The synthesis of C-substituted and N-substituted pyrrole is described by the reaction of phenacyl bromides, pentane-2, 4-dione and amine in aqueous medium using DABCO as a catalyst. The method is very convenient and applicable for alkyl as well as aryl amines and phenacyl bromides. The procedure is amenable for the synthesis of new substituted pyrroles. Moreover, aqueous medium makes the method more eco-friendly.
The pyrrole ring is found in porphyrin, bile pigment and in bioactive natural products [1-3]. Pyrrole oligomers also have applications as conducting material [4,5]. Due to their diverse potential applications in biological and pharmaceutical activities [6-9], there is a continuous interest for the synthesis of pyrroles by simple methods, though there are numerous methods [10,11] known. Three components coupling of amines, aldehydes and nitroalkanes catalyzed by SmI2 is reported lead to pyrroles in fair yield [
Recently, more emphasis is given to formulate the reactions based on green chemistry principles [
In continuation of our research [22-28] program to develop environmentally friendly reactions, herein we wish to report a simple, practical and general three component reaction for the construction of pyrrole derivatives by the reaction of substituted phenacyl bromide, aryl/alkyl amines with pentane-2,4-dione in aqueous medium in the presence of DABCO (Scheme 1).
The initial reaction of phenacyl bromide (1 mmol), phenyl ethylamine (1 mmol) and pentane-2,4-dione (1 mmol) in water (5 ml) at room temperature gave low yield (20%) of corresponding pyrrole even after stirring for extended time (10 hr). Even after heating the reaction mixture at 60˚C for 5 hr did not improve the yield. However, the reaction was forced to completion by the addition of catalytic amount of DABCO (10 mol%) and desired pyrrole was isolated in high yield (84%).
After extensive screening of the mole ratio (5, 10, 15 mol%) of DABCO, we found that 10 mol% was suitable for maximum conversion of product. The increase in the mole ratio of DABCO did not improve the yield. Among the solvents like, water, THF, DCM, methanol, water appears to give the best result. This remarkable improvement by the catalytic activity of DABCO provided an incentive for further study of reactions with other amines.
We have studied the reaction of various substituted anilines and phenacyl bromides to demonstrate the generality of method and the results are summarized in
Possible mechanism for the formation of pyrrole is shown in the Scheme 2. We presume that initially pentane-2,4-dione 2 reacts with amine 3 to form the unsaturated amino ketone 5 and tautomerised to form intermediate 6 [29,30]. DABCO reacts with phenacyl bromide 1 and forms quaternary salt 7 [
All reactions were carried out without any special precautions in an atmosphere of air. Chemicals were purchased from Fluka and S. D. Fine Chemicals. TLC: precoated silica gel plates (60 F254, 0.2 mm layer; E. Merk 1H-NMR Spectra: Varian 200 or Bruker 300 spectrometer; in CDCl3; d in ppm, J in Hz. Mass spectra: VG Autospec; in m/z.
A mixture of phenacyl bromide (1 mmol), acetyl acetone (1 mmol), amine (1 mmol) and DABCO (5 mol%) was stirred in 5 ml water at 60˚C for the stipulated time (
