Pfitzinger reaction of dialkyl(aryl)(2-methyl-4-oxopent-2-yl)phosphine oxides

Article abstract of DOI:10.1134/S1070428014040137

New phosphorus-containing derivatives of quinoline-4-carboxylic acid were synthesized by the Pfitzinger reaction from isatin and dialkyl(aryl)(2-methyl-4- oxopent-2-yl)phosphine oxides.

Full text of DOI:10.1134/S1070428014040137

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 4, pp. 518–520. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © D.A. Tatarinov, A.V. Bogdanov, B.I. Buzykin, V.F. Mironov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50,
No. 4, pp. 529–531.
Pfitzinger Reaction
of Dialkyl(aryl)(2-methyl-4-oxopent-2-yl)phosphine Oxides
D. A. Tatarinov, A. V. Bogdanov, B. I. Buzykin, and V. F. Mironov
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: datint@iopc.ru
Received January 14, 2014
Abstract—New phosphorus-containing derivatives of quinoline-4-carboxylic acid were synthesized by the
Pfitzinger reaction from isatin and dialkyl(aryl)(2-methyl-4-oxopent-2-yl)phosphine oxides.
DOI: 10.1134/S1070428014040137
Derivatives of quinolinecarboxylic acids exhibit
a broad spectrum of biological activity. Quinoline-4-
carboxylic acid amides and hydrazides display anti-
microbial [1], antitubercular, anti-inflammatory, and
analgesic activity [2–5]. Some derivatives were found
to possess antiproliferative activity [6].
In recent years, quinoline derivatives containing
a phosphonate or phosphine oxide fragment have been
reported [7, 8] and shown to exhibit biological activity,
e.g., anti-inflammatory [9]; some compounds are nu-
cleoside analogs and are active against human im-
munodeficiency virus [10]. Nevertheless, no quinoline-
4-carboxylic acid derivative with a phosphorus-con-
taining substituent on C2 has been reported so far.
We have recently shown that conjugation of
Isoniazid with the anti-acidotic drug Dimephosphon,
dimethyl (2-methyl-4-oxopent-2-yl)phosphonate [11],
or its P,C-analogs, dialkyl(2-methyl-4-oxopent-2-yl)-
phosphine oxides [12], considerably reduces the toxic-
ity without affecting the therapeutic effect [13, 14].
Therefore, it seemed reasonable to synthesize quino-
line-4-carboxylic acid derivatives containing a dialkyl-
(or aryl)phosphorylalkyl substituent in the 2-position.
In the present article we describe the synthesis of
new phosphorus-containing quinoline-4-carboxylic
acid derivatives by the Pfitzinger reaction of isatin
with dialkyl(aryl)(2-methyl-4-oxopent-2-yl)phosphine
oxides. Unlike the procedure reported in [15] where
the reactions of isatins were carried out using a large
excess of volatile carbonyl compounds, we used equi-
molar amounts of isatin and oxoalkylphosphine oxides
I (Scheme 1). The yields of quinolines IIa–IIc were
50–70%, and the reaction mixtures contained some
amounts of unreacted isatin and aldolization products
of initial phosphorus-containing ketone I. Pure quino-
linecarboxylic acids IIa–IIc were isolated by recrys-
tallization from acetone. The reaction involves exclu-
sively the methyl group neighboring to the carbonyl
group with formation of only one regioisomer, which
may be rationalized by the effect of steric factor on the
Pfitzinger reaction [15].
The product structure was determined by spectral
methods. The MALDI mass spectra of IIa–IIc dis-
played peaks corresponding to the protonated molec-
1
ular ions [M + H]+·. Their H NMR spectra contained
upfield signals from protons of the methyl groups in
Scheme 1.
COOH
O
O
KOH, EtOH
Me
P
R
+
Me
Me
O
R
O
Me
N
Me
O
N
P
R
H
R
Ia–Ic
IIa–IIc
R = Ph (a), Et (b), Bu (c).
518

