Microwave assisted one-pot synthesis of 2-amino-4hchromenes and spiropyrano[2,3-d]pyrimidine

Article abstract of DOI:10.1002/cjoc.201090041

A convenient and efficient method using microwave assisted one pot synthesis reactions for synthesis of 4H-benzo[f]chromenes by the reaction of aromatic aldehydes with a mixture of malononitrile and naphthols was examined. The synthesis of spiropyrano[2,3-d]pyrimidines by the reaction of isatin with malononitrile and barbituric acid and/or thiobarbituric acid was investigated. The versatility of the method was also examined through the reaction of aromatic aldehydes and malononitrile with various reagents.

Full text of DOI:10.1002/cjoc.201090041

FULL PAPER
Microwave Assisted One-pot Synthesis of 2-Amino-4H-
chromenes and Spiropyrano[2,3-d]pyrimidine
Mahmoud, Alaa F.*,a
Abd El-Latif, Fathy F.b
Ahmed, Amira M.b
a Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, El-Areesh, North Sinai, Egypt
b Department of Chemistry, Faculty of Science, El Minia University, El Minia, Egypt
A convenient and efficient method using microwave assisted one pot synthesis reactions for synthesis of
4H-benzo[f]chromenes by the reaction of aromatic aldehydes with a mixture of malononitrile and naphthols was
examined. The synthesis of spiropyrano[2,3-d]pyrimidines by the reaction of isatin with malononitrile and barbi-
turic acid and/or thiobarbituric acid was investigated. The versatility of the method was also examined through the
reaction of aromatic aldehydes and malononitrile with various reagents.
Keywords
microwave, 2,7-dihydroxynaphthalene, malononitrile, 2-aminochromene, spiropyrano[2,3-d]
pyrimidine
Introduction
Microwave heating has been known for accelerating
the organic reactions.23-26 Cyclocondensation reactions
2-Aminochromenes are an important class of het-
erocyclic compounds having important biological ac-
tivities. During the last decade, such compounds have
shown interesting pharmacological properties including,
antimicrobial,1 antiviral,2,3 mutagenicity,4 antiprolifera-
tive,5 sex hormone,6 antitumor,7 cancer therapy,8,9 and
central nervous system activities.10 2-Aminochromenes
were also used as biodegradable agrochemicals and
components of many natural products.11-14
Recently, several procedures for the preparation of
2-aminochromenes have been described.15,16 Various
catalysts such as piperidine,17,18 morpholine,19 CTACI
(cetyltrimethylammonium chloride),20 TEBA (triethyl-
benzylammonium chloride),21 and alumina22 have been
used for this preparation. However, most of the reported
methods require prolonged reaction time, stoichiometric
reagents, toxic solvents but generate only moderate
yields of the product.
The development of an efficient methodology of
preparing 2-aminochromenes is highly essential. The
most straightforward synthesis of this heterocyclic sys-
tem involves three-component coupling of aromatic
aldehyde, malononitrile and activated phenol catalyzed
by a base.
With the increasing public concern over environ-
mental degradation, the use of environmentally benign
solvents like water and solvent-free reactions represents
very powerful green chemical technology procedures
from both the economical and synthetic point of view.
They have many advantages, such as reduced pollution,
lower cost and simplicity in processing, which are bene-
ficial to the industry as well as to the environment.
in “dry media” leading to heterocyclic systems have
been performed under microwave irradiation.27-31 The
reactions were carried out in a neat or solvent-free state
under microwave irradiation help to generate products
not attainable through classical heating methods.
Experimental
All melting points were measured with a Gallenk-
1
amp melting point apparatus and uncorrected. H NMR
were recorded in DMSO with Varian EM-390 and Bro-
kers MW 400 spectrometers at ambient temperature.
Chemical shifts are relative to TMS. IR spectra were
registered with a Shimadzu 400 spectrometer in KBr
pellets. Mass spectra (EI＝70 eV) were recorded di-
rectly with a Finnigan 50 spectrometer. Elemental
analysis was carried out at the Micro-analytical Labora-
tories of the Faculty of Science, Cairo University.
