Heteroannulation of chromene derivatives. Synthesis of chromeno[4,3-e] indazolone, chromeno4,3-flquinazoline and pyrano[3,2-c]chromene derivatives

Article abstract of DOI:10.3184/030823409X393727

Pentane-2,4-dione and 3-ethoxycarbonylcoumarin react in the presence of sodium ethoxide to form 10-acetyl-7,9-dihydroxy-6H-benzo[c]chromen-6-one (2). Compound 2 reacted with aromatic aldehydes and ethyl cyanoacetate to give the chromeno-chromenediones 3 and 4 respectively, with hydrazine hydrate to form the azine 5, with phenyl hydrazine giving the chromeno-indazole 6, with primary amines to form the imines 7a-f, and with thiourea to give the chromeno-quinazoline 8. Methyl 2-amino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydro- pyrano[3,2-c]chromene-3-carboxylate (9a) and the corresponding 3-carbonitrile 9b were prepared, and the reactions of the ester 9a with phenacyl chloride, furoyl chloride, and hydrazine hydrate were investigated.

Full text of DOI:10.3184/030823409X393727

JOURNAL OF CHEMICAL RESEARCH 2009
JANUARY, 41–45
RESEARCH PAPER 41
Heteroannulation of chromene derivatives. Synthesis of chromeno[4,3-e]
indazolone, chromeno[4,3-f]quinazoline and pyrano[3,2-c]chromene
derivatives
Mahmoud R. Mahmoud*, Fakhry A. El-Bassiouny, Mohamed E. Azab, Mohamed Y. El-Kady
and Hesham M. Rashed
Pentane-2,4-dione and 3-ethoxycarbonylcoumarin react in the presence of sodium ethoxide to form 10-acetyl-7,9-
dihydroxy-6H-benzo[c]chromen-6-one (2). Compound 2 reacted with aromatic aldehydes and ethyl cyanoacetate to
give the chromeno-chromenediones 3 and 4 respectively, with hydrazine hydrate to form the azine 5, with phenyl
hydrazine giving the chromeno-indazole 6, with primary amines to form the imines 7a–f, and with thiourea to give
the chromeno-quinazoline 8. Methyl 2-amino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydro-pyrano[3,2-c]chromene-
3-carboxylate (9a) and the corresponding 3-carbonitrile 9b were prepared, and the reactions of the ester 9a with
phenacyl chloride, furoyl chloride, and hydrazine hydrate were investigated.
Keywords: 1-benzopyrans, fused pyrans, pyrazoles, indazoles, pyrimidines, coumarins, phenols, imines
Chromene derivatives exhibit various biological activities.
They act as anticoagulants, photointercalants or enzyme
inhibitors,1,2 antibacterials,3-5 fungicides,6ꢀDQWLꢁLQÀDPPDWRU\7
and antitumor8,9 agents, and several studies from the
viewpoint of chemical taxonomy10,11 have been made.
A variety of pyrans and condensed pyrans have been prepared
using nitriles as starting materials.12-15 Within this context
and also as a contribution to our work on the synthesis of new
heterocyclic derivatives of potential biological activity,16-20
we present here our efforts in the synthesis of several new
compounds featuring different heterocyclic rings fused onto
the chromene moiety with the aim of obtaining more and
better pharmacologically active compounds.
of phenolic OH groups. The remaining spectroscopic
and analytical data lent further support to structure 2
(see Experimental). The reaction proceeded by a simple
Michael addition followed by cyclisation and dehydrogenation
to give the more stable product 2.
The reactions of 2 with electrophilic and nucleophilic
reagents were also investigated. Thus, treatment of compound
2 with aromatic aldehydes, namely 4-methoxybenzaldehyde,
4-(dimethylamino)benzaldehyde, 4-chlorobenzaldehyde and
cinnamaldehyde, in the presence of anhydrous sodium
methoxide by fusion at 170°&ꢀ RUꢀ E\ꢀ UHÀX[ꢀ LQꢀ QꢁEXWDQROꢀ LQꢀ
the presence of a few drops of piperidine afforded 3-aryl-6-
hydroxy-2,3-dihydro-1H,7H-chromeno[6,5-c]chromene-1,7-
diones 3a–d.
The structures of compounds 3 were deduced from their
microanalytical and spectral data. The 1H NMR spectra show
the ABX pattern of the CO–CH2–CH moiety. The magnetic
nonequivalence of the protons HA and HB of the methylene
group adjacent to the carbonyl shows an AB system associated
with these protons with a geminal coupling of 11.3 Hz and
affords the eight lines of the AB part of an ABX system,22 on
account of its attachment to an asymmetric centre.
Fusing compound 2 with ethyl cyanoacetate in the presence
of metallic sodium afforded 6-hydroxy-1-methyl-3,7-dioxo-
chromeno[4,3-f]chromene-2-carbonitrile (4). (Scheme 2)
The reaction of 2 with hydrazine hydrate (80%) yielded
the corresponding azine 5 in which hydrazine has condensed
with two molecules of 2 through nucleophilic attack at the
ketonic side chain. On the other hand, the reaction of 2 by
fusion with phenylhydrazine afforded 5-hydroxy-1-methyl-
3-phenylchromeno[4,3-e]indazol-6(3H)-one (6ꢄꢂꢀ 5HÀX[LQJꢀ
of 2 with primary amines, namely aniline, benzylamine,
n-butylamine, dodecylamine, ethylamine, hexdecylamine,
octdecylamine, and p-toluidine, in n-butanol yielded the
corresponding imine condensation products 7a–h (Scheme 2).
