Synthesis and characterization of N, N'-substituted bis(2,5-dimethyl-3,4- diethoxycarbonyl) pyrrole derivatives

Received Oct. 12, 2006.

Abstract N, N'-Substituted bis(2, 5-dimethyl-3, 4-diethoxycarbonyl) pyrrole derivatives were synthesized via Paal-Knorr reaction of 3, 4–diethoxycarbonyl-2, 5 –hexanedione with diamine in the solvent of acetic acid. The structures of products were characterized by IR, ¹H NMR spectra and elemental analysis.
Keyword pyrrole derivatives, synthesis, Paal-Knorr reaction, diamine.

1 INTRODUCTION
Pyrrole and its derivatives are very important compounds as they occur in a large number of natural products and display a variety of physiological activities,^[1] in particular, 1, 2, 3, 5-tetrasubstituted pyrrole derivatives have been proven to display antibacterial, ^[2] antiviral, ^[3] antiinflammatory^[4] and antioxidant activities and to inhibit cytokine-mediated diseases. ^[5] Additionally, they have been found to show potent inhibiting platelet aggregation^[6] and antihypertensive activities. ^[7] There are many methods to synthesize polysubstituted single pyrrole derivatives in recent years, however, few of polysubstituted bispyrrole compounds have been reported. The authors have synthesized a series of polysubstituted bispyrrole derivatives by Paal-Knorr reaction^{[8] [9] [10]}. In this paper, ten N, N′- Substituted Bis(2, 5-dimethyl-3, 4- diethoxycarbonyl) pyrrole derivatives have been synthesized via Paal-Knorr reaction of 3, 4– diethoxycarbonyl-2, 5–hexanedione with diamine and acetic acid as solvent. The structures of products were characterized by IR, ¹H NMR spectra and elemental analysis.

2 EXPERIMENT
2.1 Materials and instruments
The new compounds were characterized by data of ¹H NMR, IR and element analyses and were described in the experimental section. IR spectra were recorded on a HITACHI 260-50 spectrometer(KBr). ¹H NMR spectra were measured on an AVAVCE-400 spectrometer using TMS as internal standard and CDCl₃ as solvent. Elemental analysis measured on a HERAEUS (CHN, Rapid) analyzer. M.p were measured on a XT-4 melting point instrument (thermometer uncorrected).
    All of the reagents and solvents were AR grade. Absolute alcohol was dehydrated by distillation after sodium addition 3,4 –diethoxycarbonyl-2,5 –hexanedione was prepared by the method in literature. ^[11]
2.2 Preparation of N,N'-Substituted Bis(2,5-dimethyl-3,4-diethoxycarbonyl) pyrrole derivatives
To a flask with condensator were added 3,4 –diethoxycarbonyl-2,5 –hexanedione (0.516g, 2.00mmol) and diamine (1.00mmol) and acetic acid (15 mL) as solvent. The mixture was stirred and refluxed several hours. The procedure was monitored by TLC. (Scheme 1) After completion of the reactions, the mixture was cooled to room temperature and the products were purified by various methods.

                1                                                                                                  2a ~ 2j

Scheme 1
2a Y = C₆H₄OC₆H_{4 ;} 2b Y = C₆H₄SO₂C₆H_{4 ;} 2c Y = C₆H₄CH₂C₆H_4; 2d Y = CH₃C₆H₃C₆H₃CH_3; 2e Y = C₆H₄C₆H_4; 2f Y = C₆H₄SO₂NHC₆H_4; 2g Y = (CH₂)_2; 2h Y = (CH₂)_4; 2i Y = (CH₂)_6; 2j Y = (CH₂)₂ NH (CH₂)₂ NH (CH₂)₂.

