Synthesis of polyfunctionally substituted heteroaromatic compounds via benzotriazolyl chalcones with antimicrobial and antifungal activities

Article abstract of DOI:10.1002/jhet.5570410304

The utility of both 3-(1-benzotriazolyl) chalcone derivatives 3a-c and 2-(1-benzotriazolyl)-1,4-pentadien-3-one (18) in the synthesis of some new 2-(1H)-pyridone, pyridine, pyrazole and isoxazole derivatives is reported. Antimicrobial and antifungal screening of some selected examples from the synthesized products were carried out. The structure of the newly synthesized compounds was elucidated by elemental analysis, ir, ¹H and ¹³C nmr investigations.

Full text of DOI:10.1002/jhet.5570410304

May-Jun 2004
327
Synthesis of Polyfunctionally Substituted Heteroaromatic Compounds
via Benzotriazolyl Chalcones with Antimicrobial
and Antifungal Activities
Fatima Al-Omran* and Adel Abou El-Khair
Chemistry Department, Faculty of Science, Kuwait University
P.O. Box 5969, 13060 Safat, Kuwait
Received November 20, 2003
The utility of both 3-(1-benzotriazolyl) chalcone derivatives 3a-c and 2-(1-benzotriazolyl)-1,4-pentadien-
3-one (18) in the synthesis of some new 2-(1H)-pyridone, pyridine, pyrazole and isoxazole derivatives is
reported. Antimicrobial and antifungal screening of some selected examples from the synthesized products
were carried out. The structure of the newly synthesized compounds was elucidated by elemental analysis,
1
13
ir, H and C nmr investigations.
J. Heterocyclic Chem., 41, 327 (2004).
The increasing importance of both chalcone and benzo-
triazole derivatives as intermediates to biologically active
compounds [1-7] and in continuation of our current inter-
est in the synthesis of polysubstituted heterocycles incor-
porating benzotraizole moiety as potential pharmaceuticals
[8-11], we reported here on the utility of unreported 3-(1-
benzotriazolyl) chalcone derivatives 3a-c and 2-(1-benzo-
triazolyl)-1,4-pentadien-3-one derivative 18 as building
blocks for synthesis of new polyfunctionally substituted
heteroaromatic compounds of expected potential antimi-
crobial and antifungal activities.
Thus, refluxing an equimolar amount of 1-(1-benzotria-
zolyl)acetone 1 with aromatic aldehydes 2a-c in dimethyl-
formamide (DMF) and in the presence of a catalytic amount
of triethylamine afforded in each case of 3-(1-benzo-
triazolyl) chalcones 3a-c in good yield. The reactivity of
the new chalcones 3a-c obtained was investigated toward
carbon nucleophiles. Treatment of compounds 3a-c with
malononitrile in ethanolic piperidine solution at refluxed
temperature (Method A), furnished in each case, one
isolable product that could be formulated as 2-(1H)-pyri-
done 4 or its isomer 5. The compound 5 was obtained by
an independent synthetic route via treatment of 1 with
malononitrile in refluxing ethanol to afforded product 6.
The latter compound was treated with 2c to afford a deep
brown product identified as 5-(1-benzotriazolyl)-4-
methyl-6-(p-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-
carbonitrile (5) with different melting point than the prod-
uct obtained from reaction of 3c with malononitrile but
with similar spectral data. The compounds 4c-d could be
obtained in situ, via a one step process by treatment of 1
with p-methoxybenzaldehyde (2b) or p-nitrobenzaldehyde
(2c) in refluxing DMF followed by treatment of the reac-
tion mixture with malononitrile (Method B) to afford a
product identical in all respects (mp and spectra) with that
obtained from the reaction of compounds 3b-c with mal-
ononitrile. The formation of 4 was assumed to proceed via
initial addition of active methylene reagent across the
double bond in 3c followed by hydrolysis of one of the
cyano groups and then cyclization to 4.
In a similar manner, treatment of chalcones 3a,b with
malononitrile in ethanolic sodium ethoxide and in the pres-
ence of a catalytic amount of piperidine at refluxed tem-
perature gave a product that could be formulated as 7 or its
isomer 8. Spectral data seemed to be little help in discrim-
inating 7 or 8. However, the structure 8 was ruled out on
the basis of the reaction 6 with p-methoxybenzaldehyde
(2b) in ethanolic sodium ethoxide at refluxed temperature
to afford a product with different melting point than the
product obtained previously from the reaction of 3b with
malononitrile in ethanolic sodium ethoxide. Compound 7
was assumed to proceed via initial addition of the carban-
ion of malononitrile across the activated double bond sys-
tem in 3b followed by the addition of ethoxide ion to one
of the cyano groups to the iminoether, which readily
undergoes cyclization via a nucleophilic attack of an NH
group on a carbonyl carbon. This sequence of events has
been recently suggested to account the formation of alkoxy
pyridine [10,12].
