Synthesis and structure of novel 3,4-annelated coumarin derivatives

Article abstract of DOI:10.1002/jhet.5570450137

(Chemical Equation Presented) Condensation of 4-chloro-2-oxo-2H-chromene-3- carbonitrile (1) with heteroarylamines 2a-d in acetonitrile containing a catalytic amount of triethylamine followed by spontaneous intramolecular cyclization gave the novel coumarin derivatives 3a-d, respectively. These compounds underwent acid hydrolysis giving the corresponding oxoderivatives 4a-d. The structural assignments of the synthesized compounds were based on elemental, IR, ¹H and ¹³C NMR analyses.

Full text of DOI:10.1002/jhet.5570450137

Jan-Feb 2008
Synthesis and Structure of Novel 3,4-Annelated Coumarin
Derivatives
295
Milan S. Dekiꢀ [a], Biljana R. Dekiꢀ [b], Vidoslav S. Dekiꢀ [b],
and Stojadin V. Dekiꢀ [b]*
[a] Department of Chemistry, Faculty of Sciences and Mathematics, University of Niꢁ, 18000 Niꢁ, Serbia
[b] Department of Chemistry, Faculty of Sciences and Mathematics, University of Priꢁtina, 38220 K.
Mitrovica, Serbia
E-mail: dekic@inbox.com
Received February 4, 2007
Cl
H
CN
O
N
O
N
C
cat. Et N
3
+
N
N
3
CH CN
O
H N
2
O
1
2a-d
N
O
N
N
O
N
O
HCl
O
NH
EtOH
O
4a-d
3a-d
Condensation of 4-chloro-2-oxo-2H-chromene-3-carbonitrile (1) with heteroarylamines 2a-d in
acetonitrile containing a catalytic amount of triethylamine followed by spontaneous intramolecular
cyclization gave the novel coumarin derivatives 3a-d, respectively. These compounds underwent acid
hydrolysis giving the corresponding oxoderivatives 4a-d. The structural assignments of the synthesized
1
13
compounds were based on elemental, IR, H and C NMR analyses.
J. Heterocyclic Chem., 45, 295 (2008).
INTRODUCTION
benzothiazol-2-ylamine (2a), 4-methoxy-benzothiazol-2-
ylamine (2b), 4,5-dimethyl-thiazol-2-ylamine (2c), 3-
methyl-pyridin-2-ylamine (2d), respectively, 1:1 mole
ratio of starting materials) was reacted at reflux
temperature in the presence of triethylamine as a base
catalyst, leading to the formation of an intermediate
product. No efforts were made to isolate that intermediate,
but instead, it was cyclized in situ into the desired
heteroaromatic products 3a-d, presumably by means of a
mechanism involving a proton transfer from amino to
cyano group with the synchronous building of a
pyrimidine ring. The obtained polycyclic imines 3a-d
were subjected to acid hydrolysis to afford the
corresponding oxoderivatives 4a-d. The synthetic
approach is illustrated in Scheme 1.
The synthesis of coumarin (2-oxo-2H-chromene)
derivatives has attracted considerable attention of organic
and medicinal chemists as these are widely used as
fragrances, pharmaceuticals and agrochemicals [1].
Coumarins have a variety of bioactivities including
anticoagulant, estrogenic, dermal photosensitizing,
antimicrobial, vasodilator, molluscacidal, antihelminitic,
sedative and hypnotic, analgesic and hypothermic activity
[
1,2]. Furthermore, coumarin and its derivatives cause
significant changes in the regulation of immune
responses, cell growth and differentiation in sensitive
tumor cells [1]. Bearing in mind the wide range of
bioactivities, we thought it worthwhile to synthesize new
coumarin derivatives. As a continuation of our previous
work [3], we report on the synthesis and characterization
of new derivatives containing the coumarin moiety.
Product 3a was synthesized starting from 4-methyl-
benzothiazol-2-ylamine and obtained as
a
yellow
crystalline substance. The IR spectra showed strong band
at 1622 cm corresponding to absorption of the C=N
RESULTS AND DISCUSSION
-1
Several new coumarin derivatives (Figure 1) were
prepared in the following one-pot reaction manner [4]: an
acetonitrile solution of 4-chloro-2-oxo-2H-chromene-3-
bond. The IR absorptions due to the imino and ꢀ-pyrone
-1
-1
carbonyl functions appeared at 3280 cm and 1705 cm ,
1
respectively. In H NMR spectrum aromatic protons
carbonitrile (1) and
a
heteroarylamine (4-methyl-
appeared as a multiplet between 8.15 and 7.23 ppm.