Results and discussion
The reaction of 3-ethoxycarbonylcoumarins with pentane-2,4-
dione has previously been claimed to afford 1-acetyl-2-methyl-
4a,10b-dihydro-4H,5H-pyrano[3,4 c][1]benzopyran-4,5-dione
(1) as the major product in a moderate yield.21ꢀ:Hꢀ¿QGꢀWKDWꢀ
no pyranobenzopyrone derivative could be isolated in such
a reaction; instead we have found that the sole product
obtained, in good yield, is the benzo[c]chromene derivative 2.
[The precise relationship of the compound reported in ref. 21
as having structure 1 to the product reported here as structure 2
LVꢀQRWꢀFODUL¿HGꢂꢀ:HꢀEHOLHYHꢀWKDWꢀLWꢀPLJKWꢀEHꢀWKHꢀVDPHꢀFRPSRXQGꢃꢀ
the melting-point reported21 for structure 1 (199°C) is fairly
FORVHꢀWRꢀZKDWꢀZHꢀ¿QGꢀIRUꢀ2 (192–194°C). It should be noted
that the IR bands reported for the C=O groups of 1 (1680 and
1640 cm-1) are not compatible with that structure.]
Structure 1 could be eliminated, since the 1H NMR spectrum
revealed a single 3H singlet at G 2.4 ppm corresponding to the
acetyl group, a broad signal at G 4.8 ppm (2H), exchangeable
with D2O, characteristic for the two phenolic groups; no
signal attributable to the ring methyl group in 1 was observed.
Furthermore, the dark green colour of the alcoholic solution
formed with neutral ferric chloride indicates the presence
Me
O
OH
O
O
Me
Me
CO2Et
H2C(COMe)2
OH
O
O
O
NaOMe/MeOH
O
O
O
O
2
1
Scheme 1
* Correspondent. E-mail: mrefaee2000@yahoo.com

42 JOURNAL OF CHEMICAL RESEARCH 2009
O
O
Ar
O
N
HC
HB
O
NC
Me
HO
HO
3
a
b
c
d
Ar
O
O
HA
C6H4OMe-p
C6H4NMe2-p
C6H4Cl-p
CH=CHPh
O
OH
OH
Me
O
O
O
N
OH
Me
3
4
O
OH
a
b
c
Me
OH
N
OH
O
f
O
O
O
5
e
S
2
d
7
a
b
c
d
e
f
R
Ph
R
C6H4Me-p
CH2Ph
N
NH
N
N
OH
Me
Me
Ph
Et
Me
OH
OH
OH
n-butyl
n-dodecyl
n-hexadecyl
n-octadecyl
g
h
O
O
O
O
O
O
8
6
7
Reagents: a, ArCHO/NaOMe; b, NCCH2CO2Et/Na/xylene; c, N2H4.H2O/n-BuOH;
d, PhNHNH2; e, RNH2/n-BuOH; f, H2NCSNH2/AcOH
Scheme 2
When compound 2 was reacted with thiourea in boiling
acetic acid it yielded 6-hydroxy-1-methyl-3-thioxo-3,4-
dihydrochromeno[4,3-f]quinazolin-7-one (8), as evidenced by
the microanalytical and spectroscopic data (see Experimental).
of the activated nitrile followed by 1,6-exo-dig cyclisation
DQGꢀ WUDQVHVWHUL¿FDWLRQꢂꢀ 6WUXFWXUHꢀ 9a gets more chemical
evidence through the reaction with phenacyl chloride, furoyl
chloride and hydrazine hydrate. Thus, treatment of compound
9a ZLWKꢀ SKHQDF\Oꢀ FKORULGHꢀ LQꢀ UHÀX[LQJꢀ S\ULGLQHꢀ \LHOGHGꢀ ꢅꢁ
benzoyl-7,10-dihydro-8-hydroxy-7-(4-methoxyphenyl)-4H-
4H-Pyrano[3,2-c]benzopyrones
characterised
by
a
phenanthrene-like structure as found in tetrahydrocannabinol
that belongs to the few CNS active compounds without
nitogen heteroatoms.23 Heber24 has synthesised so-
called azocannabinoids from the reaction of 4-amino-7-
hydroxycoumarins with D,E-unsaturated carbonyl compounds.
In the present work, the reaction of 4-hydroxycoumarin
with ethyl-D-cyano-4-methoxycinnamate and D-cyano-
4-methoxycinnamonitrile in the presence of anhydrous
VRGLXPꢀPHWKR[LGHꢀLQꢀDEVROXWHꢀPHWKDQROꢀXQGHUꢀUHÀX[ꢀ\LHOGHGꢀ
the corresponding 2-amino-2-carbomethoxy(cyano)-4-(4-
methoxyphenyl)-5H-pyrano[3,2-c]benzopyran-5-ones 9a and
9b, respectively (Scheme 3). The formation of compound
9a,b could be visualised according the simple Michael
addition of the carbanion (C3-coumarinyl) to the E-carbon
[1]benzopyrano[3',4':5,6]pyrano[2,3-b]pyrrol-6-one
(10).
Similarly, acylation of compound 9a with furoyl chloride
in boiling pyridine afforded methyl-2-furoylamino-4-(4-
methoxyphenyl)-5-oxo-5H-pyrano[3,2-c]benzopyran-3-
carboxylate (11). Hydrazinolysis of compound 9a using
hydrazine hydrate (80%) afforded a crude solid product (two
VSRWVꢀLQꢀ7/&ꢄꢀZKLFKꢀXSRQꢀSXUL¿FDWLRQꢀ\LHOGHGꢀVDOLF\OLFꢀDFLGꢀ
hydrazide (12) and 3-(5-amino-3-oxopyrazolin-4-yl)-3-(4-
methoxyphenyl) propanoic acid hydrazide (13).
