Synthesis of certain novel 4H-pyrano[3,2-h]quinoline derivatives

Article abstract of DOI:10.3998/ark.5550190.0012.b12

Treatment of 8-hydroxyquinoline 1a and 8-hydroxy-2-methylquinoline 1b with α-cyano-pchloro/bromocinnamonitriles 2a,b provided 4H-pyrano[3,2-h] quinoline-3-carbonitrile derivatives 3a-d, while treatment of (E) 2-(4-chlorostyryl)-8-hydroxyquinoline 7 with α

Full text of DOI:10.3998/ark.5550190.0012.b12

General Papers
ARKIVOC 2011 (xi) 134-146
Synthesis of certain novel 4H-pyrano[3,2-h]quinoline derivatives
Ahmed M. El-Agrody * and Abdullah M. Al-Ghamdi
Chemistry Department, Faculty of Scinece, King Khalid University, 9004, Abha, Saudi Arabia
E-mail: elagrody_am@yahoo.com
DOI: http://dx.doi.org/10.3998/ark.5550190.0012.b12
Abstract
Treatment of 8-hydroxyquinoline 1a and 8-hydroxy-2-methylquinoline 1b with α-cyano-p-
chloro/bromocinnamonitriles 2a,b provided 4H-pyrano[3,2-h]quinoline-3-carbonitrile derivati-
ves 3a-d, while treatment of (E) 2-(4-chlorostyryl)-8-hydroxyquinoline 7 with α-cyano-p-
chloro/bromocinnamonitriles 2a,b and ethyl α-cyano-p-chloro/bromocinnamates 2d,e provided
4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives 8a,b and ethyl 4H-pyrano[3,2-h]quinoline-
3-carboxylate derivatives 9a,b respectively. Interaction of 8-hydroxyquinoline 1a and 8-
hydroxy-2-methylquinoline 1b with α-cyano-p-fluorocinnamonitrile 2c afforded 2-[4-(piperidin-
1-yl)benzylidene]malononitrile 5 via a nucleophilic aromatic substitution reaction. The reactivity
of 2-hydroxyquinoline and its 2-substituted derivatives towards α-cyano-p-chloro/bromo-
cinnamonitriles and ethyl α-cyano-p-chloro/bromocinnamates are discussed in this work.
1
13
13
Structures of these compounds were established on the basis of IR, H NMR, C NMR, C
NMR-DEPT and MS data.
Keywords: 8-Hydroxyquinoline, 8-hydroxy-2-methylquinoline, (E) 2-(4-chlorostyryl)-8-
hydroxyquinoline, α-cyano-p-halocinnamonitriles/ethyl α-cyano-p-halocinnamates, 4H-pyrano-
[3,2-h]quinoline derivatives, 2-[4-(piperidin-1-yl)benzylidene]malononitrile
Introduction
1
Quinoline moiety is present in many classes of biologically active compounds . The biological
activity of these quinoline derivatives depends not only on the bicyclic hetero-aromatic
pharmacophore but also on the nature of the peripheral substituent and their spatial relationship.
2
3
4
5
They also exhibit antimalarial , antitumor , antioxidant , antileishmanial and antiplatelet
6
7
activities . In addition they function as pharmacologically active synthetic compounds such as
DNA binding capabilities 8 and DNA-intercalating carrier 9. A series of compounds derived from
8-hydroxyquinoline as potential HIV-1 integrate inhibitors were synthesized recently 10. In
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ARKIVOC 2011 (xi) 134-146
addition styrylquinoline derivatives have gained strong attention recently due to their activities
as perspective HIV integrase inhibitors 11 and also, for their extensive biological activities.1b-d, 11c
In continuation of the previous works 12-26, it seemed interesting to synthesize new 4H-
pyrano[3,2-h]quinoline derivatives by using α-cyano-p-halocinnamonitriles and ethyl α-cyano-
p-halocinnamates and evaluatation of their antimicrobial and antitumor activities. The
observation of the reactivity of 2-hydroxyquinoline and its 2-substitued derivatives towards α-
cyano-p-halocinnamonitriles and ethyl α-cyano-p-halocinnamates are discussed in this work.
Results and Discussion
Treatment of 8-hydroxyquinoline 1a and 8-hydroxy-2-methylquinoline 1b with α-cyano-p-
chloro/bromocinnamonitrile 2a,b in ethanolic piperidine under reflux afforded 2-amino-4-(4-
chloro/bromophenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile 3a,b and 2-amino-4-(4-chloro-
/bromophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile 3c,d, while treatment of 1a,b
with ethyl α-cyano-p-chloro/bromo/fluorocinnamate 2d-f in ethanolic piperidine under reflux
were unsuccessful, ethyl 2-amino-4-(4-halophenyl)-4H-pyrano[3,2-h]quinoline-3-carboxylate
4a-c and 2-amino-4-(4-halophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-carboxylate 4d-f
were not formed 27 (Scheme 1).
