOD FOR THE PREPARATION OF
7-HYDROXY-4-PHENYLQUINOLINE-2-CARBOXYLIC ACID
V. O. Kozminykh1,2*, E. A. Kirillova2, I. N. Nozdrin1,
O. N. Dvorskaya1, and E. N. Kozminykh3
Keywords: m-aminophenol, acetophenone, diethyl oxalate, 7-hydroxy-4-phenylquinoline-2-carboxylic acid,
triple-component heterocyclization.
Derivatives of quinoline-2-carboxylic (quinaldic) acid [1] are used as model structures of natural antibiotics
[2] and biologically active protein molecules [3] and appear in the composition of triostin [4] and saframycin A [5].
The quinaldic acid structural unit is found in Ephedra sp. alkaloids [6]. Quinoline-2-carboxylic acids substituted at
C-7 remain unavailable up to this time with the exception of the known 7-R-4-oxo derivatives.
1) Na
PhMe, 
2) AcOH
OEt
+
+
HO
O
O
NH2
– EtOH
– H2O
OEt
HO
N
CO2H
O
Me
O
1
O
AcOH, 
+
– MeOH
– H2O
N
HO
NH2
H
O
O
CO2Me
3
2
OH
_______
* To whom correspondence should be addressed, e-mail: kvoncstu@yahoo.com.
1Perm State Pedagogical University, Perm 614990, Russia.
2Orenburg State University, Orenburg 460018, Russia; e-mail: kea20072007@yandex.ru.
3Moscow State University of Technologies and Management, Perm Branch, Perm 614065, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 451-453, March 2010. Original
article submitted January 30, 2010.
358
0009-3122/10/4603-0358©2010 Springer Science+Business Media, Inc.

We have developed a very simple, novel method for preparation of 7-hydroxy-4-phenylquinoline-
2-carboxylic acid (1) through a triple-component heterocyclization of acetophenone with diethyl oxalate and
m-aminophenol. According to preliminary data this reaction may be used as a simple and convenient method for
the synthesis of a wide series of 7-hydroxy- and 7-amino-substituted 4-(het)aryl- and 4-alkylquinaldic acids [7].
It should be noted that the reaction of methyl 2,4-dioxo-4-phenylbutanoic (benzoylpyruvic) acid (2) and
m-aminophenol also gives compound 1 which was previously mistakenly assigned the structure 6-hydroxy-
2-(2-phenylethylidene-2-oxo)-1,2-dihydro-3H-indol-3-one (3) [8].
Acid 1 shows bacteriostatic activity towards Staphylococcus aureus strains.
IR spectra were recorded on an Infralum FT-02 spectrometer as a thin vaseline oil film. The H NMR
1
spectrum of acid 1 was recorded on a Bruker DRX-500 instrument (500 MHz) using DMSO-d6 and with TMS as
internal standard. The mass spectrum of compound 1 was taken on a Finnigan MAT Incos-50 instrument using
electron impact with direct introduction.
7-Hydroxy-4-phenylquinoline-2-carboxylic acid (1). Small fragments of sodium (0.58 g, 25 mmol)
were introduced with stirring into a mixture of acetophenone (2.9 ml, 25 mmol) and diethyl oxalate (3.4 ml,
25 mmol) in toluene (100 ml) and refluxed for 1 h. AcOH (20 ml) and m-aminophenol (2.73 g, 25 mmol) were
then introduced and the mixture was again refluxed for 2 h. The precipitate formed was filtered off, washed with
cold water (100 ml), dried, washed with hot EtOH, and recrystallized from AcOH. Yield 3.0 g (45%); decomp.
temperature 328-329ºC. IR spectrum, , cm-1: 3180 (C(7)OH), 1648 (COOH), 1620 (C=C, C=N), 1598, 1530,
1410 (CH in plane), 1323, 1313, 1255, 1242, 1212, 1167, 1137, 997, 973, 876, 849, 827 (CH out of plane), 777,
753, 697, 656, 575, 537. 1H NMR spectrum, , ppm (J, Hz): 7.26 (1H, d, J = 10.0, C(6)H); 7.38 (1H, s, C(8)H);
7.51-7.55, 8.21 (1H, s, C(3)H); 8.23-8.25 (5H, m, C6H5); 8.51 (1H, d, J = 11.0, C(5)H); 10.35 (1H, br. s,
C(7)OH). Mass spectrum (70 eV), m/z (Irel, % peaks with Irel > 3% are reported): 266 [M+1]+ (19), 265 [M]+
(100), 264 [M-H]+ (8), 248 [M-OH]+ (3), 247 [M-H2O]+ (4), 236 [M-CO-H]+ (4), 222 (9), 221 [M-CO2]+ (54),
220 [M-CO2-H]+ (60), 219 [M-CO2-2H]+ (6), 204 [M-CO2-H]+ or [C15H10N]+ (7), 191 [
]+ or
HN
[C14H9N]+ (10), 190 [C14H8N]+ (9), 165 (7), 110 (6), 95 (8), 91 (6), 89 (12), 88 (5), 77 [C6H5]+ (13), 76 (6), 75
(5), 63 (22), 62 (10), 53 (5), 51 (12), 50 (7), 45 (15), 43 (7), 39 (12). Found, %: C 72.69; H 4.32; N 5.11.
C16H11NO3. Calculated, %: C 72.45; H 4.18; N 5.28.
Condensation of Methyl 2,4-Dioxo-4-phenylbutanoate (2) with m-Aminophenol. A mixture of
compound 2 (1.0 g, 5 mmol) and m-aminophenol (0.55 g, 5 mmol) in AcOH (30 ml) was refluxed for 1 h. The
precipitate formed was filtered off and recrystallized from AcOH to give compound 1 (0.65 g, 49%).
This work was carried out with the financial support of the Russian Federation Development Agency in
2009-2010 (project No. 1.3.09).
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