3-(2,2-Dicyano-1-methylvinyl)coumarin in Heterocyclic Synthesis: Synthesis of Some New Coumarin Derivatives

Article abstract of DOI:10.1039/a703506c

The reaction of 3-acetylcoumarin with activated nitrites provides a convenient route to a range of new coumarin derivatives.

Full text of DOI:10.1039/a703506c

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84 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 84±85
3-(2,2-Dicyano-1-methylvinyl)coumarin in Heterocyclic
Synthesis: Synthesis of Some New Coumarin
Derivatives{
Mohamed R. Selim
Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
The reaction of 3-acetylcoumarin with activated nitriles provides a convenient route to a range of new coumarin derivatives.
Cyanocoumarins are of considerable interest as potential
building blocks for nitrogen-containing heterocyclic systems.
In addition to the study of the behaviour of a variety of
aromatic or heterocyclic amino compounds with activated
nitriles, interest has been shown in coumarin derivatives on
account of their pharmacological activity.1±3 In continuation
of our work4±7 on coumarins, we sought to synthesize new
coumarin derivatives which might be biologically active.
Thus condensation of 3-acetylcoumarin (1) with malono-
nitrile in boiling benzene containing ammonium acetate and
acetic acid using a Dean±Stark water separator a€orded 3-
(2,2-dicyano-1-methylvinyl)coumarin (2)8 (Scheme 1).
coumarins (5a±d) resulting from initial attack of the nucleo-
phile at C-b of the ole®nic bond of the dicyano derivatives
(Scheme 1).
Reaction of
2 with sulfur in a
Gewald reaction11
produced 3-(5-amino-4-cyano-3-thienyl)coumarin (6). Inter-
action of 6 with maleic anhydride in a Diels±Alder reaction
furnished 7, while its acetylation produced the correspond-
ing acylated compound 8 (Scheme 1). Passing hydrogen
sul®de gas into a solution of 2 in ethanol containing a
few drops of triethylamine a€orded 3-(2-cyano-1-methyl-2-
thiocarboxamidovinyl)coumarin (9) (Scheme 1).
Condensation of 2 with various substituted a-cyano-
cinnamonitriles 10a±c in boiling ethanol containing a few
drops of piperidine produced 3-(3-amino-2,4-dicyano-5-aryl-
phenyl)coumarins 13a±c (Scheme 2). These are assumed to
be formed via Michael addition of the methyl function in 2
to the activated double bond in 10, yielding the adduct 11
which then cyclizes into 12, the latter readily losing hydro-
gen cyanide to yield the stable compound 13. In contrast to
the anticipated formation of the ester 14, the reaction of 2
Ph
Ph
CN
CN
N
N
NHPh
Me
–H2C
NH
N
NH2
H
R
N
C
NH
CN
R
R
Me
CN
4
Me
3
NH2
PhNHNH2
PhNHNH2
CN
PhNHNH2
NC
S
CN
CN
CN
H2C
2
+
ArCH
C
NC
R
O
H2S
R
Me
X
9
10
R
Me
R′
Me
a Ar = Ph, X = CN
RNH2
1
2
b Ar = C6H4Me-4, X = CN
c Ar = C6H4OMe-4, X = CN
d Ar = Ph, X = CO2Et
NH
C
TEA
CN
CN
S
H2N
R
O
NH2
O
e Ar = C6H4NO2-4, X = CO2Et
O
O
Me
NC
R
NC
R
5a R′ = Ph
S
O
b R′ = C6H4NH2-2
c R′ = C6H4Cl-2
d R′ = C6H4Me-4
O
6
NC
R
CN
CN
CO2Et
NC
R
CN
CN
CN
7
Ac2O
Ar
Ar
NHAc
NC
11b
11a
R =
S
O
O
R
NH
NH
8
NC
CN
CO2Et
NC
CN
CN
Scheme 1
R
Ar
R
H
H
Ar
In contrast to the anticipated formation of pyrazoline
derivatives 3,9 the reaction of 2 with phenylhydrazine in
boiling ethanol gave the imino compound 4. This is assumed
to proceed via elimination of malononitrile. The suggested
structure for 4 was con®rmed by its independent synthesis
from 1 on re¯uxing with phenylhydrazine in boiling etha-
nol10 (Scheme 1).
