Ethynyl-3-hydroxyquinoline-4-carboxylic acids Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
1461
1-hydroxypropan-2-one (1) (65 mg, 0.35 mmol) was dissolved
in ethanol (2 mL) and added in two portions to the solution.
The reaction mixture was heated to reflux for 4 h, then cooled
down to room temperature, and the solvents were removed
under reduced pressure. The residue was dissolved in water
and filtered. The filtrate was acidified to pH 1 with 1 M HCl
solution. The precipitate was filtered and washed with water.
Purification was performed using column chromatography
(EtOAc—CH3CN—MeOH, 70/5/2.5 + 0.5% Et3N, v/v). The
isolated fraction was dissolved in acetonitrile—water mixture,
1 M HCl solution was added to pH 1, and the product was
collected by filtration, washed with water, and dried.
In our case, the yield of the target product of cross-coup-
ling 2 was 48% and compounds 2 and 3 were characterized
by a complex of physico-chemical methods of analysis.
In order to synthesize the target quinolines, -hydr-
oxyketone 1 was introduced into the Pfitzinger reaction
with isatin 2 and 3 containing triple bonds (see Scheme 2).
The trimethylsilyl group was removed under alkaline
conditions. Therefore, no additional step was required
to obtain a free terminal alkyne.
3-Hydroxyquinoline-4-carboxylic acids containing
ethynyl moiety in positions 6 and 8, were obtained for the
first time. Their composition was confirmed using high-
resolution mass spectrometry, and their structures were
confirmed by 1Н and 13С NMR and IR spectroscopy.
2-(4-Chlorobenzyl)-8-ethynyl-3-hydroxyquinoline-4-carb-
oxylic acid (4). Brown crystalline compound was obtained, the
yield was 16 mg (16%), m.p. 110—112 C. IR (KBr), /cm–1
:
3560 (O—H); 3276 (≡С—H); 1658 (C=O). 1Н NMR (DMSO-d6),
: 8.58 (d, 1 Н, Harom, J = 8.6 Hz); 7.73 (d, 1 H, Harom, J = 7.4 Hz);
7.53 (td, 1 H, Harom, J = 8.6 Hz, J = 2.0 Hz); 7.32 (s, 4 H, Harom);
4.41 (s, 1 Н, С≡СН); 4.30 (s, 2 H, СН2). 13С NMR (DMSO-d6),
: 171.2, 155.5, 152.5, 141.8, 137.7, 131.5, 131.3, 131.2, 128.7,
127.7, 125.9, 125.4, 122.2, 115.2, 86.3, 82.3, 38.9. MS: found
m/z 336.0430 [M – Н]–; C19H11ClNO3; calculated: 336.0433.
2-(4-Chlorobenzyl)-6-ethynyl-3-hydroxyquinoline-4-carb-
oxylic acid (5). Brown crystalline compound was obtained, the
yield was 14 mg (14%). IR (KBr), /cm–1: 3298 (O—H); 2917
Experimental
1Н and 13С NMR spectra were registered using a Bruker Avance
400 spectrometer with working frequencies 400 and 100 MHz.
High-resolution mass spectra were recorded using a Orbitrap
Elite spectrometer (Thermo Fischer Scientific). The solutions
of the samples in acetonitrile with the addition of 1% of formic
acid were introduced into the ionization source by the electro-
spray method. IR spectra were recorded using an IR200 FTIR
1
(≡С—H); 1658 (C=O). Н NMR (DMSO-d6), : 8.87 (s, 1 H,
spectrometer (TermoNicolet, USA) with resolution of 4 cm–1
.
Harom); 7.90 (d, 1 Н, Harom, J = 8.6 Hz); 7.56 (dd, 1 H, Harom,
Synthesis of indoline-2,3-diones 2 and 3 (general procedure).
5-Iodo- or 7-iodoisatine (550 mg, 2.0 mmol), Pd(PPh3)4 (50 mg,
0.04 mmol), CuI (40 mg, 0.2 mmol) were dissolved in DMF
(5 mL), then Et3N (700 μL, 5.0 mmol) was added, and the mixture
was stirred under inert atmosphere (N2) for 1 h. Trimethyl-
silylacetylene (430 μL, 3.0 mmol) was added and the reaction
mixture was stirred at 80 C for 4 h, then cooled down, and filtered
via Celite layer. Then EtOAc was added, the mixture was washed
with water and saturated NaCl solution, dried with Na2SO4. The
solvent was removed under reduced pressure, and product was
purified by column chromatography (CHCl3).