The maximum power of microwave irradiation was
optimized by carrying out the same reaction at different
Watt powers. Microwave radiations at 300 W gave the
highest yield, and therefore microwave power of 300 W
was chosen as the optimum power.
General procedure for the synthesis of 4H-benzo[f]-
chromene 4a— 4d
An equimolar mixture of an aldehyde 1a — 1c,
malononitrile 2a and a naphthol 3a, 3b with a few drops
of TEA was thoroughly mixed and irradiated at 300 W
in a Samsung M9245 microwave for 1—3 min (the re-
actions were monitored by TLC). Then, the reaction
mixture was cooled, triturated with methanol and the
*
E-mail: afmahmoud@su.edu.eg, afmahmoud@yahoo.com; drfathyfahim@yahoo.com
Received April 14, 2009; revised May 20, 2009; accepted June 25, 2009.
Chin. J. Chem. 2010, 28, 91— 96
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
91

Mahmoud, Abd El-Latif & Ahmed
FULL PAPER
solid formed was collected by filtration and crystallized
from the appropriate solvent.
methanol/DMF); 1H NMR δ: 3.69 (s, 6H, 2OCH3), 5.25
(s, 2H, H-4, H-10), 7.02 (br.s, 4H, 2NH2), 7.21—7.96
(m, 12H, ArH); IR (KBr) ν: 3330, 3192 (NH2), 2188
2-Amino-3-cyano-6-hydroxy-4-phenyl-4H-benzo-
[f]chromene (4a) Pale green solid, yield 82%, m.p.
＋
－1
(CN) cm ; MS m/z (%): 528 (M , 11). Anal. calcd for
C32H24N4O4 (528.56): C 72.72, H 4.58, N 10.60; found
C 72.53, H 4.42, N 10.72.
1
295—297 ℃ (from DMF); H NMR δ: 4.93 (s, 1H,
H-1), 6.92 (br, 2H, NH2), 6.82—7.97 (m, 10H, Ar-H);
9.83 (s, 1H, OH); IR (KBr) ν: 3492 (O—H); 3376, 3279
＋
－1
General procedure for the synthesis of 2-amino-
4H-chromene (7a, 7b)
(NH2), 2192 (CN) cm ; MS m/z (%): 314 (M , 23).
Anal. calcd for C20H14N2O2 (314.34): C 76.42, H 4.49,
N 8.91; found C 76.61, H 4.32, N 8.75.
A mixture of aromatic aldehyde 1b, 1d (5 mmol),
malononitrile 2 (5 mmol) and resorcinol 7a and/or
4-chlorobenzene-2,4-diol 7b (5 mmol) with a few drops
of TEA was thoroughly mixed and irradiated at 300 W
in a Samsung M9245 microwave for 5—6 min (the re-
actions were monitored by TLC). After cooling, the re-
action mixture was triturated with methanol, and the
solid formed was collected by filtration and crystallized
from the appropriate solvent.
2-Amino-3-cyano-4-(2-chlorophenyl)-6-hydroxy-
4H-benzo[f]chromene (4b) Buff solid, yield 75%,
m.p. 260—262 ℃ (decomp., from toluene/methanol);
1H NMR δ: 5.52 (s, 1H, H-4), 6.83 (br, 2H, NH2), 6.89
—7.45 (m, 9H, ArH), 9.92 (s, 1H, OH); IR (KBr) ν:
－1
3490 (O—H), 3380, 3256 (NH2), 2196 (CN) cm ; MS
m/z (%): 348 (M＋, 90), 350 (M＋＋2, 28). Anal. calcd
for C20H13ClN2O2 (348.78): C 68.87, H 3.76, N 8.03, Cl
10.16; found C 68.77, H 3.65, N 8.10, Cl 10.26.
2-Amino-4-(2-chlorophenyl)-3-cyano-7-hydroxy-
4H-chromene (8a) Colorless needles, yield 84%, m.p.
