JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39
RESEARCH PAPER 311
JUNE, 311–313
Synthesis of polysubstituted pyrroles derivatives by PPh3 -promoted condensation reaction between ninhydrin, 2-amino pyridine derivatives and acetylenes Nasim Shamsa, Mohammad Hossein Mosslemina* and Hossein Anaraki-Ardakanib a
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran Department of Chemistry, College of Chemical Engineering, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
b
An efficient route for the synthesis of polysubstituted pyrrole derivatives through a three-component intermolecular Wittig reaction is described. This simple fragment assembly strategy uses mild conditions and affords a broad range of polysubstituted pyrroles in moderate to good yield from simple and readily available starting materials. Keywords: ninhydrin, dialkyl acetylenedicarboxylates, 2-amino pyridine derivatives, polysubstituted pyrroles ring using a three-component reaction of ninhydrin 1, 2-amino pyridine derivatives 2 and dialkyl acetylenedicarboxylates (DAADs) 3 in the presence of triphenylphosphine under mild conditions (Scheme 1).
Multi-heterocyclic compounds have diverse biological and pharmaceutical activities and are, therefore, interesting templates for medicinal chemistry.1,2 Among multi-heterocyclic compounds, pyrroles and their derivatives are structural units in many natural products and pharmaceuticals and are key intermediates for the synthesis of a variety of biologically active molecules and functional materials.3 As the world’s leading cholesterol-lowering drug, atorvastatin calcium (Lipitor) is a prime example.4 The conventional methods for the construction of a pyrrole ring include the Hantzsch reaction.5,6 the Paal-Knorr synthesis,7,8 and various cycloaddition methods.9 A number of metal-catalysed approaches have also been developed.10 General and efficient strategies for the synthesis of pyrroles from simple and readily available precursors are valuable due to the importance of the pyrrole core in both biological and chemical fields. Multicomponent reactions (MCRs) have emerged as powerful bond-forming tools in organic, combinatorial, and medicinal chemistry because of their efficiency in organic synthesis.11,12 These features make MCRs well suited for the construction of diversified heterocyclic scaffolds from readily available materials.13 Recently, this strategy has been applied to the synthesis of pyrroles.14,15 As a part of our ongoing research on development of multicomponent approaches to heterocycles,16,17 we considered the rapid construction of a polysubstituted pyrrole
Results and discussion The structures of compounds 4a–i were deduced from their elemental analyses and their IR, 1H NMR, 13C NMR spectra. For example, the mass spectrum of 4a displayed the molecularion peak at m/z = 376. The 400 MHZ 1H NMR spectrum of 4a exhibited a signal at 2.30 for methyl group and two sharp signals at δ 3.77 and 3.94 ppm for protons of two methoxy groups. The aromatic protons were observed at 6.93–8.07 ppm. The 13C NMR spectrum of compound 4a showed 21 distinct resonances in agreement with the proposed structure. The structural assignments made on the basis of the NMR spectra of compound 4a were supported by the IR spectrum. The carbonyl groups exhibited strong absorption bands at 1739 and 1690 cm-1. A mechanistic rationalisation for the reaction is given in Scheme 2. On the basis of the well-established chemistry of trivalent phosphorus nucleophiles,18-22 it is reasonable to assume that the initial event is the formation of the zwitterion 6 from the triphenyl phosphine and the acetylenic ester. Next, the zwitterion is protonated by 2-hydroxy-2-[(4-methylpyridin-2X
O H2N O
O
CO2R
N
+
+ X
O
N
PPh3, -OPPh3
N
CH2Cl2, r.t, 24h
CO2R
CO2R CO2R
1
2
4
3
4
X
R
a b c d e f h i
3-Me 3-Me 4-Me 4-Me H H 4-Br 4-Br
Me Et Me Et Me Et Me Et
Yield* (%) 90 85 88 84 83 82 89 91
*Isolated yields
Scheme 1 Reaction between ninhydrin, 2-amino pyridine derivatives, DAADs, and triphenylphosphine. * Correspondent. E-mail:
[email protected]
312 JOURNAL OF CHEMICAL RESEARCH 2015 yl)amino]-1H-indene-1,3(2H)-dione 5. The resulting positively charged phosphonium ion 6 is attacked by the conjugate base of the NH-acid 7, leading to phosphorane 8. This phosphorane is converted to 9 by intramolecular Wittig reaction and finally compound 9 is converted to 4 by aromatisation.
