Ultrasonic synthesis, characterization, and antibacterial evaluation of novel heterocycles containing hexahydroquinoline and pyrrole moieties

Article abstract of DOI:10.1515/hc-2016-0164

Condensation reaction of dimedone with 2-amino-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile in ethanol containing a catalytic amount of p-toluenesulfonic acid (TsOH) afforded 2-(5,5-dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5-diphenyl-1H-pyrrole-3

Full text of DOI:10.1515/hc-2016-0164

Heterocycl. Commun. 2017; aop
Simin Vazirimehr, Abolghasem Davoodnia*, Mahboobeh Nakhaei-Moghaddam
and Niloofar Tavakoli-Hoseini
Ultrasonic synthesis, characterization, and
antibacterial evaluation of novel heterocycles
containing hexahydroquinoline and pyrrole
moieties
DOI 10.1515/hc-2016-0164
Received October 12, 2016; accepted December 28, 2016
Introduction
Abstract: Condensation reaction of dimedone with The 1,4-dihydropyridine (1,4-DHP) core is present in a
2-amino-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbon- range of compounds exhibiting a broad spectrum of bio-
itrile in ethanol containing a catalytic amount of logical activities [1, 2] including antimicrobial [3], antitu-
p-toluenesulfonic acid (TsOH) afforded 2-(5,5-dime- bercular [4], insecticidal [5], and neuroprotectant [6]
thyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5-diphe- properties. In particular, 4-aryl-1,4-DHPs are well known
nyl-1H-pyrrole-3-carbonitrile. This compound was then as calcium channel blockers and have emerged as one
treated with olefins, formed by Knoevenagel condensa- of the most important class of drugs for the treatment
tion of aryl aldehydes and malononitrile, in ethanol in the of cardiovascular diseases [7, 8]. On the other hand, the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as pyrrole moiety has emerged as a privileged scaffold in
catalyst to give novel cyclic compounds in high yields. A drug design and discovery [9] and generated great atten-
new hexacyclic heterocyclic compound was formed when tion because of various important biological properties
2-hydroxybenzaldehyde was used as the aldehyde. The such as anticancer [10–12], antiviral [12], antitubercular
reactions were done using ultrasonic irradiation. The syn- [13], antibacterial [14], analgesic [15], anti-inflammatory
1
thesized compounds were characterized by IR, H NMR, [15, 16], and antifungal [17] activities. They have also been
and 13C NMR spectra, elemental analysis and evaluated widely employed as selective aldose reductase [18], CHK1
for their antibacterial activity against Gram-positive bac- [19], JAK2 [20], and COX-2 [21] inhibitors. Because of the
teria (Staphylococcus aureus and Micrococcus luteus) and importance of these heterocycles we became interested in
Gram-negative bacterium (Escherichia coli).
the synthesis of some novel heterocyclic compounds con-
taining both hexahydroquinoline and pyrrole scaffolds.
Ultrasonic irradiation has increasingly been used as
a very significant nontraditional technique for accelerat-
ing organic reactions [22, 23]. Compared with traditional
methods, the salient features and benefits of ultrasonic
irradiation technique includes reduced reaction times,
reduced energy consumption, enhanced selectivity, and
improved yields [24, 25]. Often, the reactions under ultra-
sound irradiation are commonly easier to work up than
those in conventional methods [26–28].
Inspired by these facts and due to our interest in the
synthesis of heterocyclic compounds with potential bio-
logical activities [29–38], we report here a convenient
ultrasonic assisted synthesis of new compounds contain-
ing hexahydroquinoline and pyrrole moieties (Scheme 1).
Antibacterial assay of the synthesized compounds was
also conducted against two strains of Gram positive bac-
teria, Staphylococcus aureus (S. aureus, PTCC 1112) and
Micrococcus luteus (M. luteus, PTCC 1110), and one strain
Keywords: antibacterial; hexahydroquinoline; pyrrole;
ultrasonic irradiation.