The reactivity of chalcone 3b towards nitrogen nucleo-
phile was also investigated. Thus, treatment of compound
3b with hydrazine hydrate in refluxing ethanol afforded
yellow crystals that were identified as a pyrazolylbenzotria-
zole (Scheme 1). The formation of 9 is assumed to proceed
via condensation of hydrazine with the carbonyl group in
chalcone and subsequent cyclisation into the pyrazole
derivative 9. This is similar to the well accepted mecha-
nism of the reaction of chalcones with nitrogen nucleophile
[13]. Treatment of 1-(1-benzotriazolyl)-acetone 1 with
p-methoxybenzaldehyde (2 b) followed by treatment of the
reaction mixture with benzoylacetonitrile in refluxing DMF
and piperidine afforded 1 0. The structure of 10 was estab-
lished on the basis of its elemental analysis and spectral
data. Thus, the ir spectrum of the reaction product shows
the NH and two carbonyl functions (ketone and amide) at
νmax 3652, 1692 and 1650 cm−1, respectively (Scheme 1).

328
F. Al-Omran and A. A. El-Khair
Vol. 41
Scheme 1
Scheme 2
excellent yield. The products structure was established on
the basis of its elemental analysis and spectral data
(Scheme 3). The reactivity of compound 18 towards some
nitrogen and carbon nucleophilies was also investigated.
Thus, treatment of 1 8 with hydrazine hydrate or
hydroxyl amine in ethanol afforded in each case a product
that formulated as pyrazolylbenzotriazole and isoxazolyl-
benzotriazole derivatives 19 and 20, respectively. The for-
mation of 19 and 20 is assumed to proceed via initial addi-
tion of hydrazine or hydroxylamine to the carbonyl group
in system 18 and the resulting product then cyclises into
the pyrazole or isoxazole derivatives 19 and 20 respec-
tively [13].
On other hand, treatment of 18 with malononitrile or
benzoylacetonitrile in refluxing ethanolic piperidine
a fforded the 2-(1H)-pyridinone derivatives 21 and 22 ,
respectively in good yield. Both elemental analysis and
spectral data were in complete agreement with the
assigned structures. The structure 21 and 22 are consid-
ered most likely for the products based on its similarity to
the well established behaviour, which was assumed to pro-
ceed via initial addition of active methylene reagent across
the activated double bond system in dienone 18 followed
by hydrolysis and cyclization via loss of water a molecule
[12].
Treatment of 8 with each of benzylidenemalononitrile or by
refluxing it in a mixture of DMF/ethanol in the presence of
elemental sulfur and a catalytic amount of piperidine gave
compounds 11 and 12, respectively in good yield [14-16].
Treatment of 12 with dimethyl acetylenedicarboxylate
(DMAD) afforded the thiepine derivative 15, which is
believed to be formed via the non-isolated intermediates 13
and 14 (c f. Scheme 2). Similar formation of theipins has
been reported from our laboratorie [15-17] as well as by
Dopp et al [18]. The structure of the isolated product 15
was confirmed on the basis of elemental analysis and spec-
tral data. On the other hand, treatment of compound 12 with
enaminone 16 in refluxing dioxane and in the presence of a
catalytic amount of acetic acid afforded only the C-1 alkyl-
1
ated product 17 in a good yield. Both the ir and H nmr
spectra indicated that the amino function was not involved
in the reaction. The 1H nmr spectrum indicated the presence
of twotrans vinylic protons at δH = 5.85 and 6.39 ppm with
J = 15 Hz. Thus, structure 17 was established as the reaction
product, which was similar to the well accepted reaction of
condensed thiophenes with enaminones, reported from our
laboratories [16,19] (cf. Scheme 2).
Furthermore, treatment of 1-(1-benzotriazolyl)acetone 1
with an excess of p-nitrophenylbenzaldehyde (2c) in
DMF and in presence of a catalytic amount of triethyl-
amine at reflux temperature afforded the dienone 18 in
In a similar manner, dienone 18 reacted with malononi-
trile in refluxing ethanolic sodium ethoxide to give the

May-Jun 2004
Synthesis of Polyfunctionally Substituted Heteroaromatic Compounds
329
product that was established as 2-ethoxypyridine 3-car-
bonitrile derivative 23 in good yield. The ir spectrum of
compound 23 showed a characteristic absorption band at
2191 cm−1 due to the nitrile function. The structure may
be formed via initial addition of the carbanion of malonon-
itrile across the activated double bond system in dienone
18 followed by addition of ethoxide ion to one of the cyano
groups which subsequently cyclises via loss of water to
afford 2-ethoxypyridine-3-carbonitrile derivative 23
(Scheme 3) [12].
Biological Activity.
The biological activities of some newly synthesized
compounds were screened for their antifungal activity
against Aspergillus niger and Fusarium oxysporium, while
the antibacterial activity was tested against Eschirichia
coli, Bacillus subtilis and Staphylococcus aureus. Most of
the tested sample showed strong antibacterial and fungici-
dal activity (Table 1). Bacteria and Fungi were maintained
on nutrient agar slops (NA) and sabouraud agar (SA),
respectively. When calculated, a loop full of baceria was
grown on tryplic Saaybroth, while Fungi were subcultured
on a yeast nitrogen base supplemented with glucose
(YNBG). All media used were of dificagrade.
