The synthesis of some new fused and substituted chromenes

Article abstract of DOI:10.1080/10426500600864221

Some new chromeno[2,3-b]pyrimidines, chromeno[3,2-c]pyridines, chromeno[2,3-b]pyridines and 3-chromenyl-1,3-thiazines were synthesized via the synthetic studies of the reaction of 2-imino-2H-chromen-3-thiocarboxamide with some aromatic aldehydes, active nitriles, and their ylidene derivatives. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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The Synthesis of Some
New Fused and Substituted
Chromenes
Ahmed M. El-Sayed a
a Chemistry Department, South Valley University,
Sohag, Egypt
Published online: 22 Nov 2006.
To cite this article: Ahmed M. El-Sayed (2006) The Synthesis of Some New Fused and
Substituted Chromenes, Phosphorus, Sulfur, and Silicon and the Related Elements,
181:12, 2709-2723, DOI: 10.1080/10426500600864221
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Phosphorus, Sulfur, and Silicon, 181:2709–2723, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600864221
The Synthesis of Some New Fused and Substituted
Chromenes
Ahmed M. El-Sayed
Chemistry Department, South Valley University, Sohag, Egypt
Some new chromeno[2,3-b]pyrimidines, chromeno[3,2-c]pyridines, chromeno[2,3-
b]pyridines and 3-chromenyl-1,3-thiazines were synthesized via the synthetic stud-
ies of the reaction of 2-imino-2H-chromen-3-thiocarboxamide with some aromatic
aldehydes, active nitriles, and their ylidene derivatives.
Keywords Chromenopyridines; chromenothiazines; malononitrile; ylidenenitriles
INTRODUCTION
Fused coumarins comprise a very interesting class of compounds for
their significant antibacterial1−7 and novobiocin8,9 activities. For these
reasons we continue our previous work,6,7 which deals with the
synthesis of chromenopyrazoles, chromenopyridines, and chromenoaze-
pines. We report here the synthesis of some new chromenopyrimidines,
chromenopyridines, and 3-chromenyl-1,3-thiazines.
RESULTS AND DISCUSSION
The treatment of 2-imino-2H-chromene-3-thiocarboxamide 110 with
different aromatic aldehydes, namely benzaldehyde, p-anisaldehyde,
p-nitrobenz-aldehyde, and 2-naphthaldehyde, in a 1:1 molar ratio in
refluxing tetra-hydrofuran containing a catalytic amount of piperidine
gave the cyclized products 2-phenyl-2,3-dihydro-4H-chromeno[2,3-d]-
pyrimidine-4-thione, 2-(4-methoxyphenyl)-2,3-dihydro-4H-chromeno-
[2,3-d]pyrimidine-4-thione, 2-(4-nitrophenyl)-2,3-dihydro-4H-chrome-
no[2,3-d]pyrimidine-4-thione, and 2-(2-naphthyl)-2,3-dihydro-4H-chro-
menomeno[2,3-d]pyrimidine-4-thiones 2a–d. The effect of a cyclic
ketone on compound 2b was tested via its reaction with cyclohexanone
in refluxing dioxan in the presence of triethylamine as a catalyst where
Received March 7, 2006; accepted May 4, 2006.
Address correspondence to Ahmed M. El-Sayed, South Valley University, Chemistry
Department, Faculty of Science, Sohag, 82524 Egypt. E-mail: elsayed-a@lycos.com
2709

2710

2711

2712

2713

2714
A. M. El-Sayed
SCHEME 1
4-(8,8a,10,11,12,13-hexahydro-7H-5-oxa-9-thia-6,8-diazanaphtho [2,-
3,4-de]anthracen-7-yl)phenyl methyl ether 3b was obtained (Scheme 1,
Table I).
The formation of compound 3b is assumed to proceed through the
addition of the active methylene group of cyclohexanone on C3 = C4 of
the chromene moiety followed by the elimination of a water molecule
from the interaction of the tautomeric SH group and the carbonyl group.
The acetylation of compound 1 was achieved by treating compound
1 with glacial acetic acid at r.t. to give N-[(2-imino-2H-chromen-3-
yl)carbonothioyl]acetamide 4, which in turn cyclized to 2-methyl-4H-
chromeno[2,3-d] pyrimidine-4-thione 5 in an 81% yield on heating
with acetic anhydride. The same compound 5 was obtained directly
by warming compound 1 with an excess amount of acetic anhydride
in 79% (Scheme 2, Table I). Also, N-formyl-2-imino-2H-chromene-3-
thiocarboxamide 6 was formed through the reaction of our starting
SCHEME 2

