[3,1]Oxazino[5′,4′:5,6]-, pyrido[3′,2′:5,6]-, pyrimidino [5′,4′:5,6]-, and pyrrolo[3′,2′:5,6]pyrano[3, 2-c]chromene derivatives from 9-amino-7-(4-chlorophenyl)-6-oxo-6H,7H-pyrano[3,2- c]chromene-8-carbonitrile

Article abstract of DOI:10.3184/030823407X268962

Pyrido[3′,2′:5,6]-, [3,1]Oxazino[5′,4′:5,6]-, pyrimidino[5′,4′:5,6]-, and pyrrolo[3′,2′:5,6] pyrano[3,2-c]chromene derivatives were obtained via the reaction of 9-amino-7-(4-chlorophenyl)-6-oxo-6H,7H-pyrano[3,2-c]chromene-8-carbonitrile 1 with diethyl mal

Full text of DOI:10.3184/030823407X268962

JOURNAL OF CHEMICAL RESEARCH 2007
NOVEMBER, 673–676
RESEARCH PAPER 673
[3,1]Oxazino[5',4':5,6]-, pyrido[3',2':5,6]-, pyrimidino[5',4':5,6]-,
and pyrrolo[3',2':5,6]pyrano[3,2-c]chromene derivatives from 9-amino-
7-(4-chlorophenyl)-6-oxo-6H,7H-pyrano[3,2-c]chromene-8-carbonitrile
Mahmoud R. Mahmoud, Hassan M.F. Madkour, Eman A. El-Bordainy and El-Said A. Soliman
Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
Pyrido[3',2':5,6]-, [3,1]Oxazino[5',4':5,6]-, pyrimidino[5',4':5,6]-, and pyrrolo[3',2':5,6] pyrano[3,2-c]chromene
derivatives were obtained via the reaction of 9-amino-7-(4-chlorophenyl)-6-oxo-6H,7H-pyrano[3,2-c]chromene-
8-carbonitrile 1 with diethyl malonate, Schiff's base, acetic acid, phenyl isothiocyanate and chloroacetic acid,
1
respectively. Alkylation, acylation and hydrazinolysis of 1 were also discussed. The IR, H NMR, 13C NMR and MS
spectra of the synthesised compounds were discussed.
Keywords: pyrido[3',2':5,6]-, [3,1]-oxazino[5',4':5,6]-, pyrimidino[5',4':5,6]-, and pyrrolo[3',2':5,6]pyrano[3,2-c] chromene
derivatives
9-Amino-7-(4-chlorophenyl)-6-oxo-6H,7H-pyrano[3,2-c]
chromene-8-carbonitrile 1 has been synthesised following the
method described1 by treating 4-chloro-2-cyanocinnamonitrile
with 4-hydroxybenzopyran-2-one. Structural proof has
been obtained through two components condensation of
cinnamonitrile derivative and 4-hydroxy benzopyran-2-one in
equimolar proportions under the previous conditions to yield
1:1 adducts for which two isomeric structures 1 and 2 seemed
possible. Structure 1 is established for the reaction products
based on 1H NMR spectrum which revealed the presence
of a signal at δ 4.35 ppm for one proton linked with an sp3
carbon, signal at a similar position have been observed for
4H-pyran.2,3
10-thioxo-8,9,10,11-tetrahydro-6H,7H-pyrimidino[5',4':5,6]
pyrano[3,2-c]chromene-6-one 8.
Schiff's base resulted from the condensation of 4-dimethyl-
aminobenzaldehyde with aniline was allowed to conduct
with compound 1 in refluxing butan-1-ol and acetic acid
yielded the oxazinopyranochromene derivative 9 (Scheme 1).
The formation of 9 could be visualised in terms of the route
shown in Scheme 2.
The aminonitrile 1 was subjected to further transformation
to produce fused heterocyclic system which incorporating
pyridine nucleus with pyranobenzopyranone moiety. Thus, the
reaction of 1 with diethyl malonate in the presence of sodium
ethoxide yielded ethyl 8-amino-7-(4-chlorophenyl)-6,10-
dioxo-10,11-dihydro-6H,7H-pyrido[3',2':5,6]pyrano[3,2-c]
chromene-9-carboxylate 10.