*Corresponding author: Abolghasem Davoodnia, Department of
Chemistry, Mashhad Branch, Islamic Azad University, Mashhad,
Iran, e-mail: adavoodnia@mshdiau.ac.ir; adavoodnia@yahoo.com
Simin Vazirimehr: Department of Chemistry, Mashhad Branch,
Islamic Azad University, Mashhad, Iran
Mahboobeh Nakhaei-Moghaddam: Department of Biology, Mashhad
Branch, Islamic Azad University, Mashhad, Iran
Niloofar Tavakoli-Hoseini: Department of Chemistry, Mashhad
Branch, Islamic Azad University, Mashhad, Iran; and Department of
Biochemistry and Clinical Laboratories, Tabriz University of Medical
Sciences, Tabriz, Iran
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2ꢀ
ꢀS. Vazirimehr et al.: Novel heterocycles containing hexahydroquinoline and pyrrole moieties
O
Ar
N
O
Ar
N
CN
N
CN
for Ar = 2-ClC 6H4 and 3-BrC6H4
NH2
CN
Me
NH2
Me
N
N
Ph
Ph
Ph
Ph
8a: Ar = 2-ClC6H4
: Ar = 3-BrC6H4
7a: Ar = 2-ClC6H4
7b: Ar = 3-BrC6H4
8b
CN
Ar
CN
CN
O
Ar
H
O
Ar
N
CN
H
CN
CN
4a
: Ar = 2-ClC6H4
4b: Ar = 3-BrC6H4
4c: Ar = 2-HOC6H4
5
6a
: Ar = 2-ClC6H4
6b: Ar = 3-BrC6H4
6c: Ar = 2-HOC6H4
EtOH, DBU
NH
ultrasonic
Me
Ph
CN
Ph
O
O
Ph
CN
NH2
I
EtOH, TsOH
ultrasonic
NH
Ph
Me
CN
Ph
N
O
N
Me
1
2
3
Ph
OH
CN
O
O
O
N
N
H
for Ar = 2-HOC6H4
N
NH2
CN
N
Me
Me
NH2
N
N
Ph
Ph
Ph
Ph
9
7c
Scheme 1ꢁ
of Gram negative bacterium, Escherichia coli (E. coli, PTCC preparation of this compound was also investigated by
1330) by agar dilution method using 24-well microtiter refluxing 1 with 2 in the presence of TsOH in ethanol. The
plates. Gentamicin and chloramphenicol (100 μg/mL) results showed that the classical approach for the synthe-
were used as positive controls.
sis of compound 3 is a tedious method affording a rela-
tively lower yield (78%) of 3 after a much longer reaction
time (120 min).
Compound 3 was allowed to react with olefins 6a and
6b, that had been obtained by Knoevenagel condensa-
tion of aromatic aldehydes 4a and 4b with malononitrile
Results and discussion
Condensation of dimedone (1) with 2-amino-1-methyl- 5 [40, 41], in the presence of a basic catalyst under ultra-
4,5-diphenyl-1H-pyrrole-3-carbonitrile (2) [39] in ethanol sonic irradiation at 60°C. Under these conditions, nucleo-
in the presence of p-toluenesulfonic acid (TsOH) as philic conjugate addition followed by cyclization reaction
catalyst under ultrasonic irradiation at 60°C afforded occurred with the involvement of the presumed interme-
2-(5,5-dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5- diate product I, giving the final new 1,4,5,6,7,8-hexahyd-
diphenyl-1H-pyrrole-3-carbonitrile (3) in high yield (92%) roquinolines 7a and 7b in high yields and short reaction
after short reaction time (20 min) as the sole product. Only times. Without a catalyst, the yields were low even after
a trace amount of compound 3 was formed in the absence a long time. Several bases including DBU, DMAP, mor-
of TsOH. For comparison, a traditional method for the pholine, piperidine and Et3N were tested as catalysts. The
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S. Vazirimehr et al.: Novel heterocycles containing hexahydroquinoline and pyrrole moietiesꢀ
ꢀ3
reaction was also conducted in various solvents includ-
ing EtOH, MeOH, H2O, CH3CN and CHCl3. It was found
that the reaction was more facile and proceeded with the
highest yields with DBU in EtOH. Furthermore, to draw
a comparison between ultrasonic irradiation and con-
ventional heating for the preparation of the products 7a
and 7b, a mixture of 3 and 6a or 6b in ethanol was heated
under reflux. It was shown that the ultrasonic irradiation
approach for the synthesis of compounds 7a and 7b is
faster and the yields are higher than those using the con-
ventional heating method. It should be mentioned that
two cyano absorption bands in the IR spectra of the prod-
ucts are seen, which rules out the formation of the alterna-
tive cyclized isomers 8a and 8b.