The Synthesis of Some New Fused and Substituted Chromenes
2715
material with warmed formic acid, which underwent intramolecular cy-
clization into benzo[g]quinazoline-4(10H)-thione 7 in refluxing ethanol
containing piperidine as a catalyst (Scheme 2, Table I).
The action of active nitriles on our starting material was studied.
So, on treating compound 1 with malononitrile at r.t. in ethanol using
piperidine as a catalyst, 3-imino-1-thioxo-2,3-dihydro-1H-chromeno-
[3,2-c] pyridine-4-carbonitrile 8 was yielded (Scheme 3, Table I).
SCHEME 3
Also, the treatment of compound 1 with ethyl cyanoacetate
or cyanothio-acetamide in ethanol containing
piperidine at r.t. afforded 2-cyano-N-[(2-imino-2H-chromen-3-
yl)carbonothioyl]acetamide or 2-cyano-N-[(2-imino-2H-chromen-
a few drops of
9
3-yl)carbono-thioyl]ethanimidothioic acid 10. Both compounds 9
and 10 gave the same cyclized product (4-thioxo-4H-chromeno[2,3-
d]pyrimidin-2-yl)-acetonitrile 11 in 83% and 80% yields in refluxing
tetrahydrofuran along with few drops of piperidine. Compound 11 was
obtained directly in a 71% yield by refluxing compound 1 with ethyl
cyanoacetate or cyanothioacetamide in tetrahydrofura along with
piperidine as a catalyst (Scheme 4, Table I).
SCHEME 4

2716
A. M. El-Sayed
SCHEME 5
It has been reported11 that the reaction of compound 1 with mal-
ononitrile or ethyl cyanoacetate along with ammonium acetate in a
1:1:1.5 molar ratio, respectively, in refluxing ethanol afforded the cor-
responding benzopyrano[3,4-c]pyridine-4H-thiones. Herein we report
that the reaction of compound 1 with malononitrile, ethyl cyanoac-
etate, or cyanothioacetamide in refluxing ethanol using piperidine
as a catalyst afforded 2-amino-4-imino-2H-chromeno[2,3-b]pyridine-
3-carbonitrile 12, ethyl 2-cyano-3-imino-3-(2-imino-2H-chromen-3-
yl)propanoate 13, 2-hydroxy-4-imino-4H-chromeno[2,3-d]pyridine-3-
carbonitrile 14, or 4-imino-2-mercapto-4H-chromeno[2,3-b]pyridine-3-
cabonitrile 15, respectively (Scheme 5, Table I). The reaction pathway is
believed to be a nucleophilic attack of the methylene anion at the thione
group with elimination of H2S molecule to give the condensation prod-
uct (this was confirmed by isolating the intermediate 13) followed by
intramolecular cyclization through the nucleophilic attack of the imino
group at the cyano, carbonyl or thione group respectively.
The reaction of compound 1 with arylidene(benzylidene, p-nitro-
benzylidene, p-methoxybenzylidene)malononitrile, ethyl p-nitrobezyli-
denecyano-acetate, and ethyl 2-naphthylidenecyanoacetate at r.t. in the
presence of piperidine as a catalyst afforded 6-amino-2-(2-imino-2H-
chromen-3-yl)-4-phenyl-4H-1,3-thiazine-5-carbonitrile 16a, 6-amino-2-
(2-imino-2H-chromen-3-yl)-4-(4-nitrophenyl-4H-1,3-thiazine-5-carbo-
nitrile 16b, 6-amino-2-(2-imino-2H-chromen-3-yl)-4-(4-methoxyphen-
yl-4H-1,3-thiazine-5-carbonitrile 16c, ethyl 6-amino-2-(2-imino-2H-
chromen-3-yl)-4-(4-nitophenyl)-4H-1,3-thiazine-5-carboxylate
16d,