The behaviour of 1 towards the action of hydrazine hydrate
was also investigated. Thus, when compound 1 was treated
with hydrazine hydrate in boiling ethanol, a crystalline
product with molecular formula C16H13N2O3Cl was formed.
The IR spectrum of this product devoid absorption bands for
C≡N and C=O of δ-lactone and showed bands corresponding
to νNH, OH (br) and νC=N at 3352, 3170 cm-1 and 1668 cm-1,
respectively. Structure of the pyrazolidinone derivative 11
was deduced for this product on the basis of the following
arguments: (1) The correct elemental analysis. (2) The
alcoholic solution of 11 shows dark green colour with ferric
chloride solution, which indicate the cleavage of the δ-lactone
ring and the presence of phenolic –OH group. (3) The mass
spectrum shows fragmentation pattern which in accord with
the proposed structure (c.f. Experimental). The conversion of
the iminocarbonitrile 1 to the compound 11 using hydrazine
hydrate could be visualised in terms of the forgoing pathway
(Scheme 3).
Ar
O
NH2
CN
O
H
O
O
CN
H
Ar
O
O
NH2
(1)
(2)
The formation of 1 is assumed to proceed via addition of
coumarinyl-C-3 to the activated double bond of cinnamonitrile
derivative followed by 1,6-exo-dig. cyclisation of Michael
adduct.4-6 Structure 1 get more support through chemical
reactions with electrophilic reagents such as furoyl chloride,
acetic acid, acetic anhydride, ethyl chloroacetate, chloroacetic
acid, phenyl isothiocyanate, Schiff's base, diethyl malonate
and nucleophilic reagents such as hydrazine hydrate.
7-(4-Chlorophenyl)-9-furoylamino-6-oxo-6H,7H-pyrano
[3,2-c]chromene-8-carbonitrile 3 has been synthesised by
treating the compound 1 with furoyl chloride in refluxing
pyridine. Treatment of compound 1 with acetic acid afforded
7-(4-chlorophenyl)-10-methyl-6H,7H,8H-[3,1]oxazino[5',4':
5,6]pyrano[3,2-c]chromene-6,8-dione 4. Similar treatment of
compound 1 with acetic anhydride yielded the N,N-diacetyl
derivative 5. Alkylation of 1 using ethyl chloroacetate
in refluxing pyridine afforded 7-(4-chlorophenyl)-9-
Experimental
All melting points were taken on Griffin and Geory melting point
apparatusandareuncorrected.IRspectrawererecordedonPyeUnicam
1
SP 1200 spectrophotometer using KBr wafer technique. H NMR
and 13C NMR spectra were determined on a Varian Gemini 200 MHz,
Brucher Ac-200 MHz using TMS as internal standard (chemical
shifts in d-scale). EI-MS were measured on a Schimadzu-GC-MS
instrument operating at 70 eV. Microanalysis measurements were
carried out at Ain Shams University labs and satisfactory analytical
data (± 0.4) were obtained for all compounds.
ethoxycarbonylmethylamino-6-oxo-6H,7H-pyrano
chromene-3-carbonitrile 6.
[3,2-c]
Treatment of 1 with chloroacetic acid in boiling pyridine
resulted in the formation of the pyrrolo[2',3':5,6]pyrano
[3,2-c]chromene derivative 7. The aminonitrile 1 reacted
with phenylisothiocyanate in refluxing pyridine followed by
acidification and produced an insoluble red crystalline product
which was identified as 7-(4-chlorophenyl)-8-imino-9-phenyl-
9-Amino-7-(4-chlorophenyl)-6-oxo-6H,7H-pyrano[3,2-c]chromene-
8-carbonitrile(1):Amixtureof4-chloro-2-cyanocinnamonitrile(1.89g,
10 mmole) and 4-hydroxybenzopyran-2-one (1.62 g, 10 mmole) in
absolute ethanol (30 ml) containing triethylamine (0.5 ml) was heated
under reflux for 3 h (TLC). The solid product precipitated during reflux
was filtered off, washed with hot ethanol, dried and recrystallised
from dioxane to give 1 as white crystals, m.p. 268–270°C, yield 55%.