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.40 - 7.21 (m, 5H), 6.39 (s, 1H), 3.56 (s, 3H), 2.47 (s, 3H), 1.94 (s, 3H); MS (ESI): m/z = 214 [M + 1]+; IR (KBr): 2924, 1654, 1599, 1405, 1223 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.41 - 7.11 (m, 5H), 6.42 (s, 1H), 3.91 (t, J = 7 Hz, 2H), 2.47 (s, 3H), 2.37 (s, 3H), 1.72 (m, 2H), 1.02 - 0.95 (m, 2H), 0.80 (t, J = 7 Hz, 3H); MS (ESI): m/z = 256 [M + 1]+; IR (KBr): 2940, 1665, 1605, 1490, 755 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.53 - 7.21 (m, 5H), 6.65 (s, 1H), 3.77 (t, J = 7 Hz, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 1.79 - 1.67 (m, 4H), 1.02 - 0.95 (m, 8H), 0.80 (t, J = 7 Hz, 3H); MS (ESI): m/z = 312 [M + 1]+; IR (KBr): 2944, 1695, 1450, 1600, 1223 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.40 - 7.20 (m, 10H), 6.36 (s, 1H), 4.04 (t, J = 7 Hz, 2H), 3.00 (t, J = 7 Hz, 2H), 2.38 (s, 3H), 2.26 (s, 3H); MS (ESI): m/z = 304 [M + 1]+; IR (KBr): 3060, 3027, 1649, 1501, 1415 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.20 - 6.90 (m, 9H), 6.57 (s, 1H), 6.05 (s, 1H), 2.30 (s, 3H), 2.06 (s, 3H); MS (ESI): m/z = 314 [M+Na]+; IR (KBr): 3341, 2924, 1708, 1599, 1495 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 9.86 (s, 1H), 7.51 - 7.12 (m, 9H), 6.57 (s, 1H), 2.27 (s, 3H), 2.06 (s, 3H); MS (ESI): m/z = 314 [M + Na]+; IR (KBr): 3331, 2994, 1665, 1519, 1220 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.49 - 7.13 (m, 8H), 6.63 (s, 1H), 2.45 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H); MS (ESI): m/z = 368 [M]+; IR (KBr): 3050, 3012, 1677, 1612, 1405, 1220, 753, 697 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 8.06 - 7.17 (m, 9H), 6.62 (s, 1H), 2.56 (s, 3H), 2.39 (s, 3H); MS (ESI): m/z = 354 [M + 1]+; IR (KBr): 3012, 1677, 1612, 1405, 1220, 753, 697 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 8.06 - 7.72 (m, 9H), 6.67 (s, 1H), 2.38 (s, 3H), 2.06 (s, 3H); MS (ESI): m/z = 354 [M + 1]+; IR (KBr): 2992, 1654, 1595, 1450, 1313, 790, 715 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.45 - 7.13 (m, 8H), 6.64 (s, 1H), 2.45 (s, 3H), 2.43 (s, 3H); MS (ESI): m/z = 344 [M]+; IR (KBr): 3029, 1715, 1545, 1415, 789, 720 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.53 - 7.15 (m, 12H), 6.70 (s, 1H), 2.48 (s, 3H), 2.45 (s, 3H); MS (ESI): m/z = 420 [M]+; IR (KBr): 2964, 1659, 1514, 770 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.56 - 7.14 (m, 7H), 6.65 (s, 1H), 2.45 (s, 3H), 2.42 (s, 3H); MS (ESI): m/z = 424 [M + 1]+; IR (KBr): 3112, 1689, 1495, 812, 799, 712 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.53 - 7.13 (m, 4H), 6.44 (s, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H); MS (ESI): m/z = 293 [M + 1]+; IR (KBr): 2924, 1654, 1595, 1405, 1223 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.53 - 7.13 (m, 9H), 6.44 (s, 1H), 2.99 (t, J = 7 Hz, 2H), 2.86 (t, J = 7 Hz, 2H), 2.54 (s, 3H) 2.38 (s, 3H); MS (ESI): m/z = 382 [M]+; IR (KBr): 2920, 1654, 1595, 1415, 1203, 717 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.48 - 7.12 (m, 7H), 6.71 (s, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H); MS (ESI): m/z = 448 [M + 1]+; IR (KBr): 2924, 1695, 1551, 1400, 1223, 727 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.43 - 7.11 (m, 8H), 6.78 (s, 1H), 2.52 (s, 3H), 2.37 (s, 3H); MS (ESI): m/z = 373 [M + 1]+; IR (KBr): 3029, 1716, 1455, 1239, 745, 723 cm–1.
Yellow oil; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.42 - 7.12 (m, 8H), 6.85 (s, 1H), 6.65 (s, 1H), 2.58 (s, 3H), 2.37 (s, 3H); MS (ESI): m/z = 373 [M + 1]+; IR (KBr): 3411, 3024, 1654, 1595, 1405, 789 cm–1.
In summary, we have demonstrated a simple, general practical approach for the synthesis of substituted pyrroles. The method is applicable for a variety of alkyl, aryl and benzylic amines as well as for substituted phenacyl halides which can provide easy access to required substituted pyrroles. The method avoids the metal containing toxic waste and thus makes the procedure more advantage. Moreover, the use of aqueous medium makes the procedure more eco-friendly.
V. M. B., B. C. K. R., G. S. K. and P. B. T. thanks CSIRUGC for the award of a fellowship and to Dr. J. S. Yadav, Director IICT, for his support and encouragement.