Experimental
0HOWLQJꢀ SRLQWVꢀ ZHUHꢀ WDNHQꢀ RQꢀ Dꢀ *ULI¿Qꢀ DQGꢀ *HRUJHꢀ PHOWLQJꢀ SRLQWꢀ
apparatus. IR spectra were recorded on a Pye Unicam SP 1200
NH2
Ph
OH
CN
X
O
O
O
Ar
HN
X
a
Ar
OH
O
O
(9a)
O
O
NaOMe/MeOH
O
Ar
9
Ar = C6H4OMe-p
O
a, X = CO2Me
b, X = CN
c
b
(9a)
(9a)
10
O
H
NH2
O
Ar
O
N
O
O
CO2Me
NHNH2
NH
NH
H2NNH
O
+
OH
12
O
Ar
O
11
13
Reagents: a, PhCOCH2Cl/Py; b, 2-furoyl chloride/Py; c, N2H4.H2O/EtOH
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2009 43
1
spectrophotometer using the KBr wafer technique. H NMR spectra
times with water, dried and then recrystallised from acetic acid to
give 4 as light brown crystals (34%), m.p. 340–342°C. IR: Qmax 3437
EUꢀꢊ2+ꢄꢉꢀꢍꢍꢍꢎꢀꢊ&Ł1ꢄꢉꢀꢆꢇꢏꢌꢀꢊODFWRQHꢀ&2ꢄꢉꢀꢆꢌꢇꢆꢀFP-1 (chelated ketone
CO). NMR (DMSO-d6): GH 7.6–6.6 (m, 5Har), 5.2 (s, 1H, OH), 1.67
(s, 3H, CH3); GC 128.1, 125.9, 127.7, 124.3 (C9–C12), 152.3 (C8a),
131.4 (C12a), 161.1 (C7), 108.6 (C6a), 160.9 (C6), 109.2 (C5), 157.7
ꢊ&ꢏꢄꢉꢀꢅꢌꢂꢐꢀꢊ&ꢍꢄꢉꢀꢆꢆꢋꢂꢏꢀꢊ&Ł1ꢄꢉꢀꢆꢇꢈꢂꢆꢀꢊ&ꢆꢄꢉꢀꢆꢐꢂꢐꢀꢊ&+3), 118.4, 144.6,
130.9. EI MS: m/z (%) 319 (M+, 84), 291(M-CO, 100), 262 (33), 76
(40). Anal. Calcd for C18H9NO5 (319.27): C, 67.71; H, 2.84; N, 4.38.
Found: C, 68.08; H, 2.60; N, 4.6%.
Reaction of 2 with hydrazine: formation of azine 5: To a solution of
2 (2.7 g, 0.01 mole) in n-butanol, hydrazine hydrate (80%) (0.01 mole)
ZDVꢀDGGHGꢀZLWKꢀVWLUULQJꢂꢀ7KHꢀPL[WXUHꢀZDVꢀUHÀX[HGꢀIRUꢀꢎꢀKꢀXQWLOꢀQRꢀ
more substrate remained (TLC). Evaporation of the excess solvent
left a solid product which recrystallised from acetic acid as orange
crystals (35%), m.p. 346–348°C. IR: Qmax 3413 br (OH), 1693 (CO),
1634 cm-1 (C=N). NMR (DMSO-d6): GH 7.8–6.67 (m, 10Har), 5.1 (br.
s, 4H), 2.1 (s, 6H). EI MS: m/z (%) 536 (M+, 28), 268 (100), 228
(60). Anal. Calcd for C30H20N2O8 (536.50): C, 67.16; H, 3.75; N,
5.22. Found: C, 66.87; H, 3.52; N, 5.45%.
were determined on a Varian Gemini 200 MHz using TMS as
internal standard. 13C NMR spectra were measured on a JEOL 75
MHz spectrometer. EI MS were measured on a Shimadzu-GC-MS,
QP 1000 EX instrument operating at 70 eV. Elemental analyses were
carried out at the Microanalytical Unit, Faculty of Science, Ain Shams
University with a Perkin-Elmer Series II CHNS/O elemental analyser.
The homogeneity of the synthesised compounds was checked using
TLC with aluminium sheets silica gel F254 (Merck).
10-Acetyl-7,9-dihydroxy-6H-benzo[c]chromen-6-one (2): Ethyl
coumarin-3-carboxylate (4.4 g, 0.02 mol), dry sodium ethoxide (1.1 g,
0.02 mole) and pentane-2,4-dione (2.4 ml, 0.024 mole) were stirred
WRJHWKHUꢀLQꢀDꢀÀDVNꢀKHDWHGꢀLQꢀDQꢀRLOꢁEDWKꢀDWꢀꢆꢇꢈ°C for 3 h. After cooling,
the reaction mixture was treated with cold dilute hydrochloric acid. The
VROLGꢀWKDWꢀVHSDUDWHGꢀZDVꢀ¿OWHUHGꢀRIIꢉꢀZDVKHGꢀVHYHUDOꢀWLPHVꢀZLWKꢀZDWHUꢉꢀ
dried,andrecrystallisedfromethanolasorangecrystals(67%),m.p.192–
194°C. IR: Qmax 3449 br (OH), 1697 (lactone CO), 1673 cm-1 (chelated
ketone CO). NMR (CDCl3): GH 8.1–7.1 (m, 4H), 6.7 (s, 1H, C8-H),
5.3 (br.s, 2H, 2OH), 2.4 (s, 3H, CH3); GC, see inset structure. EI MS:
m/z (%) 270 (M+, 51), 255 (M–CH3, 100), 227 (M–COCH3, 96), 171
(8.5), 143 (12), 115 (19), 89 (20), 77 (42). Anal. Calcd for C15H10O5
(270.24): C, 66.66; H, 3.72. Found: C, 67.0; H, 3.49%.