R
9
10
8
7
N
1
O
NH2
CN
2
3
6a
6
a, R = H
b, R = H
c, R = CH3 Ar = p-ClC6H4
d, R = CH3 Ar = p-BrC6H4
Ar = p-ClC6H4
Ar = p-BrC6H4
OH
60 min.
2a,b
4a
4
5
R
N
CN
EtOH
piperidin
Ar
3a-d
+
Ar-C
H=C
R
X
X
e
reflux
2d-f
1a,b
2a-f
N
a, Ar = p-ClC6H4 X = CN
b, Ar = p-BrC6H4 X = CN
c, Ar = p-FC6H4 X = CN
d, Ar = p-ClC6H4 X = CO2Et
e, Ar = p-BrC6H4 X = CO2Et
f, Ar = p-FC6H4 X = CO2Et
O
NH2
CO2Et
a, R = H
b, R = CH3
a, R = H
b, R = H
c, R = H
d, R = CH3 Ar = p-ClC6H4
e, R = CH3 Ar = p-BrC6H4
f, R = CH3 Ar = p-FC6H4
Ar = p-ClC6H4
Ar = p-BrC6H4
Ar = p-FC6H4
Ar
4a-f
Scheme 1. Synthesis of 4H-pyrano[3,2-h]quinoline derivatives 3a-d.
The formation of 3 indicates that the phenolate anion (C-7) of 1a and 1b attacks at the β-
carbon of 2 to yield an acyclic Michael adduct, which underwent cyclization as shown in
(Scheme 2) to give 3.
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Scheme 2. Mechanism formation of compounds 3.
Furthermore, reaction of 1a,b with α-cyano-p-fluorocinnamonitrile 2c afforded 2-[4-
(piperidin-1-yl)benzylidene]malononitrile 5 instead of the formation of 2-amino-4-(4-
fluorophenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile 3e and the 2-amino-4-(4-fluorophenyl)-
9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile 3f. In the case of compound 5 the fluorine
atom of 2c had simply been displaced by piperidine 28-31 via a nucleophilic aromatic substitution
reaction (Scheme 3). Attempts to react 1a,b with 5 was unsuccessful, 2-amino-4-(4-piperidin-1-
ylphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile 3g and 2-amino-4-(4-piperidin-1-ylphenyl)-
9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile 3h were not formed 28 (Scheme 3).
Scheme 3. Synthesis of 2-[4-(piperidin-1-yl)-benzylidene]malononitrile.
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Structure of 5 was also supported by an independent synthesis of the same compound by
28
nucleophilic substitution of the fluorine atom of 2c with piperidine in ethanol under reflux
(m.p. and mixed m.p.) (Scheme 3).
Structure 3 was established on the basis of spectral data. The IR spectra of 3a-d showed the
presence of a NH2 stretch at υ 3464-3395, 3344-3310 cm-1 and a CN stretch at υ 2196-2188 cm-1.
NMR spectra of 3a-d showed characteristic signals for 4H-pyran: singlets at δ 4.98-4.82 ppm in
1
13
the H NMR and 41.51-40.46 ppm in the C NMR. The mass spectra of compounds 3a-d gave
additional evidences for the proposed structures.
Condensation of 8-hydroxy-2-methylquinoline 1b with p-chlorobenzaldehyde in acetic
anhydride under reflux give (E) 2-(4-chlorostyryl)-8-hydroxyquinoline 7 via the intermediate (E)
8-acetoxy-2-(4-chlorostyryl)quinoline 6, while condensation of 1b with p-chlorobenzaldehyde
under Microwave irradiation furnished 7 1f,g (Scheme 4).
The relative (E) configuration of compounds 6 and 7 were established from the coupling
constant values (J = 17 Hz) for 6 and (J = 16 Hz) for 7.
Scheme 4. Preparation of (E) 8-acetoxy-2-(4-chlorostyryl)quinoline 6 and (E) 8-hydroxy-2-(4-
chlorostyryl)quinoline 7.
The structures of 6 and 7 were established on the basis of spectral data. The IR spectra of 6
showed the presence of a CO stretch at υ 1760 cm,-1 while for 7 showed the appearance of a OH
1
13
stretch at υ 3349 cm.-1 The H and C NMR spectra of 6 revealed the presence of signals at δ
7.63 (d, J = 17 Hz, 1H, =CH), 7.47 (d, J = 17 Hz, 1H, =CH), 2.60 ppm (s, 3H, COCH3) and
134.42 (=CH), 129.35 (=CH), 21.06 ppm (CH3). The 13C NMR-DEPT spectrum at 45°, 90° and
13
135° of 6 provided additional evidence in support of the proposed structure. The C NMR-
DEPT spectrum of 6 at δ 135о CH, CH3 [positive (up)], CH2 [negative (down)], revealed the
following signals at δ 134.42 (=CH ↑), 129.35 (=CH ↑), 21.06 (CH3 ↑), while at 90° only CH
signals are positive (up) and showed at δ 134.42 (=CH ↑), 129.35 (=CH ↑) and at 45° (CH, CH2
and CH3 positive) revealed signals at δ 134.42 (=CH ↑), 129.35 (=CH ↑), 21.06 (CH3 ↑).