IR (KBr): 3379, 3290, 3187 cm-1 (NH2), 2190 cm-1 (C≡N), 1713 cm-1
* Correspondent. E-mail: eman.elbordainy@gmail.com
PAPER: 07/4845

674 JOURNAL OF CHEMICAL RESEARCH 2007
O
NH
O
O
OH
Ar
CO2Et
O
H
O
Ar
NH2
O
N
O
Ar/
NH
(10)
N
O
O
O
H
(11)
O
Ar
Ph
CO2Et
N
(9)
n-BuOH N2H4.H2O
C2H5ONa
Ar/
n-BuOH / H+
CO2Et
O
NH
S
Py.
Cl
O
NH
CN
O
N
O
NH2
CN
O
O
Ph
PhN=C=S
O
O
O
O
Py.
NH
Ar
O
(8)
O
Ar
O
Cl
CO2H
Ar
(1)
AcOH
(3)
Py.
O
N
O
CO2H
Py.
CH3
Cl
CO2Et
O
NH
Ac2O
H
O
O
O
NH
O
Ar
O
Ar
(4)
O
NH
CN
CO2Et
O
NAc2
(7)
O
O
NH2
O
Ar
O
O
Ar
(6)
(5)
Scheme 1
H
N
/
N
Ar
/
/
Ar
H
Ar
NH
2
-PhNH
2
H
N
HN
CN
Ph
Ph
N
+
CN
H
O
(1)
3
/
Ar
/
Ar
N
N
-H
2
H
O
OH
O
O
(9)
Scheme 2
(C=O), 1645 cm-1 (C=N). 1H NMR (CDCl3, δ ppm) 7.9–7.2 (m, 8H),
6.9 (br.s, 2H, exchangeable with D2O), 4.35 (s, 1H). EI-MS m/z (%):
351 (M, 13.9), 347 (100), 239 (25.3), 189 (71.7), 121 (13.4). Anal.
Calcd. for C19H11ClN2O3 (350.76): C, 65.06; H, 3.16; N, 7.98; Cl,
10.10. Found: C, 64.87; H, 3.32; N, 8.21; Cl, 10.11.
13C NMR (CDCl3)
125.6
129.2
122.7
126.8
115.7
150.2
O
NH2
Formation of 7-(4-Chlorophenyl)-9-furoylamino-6-oxo-6H,7H-
pyrano[3,2-c]chromene-8-carbonitrile(3):2-Furoylchloride(0.66ml,
5 mmole) was added dropwise to a solution of pyranobenzopyran-5-
one 1 (1.75 g, 5 mmole) in pyridine (20 ml), and the reaction mixture
was refluxed for 30 min, left to cool and acidified with cold dilute
hydrochloric acid. The crude solid product which deposited was
collected by suction, washed several times with water, dried and then
recrystallised from benzene as white crystals, m.p. > 300°C, yield
80%. IR (KBr): br. 3389 cm-1 (NH, OH), 2197 cm-1 (C≡N), 1730 cm-
160.1
157.9
61.6
O
164.1
116.2
36.9
94.6
H
N
129.1
139.3
O
128.2
129.1
130.1
Cl
128.2
1
1 (C=Oδ-lactone), 1672 cm-1 (C=Oamide). H NMR (DMSO-d6, δ ppm)
PAPER: 07/4845

JOURNAL OF CHEMICAL RESEARCH 2007 675
NH2-NH2
H
O
NH
CN
O
NH
O
HN
NH-NH2
CN
NH2-NH2
O
O
OH
O
CN
NH2
NH2
O
O
Ar
Ar
Ar
NH-NH2
NH2-NH2
(1)
OH
O
O
H
OH
O
H
Ar
Ar
NH
NH
NH2
N
H
O
(11)
Scheme 3
9.1 (br.s, 1H, exchangeable with D2O), 7.7–6.59 (m, 11H), 4.1 (s,
1H). EI-MS m/z (%): 445 (M, 53.6), 350 (12.6), 317 (100), 95 (69.9).