bottom flask, triphenylphosphine was added (1 mmol) and finally a mixture of a dialkyl acetylenedicarboxylate (1 mmol) in CH2Cl2 (2 mL) was added dropwise over 2 min. The solution was stirred at room temperature for 8 h. The progress of the reaction was monitored by TLC with n-hexane – ethyl acetate (3:1 v/v) mixture as eluent. After completion of the reaction, the reaction mixture was purified by column chromatography on silica gel (60, 230–400 mesh) using ethyl acetate–hexane mixtures to afford a pure product. Dimethyl 1-(3-methylpyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b] pyrrole-2,3-dicarboxylate (4a): Yellow powder; m.p. 152–154 oC, IR (KBr) (νmax, cm-1): 1739 (2C=O, ester), 1690 (C=O, ketone). Anal. calcd for C21H16N2O5: C, 67.02; H, 4.28; N, 7.44; found: C, 66.90; H, 4.39; N, 7.36%. 1H NMR (400 MH Z, CDCl3): δ 2.30 (3H, s, CH3), 3.72 and 3.75 (6H, 2s, 2OCH3), 6.94 (1H, d, 3 JHH =8Hz, CH for pyridine), 6.98–7.53 (4H, m, aromatic), 7.81 (1H, t, 3 JHH =8Hz, CH for pyridine), 8.06 (1H, d, 3 JHH =8Hz, CH for pyridine). 13C NMR (100 MH Z, CDCl3): δ 21.31 (CH3), 52.09, 53.02 (2 OCH3), 117.73, 121.64, 121.78, 124.56, 128.31, 128.59, 132.47, 134.23, 135.42, 135.93, 144.22, 145.65, 147.51, 148.03, 162.23 (aromatic carbons), 162.75 and 187.91 (3C=O). MS, m/z (%) = 376 (M+, 21). Diethyl 1-(3-methylpyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b] pyrrole-2,3-dicarboxylate (4b): Yellow powder; m.p. 161–163 oC, IR (KBr) (νmax, cm-1): 1741 (2C=O, ester), 1695 (C=O, ketone). Anal. calcd for C23H20N2O5: C, 68.31; H, 4.98; N, 6.93; found: C, 68.44; H, 4.87; N, 6.76%. 1H NMR (400 MH Z, CDCl3): δ 1.26, 1.34 (6H, 2t, 3 JHH = 7Hz, 2 CH3), 2.28 (3H, s, CH3), 3.60, 4.06 (4H, 2m, 2OCH2), 6.95 (1H, d, 3 JHH =8Hz, CH for pyridine), 7.06–7.85 (4H, m, aromatic), 7.86 (1H, t, 3 JHH =8Hz, CH for pyridine), 8.29 (1H, d, 3 JHH =8Hz, CH for pyridine). 13C NMR (100 MHz, CDCl3): δ 13.95, 14.51 (2CH3), 21.65 (CH3), 61.50, 61.92 (2OCH2), 117.69, 120.55, 121.04, 123.00, 127.51, 128.78, 132.24, 134.19, 135.82, 137.09, 143.97, 145.13, 146.86, 147.32 and 150.94 (aromatic carbons), 161.82, 167.36 and 185.03 (3C=O). Mass, m/z (%) = 404 [M+,19]. Dimethyl 1-(4-methylpyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b] pyrrole-2,3-dicarboxylate (4c): Yellow powder; m.p. 155–158 oC,
Conclusion In summary, we have developed a simple one-pot, threecomponent intermolecular Wittig reaction using ninhydrin, 2-amino pyridine and dialkyl acetylenedicarboxylates in the presence of triphenylphosphine to give polysubstituted pyrrole derivatives. The advantages of this method include mild conditions, and readily available starting materials. No base nor acid is required, and the reaction proceeds at room temperature. This mild annulation strategy may offer a protocol for synthesising other N-heterocyclic compounds of interest to medicinal chemists.