Characteristic resonances were observed at δ 9.85 (bs, 1H, OH), 8.14 (d, J = 16 Hz, 1H, =CH),
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7.51 ppm (d, J = 16 Hz, 1H, =CH) and 135.15 (=CH), 131.62 ppm (=CH) for 7. The mass
spectra of compounds 6 and 7 gave additional evidences for the proposed structures.
Treatment of (E) 2-(4-chlorostyryl)-8-hydroxyquinoline 7 with 2a,b,d,e in ethanolic
piperidine under reflux afforded (E) 2-amino-4-(4-chloro/bromophenyl)-9-(4-chlorostyryl)-4H-
pyrano[3,2-h]quinoline-3-carbonitrile 8a,b and ethyl (E) 2-amino-4-(4-chloro/bromophenyl)-9-
(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3-carboxylate 9a,b respectively (Scheme 5).
The relative (E) configuration of compounds 8 and 9 were established from the coupling
constant values (J = 16.5 Hz) for 8a,9a and (J = 16 Hz) for 8b,9b.
Ar1
N
O
NH2
CN
15 min.
2a,b
CN
X
Ar
EtOH
8a,b
Ar1
Ar-CH=C
+
piperdine
reflux
N
Ar1
2d,e
30 min.
2a,b,d,e
OH
7
N
a, Ar = p-ClC6H4
b, Ar = p-BrC6H4
d, Ar = p-ClC6H4
e, Ar = p-BrC6H4
X = CN
X = CN
X = CO2Et
X = CO2Et
Ar1 = p-ClC6H4
O
NH
CO
Ar
9a,b
Scheme 5. Synthesis of 9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline derivatives 8a,b and 9a,b.
The structures 8 and 9 were established on the basis of spectral data. The IR spectra of 8a,b
showed the appearance of the a NH2 stretch at υ 3417-3384, 3315-3310, 3199-3182 cm,-1 a CN
stretch at υ 2198-2189 cm,-1 while a NH2 stretch at υ 3409-3380, 3349-3296 cm-1 and a CO
1
13
stretch at υ 1677-1643 cm-1 for 9a,b. The H and C NMR spectra of 8a,b and 9a,b revealed
the presence of 4H signals at δ 5.09-5.00 (s, 1H, H-4) and 40.71-40.09 ppm (C-4). In compounds
9a,b the ester group gave 1H signals at 4.13-4.01 (q, J = 7 Hz, 2H, CH2), 1.22-1.10 (t, J = 7 Hz,
13
3H, CH3) with the corresponding signals in the C spectra at δ 59.59-58.75 (CH2) and 14.39-
14.27 ppm (CH3) respectively. The 13C NMR-DEPT spectra at 45°, 90° and 135° of compounds
8a,b provided additional evidence in support of the proposed structures. Also,t he mass spectra
of compounds 8 and 9 gave additional evidences for the proposed structures.
From the experimental observations (reaction time and yield), the authors pointed out that,
the tendency of the 8-hydroxyquinoline 1a and 2-substituted-8-hydroxyquinoline 1b,7 towards
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the electrophilic β-carbon of α-cyano-p-chloro/bromocinnamonitriles 2a,b and ethyl α-cyano-p-
chloro/bromocinnamates 2d,e follows the following sequence:
8-Hydroxy-2-styrylquinoline > 8-hydroxyquinoline > 8-hydroxy-2-methylquinoline
Thus, the reactivity was enhanced with the presence of the styryl group in the 2-position and
deactivated with the methyl group in the 2-position and this was explained through the
mesomeric effect between the quinoline-N and the hydroxyl group in the 8-position as shown in
(Scheme 6).
Scheme 6. The reactivity of (E) 2-(4-chlorostyryl)-8-hydroxyquinoline 7.
Also, this observation was supported by the easy attacks of phenolate anion (C-7) of 7 at the
β-carbon of ethyl α-cyano-p-chloro/bromocinnamates 2d,e rather than 1a and 1b to yield an
acyclic Michael adduct, which underwent cyclization to give 9.
