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

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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 23 Issue 1

Abstract

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-carbonitrile. This compound was then treated with olefins, formed by Knoevenagel condensation of aryl aldehydes and malononitrile, in ethanol in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst to give novel cyclic compounds in high yields. A new hexacyclic heterocyclic compound was formed when 2-hydroxybenzaldehyde was used as the aldehyde. The reactions were done using ultrasonic irradiation. The synthesized compounds were characterized by IR, 1H NMR, and 13C NMR spectra, elemental analysis and evaluated for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Micrococcus luteus) and Gram-negative bacterium (Escherichia coli).

Keywords: antibacterial; hexahydroquinoline; pyrrole; ultrasonic irradiation

Introduction

The 1,4-dihydropyridine (1,4-DHP) core is present in a range of compounds exhibiting a broad spectrum of biological activities [1], [2] including antimicrobial [3], antitubercular [4], insecticidal [5], and neuroprotectant [6] properties. In particular, 4-aryl-1,4-DHPs are well known as calcium channel blockers and have emerged as one of the most important class of drugs for the treatment of cardiovascular diseases [7], [8]. On the other hand, the pyrrole moiety has emerged as a privileged scaffold in drug design and discovery [9] and generated great attention because of various important biological properties such as anticancer [10], [11], [12], antiviral [12], antitubercular [13], antibacterial [14], analgesic [15], anti-inflammatory [15], [16], and antifungal [17] activities. They have also been widely employed as selective aldose reductase [18], CHK1 [19], JAK2 [20], and COX-2 [21] inhibitors. Because of the importance of these heterocycles we became interested in the synthesis of some novel heterocyclic compounds containing both hexahydroquinoline and pyrrole scaffolds.

Ultrasonic irradiation has increasingly been used as a very significant nontraditional technique for accelerating 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 ultrasound irradiation are commonly easier to work up than those in conventional methods [26], [27], [28].

Inspired by these facts and due to our interest in the synthesis of heterocyclic compounds with potential biological activities [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], we report here a convenient ultrasonic assisted synthesis of new compounds containing hexahydroquinoline and pyrrole moieties (Scheme 1). Antibacterial assay of the synthesized compounds was also conducted against two strains of Gram positive bacteria, Staphylococcus aureus (S. aureus, PTCC 1112) and Micrococcus luteus (M. luteus, PTCC 1110), and one strain of Gram negative bacterium, Escherichia coli (E. coli, PTCC 1330) by agar dilution method using 24-well microtiter plates. Gentamicin and chloramphenicol (100 μg/mL) were used as positive controls.

Scheme 1
Scheme 1

Results and discussion

Condensation of dimedone (1) with 2-amino-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (2) [39] in ethanol in the presence of p-toluenesulfonic acid (TsOH) as catalyst under ultrasonic irradiation at 60°C afforded 2-(5,5-dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (3) in high yield (92%) after short reaction time (20 min) as the sole product. Only a trace amount of compound 3 was formed in the absence of TsOH. For comparison, a traditional method for the preparation of this compound was also investigated by refluxing 1 with 2 in the presence of TsOH in ethanol. The results showed that the classical approach for the synthesis of compound 3 is a tedious method affording a relatively 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 condensation of aromatic aldehydes 4a and 4b with malononitrile 5 [40], [41], in the presence of a basic catalyst under ultrasonic irradiation at 60°C. Under these conditions, nucleophilic conjugate addition followed by cyclization reaction occurred with the involvement of the presumed intermediate product I, giving the final new 1,4,5,6,7,8-hexahydroquinolines 7a and 7b in high yields and short reaction times. Without a catalyst, the yields were low even after a long time. Several bases including DBU, DMAP, morpholine, piperidine and Et3N were tested as catalysts. The reaction was also conducted in various solvents including 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 conventional 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 conventional heating method. It should be mentioned that two cyano absorption bands in the IR spectra of the products are seen, which rules out the formation of the alternative cyclized isomers 8a and 8b.

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 heterocyclic 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 cm−1 and a strong band at 1662 cm−1 for C=O, in addition to two sharp bands at 2223 and 2188 cm−1 for two CN groups. The 13C NMR spectrum of 7a is also fully consistent with the assigned structure. Finally, this compound gave satisfactory results of elemental analysis corresponding to the molecular formula C36H30ClN5O.

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 J=3.6 Hz. Long-range couplings across five bonds are rare, but can be observed under favorable circumstances in rigid conformations.

Figure 1 Expanded views of 1H NMR spectra of compounds 7a, 7b and 9 in the methine group region.
Figure 1

Expanded views of 1H NMR spectra of compounds 7a, 7b and 9 in the methine group region.

Antibacterial activity

The synthesized compounds 3, 7a, 7b and 9 were screened for the antibacterial activity against reference strains of S. aureus, M. luteus and E. coli bacteria. All compounds inhibit the growth of tested bacteria at the concentration of 6 mg/mL. The growth of S. aureus and E. coli is observed at the concentrations of 4 mg/mL and 5 mg/mL, respectively, 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.

Conclusion

Synthesis of new heterocyclic compounds 3, 7a, 7b and 9 under ultrasonic irradiation and using a conventional heating method was reported. Their growth-inhibiting effects on S. aureus, M. luteus and E. coli bacteria were assayed.

Experimental

Ultrasonication was performed using a Soltec sonicator at a frequency 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 melting point apparatus and are not corrected.

