A new general method for the synthesis of 2,6′-diquinoline derivatives

Full text of DOI:10.1007/s10631-005-0013-6

Doklady Chemistry, Vol. 400, Part 2, 2005, pp. 21–24. Translated from Doklady Akademii Nauk, Vol. 400, No. 5, 2005, pp. 636–639.
Original Russian Text Copyright © 2005 by Kondrashova, Shvekhgeimer.
CHEMISTRY
A New General Method for the Synthesis
of 2,6'-Diquinoline Derivatives
N. N. Kondrashova and M.-G. A. Shvekhgeimer
Presented by Academician N.K. Kochetkov October 25, 2004
Received November 12, 2004
The best-known methods for the synthesis of 2,6'-diquinolines are as follows:
(1) the Pfitzinger reaction of isatins and acetylquinolines, for example [1],
COOH
O
O
CH3CO
base
+
N
N
N
;
H
N
(2) the heating of anilines with quinoline hydrochloride in the presence of a platinum catalyst, for example [2],
O2, Pt–asbestos
+ C6H5NH2
175–180°C
+
N
N
Cl–
H
N
We suggest a new and more general method for the synthesis of 2,6'-diquinoline derivatives on the basis
of 6-R-2-(4-aminophenyl)quinoline-4-carboxylic acids (1); previously [3, 4], we reported on a convenient
and simple method of synthesis of 1:
O
CH3
COOH
R
R
O
O
KOH, H2O, C2H5OH
+
NH2
N
N
H
NH2
1
R = H, Br, NO2
Using the known two-step Sandmeyer method of synthesis of isatins [5], we obtained the corresponding isoni-
trosoacetanilides (2) in 76–87% yields by the reaction of amines 1 with chloral hydrate and hydroxylamine hydro-
chloride in a DMF medium:
COO–
COOH
R
R
DMF
O
+ Cl3CCH(OH)2 + NH2OH · HCl 100°C, 2 h
+
NH3
NHCCH NOH
N
N
R = H, Br
1
2
Kosygin State Textile University, ul. Malaya Kaluzhskaya 1, Moscow, 119991 Russia
0012-5008/05/0002-0021 © 2005 Pleiades Publishing, Inc.

22
KONDRASHOVA, SHVEKHGEIMER
In [6], the preparation of compound 2 (R = H) in ing isonitrosoacetanilide into isatin using sulfuric acid
as a cyclization agent.
We also failed to convert compounds 2 (R = H, Br)
into corresponding isatins in a sulfuric acid medium.
We managed to convert compounds 2 (R = H, Br)
into corresponding isatins 3 (R = H, Br) in 78–93%
yields using boron trifluoride etherate in DMF under an
38% yield was reported, but the compound was not
characterized.
The second step of the isatin synthesis by the Sand-
meyer method consists in the cyclization of isoni-
trosoacetanilides 2 under the action of strong acids.
However, the author of [6] failed to convert the result- argon atmosphere as the cyclization reagent.
COOH
COOH
R
R
O
BF3 · Et2O, DMF, argon
O
NHCCH NOH
N
N
O
N
H
2
3 (R = H, Br)
We conducted the Pfitzinger reaction of isatins 3 (R = H, Br) with certain ketones in an aqueous alcohol medium in
the presence of KOH, which gave the corresponding derivatives of 2,6'-diquinoline (4) in 38–82% yields:
COOH
COOH
R
R
COOH
R1
R2
O
O
O
KOH, C2H5OH, H2O
R1CH2CR2
+
N
reflux 20–24 h
N
N
H
N
R = H, Br
3
4
R, R1, R2 = H, CH3, CH3; H, H, C6H5; H, H, ferrocenyl; Br, H, C6H4NH2-4
EXPERIMENTAL
simultaneously and heated to 80°ë, and then the first
combined mixture was added. The resulting mixture
was heated to 95°ë and kept at this temperature for 2 h.