7a
6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6
(ppm)
Surprisingly, the reaction of compound 3 with the olefin
6c, conducted under similar conditions, using DBU in EtOH
under ultrasonic irradiation, gave the new hexacyclic heter-
ocyclic compound 9. This result can be explained in terms
of nucleophilic attacks of the hydroxy and amino groups at
the cyano moieties in the presumed intermediate product
7c. As expected, the IR spectrum of 9 is devoid of the CN
absorption bands. Structures of products 3, 7a, 7b and 9
were established from their spectral and microanalytical
data. For example, the 1H NMR spectrum of 7a in DMSO-d6
shows two singlets at δ 0.95 and 1.02 for methyl groups, two
doublets at δ 1.94 and 2.09 and two overlapping doublets at
δ 2.27 for diastereotopic protons in two methylene groups.
The IR spectrum of 7a shows NH2 absorption bands at 3456
and 3317 cmꢀ−ꢀ1 and a strong band at 1662 cmꢀ−ꢀ1 for C=O, in
addition to two sharp bands at 2223 and 2188 cmꢀ−ꢀ1 for two
7b
6.6
6.2
5.8
5.4
(ppm)
5.0
4.6
4.2
9
13
CN groups. The C NMR spectrum of 7a is also fully con-
5.6
5.4
5.2
5.0
4.8
4.6 (ppm)
sistent with the assigned structure. Finally, this compound
gave satisfactory results of elemental analysis correspond-
ing to the molecular formula C36H30ClN5O.
Figure 1ꢁExpanded views of 1H NMR spectra of compounds 7a, 7b
and 9 in the methine group region.
As shown in the expanded views of 1H NMR spectra of
compounds 7a, 7b and 9 (Figure 1), the methine group in
compounds 7a and 7b appears as singlet, as expected. By
contrast, the signals for the methine and NH groups in the
1H NMR spectrum of compound 9 are two doublets at δ 4.67
and 5.06 with the coupling constant Jꢀ=ꢀ3.6 Hz. Long-range
couplings across five bonds are rare, but can be observed
under favorable circumstances in rigid conformations.
at the concentrations of 4 mg/mL and 5 mg/mL, respec-
tively, for all compounds. Growth inhibition of bacteria
is observed in the presence of the antibiotics gentamicin
and chloramphenicol at a concentration of 100 μg/mL.
Thus, the antibacterial activity of these compounds
against tested bacteria is less than those of gentamicin
and chloramphenicol.
Antibacterial activity
The synthesized compounds 3, 7a, 7b and 9 were screened
for the antibacterial activity against reference strains of Conclusion
S. aureus, M. luteus and E. coli bacteria. All compounds
inhibit the growth of tested bacteria at the concentration Synthesis of new heterocyclic compounds 3, 7a, 7b and
of 6 mg/mL. The growth of S. aureus and E. coli is observed 9 under ultrasonic irradiation and using a conventional
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4ꢀ
NCH3), 5.06 (s, 1H, =CH), 6.93 (s br., 1H, NH), 7.08–7.32 (m, 10H, HAr);
13C NMR (CDCl3): δ 28.2, 31.6, 33.2, 41.8, 50.4, 89.2, 100.6, 115.8, 123.3,
126.9, 128.4, 128.7, 128.8, 128.9, 130.1, 130.2, 130.9, 132.4, 134.1, 163.4,
198.5. Anal. Calcd for C26H25N3O: C, 78.96; H, 6.37; N, 10.62. Found: C,
78.81; H, 6.24; N, 10.81.
heating method was reported. Their growth-inhibiting
effects on S. aureus, M. luteus and E. coli bacteria were
assayed.