Conclusions
In this paper we report the synthesis of some 4H-pyrano[3,2-h]quinoline derivatives 3a-d, 8a,b
and 9a,b via interaction of 8-hydroxyquinoline 1a and 2-substituted-8-hydroxyquinoline 1b,7
with α-cyano-p-chloro/bromocinnamonitriles 2a,b and ethyl α-cyano-p-chloro/bromo-
cinnamates 2d,e. The tendency of the 8-hydroxyquinoline and 2-substituted-8-hydroxyquinoline
towards the electrophilic β-carbon of α-cyano-p-chloro/bromocinnamonitriles and ethyl α-cyano-
p-chloro/bromocinnamates illustrated that the order of reactivity of 8-hydroxyquinoline 1a and
2-substituted-8-hydroxyquinoline 1b,7 follows the following sequence:
8-Hydroxy-2-styrylquinoline > 8-hydroxyquinoline > 8-hydroxy-2-methylquinoline
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This is can be explained through the mesomeric effect between the quinoline-N and the hydroxyl
group in the 8-position.
Experimental Section
General. Melting points were determined with a Stuart Scientific Co. Ltd apparatus. IR spectra
1
were determined as KBr pellets on a Jasco FT/IR 460 plus spectrophotometer. H NMR and 13C
NMR spectra were recorded on using a Bruker AV 500 MHz spectrometer using
tetramethylsilane (TMS) as an internal reference and results are expressed as δ (ppm) values. 13C
NMR spectra were obtained using distortionless enhancement by polarization transfer (DEPT),
with this technique, the signals of CH & CH3 carbon atoms appears normal (up) and the signal of
carbon atoms in CH2 environments appears negative (down). The MS were measured on a
Shimadzu GC/MS-QP5050A spectrometer. Elemental analyses for C, H and N were performed
on a Perkin-Elmer 240 microanalyser in the Faculty of Science Cairo University.
General procedure for the preparation of 4H-pyrano[3,2-h]quinoline derivatives (3a-d) and
2-[4-(piperidin-1-yl)benzylidene]malononitrile (5)
A solution of 8-hydroxyquinoline 1a or 8-hydroxy-2-methylquinoline 1b (0.01 mmol) in EtOH
(30 ml) was treated with α-cyano-p-chloro/bromo/fluorocinnamonitriles 2a-c (0.01 mmol) and
piperidine (0.5 ml). The reaction mixture was heated until complete precipitation occurred
(reaction times: 60 min.). The solid product which formed was collected by filtration and
recrystallised from benzene for compounds 3a-d and from ethanol for compound 5. The physical
and spectral data of compounds 3a-d and 5 are as follows:
2-Amino-4-(4-chlorophenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile (3a). Buff needles,
ο
27
yield 83%, m.p. 249-250 C; [Lit. M.p. 223-224 οC] ; IR (KBr) υ (cm-1): 3409, 3310, (NH2),
1
3060, 2972, 2870 (CH), 2190 (CN); H NMR (500 MHz, DMSO-d6) δH: 8.95-7.16 (m, 9H,
aromatic), 5.00 (bs, 2H, NH2), 4.98 (s, 1H, H-4); 13C NMR (125 MHz, DMSO-d6) δc: 160.33 (C-
2), 150.24 (C-10b), 144.52 (C-9), 137.46 (C-10a), 135.97 (C-7), 128.71 (C-5), 127.75 (C-6a),
123.66 (C-4a), 122.18 (C-8), 121.35 (C-6), 120.35 (CN), 55.66 (C-3), 40.64 (C-4), 143.01,
131.68, 129.57, 126.73 (aromatic); Anal. Calcd for C19H12ClN3O: C, 68.37; H, 3.62; N, 12.59.
Found: C, 68.29; H, 3.56; N, 12.48 %.
2-Amino-4-(4-bromophenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile (3b). Pale yellow
ο
needles, yield 81%; m.p. 230-231 C; IR (KBr) υ (cm-1): 3395, 3320, (NH2), 3060, 3020, 2962,
1
2861 (CH), 2196 (CN); H NMR (500 MHz, CDCl3) δH: 9.00-7.09 (m, 9H, aromatic), 5.22 (bs,
13
2H, NH2), 4.89 (s, 1H, H-4); C NMR (125 MHz) (CDCl3) δc: 159.44 (C-2), 150.57 (C-10b),
143.39 (C-9), 137.92 (C-10a), 136.31 (C-7), 128.35 (C-5), 127.07 (C-6a), 122.18 (C-4a), 121.62
(C-8), 121.17 (C-6), 119.45 (CN), 59.85 (C-3), 41.28 (C-4), 143.22, 132.14, 129.85, 124.02
(aromatic); MS m/z (%): 379 [M++2] (7), 377 [M]+ (7), 222 (100), 155 (43), 113 (13), 75 (59);
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Anal. Calcd for C19H12BrN3O: C, 60.34; H, 3.20; N, 11.11. Found: C, 60.26; H, 3.18; N, 11.03
%.
2-Amino-4-(4-chlorophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile
(3c).