The reaction mixture was cooled in an ice bath, and
ç2é cooled to 0°ë was added until the formation of a
precipitate was observed. The precipitate was washed
with water on a filter and dried in air. Yield, 1.27 g
(76%), mp 263–265°ë (DMF–H2é). IR (KBr, ν, cm–1):
764 (1,2-disubstituted benzene ring), 840 (1,4-disubsti-
tuted benzene ring), (3430 (OH), 930 (OH), 1740
(C=O) (in COOH)), (3452 (OH), 1650 (C=N), 980
(N−O) in (CH=NOH)), (3420 (NH), 1640 (C=O) (in
IR spectra were recorded on a Specord M-80
spectrophotometer (as KBr pellets). UV spectra were
obtained on a Uvidek-610 spectrophotometer in a
1
1% aqueous sodium hydroxide solution. H NMR
spectra were recorded on a Bruker AC-300 or WM-
250 spectrometer in DMSO-d6–CCl4 solutions. The
reaction course and purity of resulting compounds
were monitored by paper chromatography and thin-
layer chromatography (TLC) on Silufol UV-254
plates with development in iodine vapors. The syn-
thesis of 6-R-2-(4-aminophenyl)quinoline-4-carbox-
ylic acids 1 was described in [3, 4].
CONH)). UV (λmax, nm (logε )): 232.5 (2.87), 290.53
Isonitrosoacetanilide 2 (R = H). Chloral hydrate
(0.92 g, 0.006 mol) was dissolved in 2.5 mL of ç2é,
and 7.9 g (0.56 mol) of Na2SO4 was added. The mixture
was heated to 60°ë. A solution of 1.1 g (0.016 mol) of
NH2OH · HCl in 2 mL of ç2é was prepared separately
under heating. The heated mixture was combined with
the solution. A mixture of 1.32 g (0.005 mol) of 2-(4-
aminophenyl)quinoline-4-carboxylic acid in 14 mL of
(2.89), 339.44 (2.84). 1H NMR (250 kHz, δ, ppm): 7.68
(m, 1H, 7-H), 7.71 (s, 1H, 14-H), 7.83 (m, 1H, 6-H),
7.92 (d, 2H, 10,12-H), 8.13 (d, 1H, 5-H), 8.28 (d, 2H,
9,11-H), 8.44 (s, 1H, 3-H), 8.63 (d, 1H, 8-H), 10.29
(s, 1H, NOH), 12.15 (s, 1H, COOH).
For C18H13N3O4 anal. calcd. (wt %): C, 64.47;
DMF and 0.4 mL of concentrated HCl was prepared H, 3.90; N, 12.53.
DOKLADY CHEMISTRY Vol. 400 Part 2 2005

A NEW GENERAL METHOD FOR THE SYNTHESIS OF 2,6'-DIQUINOLINE DERIVATIVES
23
Found (wt %): C, 64.09; H, 3.72; N, 12.21.
Isonitrosoacetanilide 2 (R = Br). Yield, 1.8 g
(87%); 2 does not melt up to 300°ë (DMF–H2é). IR
ice water, and acidified with diluted hydrochloric
acid to pH 6. The precipitate was filtered off, washed,
and dried in air. Yield, 1.03 g (55%); mp 280–283°ë
(from DMF–H2é). IR (KBr, ν, cm–1): 756 (1,2-dis-
ubstituted benzene ring); 816, 880 (1,2,4-trisubsti-
tuted benzene ring); (3356 (OH); 3200 (OH); 976 (OH);
960 (OH); 1644, 1608 (C=O) (two COOH)). UV
(KBr, ν, cm–1): 828 (1,4-disubstituted benzene ring),
868 (1,2,4-trisubstituted benzene ring), (3762 (OH),
980 (OH), 1720 (C=O) (in COOH)), (3340 (OH), 1681
(C=N), 1016 (N–O) (in CH=NOH)), (3430 (NH), 1664
(C=O) (in CONH)), 652 (C–Br). UV (λmax, nm
(λmax, nm ( logε )): 282.80 (2.83), 346.26 (2.69),
473.48 (1.41), 482.62 (1.40). 1H NMR (250 MHz, δ,
ppm): 2.39 (s, 6H, 2 CH3), 6.73 (d, 2H, 10,11-H),
7.56 (m, 1H, 7-H), 7.75 (m, 1H, 6-H), 8.03 (d, 1H,
5-H), 8.28 (s, 1H, 3-H), 8.43 (s, 1H, 9-H), 8.57
(d, 1H, 8-H), 9.16 (s, 1H, COOH).