Experimental Melting points were measured on an Electrothermal 9100 apparatus. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H NMR spectra were recorded on a Bruker DRX400 Avance spectrometer at 400 MHz; chemical shifts (δ scale) are reported in ppm. 13C NMR spectra were recorded on Bruker DRX-400 Avance spectrometers at 100 MHz; chemical shifts (δ scale) are reported in ppm. The mass spectra were recorded on an Agilent 5973 mass spectrometer operating at an ionisation potential of 70 eV. The elemental analyses were performed with an ElementarAnalysensysteme GmbH VarioEL. The chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification. General procedure A mixture of ninhydrin (1 mmol) and 2-amino pyridine (1 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 10 min in a round-
O
O OH
X
N
H2N
OH
+
N H
OH X
1
O
O
5
2
O
X
RO2C
+
OH N H
N
6
5
Ph3P
CO2R
Ph3P
O
RO2C
N
RO2C
H
PPh3
O
CO2R
N
HO N
RO2C
N HO
O
N
X
O
O X
7
8
CO2R CO2R -H2O
O=PPh3
N OH
4
N
O
9
X
Scheme 2 Suggested mechanism for formation of dihydroindeno[2,1-b]pyrrole.
JOURNAL OF CHEMICAL RESEARCH 2015 313 IR (KBr) (νmax, cm-1): 1738 (2C=O, ester), 1691 (C=O, ketone). Anal. calcd for C21H16N2O5: C, 67.02; H, 4.28; N, 7.44; found: C, 67.16; H, 4.35; N, 7.29%. 1H NMR (400 MH Z, CDCl3): δ 2.21 (3H, s, CH3), 3.51 and 3.86 (6H, 2s, 2OCH3), 7.19 (1H, s, CH for pyridine), 7.23–7.80 (4H, m, aromatic), 7.86 (1H, d, 3 JHH = 8Hz, CH for pyridine), 8.26 (1H, d, 3 JHH = 8Hz, CH for pyridine). 13C NMR (100 MH Z, CDCl3): δ 22.95 (CH3), 52.10, 52.31 (2 OCH3), 116.21, 119.08, 122.48, 124.45, 128.10, 128.78, 132.38, 133.16, 135.72, 135.93, 144.22, 147.08, 149.18, 150.00 and 162.00 (aromatic carbons), 163.13, 168.17 and 189.59 (3C=O). Mass, m/z (%) = 376 [M+, 16]. Diethyl 1-(4-methylpyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b] pyrrole-2,3-dicarboxylate (4d): Yellow powder; m.p. 141–143 oC, IR (KBr) (νmax, cm-1): 1738 (2C=O, ester), 1694 (C=O, ketone). Anal. calcd for C23H20N2O5: C, 68.31; H, 4.98; N, 6.93; found: C, 68.20; H, 4.91; N, 7%. 1H NMR (400 MH Z, CDCl3): δ 0.87, 1.25 (6H, 2t, 3 JHH = 7Hz, 2 CH3), 2.46 (3H, s, CH3), 4.22, 4.37 (4H, 2m, 2OCH2), 6.83 (1H, s, CH for pyridine), 7.10–7.83 (4H, m, aromatic), 7.88 (1H, d, 3 JHH = 8Hz, CH for pyridin), 8.25 (1H, d, 3 JHH = 8Hz, CH for pyridine). 13 C NMR (100 MHz, CDCl3): δ 14.02, 14.37 (2CH3), 23.09 (CH3), 61.69, 62.15 (2OCH2), 118.01, 121.11, 121.18, 122.95, 128.51, 128.66, 133.34, 134.47, 136.04, 137.11, 144.14, 146.03, 149.41, 150.24 and 161.77 (aromatic carbons), 161.50, 167.00 and 184.11 (3C=O). Mass, m/z (%) = 404 [M+, 18]. Dimethyl 1-(pyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b]pyrrole2,3-dicarboxylate (4e): Yellow powder; m.p. 126–128 oC, IR (KBr) (νmax, cm-1): 1746 (2C=O, ester), 1693 (C=O, ketone). Anal. calcd for C20H14N2O5: C, 66.30; H, 3.89; N, 7.73; found: C, 66.44; H, 4.02; N, 7.56%. 