2-Amino-3-cyano-4-(4-chlorophenyl)-6-hydroxy-
4H-benzo[f]chromene (4c) Buff solid, yield 75%,
m.p. 286—288 ℃ (decomp., from toluene/methanol);
1H NMR δ: 5.09 (s, 1H, H-4), 6.90 (br, 2H, NH2), 6.89
—7.87 (m, 9H, ArH), 9.90 (s, 1H, OH-9); IR (KBr) ν:
1
185—187 ℃ (from ethanol); H NMR δ: 5.05 (s, 1H,
H-4), 6.85 (br.s, 2H, NH2), 6.85—7.35 (m, 7H, ArH),
10.35 (s, 1H, OH); IR (KBr) ν: 3405 (O—H), 344＋0,
－1
3180 (NH2), 2200 (CN) cm ; MS m/z (%): 298 (M ,
38), 300 (M＋＋2, 12). Anal. calcd for C16H11ClN2O2
(298.72): C 64.33, H 3.71, N 9.38; found C 62.53, H
4.42. N 10.72.
－1
3495 (O—H), 3370, 3260 (NH2), 2190 (CN) cm ; MS
m/z (%): 348 (M＋, 91), 350 (M＋＋2, 29). Anal. calcd
for C20H13ClN2O2 (348.78): C 68.87, H 3.76, N 8.03, Cl
10.16; found C 68.77, H 3.65, N 8.10, Cl 10.26.
2-Amino-6-chloro-3-cyano-7-hydroxy-4-(2-meth-
oxyphenyl)-4H-chromene (8b) Brown powder, yield
2-Amino-3-cyano-4-(2-chlorophenyl)-4H-benzo-
[f]chromene (4d) Colorless solid, yield 83%, m.p.
1
75%, m.p. 257—259 ℃ (from ethanol); H NMR δ:
1
3.80 (s, 3H, CH3), 5.00 (s, 1H, H-4), 6.70 (s, 2H, NH2),
6.80—7.80 (m, 6H, ArH), 10.50 (s, 1H, OH); IR (KBr)
ν: 3400 (O—H), 3340, 3＋180 (NH2), 2190 (CN)
256—258 ℃ (from dioxane); H NMR δ: 4.85 (s, 1H,
H-4), 6.55 (br, 2H, NH2), 6.65—7.75 (m, 10H, ArH); IR
－1
(KBr) ν: 3368, 3269 (NH2), 2196 (CN) cm ; MS m/z
＋
－1
(%): 332 (M＋, 66), 334 (M＋＋2, 21). Anal. calcd for
C20H13ClN2O (332.78): C 72.18, H 3.94, N 8.42, Cl
10.65; found C 72.07, H 3.90, N 8.30, Cl 10.60.
cm ; MS m/z (%): 328 (M , 35), 330 (M ＋2, 10).
Anal. calcd for C17H13ClN2O3 (328.75): C 62.11, H 3.99,
N 8.52, Cl 10,78; found C 61.88, H 4.23, N 8.53, Cl
11.0.
General procedure for the synthesis of 4H,10H-
chromeno[8,7-h]chromene (6a, 6b)
General procedure for the synthesis of spiro[indole-
3,5'-pyrano[2,3-d]pyrimidine 10a— 10h
A mixture of aromatic aldehyde 1b, 1d (10 mmol),
malononitrile 2 (10 mmol) and 1,5-naphthalenediol 5 (5
mmol) with a few drops of TEA was thoroughly mixed
and irradiated at 300 W in a Samsung M9245 micro-
wave for 5—6 min (the reactions were monitored by
TLC). Then, the reaction mixture was cooled, triturated
with methanol and the solid formed was collected by
filtration and crystallized from the appropriate solvent.
2,8-Diamino-4,10-di(2-chlorophenyl)-3,9-dicyano-
A mixture of isatin or bromoisatin 8a, 8b (5 mmol),
malononitrile or ethyl cyanoacetate 2a, 2b (5 mmol) and
barbituric or thiobarbituric acid 9a, 9b (5 mmol) with a
few drops of TEA was mixed and irradiated at 300 W in
a Samsung M9245 microwave for 5—6 min (the reac-
tions were monitored by TLC). Then, the reaction mix-
ture was cooled, triturated with methanol, and the solid
formed was collected by filtration and crystallized from
the appropriate solvent.