(logε )): 296.21 (2.74), 299.33 (2.74), 347.22 (2.64).
For C18H12BrN3O4 anal. calcd. (wt %): C, 52.19;
H, 2.92; N, 10.14.
Found (wt %): C, 52.38; H, 3.18; N, 9.79.
5-(4-Hydroxycarbonylquinolyl-2)isatin 3 (R = H).
An argon flow was passed through a solution of 0.84 g
(0.0025 mol) of isonitrosoacetanilide 2 (R = H) in 3 mL
of DMF, and 1.3 mL of freshly distilled BF3 · Et2O was
added. The mixture was heated for 2 h at 90°ë and
another 3 h at 120°ë. After cooling, the reaction mix-
ture was poured into a water–ice mixture. The resulting
precipitate was filtered off, washed with water, and
dried in air. Yield, 0.68 g (78%); mp 223–225°ë
(decomp.) (from DMF–H2é). IR (KBr, ν, cm–1): 764
(1,2-disubstituted benzene ring); 808, 864 (1,2,4-
trisubstituted benzene ring); 3372 (NH); 1664 (ë14=é);
(3490 (OH), 860 (OH), 1704 (C=O) (in COOH)). UV
For C22H16N2O4 anal. calcd. (wt %): C, 70.96;
H, 4.33; N, 7.52.
Found (wt %): C, 71.28; H, 4.48; N, 7.17.
2,6'-Diquinoline 4 (R = H, R1 = H, R2 = C6H5).
Yield, 0.8 g (38%); mp 263–265°ë (from DMF–H2é).
IR (KBr, ν, cm–1): 756 (1,2-disubstituted benzene ring);
668, 737 (monosubstituted benzene ring); 816, 828
(1,2,4-trisubstituted benzene ring); (3360 (OH); 3198
(OH); 910 (OH); 880 (OH); 1685, 1640 (C=O) (two
COOH)). UV (λmax, nm (logε )): 282.68 (2.79), 345.11
1
(2.65). H NMR (250 MHz, δ, ppm): 6.74 (d, 2H,
10,11-H), 7.57 (m, 1H, 7-H), 7.75 (m, 1H, 6-H),
7.64−7.94 (m, 5H, C6H5), 8.02 (s, 1H, 9-H), 8.04
(d, 1H, 5-H), 8.31 (s, 1H, 3-H), 8.44 (d, 1H, 14-H), 8.57
(d, 1H, 8-H), 9.14 (s, 1H, COOH).
(λmax, nm (logε )): 283.93 (2.82), 285.88 (2.82), 287.85
1
(2.82), 289.85 (2.82). H NMR (250 MHz, δ, ppm):
7.72 (m, 1H, 7-H), 7.83 (m, 1H, 6-H), 7.94 (s, 1H,
10-H), 8.14 (d, 1H, 5-H), 8.28 (d, 2H, 11,12-H), 8.43
(s, 1H, 3-H), 8.65 (d, 1H, 8-H), 9.14 (s, 1H, NH), 11.06
(s, 1H, COOH).
For C26H16N2O4 anal. calcd. (wt %): C, 74.27;
H, 3.83; N, 6.66.
Found (wt %): C, 74.58; H, 3.54; N, 6.31.
For C18H10N2O4 anal. calcd. (wt %): C, 67.89;
H, 3.46; N, 8.79.
2,6'-Diquinoline 4 (R = H, R1 = H, R2 = ferroce-
nyl). Yield, 2.16 g (82%); mp 163–165°ë (from DMF–
H2é). IR (KBr, ν, cm–1): 764 (1,2-disubstituted ben-
zene ring); 828, 880 (1,2,4-trisubstituted benzene ring);
1004, 1116, 1280 (ferrocenyl); (3356 (OH); 3204
(OH); 848 (OH); 860 (OH); 1652, 1592 (C=O) (two
Found (wt %): C, 67.47; H, 3.37; N, 8.37.
5-(6-Bromo-4-hydroxycarbonylquinolyl-2)isatin 3.
