1 Introduction
Substituted pyrrole derivatives are very important heterocycles. Many biologically active compounds, potent pharmaceuticals, and natural products contain the pyrrole structural motif [1]. Among the pyrrole derivatives, dihydro-2-oxoypyrroles show such versatility and they are important substructures in a variety of pharmacy, including products active against viral infections (HIV [2,3], influenza [4] cytomegalovirus [5]), anticancer agents [6] and products active against microbiological diseases [7–9] (bacterial or fungal). Furthermore, dihydro-2-oxoypyrrole derivatives have been used as PI-091 [10], which is a novel platelet aggregation inhibitor, and EBPC, which is a highly specific aldose reductase inhibitor [11], as shown in Fig. 1. Besides, the well-known 5-alkyl-2-oxopyrroles [12], first described in 1890 by Emery [13], relatively little attention was given toward 5-aryl-2-oxopyrrole derivatives in the open literature.
Biologically active compounds having dihydro-2-oxypyrrole unit.
As part of our continuing effort into design of new routes for the preparation of biologically active compounds using N,N′-bis(phenylmethylidene)phenylmethane and application of this reagent in the synthesis of numerous organic compounds, especially aza-cyclic compounds [14], herein, we describe a simple, one-pot, three-component synthesis of 5-phenyl-2-oxopyrrole derivatives 3 by the three-component reaction of N,N′-bis(phenylmethylidene)phenylmethane, primary amines 1 and dialkyl acetylenedicarboxylate 2 (Scheme 1).
Synthesis of 5-phenyl-2-oxopyrrole derivatives.
2 Results and discussion
Firstly, an easily available starting material N,N′-bis (phenylmethylidene)phenylmethane was reacted with benzylamine 1a and diethyl acetylenedicarboxylate 2a in MeOH under refluxing temperature for 6 h. The 5-phenyl-2-oxopyrrole 3a was successfully obtained in 85% yield (Scheme 1). Different types of amines, such as benzyl and aliphatic amines were used to investigate the scope and limitation of the reaction.
A variety of benzylamines with substitutents Me, Cl at para position and aliphatic amines, such as propyl- and isobutylamine, were examined with DMAD and N,N′-bis(phenylmethylidene)phenylmethane under the same conditions and the corresponding dihydro-2-oxypyrrole derivatives 3a–i were obtained in good yields as shown in Table 1.
5-Phenyl-2-oxopyrrole derivatives were prepared by the mentioned reaction.
| Entry | Product | R | R′ | Time (h) | Yield (%) |
| 1 | 3a | Bn | Et | 6 | 85 |
| 2 | 3b | 4-Cl-Bn | Me | 6 | 81 |
| 3 | 3c | 4-Cl-Bn | Et | 7 | 74 |
| 4 | 3d | 4-Me-Bn | Me | 5 | 77 |
| 5 | 3e | 4-Me-Bn | Et | 6 | 82 |
| 6 | 3f | Propyl | Me | 6 | 74 |
| 7 | 3g | Propyl | Et | 5 | 75 |
| 8 | 3h | Isobutyl | Me | 5 | 80 |
| 9 | 3i | Isobutyl | Et | 5 | 79 |
Dialkyl acetylenedicarboxylate also showed very high reactivity in this reaction under the same conditions. All new compounds 3a–i were fully characterized on the basis of elemental analysis, IR, 1H NMR, 13C NMR and mass spectra. The structure of product 3h was further confirmed by X-ray crystallographic analysis (Fig. 2). The mass spectrum of 3a displayed the molecular ion peak at the appropriate m/z value. The IR spectrum of compound 3a showed two absorption bands due to the NH stretching frequency at 3338 and 3192 cm−1, respectively. Absorption bands at 1705 and 1666 cm−1 are due to the COOEt and CONH groups, respectively. The 1H NMR spectrum of 3a showed a triplet for the CH3 group (δ = 1.02 ppm, 3JHH = 7.1 Hz), three singlets for the two NH and CH groups at δ = 1.6, 5.18 and 6.28, respectively, one quartet for the O–CH2 group (δ = 3.99 ppm, 3JHH = 6.8 Hz), doublet of doublet for the CH2 group (δ = 5.06 ppm, 3JHH = 6.6 Hz, and 5.15 ppm, 3JHH = 6.6 Hz), and the phenyl moiety gave rise to characteristic signals in the aromatic region of the spectrum. The 1H-decoupled 13C NMR spectrum of 3a showed 16 distinct resonances in agreement with the suggested structure.