2
96
M. Dekiꢀ, B. Dekiꢀ, V. Dekiꢀ, and S. Dekiꢀ
Vol 45
ring into carbonyl group. As expected, this conversion
was smoothly achieved with boiling 15%-ethanolic
solution of hydrochloric acid leading to corresponding
oxoderivatives 4a-d. The hydrolysis was confirmed by
elemental and spectral analyses. The IR spectra of
compounds 4a-d revealed a strong band in the 1767-1755
1
1
10
S
9
S
1
2
8
N
N
N
O
N
O
1
3
OMe
1
4
7
2
3
X
X
6
5
O
O
-1
cm region due to the absorption of carbonyl group of the
pyrimidone ring, whereas the carbonyl group constituting
3
4
a
: X = NH
3b: X = NH
4b: X = O
a: X = O
a part of the ꢁ-pyrone ring revealed band at 1715-1702
-1
cm . The disappearance of ꢂ N-H bands in the IR spectra
S
is compatible with their assigned structures. As expected,
the H NMR spectra showed a loss of NH proton.
All structures were corroborated by comparison of their
spectral data to those published in the literature for related
systems [3, 5-8].
1
N
N
O
N
O
N
O
X
X
O
This paper describes the synthesis, characterization and
chemical transformation of 3,4-annelated coumarin
derivatives, which could possess interesting physiological
properties. Moreover, this one-pot reaction can success-
fully be employed in the preparation of new polyhetero-
cyclic coumarin derivatives having useful biological
activity.
3
c
: X = NH
3d: X = NH
4d: X = O
4
c: X = O
Figure 1. Structures of the new synthesized 3,4-annelated coumarin
derivatives
Singlet at ꢀ 9.72 ppm corresponding to the proton of the
1
3
pyrimidine ring NH group. The C NMR showed 18
resonances, one conjugated lactone carbonyl (ꢀ 162.4
ppm), additional six signals (C-12a, C-4a, C-7, C-13a, C-
EXPERIMENTAL
7
b, C-11a) corresponding to quaternary heteroatom
2
bonded C-sp with chemical shifts at ꢀ 158.7-135.6 ppm,
three signals corresponding to quaternary C-sp (C-8, C-
General Methods. Melting points were determined on a
Kofler hot-plate apparatus and are uncorrected. Microanalysis of
carbon, hydrogen, nitrogen and sulfur were carried out with a
Carlo Erba 1106 microanalyser. The IR measurements were
carried out with a Perkin-Elmer 457 grating FT instrument in
KBr tablets. The NMR spectra were recorded on a Varian
2
6
a, C-13b), seven aromatic methyne shifts (C-1, C-2, C-3,
C-4, C-9, C-10, C-11) and CH carbon atom shift at ꢀ
2
analogous synthetic method and characterized by
elemental analysis, IR, H and C NMR spectroscopy.
An additional proof of 3a-d was obtained by chemical
transformation of the imino function of the pyrimidine
3
0.1 ppm. The compounds 3b-d were prepared by
1
13
Gemini 200 ( H at 200 MHz, C at 50 MHz) spectrometer,
1
13
using DMSO-d as the solvent. Chemical shifts are expressed in
6
ꢀ (ppm) using TMS (tetramethylsilane) as an internal standard.
For TLC, silica gel plates (Kiesel 60 F254, Merck) were used.
Starting Material. 4-Hydroxy-2-oxo-2H-chromene-3-
carbonitrile was prepared following the method of Anschutz [9].