Anal. Calcd. for C24H13ClN2O5 (444.83): C, 64.80; H, 2.94; N, 6.29;
Cl, 7.97. Found: C, 64.55; H, 3.21; N, 5.89; Cl, 8.12.
The crude solid product was collected by filtration and dissolved
in NaHCO3 solution (10%). The alkaline filtrate then acidified with
cold diluted hydrochloric acid. The deposited solid was dried, and
recrystallised from benzene to give the compound 7 as light brown
crystals, m.p. 150–152°C, yield 20%. IR (KBr):br. 3500–2500 cm-1
(NH), 1717 cm-1 (C=O), 1705 cm-1 (C=Oacid), 1632 cm-1 (C=N).
1H NMR (CDCl3, δ ppm) 12.3 (s, 1H, exchangeable with D2O), 10.1
(br.s, 1H, exchangeable with D2O), 7.3–7.1 (m, 8Harom.), 4.9 (m, 2H),
4.13 (s, 1H). EI-MS m/z (%): 326 (54.2), 300 (42.8), 298 (100), 263
(42), 248 (26.9), 178 (24.8). Anal. Calcd. for C21H13ClN2O5 (408.8):
C, 61.70; H, 3.20; N, 6.85; Cl, 8.67. Found: C, 62.08; H, 3.41; N,
7.11; Cl, 9.19.
7-(4-Chlorophenyl)-8-imino-9-phenyl-10-thioxo-8,9,10,11-
tetrahydro-6H,7H-pyrimidino[5',4':5,6] pyrano[3,2-c]chromene-6-
one (8): A mixture of 1 (1.75 g, 5 mmole) and phenyl isothiocyanate
(0.6 ml, 5 mmole) in pyridine (15 ml) was refluxed for 6 h until no
more substrate (TLC). The solvent was removed under vacuum, and
the reaction mixture was diluted with water to give a crude solid
which was filtered off, washed several times with water, dried and
recrystallised from ethanol to give 8 as dark red crystals, m.p. 223–
225°C, yield 33%. IR (KBr): 3389 cm-1 (NH), 1719 cm-1 (C=O),
1640 cm-1 (C=N), 1132 cm-1 (C=S). 1H NMR (DMSO-d6, δ ppm)
11.12 (s, 1H, exchangeable with D2O), 7.8–6.27 (m, 13Harom.), 4.7
(s, 1H), 3.8 (br.s, 1H, exchangeable with D2O). EI-MS m/z (%): 470
(M, 14.7), 315 (25.1), 221 (20.3), 92 (25.9), 77 (100). Anal. Calcd.
for C26H16ClN3O3S (485.94): C, 64.26; H, 3.31; N, 8.64; Cl, 7.29; S,
6.59. Found: C, 64.71; H, 3.41; N, 8.26; Cl, 7.08; S, 6.61.
7-(4-Chlorophenyl)-10-methyl-6H,7H,8H-[3,1]-oxazino[5',4':5,6]
pyrano[3,2-c] chromene-6,8-dione (4): A mixture of 1 (1.75 g,
5 mmole) and acetic acid (20 ml) was refluxed for 3 h until no more
substrate was observed by TLC. The solvent was concentrated
under vacuum and diluted with water. The precipitate was filtered
off, washed several times with water, dried and recrystallised from
benzene to give 4 as pale brown crystals, m.p. 158–160°C, yield
68%. IR (KBr): 1770 cm-1 (C=Ooxazinone), 1717 cm-1 (C=Oδ-lactone),
1643 cm-1 (C=N). 1H NMR (CDCl3, δ ppm) 7.7-7.1 (m, 8Harom.), 5.1
(s, 1H, C4-H), 2.1 (s, 3H, Me). EI-MS m/z (%): 394 (M, 16.9), 358
(12.2), 350 (33.1), 311 (100), 282 (22.7), 95 (66.3). Anal. Calcd. for
C21H12ClNO5 (393.78): C, 64.05; H, 3.07; N, 3.55; Cl, 9.00. Found:
C, 63.77; H, 3.11; N, 4.0; Cl, 8.88.