The Synthesis of Some New Fused and Substituted Chromenes
2717
SCHEME 6
6-hydroxy-2-(2-imino-2H-chromen-3-yl)-4-(2-naphthyl)-4H-1,3-thia-
zine-5-carbonitrile 16e, and ethyl 6-amino-2-(2-imino-2H-chromen-
3-yl)-4-(2-naphthyl)-4H-1,3-thiazine-5-carboxylate 16f (Scheme 6,
Table I).
Moreover, compound 1 was subjected to react with ethoxymethylene-
malononitrile in ethanol using piepridine as a catalyst at r.t. in
which a mixture of N- (2,2-dicyanovinyl)-2-imino-2H-chromene-3-carb-
imidothioic acid 17, benzo[g]quinazoline-4(10H)-thione 7, and 6-imino-
2-(2-imino-2H-chromen-3-yl)-6H-1,3-thiazine-5-carbonitrile 18 were
isolated in 20%, 28%, and 48% yields, respectively. Carrying out the
same reaction in refluxing ethanol afforded compound 18 only in an
80% yield. (Scheme 7, Table I).
Similarly, the reaction of compound 1 with(1-ethoxyethylidene)-
malononitrile in ethanol in the presence of piperidine as a cat-
alyst at r.t. gave the open structure 19 in a 26% yield. But
the reaction of the same reagents in refluxing ethanol afforded
a mixture of N-(2,2-dicyano-1-methylvinyl)-2-imino-2H-chromene-3-
carbimidothioic acid 19 and 6-imino-2-(2-imino-2H-chromen-3-yl)-4-
methyl-6H-1,3-thiazine-5-carbonitrile 20 in 30% and 51% yields,
respectively. Also, the treatment of compound
1 with ethyl
ethoxymethylenecyanoacetate in refluxing ethanol using a piperi-
dine catalyst afforded N-[2-cyano-3-ethoxy-3-oxoprop-1-enyl]-2-imino-
2H-chromene-3-carbimidothioi acid 21 and 2-(2-imino-2H-chromen-3-
yl)-6-oxo-6H-1,3-thiazine-5-carbonitrile 22 (Scheme 8, Table I).

2718
A. M. El-Sayed
SCHEME 7
SCHEME 8

The Synthesis of Some New Fused and Substituted Chromenes
2719
CONCLUSION
This synthetic study reveals that the reaction of the starting material
2-imino-2H-chromene-3-thiocarboxamide with the active nitriles and
their ylidene derivatives depends on reaction conditions (temperature
and time).
EXPERIMENTAL
The synthesis of 2-phenyl-2,3-dihydro-4H-chromeno[2,3-d]pyri-
midine-4-thione,2-(4-methoxyphenyl)-2,3-dihydro-4H-
chrome-
no[2,3-d]pyrimi–dine-4-thione, 2-(4-nitrophenyl)-2,3-dihydro-4H-
chromeno[2,3-d]pyri–midine-4-thione and 2-(2-naphthyl)-2,3-dihydro-
4H-chromeno[2,3-d]pyrimidine-4-thione 2a–d
General Procedure
To a solution of compound 1 (1.02 g, 0.005 mole) and benzaldehyde
(0.50 mL), p-anisaldehyde (0.57 mL), p-nitrobenzaldehyde (0.75 g) or
2-naphthaldehyde (0.79 g) in tetrahydrofuran (50 mL), and 3 drops of
piperidine were added. The reaction mixture was refluxed for 4 h. Com-
pound 2d was precipitated on heating, collected by filtration, and crys-
tallized. The reaction mixture was left to cool where compounds 2a and
2b were separated, collected by filtration, and crystallized. The reaction
mixture was evaporated, and the solid residue was washed with a water/
ethanol mixture and crystallized where compound 2c was obtained
(Table I).
The Synthesis of 4-(8,8a,10,11,12,13-Hexahydro-7H-5-oxa-9-
thia-6,8-diazanaphtho[2,3,4-de]anthracen-7-yl)phenyl Methyl
Ether 3b
A mixture of compound 2b (0.80 g, 0.0025 mole), cyclohexanone
(0.26 mL, 0.0025 mole), and 2 drops of triethylamine and dioxane
(20 mL) was stirred at r.t. for 1 h and then refluxed for 2 h. The reac-
tion mixture was evaporated, and the residual solid was washed with
a water/ethanol mixture and crystallized (Table I).
The Synthesis of N-[(2-imino-2H-chromen3-yl)-
carbonothioyl]acetamide 4
Compound 1 (1.02 g, 0.005 mole) was dissolved in glacial acetic acid
(20 mL) and stirred for 2 h at r.t. The separated solid was collected by
filtration, washed with ethanol, and crystallized (Table I).