Scheme 3
EXPERIMENTAL
All melting points are uncorrected; ir spectra (KBr) were
recorded on a Perkin Elmer 2000 FT-ir spectrophotometer. Both
1
13
H and C nmr spectra were recorded on a Brucker 400 MHz
spectrometer with DMSO-d or CDCl as solvent using TMS as
6
3
internal standard with chemical shifts reported in ppm (δ). Mass
spectra were measured on GS/MS INCOL XL, Finingan MAT.
Microanalyses were performed on a LECO CHNS 932 analyzer.
General Procedure for the Synthesis of 3a-c.
A mixture of 1 (1.75 g, 0.01 mol) in DMF (20 ml) containing
2-3 drops of triethylamine was treated with each of arylaldehydes
2a-c (0.01 mol). The reaction mixture was refluxed for 10-12
hours. The solid product, so formed, was collected by filtration
and recrystallized from the proper solvent.
3-(1'-Benzotriazolyl)-4-phenyl-3-buten-2-one (3a).
This compound was recrystallized from ethanol to give yellow
crystals in 69% yield, mp 88-89 °C; ir: ν
-1
1697 cm (CO),
max
H nmr (DMSO-d ): δ : 2.68 (s, 3H, Me); 6.45 (s, 1H, =CH);
13
1
6
7.28-8.45 ppm (m, 9H, Ar-H); C nmr (DMSO-d ): 194.78
H
6
(CO), 163.27, 145.80, 143.11, 134.09, 132.29, 130.93, 129.94,
128.58, 125.38, 120.33, 118.81 and 111.28 (aromatic and
vinylic carbons) and 26.63 ppm (Me).
Anal. Calcd for C H N O: C, 72.99; H, 4.97; N, 15.95.
16 13 3
Found: C, 72.79; H, 5.06; N, 15.79.
Table 1
In vitro Bactericidal and Fungicidal Activity of Newly Synthesized
3-(1'-Benzotriazolyl)-4-(p-methoxyphenyl)-3-buten-2-one (3b).
This compound was recrystallized from ethanol to give yellow
Compounds
Compound E-coli
B-subtilis S-aureus A-niger F-oxysporium
−1
crystals in 81% yield, mp 123-125°C, ir: ν : 1675 cm (CO);
max
H nmr (DMSO-d ): δ : 2.72 (s, 3H, Me); 3.82 (s, 3H, OMe);
1
6
H
3c
7b
10
11
12
15
17
18
20
22
++++
++++
++
++
+++
-
++
+++
+++
+++
++
++
-
+++
++++
+++
++++
+++
++++
+++
+++
++
+++
+++
+++
+++
+++
+++
+++
-
+++
+++
+++
+++
+++
+++
+++
+++
+++
+++
13
6.38 (s, 1H, =CH); 6.73-8.38 ppm (m, 8H, Ar-H); C nmr
(DMSO-d ): δ 194.49 (CO), 162.77, 159.72, 145.91, 142.92,
6
C
134.07, 133.38, 129.94, 125.31, 124.34, 120.38, 115.81 and
111.27 (aromatic and vinylic carbons), 56.27 (OMe) and 26.63
ppm (Me).
+++
++++
++++
+++
Anal. Calcd for C
H N O : C, 69.61; H, 5.15; N, 14.32.
17 15 3 2
Found : C, 69.79; H, 5.08; N, 14.47.
+++
+++
+++
-
++
3-(1'-Benzotriazolyl)-4-(p-nitrophenyl)-3-buten-2-one (3c).
This compound was recrystallized from a mixture of
ethanol/DMF (2:1) as brown crystals in 71% yield; mp 197-199
-
No effect = - ; slight effect = + ; Moderate effect = ++ ; strong effect =
+++, ++++
1
°C; ir: ν
1662 (CO); H nmr (DMSO-d ): δ 2.67 (s, 3H,
6
max
H

330
F. Al-Omran and A. A. El-Khair
Vol. 41
Me); 7.13-8.50 ppm (m, 9H, Ar-H & =CH); ms (EI): m/z= 308
+
(M ).
refluxed for 5 hours, then allowed to cool, poured onto ice-cold
water. The solid product, so formed, was collected by filtration and
recrystallized from a mixture of EtOH/DMF (2:1) as deep brown
A n a l. Calcd. for C
H N O : C, 62.33; H, 3.92; N, 18.17.
16 12 4 3
crystals in 71 % yield, mp 110-112 °C. ir: ν : 3345 (NH), 2203
−1
Found: C, 62.24; H, 3.86; N, 18.12.
General Procedure for the Synthesis of 4a-c.
Method A.
max
(CN) and 1631 cm (CO); H nmr (DMSO-d ): δ 2.31 (s, 3H,
1
6
H
Me); 7.18 -8.26, (m, 8H, Ar-H); 10.50 ppm (b, H, NH).