J = 8.6 Hz, J = 1.7 Hz); 7.33 (s, 4 H, Harom); 4.34 (s, 1 Н,
С≡СН); 4.32 (s, 2 H, СН2). 13С NMR (DMSO-d6), : 171.2,
156.4, 151.8, 141.5, 137.3, 131.5, 131.3, 129.1, 128.9, 128.8,
128.7, 124.3, 121.4, 111.7, 84.2, 82.3, 38.4. MS: found m/z
336.0436 [M – Н]–; C19H11ClNO3; calculated: 336.0433.
The work was financially supported by the Russian
Foundation for Basic Research (Project No. 18-33-
01237\18). The authors are grateful to Thermo Fisher
Scientific, Inc., MS Analytics (Moscow), and to Professor
A. A. Makarov for providing the equipment used in this work.
7-[(Trimethylsilyl)ethynyl]indoline-2,3-dione (2). Orange
crystalline compound was obtained, the yield was 236 mg (48%),
m.p. 189—190 C. IR (СDCl3), /cm–1: 3181 (N—H); 2166
(С≡С); 1747 (overlapping contour of two C=O). 1Н NMR
(CDCl3), : 8.31 (br.s, 1 H, NH); 7.60 (dd, 1 H, Harom, J = 7.8 Hz,
References
1.N. Kaila, K. Janz, A. Huang, A. Moretto, S. DeBernardo,
P. W. Bedard, S. Tam, V. Clerin, J. C. Keith, D. H. H. Tsao,
N. Sushkova, G. D. Shaw, R. T. Camphausen, R. G. Schaub,
Q. Wang, J. Med. Chem., 2007, 50, 40.
2.N. Kaila, K. Janz, S. DeBernardo, P. W. Bedard, R. T.
Camphausen, S. Tam, D. H. H. Tsao, J. C. Keith, C. Nickerson-
Nutter, A. Shilling, R. Young-Sciame, Q. Wang, J. Med.
Chem., 2007, 50, 21.
3.A. Huang, A. Moretto, K. Janz, M. Lowe, P. W. Bedard,
S. Tam, L. Di, V. Clerin, N. Sushkova, B. Tchernychev,
D. H. H. Tsao, J. C. Keith, G. D. Shaw, R. G. Schaub,
Q. Wang, N. Kaila, J. Med. Chem., 2010, 53, 6003.
4. M. G. A. Shvekhgeimer, Chem. Heterocycl. Compd., 2004, 40, 257.
5.V. V. Melyshenkova, D. N. Kuznetsov, A. G. Ruchkina, K. I.
Kobrakov, Russ. Chem. Bull., 2018, 67, 878.
6.M. K. Uddin, S. G. Reignier, T. Coulter, C. Montalbetti,
C. Grånäs, S. Butcher, C. Krog-Jensen, J. Felding, Bioorg.
Med. Chem. Lett., 2007, 17, 2854.
J = 1.2 Hz); 7.56 (d, 1 H, Harom, J = 7.5 Hz); 7.08 (t, 1 H, Harom
,
J = 7.7 Hz); 0.30 (s, 9 H, Si(CH3)3). 13С NMR (DMSO-d6), :
183.7, 159.9, 152.0, 140.0, 131.4, 124.9, 122.7, 118.3, 106.7,
98.0, –0.2. MS: found m/z 242.0633 [M – Н]–; C13H12NO2Si;
calculated: 242.0643.
5-[(Trimethylsilyl)ethynyl]indoline-2,3-dione (3). Orange
crystalline compound was obtained, the yield was 108 mg (22%),
m.p. 216—218 C. IR (СDCl3), /cm–1: 3222 (N—H); 2150 (С≡С);
1763, 1745 (C=O). 1Н NMR (CDCl3), : 8.04 (br.s, 1 H, NH);
7.72 (d, 1 Н, Harom, J = 1.7 Hz); 7.66 (dd, 1 Н, Harom, J = 8.2 Hz,
J = 1.7 Hz); 6.88 (d, 1 Н, Harom, J = 8.2 Hz); 0.26 (s, 9 Н,
Si(CH3)3). 13С NMR (CDCl3+СD3OD), : 183.3, 159.3, 149.8,
141.5, 128.3, 118.2, 117.3, 112.2, 102.7, 94.6, –0.65. MS: found
m/z 242.0643 [M – Н]–; C13H12NO2Si; calculated: 242.0643.
Synthesis of 3-hydroxyquinoline-4-carboxylic acids 4 and 5
(general procedure). The corresponding indolin-2,3-dione
(75 mg, 0.30 mmol) in 6 M KOH aqueous solution (2 mL)
was placed in a two-neck round-bottomed flask equipped with
a reflux condenser and heated to 100 °C. 3-(4-Chlorophenyl)-
Received December 31, 2018;
in revised form April 12, 2019;
accepted April 18, 2019