Starting compound (1) was prepared from 4-hydroxy-2-oxo-2H-
chromene-3-carbonitrile according to the method of Chechi et
al. [4], modified by Kaljaj et al. [6] that allowed obtaining the
compound in higher yield (96%) and shorter time (less then 1
hour), instead of 35-40% within 7 h reported for the original
method. The preparation was carried out in the following
manner: 1.85 mL of N,N-dimethylformamide (DMF) was cooled
N
H N
2
H
+
Cl
O
N
O
N
C
CN
N
cat. Et N
3
3
CH CN
O
O
to 10°C using an ice bath. Under stirring, 4 g of POCl was
3
1
2a-d
added dropwise, and the prepared mixture was stirred for 15
min. Then, the ice bath was removed and the reaction proceeded
at room temperature for additional 15 min. Finally, the solution
of 4-hydroxy-2-oxo-2H-chromene-3-carbonitrile (4.67 g) in
DMF (12.5 mL) was added dropwise. After 15 minutes of
stirring, the reaction was stopped by adding cold water (15 mL).
The precipitate solid was collected by filtration and washed with
N
O
N
N
N
O
HCl
O
NH
EtOH
O
O
a
saturated sodium-bicarbonate solution and with water.
4
a-d
3a-d
Recrystallization from glacial acetic acid yielded yellow crystals
of 1 (4.8 g) in 96% yield, mp 199-200°C. Finally, all other
chemicals were commercially available and used as received,
except that the solvents were purified by distillation.
Scheme 1. General reaction sequence leading to the new heterocyclic
,4-annelated coumarin derivatives
3

Jan-Feb 2008
Synthesis and Structure of Novel 3,4-Annelated Coumarin Derivatives
297
General Procedure for the Synthesis of 3a-d. A solution of
(2.0 g, 10 mmol) and the appropriate heteroarylamine (4-
General Procedure for the Preparation of 4a-d. Each of
compounds 3a-d (1 g) was heated under reflux (1-2 hours) with
15% hydrochloric acid (20 mL) in ethanol (50 mL). After
cooling, a precipitate was formed which was collected by
filtration and washed with a saturated sodium bicarbonate
solution, and then with water. Recrystallization from the stated
solvents yielded compounds 4a-d, respectively.
1
methyl-benzothiazol-2-ylamine (2a), 4-methoxy-benzothiazol-2-
ylamine (2b), 4,5-dimethyl-thiazol-2-ylamine (2c), 3-methyl-
pyridin-2-ylamine (2d), 10 mmol) in acetonitrile (30 mL) in the
presence of catalytic amounts of triethylamine (2 mL) was
refluxed for 1-2 hours. After cooling, the precipitate solid was
collected by filtration and washed with acetonitrile.
Recrystallization from the stated solvents yielded compound 3a-
d, respectively. The purity of the synthesized compounds was
checked by TLC.
8-Methyl-5-oxa-12-thia-7a,13-diaza-indeno[1,2-b]phenan-
threne-6,7-dione (4a). Yellow crystals (from EtOH), yield 75%
-1
(0.75 g), mp 225-228°C; IR ꢀ (KBr, cm ): 3106 (Ar-H), 2950
(C-H), 1758 (C=O), 1711 (C=O), 1628 (C=N), 1607 (C=C),
1
7
-Imino-8-methyl-7H-5-oxa-12-thia-7a,13-diazaideno[1,2-b]-
761; H NMR (DMSO-d ): ꢁ = 8.02-7.09 (m, 7H, arom.), 2.70
6
phenanthren-6-one (3a). Yellow crystals (from CH CN), yield
(s, 3H, CH ) ppm. Anal. Calcd. for C H N O S (334.36): C,
64.66; H, 3.01; N, 8.38; S, 9.59. Found: C, 64.52; H, 2.85; N,
8.54; S, 9.50.
