Synthesis, characterisation and bioactivity of polysubstituted 1-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole derivatives

Article abstract of DOI:10.3184/174751912X13353579628083

1,4-Phenylenediamine reacted readily with chloroacetone to give 1,4-bis[(2-oxopropyl)amino]benzene which was used to prepare 1-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole derivatives in a one pot reaction with dimethylformamide dimethylacetal or triethyl orthof

Full text of DOI:10.3184/174751912X13353579628083

328 RESEARCH PAPER
JUNE, 328–332
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis, characterisation and bioactivity of polysubstituted
1-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole derivatives
Abdel-Zaher A. Elassar
Chemistry Department, Faculty of Science, Helwan University, Ain Helwan, Cairo, Egypt
1,4-Phenylenediamine reacted readily with chloroacetone to give 1,4-bis[(2-oxopropyl)amino]benzene which was
used to prepare 1-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole derivatives in a one pot reaction with dimethylformamide
dimethylacetal or triethyl orthoformate and an active methylene nitrile, an active methylene ketone or an ylidene-
malononitrile. Reaction of 1,4-bis[(2-oxopropyl)amino]benzene with arene diazonium salts afforded the hydrazone
derivatives which readily cyclised when reacted with malononitrile to give bispyrrole derivatives. The antibacterial
activity of some of the products was determined.
Keywords: bispyrrole, chloroacetone, phenylenediamine, antibacterials
Pyrrole and its fused derivatives have aroused recent attention
as potent anticancer agents.1–4 Several mechanisms are involved
in their cytotoxic activities as being dihydrofolate reductase
inhibitors,5 tyrosine kinase inhibitors,6 cyclin dependant kinase
inhibitors7 or adenosine receptor antagonist.8 Pyrroles show
many types of biological activity, for example, in vitro antibac-
terial activity of novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone
analogues of PNU-100480,9 antiproliferative activity in HL60
cells by tetrasubstituted pyrroles,10 and cyclase inhibitors.11
Recently, aryl pyrroles have been reported as potent inhibitors
of Ras farnesyltransferase with regression of tumors grown in
nude mouse xenograft models.12
Many natural products contain a pyrrole subunit 8 as the
basic core. Of particular interest is the remarkable diversity
of biological activity associated with the 3,4-disubstituted
1H-pyrrole scaffold. From a synthetic point of view, pyrroles
substituted in position 3 and 4 are difficult to prepare, most
of the reactivity being concentrated at the α-position of the
pyrrole. We now report the preparation of polysubstituted
bispyrroles in one pot reactions upon treating 1,4-bis[(2-
oxopropyl)amino]benzene with DMFDMA, and an active
methylene nitrile or an active methylene ketone.
Compound 3 reacted with dimethylformamide dimethyl
acetal (DMFDMA) to give α,β-unsaturated ketone 4a or 5. The
latter Compound 5 was ruled out based on the 1H NMR, which
confirmed Compound 4a as the E-structure, the ethylenic
protons appearing at δ 5.12 and 7.63 ppm with J = 13 Hz as
required for such E-coupled protons.14 Compound 4a cyclised
under basic conditions to give via loss of two molecules
dimethylamine, 6, which tautomerised to 1-(4-(3-hydroxy-1H-
pyrrol-1-yl)phenyl)-1H-pyrrol-3-ol, 6a. The same reaction
product 6a was obtained from reaction of Compound 3 and
triethyl orthoformate in a one-pot reaction. This product was
believed to proceed through formation of the non isolated
intermediate 4b followed by loss of two ethanol molecules to
give the final isolated product 6a. The IR (KBr disc) revealed
the presence of a hydroxyl group at 3419 cm-1 which means
Compound 6 must predominate as 6a in the solid state. MS
showed accurate mass at m/z 240.09 which agreed with the
1
molecular formula C14H12N2O2. H NMR showed a singlet
aromatic proton at δ 6.91 ppm which reflects the symmetry of
the 1,4-substitutent. Pyrrole protons appeared as two compiled
doublets at δ 6.85 and 6.53 ppm (J = 8.4 Hz) and a singlet at
δ 6.35 ppm. The hydroxyl proton appeared at δ 5.03 ppm.
Bispyrroles could also be obtained upon treating Compound
3 with an active methylene nitrile or an active methylene
ketone. For example, Compound 3 reacted with malononitrile
to give 2-amino-4-methyl-1-(4-(2-amin-3-cyano-4-methyl-1H-
pyrrol-1-yl)phenyl)-1H-pyrrol-3-carbonitrile 8. The reaction
product is assumed to form via addition of the methylene group
of malononitrile to the electrophilic carbonyl carbon
followed by loss of a water molecule to give the non isolated
condensation intermediate 7. The intermediate 7 cyclised
under the reaction conditions via addition of NH to the cyano
group to give the final isolated product 8. Compound 8 showed
accurate mass 316.14, in addition IR revealed the presence of
an amino and a cyano group at 3358, 3226 and 2187 cm−1,
respectively. Similarly, Compound 3 reacted with ethyl
cyanoacetate, ethyl acetoacetate and acetyl acetone to give
bispyrrole derivatives 9, 10 and 11, respectively. The reaction
products were formed via condensation followed by cyclisa-
tion and tautomerisation. Structure elucidation was confirmed
by elemental analysis and spectral data (see Experimental).