1H NMR (400 MH Z, CDCl3): δ 3.66 and 3.79 (6H, 2s, 2OCH3), 6.90–8.16 (7H, m, aromatic). 13C NMR (100 MHz, CDCl3): δ 50.98, 52.06 (2OCH3), 113.12, 119.33, 120.78, 123.07, 126.59, 130.18, 131.95, 134.41, 135.52, 136.58, 143.29, 144.71, 146.15, 149.02 and 160.88 (aromatic carbons), 161.82, 167.36 and 185.03 (3C=O). Mass, m/z (%) = 362 [M+, 23]. Diethyl 1-(pyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b]pyrrole2,3-dicarboxylate (4f): Yellow powder; m.p. 135–137 oC, IR (KBr) (νmax, cm-1): 1742 (2C=O, ester), 1700 (C=O, ketone). Anal. calcd for C22H18N2O5: C, 67.69; H, 4.65; N, 7.18; found: C, 67.51; H, 4.72; N, 9.98%. 1H NMR (400 MH Z, CDCl3): δ 0.96, 1.20 (6H, 2t, 3 JHH = 7Hz, 2 CH3), 3.99, 4.18 (4H, 2m, 2OCH2), 6.94 (1H, d, 3 JHH = 8Hz, CH for pyridine), 6.98–7.53 (4H, m, aromatic), 7.81 (1H, t, 3 JHH = 8Hz, CH for pyridine), 8.06 (1H, d, 3 JHH = 8Hz, CH for pyridine), 6.91–8.28 (7H, m, aromatic). 13C NMR (100 MHz, CDCl3): δ 13.95, 14.51 (2CH3), 61.50, 61.92 (2OCH2), 113.15, 120.43, 121.62, 123.16, 126.86, 131.01, 131.99, 135.17, 135.77, 138.04, 144.13, 144.85, 147.11, 150.06 and 160.71 (aromatic carbons), 162.17, 168.63 and 184.23 (3C=O). Mass, m/z (%) = 390 [M+, 17]. Dimethyl 1-(3-bromopyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b] pyrrole-2,3-dicarboxylate (4g): Yellow powder; m.p. 171–173 oC, IR (KBr) (νmax, cm-1): 1735 (2C=O, ester), 1699 (C=O, ketone). Anal. calcd for C20H13BrN2O5: C, 54.44; H, 2.97; 6.35,N; found: C, 54.61; H, 3.02; N, 6.54%. 1H NMR (400 MH Z, CDCl3): δ 3.58 and 3.67 (6H, 2s, 2OCH3), 7.81 (1H, t, 3 JHH = 8Hz, CH for pyridine), 6.99–7.84 (4H, m, aromatic), 8.01 (1H, d, 3 JHH =8Hz, CH for pyridine), 8.06 (1H, d, 3 JHH = 8Hz, CH for pyridine). 13C NMR (100 MHz, CDCl3): δ 52.13,
52.34 (2OCH3), 114.09, 119.63, 120.15, 123.16, 126.76, 131.10, 132.00, 135.00, 135.77, 136.36, 145.19, 145.61, 146.84, 149.03 and 162.37 (aromatic carbons), 163.76, 168.55 and 188.41 (3C=O). Mass, m/z (%) = 440 [M+, 13]. Diethyl 1-(3-bromopyridin-2-yl)-8-oxo-1,8-dihydroindeno[2,1-b] pyrrole-2,3-dicarboxylate (4h): Yellow powder; m.p. 179–181 oC, IR (KBr) (νmax, cm-1): 1743 (2C=O, ester), 1701 (C=O, ketone) Anal. calcd for C22H17BrN2O5: C, 56.31; H, 3.65; N, 5.97; found: C, 56.25; H, 3.70; N, 6.15%. 1H NMR (400 MH Z, CDCl3): δ 1.14, 1.34 (6H, 2t, 3 JHH = 7Hz, 2 CH3), 4.01, 4.59 (4H, 2m, 2OCH2), 7.74 (1H, t, 3 JHH = 8Hz, CH for pyridine), 7.11–8.01 (4H, m, aromatic)., 8.05 (1H, d, 3 JHH =8Hz, CH for pyridine), 8.09 (1H, d, 3 JHH = 8Hz, CH for pyridine). 13C NMR (100 MHz, CDCl3): δ 14.23, 14.74 (2CH3), 60.77, 61.53 (2OCH2), 113.61, 120.11, 122.41, 123.45, 127.06, 130.97, 131.39, 135.94, 135.69, 139.12, 144.17, 144.79, 148.07, 150.15 and 161.28 (aromatic carbons), 162.86, 168.04 and 187.67 (3C=O). Mass, m/z (%) = 468 [M+, 20].
Received 3 April 2015; accepted 4 May 2015 Paper 1503289 doi: 10.3184/174751915X14316237301775 Published online: 4 June 2015
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