Colourless needles, yield 78%; m.p. 262-263 C; IR (KBr) υ (cm-1): 3464, 3343 (NH2), 3056,
2900, 2870 (CH), 2188 (CN); 1H NMR (500 MHz, CDCl3) δH: 8.00-6.94 (m, 8H, aromatic), 4.98
(bs, 2H, NH2), 4.82 (s, 1H, H-4), 2.74 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3) δc: 159.94 (C-
2), 159.46 (C-9), 142.95 (C-10b), 137.61 (C-10a), 136.20 (C-7), 129.13 (C-5), 125.96 (C-6a),
123.85 (C-8), 123.08 (C-4a), 121.08 (C-6), 119.56 (CN), 60.13 (C-3), 41.20 (C-4), 25.62 (CH3),
142.90, 133.36, 129.40, 126.59 (aromatic); MS m/z (%): 349 [M++2] (5), 347 [M]+ (15), 236
(100), 208 (5), 180 (2), 124 (4), 98 (2), 75 (19); Anal. Calcd for C20H14ClN3O: C, 69.07; H, 4.06;
N, 12.08. Found: C, 69.14; H, 4.14; N, 12.15 %.
ο
2-Amino-4-(4-bromophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile
(3d).
ο
Colourless needles, yield 75%; m.p. 277-278 C; IR (KBr) υ (cm-1): 3464, 3344 (NH2), 3079,
1
3059, 2950, 2870 (CH), 2188 (CN); H NMR (500 MHz, DMSO-d6) δH: 8.21-7.10 (m, 8H,
aromatic), 7.18 (bs, 2H, NH2), 4.97 (s, 1H, H-4), 2.70 (s, 3H, CH3); 13C NMR (125 MHz,
DMSO-d6) δc: 160.32 (C-2), 159.08 (C-9), 145.13 (C-10b), 137.01 (C-10a), 136.10 (C-7),
130.77 (C-5), 129.89 (C-6a), 126.12 (C-8), 125.75 (C-4a), 121.32 (C-6), 120.10 (CN), 142.59,
132.06, 131.62, 123.50 (aromatic), 55.66 (C-3), 41.51 (C-4), 24.96 (CH3); MS m/z (%): 393
[M++2] (11), 391 [M]+ (11), 236 (100), 208 (6), 180 (1), 124 (5), 99 (2), 77 (6); Anal. Calcd for
C20H14BrN3O: C, 61.24; H, 3.60; N, 10.71. Found: C, 61.21; H, 3.56; N, 10.68 %.
2-[4-(Piperidin-1-yl)benzylidene]malononitrile (5). Orange crystals, yield 76%; m.p. 122-123
οC; [Lit. M.p. 120-121 οC] 28; IR (KBr) υ (cm-1): 3070, 3027, 2990, 2941, 2860 (CH), 2215 (CN);
1H NMR (500 MHz, CDCl3) δH: 7.45 (s, 1H, (=CH), 7.91-6.85 (m, 4H, aromatic), 3.53-3.51 (m,
13
4H, 2CH2), 1.76-1.67 (m, 6H, 3CH2); C NMR (125 MHz, CDCl3) δc: 157.78 (=CH), 115.98
(CN), 154.43, 134.00, 112.96 (aromatic), 72.14 (C-2), 48.03, 25.40, 24.30 (piperidine); Anal.
Calcd for C15H15N3: C, 75.92; H, 6.37; N, 17.71. Found: C, 76.00; H, 6.42; N, 17.84 %.
Preparation of 2-[4-(piperidin-1-yl)benzylidene]malononitrile (5) from α-cyano-p-fluoro-
cinnamonitriles (2c). This compound was prepared according to the literature procedure 28.
Reaction of 8-hydroxy-2-methylquinoline (1b) with p-chlorobenzaldehyde
Method A. A mixture of 8-hydroxy-2-methylquinoline 1b (0.01 mmol), p-chlorobenzaldehyde,
о
(0.08 mmol) and acetic anhydride (100 ml) was heated at 150 C for 30 h (TLC monitoring).