7-(4-Chlorophenyl)-9-(N,N-diacetylamino)-6-oxo-6H,7H-
pyrano[3,2-c]chromene-8-carboxamide (5): A suspension of 1
(1.75 g, 5 mmole) in freshly distilled acetic anhydride (15 ml) was
heated under reflux for 3 h. 100 ml of water was added and the
residue was basified with Na2CO3 and extracted with CH2Cl2. The
organic layer was dried over Na2SO4, filtered and evaporated under
reduced pressure. The crude residue was crystallised from methanol
as colourless crystals, m.p. 316–318°C, yield 31%. IR (KBr):
3432, 3310, 3210 cm-1 (NH2), 1726 cm-1 (C=Oδ-lactone), 1668 cm-1
(C=Oamide). 1H NMR (DMSO-d6, δ ppm) 8.2 (br.s, 2H, exchangeable
with D2O), 7.8–7.3 (m, 8Harom.), 4.6 (s, 1H, C5-H), 2.38 (s, 6H). EI-
MS m/z (%): 428 (M-HCN, 25.6), 293 (23.9), 317 (100). Anal. Calcd.
for C23H17ClN2O6 (452.85): C, 61.0; H, 3.78; N, 6.18; Cl, 7.82.
Found: C, 60.62; H, 3.76; N, 5.68; Cl, 7.77.
7-(4-Chlorophenyl)-9-ethoxycarbonylmethylamino-6-oxo-6H,7H-
pyrano[3,2-c] chromene-3-carbonitrile (6):A mixture of 1 (1.75 g,
5 mmole) and ethyl chloroacetate (0.61 ml, 5 mmole) in pyridine
(20 ml) was refluxed for 10 h until no more substrate was observed
by TLC. After cooling at r.t., the solvent was concentrated under
vacuo and the reaction mixture was acidified with cold diluted HCl.
The crude solid product that deposited was collected by suction,
washed with water, dried and then recrystallised from benzene to
give the compound 6 as white crystals, m.p. 144–146°C, yield 36%.
IR (KBr): 3316 cm-1 (NH), 2198 cm-1 (C≡N), 1738 cm-1 (C=O), 1718
cm-1 (C=Oester). 1H NMR (CDCl3, δ ppm) 8.1 (br.s, 1H, exchangeable
with D2O), 7.9–6.9 (m, 8Harom.), 4.8 (s, 1H), 4.2 (q, 2H), 3.5–3.2 (d,d,
2H), 1.2 (t, 3H). EI-MS m/z (%): 437 (M, 37.5), 363 (11.9), 311 (100),
297 (58.3), 239 (41.7), 121 (56.1). Anal. Calcd. for C23H17ClN2O5
(436.85): C, 63.23; H, 3.92; N, 6.41; Cl, 8.13. Found: C, 63.69; H,
4.2; N, 6.22; Cl, 7.94.
7-(4-Chlorophenyl)-10-[4-(dimethylamino)phenyl]-8,9,10,11-
tetrahydro-6H,7H,8H-[3,1]oxazino[5',4':5,6]pyrano[3,2-c]chromene-
6,8-dione (9): A mixture of 1 (1.75 g, 5 mmole) and 4-dimethyl-
aminobenzylidene aniline (1.22 g, 5 mmole) was refluxed in
n-butanol (20 ml) for 10 h. The reaction mixture was concentrated,
left to cool and the solid deposited was filtered off by suction, washed
with light petroleum ether and then recrystallised from benzene to
afford 9 as orange crystals, m.p. 210–212°C, yield 30%. IR (KBr):
1
1792 cm-1 (C=O), 1722 cm-1 (C=O), 1645 cm-1 (C=N). H NMR
(CDCl3, δ ppm) 8.1–7.0 (m, 12Harom.), 4.3 (s, 1H), 2.79 (s, 6H).
EI-MS m/z (%): 501 (6.6), 326 (46.8), 300 (27.5), 298 (100), 263
(29.4), 121 (67.3), 92 (40),. Anal. Calcd. for C28H19ClN2O5 (498.92):
C, 67.40; H, 3.83; N, 5.61; Cl, 7.10. Found: C, 68.03; H, 4.1; N, 5.38;
Cl, 6.67.