4H,10H-chromeno[8,7-h] chromene (6a)
Yellow
powder, yield 82%, m.p. 295—297 ℃ (decom., from
7'-Amino-6'-cyano-2,2',4'-trioxo-1,1',2,2',3',4'-
hexahydrospiroindole-3,5'-pyrano[2,3-d]pyrimidine
(10a) Yellow powder, yield 84%, m.p. 264—266 ℃,
1
DMF); H NMR δ: 5.43 (s, 2H, H-4, H-10), 7.12 (br.s,
4H, 2NH2), 7.29—7.94 (m, 12H, ArH); IR (KBr) ν:
－1
1
3324, 3196 (NH2), 2200 (CN) cm ; MS m/z (%): 536
(from ethanol). H NMR δ: 6.95 (s, 2H, NH2), 6.85—
(M＋, 26), 538 (M＋＋2, 8). Anal. calcd for C30H18Cl2-
N4O2 (537.40): C 67.05, H 3.38, N 10.43, Cl 13.19;
found C 67.23, H 3.22, N 10.52, Cl 13.02.
7.35 (m, 4H, ArH), 10.05 (s, 1H, NH), 11.05 (s, 1H,
NH), 11.35 (s, 1H, NH); IR (KBr) ν: 3353—3305 (NH,
－1
NH2), 2204 (CN), 1710—1725 (C＝O) cm ; MS m/z
(%): 323 (M＋, 21). Anal calcd for C15H9N5O4 (323.26):
C 55.73, H 2.81, N 21.66; found C 55.39, H 3.41, N
2,8-diamino-3,9-dicyano-4,10-di(2-methoxyphen-
yl)-4H,10H-chromeno[8,7-h]chromene (6b) Yellow
powder, yield 84%, m.p. 215—217 ℃ (decomp., from
92
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Chin. J. Chem. 2010, 28, 91— 96

Synthesis of 2-Amino-4H-chromenes and Spiropyrano[2,3-d]pyrimidine
21.53.
powder, yield 72%, m.p. 240—242 ℃ (from ethanol);
1H NMR δ: 1.38 (t, J＝7.2 Hz, 3H, CH3), 3.57 (q, J＝
8.0 Hz, 2H, CH2), 6.75 (s, 2H, NH2), 6.85—7.35 (m, 4H,
ArH), 9.70 (s, 1H, NH), 10.25 (s, 1H, NH), 10.55 (s, 1H,
NH); IR (KBr) ν: 3353—3305 (NH, NH2), 2204 (CN),
7'-Amino-5-bromo-6'-cyano-2,2',4'-trioxo-1,1',2,
2',3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-d]pyri-
midine (10b) Pale violet, yield 72%, m.p. 220－222
1
℃ (from ethanol); H NMR δ: 6.85 (s, 2H, NH2), 6.80
－1
—7.40 (m, 3H, ArH), 10.00 (s, 1H, NH), 11.00 (s, 1H,
NH), 11.25 (s, 1H, NH); IR (KBr) ν: 3350—3310 (NH,
170＋0—1725 (C＝O's) cm ; MS m/z (%): 386
(M , 94), 388 (M ＋ ＋ 2, 4.3). Anal. calcd for
C17H14N4O5S (386.38): C 52.84, H 3.65, N 14.50, S
8.30; found C 52.75, H 3.75, N 14.43, S 8.33.
－1
NH2), 2210 (CN), 1710—1715 (C＝O) cm ; MS m/z
(%): 401 (M＋, 45), 403 (M＋＋2, 48). Anal. calcd for
C15H8BrN5O4 (402.16): C 44.80, H 2.01, N 17.41, Br
19.87; found C 44.39, H 2.11, N 17.52, Br 19.63.