Anal . Calcd. C N O : C, 61.29; H, 3.24; N, 22.56.
Found: C, 61.46; H, 3.40; N, 22.79.
H
19 12
6 3
A mixture of compound 3a-c (0.01 mol) and malononitrile
(0.66 g, 0.01 mol) in absolute ethanol (20 ml) and a few drops of
piperidine was refluxed for 4 hours, then poured onto cold water.
The solid product, so formed, was collected by filtration and
recrystallized from ethanol as pale yellow crystals.
4-(1'-Benzotriazolyl)-2-cyano-3-methyl-2-butenamide (6).
A mixture of 1 (1.75 g, 0.01 mol) and malononitrile (0.66 g,
0.01 mmol) in ethanol (20 ml) and few drops of triethylamine.
The reaction mixture was refluxed for 2 hours, then poured onto
ice-cold water and neutralized with HCl (10%). The solid prod-
uct so formed was collected by filtration and recrystallized from
ethanol to give yellow crystal in 89% yield; mp 130-132 °C; ir:
Method B.
A mixture of compound 1 (1.75 g, 0.01 mol) and p-methoxy-
benzaldehyde (2b) (1.36 g, 0.1 mol) or p-nitrobenzaldehyde (2c)
(1.51 g, 0.01 mol) in DMF (20 ml) and a few drops of piperidiene
was refluxed for 8 hours. The mixture was then treated with mal-
ononitrile (0.66 g, 0.1 mol), refluxed for 5 hours, then allowed to
cool, and poured onto ice-cold water. Each of the solid product
so formed, was collected by filtration and recrystallized from a
mixture of EtOH/DMF (2:1).
−1
1
ν
nmr (DMSO-d ); δ 2.30 (s, 3H, Me), 6.02 (s, 2H, CH ), 7.27-
: 3405-3339 (NH ), 2190 (CN) and 1666 cm (CO); H
2
max
6
8.10 (m, 4H, Ar-H) and 8.60 ppm (b, 2H, NH ).
H
2
2
Anal . Calcd. for C H N O: C, 59.74; H, 4.60; N, 29.03.
12 11
Found: C, 59.82; H, 4.70; N, 29.10.
5
General Procedure for the Synthesis of 7a-b.
5-(1'-Benzotriazolyl)-6-methyl-2-oxo-4-phenyl-1,2-dihydropyri-
dine-3-carbonitrile (4a).
A solution of each 3a-b (0.01 mol) in absolute ethanol (30 ml)
was treated with malononitrile (0.66 g, 0.01 mol) and sodium
ethoxide (prepared from 0.60 g of sodium metal and 60 ml of
ethanol). The mixture was refluxed for 5 hours, then poured onto
ice cold water and neutralized with hydrochloric acid (10%).
Each of the solid product so formed was collected by filtration
and recrystallized from ethanol.
This compound was obtained as pale yellow crystals in 75%
yield, mp 175-177 °C, ir: ν : 3411 (NH), 2193 (CN) and 1646
max
cm (CO); H nmr (DMSO-d ): δ 2.20 (s, 3H, Me), 7.03-7.65
−1
1
6
(m, 9H, Ar-H) and 10.20 ppm (br, 1H, NH, D O-exchangeable).
H
2
H N O: C, 69.71; H, 4.00; N, 21.40.
Anal. Calcd. for C
19 13 5
Found: C, 70.03; H, 4.08; N, 21.31.
5-(1'-Benzotriazolyl)-2-ethoxy-6-methyl-4-phenylpyridine-3-
carbonitrile (7a).
5-(1'-Benzotriazolyl)-4-(p-methoxyphenyl)-6-methyl-2-oxo-1,2-
dihydropyridine-3-carbonitrile (4b).
This compound was obtained as brown crystals in 76% yield;
−1
mp 135-137°C; ir: ν : 2203 cm (CN); H nmr (DMSO-d ): δ
1
This compound was obtained as deep brown crystals in 85%
yield, mp 107-109 °C; ir: ν : 3336 (NH), 2186 (CN) and 1658
max
6
1.06 (t, 3H, J=7Hz, Me), 2.22 (s, 3H, Me), 3.45 (q, 2H, J=7Hz,
max
cm (CO); H nmr (CDCl ): δ 2.31 (s, 3H, Me), 3.81 (s, 3H,
−1
1
OCH ) and 7.16-8.32 ppm (m, 9H, Ar-H).
2
Anal. Calcd. C
C, 70.79; H, 4.97; N, 19.18.
3
OMe), 6.81-8.21 (m, 8H, Ar-H), 9.50 ppm (b, 1H, NH, D O-
H
H N O: C, 70.96; H, 4.82; N, 19.71. Found:
21 17 5
2
exchangeable); C nmr (DMSO-d ): δ 163.16 (C-2), 161.77
13
6
C
(C-6), 158.33, 146.05, 133.98, 131.41, 130.30, 129.52, 128.62,
128.15, 125.15, 120.14, 119.07, 115.10, 114.17 (aromatic carbons
& CN), 111.50 (C-3), 55.51 (OMe) and 25.45 ppm (Me).