2.2.1 Preparation of 4,4'-Bis (2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl) diphenyl ether (2a)
Diamine was 4,4'-bisamidobisphenylether. The product was extracted by absolute ether. The solvent was evaporated to give the crude product. The crude product was recrystallized by using 50% acetic acid as solvent to give white crystal 0.518g. The yield was 80.3%, m.p.138^oC. ¹H NMR (CDCl₃, 400 MHz) d: 7.21 ( s, 8H, 8ArH ), 4.33 ( q, J = 7.2Hz, 8H, 4CH₂ ), 2.20 ( s, 12H , 4Py-CH₃。), 1.37 ( t, J = 7.2Hz, 12H, 4CH₃). IR (KBr ) n: 3045, 1702, 1287, 1058, 1439, 1392, 1511, 1558, 847 cm^-1; Anal.calcd for C₃₆H₄₀O₉N₂: C 67.06, H 6.25, N 4.35; found C 67.06, H 6.26, N 4.36.
2.2.2 Preparation of 4,4'-Bis ( 2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl ) diphenyl sulphone (2b)
Diamine was 4,4'-bisamidobisphenylsulphone. The product was extracted by absolute ether. The solvent was evaporated to give the crude product. The crude product was recrystallized by using anhydrous alcohol as solvent to give white crystal 0.567g. The yield was 81.9%. m.p. 174-176 ^oC. ¹H NMR(CDCl₃, 400 MHz) d: 8.19 ( d, J = 8.4Hz, 4H, 4ArH ), 7.42 ( d, J = 8.4Hz, 4H, 4ArH ), 4.32 ( q, J = 7.2Hz, 8H, 4CH₂ ), 2.15 ( s, 12H, 4Py-CH₃ ), 1.36 ( t, J = 7.2Hz, 12H, 4CH₃ ). IR ( KBr ) n: 3035, 1700, 1283, 1022, 1431, 1397, 1500, 1558, 858 cm^-1. Anal.calcd for C₃₆H₄₀O₁₀N₂S: C 62.42, H 5.82, N 4.05; found C 62.40, H 5.86, N 4.07.
2.2.3 Preparation of 4,4'-Bis ( 2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl ) diphenylmethane (2c)
Diamine was 4,4'-bisamidobisphenylmethane. The product was separated by Column chromatography [Petroleum ether and ethyl acetate (v/v: 2:1) as eluant] to give white crystal 0.465g. The yield was 72.4%, m.p. 147-148 ^oC. ¹H NMR (CDCl₃ 400 MHz) d: 7.36 ( d, J = 8Hz, 4H, 4ArH ), 7.15 ( d, J = 8Hz, 4H, 4ArH ), 4.32 ( q, J = 7.2Hz, 8H, 4Et-CH₂ ), 4.16 ( s, 2H, CH₂ ), 2.17 ( s, 12H, 4Py-CH₃ ), 1.36 ( t, J = 7.2Hz, 12H, 4Et-CH₃ ). IR ( KBr ) n: 3046, 1705, 1289, 1024, 1417, 1396, 1521, 1557, 833 cm^-1. Anal. calcd for C₃₇H₄₂O₈N₂: C 69.14, H 6.59, N 4.36; found C 69.10, H 6.60, N 4.37.
2.2.4 Preparation of 3,3'-dimethyl-4,4'-Bis ( 2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl )diphenyl (2d)
Diamine was 3, 3'-bismethyl-4, 4'-bisamidobiphenyl. The water was added to the reactive mixture to give yellow precipitation. The precipitate was filtrated and recrystallized by using 75% acetic acid as solvent to give pale yellow crystal 0.519g. The yield was 79.1%, m.p.167-168^oC. ¹H NMR(CDCl₃, 400 MHz) d: 7.21 ( d, J = 8Hz, 2H, 2ArH ), 7.12 ( m,, 4H, 4ArH ), 4.34 ( q, J = 7.2Hz, 8H, 4CH₂ ), 2.15 ( s, 12H, 4Py-CH₃ ), 2.09 ( s, 6H, 2Ar-CH₃ ), 1.39 ( t, J = 7.2Hz, 12H, 4Et-CH₃ ). IR ( KBr ) n: 3030, 1712, 1292, 1031, 1435, 1392, 1500, 1559, 840, 773 cm^-1. Anal.calcd for C₃₈H₄₄O₈N₂: C 69.49, H 6.75, N 4.27; found C 69.51, H 6.76, N 4.28.
2.2.5 Preparation of 4,4'-Bis(2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl) diphenyl (2e)
Diamine was 4,4'-bisamidobiphenyl. The water was added to the reactive mixture to give white precipitation. The precipitate was filtrated and recrystallized by using acetic acid and water as solvent to give pale white crystal 0.495g. The yield was 78.7%, m.p.200-202^oC. ¹H NMR(CDCl₃, 400 MHz) d: 7.42 ( d, J = 8Hz, 4H, 4ArH ), 7.24 ( d, J = 8Hz, 4H, 4ArH ), 4.32 ( q, J = 7.2Hz, 8H, 4CH₂ ), 2.16 ( s, 12H, 4Py-CH₃ ), 1.36 ( t, J = 7.2Hz, 12H, 4CH₃ ). IR ( KBr ) n 3035, 1710, 1295, 1025 , 1435, 1385, 1500, 1550, 840, 780 cm^-1. Anal.calcd for C₃₆H₄₀O₈N₂: C 68.77, H 6.41, N 4.46; found C 68.76, H 6.43, N 4.43.