X-ray crystal structure of compound 3h.
To explain the mechanism of this reaction, we propose that the compound 3 could result from the initial addition of the primary amines 1 to dialkyl acetylenedicarboxylate 2 and subsequent attack of the resulting enaminone 4 on the diamine to yield intermediate 6. Cyclization of the intermediate 6 gives intermediate 7 and subsequent hydrolysis of intermediate 7 leads to compound 3. To confirm the mechanism hypothesis initially, we mentioned Zhu et al.’s paper [15]. In this report, solvent has an important role in the stereochemistry of compound 4. In MeOH, Z/E ratio is 95:5 and in DMF, this ratio is 2:98. After considering this issue, we carried out the reaction in MeOH as a protic solvent and DMF as an aprotic solvent in the same time and the progress of the reactions was followed by thin layer chromatography. After completion, the solvent was removed under reduced pressure and the residue was purified by column chromatography (n-hexane/EtOAc, 3:1). Then, by the spectral analysis of two product of reactions, we observed that this process was independent of the stereochemistry of the intermediate 4 (Scheme 2).
Probing the mechanism for the formation of title compounds.
3 Conclusions
In summary, we have developed a simple, one-pot, three-component synthesis of 5-phenyl-2-oxopyrrole derivatives, which is of potential synthetic interest. High yields of the products, relatively short reaction times, using simple and cheap starting materials are the main advantages of this method. Also, the product could have high diversity via various functional groups instead of amine and ester groups. The simplicity of the present procedure makes it an interesting alternative to the complex multi-step approaches.
4 Experimental
4.1 Materials and techniques
Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. IR spectra were recorded on a Shimadzu IR-460 spectrometer. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. 1H and 13C NMR spectra were recorded at 500.1 and 125.7 MHz, respectively, on a BRUKER DRX 500-AVANCE FT-NMR instrument with CDCl3 as solvent. The reagents and solvents used in this work were obtained from Fluka (Buchs, Switzerland) and were used without further purification.
4.2 General procedure for the preparation of compounds 3a–i, exemplified on 3a
To a magnetically stirred 5 mL flat bottom flask containing benzylamine (0.107 g, 1 mmol) was added diethyl acetylenedicarboxylate (0.170 g, 1 mmol). After 30 min, N,N′-bis (phenylmethylidene)phenylmethane (0.298 g, 1 mmol) was added to the reaction mixture which was allowed to stir for 6 h. Purification of the crude product by column chromatography [silica gel (Merck 230–240 mesh), n-hexane/EtOAc (6:1)] gave the title compound 3a.
4.3 Spectral data
4.3.1 Ethyl 4-(benzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3a)
White crystals, mp: 120–122 °C; IR (KBr) (νmax, cm−1): 3338 (NH), 3192 (NH), 2924 (CH), 1705 and 1666(CO), 1457 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 1.02 (2H, t, 3JHH = 7.1 Hz, CH3), 1.60 (1H, s, NH), 3.99 (3H, q, 3JHH = 6.8 Hz, CH3), 5.06 (1H, dd, 3JHH = 6.6 Hz, 2JHH = 15 Hz, CH), 5.15 (1H, dd, 3JHH = 6.6 Hz, 2JHH = 15 Hz, CH), 5.18 (1H, s, CH), 6.28 (1H, s, NH), 7.23-7.42 (10H, m, CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 14.03 (CH3), 46.39 (CH2–N), 57.80 (CH), 59.53 (CH2–O), 107.45 (C–CH), 127.31 (2 CH of Ar), 127.38 (CHpara of Ph), 127.55 (2 CH of Ar), 128.09 (CHpara of Ph), 128.37 (2 CH of Ar), 128.70 (2 CH of Ar), 134.18 (Cipso), 138.67 (2 Cipso), 139.41 (C–NH), 165.90 (CO), 167.53 (CO). MS (EI, 70 eV): m/z (%) = 336 (M+, 32), 307 (28), 263 (92), 91 (100). Anal. calcd for C20H20N2O3 (336.38): C, 71.41; H, 5.99; N, 8.33%. Found: C, 71.37; H, 5.89; N, 8.26%.