2720
A. M. El-Sayed
The Synthesis of 2-Methyl-4H-chromeno[2,3-d]-
pyrimidine-4-thione 5
Compound 4 (0.615 g, 0.0025 mole) or compound 1 (1.02 g, 0.005 mole)
was refluxed in acetic anhydride (10 mL) for 10 min. The reaction mix-
ture was poured into an ice-water mixture, and the separated solid was
filtered off, washed with water, and crystallized (Table I).
The Synthesis of N-formyl 2-Imino-2H-chromene-3-
thiocarboxamide 6
A solution of compound 1 (1.02 g, 0.005 mole) in 10 mL of formic acid
(85%) was heated (60–65◦C) for 10 min. The reaction mixture was evap-
orated in vacuo. The residual solid was washed with water and crystal-
lized (Table I).
The Synthesis of Benzo[g]quinazoline-4(10H)-thione 7
A mixture of compound 6 (0.697 g, 0.003 mole) and 2 drops of piperidine
and 15 mL of ethanol was refluxed for 2 h. The reaction mixture was
evaporated. The residual solid was washed with water and crystallized
(Table I).
The Synthesis of 3-Imino-1-thioxo-2,3-dihydro-1H-
chromeno[3,2-c]pyridine-4-carbonitrile 8,2-Cyano-N-[(2-
imino-2H-chromen-3-yl)carbonothioyl]acetamide 9, and
2-Cyano-N-[(2-imino-2H-chromen-3-yl)carbonothioyl]-
ethanimidothioic Acid 10: General Procedure
A solution of compound 1 (1.02 g, 0.005 mole) and malononitrile, (0.33 g,
0.005 mole), ethyl cyanoacetate (0.503 mL, 0.005 mole), or cyanothioac-
etamide (0.50 g, 0.005 mole) in ethanol (50 mL) was treated with 2 drops
of piperidine. The reaction mixture was stirred for 15 min and left for
72 h. The precipitate was collected by filtration and crystallized from
the proper solvent (Table I).
The Synthesis of
(4-Thioxo-4H-chromeno[2,3-d]pyrimidin-2-yl)-
acetonitrile 11
A mixture of compound 1, 9, or 10 (0.002 mole), tetrahydrofuran
(40 mL), and 2 drops of piperidine was refluxed for 3 h. The solvent
was evaporated in vacuo. The solid residue was washed with water

