Synthesis of bisarylmethyl-substituted pyrimidines and quinolines

Article abstract of DOI:10.1134/S1070428014010114

The condensation of 2-chloro-8-methylquinoline-3-carbaldehyde, 2-chloroand 2-chloro-7,8,9,10-tetrahydrobenzo[h]quinoline-3-carbaldehydes, 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, 6-methyl-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-carbaldehyde, and 2-chloropyrido[1,2-a]pirimidine-3- carbaldehyde with N-substituted anilines gave the corresponding diaryl(hetaryl)methanes.

Full text of DOI:10.1134/S1070428014010114

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 59–62. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.A. Harutyunyan, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 1, pp. 66–68.
Synthesis of Bisarylmethyl-Substituted Pyrimidines
and Quinolines
A. A. Harutyunyan
Mndzhoyan Institute of Fine Organic Chemistry, Research Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: harutyunyan.arthur@yahoo.com
Received December 12, 2012
Abstract—The condensation of 2-chloro-8-methylquinoline-3-carbaldehyde, 2-chloro- and 2-chloro-7,8,9,10-
tetrahydrobenzo[h]quinoline-3-carbaldehydes, 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, 6-meth-
yl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, and 2-chloropyrido[1,2-a]pirimidine-3-carbalde-
hyde with N-substituted anilines gave the corresponding diaryl(hetaryl)methanes.
DOI: 10.1134/S1070428014010114
It is known that substituted triphenylmethanes
(leuco bases of the corresponding triphenylmethane
dyes) are potent chemotherapeutic and photodynamic
agents [1]; they also exhibit nonlinear optical prop-
erties due to specific π-electron density distribution in
their molecules [2].
Aryl and hetaryl triphenylmethane analogs contain-
ing five- and six-membered heterocycles and fused
heterocyclic systems have recently been synthesized
[3]. It should be noted that only a few examples of
pyrimidine analogs of triphenylmethane and triphenyl-
methanol have been reported [4, 5]; some of them were
tested as antiestrogens (aromatase inhibitors) [5].
a number of heterocyclic aldehydes were brought into
condensation with N-substituted anilines in the pres-
ence of various catalysts, in particular H2SO4, poly-
phosphoric acid, HCl, and ZnCl2. The best results were
obtained when a suspension of aldehyde I–V and the
corresponding aniline in 30% aqueous HCl was heated
under reflux for 12 h (Scheme 1). As a result, diaryl-
(hetaryl)methanes VI–X were isolated in good yields.
However, 6-styryl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
dine-5-carbaldehyde [6] failed to react with N,N-di-
methyl- and N,N-diethylanilines under the above con-
ditions, and the initial aldehyde was recovered from
the reaction mixture.
In order to find new potential biologically active
compounds in the series of diaryl(hetaryl)methanes,
The structure of compounds VI–X was confirmed
by elemental analyses and IR and 1H NMR spectra.
Scheme 1.
R1R2N
NR1R2
HCl
Ht CHO
+
PhNR1R2
Ht
I–V
VI–X
O
O
N
HN
Ht =
N
N
Cl
N
Cl
N
Cl
O
N
H
R3
Me
Cl
I, VI
II, VII
III, VIII
IV, IX
V, X
III, R3 = H (a), Me (b); VI, VII, IX, R1 = R2 = Me (a), Et (b); VIII, R3 = H, R1 = R2 = Me (a), Et (b);
R1 = R3 = H, R2 = i-Bu (c); R3 = H: R1 = R2 = Me (d), Et (e); X, R1 = R2 = Me.
59

HARUTYUNYAN
Diaryl(hetaryl)methanes VI–X were tested for
was synthesized from aldehyde I and N,N-dimethyl-
60
aniline. Yield 68%, mp 255–256°C (from 2-ethoxy-
ethanol), Rf 0.80 (i-BuOH–H2O–AcOH, 2:2:1). IR
spectrum: ν 1611 cm–1, s (C=Carom). 1H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 1.84–1.96 m (4H, 8-H,
9-H), 2.90 m (2H, 7-H or 10-H), 2.93 s (12H, NCH3),
3.21 m (2H, 10-H or 7-H), 5.71 s (1H, CH), 6.56–
6.67 m and 6.83–6.89 m (4H each, C6H4), 7.17 d
and 7.40 d (1H each, 5-H, 6-H, J = 8.4 Hz), 7.51 s
(1H, 4-H). Found, %: N 8.74. C30H32ClN3. Calculated,
%: N 8.94.
antibacterial activity against S. aureus 209, p 1,
Sh. dysenteriae Flexneri 6858, and E. coli 0-55. Com-
pound VIIa turned out to be weakly active against
Gram-negative bacteria, compounds VIIIb, VIIId, and
VIIIe were weakly active against Gram-positive bac-
teria, and compound VIIIa displayed activity against
all the examined bacterial strains. Pyrimidines VIIId
and VIIIe at a dose of 150 mg/kg inhibited by 30–40%
the growth of sarcoma 37 in mice.