PFITZINGER REACTION OF DIALKYL(ARYL)(2-METHYL-4-OXOPENT-2-YL)PHOSPHINE
519
the α-position with respect to phosphorus (doublets at
δ 1.2–1.3 ppm, JPH = 15.3–15.7 Hz). The signal from
2-[2-(Diphenylphosphoryl)-2-methylpropyl]-
quinoline-4-carboxylic acid (IIa). Yield 2.3 g (79%),
white powder, mp 217–219°C. IR spectrum, ν, cm–1:
3365, 3060, 2962, 2926, 2855, 2716, 2521, 2467,
1967, 1921, 1702, 1592, 1462, 1437, 1370, 1340,
1316, 1264, 1237, 1212, 1188, 1159, 1136, 1115, 1089,
1027, 1000, 932, 853, 801, 772, 754, 723, 707, 637,
577, 558, 540, 519. 1H NMR spectrum, δ, ppm: 1.22 d
3
protons in the 2-CH2 group appeared as a doublet in
a weaker field (δ 3.2–3.4 ppm, 3JPH = 7.2–8.0 Hz). The
position and multiplicity of signals from the alkyl or
aromatic groups on the phosphorus atom in the
1H NMR spectra of compounds II were identical to
those observed for previously described phosphine
oxides I [12]. Signals from protons in the quinoline
fragment were typical of 2-substituted quinoline-4-
carboxylic acids.
3
3
(6H, CH3, JPH = 15.7 Hz), 3.21 d (2H, CH2, JPH
=
8.0 Hz), 7.40–7.56 m (7H, m-H, p-H, 6-H), 7.64 m
(1H, 7-H, 3JHH = 7.4 Hz), 7.69 s (1H, 3-H), 7.94 d (1H,
3
3
8-H, JHH = 8.9 Hz), 7.99 br.d.d (4H, o-H, JHH = 8.4,
Phosphorus-containing quinoline-4-carboxylic
acids IIa–IIc attract interest as potential biologically
active compounds. In addition, the presence in their
molecules of phosphine oxide and carboxy groups
makes these compounds promising as complexing
agents.
3JPH = 8.3–8.5 Hz), 8.69 d (1H, 5-H, JHH = 8.4 Hz).
3
31P–{1H} NMR spectrum: δP 37.2 ppm. Mass spectrum
(MALDI): m/z 430 [M + H]+·. Found, %: C 72.61;
H 5.56; N 3.25; P 7.19. C26H24NO3P. Calculated, %:
C 72.72; H 5.63; N 3.26; P 7.21. M 429.0.
2-[2-(Diethylphosphoryl)-2-methylpropyl]-
quinoline-4-carboxylic acid (IIb). Yield 1.3 g (57%),
yellow powder, mp 211–212°C. IR spectrum, ν, cm–1:
3368, 3069, 3040, 2976, 2959, 2922, 2885, 2720,
2422, 1925, 1691, 1587, 1506, 1466, 1422, 1404,
1392, 1356, 1338, 1311, 1265, 1238, 1212, 1189, 1162,
1119, 1036, 1006, 981, 967, 913, 850, 808, 774, 760,
701, 656, 636, 555, 509, 479, 432. 1H NMR spectrum,
δ, ppm: 1.29 d (6H, CH3, 3JPH = 15.4 Hz), 1.35 d.t (6H,
EXPERIMENTAL
The H and 31P–{1H} NMR spectra were recorded
1
on a Bruker Avance-400 spectrometer at 400 and
161.0 MHz, respectively, from solutions in CDCl3
using the residual proton signal of the solvent as
reference. The IR spectra were measured on a Bruker
Vector-22 instrument from samples dispersed in
mineral oil or films placed between KBr plates. The
MALDI mass spectra were obtained on a Bruker
Daltonics UltraFlex III TOF/TOF mass spectrometer in
the linear mode (Nd:YAG laser, λ 355 nm). The data
were processed using FlexAnalysis 3.0 program
(Bruker Daltonics), positive ions were detected,
samples were deposited onto a metal target, and 2,5-di-
hydroxybenzoic acid was used as matrix.
3
3
PCH2CH3, JHH = 7.3, JPH = 16.0 Hz), 1.85 m (2H,