3
3
18 10
2
3
-
1
5
3
0% (1.83 g), mp 238-240°C; IR ꢀ (KBr, cm ): 3280 (N-H),
105 (Ar-H), 2944 (C-H), 1705 (C=O), 1622 (C=N), 1611
1
(C=C), 1596, 765; H NMR (DMSO-d ): ꢁ = 9.72 (brs, 1H, N-
8-Methoxy-5-oxa-12-thia-7a,13-diaza-indeno[1,2-b]phenan-
6
1
3
H), 8.15-7.23 (m, 7H, arom.), 2.82 (s, 3H, CH ) ppm; C NMR
threne-6,7-dione (4b). Yellow crystals (from CH CN), yield 45%
3
3
-1
(
DMSO-d ): ꢁ = 162.4 (C-6), 158.7 (C-12a), 153.3 (C-4a), 150.9
(0.45 g), mp 278-280°C; IR ꢀ (KBr, cm ): 3096 (Ar-H), 2940 (C-
6
1
(C-7), 148.8 (C-13a), 142.1 (C-7b), 135.6 (C-11a), 133.9 (C-8),
H), 1760 (C=O), 1715 (C=O), 1621 (C=N), 1611 (C=C), 755; H
1
9
30.2, 127.2, 126.7, 125.5, 122.4, 121.8, 119.4 (C-6a), 117.9,
NMR (DMSO-d ): ꢁ = 8.15-7.08 (m, 7H, arom.), 3.82 (s, 3H,
6
6.0 (C-13b), 20.1 (CH ) ppm. Anal. Calcd. for C H N O S
CH O) ppm. Anal. Calcd. for C H N O S (350.36): C, 61.71; H,
3
18 11
3
2
3
18 10
2
4
(
333.37): C, 64.85; H, 3.33; N, 12.60; S, 9.62. Found: C, 64.90;
H, 3.56; N, 12.44; S, 9.39.
-Imino-8-methoxy-7H-5-oxa-12-thia-7a,13-diazaindeno-
1,2-b]phenanthren-6-one (3b). Yellow crystals (from DMF),
2.88; N, 8.00; S, 9.15. Found: C, 61.55; H, 3.07; N, 8.07; S, 8.93.
8,9-Dimethyl-5-oxa-10-thia-7a,11-diazacyclopenta[b]phen-
anthrene-6,7-dione (4c). Yellow crystals (from DMF), yield
7
-
1
[
72% (0.72 g), mp 336-338°C; IR ꢀ (KBr, cm ): 3087 (Ar-H),
-1
yield 33% (1.25 g), mp 260-262°C; IR ꢀ (KBr, cm ): 3284 (N-
H), 3089 (Ar-H), 2955 (C-H), 1720 (C=O), 1621 (C=N), 1609
2946 (C-H), 2930, 1755 (C=O), 1702 (C=O), 1606 (C=C), 761;
1
H NMR (DMSO-d ): ꢁ = 8.15 (d, 1H, H-1), 7.79 (t, 1H, H-3),
6
1
(C=C), 752; H NMR (DMSO-d ): ꢁ = 9.95 (brs, 1H, N-H),
7.52 (t, 1H, H-2), 7.28 (d, 1H, H-4), 2.67 (s, 6H, CH ) ppm.
6
3
1
3
8
.06-6.95 (m, 7H, arom.), 3.82 (s, 3H, CH O) ppm; C NMR
Anal. Calcd. for C H N O S (298.32): C, 60.39; H, 3.38; N,
3
15 10
2
3
(
DMSO-d ): ꢁ = 161.8 (C-6), 160.3 (C-12a), 155.6 (C-8), 152.8
9.39; S, 10.75. Found: C, 60.26; H, 3.43; N, 9.32; S, 10.69.
11-Methyl-5-oxa-7a,12-diaza-benzo[a]anthracene-6,7-di-
one (4d). Yellow crystals (from EtOH), yield 80% (0.80 g), mp
6
(C-4a), 151.3 (C-7), 149.8 (C-13a), 140.8 (C-7b), 134.0 (C-11a),
1
1
29.6, 123.8, 121.8, 119.0, 118.3, 117.6 (C-6a), 117.0, 94.5 (C-
-
1
3b), 55.2 (OCH ) ppm. Anal. Calcd. for C H N O S (349.37):
290-291°C; IR ꢀ (KBr, cm ): 3102 (Ar-H), 2945 (C-H), 1767
3
18 11
3
3
1
C, 61.88; H, 3.17; N, 12.03; S, 9.18. Found: C, 61.96; H, 3.30;
N, 12.05; S, 9.12.