5-(1'-Benzotriazolyl)-2-ethoxy-4-(p-methoxyphenyl)-6-methyl-
pyridine-3-carbonitrile (7b).
This compound was obtained as pale brown crystals in 78%
Anal. Calcd. For C
Found: C, 67.36, H, 4.18; N, 19.46.
H N O : C, 67.22, H, 4.23, N, 19.59.
20 15 5 2
−1
1
: 2216 cm (CN), H nmr
yield; mp 174-176 °C; ir: ν
(CDCl ): δ 1.33 (t, 3H, J=7Hz, Me), 2.30 (s, 3H, Me), 3.86 (s,
max
3
3H, OMe), 4.19 (q, 2H, J=7Hz, OCH ), 6.40-8.35 (m, 8H, Ar-H);
H
5-(1'-Benzotriazolyl)-6-methyl-4-(p-nitrophenyl)-2-oxo-1, 2-
dihydropyridine-3-carbonitrile (4c).
2
C nmr (DMSO-d ): δ 168.36 (C-2), 166.32 (C-6), 161.58,
13
6
C
159.24, 134.41, 132.16, 131.09, 130.64, 130.00, 129.72, 129.12,
128.65, 119.97, 117.45, 114.87 and 111.31 (aromatic carbons and
CN), 55.86 and 52.92 (OCH & OMe), 25.48 (Me) and 16.08
This compound was obtained as deep brown crystals in 92%
yield, mp 160-162 °C; ir: ν : 3345 (NH), 2203 (CN) and 1631
max
cm (CO); H nmr (DMSO-d ): δ 2.21 (s, 3H, Me), 7.18-8.26 (m,
13
−1
1
2
6
8H, Ar-H), 10.60 ppm (b, 1H, NH); C nmr (DMSO-d ): δ 166.77
H
ppm (Me).
Anal. Calcd. for C
Found: C, 68.38, H, 4.86, N, 18.36.
6
C
H N O : C, 68.56, H, 4.97, N, 18.17.
22 19 5 2
(C-2); 165.12 (C-6), 154.00, 149.72, 145.94, 143.70, 136.12,
133.90, 131.41, 128.76, 127.53, 125.10, 124.73, 120.18 (aromatic
carbons), 118.21 (CN), 115.58 (C-3) and 21.83 ppm (Me).
A n a l . Calcd. for C H N O : C, 61.29; H, 3.24; N,
1 9 1 2 6 3
22.56.Found: C, 61.39; H, 3.24; N, 22.65.
5-(1'-Benzotriazolyl)-2-ethoxy-6-(p-methoxyphenyl)-4-methyl-
pyridine-3-carbonitrile hydrochloride (8).
A mixture of compound 6 was treated with p-methoxybenzalde-
hyde (1.54 g, 0.01 mol) in sodium ethoxide solution (30 ml of
ethanol in 0.6 g sodium). The reaction mixture was refluxed for 3
hours, left to cool then acidified with 10% of HCl. The solid prod-
uct, so formed, was collected by filtration and recrystallized from a
5-(1'-Benzotriazolyl)-4-methyl-6-(p- nitrophenyl)-2-oxo-1, 2-
dihydropyridine-3-carbonitrile (5).
A mixture of compound 6 (2.41 g, 0.01 mol) and p-nitroben-
zaldehyde 2c (1.51 g, 0.01 mol) in absolute ethanol (20 ml) was

May-Jun 2004
Synthesis of Polyfunctionally Substituted Heteroaromatic Compounds
331
mixture of EtOH/DMF (2:1) to give pale yellow crystals in 92%
piperidine (0.2 ml). The mixture was refluxed for 4 hours then
poured onto water. The solid product, so formed, was collected
by filtration and recrystallization from a mixture of EtOH/DMF
(2:1) to give green crystals in 76% yield, mp 155-157 °C; ir:
−1
yield; mp 140-142 °C ir: ν : 2216 cm (CN). H nmr (DMSO-
1
max
d ): δ 1.12 (t, 3H, J=7H), 2.37 (s, 3H, Me); 3.81 (s, 3H, OMe);
6
4.16 (q, 2H, J=7Hz, OCH ); 6.72-7.88 (m, 8H, Ar-H).
H
2
−1
1
ν
(t, 3H, J=7Hz, Me); 3.81 (s, 3H, OMe); 4.14 (q, 2H, J=7Hz,
: 3448, 3383 cm (b, NH ); H nmr (DMSO-d ): δ 1.21
Anal. Calcd. for C H N O Cl: C, 62.63; H, 4.77; N, 16.60.
22 20 5 2
Found: C, 62.50; H, 5.11; N, 16.32.
max
2 6 H
OCH ), 6.64-7.86 (m, 9H, Ar-H & H-1) and 8.54 (bs, 2H, NH ,
2
2
D O-exchangeable).
1-[(3'-Methyl-(1H' ) - 5 ' - (p-methoxyphenyl)pyrazol-4'-yl)]benzo -
triazole (9).