EXPERIMENTAL
4,4′-[(2-Chloro-7,8,9,10-tetrahydrobenzo[h]quin-
olin-3-yl)methylene]bis(N,N-diethylaniline) (VIb)
was synthesized from aldehyde I and N,N-diethyl-
aniline. Yield 72%, mp 201–202°C (from DMF–
2-ethoxyethanol), Rf 0.73 (i-BuOH–H2O–AcOH,
The IR spectra were recorded in mineral oil on
a Nicolet Avatar 330 spectrometer. The 1H NMR spec-
tra were measured on a Varian Mercury-300 instru-
ment at 300 MHz using tetramethylsilane as internal
reference. Silufol UV-254 were used for thin-layer
chromatography; spots were visualized by treatment
with iodine vapor.
1
2:2:1). IR spectrum: ν 1610 cm–1, s (C=Carom). H NMR
spectrum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.15 t (12H,
CH2CH3, J = 7.0 Hz), 1.84–1.96 m (4H, 8-H, 9-H),
2.90 m and 3.21 m (2H each, 7-H, 10-H), 3.33 q (8H,
CH2CH3, J = 7.0 Hz), 5.66 s (1H, CH), 6.49–6.56 m
and 6.78–6.85 m (4H each, C6H4), 7.16 d and 7.42 d
(1H each, 5-H, 6-H, J = 8.4 Hz), 7.55 s (1H, 4-H).
Found, %: N 7.82. C34H40ClN3. Calculated, %: N 7.99.
2-Chloro-7,8,9,10-tetrahydrobenzo[h]quinoline-
3-carbaldehyde (I). Vilsmeier reagent prepared from
18.3 g (0.25 mol) of dimethylformamide and 107.5 g
(0.7 mol) of phosphoryl chloride was cooled to –5 to
0°C, 18.9 g (0.1 mol) of N-(1,2,3,4-tetrahydronaphtha-
len-5-yl)acetamide [7] was added in portions, and the
mixture was allowed to warm up to room temperature,
heated for 2 h under reflux, and evaporated under
reduced pressure. The residue was poured onto 0.5 kg
of ice, the mixture was left to stand for 3 h in the cold,
and the precipitate was filtered off and dried. Yield
15.6 g (64%), mp 160–162°C (from EtOH), Rf 0.70
(EtOH–dichloroethane, 1:10). IR spectrum, ν, cm–1:
4,4′-[(2-Chlorobenzo[h]quinolin-3-yl)methylene]-
bis(N,N-dimethylaniline) (VIIa) was synthesized
from aldehyde II [8] and N,N-dimethylaniline. Yield
60%, mp 221–222°C (from 2-ethoxyethanol), Rf 0.64
(i-BuOH–H2O–AcOH, 2:2:1). IR spectrum:
1
ν 1610 cm–1, s (C=Carom). H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 2.94 s (12H, CH3),
5.79 s (1H, CH), 6.63 m and 6.90 m (4H each, C6H4),
7.62 d and 7.80 d (1H each, 5-H, 6-H, J = 8.8 Hz),
7.63–7.72 m (2H, 8-H, 9-H), 7.71 s (1H, 4-H), 7.90 m
(1H, 7-H), 9.10 m (1H, 10-H). Found, %: N 8.86.
C30H28ClN3. Calculated, %: N 9.02.
1
1682 (C=O), 1608 s (C=Carom). H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 1.85–2.00 m (4H,
CH2CH2CH2CH2), 2.96 br.t and 3.24 br.t (2H each,
CH2CH2CH2CH2, J = 5.4 Hz), 7.34 d and 7.79 d (1H
each, 5-H, 6-H, J = 8.4 Hz), 8.69 s (1H, 4-H), 10.45 s
(1H, CHO). Found, %: N 5.86. C14H12ClNO. Calculat-
ed, %: N 5.70.