Ethyl-7'-amino-5-bromo-2,4'-dioxo-2'-thioxo-1,1',
2,2',3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-d]-
7'-Amino-6'-cyano-2,4'-dioxo-2'-thioxo-1,1',2,2',
3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-d]pyri-
midine (10c) Pale buff, yield 79%, m.p. 235－237 ℃
pyrimidine-6'-carboxylate (10h)
Brown powder,
yield 79%, m.p. 250—252 ℃ (from ethanol); 1H NMR
δ: 1.35 (t, J＝6.0 Hz, 3H, CH3), 3.55 (q, J＝8.0 Hz, 2H,
CH2), 6.72 (s, 2H,NH2), 6.88—7.37 (m, 3H, ArH), 9.75
(s, 1H, NH), 10.35 (s, 1H, NH), 10.50 (s, 1H, NH); IR
(KBr) ν: 3353—3305 (NH, NH2), 1700—17＋25 (C＝O's)
1
(from dioxane); H NMR δ: 6.82 (s, 2H, NH2), 6.88—
7.52 (m, 4H, ArH), 10.10 (s, 1H, NH), 11.15 (s, 1H,
NH), 11.35 (s, 1H, NH); IR (KBr) ν: 3350—3310 (NH,
－1
－1
＋
NH2), 2208 (CN), 1710—1725 (C＝O's) cm ; MS m/z
cm ; MS m/z (%): 464 (M , 100), 466 (M ＋2, 98.7),
468 (4.4). Anal. calcd for C17H13BrN4O5S (465.28): C
43.88, H 2.82, N 12.04, Br 17.17, S 6.89; found C 43.79,
H 2.75, N 12.17, Br 17.08, S 6.85.
(%): 339 (M＋, 94), 341 (M＋＋2, 4.4). Anal. calcd for
C15H9N5O3S (339.33): C 53.09, H 2.67, N 20.64, S 9.45;
found C 53.19, H 2.59, N 20.57, S 9.33.
7'-Amino-5-bromo-6'-cyano-2,4'-dioxo-2'-thioxo-
1,1',2,2',3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-
d]pyrimidine (10d) Pale violet, yield 76%, m.p. 246
Synthesis of 2-amino-4-(4-chlorophenyl)-6-(2-thienyl)-
nicotinonitrile (11)
1
4-Chlorobenzaldehyde 1c (5 mmol), malononitrile 2
(5 mmol) and 2-acetylthiophene (5 mmol) were thor-
oughly mixed with ammonium acetate (10 mmol) and
irradiated at 300 W in a Samsung M9245 microwave for
3 min (the reactions were monitored by TLC). The solid
formed was collected and crystallized from dioxane to
give yellow powder, yield 82%, m.p. 230—232 ℃
—248 ℃ (from ethanol); H NMR δ: 6.85 (s, 2H,
NH2), 6.88—7.52 (m, 3H, ArH), 10.15 (s, 1H, NH),
11.10 (s, 1H, NH), 12.25 (s, 1H, NH); IR (KBr) ν: 3350
—3310 (NH, NH2), 2210 (＋CN), 1715—1725 (C＝O's)
＋
－1
cm ; MS m/z (%): 417 (M , 100), 419 (M ＋2, 97.9),
421 (4.8). Anal. calcd for C15H8BrN5O3S (418.22): C
43.08, H 1.93, N 16.75, Br 19.11, S 7.67; found C 43.19,
H 2.01, N 16.62, Br 19.17, S 7.61.
1
(from dioxane); H NMR δ: 6.90 (s, 2H, NH2), 6.75 (s,
1H, H-3), 6.85—7.77 (m, 7H, ArH＋thienyl H); IR
Ethyl-7'-amino-2,2',4'-trioxo-1,1',2,2',3',4'-hexa-
hydrospiroindole-3,5'-pyrano[2,3-d]pyrimidine-6'-
carboxylate (10e) Brown powder, yield 84%, m.p.
184—186 ℃ (from methanol); 1H NMR δ: 1.35 (t, J＝
7.2 Hz, 3H, CH3), 3.50 (q, J＝8.0 Hz, 2H, CH2), 6.83 (s,
2H, NH2), 6.85—7.35 (m, 4H, ArH), 9.50 (s, 1H, NH),
10.05 (s, 1H, NH), 10.35 (s, 1H, NH); IR (KBr) ν: 33－53
－1
(KBr) ν: 3350—3305 (NH2), 2200 (CN) cm ; MS m/z
(%): 311 (M＋, 33), 313 (M＋＋2, 11). Anal. calcd for
C16H10ClN3S (311.79): C 61.63, H 3.23, N 13.48, Cl
11.37, S 10.28; found C 61.51, H 3.05, N 13.64, Cl
11.51, S 10.42.