OH
O
Reaction of 2 with phenyl hydrazine; formation of 5-hydroxy-1-
methyl-3-phenylchromeno[4,3-e]indazol-6(3H)-one (6): A mixture of
compound2(2.7g, 0.01mole)andphenylhydrazine(1.08g, 0.01mole)
was heated on an oil-bath at 180°C for 3 h (TLC). The reaction
mixture was then poured into ice-cold hydrochloric acid. The solid
REWDLQHGꢀ ZDVꢀ ¿OWHUHGꢀ RIIꢉꢀ ZDVKHGꢀ VHYHUDOꢀ WLPHVꢀ ZLWKꢀ ZDWHUꢉꢀ GULHGꢀ
and recrystallised from acetic acid to give the chromeno-indazole
derivative 6 as yellow crystals (24%), m.p. 265–267°C. IR: Qmax
3422, 1691 (CO), 1640 cm-1 (C=N). NMR (DMSO-d6): GH 7.8–6.9
(m, 10Har), 5.3 (s, 1H), 2.6 (s, 3H). EI MS: m/z (%) 342 (M+, 100),
282 (36), 238 (14), 77 (66). Anal. Calcd for C21H14N2O3 (342.33): C,
73.68; H, 4.11; N, 8.18. Found: C, 73.72; H, 4.16; N, 8.44%.
Reaction of 2 with primary amines; formation of 10-[1-(substituted
imino)ethyl]-7,9-dihydroxy-6H-benzo[c]chromen-6-one 7a–h: To
a solution of 2 (0.9 g, 0.0033 mole) in n-butanol, a primary amine
(p-toluidine, benzylamine, aniline, ethylamine, n-butylamine,
dodecylamine, hexdecylamine or octdecylamine) was added and the
ZKROHꢀPL[WXUHꢀZDVꢀUHÀX[HGꢀIRUꢀꢌꢀKUVꢀXQWLOꢀQRꢀPRUHꢀVXEVWUDWHꢀꢊ7/&ꢄꢀZDVꢀ
detected. The reaction mixture was poured onto ice-cold hydrochloric
acid. The solid deposited was washed several times with water, dried
and recrystallised from the indicated solvent to give 7a–h.
p-Tolylimine 7a: Yellow crystals (78%) from AcOH, m.p. 214–
216°C. IR: Qmax 3462 br. (OH), 1680 (CO), 1640 cm-1 (C=N). NMR
(DMSO-d6): GH 8–7.2 (m, 8Har), 6.3 (s, 1H, C8-H), 4.66 (br.s, 2H, OH
exchangeable with D2O), 2.3 (s, 3H, Ar-Me), 0.9 (s, 3H, Me). EI MS:
m/z (%) 359 (M+, 100), 344 (58), 254 (44), 91 (41), 65 (38). Anal.
Calcd for C22H17NO4 (359.36): C, 73.53; H, 4.76; N, 3.89. Found: C,
73.74; H, 4.61; N, 3.67%.
Benzylimine7b:paleyellowcrystals(71%)frombenzene, m.p. 145–
146°C. IR: Qmax 3436 br (OH), 1682 (CO), 1632 cm-1 (C=N). NMR
(DMSO-d6): GH 7.8–7.1 (m, 9Har), 6.48 (s, 1H, C8-H), 5.0 (br.s,
2H, exchangeable with D2O), 4.81 (s, 2H, CH2Ph), 1.2 (s, 3H, Me).
EI MS: m/z (%) 359 (M+, 33), 263 (100), 91 (82), 65 (32). Anal.
Calcd for C22H17NO4 (359.36): C, 73.53; H, 4.76; N, 3.89. Found: C,
73.74; H, 4.61; N, 3.67%.
167.7
28.9
Me
128.4
104.3
168.4
196.8
118.3
149.5
130.9
126.6
128.7
OH
107.7
152.1
160.2
O
O
124.2
13C NMR of compound 2
3-Aryl-2,3-dihydrochromeno[6,5-c]chromene-1,7-diones
(3a-d):
Compound 2 (2.7 g, 0.01 mol), an aromatic aldehyde (0.01 mol) and
SLSHULGLQHꢀꢊꢈꢂꢋꢀPOꢄꢀZHUHꢀUHÀX[HGꢀLQꢀQꢁEXWDQROꢀꢊꢋꢈꢀPOꢄꢀIRUꢀꢌꢀKꢉꢀZKHQꢀ
no more substrate was detected (TLC). The solid deposited from the
KRWꢀVROXWLRQꢀZDVꢀ¿OWHUHGꢀRIIꢉꢀGULHGꢀDQGꢀUHFU\VWDOOLVHGꢀWRꢀJLYHꢀ3a–d.