After cooling, the solvent was removed in vacuum, and the residue was recrystallised from
о
ethanol/benzene to give 6. Compound 6 was heated at 100 C for 1 h (TLC monitoring) in
pyridine/water (v/v = 4:1) (100 ml). After cooling, the solvent was removed in vacuum to
provide the crude product which recrystallised from ethanol to give 7. The physical and spectral
data of compounds 6 and 7 are as follows:
(E) 8-Acetoxy-2-(4-chlorostyryl)quinoline (6). Pale yellow crystals, yield 41%; m.p. 100-101
1
οC; IR (KBr) υ (cm-1): 3090, 3050, 3010, 2942, 2961 (CH), 1760 (CO); H NMR (500 MHz,
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CDCl3) δH: 8.12-7.38 (m, 9H, aromatic), 7.63 (d, J = 17 Hz, 1H, =CH), 7.47 (d, J = 17 Hz, 1H,
=CH), 2.60 (s, 3H, COCH3); 13C NMR (125 MHz, CDCl3) δc: 169.83 (CO), 155.45 (C-2),
147.35 (C-8), 140.87 (C-1a), 136.53 (C-4), 134.42 (=CH), 129.35 (=CH), 128.63 (C-4a), 125.88
(C-6), 125.57 (C-5), 121.78 (C-7), 120.20 (C-3), 21.06 (CH3), 134.96, 133.47, 129.01, 128.57
(aromatic); 13 C NMR-DEPT spectrum at 135о CH, CH3 [positive (up)], CH2 [negative (down)],
revealed the following signals at δc: 136.53 (C-4 ↑), 134.42 (=CH ↑), 129.35 (=CH ↑), 129.01
(aromatic ↑), 128.57 (aromatic ↑), 125.88 (C-6 ↑), 125.57 (C-5 ↑), 121.78 (C-7 ↑), 120.20 (C-3
↑), 21.06 (CH3 ↑). In the DEPT spectrum at 90° only CH signals are positive (up) and showed δc:
136.53 (C-4 ↑), 134.42 (=CH ↑), 129.35 (=CH ↑), 129.01 (aromatic ↑), 128.57 (aromatic ↑),
125.88 (C-6 ↑), 125.57 (C-5 ↑), 121.78 (C-7 ↑), 120.20 (C-3 ↑). In the DEPT spectrum at 45°
(CH, CH2 and CH3 positive) revealed signals at δc: 136.53 (C-4 ↑), 134.42 (=CH ↑), 129.35
(=CH ↑), 129.01 (aromatic ↑), 128.57 (aromatic ↑), 125.88 (C-6 ↑), 125.57 (C-5 ↑), 121.78 (C-7
↑), 120.20 (C-3 ↑), 21.06 (CH3 ↑); MS m/z (%): 325 [M++2], (0.3), 323 [M]+, (1), 283 [M]+ (11),
281 [M++2] (33), 280 (100), 170 (3), 144 (4), 113 (44), 74 (54), 50 (72); Anal. Calcd for
C19H14ClNO2: C, 70.48; H, 4.36; N, 4.33. Found: C, 70.49; H, 4.39; N, 4.36 %.
(E) 2-(4-Chlorostyryl)-8-hydroxyquinoline (7). Yellow needles, yield 34%; m.p. 142-143 οC;
1
[Lit. m.p. 150 οC] 1f,g; IR (KBr) υ (cm-1): 3349 (OH), 3050, 3020, 2972, 2865 (CH); H NMR
(500 MHz, CDCl3) δH: 9.85 (bs, 1H, OH), 8.32-7.12 (m, 9H, aromatic), 8.14 (d, J = 16 Hz, 1H,
=CH), 7.51 (d, J = 16. Hz, 1H, =CH); 13C NMR (125 MHz, CDCl3) δc: 160.25 (C-2), 153.10 (C-
8), 138.12 (C-1a), 136.54 (C-4), 135.15 (=CH), 131.62 (=CH), 129.58 (C-4a), 127.72 (C-6),
121.04 (C-3), 117.55 (C-5), 111.21 (C-7), 135.44, 133.18, 128.96, 128.91 (aromatic); MS m/z
(%): 283 [M++2] (32), 281 [M]+ (100), 170 (2), 144 (4), 113 (31), 74 (18), 50 (31); Anal. Calcd
for C17H12ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C, 72.50; H, 4.31; N, 4.99 %.
Method B. 8-Hydroxy-2-methylquinoline 1b (0.01 mmol) and p-chlorobenzaldehyde (0.02
mmol) were mixed thoroughly using mortar and put in an open vessel. Then the mixture was
exposed to Microwave irradiation for 4 min. The oven was operated at 70% power (560W) in a
two step mode with interval (2 min-30s-2 min). After the reaction, the mixture was allowed to
cool down and Et2O (10 ml) was added. The crude product was filtered, washed with Et2O (15
ml) and purified by recrystallization from ethanol to give 7 (m.p. and mixed m.p.) yield 40%;
(Lit. m.p. 150 οC)1f,g
General procedure for the preparation of 9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline
derivatives (8a,b and 9a,b)
A solution of (E) 2-(4-chlorostyryl)-8-hydroxyquinoline 7 (0.01 mmol) in EtOH (30 ml) was
treated with α-cyano-p-chloro/bromocinnamonitrile 2a,b (0.01 mmol) or ethyl α-cyano-p-
chloro/bromocinnamate 2d,e (0.01 mmol) and piperidine (0.5 ml). The reaction mixture was
heated until complete precipitation occurred (reaction times: 15 min. for 2a,b and 30 min. for