12b
12a
NH2
NH2
NC
R
CO2Et
Ar
NC
CN
Ar
R
Interaction of 2 with primary aromatic amines in boiling
ethanol a€orded 3-(2,2-dicyano-1-arylamino-1-methylethyl)-
14
13
a Ar = Ph
b Ar = C6H4Me-4
c Ar = C6H4OMe-4
d Ar = C6H4NO2-4
This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Scheme 2 R as in Scheme1

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J. CHEM. RESEARCH (S), 1998 85
8.95 (1 H, s, H-4) (Found: C, 65.10; H, 2.50. C18H8N2O5 requires
C, 65.06; H, 2.40%).
with 10d,e a€orded 13a,d, presumably via elimination of
ethyl formate from the intermediate 12b (Scheme 2).
3-(5-Acetamido-4-cyano-3-thienyl)coumarin (8).ÐA solution of 6
(0.01 mol) in acetic anhydride (30 ml) was heated under re¯ux for
3 h. The reaction mixture was cooled to give a solid which was
®ltered o€ and crystallized from ethanol to give the title compound
Experimental
Mps are uncorrected. Elemental analyses were carried out in the
microanalytical laboratories of the Faculty of Science, Cairo
University. IR spectra (KBr) were measured on a Shimadzu IR 440
spectrophotometer. 1H NMR spectra were recorded on a JEOL FX
90Q (90 MHz) spectrometer and mass spectra on a Shimadzu GC-
MS-QPm 1000 EX spectrometer using the direct-inlet system.
1
8 (85%), mp 266 8C; max/cm 3450 (NH), 3040, 2975, 2215 (CN),
1705 (C1O), 1680 (C1O);
(CDCl3) 3.5 (3 H, s, CH3), 7.1 (1 H,
H
s, CH), 7.5±8.7 (4 H, m, ArH), 9.1 (1 H, s, H-4), 9.4 (1 H, br, NH)
(Found C, 62.10; H, 3.40. C16H10N2O3S requires C, 61.93; H,
3.22%).
3-(2,2-Dicyano-1-methylvinyl)coumarin (2).ÐTo a solution of 3-
acetylcoumarin 1 (0.1 mol) in dry benzene (10 ml) was added
malononitrile (0.1 mol), ammonium acetate (2 g) and acetic acid
(2 ml). The reaction mixture was heated under re¯ux using a Dean±
Stark water separator until water ceased to be collected. The pro-
duct obtained was crystallized from ethanol to give the title com-
3-(2-Cyano-2-methyl-2-thiocarboxamidovinyl)coumarin (9).ÐA sol-
ution of 2 (0.01 mol) in ethanol (30 ml) and a few drops of triethyl-
amine was treated with hydrogen sul®de gas for 2 h to give a solid,
which was ®ltered o€ and crystallized from benzene to give the title
compound 9 (75%), mp 183 8C; max/cm 3354, 3312 (NH2), 3113,
2214 (CN), 1694 (C1O) (Found: C, 62.40; H, 3.80. C14H10N2O2S
requires C, 62.22; H, 3.70%).
Reaction of 2 with Cinnamonitrile Derivatives 10a±e.ÐA suspen-
sion of 2 (0.01 mol) in ethanol (30 ml) was treated with 10a±e (0.01
mol) and a catalytic amount of piperidine (0.1 ml). The reaction
mixture was heated under re¯ux for 2 h. The precipitate was ®ltered
o€ and crystallized to give 3-(3-amino-2,4-dicyano-5-arylphenyl)-
coumarins 13a±d.
1
1
pound 2, (85%), mp 155 8C, max/cm 2200 (CN), 1720 (C1O),
1620 (C1C);
([2H6]DMSO) 2.7 (3 H, s, CH3), 7.7±8.3 (4 H, m,
H
ArH), 8.9 (1 H, s, H-4) (Found: C, 71.30; H, 3.40 C14H8N2O2
requires C, 71.18, H 3.38%).