3-(4-Methoxyphenyl) compound (3a): Recrystallised from AcOH
as yellow crystals (73%), m.p. 230–232°C. IR: Qmax br. 3500 (OH),
1687, 1670 cm-1 (CO). NMR (DMSO-d6): GH 7.7–6.5 (m, 9Har), 5.8
(s, 1H, exchangeable with D2O), 5.3 (t, Ha, Jac = 5.8 Hz, Jab = 6.4 Hz),
3.9 (s, 3H, OMe), 3.2 (d,d, Hc, Jcb = 16.8 Hz, Jac 7.1 Hz), 2.9 (d,d,
Hb, Jbc = 17.4 Hz, Jab = 5.7 Hz). 13C NMR (DMSO-d6); GC 190.2
(CO), 50.6 (C2), 48.7 (C3), 107.3 (C5), 166.4 (C6) 108.2 [(C6a),
159.3 (CO), 153.3 (C–O), 123.7, 128.3, 126.4, 127.3, 130.7, 148.6
coumarinyl carbons], 164.1 (C4a), 123.7, 127.8, 118.2, 158.3 Car,
55.4 (MeO). EI MS: m/z (%) 388 (M+, 100), 255 (29), 227 (3.4), 134
(73), 120 (60). Anal. Calcd for C23H16O6 (388.37): C, 71.13; H, 4.15.
Found: C, 71.41; H, 4.08%.
3-(4-Dimethylaminophenyl) compound (3b): Recrystallised from
dioxan as red crystals (65%), m.p. 277–279°C. IR: Qmax 3473 br (OH),
1692, 1678 cm-1 (CO). NMR (DMSO-d6): GH 7.9–6.6 (m, 9Har), 5.9 (s,
1H, OH, exchangeable with D2O), 5.1 (t, Ha, Jac = 6.1 Hz, Jab = 6.7 Hz),
3.4 (d,d, Hc, Jbc = 17.1 Hz, Jac = 6.7 Hz), 3.1 (d,d, Hb, Jbc = 17.6 Hz, Jab
= 6.2 Hz), 2.85 (s, 6H, NMe2). EI MS: m/z (%) 401 (M+, 35), 357 (63),
120 (100). Anal. Calcd for C24H19NO5 401.42): C, 71.81; H, 4.77; N,
3.48. Found: C, 72.01; H, 4.51; N, 3.77%.
3-(4-Chlorophenyl) compound (3c): Recrystallised from AcOH as
orange crystals (51%), m.p. 280–281°C. IR: Qmax 3472 br (OH), 1687,
1670 cm-1 (CO). NMR (DMSO-d6): GH 8.1–7.2 (m, 9Har), 5.6 (s, 1H,
exchangeable with D2O), 4.99 (t, Ha, Jac = 5.2 Hz, Jab = 7.1 Hz),
3.3 (d,d, Hc, Jbc = 15.8 Hz, Jac = 6.44 Hz), 3.0 (d,d, Hb, Jbc = 16.8 Hz,
J
ba = 6.0 Hz). EI MS: m/z (%) 394 (M+, 32.4), 392 (M+, 100). Anal.
Phenylimine 7c: Recrystallised from toluene as pale yellow crystals
(67%), m.p. 150–152°C. IR: Qmax 3426 br (OH), 1676 (CO), 1628
cm-1 (C=N). NMR (CDCl3): GH 7.7–7.1 (m, 9Har), 6.4 (s, 1H, C8–H),
4.7 (br.s, 2H, exchangeable with D2O), 1.08 (s, 3H, Me). EI MS: m/z
(%) 345 (M+, 100). Anal. Calcd for C21H15NO4 (345.33): C, 73.04;
H, 4.37; N, 4.05. Found: C, 72.91; H, 4.17; N, 4.20%.
Calcd for C22H13ClO5 (392.79): C, 67.27; H, 3.33; Cl, 9.02. Found:
C, 67.51; H, 3.50; Cl, 9.20%.
3-(E-Styryl) compound (3d): Recrystallised from AcOH as orange
crystals (60%), m.p. 268–269°C. IR: Qmax 3492 br (OH), 1688, 1669
cm-1 (CO). EI MS: m/z (%) 384 (M+, 33), 281 (66), 104 (100), 77
(41). Anal. Calcd for C24H16O5 (384.39): C, 74.99; H, 4.19. Found:
C, 75.28; H, 4.37%.
Reaction of 2 with ethyl cyanoacetate; formation of 6-hydroxy-1-
methyl-3,7-dioxo-3H,7H-chromeno[4,3-f]chromene-2-carbonitrile
(4): A mixture of the acetyl compound 2 (2.7 g, 0.01 mole) and
ethyl cyanoacetate (1.13 g, 0.01 mole) was stirred in the presence of
sodium metal (0.5 g, 0.02 mole) in dry xylene on an oil-bath at 180°C
for 3 h. The reaction mixture was cooled and poured into cold dilute
K\GURFKORULFꢀDFLGꢂꢀ7KHꢀGHSRVLWHGꢀVROLGꢀZDVꢀ¿OWHUHGꢀRIIꢉꢀZDVKHGꢀVHYHUDOꢀ
Ethylimine 7d: Recrystallised from AcOH as pale yellow crystals
(61%), m.p. 207–209°C. IR: Qmax 3470 br (OH), 1686 (CO), 1632
cm-1 (C=N). NMR (DMSO-d6): GH 7.6–7.1 (m, 4Har), 6.3 (s, 1H, C8-
H), 3.56 (q, 2H), 1.2 (t, 3H), 0.99 (s, 3H, Me); GC, see inset structure.