2d,e). The solid product which formed was collected by filtration and recrystallised from
benzene or ethanol to give 8a,b and 9a,b. The physical and spectral data of compounds 8a,b and
9a,b are as follows:
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(E) 2-Amino-4-(4-chlorophenyl)-9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3-carbonit-
rile (8a). Pale yellow needles, yield 91%; m.p. 244-245 οC; IR (KBr) υ (cm-1): 3417, 3310, 3182
(NH2), 3070, 3040, 2950, 2872 (CH), 2189 (CN); 1H NMR (500 MHz, DMSO-d6) δH: 8.34-7.14
(m, 12H, aromatic), 8.00 (d, J = 16.5 Hz, 1H, =CH), 7.52 (d, J = 16.5 Hz, 1H, =CH), 7.21 (bs,
13
2H, NH2 cancelled by D2O), 5.01 (s, 1H, H-4); C NMR (125 MHz, DMSO-d6) δc: 160.25 (C-
2), 155.13(C-9), 144.59 (C-10b), 137.44 (C-10a), 136.53 (C-7), 133.18 (=CH), 128.95 (=CH),
128.72 (C-5), 126.89 (C-6a), 123.41 (C-8), 121.72 (C-4a), 121.00 (C-6), 120.28 (CN), 56.00 (C-
13
3), 40.42 (C-4), 142.82, 135.15, 133.42, 131.26, 129.57, 128.89, 126.34 (aromatic); C NMR-
DEPT spectrum at 135о CH, CH3 [positive (up)], CH2 [negative (down)], revealed the following
signals at δc: 136.53 (C-7 ↑), 133.42 (aromatic ↑), 133.18 (=CH ↑), 129.57 (aromatic ↑), 128.95
(=CH ↑), 128.89 (aromatic ↑), 128.72 (C-5 ↑), 126.34, (aromatic ↑), 123.41 (C-8 ↑), 121.00 (C-6
↑), 40.42 (C-4 ↑). In the DEPT spectrum at 90° only CH signals are positive (up) and showed δc:
136.53 (C-7 ↑), 133.42 (aromatic ↑), 133.18 (=CH ↑), 129.57 (aromatic ↑), 128.95 (=CH ↑),
128.89 (aromatic ↑), 128.72 (C-5 ↑), 126.34, (aromatic ↑), 123.41 (C-8 ↑), 121.00 (C-6 ↑), 40.42
(C-4 ↑). In the DEPT spectrum at 45° (CH, CH2 and CH3 positive) revealed signals at δc: 136.53
(C-7 ↑), 133.42 (aromatic ↑), 133.18 (=CH ↑), 129.57 (aromatic ↑), 128.95 (=CH ↑), 128.89
(aromatic ↑), 128.72 (C-5 ↑), 126.34, (aromatic ↑), 123.41 (C-8 ↑), 121.00 (C-6 ↑), 40.42 (C-4
↑); MS m/z (%): 473 [M++4] (2.71), 471 [M++2] (18.51), 469 [M]+ (28.91), 360 [M++2] (30.97),
358 [M]+ (93.49), 247 (3), 221(3), 166 (29), 126 (68), 74 (100), 50 (75); Anal. Calcd for
C27H17Cl2N3O: C, 68.95; H, 3.64; N, 8.93. Found: C, 69.01; H, 3.69; N, 8.99 %.
(E) 2-Amino-4-(4-bromophenyl)-9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3-carbonit-
rile (8b). Pale yellow needles, yield 90%; m.p. 254-255 οC; IR (KBr) υ (cm-1): 3384, 3315, 3199
(NH2), 3080, 3050, 2968, 2872 (CH), 2198 (CN); 1H NMR (500 MHz, DMSO-d6) δH: 8.34-7.14
(m, 12H, aromatic), 8.00 (d, J = 16 Hz, 1H, =CH), 7.53 (d, J = 16 Hz, 1H, =CH), 7.21 (bs, 2H,
13
NH2, cancelled by D2O), 5.00 (s, 1H, H-4); C NMR (125 MHz, DMSO-d6) δc: 160.25 (C-2),
155.14 (C-9), 145.00 (C-10b), 137.43, (C-10a), 136.53 (C-7), 133.43 (=CH), 128.95 (=CH),
126.89 (C-6a), 126.33 (C-5), 121.65 (C-4a), 123.41 (C-6), 121.00 (C-8), 120.15 (CN), 56.01 (C-
3), 40.50 (C-4), 142.82, 135.15, 133.19, 131.64, 129.94, 128.89, 128.29, 120.28 (aromatic); 13 C
NMR-DEPT spectrum at 135о CH, CH3 [positive (up)], CH2 [negative (down)], revealed the
following signals at δc: 136.53 (C-7 ↑), 133.43 (=CH ↑), 131.64 (aromatic ↑), 129.94 (aromatic
↑), 128.89 (aromatic ↑), 128.29 (aromatic ↑), 128.95 (=CH ↑), 126.33 (C-5 ↑), 123.41 (C-6 ↑),
121.00 (C-8 ↑), 40.50 (C-4 ↑). In the DEPT spectrum at 90° only CH signals are positive (up)
and showed δc: 136.53 (C-7 ↑), 133.43 (=CH ↑), 131.64 (aromatic ↑), 129.94 (aromatic ↑),
128.89 (aromatic ↑), 128.29 (aromatic ↑), 128.95 (=CH ↑), 126.33 (C-5 ↑), 123.41 (C-6 ↑),
121.00 (C-8 ↑), 40.50 (C-4 ↑). In the DEPT spectrum at 45° (CH, CH2 and CH3 positive)
revealed signals at δc: 136.53 (C-7 ↑), 133.43 (=CH ↑), 131.64 (aromatic ↑), 129.94 (aromatic
↑), 128.89 (aromatic ↑), 128.29 (aromatic ↑), 128.95 (=CH ↑), 126.33 (C-5 ↑), 123.41 (C-6 ↑),
121.00 (C-8 ↑), 40.50 (C-4 ↑); MS m/z (%): 517 [M++4] (1.55), 515 [M++2] (5.95), 513 [M]+
(4.55), 360 [M++2] (33.42), 358 [M]+ (100), 221 (2), 166 (19), 101 (26), 75 (70), 50 (42); Anal.