2-Amino-4-(2-chlorophenyl)-1-(3-cyano-1-methyl-4,5-diphenyl-
1H-pyrrol-2-yl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquino-
line-3-carbonitrile (7a)ꢁWhite powder; mp 291–293°C; IR: νꢀ=ꢀ3456
Experimental
and 3317 (NH2), 2223 and 2188 (two C≡N), 1662 cmꢀ−ꢀ1 (C=O); H NMR
Ultrasonication was performed using a Soltec sonicator at a fre-
quency of 40 kHz and a nominal power of 260 W. IR spectra were
obtained in KBr pellets using a Tensor 27 Bruker spectrophotometer.
The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a Bruker 300 FT spectrometer, using TMS as internal standard.
Elemental analyses were performed on a Thermo Finnigan Flash EA
microanalyzer. Melting points were recorded on a Stuart SMP3 melt-
ing point apparatus and are not corrected.
1
DMSO-d6): δ 0.95 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.94 (d, 1H, Jꢀ=ꢀ18.0 Hz,
one proton of diastereotopic protons in CH2), 2.09 (d, 1H, Jꢀ=ꢀ15.0 Hz,
one proton of diastereotopic protons in CH2), 2.27 (d, two overlapping
doublets, 2H, Jꢀ=ꢀ15.0 Hz, two protons of diastereotopic protons in
2CH2), 3.33 (s, 3H, NCH3), 5.03 (s, 1H, CH), 6.29 (s br., 2H, NH2), 7.18–
7.57 (m, 14H, HAr); 13C NMR (CDCl3): δ 27.4, 29.5, 32.4, 35.3, 40.3, 49.8,
66.3, 94.2, 113.5, 113.7, 119.1, 124.2, 126.9, 127.8, 128.3, 128.7, 128.8, 129.1,
129.2, 129.3, 129.6, 130.0, 130.5, 130.9, 131.1, 132.1, 133.2, 141.4, 149.0,
149.1, 195.1. Anal. Calcd for C36H30ClN5O: C, 74.02; H, 5.18; N, 11.99.
Found: C, 73.87; H, 5.35; N, 12.16.
Synthesis of 2-(5,5-dimethyl-3-oxocyclohex-1-
enylamino)-1-methyl-4,5-diphenyl-1H-pyrrole-3-
carbonitrile (3)
2-Amino-4-(3-bromophenyl)-1-(3-cyano-1-methyl-4,5-diphenyl-
1H-pyrrol-2-yl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroqui-
noline-3-carbonitrile (7b)ꢁWhite powder; mp 283–285°C; IR: ν
1
3446 and 3314 (NH2), 2224 and 2189 (two C≡N), 1655 cmꢀ−ꢀ1 (C=O); H
Method A (ultrasonic irradiation) A mixture of dimedone 1 (0.140 g,
1 mmol), 2-amino-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile 2
(0.273 g, 1 mmol), and TsOH (0.034 g, 0.2 mmol, 20 mol% based on
dimedone) in ethanol (5 mL) was sonicated at 60°C for 20 min. The
reaction was monitored using TLC plates eluting with n-hexane/ethyl
acetate (volume ratio, 3:1). After completion of the reaction, the sol-
vent was removed under reduced pressure. The residue was washed
with cold water (2ꢀ×ꢀ5 mL), cold 96% ethanol (5 mL) and crystallized
from ethanol/water to give the pure product 3 in 92% yield.
NMR (DMSO-d6): δ 0.94 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.05 (d, 1H,
Jꢀ=ꢀ18.0 Hz, one proton of diastereotopic protons in CH2), 2.15 (d, 1H,
Jꢀ=ꢀ15.0 Hz, one proton of diastereotopic protons in CH2), 2.32 (t, two
overlapping doublets, 2H, Jꢀ=ꢀ15.0 Hz, two protons of diastereotopic
protons in 2CH2), 3.33 (s, 3H, NCH3), 4.54 (s, 1H, CH), 6.30 (s br., 2H,
NH2), 7.24–7.51 (m, 14H, HAr); 13C NMR (DMSO-d6): δ 27.1, 28.9, 31.9, 32.7,
36.9, 49.8, 60.8, 94.1, 113.0, 115.0, 121.0, 122.2, 123.4, 126.5, 127.7, 128.9,
129.2, 129.3, 129.5, 129.8, 130.0, 130.3, 131.3, 131.5, 131.8, 132.6, 148.9,
150.5, 150.9, 195.5. Anal. Calcd for C36H30BrN5O: C, 68.79; H, 4.81; N,
11.14. Found: C, 68.96; H, 4.93; N, 11.01.
Method B (conventional heating) A mixture prepared as described
above was heated under reflux for 120 min. Workup and purification
conducted as described above gave product 3 in 78% yield.