Anal. Calcd for C17H15NO4 (297.29): C, 68.68; H, 5.07; N, 4.71.
Found: C, 68.76; H, 5.2; N, 4.52%.

44 JOURNAL OF CHEMICAL RESEARCH 2009
21.6
56.3
NH2
O 161.2
O
49.3
N
OH
53.4
N
OH
14.1
169.1
O
14.3
33.9
167.0
105.9
116.1
150.2
166.1
104.9
116
144.4
18.3
77.3
16.6
164.4
Me
Me 163.9
128.1
124.6
39.7
131.2
119.7
160.1
128.4
126.3
127.7
128.7
131
165.9
115.6
165.7
130.7
108.1
126.4
128.6
126.1
127.9
OH
OH
109.2
108.2
55.1
159.6
155.6
O
128.1
O
O
164.3
151.2
153.4
124.1
161.2
161.3
O
O
O
O
123.6
13C NMR of compound 9a
13C NMR of compound 7d
13C NMR of compounds 7e
n-Butylimine 7e: Recrystallised from toluene as pale yellow crystals
(56%), m.p. 165–167°C. IR: Qmax br. 3444 (OH), 1688 (CO), 1638 cm-1
(C=N). NMR (CDCl3): GH 7.8–7.2 (m, 4Har), 6.6 (s, 1H, C8-H), 5.2 (br.
s, 2H, exchangeable with D2O), 3.6 (t, 2H), 1.7–1.3 (m, 4H), 1.08 (s,
3H, Me), 0.92 (s, 3H, Me); GC, see inset structure. EI MS: m/z (%) 325
(M+, 71), 268 (100), 226 (43). Anal. Calcd for C19H19NO4 (325.34): C,
70.14; H, 5.87; N, 4.30. Found: C, 70.32; H, 5.60; N, 4.55%.
n-Dodecylimine 7f: Recrystallised from benzene as pale yellow
crystals (52%), m.p. 142–143°C. IR: Qmax 3462 br (OH), 1682 (CO),
1633 cm-1 (C=N). NMR (CDCl3): GH 7.6–7.1 (m, 4Har), 6.4 (s, 1H,
C8-H), 5.1 (br.s, 2H, exchangeable with D2O), 3.6 (t, 2H), 1.66–1.3
(m, 20H), 1.03 (t, 3H), 0.94 (s, 3H, Me). EI MS: m/z (%) 437 (M+,
66), 268 (100). Anal. Calcd for C27H35NO4 (437.53): C, 74.12; H,
8.05; N, 3.20. Found: C, 74.42; H, 7.76; N, 3.0%.
n-Hexadecylimine 7g: Recrystallised from light petroleum ether as
pale yellow crystals (49%), m.p.110–111°C. IR: Qmax 3446 br (OH),
1688 (CO), 1636 cm-1 (C=N). NMR (CDCl3): GH 7.8–7.2 (m, 4Har),
6.6 (s, 1H, C8-H), 5.19 (br.s, 2H), 3.56 (t, 2H), 1.69–1.36 (m, 28H),
1.03 (t, 3H), 0.99 (s, 3H, Me). EI MS: m/z (%) 493 (M+, 40), 267
(100). Anal. Calcd for C31H43NO4 (493.63): C, 75.43; H, 8.76; N,
2.83. Found: C, 75.29; H, 8.49; N, 2.61%.
n-Octadecylimine 7h: Recrystallised from benzene as pale yellow
crystals (56%), m.135–137°C. IR: Qmax 3470 br (OH), 1686 (CO),
1636 cm-1 (C=N). NMR (CDCl3): GH 7.7–7.2 (m, 4Har), 6.48 (s, 1H,
C8-H), 4.98 (br.s, 2H), 3.54 (t, 2H), 1.65–1.3 (m, 32H), 1.1 (t, 3H),
0.97 (s, 3H, Me). EI MS: m/z (%) 521 (M+, 17), 268 (100). Anal.
Calcd for C33H47NO4 (521.68): C, 75.97; H, 9.06; N, 2.68. Found: C,
75.77; H, 9.24; N, 2.91%.
6-Hydroxy-1-methyl-3-thioxo-3,4-dihydrochromeno[4,3-f]
quinazolin-7-one (8): A mixture of 2 (2.7 g, 0.01 mole) and thiourea
(1.52 g, 0.02 mole) was dissolved in acetic acid and heated under
UHÀX[ꢀ IRUꢀ ꢏꢀ Kꢀ ꢊ7/&ꢄꢂꢀ 7KHꢀ UHDFWLRQꢀ PL[WXUHꢀ ZDVꢀ SRXUHGꢀ RQWRꢀ FROGꢀ
ZDWHUꢀDQGꢀWKHꢀVROLGꢀWKDWꢀVHSDUDWHGꢀZDVꢀ¿OWHUHGꢀRIIꢉꢀZDVKHGꢀZLWKꢀGLOXWHꢀ
ethanol, dried and recrystallised from dioxan to give 8 as deep yellow
crystals (41%), m.p. 183–185°C. IR: Qmax 3492 br (NH, OH), 1691
(CO), 1632 (C=N), 1324 cm-1 (C=S). NMR (DMSO-d6): GH 7.3–6.6
(m, 5Har), 5.3 (br.s, 1H), 3.0 (br.s, 1H), 1.5 (s, 3H, Me). EI MS:
m/z (%) 310 (M+, 11), 282 (100), 223 (60), 76 (32). Anal. Calcd for
C16H10N2O3S (310.25): C, 61.94; H, 3.24; N, 9.03; S, 10.32. Found:
C, 62.34; H, 2.98; N, 8.82; S, 10.07%.