4,4′-[(2-Chlorobenzo[h]quinolin-3-yl)methylene]-
bis(N,N-diethylaniline) (VIIb) was synthesized from
aldehyde II and N,N-diethylaniline. Yield 66%,
mp 224–225°C (from 2-ethoxyethanol), Rf 0.61
(i-BuOH–H2O–AcOH, 2 : 2 : 1). IR spectrum:
Diaryl(hetaryl)methanes VI–X (general proce-
dure). A mixture of 0.01 mol of aldehyde I–V, 2.4 g
(0.02 mol) of 30% aqueous HCl, and 0.03 mol of the
corresponding N-substituted aniline was stirred and
heated for 12 h under reflux. The resulting suspension
was made alkaline by treatment with aqueous am-
monia, excess N-substituted aniline was removed by
steam distillation, and the precipitate was filtered off,
washed with water, and dried.
1
ν 1610 cm–1, s (C=Carom). H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 1.16 t (12H, CH2CH3,
J = 7.0 Hz), 3.34 q (8H, CH2CH3, J = 7.0 Hz), 5.74 s
(1H, CH), 6.54 m and 6.87 m (4H each, C6H4), 7.63 d
and 7.80 d (1H each, 5-H, 6-H, J = 8.9 Hz), 7.64–
7.72 m (2H, 8-H, 9-H), 7.75 s (1H, 4-H), 7.89 m
(1H, 7-H), 9.11 m (1H, 10-H). Found, %: N 8.26.
C34H36ClN3. Calculated, %: N 8.05.
4,4′-[(2-Chloro-7,8,9,10-tetrahydrobenzo[h]quin-
olin-3-yl)methylene]bis(N,N-dimethylaniline) (VIa)
5-{Bis[4-(dimethylamino)phenyl]methyl}pyrimi-
dine-2,4(1H,3H)-dione (VIIIa) was synthesized from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

SYNTHESIS OF BISARYLMETHYL-SUBSTITUTED PYRIMIDINES AND QUINOLINES
61
aldehyde IIIa [9] and N,N-dimethylaniline. Yield 76%,
mp 299–301°C (from EtOH), Rf 0.53 (i-BuOH–H2O–
AcOH, 2:2:1). IR spectrum, ν, cm–1: 3343 br (OH),
1707, 1672 (C=O), 1607 (C=Carom). 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.84 s (12H, CH3), 5.05 s (1H,
CH), 6.48 d (1H, 6-H, J = 5.8 Hz), 6.64 m and 6.89 m
(4H each, C6H4), 10.52 d.d (1H, 1-H, J = 5.8, 1.5 Hz),
11.02 d (1H, 3-H, J = 1.5 Hz). Found, %: N 15.26.
C21H24N4O2. Calculated, %: N 15.37.
(DMSO-d6), δ, ppm: 1.06 t (12H, CH2CH3, J =
7.0 Hz), 1.79 s (3H, CH3), 3.28 q (8H, CH2CH3, J =
7.0 Hz), 5.37 s (1H, CH), 6.56 m and 6.88 m (4H each,
C6H4), 10.54 d (1H, 1-H, J = 1.5 Hz), 10.90 d (1H,
3-H, J = 1.5 Hz). Found, %: N 12.68. C26H34N4O2.
Calculated, %: N 12.89.
4,4′-[(2-Chloro-8-methylquinolin-3-yl)methy-
lene]bis(N,N-dimethylaniline) (IXa) was synthesized
from aldehyde IV [11] and N,N-dimethylaniline. Yield
65%, mp 205–206°C (from EtOH), Rf 0.44 (i-BuOH–
H2O–AcOH, 2:2:1). IR spectrum: ν 1612 cm–1, s
5-{Bis[4-(diethylamino)phenyl]methyl}pyrimi-
dine-2,4(1H,3H)-dione (VIIIb) was synthesized from
aldehyde IIIa and N,N-diethylaniline. Yield 85%,
mp 280–281°C (from EtOH), Rf 0.43 (i-BuOH–H2O–
AcOH, 2:2:1). IR spectrum, ν, cm–1: 3232 br, 3155 br
1
(C=Carom). H NMR spectrum (DMSO-d6–CCl4, 1:3),
δ, ppm: 2.75 s (3H, 8-CH3), 2.93 s (12H, NCH3),
5.72 s (1H, CH), 6.60 m and 6.87 m (4H each, C6H4),
7.36 d.d (1H, J = 7.9, 7.3 Hz) and 7.48–7.55 m (2H)
(5-H, 6-H, 7-H), 7.59 s (1H, 4-H). Found, %: N 9.50.
C27H28ClN3. Calculated, %: N 9.77.