3-[1-(Phenylhydrazonoethyl]coumarin (4).ÐA mixture of 1 or 2
(0.01 mol) and phenylhydrazine (0.01 mol) in ethanol (30 ml) was
heated under re¯ux for 2 h. The reaction mixture was cooled to
give a solid which was ®ltered o€ and crystallized from ethanol to
The 5-phenyl compound 13a (70%) had mp 257 8C (from EtOH);
1
1
give the title compound 4 (80%), mp 180 8C, max/cm 3484, 3298
max/cm 3472, 3332 (NH2), 3056, 2211 (CN), 1722 (C1O). dH
(NH), 1720 (C1O), 1601 (C1);
(CDCl3) 2.50 (3 H, s, CH3),
(CDCl3) 5.4 (2 H, br, NH2 exchangeable with D2O), 7.6±8.8 (10 H,
m, ArH), 8.9 (1 H, s, H-4); m/z 363 (M+, 100%), 336 (24), 335
(30), 306 (7), 279 (9), 182 (6), 139 (7), 126 (8), 113 (7), 77 (6)
(Found: C, 76.10; H, 3.70. C23H13N3O2 requires C, 76.03; H,
3.58%).
H
7.5±8.8 (9 H, m, ArH), 8.9 (1 H, s, H-4) and 9.3 (1 H, br, NH
exchangeable with D2O) (Found: C, 73.20; H, 4.90 C17H14N2O2
requires C, 73.38, H, 5.03%).
Reaction of 3-(2,2-Dicyano-1-methylvinyl)coumarin (2) with Aro-
matic Amines.ÐTo a solution of 2 (0.01 mol) in ethanol (30 ml) was
added the amine (0.01 mol) in ethanol (30 ml) in portions. The mix-
ture was heated under re¯ux for 2 h and then left to cool. The pre-
cipitated product was ®ltered o€, dried and crystallized from
ethanol to give 3-(2,2-dicyano-1-arylamino-1-methylethyl) coumarins
5a±d.
The 5-p-tolyl compound 13b (75%) had mp 268 8C (from EtOH);
1
max/cm 3460, 3340 (NH2), 3050, 2220 (CN), 1715 (C1O); dH
(CDCl3), 2.47 (3 H, s, CH3), 5.6 (2 H, br, NH2 exchangeable with
D2O), 7.6±8.1 (9 H, m, ArH), 8.8 (1 H, s, H-4) (Found: C, 75.20;
H, 4.30. C24H15N3O2 requires C, 76.39; H, 3.97%).
The 5-(4-methoxyphenyl) compound 13c (80%) had mp 320 8C
(from benzene); max/cm 3440, 3340 (NH2), 2950, 2210 (CN), 1715
1
1
The anilino compound 5a (60%) had mp 142 8C, max/cm 3440
(NH), 3050, 2965, 2220 (CN), 1715 (C1O); dH (CDCl3) 2.7 (3 H, s,
CH3), 2.8 (1 H, s, CH), 7.5±8.6 (9 H, m, ArH), 8.9 (1 H, s, H-4)
and 9.2 (1 H, br, NH exchangeable with D2O) (Found: C, 72.54; H,
4.60. C20H15N3O2 requires C, 72.94; H, 4.55%).
(C1O); dH (CDCl3) 4.2 (3 H, s, OCH3), 5.4 (2 H, br, NH2
exchangeable with D2O), 7.3±8.5 (9 H, m, ArH), 8.9 (1 H, s, H-4)
(Found: C, 73.20; H, 4.10. C24H15N3O3 requires C, 73.28; H,
3.81%).
The 2-aminophenylamino compound 5b (55%) had mp 130 8C,
max/cm 3430, 3350 (NH2, NH), 2930, 2230 (CN), 1725 (C1O);
The 5-(4-nitrophenyl) compound 13d (78%) had mp 310 8C (from
1,4-dioxane), max/cm 3450, 3320 (NH2), 3010, 2220 (CN), 1720
1
1
dH (CDCl3) 2.6 (3 H, s, CH3), 2.9 (1 H, s, CH), 5.3 (2 H, br, NH2),
7.4±8.7 (8 H, m, ArH), 8.9 (1 H, s, H-4) and 9.3 (1 H, br, NH,
exchangeable with D2O) (Found: C, 69.30; H, 4.30. C20H16N4O2
requires C, 69.76; H, 4.65).