Synthesis of 2-amino-4-(2-bromophenyl)-6-(2-thienyl)-
nicotinonitrile (12)
1
—3305 (NH, NH2), 1697, 1700—1725 (C＝O) cm ;
MS m/z (%): 370 (M＋, 76). Anal. calcd for C17H14N4O6
(370.32): C 55.14, H 3.81, N 15.13; found C 55.29, H
3.75, N 15.23.
2-Bromobenzaldehyde 1e (5 mmol), malononitrile 2
(5 mmol), 2-acetyl thiophene (5 mmol) and ammonium
acetate (10 mmol) were thoroughly mixed and irradiated
at 300 W in a Samsung M9245 microwave for 3 min
(the reactions were monitored by TLC). The solid
formed was collected and crystallized from ethanol to
Ethyl-7'-amino-5-bromo-6'-cyano-2,2',4'-trioxo-1,
1',2,2',3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-
d]pyrimidine-6'-carboxylate (10f) Pale brown pow-
der, yield 87%, m.p. 230—232 ℃ (from methanol); 1H
NMR δ: 1.38 (t, J＝6.0 Hz, 3H, CH3), 3.70 (q, J＝8.0
Hz, 2H, CH2), 6.85 (s, 2H, NH2), 6.85—7.35 (m, 3H,
ArH), 9.75 (s, 1H, NH), 10.35 (s, 1H, NH), 10.65 (s, 1H,
NH); IR (KBr) ν: 3353—3305 (NH, NH2), 1697, 1700
1
give yellow powder, yield 77%, m.p. 240—242 ℃; H
NMR δ: 6.83 (s, 2H, NH2), 6.88 (s, 1H, H-3), 6.85—
7.35 (m, 7H, ArH＋thienyl H); IR (KBr) ν: 3370 (NH2),
－1
2210 (CN) cm . Anal. calcd for C16H10BrN3S (356.24):
＋
－1
C 53.94, H 2.83, N 11.80, Br 22.43, S 9.00; found C
53.86, H 2.69, N 11.95, Br 22.25, S 9.19.
—1725 (C＝O's) cm ; MS m/z (%): 448 (M , 100),
450 (M＋ ＋2, 97.9). Anal. calcd for C17H13BrN4O6
(449.21): C 45.55, H 2.92, N 12.47, Br 17.79; found C
45.33, H 2.75, N 12.27, Br 17.68.
Synthesis of 6-amino-5-cyano-4-(4-chlorophenyl)-2,3'-
bipyridine (13)
Ethyl-7'-amino-6'-cyano-2,4'-dioxo-2'-thioxo-1,1',
2,2',3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-d]-
pyrimidine-6'-carboxylate (10g) Yellowish green
4-Chlorobenzaldehyde 1c (5 mmol), malononitrile 2
(5 mmol), 3-acetylpyridine (5 mmol) and ammonium
acetate (10 mmol) were thoroughly mixed and irradiated
Chin. J. Chem. 2010, 28, 91— 96
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93

Mahmoud, Abd El-Latif & Ahmed
FULL PAPER
at 300 W in a Samsung M9245 microwave for 3 min
(the reactions were monitored by TLC). The solid
formed was collected and crystallized from dioxane to
that condensation of 2,7-dihydroxynaphthalene 3a,
benzaldehyde 1a and malononitrile 2a under microwave
irradiation and solvent free condition afforded
2-amino-3-cyano-6-hydroxy-4-phenyl-4H-benzo[f]chro-
mene 4a (Scheme 1). The formation of 4a was ex-
plained through the formation of the phenylmethylene-
malononitrile, then 2,7-dihydroxynaphthalene attacks on
the β-carbon of the phenylmethylenemalononitrile to
yield an acyclic Michael adduct which undergoes in-
tramolecular cyclization to compound 4a.