Compound 3 also reacted with a series of ylidenemalononi-
triles 12a–d to give 5-acetyl-2-amino-4-aryl-1-(4-(5-acetyl-2-
amino-3-cyano-4-aryl-1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-
carbonitriles, 14a–d or 15.Compound 15 was ruled out based
on IR which revealed the presence of a carbonyl group at 1684
to 1704 cm−1 as expected for 14a–d. The isolated product 14a–
d were believed to be formed via Michael addition of the active
methylene group in Compound 3 to the ylidene double bond to
give intermediate 13. This intermediate cyclised under the
reactions condition to give the final isolated products 14a–d.
Results and discussion
1,4-Phenylenediamine 1 reacted with chloroacetone 2 with
molar ratio1:2 in the presence of sodium hydrogen carbonate
to give the bis alkylated product 313 (Scheme 1). The structure
of Compound 3 was confirmed by elemental analysis and
spectral data. The accurate mass showed m/z at 220.12, in
1
addition H NMR revealed the presence of methylene and
methyl protons as singlets at δ 4.16 and 2.50 ppm, respectively.
In addition, the aromatic protons appeared at δ 6.92 ppm. 13
C
NMR showed carbonyl carbon at δ 206.4 and aromatic and
sp3 carbons appeared at δ 148.9, 145.1, 126.4, 125.8, 65.0,
25.3 ppm.
Scheme 1
* Correspondent. E-mail: aelassar@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 329
Scheme 2
Scheme 3

330 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 4
The nitrogen electrophile of arene diazonium salts 16a–c
coupled with compound 3 to form hydrazone derivatives
17a–c (Scheme 5). The MS of products 17a–c showed m/z at
428.5, 518.5 and 497.0, respectively. IR, showed a carbonyl
group at 1689 cm−1 for each of 17a–c; this is may be due to
Experimental
All melting points are uncorrected. IR spectra were recorded in KBr
with an IR spectrophotometer Shimadzu 408. 1H NMR and 13C NMR
spectra were recorded on Varian EM-390 MHz spectrometer using
TMS as internal standard reference and chemical shifts are expressed
as δ ppm. Mass spectra were measured on a Shimadzu GCMS-QP
1000 Ex mass spectrometer. Microanalytical data were obtained from
the Microanalytical Data Unit at Cairo University, Egypt.
1
hydrogen bonding with the NH group. All other data e.g. H
NMR, 13C NMR and elemental analysis confirmed the forma-
tion of the reaction products 17a–c (see experimental). Heat-
ing of compound 17 with malononitrile in the presence of
ammonium acetate at 160 °C gave the bispyrrole derivatives
18a–c. The latter could also be obtained via coupling of
compound 8 with an arene diazonium salt 16a–c.
Bioactivity of synthesised compounds: The diverse biologi-
cal activities of pyrroles3,9–11,15–20 prompted us to test and study
the biological activities of some of the newly synthesised
products. Table 1 shows that most of the tested compounds
had high activity. Indeed, compounds 18c with E. Coli; 6, 9, 10
with S. Aureus; 9 with B. Subtilis and 8 with P. Aeruginosa
showed high 8 effects. While Compounds 6, 8, 11, 18b with
E. coli; 18a with S. aureus; 3, 6, 10, 18b with B. subtilis and
10, 11 with P. Aeruginosa showed high effects. Other Com-
pounds showed with different microorganisms a moderate to
weak effect (see Table 1).
Synthesis of 1,4-bis[(2-oxopropyl)amino]benzene (3):13 To a solu-
tion of p-phenylenediamine (0.01 mol) in acetone (30 mL) containing
sodium hydrogen carbonate (0.01 mol), 1-chloropropanone (0.01 mol)
was added drop wise over a period of 1h. The reaction mixture was
left overnight at room temperature and then the solid product formed
collected by filtration, washed thoroughly with water and then dried
over anhydrous sodium sulfate and recrystallised.
Pale brown crystals (80%) from DMSO/EtOH, m.p. > 250 °C; IR:
3327 (NH), 1704 cm−1 (CO); H NMR: δ 8.03 (br, 2H, 2NH, D2O-
1
exchange), 6.92 (s, 4H, aromatic-H), 4.16 ppm (s, 4H, 2CH2), 2.50
(s, 6H, 2Me); 13C NMR: δ 206.4 (CO), 148.9, 145.1, 126.4, 125.8,
65.0, 25.3 (aromatic, carbons methylene and methyl carbons); Accu-
rate mass: m/z 220.12; Anal. Calcd for C12H16N2O2 (220.27): C, 65.43;
H, 7.32; N, 12.72. Found: C, 65.33; H, 6.96; N, 12.64%.