Synthesis of 2-(5,5-dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (3)

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 solvent was removed under reduced pressure. The residue was washed with cold water (2×5 mL), cold 96% ethanol (5 mL) and crystallized from ethanol/water to give the pure product 3 in 92% yield.

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.

General procedure for the synthesis of compounds 7a, 7b and 9

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%.

2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-1-methyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (3)

Creamy crystals; mp 222–224°C; IR: ν 3196 (NH), 2221 (C≡N), 1635 cm−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, 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.

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-hexahydroquinoline-3-carbonitrile (7a)

White powder; mp 291–293°C; IR: ν=3456 and 3317 (NH2), 2223 and 2188 (two C≡N), 1662 cm−1 (C=O); 1H NMR DMSO-d6): δ 0.95 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.94 (d, 1H, J=18.0 Hz, one proton of diastereotopic protons in CH2), 2.09 (d, 1H, J=15.0 Hz, one proton of diastereotopic protons in CH2), 2.27 (d, two overlapping doublets, 2H, J=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.

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-hexahydroquinoline-3-carbonitrile (7b)

White powder; mp 283–285°C; IR: ν 3446 and 3314 (NH2), 2224 and 2189 (two C≡N), 1655 cm−1 (C=O); 1H NMR (DMSO-d6): δ 0.94 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.05 (d, 1H, J=18.0 Hz, one proton of diastereotopic protons in CH2), 2.15 (d, 1H, J=15.0 Hz, one proton of diastereotopic protons in CH2), 2.32 (t, two overlapping doublets, 2H, J=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.

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; IR: ν=3429, 3309 and 3158 (NH2 and NH), 1636 cm−1 (C=O); 1H NMR (CDCl3): δ 0.94 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.43 (s, 2H, CH2), 2.65 (ABq, 2H, Δν=39.9 Hz, JAB=17.4 Hz, CH2), 3.70 (s, 3H, NCH3), 4.67 (d, 1H, J=3.6 Hz, CH), 5.06 (d, 1H, J=3.6 Hz, =NH), 5.28 (s br., 2H, NH2), 6.51 (d, 1H, J=7.2 Hz, HAr), 6.88 (t, 1H, J=7.2 Hz, HAr), 7.11 (d, 1H, J=7.8 Hz, HAr), 7.22 (t, 1H, J=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.

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 bacterium 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-wellmicrotiter plates by using a standard procedure. All tests were repeated three times with controls.

Acknowledgements

The authors express their gratitude to the Islamic Azad University, Mashhad Branch for its financial support.

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Received: 2016-10-12
Accepted: 2016-12-28
Published Online: 2017-1-31
Published in Print: 2017-2-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

  1. Frontmatter
  2. Preliminary Communications
  3. Tandem hetero-Diels–Alder-hemiacetal reaction in the synthesis of new chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles
  4. A new method for the reaction of cross-coupling: preparation of 5,5′-bi(1,10-phenanthroline)
  5. Design and synthesis of 4,5-diaryl/heteroarylthiophene-2-carboxylic acid derivatives and evaluation of their biological activities
  6. Research Articles
  7. Synthesis and properties of dicarbazolyltriphenylethylene-substituted fluorene derivatives exhibiting aggregation-induced emission enhancement
  8. Synthesis of a new polycyclic heterocyclic ring system. Part III. Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones
  9. Br2- or HBr-catalyzed synthesis of asymmetric 3,3-di(indolyl)indolin-2-ones
  10. Mono- and bis-dipicolinic acid heterocyclic derivatives – thiosemicarbazides, triazoles, oxadiazoles and thiazolidinones as antifungal and antioxidant agents
  11. Synthesis and antimicrobial activity of new piperazine-based heterocyclic compounds
  12. Synthesis and evaluation of chromene-based compounds containing pyrazole moiety as antimicrobial agents
  13. Ultrasonic synthesis, characterization, and antibacterial evaluation of novel heterocycles containing hexahydroquinoline and pyrrole moieties
https://doi.org/10.1515/hc-2016-0164
Keywords for this article
antibacterial; hexahydroquinoline; pyrrole; ultrasonic irradiation
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Preliminary Communications
  3. Tandem hetero-Diels–Alder-hemiacetal reaction in the synthesis of new chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles
  4. A new method for the reaction of cross-coupling: preparation of 5,5′-bi(1,10-phenanthroline)
  5. Design and synthesis of 4,5-diaryl/heteroarylthiophene-2-carboxylic acid derivatives and evaluation of their biological activities
  6. Research Articles
  7. Synthesis and properties of dicarbazolyltriphenylethylene-substituted fluorene derivatives exhibiting aggregation-induced emission enhancement
  8. Synthesis of a new polycyclic heterocyclic ring system. Part III. Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones
  9. Br2- or HBr-catalyzed synthesis of asymmetric 3,3-di(indolyl)indolin-2-ones
  10. Mono- and bis-dipicolinic acid heterocyclic derivatives – thiosemicarbazides, triazoles, oxadiazoles and thiazolidinones as antifungal and antioxidant agents
  11. Synthesis and antimicrobial activity of new piperazine-based heterocyclic compounds
  12. Synthesis and evaluation of chromene-based compounds containing pyrazole moiety as antimicrobial agents
  13. Ultrasonic synthesis, characterization, and antibacterial evaluation of novel heterocycles containing hexahydroquinoline and pyrrole moieties
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