Formation of the pyrano-chromenones 9a and 9b: A mixture of 4-
hydroxycoumarin (1.62 g, 0.01 mole), sodium methoxide (0.5 g sodium
LQꢀꢋꢈꢀPOꢀDEVROXWHꢀPHWKDQROꢄꢀDQGꢀHWK\OꢁĮꢁF\DQRꢁꢐꢁPHWKR[\FLQQDPDWHꢀ
RUꢀĮꢁF\DQRꢁꢐꢁPHWKR[\FLQQDPRQLWULOHꢀꢊꢈꢂꢈꢆꢀPROHꢄꢀZDVꢀUHÀX[HGꢀZLWKꢀ
stirring for 3 h (TLC). The reaction mixture was poured on cold dilute
acetic acid and allowed to stand for 1 h at room temperature. The solid
WKDWꢀVHSDUDWHGꢀLQꢀHDFKꢀFDVHꢀZDVꢀ¿OWHUHGꢀRIIꢉꢀZDVKHGꢀZLWKꢀZDWHUꢉꢀGULHGꢀ
and recrystallised from the indicated solvent.
Methyl 2-amino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrano
[3,2-c]chromene-3-carboxylate (9a): Yellow crystals (66%) from
benzene, m.p. 165–167°C. IR: Qmax 3422, 3306, 3271 (NH2), 1695
(CO unsaturated G-lactone), 1658 cm-1 (chelated CO ester). NMR
(CDCl3): GH 7.4–6.9 (m, 8Har), 4.7 (s, 1H, C4-H), 4.0 (br.s, 2H,
exchangeable with D2O), 3.85 (s, 3H, OMe), 3.7 (s, 3H, COOMe);
GC, see inset structure. EI MS: m/z (%) 379 (M+, 38), 320 (35), 272
(99), 249 (69), 240 (100), 145 (27), 121 (64), 117 (52), 89 (64). Anal.
Calcd for C21H17NO6 (379.35): C, 66.49; H, 4.51; N, 3.69. Found: C,
66.70; H, 4.21; N, 3.82%.
2-Amino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]
chromene-3-carbonitrile (9b): Yellow crystals (52%) from acetic
acid, m.p. 231–233°C. IR: Qmax 3399, 3322, 3171 (NH2), 2194
ꢊ&Ł1ꢄꢉꢀ ꢆꢇꢈꢅꢀ FP-1 (CO unsaturated G-lactone). NMR (DMSO-d6):
GH 7.3–6.9 (m, 8Har), 4.7 (s, 1H, C4-H), 4.0 (br.s, 2H, exchangeable
with D2O), 3.85 (s, 3H, OMe); GC, see inset structure. EI MS:
m/z (%) 346 (M+, 17), 280 (92), 279 (100), 249 (75), 240 (26),
145 (22), 121 (19), (89 (40), 66 (74). Anal. Calcd for C20H14N2O4
NH2
116.8
N
O
155.7
60
127.6
129.7
38.9
135.1
119.7
126.1
128.2
120.3
160.7
108.3
56.1
150.2
160.1
O
O
O
166.4
123.9
13C NMR of compound 9b
(346.32): C, 69.36; H, 4.06; N, 8.09. Found: C, 69.52; H, 4.11;
N, 8.43%.
3-Aryl-2,3-dihydrochromeno[6,5-c]chromene-1,7-dionIf 9-Benzoyl-
8-hydroxy-7-(4-methoxyphenyl)-7,10-dihydro-6H-chromeno[3',4':5,6]
pyrano[2,3-b]pyrrol-6-one (10)
Phenacyl chloride (1.5 g, 0.01 mole) was added dropwise with
stirring to the ester 9a (3.79 g, 0.01 mole) in pyridine (20 ml) over
ꢆꢀKꢀDQGꢀWKHꢀPL[WXUHꢀZDVꢀWKHQꢀKHDWHGꢀXQGHUꢀUHÀX[ꢀIRUꢀDQRWKHUꢀꢆꢀKꢉꢀ
monitoring the progress of the reaction by TLC. Evaporation of the
solvent in vacuo left a semisolid product which was triturated with
DFHWRQHꢀ DQGꢀ WKHꢀ VROLGꢀ ZKLFKꢀ VHSDUDWHGꢀ ZDVꢀ ¿OWHUHGꢀ RIIꢉꢀ GULHGꢀ DQGꢀ
recrystallised from dioxan to give compound 10 as yellow crystals
(41%), m.p. 324–326°C. IR: Qmax 3425 br (NH, OH), 1727 (CO),
1661 cm-1 (chelated ketone CO). NMR (DMSO-d6): GH 8.3–7.2 (m,
14Har + NH.), 6.8 (br.s, 1H), 4.7 (s, 1H, C4-H), 3.65 (s, 3H, OMe).