2
Anal. Calcd. for C
Found: C, 63.29; H, 4.71; N, 16.72.
H
N O S: C, 63.30; H, 4.59; N, 16.78.
22 19
5 2
A solution of 3b (2.93 g, 0.01 mol) in ethanol (20 ml) was
treated with hydrazine hydrate (0.5 g, 0.01 mol). The reaction
mixture was refluxed for 2 hours then allowed to cool. The solid
product, so formed, was collected by filtration and recrystallized
from ethanol to give yellow crystals in 73% yield; mp 160-162
Dimethyl-4-amino-9-(1'-Benzotriazolyl)-6-ethoxy-8-(p -methoxy-
phenyl)thiepino[3,4-c]pyridine-2,3-dicarboxylate (1 5) .
A mixture of 12 (4.17g, 0.01 mol) and DMAD (1.23 g, 0.01
mol) in dioxane (20 ml) and acetic acid (2 ml) was refluxed for
8 hours then poured onto ice cold water. The solid product, so
formed, was collected by filtration and recrystallized from a
−1
1
°C; ir: ν
3402 cm (NH); H nmr (DMSO-d ): δ 2.17 (s,
6 H
max
3H, Me), 3.42 (s, 3H, OMe), 6.20-8.20 (m, 8H, Ar-H) and 10.50
ppm (b, 1H, NH).
A n a l. Calcd. for C
Found: C, 66.97; H, 5.02; N, 22.83.
H N O: C, 66.87; H, 4.95; N, 22.93.
17 15 5
mixture of DMF/EtOH (2:1) as green crystals in 74% yield, mp
170-172 °C ; ir: ν
−1
3410, 3380 (NH ) and 1735 cm (2CO);
max
2
H nmr (DMSO-d ): δ 1.17 (t, 3H, J=7H, Me), 3.70 (s, 3H,
1
6
H
5-(1'-Benzotriazolyl)-3-benzoyl-4-(p-methoxyphenyl)-6-methyl-
2-oxo-1,2-dihydropyridine (10).
OMe), 3.75 (s, 3H, OMe), 3.80 (s, 3H, OMe), 4.05 (q, 2H,
J=7Hz, OCH ), 6.99 (s, 1H, H-1), 7.05-8.00 (m, 8H, Ar-H) and
13
2
8.02 ppm (bs, 2H, NH ); C nmr (DMSO-d ): δ 166.66 (CO),
A solution of compound 1 (1.75 g, 0.01 mol) in DMF (20 ml)
was treated with p-methoxybenzaldehyde (2b) (1.21 g, 0.01 mol)
and a few drops of piperidine. The reaction mixture was refluxed
for 8 hours then treated with benzoylacetonitrile (1.45 g, 0.01
mol) and refluxed for another 5 hours then poured onto ice-cold
water. The solid product, so formed, was collected by filtration
and recrystallized from a mixture of EtOH/DMF (2:1) to give
2
6
C
164.85 (CO), 161.61 (C-6), 155.28 (C-8), 148.03, 146.09,
145.57, 144.63, 142.13, 135.39, 130.75, 129.89, 129.25,
128.88, 128.22, 125.38, 123.48,120.46, 117.46, 115.57, 114.68
(aromatic carbons), 67.38 (OCH ), 56.30 (3OMe) and 19.45
2
ppm (Me).
Anal. Calcd. for C
Found: C, 60.20; H, 4.41; N, 12.81.
H N O S: C, 60.10; H, 4.50; N, 12.52.
28 25 5 6
yellow crystals in 72% yield, mp 118-120 °C; ir: ν : 3352
−1
max
(NH), 1692 (CO) and 1650 cm (CO); H nmr (DMSO-d ); δ
1
6
H
3-[3'-Amino-7'-(1"-benzotriazolyl)-4'-ethoxy-6'-( p-methoxy-
phenyl)thieno-[3,4-c ]pyridin-1-yl]-1-(2-thienyl)-2-propen-1-one
(17).
2.20 (s, 3H, Me), 3.82 (s, 3H, OMe), 6.88-7.95 (m, 13H, Ar-H)
and 8.25 ppm (b, 1H, NH).
Anal. Calcd. For C
H N O : C, 71.55; H, 4.62; N, 12.82.
26 20 4 3
Found: C, 71.87; H, 4.32; N, 13.09.
To a solution of 12 (4.17 g, 0.01 mol) in a mixture of dioxane
(20 ml) and acetic acid (2 ml) was treated with 3-(N , N -
dimethylamino)-1-(2'-thienyl)-2-propen-1-one (16) (1.81 g,
0.01 mol). The reaction mixture was refluxed for 8 hours and
poured onto ice cold water. The solid product, so formed, was
collected by filtration and recrystallized from a mixture of
8-Amino-4-(1'-Benzotriazolyl)-1-ethoxy-3-(p-methoxyphenyl)-
6-phenyl-6,7-dihydroisoquinoline-7,7-dicarbonitrile hydrochlo-
ride (11).