To explore the scope and versatility of this method,
various similar reactions were investigated using dif-
ferent aromatic aldehydes 1a—1c with malononitrile 2a
and 2,7-dihydroxynaphthalene 3a or β-naphthol 3b
yielding different 4H-benzo[f]chromene 4b — 4d
(Scheme 1). The structures of previously known com-
pounds were confirmed by spectroscopic methods and
elemental analysis (see Experimental).
1
give yellow powder, yield 82%, m.p. 230—232 ℃; H
NMR δ: 7.25 (s, 2H, NH2), 7.35 (s, 1H, H-3), 7.55—
8.75 (m, 7H, ArH＋pyri－dyl H); IR (KBr) ν: 3380—3350
1
(NH2), 2200 (CN) cm . Anal. calcd for C17H11ClN4
(306.75): C 66.56, H 3.61, N 18.26, Cl 11.56; found C
66.38, H 3.43, N 18.51, Cl 11.74.
Synthesis of 6-amino-7-cyano-8-(2-chlorphenyl)-3-
hydroxy-8H-pyrano[3,2-c]pyridazine (14)
2-Chlorobenzaldehyde 1b (5 mmol), malononitrile
2a (5 mmol), pyridazine-3,5-diol (5 mmol) and a few
drops of TEA were thoroughly mixed and irradiated at
300 W in a Samsung M9245 microwave for 3 min (the
reactions were monitored by TLC). The solid formed
was collected and crystallized from ethanol to give pale
yellow powder, yield 78%, m.p. 238—240 ℃; 1H NMR
δ: 4.90 (s, 1H, H8), 7.25 (s, 2H, NH2), 7.55—8.15 (m,
4H, ArH＋H4), 8.88 (s, 1H, OH); IR (KBr) ν: 3370
(NH2), 2210 (CN) cm－１; MS m/z (%): 300 (M＋, 29),
302 (M＋＋2, 7). Anal. calcd for C14H9ClN4O2 (300.70):
C 55.90, H 3.02, N 18.63, Cl 11.79; found C 55.78, H
3.19, N 18.51, Cl 11.74.
In order to expand the scope of the present method
under the above optimized reaction conditions, the reac-
tion of o-chlorobenzaldehyde 1b and malononitrile 2a
with 1,5-naphthalenediol 5 in a molar ratio of 2∶2∶1
was investigated under the previous condition to afford
the diadduct 2,8-diamino-4,10-di(2-chlorophenyl)-
3,9-dicyano-4H,10H-chromeno[8,7-h]chromene 6a
(Scheme 2). The IR spectrum for compound 6a revealed
bot－h amino and cyano functions at 3324, 3196 and 2200
Results and discussion
1
1
cm , respectively. H NMR spectrum of this product
revealed signals that are in agreement with the proposed
structure. For example, there is a singlet at δ 5.43 with
integration of two protons for H-4 and H-10 protons as
indication for the diadduct formation. Similarly,
o-methoxybenzaldehyde 1d, malononitrile 2a and
1,5-naphthalenediol 5 were allowed to react under the
same condition to yield 2,8-diamino-3,9-dicyano-4,10-
di(2-methoxyphenyl)-4H,10H-chromeno[8,7-h]chrom-
ene 6b.
In continuation of our efforts to develop efficient en-
vironmentally benign protocols for the synthesis of
various heterocycles through one pot multi-component
reactions,32-35 we report herein the synthesis of
amino(benzo)chromenes through three component con-
densation of aromatic aldehydes, malononitrile and
phenols or naphthols.
An earlier attempt to synthesize benzochromenes
from 2,7-naphthalenediol and arylmethylidene-
malononitrile has failed.35 We were interested in study-
ing new approaches in which 2,7-dihydroxynaphthalene
Scheme 2
reacted with aldehyde and malononitrile in
a
three-component condensation system in the presence of
a catalytic amount of triethylamine in ethanolic solution
to afford amino(benzo)chromenes.36
In conjugation of this work, we report herein further
investigation to clear this conflict of results. We found
Scheme 1
To examine the scope of such technique, aromatic
aldehyde 1b, 1d, malononitrile 2a and resorcinol 7a or
4-chlorobenzene-1,3-diol 7b were also used and the
94
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Chin. J. Chem. 2010, 28, 91— 96

Synthesis of 2-Amino-4H-chromenes and Spiropyrano[2,3-d]pyrimidine
corresponding 2-amino-chromene derivatives 8a, 8b
were obtained in high yields (Scheme 3). The IR spec-
trum for compound 8a revealed hydroxyl, amino and
dine and 6'-cyano-2,4'-dioxo-2'-thioxo-1,1',2,2',3',4'-
hexahydrospiroindole-3,5'-pyrano[2,3-d]-pyrimidine
10b— 10i in excellent yields. The spectroscopic data for
the prepared compounds add a sharp evidence for their
formation (see Experimental).