(E)-4-(dimethylamino)-1-(phenylamino)but-3-en-2-one (4a): To a
solution of 3 (0.01 mol) in DMF (30 mL), dimethyl formamide
dimethyl acetal (0.01 mol) was added. The reaction mixture was
warmed and left overnight. The solid product formed was collected by
filtration, washed thoroughly with water and then recrystallised.
Brown crystals (70%) from DMF/EtOH, m.p. 140 °C; IR: 3327 (NH),
Conclusions
In summary, using N-alkylated p-phenylenediamine provided
an efficient synthesis of substituted bisazoles.
Scheme 5

JOURNAL OF CHEMICAL RESEARCH 2012 331
Table 1 Biological activity of the prepared compounds
2.08 (s, 6H, 2Me); 13C NMR: δ 201.0 (CO), 137.9, 122.1 (C6H4 carbons).
121.0, 120.8, 120.6, 114.3 (pyrrole carbons), 28.6, 14.7 (2Me); Accu-
rate mass: m/z 352.14; Anal. Calcd for C20H20N2O4 (352.38): C, 68.17;
H, 5.72; N, 7.95. Found: C, 68.33; H, 5.98; N, 7.64%.
11: Pale brown crystals (70%) from acetone, m.p. > 250 °C; IR:
1711 cm−1 (CO); 1H NMR: δ 6.92 (s, 4H, C6H4), 6.78 (s, 2H, pyrrole-
H), 2.55 (s, 6H, 2Me), 2.23 (s, 6H, 2Me), 2.08 (s, 6H, 2Me); 13C NMR:
δ 200.9 (CO), 137.9, 122.1 (C6H4 carbons), 136.4 122.0, 120.8, 120.6
(pyrrole carbons), 29.0, 14.7, 12.8 (3Me); Accurate mass: m/z 348.18;
Anal. Calcd for C22H24N2O2 (348.44): C, 75.83; H, 6.94; N, 8.04.
Found: C, 75.76; H, 6.98; N, 7.98%.
Cpd
E. Coli
S. Aureus
B. Subtilis P. Aeruginosa
3
++
+++
+++
+
+++
++++
++
++++
++++
++
+++
++
++
+++
+++
++
++++
+++
++
++
+++
++
++
++
++++
+
+++
+++
++
6
8
9
10
11
17a
17b
17c
++
+++
++
+++
++++
++
+
Synthesis of 2-(anthracen-9-ylmethylene)malononitrile (12d)
To a solution of anthracene-9-carbaldehyde (0.01 mol) and malono-
nitrile (0.01 mol) in ethanol (20 mL), triethylamine (five drops) was
added. The reaction mixture was warmed and then left at room
temperature for 2 h. The solid product was collected by filtration and
recrystallised.
++++ Severe effect (>30 mm), +++ high effect (25–29 mm),
++ moderate effect (20–24 mm), + weak effect (< 20 mm)
1704 cm−1 (CO); 1H NMR: δ 8.03 (br, 2H, 2NH, D2O-exchange), 6.78
(s, 4H, aromatic-H), 5.12 and 7.63 (d, 4H, 4CH=, J = 13 Hz), 4.32
ppm (s, 4H, 2CH2), 2.96 (s, 12H, 2NMe2); 13C NMR: δ 196.4 (CO),
152.2, 140.9, 136.1, 101.1 (aromatic and ethylenic carbons), 62.2
(CH2), 43.3 (NMe2); Accurate mass: m/z 330.21; Anal. Calcd for
C18H26N4O2 (330.42): C, 65.43; H, 7.93; N, 16.96. Found: C, 65.49; H,
7.69; N, 16.76%.
12d: Orange crystals (90%) from ethanol, m.p. 202–204 °C; IR:
2229 cm−1 (CN); 1H NMR: δ 8.86 (s, 1H, ethylenic-H)), 9.66 (s, 1H,
anthracene-H8), 8.22–8.17 (t, 4H, anthracene-H), 7.71–7.64 (m, 4H,
anthracene-H); 13C NMR: δ 162.5 (CH=), 135.2, 131.4, 130.6, 129.3,
128.4, 125.8, 125.1 (anthracene carbons), 113.4, 112.2 (2CN), 92.0
(C=); accurate mass: m/z 254.08; Anal. Calcd for C18H10N2 (254.29):
C, 85.02; H, 3.96; N, 11.02. Found: C, 85.12; H, 3.98; N, 10.99%.