A solution of 8 (4.21 g, 0.01 mol) in 20 ml of ethanol and few
drops of piperidine was treated with benzylidenemalononitrile
(1.54 g, 0.01 mol). The reaction mixture was refluxed for 5 hours
and then poured onto cold water. The solid product, so formed,
was collected by filtration and recrystallized from a mixture of
DMF/EtOH (2:1) as brown crystals in 83% yield; mp 167-169
DMF/EtOH (2:1) to give green crystals in 73% yield, mp 158-
−1
160 °C, ir: ν : 3447 and 3342 (NH ) and 1654 cm (CO);
max
H nmr (DMSO-d ): δ 1.21 (t, 3H, J=7Hz, Me), 3.81 (s, 3H,
2
1
6
OMe), 4.18 (q, 2H, J=7Hz, OCH ), 5.85 (d, 1H, J=15 Hz,
H
2
vinylic-H) 6.39 (d, 1H, J=15Hz, vinylic-H), 6.38-8.30 (m, 11H,
−1
1
13
A r-H) and 8.42 ppm (b, 2H, NH ); C (DMSO-d ): δ 188.99
°C; ir: ν : 3339-3195 (NH ); 2223 and 2189 cm (2CN); H
max
2
nmr (DMSO-d ): δ 1.34 (t, 3H, J-7Hz, Me), 2.55 (m, 1H, H-6),
2
6
C
(CO ketone), 165.66, 164.84, 161.27, 155.28, 148.04, 145.70,
144.63, 143.83, 142.12, 135.39, 130.75, 129.89, 129.53,
128.88, 128.32, 125.46, 123.47, 120.46, 115.70, 115.10, 114.68,
6
3.75 (s, 3H, OMe), 4.42 (q, 2H, J=7Hz, OCH ), 6.60-7.86 (m,
H
2
13
14H, Ar-H & H-5), 7.97 ppm (bs, 2H, NH ); C nmr (DMSO-
2
d ): δ 165.68 (C-1), 162.61, 161.63 (C & C ), 155.22, 146.11,
111.23, 110.85 (aromatic & vinylic carbons), 67.37 (OCH ),
2
6
C
4
8
145.71, 144.65, 143.86, 135.41, 131.52, 130.56, 129.68, 129.41,
129.38, 129.28, 129.17, 128.78, 120.11, 119.82, 115.49, 114.68,
111.74 and 107.30 (aromatic carbons 2CN) 56.21 and 56.83
(OCH & OCH ), 26.52 (C-6), 21.87 (Me) and 18.90 ppm (C-7).
56.24 (OMe) and 19.46 ppm (Me).
Anal. Calcd. for C
H N O S : C, 62.92, H, 4.19, N, 12.65.
29 23 5 3 2
Found: C, 63.06, H, 4.37, N, 12.40.
2
3
2-(1'-Benzotriazolyl)-1,5-bis(p-nitrophenyl)-1,4-pentadien-3-
one (18).
Anal. Calcd. For C
H N O Cl: C, 66.72, H, 4.54, N, 17.02.
32 26 7 2
Found: C, 66.80, H, 4.29, N, 17.17.
A mixture of 1 (1.75 g, 0.01 mol) in DMF (20 ml) containing
2-3 drops of triethylamine was treated with p-nitrobenzaldehyde
(2c) (3.02 g, 0.02 mol). The reaction mixture was refluxed for
12-14 hours then poured onto ice-cold water. The solid product,
so formed, was collected by filtration and recrystallized from a
3-Amino-7-(1'-Benzotriazolyl)-4-ethoxy-6-(p-methoxyphenyl)-
thieno[3,4-c]pyridine (12).
A solution of 8 (4.21 g, 0.01 mol) in 20 ml of EtOH/DMF
(2:1) was treated with element al sulfur (0.32 g, 0.01 mol) and

332
F. Al-Omran and A. A. El-Khair
Vol. 41
mixture of EtOH/DMF (2:1) as brown crystals in 81% yield, mp.
1
166-168 °C, ir: ν : 1662 (CO); H nmr (DMSO-d ): δ 6.84 (s,
ethoxide (prepared from 0.6 g sodium metal and 60 ml of ethanol).
The reaction mixture was refluxed for 3 hours, then poured onto
cold water and neutralized with hydrochloric acid (10%). The
solid product was collected by filtration and recrystallized from a
mixture of EtOH/DMF (2:1) as brown crystals 68% yield, mp
max
1H, =CH), 7.01-8.43 (m, 14H, Ar-H & vinylic–H).
6
H
Anal. Calcd. for C
H N O : C, 62.58; H, 3.42; N, 15.87.
23 15 5 5
Found: C, 62.58; H, 3.53; N, 15.62.
−1
1
250-252 °C ir: ν
2191 cm (CN); H nmr (DMSO-d ): δ
6 H
1.23 (t, 3H, J=7Hz, Me), 4.36 (q, 2H, J=7Hz, OCH ), 6.94 (s, 1H,
max
General Procedure for the Synthesis of 19-20.