2.2.6 Preparation of 4,4'-Bis(2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl)-N-phenylbenzenesulfon- amide (2f)
Diamine was N-(p-amidophenyl)-p-amidobenzenesulfonamide. The water was added to the reactive mixture to give white precipitation. The precipitate was filtrated and recrystallized by using acetic acid as solvent to give white crystal 0.568g. The yield was 80.3%, m .p.102-104 ^oC. ¹H NMR (CDCl₃, 400 MHz) d: 8.02 ( d, J = 8.4Hz, 2H, 2ArH ), 7.33 ( d, J = 8.4Hz, 2H, 2ArH ), 7.29 ( t, J = 8.4Hz, 4H, 2ArH ), 4.32 ( q, J = 3.6Hz, 8H, 4CH₂ ), 4.20 ( s, 1H, NH ), 2.12 ( s, 6H, 2Py-CH₃ ) , 2.09 (s, 6H, 2py-CH₃ ), 1.36 ( t, J = 3.6Hz, 12H, 4CH₃ ). IR ( KBr ) n 3038, 1700 , 1291, 1029, 1438, 1394, 1521, 1559, 878 cm^-1. Anal.calcd for C₃₆H₄₁O₁₀N₃S: C 61.09, H 5.84, N 5.94; found C 61.05, H 5.85, N 5.95.
2.2.7 Preparation of 1,2-Bis(2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl) ethane (2g)
Diamine was ethylenediamine. The absolute ether was added to the reactive mixture to give precipitation. The precipitate was filtrated to give white crystal 0.388g. The yield was 76.9%, m.p. 186-187 ^oC. ¹H NMR (CDCl₃, 400 MHz) d: 4.28 ( q, J = 7.2Hz, 8H, 4Et-CH₂ ), 4.00 ( s, 4H, 2CH₂ ), 2.28 ( s, 12H, 4Py- CH₃ ), 1.33 ( t, J = 7.2Hz, 12H, 4Et-CH₃ ). IR ( KBr ) n 1703, 1315, 1056, 1438 , 1396 cm^-1. Anal.calcd for C₂₆H₃₆O₈N₂: C 61.89, H 7.19, N 5.55; found C 61.86, H 7.20, N 5.56.
2.2.8 Preparation of 1,4-Bis(2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl) butane (2h)
Diamine was butanediamine. The absolute ether was added to the reactive mixture to give pale yellow precipitation. The precipitate was filtrated and recrystallized by using acetic acid as solvent to give white crystal 0.384g. The yield was 72.1%, m.p.172-174 ^oC. ¹H NMR (CDCl₃，400 MHz) d: 4.29 ( q, J = 7.2Hz, 8H, 4Et-CH₂ ), 3.79 ( m, 4H, 2CH₂ ), 2.39( s, 12H, 4Py-CH₃ ), 1.67 ( m, 4H, 2CH₂ ), 1.34 ( t, J = 7.2Hz, 12H, 4Et-CH₃ ). IR ( KBr ) n 1698, 1284, 1058, 1387, 1438 cm^-1. Anal.calcd for C₂₈H₄₀O₈N₂: C 63.14, H 7.57, N 5.26; found C 63.30, H 7.59, N 5.27.
2.2.9 Preparation of 1,6-Bis(2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl) hexane (2i)
Diamine was hexanediamine. The water was added to the reactive mixture to give pale yellow precipitation. The precipitate was filtrated and dried to give pale yellow crystal 0.386g. The yield was 68.8%, m.p.156-158^oC. ¹H NMR (CDCl₃, 400 MHz) d: 4.28 ( q, J = 6.8Hz, 8H, 4Et-CH₂ ), 3.77 ( t, J = 7.6 Hz, 4H, 2CH₂), 2.39 ( s, 12H, 4Py-CH₃ ), 1.63 ( m, 4H, 2CH₂ ), 1.38 (m, 4H, 2CH₂), 1.35 ( t, J = 7.2Hz, 12H, 4Et-CH₃ ). IR ( KBr ) n 1697, 1281, 1059, 1418, 1392 cm^-1. Anal.calcd for C₃₀H₄₄O₈N₂: C 64.26, H 7.91, N 5.00; found C 64.23, H 7.91, N 5.02.
2.2.10 Preparation of 2,2'-Bis[2,5-dimethyl-3,4-diethoxycarbonylpyrrol-1-yl)ethyl] ethylenediamine (2j)
Diamine was triethylenetetramine. The product was separated by Column chromatography (ethyl acetate as eluant) to give pale yellow oil matter that was recrystallized by using ethyl acetate and petroleum ether as solvent to give white crystal 0.404g. The yield was 68.4%, m.p.112-114 ^oC. ¹H NMR (CDCl₃，400 MHz) d: 4.29 ( q, J = 6.8Hz, 8H, 4Et-CH₂ ), 4.00 ( s, 2H, 2NH ), 3.97 ( t, J = 7.2 Hz, 4H, 2CH₂), 3.03 ( t, J = 7.2 Hz, 4H, 2CH₂), 2.67 ( t, J = 7.0 Hz, 4H, 2CH₂), 2.16 ( s, 12H, 4Py-CH₃ ), 1.33 ( t, J = 7.2Hz, 12H, 4Et-CH₃ ). IR ( KBr ) n 1700, 1297, 1059, 1439, 1403cm^-1. Anal.calcd for C₃₀H₄₆O₈N₄: C 60.99, H 7.85, N 9.48; found C 60.97, H 7.84, N 9.46.