4.3.2 Methyl 4-(4-chlorobenzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3b)
White crystals, mp: 164–166 °C; IR (KBr) (νmax, cm−1): 3324 (NH), 3196 (NH), 2942 (CH), 1689 (CO), 1619 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm)1.26 (1H, s, NH), 3.55 (3H, s, CH3), 5.01 (1H, dd, 3JHH = 6.8 Hz, 3JHH = 14 Hz, CH), 5.14 (1H, dd, 3JHH = 6.7 Hz, 3JHH = 14 Hz, CH), 5.16 (1H, s, CH), 6.48 (1H, s, NH), 7.20–7.32 (9H, m, CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 45.55 (CH2–N), 50.75 (CH), 57.77 (OCH3), 106.00 (C–CH), 127.14 (2 CH of Ar), 128.29 (CHpara of Ph), 128.51 (2 CH of Ar), 128.83 (2 CH of Ar), 128.88 (2 CH of Ar), 132.54 (C–Cl), 133.18 (Cipso), 138.03(Cipso), 138.45 (C–NH), 165.95 (CO), 167.34 (CO). MS (EI, 70 eV): m/z (%) = 356 (M+, 26), 323(9), 297 (88), 125 (100). Anal. calcd for C19H17ClNO2 (356.09): C, 63.96; H, 4.80; N, 7.85%. Found: C, 63.90; H, 4.74; N, 7.75%.
4.3.3 Ethyl 4-(4-chlorobenzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3c)
White crystals, mp: 128–130 °C; IR (KBr) (νmax, cm−1): 3330 (NH), 3231 (NH), 2923 (CH), 1691 and 1661 (CO), 1604 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 1.03 (2H, t, 3JHH = 7.3 Hz, CH2), 4.00 (3H, q, 3JHH = 7.1 Hz, CH3), 5.01 (1H, dd, 3JHH = 6.9 Hz, 3JHH = 15 Hz, CH), 5.10 (1H, dd, 3JHH = 6.8 Hz, 3JHH = 15 Hz, CH), 5.17 (1H, s, CH), 6.34 (1H, s, NH), 7.04 (1H, s, NH), 7.21–7.32 (9H, m, 9CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 14.01 (CH3), 45.59 (CH2–N), 57.83 (CH), 59.63 (CH2–O), 106.45 (C–CH), 127.27 (2 CH of Ar), 128.14 (CHpara of Ph), 128.39 (2 CH of Ar), 128.82 (2 CH of Ar), 128.89 (2 CH of Ar), 133.16 (C–Cl), 138.08 (2 Cipso), 138.49 (C–NH), 165.41 (CO), 167.45 (CO). MS (EI, 70 eV): m/z (%) = 370 (M+, 28), 341 (29), 297 (95), 125 (100). Anal. calcd for C20H19ClN2O3 (370.83): C, 64.78; H, 5.16; N, 7.55%. Found: C, 64.71; H, 5.09; N, 7.48%.
4.3.4 Methyl 4-(4-methylbenzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3d)
White crystals, mp: 136–138 °C; IR (KBr) (νmax, cm−1): 3323 (NH), 3194 (NH), 2930 (CH), 1694 and 1667 (CO), 1617 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 2.35 (3H, s, CH3), 3.54 (3H, s, OCH3), 5.00 (1H, dd, 3JHH = 6.8 Hz, 3JHH = 15 Hz, CH), 5.08 (1H, dd, 3JHH = 6.7 Hz, 3JHH = 15 Hz, CH), 5.16 (1H, s, CH), 6.50 (1H, s, NH), 7.16 (2H, d, 3JHH = 7.8 Hz, 2CH of Ar), 7.23–7.32 (7H, m, 7 CH of Ar), 7.36 (1H, s, NH). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 21.10 (CH3), 46.16 (CH2–N), 50.72 (CH), 57.80 (OCH3), 106.05 (C–CH), 127.19 (2 CH of Ar), 127.56 (2 CH of Ar), 128.09 (CHpara of Ph), 128.47 (2 CH of Ar), 129.39 (2 CH of Ar), 132.47 (C–Me), 136.36 (Cipso), 137.04 (Cipso), 138.73 (C–NH), 165.92 (CO), 167.50 (CO). MS (EI, 70 eV): m/z (%) = 336 (M+, 89), 277 (92), 232 (31), 105 (100), 77(53). Anal. calcd for C20H20N2O3 (336.38): C, 71.41; H, 5.99; N, 8.33%. Found: C, 71.35; H, 5.91; N, 8.25%.