1
(NH), 1713, 1665 (C=O), 1607 (C=Carom). H NMR
spectrum (DMSO-d6), δ, ppm: 1.13 t (12H, CH2CH3,
J = 7.0 Hz), 3.31 q (8H, CH2CH3, J = 7.0 Hz), 5.04 s
(1H, CH), 6.46–6.58 m (5H, 6-H, m-H), 6.85 m (4H,
o-H), 10.11 br.d (1H, 1-H, J = 5.7 Hz), 10.74 br.s (1H,
3-H). Found, %: N 12.97. C25H32N4O2. Calculated, %:
N 13.32.
4,4′-[(2-Chloro-8-methylquinolin-3-yl)methy-
lene]bis(N,N-diethylaniline) (IXb) was synthesized
from aldehyde IV and N,N-diethylaniline. Yield 73%,
mp 177–178°C (from EtOH), Rf 0.48 (i-BuOH–H2O–
AcOH, 2:2:1). IR spectrum: ν 1612 cm–1, s (C=Carom).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.15 t (12H, CH3CH2, J = 7.0 Hz), 2.71 s (3H, 8-CH3),
3.33 q (8H, CH2CH3, J = 7.0 Hz), 5.68 s (1H, CH),
6.53 m and 6.83 m (4H each, C6H4); 7.36 d.d (1H, J =
8.0, 7.1 Hz), 7.49 m (1H), and 7.55 m (1H) (5-H, 6-H,
7-H), 7.63 s (1H, 4-H). Found, %: N 8.50. C31H36ClN3.
Calculated, %: N 8.64.
5-{Bis[4-(isobutylamino)phenyl]methyl}pyrimi-
dine-2,4(1H,3H)-dione (VIIIc) was synthesized from
aldehyde IIIa and N-isobutylaniline. Yield 65%,
mp 237–238°C (from EtOH), Rf 0.58 (i-BuOH–H2O–
AcOH, 2:2:1). IR spectrum, ν, cm–1: 3287, 3170, 3140
1
(NH), 1709, 1653 (C=O), 1607 (C=Carom). H NMR
spectrum (DMSO-d6), δ, ppm: 0.96 d (12H, CH3, J =
6.6 Hz), 1.86 non (2H, CHCH2, J = 6.6 Hz), 2.80 d
(4H, CH2, J = 6.6 Hz), 4.96 br.s (2H, NHCH2), 4.99 s
(1H, 5-CH), 6.43 m (4H, m-H), 6.44 d (1H, 6-H, J =
5.6 Hz), 6.76 m (4H, o-H), 10.38 d.d (1H, 1-H, J = 5.6,
1.8 Hz), 10.72 d (1H, 3-H, J = 1.8 Hz). Found, %:
N 13.48. C25H32N4O2. Calculated, %: N 13.32.
2-Chloro-3-{bis[4-(dimethylamino)phenyl]-
methyl}-4H-pyrido[1,2-a]pyrimidin-4-one (X) was
synthesized from aldehyde V [12] and N,N-dimethyl-
aniline. Yield 68%, mp 199–200°C (from EtOH),
Rf 0.47 (i-BuOH–H2O–AcOH, 2:2:1). IR spectrum, ν,
1
cm–1: 1782 (C=O), 1608 s (C=Carom). H NMR spec-
5-{Bis[4-(dimethylamino)phenyl]methyl}-
6-methylpyrimidine-2,4(1H,3H)-dione (VIIId) was
synthesized from aldehyde IIIb [10] and N,N-dimeth-
ylaniline. Yield 74%, mp 184–186°C (from EtOH),
Rf 0.30 (i-BuOH–H2O–AcOH, 2:2:1). IR spectrum, ν,
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 2.90 s (12H,
CH3), 5.74 s (1H, CH), 6.57 m and 7.09 m (4H each,
C6H4), 7.27 d.d.d (1H, 7-H, J = 7.3, 6.7, 1.3 Hz),
7.57 d.d.d (1H, 9-H, J = 8.8, 1.3, 0.8 Hz), 7.88 d.d.d
(1H, 8-H, J = 8.8, 6.7, 1.6 Hz), 8.89 d.d.d (1H, 6-H,
J = 7.3, 1.6, 0.8 Hz). Found, %: N 12.65. C25H25ClN4O.
Calculated, %: N 12.94.
1
cm–1: 1718 s (C=O), 1615 s (C=Carom). H NMR spec-
trum (DMSO-d6), δ, ppm: 1.79 s (3H, 6-CH3), 2.85 s
(12H, NCH3), 5.42 s (1H, CH), 6.64 m (4H, m-H),
6.91 m (4H, o-H), 10.55 br.s (1H, 1-H), 10.90 br.s (1H,
3-H). Found, %: N 14.58. C22H26N4O2. Calculated, %:
N 14.80.
The author is grateful to G.M. Stepanyan for per-
forming biological tests.
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