Synthesis of 5-acetyl-2-amino-4-phenyl-1-(4-(5-acetyl-2-amino-3-
cyano-4-phenyl-1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-carbonitrile
(14a); 5-acetyl-2-amino-4-p-nitrophenyl-1-(4-(5-acetyl-2-amino-3-
cyano-4-p-nitrophenyl-1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-carbo-
nitrile (14b); 5-acetyl-2-amino-4-p-methoxyphenyl-1-(4-(5-acetyl-2-
amino-3-cyano-4-p-methoxy phenyl-1H-pyrrol-2-yl)phenyl)-1H-pyr-
role-3-carbonitrile (14c); 5-acetyl-2-amino-4-anthracen-10-yl-1-(4-(5-
acetyl-2-amino-3-cyano-4-anthracen-9-yl-1H-pyrrol-2-yl)phenyl)-
1H-pyrrole-3-carbonitrile (14d)
To a solution of 3 (0.01 mol) in DMF (30 mL), benzylidenemalono-
nitrile or p-nitrobenzylidene-malononitrile or p-methoxybenzyliden-
emalononitrile or 2-(anthracen-10-ylmethylene)malon-onitrile (0.01 mol)
and 10 drops triethylamine were added. The reaction mixture was
heated under reflux for 3 h. The solid product formed upon addition of
water was collected by filtration, washed thoroughly with water then
dried over anhydrous sodium sulfate and recrystallised.
5-Acetyl-2-amino-4-phenyl-1-(4-(5-acetyl-2-amino-3-cyano-4-phenyl-
1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-carbonitrile (14a): Brown crys-
tals (56%) from acetone, m.p. 186–188 °C; IR: 3374, 3236 (NH2),
2188 (CN), 1688 cm−1 (CO); 1H NMR: δ 7.59–7.02 (m, 10H, 2C6H5),
6.93 (m, 4H, C6H4), 7.32 (br, 4H, 2NH2), 2.50 (s, 6H, 2Me); 13C NMR:
δ 201.0 (CO), 136.9, 121.6 (C6H4 carbons), 136.3, 129.3, 128.8, 127.5,
126.8 (phenyl carbons), 136.8,129.0, 127.9, 108.1 (pyrrole carbons),
20.9, 20.1 (2Me); MS: m/z 524.5;Anal. Calcd for C32H24N6O2 (524.57):
C, 73.27; H, 4.61; N, 16.02. Found: C, 73.32; H, 4.78; N, 16.42%.
5-Acetyl-2-amino-4-p-nitrophenyl-1-(4-(5-acetyl-2-amino-3-cyano-
4-p-nitrophenyl-1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-carbonitrile
(14b): Brown crystals (56%) from acetone, m.p. 117–119 °C; IR:
3359, 3256 (NH2), 2188 (CN), 1704 cm−1 (CO), 1H NMR: δ 8.37–7.78
(m, 8H, 2C6H4), 6.94 (m, 4H, 2C6H4), 7.64 (br, 4H, 2NH2), 2.50 (s,
6H, 2Me); 13C NMR: δ 153.4 (CO), 131.0, 123.4 (C6H4 carbons),
148.6, 143.9, 128.9, 120.6 (p-nitrophenyl carbons), 136.8,129.4,
127.4, 112.7 (pyrrole carbons), 20.9, 18.5 (2Me); MS: m/z 614.5;
Anal. Calcd for C32H22N8O6 (614.57): C, 62.54; H, 3.61; N, 18.23.
Found: C, 62.45; H, 3.77; N, 18.20%.
5-Acetyl-2-amino-4-p-methoxyphenyl-1-(4-(5-acetyl-2-amino-3-
cyano-4-p-methoxyphenyl-1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-car-
bonitrile (14c): Brown crystals (73%) from acetone, m.p. > 250 °C;
IR: 3417, 3386 (NH2), 2183 (CN), 1684 cm−1 (CO); 1H NMR: δ 7.87–
7.42 (m, 8H, 2C6H4), 6.96 (m, 4H, C6H4), 7.30 (br, 4H, 2NH2), 3.01 (s,
6H, 2OMe), 2.50 (s, 6H, 2Me); 13C NMR: δ 201.0 (CO), 137.9, 122.6
(C6H4 carbons), 155.4, 129.3, 128.8, 127.5, 126.8 (p-methoxyphenyl
carbons), 136.8,129.0, 127.9, 108.1 (pyrrole carbons), 49.5, 50.1
(2OMe), 20.9, 20.1 (2Me); MS: m/z 584.5;Anal. Calcd for C34H28N6O4
(584.62): C, 69.85; H, 4.83; N, 14.38. Found: C, 70.01; H, 4.77; N,
14.34%.