2
A solution of 18 (4.41 g, 0.01 mol) in 20 ml of ethanol was
treated with hydrazine hydrated (0.5 g, 0.01 mol) or hydroxy-
lamine hydrochloride (0.69 g, 0.01 mol). The reaction mixture
was refluxed for 1 hour and left cool at room temperature. Each
of the solid product so formed was collected by filtration and
recrystllized from ethanol.
=CH), 7.22-8.13 ppm (m, 13H, Ar-H & H-5).
Anal. Calcd. for C
Found: C, 59.12; H, 3.43; N, 17.01.
H N O Cl: C, 59.00; H, 3.53; N, 17.20.
28 20 7 5
Biological Testing.
The newly synthesized compounds were tested against the
specified microorganism, using 400 µg/mL (w/v) solutions in
sterile dimethyl-d sulfoxide (DMSO). A solution of the tested
6
1-{2'-(p-Nitrophenyl)-1'-[5"-(p-nitrophenyl)-1"H-pyrazol-3"-yl]-
vinyl}benzotriazole (19).
compound (0.01 mol) was poured aseptically in a well of 6 mm
diameter made by a Cork borer in the nutrient agar medium for
bacterial test and in Sabourand agar for fungal test. After placing
the same volume in wells of all tested microorganisms nutrient
agar plates were incubated at 37 °C for 24 h and sabourand dex-
trose agar plates were incubated at 25 °C for 48 hours The activ-
ities were expressed as inhibition zones (mm, diameter, as clear
areas) as antibacterial and antifungal effect. The least concentra-
tion, which showed inhibitory effect on any specific micoorgan-
ism, was considered as the minimum inhibitory concentration
(MIC) that was determined using streptomycin (50 µg/ml) as the
references.
This compound was obtained as yellow crystals in 61% yield;
mp 210-212 °C; ir: ν
1
(NH); H nmr (DMSO-d ): δ 6.30 (s,
max
6
H
1H, pyrazol-H), 6.72 (s, 1H, =CH), 7.22-8.22 (m, 12H, Ar-H) and
8.80 ppm (b, 1H, D O-exchangeable NH).
H N O : C, 60.87; H, 3.33; N, 21.62.
2
Anal. Calcd. for C
23 15 7 4
Found: C, 60.76; H, 3.13; N. 21.82.
1-{2'-(p-Nitrophenyl)-1'-[5"-(p-nitrophenyl)isoxazol-3"-yl]-
vinyl}benzotriazole (20).
This compound was obtained as a yellow brown solid in 79%
1
yield, mp 190-192 °C; H nmr (DMSO-d ): δ 6.43 (s, 1H, H-4),
6
H
6.82 (s, 1H, =CH), 7.01-8.31 (m, 12H, Ar-H).
Anal. Calcd. for C N O : C, 60.79; H, 3.10; N, 18.49.
Found: C, 61.03; H, 3.32; N, 18.67.
H
Acknowledgement.
23 14
6 5
This work was financed by University of Kuwait, Research
Grant SC 08/00. We are grateful to the Faculty of Science,
Chemistry Department, SAF facility for the analytical and spec-
tral measurement (Project G01/01 & G 03/01). We are also
grateful to Dr. I.H. Abbas for the biological activity tests.
General Procedure for the Synthesis of 21-22.
To suspension of compound 18 (4.41 g, 0.01 mol) in 20 ml of
ethanol was treated with malononitrile (0.66 g, 0.01 mol) or benzoy-
lacetonitrile (1.45g, 0.01 mol) and few drops of piperidine. The
reaction mixture was refluxed for 6 hours. The solvent was evapo-
rated under reduced pressure. Each of the solid product, so formed,
was collected by filtration and recrystallized from proper solvent.
REFERENCES AND NOTES
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max
−1
1
6
H
7.03-8.30 (m, 13H, Ar-H & H-5) and 10.80 ppm (b,1H, NH).
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H
26 16
7 5
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EtOH/DMF (2:1) as reddish brown crystals in 73% yield; mp 163-
−1
3367 (NH), 1697 and 1632 cm (2CO); H nmr
1
165 °C; ir: ν
max
(DMSO-d ): δ 7.01 (s, 1H, =CH), 7.03 (s, 1H, H-5), 7.29-7.98
6
H
(m, 17H, Ar-H), 8.05 ppm (br, 1H, NH, D O exchangeable).
2
H N O : C, 65.75; H, 3.45; N, 14.38.
A n a l. Calcd for C
32 20 6 6
Found: C, 65.38; H, 3.37; N, 14.37.
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6-[1'-(1-Benzotriazolyl)-2'-(p-nitrophenyl)vinyl]-2-ethoxy-4-(p-
nitrophenyl)pyridine-3-carbonitrile hydrochloride (23).
A mixture of 18 (4.41 g, 0.01 mol) and malononitrile (0.66 g,
0.01 mol) in absolute ethanol (50 ml) was treated with sodium
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May-Jun 2004
Synthesis of Polyfunctionally Substituted Heteroaromatic Compounds
333
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