(C1O); dH (CDCl3), 5.6 (2 H, br, NH2 exchangeable with D2O),
7.4±8.6 (9 H, m, ArH), 8.95 (1 H, s, H-4) (Found: C, 67.70; H,
3.20. C23H12N4O4 requires C, 67.64; H, 2.94%).
The 2-chlorophenylamino compound 5c (58%) had mp 135 8C,
max/cm 3440 (NH), 3040, 2960, 2210 (CN), 1700 (C1O); dH
Received, 21st May 1997; Accepted, 8th October 1997
Paper E/7/03506C
1
(CDCl3) 2.7 (3 H, S, CH3), 2.8 (1 H, s, CH), 7.6±8.8 (8 H, m,
ArH), 8.8 (1 H, s, H-4), 9.4 (1 H, br, NH, exchangeable with D2O)
(Found: C, 65.20, H, 3.50. C20H14ClN3O2 requires C, 66.02; H,
3.85%).
References
1
The p-tolylamino compound 5d (50%) had mp 140 8C, max/cm
1 Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky and
C. W. Rees, Pergamon, Oxford, 1984, vol. 1, p. 151 and vol. 3,
p. 881.
2 N. A. Stalmann, C. F. Huenter and K. P. Link, J. Biol. Chem.,
1941, 138, 513.
3 J. O. Berdy, Heterocyclic Antibiotics, CRC Press, Boca Raton,
1981.
4 M. R. Selim, A. M. El-Agrody, A. H. Bedair and F. M. Aly,
Sci. Phys. Sci., 1990, 100.
5 M. R. Selim, A. M. El-Agrody, A. H. Bedair, F. M. Aly and
M. F. Hassan, Egypt. J. Chem., 1992, 369.
6 M. R. Selim, F. A. Abu-Shanab, F. M. Aly and A. H. Bedair,
J. Indian Chem. Soc., 1992, 688.
3430 (NH), 2900, 2220 (CN), 1720 (C1O); dH (CDCl3) 2.6 (3 H, s,
CH3), 2.7 (3 H, s, CH3), 2.8 (1 H, s, CH), 7.6±8.8 (8 H, m, ArH),
8.9 (1 H, s, H-4), 9.3 (1 H, br, NH exchangeable with D2O)
(Found: C, 73.80; H, 4.80. C21H14N3O2 requires C, 73.46, H,
4.95%).
3-(5-Amino-4-cyano-3-thienyl)coumarin 6.ÐEquimolar amounts
(0.01 mol) of 2 and elemental sulfur in ethanol (30 ml) were treated
with a few drops of triethylamine (TEA). The reaction mixture was
heated under re¯ux for 2 h and then left to cool down to give a
solid which was ®ltered o€ and crystallized from ethanol to give the
1
title compound 6 (85%), mp 245 8C, max/cm 3472, 3332 (NH2),
3056, 2211 (CN) and 1722 (C1O) (Found: C, 62.50; H, 2.80.
C
14H8N2O2S requires C, 62.68; H, 2.98%).
3-Amino-4-cyano-5-(2-oxo-2H-chromen-3-yl) phathalic Anhydride
7 M. R. Selim, H. A. Emam, A. M. Radwan and A. Z. Sayed,
Proc. Indian Natl. Sci. Acad., 1996, 62, 429.
8 M. Coenen, Leibigs Ann. Chem., 1960, 85, 640.
9 S. Abdou, S. M. Fahmy, M. M. Khader and M. H. Elnagdi,
Monatsh. Chem., 1982, 113, 985.
10 A. H. Bedair, F. M. Aly and A. M. El-Agrody, J. Serb. Chem.
Soc., 1986, 51, 213.
11 K. Gewald, Chem. Ber., 1965, 98, 357.
7.ÐA mixture of 6 (0.01 mol), maleic anhydride (0.01 mol) and
1,4-dioxane (30 ml) was heated under re¯ux for 3 h. On cooling, a
solid formed which was ®ltered o€ and crystallized from ethanol to
give the title compound 7 (70%), mp 212 8C; max/cm 3430, 3350
(NH2), 3050, 2200 (CN), 1725 (C1O), 1650 (CO); (CDCl3) 5.6
(2 H, br, NH2 exchangeable with D2O), 7.6±8.6 (5 H, m, ArH),
1
H