PCH2, part A of ABMX3 spin system), 2.02 m (2H,
PCH2, part B of ABMX3 spin system), 3.43 d (2H, CH2,
3
3JPH = 7.6 Hz), 7.61 d.d.d (1H, 6-H, JHH = 8.3, 6.9,
3
4JHH = 1.2 Hz), 7.71 d.d.d (1H, 7-H, JHH = 8.3, 6.9,
4JHH = 1.3 Hz), 8.08 s (1H, 3-H), 8.11 d (1H, 8-H,
3
3JHH = 8.2 Hz), 8.93 d (1H, 5-H, JHH = 7.8 Hz).
31P–{1H} NMR spectrum: δP 63.5 ppm. Mass spectrum
(MALDI): m/z 334 [M + H]+·. Found, %: C 64.83;
H 7.31; N 4.23; P 9.27. C18H24NO3P. Calculated, %:
C 64.85; H 7.26; N 4.20; P 9.29. M 333.0.
Compounds IIa–IIc were synthesized according to
the procedure described in [16]. A mixture of 1 g
(6.8 mmol) of isatin and 1.9 g (33.9 mmol) of potas-
sium hydroxide was dissolved in a mixture of 5 mL of
ethanol and 10 mL of water, the mixture was stirred for
5 min at 20°C, 6.8 mmol of phosphine oxide Ia–Ic was
added, and the mixture was heated for 8 h under reflux
with stirring. The mixture was then cooled to 20°C and
acidified to pH ~5–6 with 10% aqueous HCl. Com-
pound IIa separated from the solution and was filtered
off. Compounds IIb and IIc were extracted into
methylene chloride (3×30 mL), the combined extracts
were dried over sodium sulfate and evaporated on
a rotary evaporator, and the residue was recrystallized
from acetone and dried at 100°C under reduced
pressure (10 mm).
2-[2-(Dibutylphosphoryl)-2-methylpropyl]-
quinoline-4-carboxylic acid (IIc). Yield 1.25 g (47%),
light yellow powder, mp 158–160°C. IR spectrum, ν,
cm–1: 3422, 3063, 3038, 2959, 2932, 2872, 2964, 2426,
1938, 1695, 1590, 1556, 1507, 1411, 1369, 1337,
1310, 1259, 1243, 1191, 1164, 1114, 1050, 1027, 1004,
968, 906, 850, 815, 801, 768, 745, 730, 716, 695, 637,
1
551, 509, 473. H NMR spectrum, δ, ppm: 0.97 t [6H,
3
3
P(CH2)3CH3, JHH = 7.3 Hz], 1.29 d (6H, CH3, JPH
=
15.3 Hz), 1.48 m [4H, P(CH2)2CH2], 1.64–2.07 m (8H,
3
PCH2CH2), 3.45 d (2H, CH2, JPH = 7.2 Hz), 7.62 m
3
3
(1H, 6-H, JHH = 7.6 Hz), 7.74 m (1H, 7-H, JHH
=
=
3
7.5 Hz), 8.10 s (1H, 3-H), 8.14 d (1H, 8-H, JHH
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

TATARINOV et al.
520
3
7.5 Hz), 8.93 d (1H, 5-H, JHH = 8.4 Hz). 31P–{1H}
NMR spectrum: δP 61.6 ppm. Mass spectrum
(MALDI): m/z 390 [M + H]+·. Found, %: C 67.79;
H 8.32; N 3.58; P 7.92. C22H32NO3P. Calculated, %:
C 67.85; H 8.28; N 3.60; P 7.95. M 389.0.
7. Palacios, F., Aparicio, D., and Vicario, J., Eur. J. Org.
Chem., 2002, p. 4131.
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Heteroatom Chem., 2011, vol. 22, p. 617.
9. Abdou, W.M., Khidre, R.E., and Shaddy, A.A.,
J. Heterocycl. Chem., 2013, vol. 50, p. 33.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 12-03-97042r_povolzh’e) and by the Academy of
Sciences of Tatarstan Republic.
10. Faro, L.V., de Almeida, J.M., Cirne-Santos, C.C.,
Giongo, V., Castello-Branco, L.R., Oliveira, I.D.B.,
Barbosa, J.E.F., Cunha, A.C., Ferreira, V.F., de
Souza, M.C., Paixão, I.C.N.P., and de Souza, M.C.B.V.,
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