Yield, 0.93 g (93%); 3 does not melt up to 300°ë
(from DMF–H2é). IR (KBr, ν, cm–1): 760 (1,2-dis-
ubstituted benzene ring); 828, 869 (1,2,4-trisubsti-
tuted benzene ring); 3364 (NH); 1664 (ë14=é);
(3486 (OH), 870 (OH), 1724 (C=O) (in COOH));
COOH)). UV (λmax, nm (logε )): 281.01 (2.74), 343.57
(2.58), 445.12 (1.28), 451.55 (1.27), 470.23 (1.24). 1H
NMR (250 MHz, δ, ppm): 4.24–4.81 (m, 9H, ferroce-
nyl), 6.72 (d, 2H, 10,11-H), 7.69 (m, 1H, 7-H), 7.76
(m, 1H, 6-H), 8.05 (d, 1H, 5-H), 8.32 (s, 1H, 3-H), 8.58
(d, 1H, 8-H).
644 (R = Br). UV (λmax, nm ( logε )): 259.87 (2.71),
293.43 (2.78), 348.19 (2.70). 1H NMR (250 MHz, δ,
ppm): 7.72 (s, 1H, 10-H), 7.96 (d, 1H, 7-H), 8.06
(s, 1H, 5-H), 8.31 (d, 2H, 11,12-H), 8.38 (s, 1H, 3-H),
8.51 (d, 1H, 8-H), 8.92 (s, 1H, NH), 9.44 (s, 1H,
COOH).
For C30H20N2O4Fe anal. calcd. (wt %): C, 68.19;
H, 3.81; N, 5.30.
Found (wt %): C, 67.87; H, 3.98; N, 5.21.
For C18H9BrN2O4 anal. calcd. (wt %): C, 54.43;
H, 2.28; N, 7.05.
2,6'-Diquinoline 4 (R = Br, R1 = H, R2 = 4-
H2NC6H4). Yield, 1.62 g (63%); mp 298–300°ë
Found (wt %): C, 54.74; H, 2.47; N, 6.74.
(from DMF–H2é). IR (KBr, ν, cm–1): 824 (1,4-dis-
ubstituted benzene ring); 815, 872 (1,2,4-trisubsti-
tuted benzene ring); (3348 (OH), 962 (OH), 1644
(C=O) (in COOH)); 3348, 1212 (NH2). UV (λmax, nm
2,6'-Diquinoline 4 (R = H, R1 = R2 = CH3).
A solution of 1.6 g (0.005 mol) of isatin 3 (R = H),
2.25 mL (0.01 mol) of methyl ethyl ketone, and
1.62 g of KOH in 13 mL of alcohol and 0.3 mL of
ç2é was heated under reflux for 24 h (TLC monitor-
( logε )): 268.70 (2.71), 271.03 (2.71), 274.60 (2.71),
ing). The reaction mixture was cooled, diluted with 291.92 (2.73), 294.67 (2.73), 354.91 (2.61). 1H NMR
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KONDRASHOVA, SHVEKHGEIMER
(250 MHz, δ, ppm): 6.72 (d, 2H, 10,11-H), 7.85 (d,
1H, 7-H), 7.88 (d, 1H, 6-H), 7.91–8.06 (m, 4H,
C6H4), 7.97 (s, 1H, 9-H), 8.02 (s, 1H, 5-H), 8.06
(s, 1H, 3-H), 8.39 (s, 1H, 12-H), 8.85 (d, 1H, 8-H),
10.48 (s, 1H, COOH).
REFERENCES
1. Waley, S.G., J. Chem. Soc., 1948, p. 2008.
2. Weidel, H., Monatsh. Chem., 1887, vol. 8, p. 120.
3. Shvekhgeimer, M.-G.A. and Kondrashova, N.N., Khim.
Geterotsikl. Soedin., 2002, no. 2, p. 275.
4. Shvekhgeimer, M.-G.A. and Kondrashova, N.N., Dokl.
Akad. Nauk, 2002, vol. 383, no. 2, pp. 221–225 [Dokl.
Chem. (Engl. Transl.), vol. 383, nos. 1–3, pp. 72–74].
For C26H16BrN3O4 anal. calcd. (wt %): C, 70.71; H,
3.70; N, 9.65.
Found (wt %): C, 70.98; H, 3.65; N, 9.48.
5. Sandmeyer, T., Helv. Chim. Acta, 1919, vol. 2, p. 230.
DOKLADY CHEMISTRY Vol. 400 Part 2 2005