Synthesis of 1-(4-(3-hydroxy-1H-pyrrol-1-yl)phenyl)-1H-pyrrol-3-ol
(6a)
Method A: To a solution of 4a (0.01 mol) in DMF (30 mL), trieth-
ylamine (10 drops) was added. The reaction mixture was heated under
reflux for 3h. The solid product formed was collected by filtration,
washed thoroughly with water and then recrystallised.
Method B: To a solution of 3 (0.01 mol) in DMF (30 mL) and
triethylamine (10 drops), triethyl orthoformate or dimethyl formamide
dimethyl acetal (0.01 mol) was added. The reaction mixture was
heated under reflux for 3 h. The solid product formed upon addition of
water was collected by filtration, washed thoroughly with water and
then dried over anhydrous sodium sulfate and recrystallised.
6a: Brown crystals (80%) from DMSO/EtOH, m.p.>250 °C; IR:
3419 cm−1 (OH); 1H NMR: δ 5.03 (br, 2H, 2OH, D2O-exchange), 6.91
(s, 4H, aromatic-H), 6.85, 6.53 (dd, 4H, 2pyrrole-H, J = 8.4 Hz),
6.35 (s, 2H, 2pyrrole-H); 13C NMR: δ 145.1, 137.3, 129.6, 120.8,
117.0, 114.2, 115.1 (aromatic and pyrrole carbons). Accurate mass:
m/z 240.09; Anal. Calcd for C14H12N2O2 (240.26): C, 69.99; H, 5.03;
N, 11.66. Found: C, 70.10; H, 4.96; N, 11.64%.
Synthesis of 2-amino-1-(4-(2-amino-3-cyano-4-methyl-1H-pyrrol-
1-yl)phenyl)-4-methyl-1H-pyrrole-3-carbonitrile (8); ethyl 2-amino-
1-(4-(2-amino-3-ethylcarboxylate-4-methyl-1H-pyrrol-1-yl)phenyl)-
4-methyl-1H-pyrrole-3-carboxylate (9); 3-acetyl-2-hydroxy-1-(4-(3-
acetyl-2-hydroxy-4-methyl-1H-pyrrol-1-yl)phenyl)-4-methyl-1H-
pyrrole (10); 3-acetyl-1-(4-(3-acetyl-2,4-dimethyl-1H-pyrrol-1-yl)-
phenyl)-2,4-dimethyl-1H-pyrrole (11).
To a solution of 3 (0.01 mol) in DMF (30 mL), triethylamine
(0.01mole), malononitrile or ethyl cyanoacetate, ethyl acetoacetate or
acetyl acetone (0.01 mol) was added. The reaction mixture was heated
under reflux for 3 h. The solid product formed upon addition of water
was collected by filtration, washed thoroughly with water and then
dried over anhydrous sodium sulfate and recrystallised.
8: Brown crystals (60%) from acetone, m.p. > 250 °C; IR: 3358,
3226 (NH2), 2187 cm−1 (CN); 1H NMR: δ 6.93 (s, 4H, C6H4), 7.24 (br,
4H, 2NH2, D2O-exchange), 6.64 (s, 2H, pyrrole-H), 2.08 (s,6H, 2Me);
13C NMR: δ 137.6, 121.0 (C6H4 carbons). 120.8, 120.7, 120.6, 114.3
(pyrrole carbons), 117.9 (CN), 24.0 (Me); Accurate mass: m/z 316.14;
Anal. Calcd for C18H16N6 (316.36): C, 68.34; H, 5.10; N, 26.56. Found:
C, 68.33; H, 4.98; N, 26.64%.
9: Pale brown crystals (70%) from acetone, m.p.> 250 °C; IR: 3358,
3226 (NH2), 1736 cm−1 (CO); 1H NMR: δ 6.91 (s, 4H, C6H4), 7.25 (br,
4H, 2NH2, D2O-exchange), 6.70 (s, 2H, pyrrole-H), 4.20 (q, 4H,
2CH2), 2.23 (s, 6 H, 2Me), 1.31 (t, 6H, 2Me); 13C NMR: δ 165.5 (CO),
137.6, 121.1 (C6H4 carbons). 121.0, 120.6, 120.6, 114.3 (pyrrole
carbons), 60.6 (CH2), 14.5 (Me); Accurate mass: m/z 410.20; Anal.
Calcd for C22H26N4O4 (410.47): C, 64.37; H, 6.38; N, 13.65. Found: C,
64.33; H, 6.38; N, 13.64%.