3 RESULTS AND DISCUSSION
The authors have synthesized ten N, N'-Substituted bis(2,5-dimethyl-3,4-diethoxycarbonyl) pyrrole derivatives in 70-80% yields conveniently.
    In the literature, to synthesize pyrroles and pyrrole derivatives by the reaction of Paal-Knorr, the current solvent was the mixture of acetic acid and alcohol. In this paper, the time of reaction was shortened and the yield improved by using acetic acid as solvent. The reason was probably that the concentration of 3,4–dietho- xycarbonyl-2,5 –hexanedione was higher and the electrophilicity of carbonyl group was stronger in acetic acid.
    To investigate study the effect of the materials ratio on products, the reaction ratio of the starting materials selected was 1:1. The result showed that primary products were bispyrrole derivatives and single pyrrole derivatives were lesser.

4 CONCLUSION
In this paper, ten pyrrole derivatives by the reaction of Paal-Knorr were synthesized. The products were all characterized by IR, ¹H NMR spectra and elemental analysis.

REFERENCES
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N,N′-取代二（2,5-二甲基-3,4-二乙氧羰基）吡咯衍生物的合成及表征
李志云；张书文；成贞辉；魏保君，郝鹏鹏
(河北大学化学与环境科学学院；中国河北保定 071002)
摘要  本文以3,4-二乙氧基羰基-2,5-己二酮和二元伯胺类化合物为原料通过 Paal-Knorr 反应，以乙酸为溶剂合成了N,N′-取代二 （ 2,5 -二甲基-3, 4-二乙氧羰基）吡咯衍生物，并通过红外光谱、核磁共振氢谱及元素分析对化合物进行了表征.
关键词  吡咯衍生物, 合成, Paal-Knorr反应, 胺类化合物

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