Calcd for C27H17BrClN3O: C, 62.99; H, 3.33; N, 8.16. Found: C, 63.02; H, 3.35; N, 8.19 %.
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(E) Ethyl 2-amino-4-(4-chlorophenyl)-9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3-
ο
carboxylate (9a). Colourless needles, from ethanol; m.p. 192-193 C; 82%; IR (KBr) υ (cm-1):
3409, 3296 (NH2), 3050, 3035, 2980, 2930, 2900 (CH), 1677 (CO); 1H NMR (500 MHz, CDCl3)
δH: 8.12-7.19 (m, 12H, aromatic), 7.67 (d, J = 16.5 Hz, 1H, =CH), 7.27 (d, J = 16.5 Hz, 1H,
=CH), 6.88 (bs, 2H, NH2), 5.09 (s, 1H, H-4), 4.13 (q, J = 7 Hz, 2H, CH2), 1.22 (t, J = 7 Hz, 3H,
13
CH3); C NMR (125 MHz, CDCl3) δc: 169.06 (CO), 160.29 (C-2), 155.69 (C-9), 145.77 (C-
10b), 142.85 (C-10a), 134.78 (C-7), 134.35 (=CH), 129.30 (=CH), 128.43 (C-5), 127.29 (C-6a),
125.48 (C-4a), 123.20 (C-6), 119.53 (C-8), 77.89 (C-3), 59.59 (CH2), 40.71 (C-4), 14.39 (CH3),
136.98, 134.64, 133.04, 132.09, 129.09, 128.57, 127.51, 126.93 (aromatic); MS m/z (%): 516
[M]+ (3), 444 (4), 282 [M++2], (31.67), 280 [M]+, (97.74), 170 (3), 101 (46), 75(100), 50 (58);
Anal. Calcd for C29H22Cl2N2O3: C, 67.32; H, 4.29; N, 5.41. Found: C, 67.28; H, 4.27; N, 5.39 %.
(E) Ethyl 2-amino-4-(4-bromophenyl)-9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3-
ο
carboxylate (9b). Colourless needles, yield 81%; m.p. 206-207 C; IR (KBr) υ (cm-1): 3418,
1
3297 (NH2), 3050, 3046, 2985, 2930 (CH), 1674 (CO); H NMR (500 MHz, DMSO-d6) δH: 9.61
(bs, 2H, NH2, cancelled by D2O), 8.33-7.23 (m, 12H, aromatic), 8.15 (d, J = 16 Hz, 1H, =CH),
7.98 (d, J = 16 Hz, 1H, =CH), 5.09 (s, 1H, H-4), 4.01 (q, J = 7 Hz, 2H, CH2), 1.10 (t, J = 7 Hz,
3H, CH3); 13C NMR (125 MHz, DMSO-d6) δc: 168.14 (CO), 160.81 (C-2), 155.11 (C-9), 152.93
(C-10b), 142.77 (C-10a), 136.51 (C-7), 135.17 (=CH), 129.64 (=CH), 128.88 (C-5), 127.72 (C-
6a), 121.5 (C-4a), 119.13 (C-6), 117.55 (C-8), 75.70 (C-3), 58.75 (CH2), 40.09 (C-4), 14.27
(CH3), 147.14, 138.12, 133.30, 132.92, 131.13, 129.12, 128.97, 124.95 (aromatic); MS m/z (%):
560 [M]+, (4), 406 (5), 280 (82), 225 (6), 101 (32), 75 (35), 62 (100) ; Anal. Calcd for
C29H22BrClN2O3: C, 61.99; H, 3.95; N, 4.99. Found: C, 62.02; H, 4.00; N, 5.03 %.
Acknowledgements
This study was supported by the King Abdulaziz City for Science and Technology (KACST),
1
No. A-S-11-0560.We also deeply thanks Mr. Ali Y. A. Alshahrani for making the H NMR and
13C NMR samples.
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