5-Acetyl-2-amino-4-anthracen-10-yl-1-(4-(5-acetyl-2-amino-3-
cyano-4-anthracen-9-yl-1H-pyrrol-2-yl)phenyl)-1H-pyrrole-3-carbo-
nitrile (14d): Brown crystals (56%) from acetone, m.p. 186–188 °C;
IR: 3374, 3226 (NH2), 2191 (CN), 1684 cm−1 (CO); 1H NMR: δ 8.86–
7.51 (m, 18H, 2 anthracene), 6.74 (m, 4H, 2C6H4), 7.39 (br, 4H,
10: Pale brown crystals (74%) from acetone, m.p. > 250 °C; IR:
3443 (OH), 1711 cm−1 (CO); 1H NMR: δ 6.90 (s, 4H, C6H4), 6.23 (br,
2H, 2OH, D2O-exchange), 6.78 (s, 2H, pyrrole-H), 2.53 (s, 6H, 2Me),

332 JOURNAL OF CHEMICAL RESEARCH 2012
2NH2), 2.53 (s, 6H, 2Me); 13C NMR: δ 162.7 (CO), 131.3, 121.9 (C6H4
carbons), 131.1, 131.0, 129.7, 128.9, 128.6, 127.4, 126.5 (anthracene
carbons), 136.8,129.0, 127.4, 114.8 (pyrrole carbons), 116.8, 116.1
(2CN), 36.2, 31.2 (2Me); MS: m/z 724.8; Anal. Calcd for C48H32N6O2
(724.81): C, 79.54; H, 4.45; N, 11.59. Found: C, 79.33; H, 4.62; N,
11.54%.
Synthesis of 1,4-bis[(2-oxopropyl-3-phenylhydrazo)amino]benzene
(17a); 1,4-bis[(2-oxopropyl-3-(p-nitrophenylhydrazo))amino]benzene
(17b); 1,4-bis[(2-oxopropyl-3-(p-chlorophenylhydr azo))amino] ben-
zene (17c).
2-amino-1-(4-(2-amino-3-cyano-4-methyl-5-p-chlorophenyldiaze-
nyl-1H-pyrrol-1-yl)phenyl)-4-methyl-5-p-chlorophenyldiazenyl-1H-
pyrrole-3-carbonitrile (18c): Brown crystals (56%) from acetone,
1
m.p. > 250 °C; IR: 3340, 3342 (2NH2), 2210, 2213 cm−1 (CN); H
NMR: δ 10.23 (br, 4H, 2NH2), 7.60–7.33 (m, 8H, p-chlorophenyl),
6.91 (m, 4H, C6H4), 2.23 (s, 6H, 2Me); δ 13C NMR: δ 128.4, 126.5,
124.6, 124.2 (pyrrole carbons), 137.4, 121.6 (C6H4 carbons), 133.5,
131.2, 122.2, 121.5 (phenyl carbons), 21.9, 21.8 (2Me); MS: m/z
593.50; Anal. Calcd for C30H20Cl2N10 (593.47): C, 60.71; H, 3.74; N,
23.60. Found: C, 60.62; H, 3.51; N, 23.74%.
A mixture of 3 (0.01 mol) in DMF (30 mL), sodium hydroxide
(1.0 g), the appropriate arene diazonium chloride (0.01 mol) [prepared
by adding sodium nitrite (0.02 mol) to the appropriate primary aro-
matic amine (0.01 mol) in concentrated HCl (2 mL) at 0–5 °C while
stirring] was added dropwise while cooling at 0–5 °C and stirring. The
reaction mixture was left at 5 °C for 3 h. The solid product that formed
was filtered off and washed many times with water and then recrystal-
lised.
1,4-Bis[(2-oxopropyl-3-phenylhydrazo)amino]benzene (17a): Brown
crystals (51%) from acetone, m.p. > 250 °C; IR: 3334, 3223 (2NH),
1689 cm−1 (CO); 1H NMR: δ 7.01–6.76 (m, 10H, 2 phenyl), 6.74 (m,
4H, 2C6H4),10.23, 7.39 (br, 4H, 4NH), 2.23 (s, 6H, 2Me); 13C NMR:
δ 176.7 (CO), 156.2 (C=N), 135.3, 121.7 (C6H4 carbons), 143.2,
131.2, 122.2, 121.3 (phenyl carbons), 28.2, 28.4 (2Me); MS: m/z
428.5; Anal. Calcd for C24H24N6O2 (428.49): C, 67.27; H, 5.65; N,
19.61. Found: C, 67.43; H, 5.56; N, 19.70%.
Bioactivity: minimum inhibitory concentration (MIC)
The selected compounds were screened for their antibacterial activity
against E. coli, P. aeruginosa, B. subtlitis and S. aureus. MIC was
evaluated by the turbidity method. A loopful of bacteria was inocu-
lated in 100 mL of nutrient broth at 37 °C for 20 h in a test-tube shaker
at 150 rev min−1. The test Compounds were prepared by dissolving in
a minimal volume of DMSO and were serially diluted in Mueller-
Hinton broth at concentrations in the range of 1–100 mg mL−1. The
24-h bacterial cultures were then transferred into 10 mL of Muller-
Hinton broth (control and test Compounds) and incubated at 37 °C for
24h. The growth of the bacteria was determined by measuring the tur-
bidity after 24h. Thus, the MIC was generally read as the smallest
concentration of drug in the series that prevents the development
of visible growth of test organism. All the experiments were done in
triplicate.