－1
cyano functions at 3440, 3180 and 2200 cm , respec-
1
tively. H NMR spectrum of this product revealed sig-
nals that are in accord with the proposed structure. For
example, there are three singlets at δ 5.05 for H-4 pro-
ton, at 6.85 for NH2 protons and at 10.50 for OH proton.
There was no effect by increasing the reaction ratio
from 1∶1∶1 to 2∶2∶1, and the only isolated product
was the single adduct 7a, 7b.
Encouraged with the above satisfactory results, the
reaction of 4-chlorobenzaldehyde 1c, malononitrile 2a
with 2-acetylthiophene in the presence of ammonium
acetate afforded 2-amino-4-(4-chlorophenyl)-6-(2-
thienyl) nicotinonitrile 11 (Scheme 5). The IR spectrum
for compound 11 revealed both amino and cyano func-
－1
tions in 3350—3305 and at 2200 cm , respectively. 1H
Scheme 3
NMR spectrum of this product revealed signals that are
in accord with the proposed structure. For example,
there are two singlets at δ 6.90 for NH2 protons and at
6.75 for H-5 proton (see Experimental). The formation
of 11 was expected to proceed via initial condensation
of aldehyde with malononitrile to afford an arylidine,
which further undergoes in situ Michael addition with
1-aryletheneamine obtained by treating aromatic ketone
with ammonia from ammonium acetate to yield an in-
termediate, which is cyclized and subsequently dehy-
drogenated to afford the final product.
Scheme 5
For further investigation for the scope of this effi-
cient and simple procedure, the reaction of isatin or
bromoisatin 8a, 8b, malononitrile or ethyl cyanoacetate
2a, 2b with barbituric or thiobarbituric acid 9a, 9b was
examined (Scheme 4). The reaction of isatin 8a,
malononitrile 2a and barbituric acid 9a afforded the
compound assigned by spectral and elemental data to be
7'-amino-6'-cyano-2,2',4'-trioxo-1,1',2,2',3',4'-hexahydro
spiroindole-3,5'-pyrano[2,3-d]pyrimidine (10a) (see
Experimental).
Scheme 4
Also, the reaction of 2-bromobenzaldehyde (1e),
malononitrile (2a) with 2-acetylthiophene in the pres-
ence of ammonium acetate yielded 2-amino-4-(2-
bromophenyl)-6-(2-thienyl) nicotinonitrile (12). The
reaction of 4-chlorobenzaldehyde (1c), malononitrile
(2a) with 2-acetylpyridine in the presence of ammonium
acetate afforded 6-amino-4-(4-chlorophenyl)-5-cyano-
2,3'-bipyridine (13). The condensation of 2-chloroben-
zaldehyde (1b), malononitrile (2a) with pyridazine-
3,5-diol yielded 6-amino-8-(2-chlorophenyl)-7-cyano-
The feasibility of employing different derivatives of
the above reaction components was also investigated,
and we obtained different 6'-cyano-2,2',4'-trioxo-1,1',2,
2',3',4'-hexahydrospiroindole-3,5'-pyrano[2,3-d]pyrimi-
Chin. J. Chem. 2010, 28, 91— 96
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www.cjc.wiley-vch.de
95

Mahmoud, Abd El-Latif & Ahmed
X. Bioorg. Med. Chem. Lett. 2005, 15, 4645.
FULL PAPER
3-hydroxy-8H-pyrano[3,2-c]pyridazine (14) (Scheme
5).
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 91— 96