(C=O), 1711 (C=O), 1630 (C=N), 1599 (C=C), 760; H NMR
(DMSO-d ): ꢁ = 8.34 (d, 1H, H-1), 8.07 (t, 1H, H-9), 7.80-7.48
6
7
-Imino-8,9-dimethyl-7H-5-oxa-10-thia-7a,11-diazacyclo-
(m, 3H, H-3, H-10, H-8), 7.33 (d, 1H, H-4), 7.18 (t, 1H, H-2),
penta[b]phenanthren-6-one (3c). Yellow crystals (from DMF),
yield 55% (1.8 g), mp 240-242°C; IR ꢀ (KBr, cm ): 3280 (N-
2.95 (s, 3H, CH ) ppm. Anal. Calcd. for C H N O (278.27): C,
3
16 10
2
3
-
1
69.06; H, 3.62; N, 10.07. Found: C, 69.23; H, 3.49; N, 10.30.
Acknowledgement. The authors acknowledge the Ministry of
Science and Environmental Protection of Serbia for financial support.
H), 3095 (Ar-H), 2945 (C-H), 1712 (C=O), 1625 (C=N), 1605
1
(
C=C), 759; H NMR (DMSO-d ): ꢁ = 9.84 (brs, 1H, N-H), 8.28
6
(
d, 1H, H-1), 7.72 (t, 1H, H-3), 7.45 (t, 1H, H-2), 7.32 (d, 1H, H-
1
3
4
6
1
1
), 2.61 (s, 6H, CH ) ppm; C NMR (DMSO-d ): ꢁ = 162.1 (C-
3
6
REFERENCES
), 159.2 (C-10a), 151.5 (C-4a), 149.8 (C-7), 148.5 (C-11a),
33.6, 128.8, 126.7, 126.1, 123.2, 120.7 (C-6a), 119.5, 96.3 (C-
1b), 12.6 (CH ), 12.4 (CH ) ppm. Anal. Calcd. for C H N O S
[
1] Coumarins–Biology, Applications and Mode of Action;
3
3
15 11
3
2
O’Kennedy, R.; Thornes, R. D., Eds.; John Wiley & Sons:
Chichester, UK, 1997.
(
297.34): C, 60.59; H, 3.73; N, 14.13; S, 10.78. Found: C, 60.70;
H, 3.72; N, 14.37; S, 10.52.
-Imino-11-methyl-7H-5-oxa-7a,12-diazabenzo[a]anthra-
cen-6-one (3d). Intensively yellow needles (from DMF), yield
[
2] Soine, T. O. J. Pharm. Sci. 1964, 53, 231.
7
[3] Radulovic, N.; Stojanovic, G.; Vukicevic, R.; Dekic, V.;
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Ital. 1968, 98, 1448.
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Serb. Chem. Soc. 1996, 61, 419.
-1
5
3
5% (1.7 g), mp 270-271°C; IR ꢀ (KBr, cm ): 3277 (N-H),
098 (Ar-H), 2948 (C-H), 1705 (C=O), 1632 (C=N), 1602
1
(C=C), 756; H NMR (DMSO-d ): ꢁ = 9.58 (brs, 1H, N-H), 8.12
6
(d, 1H, H-1), 7.95 (t, 1H, H-9), 7.72-7.65 (m, 2H, H-3, H-10),
[
6] Kaljaj, V.; Trkovnik, M.; Stefanovic-Kaljaj, L. J. Serb.
Chem. Soc. 1987, 52, 183.
7] Stefanovic-Kaljaj, L.; Kaljaj, V.; Trkovnik, M.;
Mladenovic, S. J. Serb. Chem. Soc. 1989, 54, 169.
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7
3
.57 (d, 1H, H-8), 7.44 (d, 1H, H-4), 7.36 (t, 1H, H-2), 2.72 (s,
1
3
H, CH ) ppm; C NMR (DMSO-d ): ꢁ = 161.5 (C-6), 155.4
3
6
[
(
1
(
C-11a), 152.4 (C-4a), 151.2 (C-12a), 149.7 (C-7), 130.1, 129.3,
25.6, 125.1, 122.5, 118.2 (C-6a), 115.7, 97.3 (C-12b), 17.8
CH ) ppm. Anal. Calcd. for C H N O (277.28): C, 69.31; H,
[
3
16 11
3
2
Heterocycl. Commun. 2002, 8, 129.
4
.00; N, 15.15. Found: C, 69.35; H, 4.18; N, 14.97.
[9] Anschutz, R. Ber. Dtsch. Chem. Ges. 1903, 36, 463.