1,4-Bis[(2-oxopropyl-3-(p-nitrophenylhydrazo))amino]benzene
(17b): Brown crystals (51%) from acetone, m.p. > 250 °C; IR: 3334,
3223 (2NH), 1689 cm−1 (CO); 1H NMR: δ 8.01–7.76 (m, 8H, 2
p-nitrophenyl), 6.76 (m, 4H, C6H4),10.33, 7.39 (br, 4H, 4NH), 2.33 (s,
6H, 2Me); 13C NMR: δ 193.0 (CO), 156.2 (C=N), 135.3, 121.7 (C6H4
carbons), 152.0, 143.2, 123.2, 122.0 (p-nitrophenyl carbons), 29.3,
29.4 (2Me); MS: m/z 518.5; Anal. Calcd for C24H22N8O6 (518.48): C,
55.60; H, 4.28; N, 21.61. Found: C, 55.55; H, 4.43; N, 21.71%.
1,4-Bis[(2-oxopropyl-3-(p-chlorophenylhydrazo))amino]benzene
(17c): Brown crystals (56%) from acetone, m.p. > 250 °C; IR: 3334,
3223 (2NH), 1689 cm−1 (CO); 1H NMR: δ 7.81–6.56 (m, 8H, 2 p-chlo-
rophenyl), 6.95 (m, 4H, C6H4),10.33, 7.39 (br, 4H, 4NH), 2.23 (s, 6H,
2Me); 13C NMR: δ 176.7 (CO), 156.3 (C=N), 135.4, 121.6 (C6H4
carbons), 143.8, 131.6, 122.3, 121.3 (p-chlorophenyl carbons), 28.4,
28.5 (2Me); MS: m/z 497.0; Anal. Calcd for C24H22Cl2N6O2 (497.38):
C, 57.96; H, 4.46; N, 16.90. Found: C, 58.01; H, 4.56; N, 16.71%.
Synthesis of 2-amino-1-(4-(2-amino-3-cyano-4-methyl-5-phenyldi-
azenyl-1H-pyrrol-1-yl)phenyl)-4-methyl-5-phenyldiazenyl-1H-pyr-
role-3-carbonitrile (18a); 2-amino-1-(4-(2-amino-3-cyano-4-methyl-
5-p-nitrophenyldiazenyl-1H-pyrrol-1-yl)phenyl)-4-methyl-5-p-nitro-
phenyldiazenyl-1H-pyrro-le-3-carbonitrile (18b); 2-amino-1-(4-(2-
amino-3-cyano-4-methyl-5-p-chlorophenyldiaz-enyl-1H-pyrrol-1-yl)
phenyl)-4-methyl-5-p-chlorophenyldi-azenyl-1H-pyrrole-3-carboni-
trile (18c)
A mixture of 17 (0.01 mol), ammonium acetate (5–7g) and malono-
nitrile (0.01 mol) was heated at 160 °C for 2h. The solid product so
formed was collected by filtration, washed thoroughly with water and
then dried over sodium sulfate anhydrous and recrystallised from
proper solvent.
2-Amino-1-(4-(2-amino-3-cyano-4-methyl-5-phenyldiazenyl-1H-
pyrrol-1-yl)phenyl)-4-methyl-5-phenyldiazenyl-1H-pyrrole-3-carbo-
nitrile (18a): Brown crystals (56%) from acetone, m.p. > 250 °C; IR:
3342, 3348 (2NH2), 2210, 2212 cm−1 (CN); 1H NMR: δ 10.43 (br, 4H,
2NH2), 7.61–7.32 (m, 10H, phenyl), 6.94 (m, 4H, C6H4), 2.11 (s, 6H,
2Me); δ 13C NMR: δ 128.4, 126.3, 124.7, 124.2 (pyrrole carbons),
137.4, 121.6 (C6H4 carbons), 133.6, 131.6, 122. 1, 121.5 (phenyl
carbons), 21.9, 21.7 (2Me); MS: m/z 524.5; Anal. Calcd for C30H24N10
(524.58): C, 68.69; H, 4.61; N, 26.70. Found: C, 68.63; H,4.51; N,
26.81%.
Received 8 February 2012; accepted 20 March 2012
Paper 1201154 doi: 10.3184/174751912X13353579628083
Published online: 4 June 2012
References
1
2
3
M. Minoshima, J.C. Chou, S. Lefebvre, T. Bando, K.-i Shinohara,
J.M. Gottesfeld and H. Sugiyama, Bioorg. Med. Chem., 2010, 18, 168.
A. Bennasroune, A. Gardin, D. Aunis, G. Cremel and P. Hubert, Crit. Rev.
Oncol. Hematol., 2004, 50, 23.