Ethyl-8-amino-7-(4-chlorophenyl)-6,10-dioxo-10,11-dihydro-
6H,7H-pyrido[3',2':5,6] pyrano[3,2-c]chromene-9-carboxylate (10):
To a mixture of diethyl malonate (0.8 ml, 5 mmole) and the
iminonitrile 1 (1.75 g, 5 mmole), a solution of sodium ethoxide (0.5 g
sodium in 20 ml dry ethanol) was added and the reaction mixture was
refluxed for 8 h until no more substrate (TLC).The excess solvent
was evaporated in vacuo and the remaining semisolid product was
acidified in cold dilute acetic acid. The crude solid product was
collected by suction, washed with water, dried and then recrystallised
from a mixture of light petroleum ether (b.p. 80–100°C)-ethyl acetate
to afford 10 as a pale yellow crystals, m.p. 188–190°C, yield 55%.
7-(4-Chlorophenyl)-8-imino-6-oxo-8,9-dihydro-6H,7H-pyrrolo
[3',2':5,6]pyrano [3,2-c]chromene-9-carboxylic acid (7): A mixture
of 1 (1.75 g, 5 mmole) and chloroacetic acid (0.47 ml, 5 mmole) in
pyridine (20 ml) was refluxed for 6 h (TLC). After cooling at r.t.,
the reaction mixture was acidified with cold diluted acetic acid.
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676 JOURNAL OF CHEMICAL RESEARCH 2007
IR (KBr): br. 3460, 3288, 3113 cm-1 (NH, OH), 1710 cm-1 (C=Oester),
1712 cm-1 (C=O), 1670 cm-1 (C=Oamide). 1H NMR (CDCl3, δ ppm)
9.0 (s, 1H, exchangeable with D2O), 7.84–7.12 (m, 8Harom.), 5.13 (s,
1H), 4.78 (br.s, 2H, exchangeable with D2O), 4.4 (q, 2H), 1.13 (t,
3H). EI-MS m/z (%): 437 (M-C2H4, 10.1), 402 (14.4), 326 (25.6), 298
(100). Anal. Calcd. for C24H17ClN2O6 (464.86): C, 62.01; H, 3.68; N,
6.02; Cl, 7.62. Found: C, 61.87; H, 3.90; N, 6.09; Cl, 7.88.
13C NMR (CDCl3)
Cl
138.7
O
128.6
OH
159.2
141.6
60 47.3
192.3
118.2
131.2
127.2
127.1
171.4
O
NH
128.5
3-(4-Chlorophenyl)-4-(2-hydroxybenzoyl) pyrazolidin-5-one (11):
To a solution of 1 (1.75 g, 5 mmole) in butan-1-ol (20 ml).
hydrazine hydrate (0.96 ml, 30 mmole) was added dropwise with
stirring at r.t. for 10 min. The whole mixture was refluxed for 4 h.
The solvent was removed by vacuum and the reaction mixture was
acidified with cold dilute HCl. The separated solid was collected
by suction, dried and recrystallised from light petroleum ether
(b.p. 80–100°C) as a pale brown crystals, m.p. 202–204°C, yield 40%.
IR (KBr): br. 3352, 3170 cm-1 (NH, OH), 1668 cm-1 (C=O). 1H NMR
(CDCl3, δ ppm) 10.3 (s, 1H), 8.2 (br.s, 2H), 7.6–6.95 (m, 8Harom.),
5.16 (m, 1H). EI-MS m/z (%): 317 (M, 19.7), 276 (31.3), 166 (70.6),
165 (100), 138 (28.4), 111 (46.4). Anal. Calcd. for C16H13ClN2O3
(316.74): C, 60.67; H, 4.13; N, 8.84; Cl, 11.19. Found: C, 61.05; H,
4.33; N, 8.49; Cl, 10.77.
N
H
122.09
Received 20 September 2007; accepted 12 December 2007
Paper 07/4845
doi: 10.3184/030823407X268962
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