4-Amino-6-imino-1,14,14-trimethyl-2, 3-diphenyl-1,6,
11b,13,14,15-hexahydro-12H-chromeno[3,4-c]pyrrolo[3′,2′:5,6]
pyrimido[1,2-a]quinolin-12-one (9)ꢁWhite powder; mp 270–272°C;
1
IR: νꢀ=ꢀ3429, 3309 and 3158 (NH2 and NH), 1636 cmꢀ−ꢀ1 (C=O); H NMR
General procedure for the synthesis of compounds 7a,
7b and 9
(CDCl3): δ 0.94 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.43 (s, 2H, CH2), 2.65
(ABq, 2H, Δνꢀ=ꢀ39.9 Hz, JABꢀ=ꢀ17.4 Hz, CH2), 3.70 (s, 3H, NCH3), 4.67
(d, 1H, Jꢀ=ꢀ3.6 Hz, CH), 5.06 (d, 1H, Jꢀ=ꢀ3.6 Hz, =NH), 5.28 (s br., 2H,
NH2), 6.51 (d, 1H, Jꢀ=ꢀ7.2 Hz, HAr), 6.88 (t, 1H, Jꢀ=ꢀ7.2 Hz, HAr), 7.11 (d, 1H,
Jꢀ=ꢀ7.8 Hz, HAr), 7.22 (t, 1H, Jꢀ=ꢀ8.4 Hz, HAr), 7.27–7.40 (m, 10H, HAr); 13C
NMR (CDCl3): δ 27.3, 30.0, 32.2, 35.5, 41.7, 48.1, 50.9, 100.2, 109.9, 113.5,
116.3, 116.7, 118.5, 119.9, 124.3, 126.9, 128.2, 128.4, 128.5, 128.6, 128.7,
129.7, 130.5, 130.8, 134.5, 135.4, 151.0, 151.3, 155.2, 156.8, 168.6, 197.3.
Anal. Calcd for C36H31N5O2: C, 76.44; H, 5.52; N, 12.38. Found: C, 76.71;
H, 5.30; N, 12.64.
Method A (ultrasonic irradiation) A mixture of the olefin 6a–c
(1 mmol), 2-(5,5-dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-
4,5-diphenyl-1H-pyrrole-3-carbonitrile 3 (0.395 g, 1 mmol), and DBU
(0.015 g, 0.1 mmol, 10 mol% based on dimedone) in ethanol (5 mL)
was sonicated at 60°C for 10–15 min. The reaction was monitored and
the product was isolated as described above: 7a, yield 91%; 7b, yield
92%; 9, yield 90%.
Method
B (conventional heating) The mixture prepared as
described above was heated under reflux for 100–120 min. Workup
and isolation of the product was conducted as described above: 7a,
yield 79%; 7b, yield 77%; 9, yield 76%.
Biological assays
Bacterial strains S. aureus (PTCC 1112) and M. luteus (PTCC 1110) as
Gram-positive bacteria and E. coli (PTCC 1330) as Gram negative bac-
terium were obtained from the Iranian Research Organization for
Science and Technology (IROST) in Iran. Antimicrobial assay was
conducted by an agar dilution method in 24-wellꢀmicrotiter plates by
2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5-di-
phenyl-1H-pyrrole-3-carbonitrile (3)ꢁCreamy crystals; mp 222–
224°C; IR: ν 3196 (NH), 2221 (C≡N), 1635 cmꢀ−ꢀ1 (C=O); 1H NMR (CDCl3):
δ 1.06 (s, 6H, 2CH3), 2.18 (s, 2H, CH2), 2.38 (s, 2H, CH2), 3.24 (s, 3H,
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