K.J. Moriarty, H.K. Koblish, T. Garrabrant, J. Maisuria, E. Khalil, F. Ali,
I.P. Petrounia, C.S. Crysler,A.C. Maroney, D.L. JohnsonandR.A.Galemmo,
Bioorg. Med. Chem. Lett., 2006, 16, 5778.
4
5
6
M.M. Ghorab, F.A. Ragab, H.I. Heiba, H.A. Youssef and M.G. El-Gazzar,
Bioorg. Med. Chem. Lett., 2010, 20, 6316
A. Rosowsky, H. Chen, H. Fu and S. F Queener, Bioorg. Med. Chem., 2003,
11, 59.
H.S. Choi, Z.Wang, W. Richmond, X. He, K.Yang, T. Jiang, D. Karanewsky,
X.J. Gu, V. Zhou, Y. Liu, J. Che, C.C. Lee, J. Caldwell, T. Kanazawa,
I. Umemura, N. Matsuura, O. Ohmori, T. Honda, N. Gray and Y. He,
Bioorg. Med. Chem. Lett., 2006, 16, 2689.
7
8
D.O. Morgan, Can. J. Sci. Am., 1998, 4, 1081.
A. Stefanachi, O. Nicolotti, F. Leonetti, S. Cellamare, F. Campagna,
M.I. Loza, J.M. Brea, F. Mazza, E. Gavuzzo and A. Carotti, Bioorg. Med.
Chem., 2008, 16, 9780.
9
G. Sbardella, A. Mai, M. Artico, R. Loddo, M.G. Setzu and P.L. Colla,
Bioorg. Med. Chem. Lett., 2004, 14, 1537.
10 J.M. Padrón, D. Tejedor, A. Santos-Exposito, F. Garcıa-Tellado,
V.S. Martinc and J. Villara, Bioorg. Med. Chem. Lett., 2005, 15, 2487.
11 T. Watanabe, Y. Umezawa, Y. Takahashi and Y. Akamatsu, Bioorg. Med.
Chem. Lett., 2010, 20, 5807.
12 H. Lee, J. Lee, S. Lee, Y. Shin, W. Jung, J.-H. Kim, K. Park, K. Kim,
H.S. Cho, S. Ro, S. Lee, S.W. Jeong, T. Choi, H.-H Chung and J.S. Koh,
Bioorg. Med. Chem. Lett., 2001, 11, 3069.
13 C. Jiang, J.YanandY. Lin, FamingZhuanliShenqingGongkaiShuomingshu,
2009, [CN 101407486 A 20090415] http://worldwide.espacenet.com/
publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true
&locale=en_EP&FT=D&date=20090415&CC=CN&NR=101407486A
&KC=A
14 F. Al-Omran, A.A. Elassar and A.A. El-khair, J. Heterocycl. Chem., 2003,
40, 249.
2-Amino-1-(4-(2-amino-3-cyano-4-methyl-5-p-nitrophenyldiaze-
nyl-1H-pyrrol-1-yl)phenyl)-4-methyl-5-p-nitrophenyldiazenyl-1H-
pyrrole-3-carbonitrile (18b): Brown crystals (56%) from acetone,
15 A.-L.Fan, W.-H Lin and Y.-X. Jia, J.Chin. Pharm. Sci., 2011, 20, 425.
16 L. He-Ping, Bioorg. Med. Chem. Lett., 2006, 16, 6298.
17 B.A. Schweitzer, P.J. Loida, C.A. CaJacob, R.C. Chott, E.M. Collantes,
S.G. Hegde, P.D. Mosier and S. Profeta, Bioorg. Med. Chem. Lett., 2002,
12, 1743.
1
m.p. > 250 °C; IR: 3340, 3342 (2NH2), 2210, 2212 cm−1 (CN); H
NMR: δ 10.48 (br, 4H, 2NH2), 8.51–7.32 (m, 8H, p-nitrophenyl), 6.93
(m, 4H, C6H4), 2.14 (s, 6H, 2Me); δ 13C NMR: δ 128.6, 126.2, 124.5,
124.1 (pyrrole carbons), 137.4, 121.7 (C6H4 carbons), 138.6, 137.6,
122.1, 121.5 (p-nitrophenyl carbons), 22.9, 22.8 (2Me); MS: m/z
614.5; Anal. Calcd for C30H22N12O4 (614.57): C, 58.63; H, 3.61; N,
27.35. Found: C, 58.50; H, 3.44; N, 27.55%.
18 Y. Umasankar, S.A. Kumar and S.-M. Chen, Nanostruct.Mater.
Electrochem. Biosen., 2009, 239–259.
19 E.Yasui, M. Wada and N. Takamura, Tetrahedron Lett., 2009, 50, 4762.
20 R. Rossi and F. Bellina, Tetrahedron, 2006, 62, 7213.

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