EI MS: m/z (%) 447 (M+–H2O, 15.9), 424 (56.0), 317 (100), 92
(13.0). Anal. Calcd for C28H19NO6 (465.44): C, 72.25; H, 4.11; N,
3.01. Found: C, 72.49; H, 4.19; N, 3.0%.
Methyl
2-furoylamino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydro-
pyrano[3,2-c]chromene-3-carboxylate (11): Furoyl chloride (2 g,
0.015 mol) was added dropwise with stirring to a solution of the
ester 9a (3.79 g, 0.01 mole) in pyridine (20 ml), and the mixture was
UHÀX[HGꢀIRUꢀꢍꢀKꢀꢊ7/&ꢄꢂꢀ7KHꢀUHDFWLRQꢀPL[WXUHꢀWKHQꢀSRXUHGꢀRQWRꢀFUXVKHGꢀ
LFHꢀ FRQWDLQLQJꢀ DFHWLFꢀ DFLGꢂꢀ 7KHꢀ VROLGꢀ WKDWꢀ VHSDUDWHGꢀ ZDVꢀ ¿OWHUHGꢀ
off, dried and recrystallised from light petroleum ether (b.p. 80–
100°C) to give 11 as yellow crystals (63%), m.p. 102–104°C. IR:
Qmax 3270 (NH), 1730 (CO unsaturated G-lactone), 1710 (CO ester),
1670 cm-1 (CO amide). NMR (CDCl3): GH 8.7 (s, 1H, NH), 8.18–6.82
(m, 11Har), 4.8 (s, 1H, C4-H), 3.91 (s, 3H, OMe). EI MS: m/z (%) 473
(M+, 10), 280 (77), 279 (82), 250 (64), 121(26), 92 (100), 64 (48).
Anal. Calcd for C26H19NO8 (473.41): C, 65.96; H, 4.04; N, 2.95.
Found: C, 66.10; H, 4.0; N, 3.2%.
Hydrazinolysis of ester 9a; formation of 12 and 13: A solution
of 9a with hydrazine hydrate (80%) in molar ratio 1:3 in absolute
HWKDQROꢀꢊꢏꢈꢀPOꢄꢀZDVꢀKHDWHGꢀXQGHUꢀUHÀX[ꢀIRUꢀꢎꢀKꢀꢊ7/&ꢄꢂꢀ(YDSRUDWLRQꢀ
of the excess solvent left a crude solid product (two spots in TLC)
ZKLFKꢀWULWXUDWHGꢀZLWKꢀGLHWK\OꢀHWKHUꢂꢀ7KHꢀUHVLGXHꢀZDVꢀ¿OWHUHGꢀRIIꢉꢀGULHGꢀ
and recrystallised from ethanol to give salicylic acid hydrazide 12.
Evaporation of ether left a solid product which recrystallised from
acetic acid to give 13.
3-(5-Amino-3-oxopyrazolin-4-yl)-3(4-methoxyphenyl)propanoyl
hydrazide (13):Yellowish-white crystals (41%), m.p. 156–158°C. IR:
Qmax 3462, 3376, 3290, 3176 (NH2), 1680 cm-1 (CO). NMR (CDCl3):
GH 8.3 (s, 2H, 2NH, exchangeable with D2O), 7.1–6.7 (m, 4Har), 4.9
NHNH2
174.6
34.8
O
NH2
98.3
131.1
104.2
120.3
56.7
NH
55.4
173.8
159.3
129
NH
O
O
13C NMR of compound 13

JOURNAL OF CHEMICAL RESEARCH 2009 45
10 F.M. Dean, Naturally occurring oxygen ring compounds, Butterworths,
London, 1963.
11 A. Mustafa, Furopyrans and furopyrones, Wiley Interscience, New York,
1967.
12 F.F. Abdel-Latif, Indian J. Chem., 1990, 29B, 664.
13 F.F. Abdel-Latif, M.M. Mashaly, R. Mekheimer and T.B. Abdel-Aleem,
Z. Naturforsch., 1993, 48b, 817.
14 F.F. Abdel-Latif and R.M. Shaker, Bull. Soc. Chim. Fr, 1991, 127, 87.
15 R.M. Shaker, Pharmazie, 1996, 51, 148.
16 M.R. Mahmoud, E.A.A. El-Bordany, N.F. Hassan and F.S.M. Abu El-
Azm, J. Chem. Res., 2007, 541.
(t, Ha, Jac 5.99 Hz, Jab 6.8 Hz), 3.9 (s, 3H, OMe), 3.3 (d,d, Hc, Jcb 16.8
Hz, Jac 7.1 Hz), 3.1 (d,d, Hb, Jbc 17.2 Hz, Jba 6.6 Hz), 2.2 (br.s, 5H,
exchangeable with D2O). EI MS: m/z (%) 263 (M+-N2, 100), 260 (67),
232 (17), 185 (22), 77 (80). Anal. Calcd for C13H17N5O3 (291.29): C,
53.6; H, 5.87; N, 24.04. Found: C, 53.92; H, 5.41; N, 23.74%.
Received 13 May 2008; accepted 16 November 2008
Paper 08/5280 doi:10.3184/030823409X393727
Published online: 23 January 2009
17 M.R. Mahmoud, E.A.A. El-Bordany, N.F. Hassan and F.S.M. Abu El-
Azm, J. P,S,Si and Relat. Elem., 2007, 181, 1275.
18 M.R. Mahmoud, H.M.F. Madkour, E.A.A. El-Bordany and E.A. Soliman,
J. Chem. Res., 2007, 673.
19 M.R. Mahmoud, M.M. El-Shahawi and S.E. Farahat, J. Chem. Res.,
2008, 86.
20 M.R. Mahmoud, M.M. El-Shahawi and S.E. Farahat, J. Chem. Res.,
2008, 59.
21 A. Sammour, M. Abdalla and M. El-Kady, Acta Chim. Acad. Sci. Hung.,
1974, 82, 369.
22 D.H. Williams and I. Fleming, Spectroscopic methods in organic
chemistry, Mc Graw-Hill, 3rd edn, 1980.
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8
9