4.3.5 Ethyl 4-(4-methylbenzylamino)-2,5-dihydro-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3e)
White crystals, mp: 102–104 °C; IR (KBr) (νmax, cm−1): 3347 (NH), 3209 (NH), 2924 (CH), 1712 and 1666 (CO), 1621 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 1.02 (2H, t, 3JHH = 7.1 Hz, CH2), 1.61 (1H, s, NH), 2.34 (3H, s, CH3), 3.98 (2H, q, 3JHH = 7.1 Hz, CH2), 5.00 (1H, dd, 3JHH = 6.8 Hz, 3JHH = 15 Hz, CH), 5.09 (1H, dd, 3JHH = 6.8 Hz, 3JHH = 15 Hz, CH), 5.17 (1H, s, CH), 6.28 (1H, s, NH), 7.16 (2H, d, 3JHH = 7.9 Hz, 2CH of Ar), 7.21–7.31 (7H, m, 7 CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 14.04 (CH3), 21.10 (CH3), 46.19 (CH2–N), 57.82 (CH), 59.51 (CH2–O), 105.78 (C–CH), 127.31 (2 CH of Ar), 127.56 (2 CH of Ar), 128.06 (CHpara of Ph), 128.35 (2 CH of Ar), 129.37 (2 CH of Ar), 136.39 (C–Me), 137.02 (2 Cipso), 138.74 (C–NH), 165.42 (CO), 167.56 (CO). MS (EI, 70 eV): m/z (%) = 350 (M+, 10), 321 (18), 277 (16), 105 (100), 77 (38). Anal. calcd for C21H22N2O3 (350.41): C, 71.98; H, 6.33; N, 7.99%. Found: C, 71.93; H, 6.29; N, 7.91%.
4.3.6 Methyl 2,5-dihydro-5-oxo-2-phenyl-4-(propylamino)-1H-pyrrole-3-carboxylate (3f)
White crystals, mp: 143–145 °C; IR (KBr) (νmax, cm−1): 3325 (NH), 3196 (NH), 2946 (CH), 1692 (CO), 1633 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 0.96 (3H, t, 3JHH = 7.4 Hz, CH3), 1.58–1.65 (2H, m, CH2), 3.55 (3H, s, CH3), 3.78–3.84 (2H, m, CH2), 5.14 (1H, s, CH), 6.46 (1H, s, NH), 6.98 (1H, s, NH), 7.19–7.30 (5H, m, 5 CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 11.09 (CH3), 24.55 (CH2), 44.26 (CH2–NH), 50.61 (CH), 57.75 (OCH3), 104.16 (C–CH), 127.15 (2 CH of Ar), 128.02 (CHpara of Ph), 128.42 (2 CH of Ar), 137.12 (Cipso), 138.97 (C–NH), 165.99 (CO), 167.47 (CO). MS (EI, 70 eV): m/z (%) = 274 (M+, 51), 245 (11), 215 (100), 173 (32), 77 (28). Anal. calcd for C15H18N2O3 (274.32): C, 65.68; H, 6.61; N, 10.21%. Found: C, 65.62; H, 6.55; N, 10.16%.
4.3.7 Ethyl 2,5-dihydro-5-oxo-2-phenyl-4-(propylamino)-1H-pyrrole-3-carboxylate (3g)
White crystals, mp: 169–171 °C; IR (KBr) (νmax, cm−1): 3284 (NH), 2951 (CH), 1710 and 1675 (CO), 1611(Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 0.99 (3H, t, 3JHH = 7.5 Hz,CH3), 1.05 (3H, t, 3JHH = 7.4 Hz, CH3), 1.59–1.67 (2H, m, CH2), 3.79–3.86 (2H, m, CH2), 4.01 (2H, q, 3JHH = 7.4 Hz, CH2), 5.16 (1H, s, CH), 6.22 (1H, s, NH), 6.97 (1H, s, NH), 7.23-7.37 (5H, m, 5 CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 11.11 (CH3), 14.08 (CH3), 24.54 (CH2), 44.27 (CH2-NH), 50.71 (CH), 59.39 (CH2-O), 104.20 (C-CH), 127.28 (2 CH of Ar), 128.00 (CHpara of Ph), 128.32 (2 CH of Ar), 137.99 (Cipso), 138.98 (C-NH), 165.97 (C = O), 167.53 (C = O). MS (EI, 70 eV): m/z (%) = 288 (M+, 6), 232 (14), 125 (95), 105 (100), 77 (28). Anal. calcd for C16H20N2O3 (288.34): C, 66.65; H, 6.99; N, 9.72%. Found: C, 66.60; H, 6.92; N, 9.67%.