The Synthesis of Some New Fused and Substituted Chromenes
2721
followed by ethanol and crystallized from an ethanol/dioxane mixture
(Table I).
The Synthesis of 4-Amino-2-imino-2H-chromeno[2,3-b]-
pyridine-3-carbonitrile 12, Ethyl 2-Cyano-3-imino-3-(2-imino-
2H-chromen-3-yl)propanoate 13, 2-Hydroxy-4-imino-4H-
chromeno[2,3-d]pyridine-3-carbonitrile 14, and 4-Imino-2-
mercapto-4H-chromeno[2,3-b]pyridine-3-cabonitrile 15:
General Procedure
To a mixture of compound 1 (1.02 g, 0.005 mole), ethanol(50 mL), 2 drops
of piperidine, malononitrile, and ethyl cyanoacetate or cyanothioac-
etamide (0.005 mole) was added. The reaction mixture was refluxed
until the evolution of H2S gas ceased (5 h). Compound 13 was precip-
itated on heating, which was collected by filtration and crystallized.
Compounds 12 and 15 were precipitated after cooling, collected by fil-
tration, and crystallized. Compound 14 was isolated via the evaporation
of the filtrate of compound 13 and washing the solid residue with water
followed by crystallization (Table I).
The Synthesis of Compounds 16a–f: General Procedure
A mixture of compound 1 (0.51 g, 0.0025 mole) and ethanol (40 mL)
containing 3 drops of piperidine was treated with benzylidenemalono-
nitrile (0.39 g), p-nitrobenzylidenemalononitrile, (0.59 g), p-
methoxybenz-ylidenemalononitrile (0.42 g), ethyl p-nitrobenzylidene-
cyanoacetate (0.555 g), or ethyl 2-naphthylidenecyanoacetate (0.527 g).
The reaction mixture was stirred for 15 min and left for 48 h at r.t.
The reaction mixture was evaporated in vacuo. The solid residue was
washed with water and ethanol followed by crystallization to give com-
pounds 16a, 16b, and 16d. In the case of compounds 16c and 16e, the
solid residue was treated with a CHCl3/pet. ether (40–60◦C) mixture,
and the precipitate was collected by filtration and crystallized. The
filtrate of 16e was evaporated, and the solid residue was crystallized
to give 16f (Table I).
The Synthesis of N-(2,2-dicyanovinyl)-2-imino-2H-
chromene-3-carbimidothioic Acid 17 and 6-Imino-2-(2-imino-
2H-chromen-3-yl)-6H-1,3-thiazine-5-carbonitrile 18
A mixture of compound 1 (2.04 g, 0.01 mole), ethoxymethylenemalono-
nitrile (1.22 g, 0.01 mole), ethanol (50 mL), and 3 drops of piperidine
was stirred for 30 min and left for 4 h at r.t. The precipitate was collected

2722
A. M. El-Sayed
by filtration, washed with ethanol, and crystallized to give compound
7. The filtrate was left for 6 h, and the separated solid was filtered off,
washed with ethanol, and crystallized to give compound 18. The second
filtrate was evaporated in vacuo, and the solid residue was washed with
water, and pet. ether (60–80◦C) and crystallized to give compound 17
(Table I).
Synthesis of Compound 18: Direct Method
To a solution of compound 1 (0.005 mole) and ethoxymethylenemalono-
nitrile (0.005 mole) in ethanol (30 mL), 3 drops of piperidine was added.
The reaction mixture was refluxed for 2 h and left to cool. The precipitate
was filtered off, washed with ethanol, and crystallized.
The Synthesis of N-(2,2-dicyano-1-methylvinyl)-2-imino-2H-
chromene-3-carbimidothioic Acid 19
A solution of compound 1 (0.51 g, 0.0025 mole) and 1-ethoxy-
ethylidenemalononitrile (0.33 g, 0.0025 mole) in ethanol (30 mL) was
treated with two drops of piperidine. The reaction mixture was stirred
for 6 h at r.t. and left for 24 h. The precipitate was collected by filtration,
washed with ethanol, and crystallized.
The Synthesis of and 6-Imino-2-(2-imino-2H-chromen-3-yl)-4-
methyl-6H-1,3-thiazine-5-carbonitrile 20
A mixture of compound 1 and 1-ethoxyethylidenemalononitrile
(0.0025 mole), ethanol (40 mL), and 2 drops of piperdine was refluxed
for 3 h and left to cool. The precipitate was filtered off, washed with
ethanol, and crystallized to give compound 19. The filtrate was evapo-
rated, and the solid residue was washed with water and pet. (60–80◦C)
and crystallized to give compound 20.
The Synthesis of N[2-cyano-3-ethoxy-3-oxoprop-1-enyl]-2-
imino-2H-chromene-3-carbimidothioic Acid 21 and 2-(2-Imino-
2H-3-chromen-3-yl)-6-oxo-6H-1,3-thiazine-5-carbonitrile 22
A solution of compound 1 (0.51 g, 0.005 mole) and ethyl ethoxy-
methylenecyanoacetate (0.42 g, 0.005 mole) in ethanol (40 mL) was
treated with 2 drops of piperidine. The reaction mixture was refluxed
for 5 h. The reaction mixture was concentrated to half its volume
and left to cool. The precipitate was collected by filtration and crys-
tallized to give compound 22. The filtrate was evaporated. The residual

The Synthesis of Some New Fused and Substituted Chromenes
2723
solid was washed with pet. ether (60–80◦C) and crystallized to give
compound 21.
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