4.3.8 Methyl 2,5-dihydro-4-(isobutylamino)-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3h)
White crystals, mp: 130–132 °C; IR (KBr) (νmax, cm−1): 3327 (NH), 3192 (NH), 2945 (CH), 1689 and 1645 (CO), 1614 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 0.96 (3H, d, 3JHH = 1.6 Hz, CH3), 0.97 (3H, d, 3JHH = 1.6 Hz, CH3), 1.80–1.84 (1H, m, CH), 3.55 (3H, s, CH3), 3.64–3.73 (2H, m, CH2), 5.14 (1H, s, CH), 6.55 (1H, s, NH), 7.03 (1H, s, NH), 7.21–7.32 (5H, m, 5 CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 19.80 (CH3), 30.03 (CH), 49.56 (CH2–NH), 50.61 (CH), 56.67 (OCH3), 104.18 (C–CH), 127.14 (2 CH of Ar), 128.00 (CHpara of Ph), 128.41(2 CH of Ar), 138.13 (Cipso), 139.00 (C–NH), 165.85 (CO), 167.49 (CO). MS (EI, 70 eV): m/z (%) = 288 (M+, 11), 245 (16), 229 (65), 104 (32), 77 (100). Anal. calcd for C16H20N2O3 (288.34): C, 66.65; H, 6.99; N, 9.72%. Found: C, 66.59; H, 6.94; N, 9.66%. Crystal data for 3h C16H20N2O3 (CCDC 876237): MW = 285.32, monoclinic, space group P21/c, a = 5.359(5) Å, b = 11.357(5) Å, c = 13.755(5) Å, α = 68.388(5) β = 87.730(5), γ = 88.346(5), V = 777.6(9) Å3, Z = 2, Dc = 1.219 mg/m3, F (000) = 302, crystal dimensions 0.19 × 0.12 × 0.11 mm, radiation, Mo Kα (λ = 0.71073 Å), 2.9 ≤ 2θ ≤ 25.1, intensity data were collected at 295(2) K with a Bruker APEX area-detector diffractometer, and employing ω/2θ scanning technique, in the range of −6 ≤ h ≤ 6, −12 ≤ k ≤ 13, −15 ≤ l ≤ 16; the structure was solved by a direct method, all non-hydrogen atoms were positioned and anisotropic thermal parameters refined from 2035 observed reflections with R (into) = 0.0880 by a full-matrix least-squares technique converged to R = 0.0666 and Raw = 0.1928 [I > 2sigma(I)].
4.3.9 Ethyl 2,5-dihydro-4-(isobutylamino)-5-oxo-2-phenyl-1H-pyrrole-3-carboxylate (3i)
White crystals, mp: 154–156 °C; IR (KBr) (νmax, cm−1): 3352 (NH), 3189 (NH), 2957 (CH), 1691 (C = O), 1621 (Ar). 1H NMR (500.13 MHz, CDCl3): δH (ppm) 0.97 (6H, d, 3JHH = 6.6 Hz,CH3), 1.05 (3H, t, 3JHH = 7.5 Hz,CH3), 1.81–1.86 (1H, m, CH), 3.65-3.75 (2H, m, CH2), 4.01 (2H, q, 3JHH = 7.5 Hz, CH2), 5.15 (1H, s, CH), 6.34 (1H, s, NH), 7.02 (1H, s, NH), 7.22-7.34 (5H, m, 5 CH of Ar). 13C NMR (125.8 MHz, CDCl3): δC (ppm) 13.53 (CH3), 19.27 (CH3), 29.48 (CH), 49.17 (CH), 57.14 (CH2–NH), 58.83 (O-CH2), 104.18 (C–CH), 126.58 (2 CH of Ar), 127.42 (CHpara of Ph), 127.76 (2 CH of Ar), 138.10 (Cipso), 139.45 (C–NH), 165.88 (CO), 167.03 (CO). MS (EI, 70 eV): m/z (%) = 302 (M+, 25), 259 (27), 229 (100), 213(65), 173 (18), 77 (15). Anal. calcd for C17H22N2O3 (302.37): C, 67.53; H, 7.33; N, 9.26%. Found: C, 67.48; H, 7.29; N, 9.18%.
Acknowledgements
We gratefully acknowledge financial support from the Research Council of Tarbiat Modares University.