One-Pot Synthesis of Pentasubstituted Pyrroles from Propargylic Alcohols, Amines, and Dialkyl Acetylenedicarboxylates; Tandem Amination, Propargylation and Cycloisomerization Catalyzed by Molecular Iodine^{[ 1 ]}

Abstract

A multicomponent one-pot synthesis of fully substituted pyrroles has been developed by the tandem reaction of amines, dialkyl acetylenedicarboxylates, and propargylic alcohols using iodine as a catalyst. The reaction was complete in three hours and afforded the products in high yields (75–88%). The method is simple, efficient, cost-effective, and metal-free.

Pyrrole derivatives are a class of important heterocyclics representing structural elements of various bioactive natural products such as chlorophyll, bile pigments, heme, and vitamin B₁₂.[2] [3] The pyrrole ring is also the structural unit of different drugs having anticancer,[ ^4a ] antitumor,[ ^3a ] antibacterial,[ ^3b ] and immune suppression activities.[ ^3c ] Several pyrrole derivatives are cholesterol lowering agents (atorvastatin or lipitor)[ ^4b ] and HIV fusion inhibitors. In addition, they are flexible intermediates for transformation into valuable bioactive heterocyclic systems.[ ⁵ ] Pyrrole derivatives are also applied for the preparation of semiconducting and fluorescence materials.[ ⁶ ] Consequently, a wide range of methods have been discovered for the synthesis of pyrroles[ ⁷ ] using various metal salts (Pd, Ni, Fe, Cu, Zn, Mg, etc.). However, these methods suffer from several drawbacks such as, use of toxic metals, tedious experimental procedure, and unsatisfactory yield. Recently, synthesis of pyrroles applying multi-component reaction (MCR) strategy has attracted much attention of chemists. The MCR strategy combining three or more starting materials in a single synthetic operation provides high atom economy and bond forming efficiency without isolation and purification of any intermediate, which in turn minimize the waste, labor, and cost.[ ⁸ ] Recently, we reported a simple and efficient metal-free synthesis of tetrasubstituted pyrroles by applying iodine-catalyzed four-component coupling reactions of aldehydes, amines, dialkyl acetylenedicarboxylates, and nitromethane in one pot.[ ⁹ ] Herein we wish to report a three-component metal-free synthesis of pentasubstituted pyrroles.

In continuation of our work[ ¹⁰ ] on the development of useful synthetic methodologies, we have discovered that the three-component coupling of propargylic alcohols, amines, and dialkyl acetylenedicarboxylates in the presence of molecular iodine as a catalyst in toluene afforded the corresponding pentasubstituted pyrroles under reflux condition (Scheme [1]).

Initially, the reaction of secondary propargylic alcohol (derived from the benzaldehyde and phenylacetylene) and aniline was conducted directly with dimethyl acetylenedicarboxylates in the presence of 10 mol% of Cu(OTf)₂ as a single catalyst in 1,2-dichloroethane (DCE) under reflux (Scheme [2]). After 12 hours, complete consumption of propargylic alcohol was observed and the corresponding pentasubstituted pyrrole was obtained in 61% yield (Table 1, entry 1). To extend the scope of the amination, propargylation, and cycloisomerization tandem reaction for the synthesis of pyrroles, the present reaction was screened with other different catalysts and solvent systems. When the reaction was performed in toluene in the presence of 5 mol% of AgOAc along with 10 mol% of Cu(OTf)₂ the yield increased to 70% (entry 3). By using 10 mol% of the copper-free catalyst InCl₃ the reaction furnished the expected pyrrole in 77% yield under similar conditions (entry 4). However, with the catalysts like FeCl₃, YbCl₃, BiCl₃, or AgOTf, the tandem reaction led not to the expected pyrrole but to the intermediate γ-alkynylamine B (Scheme [2], vide infra) (entries 5–8). Further to extend the scope for better catalytic system, the reaction mixture was treated with 10 mol% of molecular iodine in DCE; after refluxing for six hours, the expected pyrrole was obtained in 72% yield (entry 9). To get better yield the mixture was again treated with 5 mol% of AgOAc along with 10 mol% of molecular iodine affording the pyrrole in 83% yield. Use of CuOAc instead of AgOAc did not lead to better result. Finally, when the reaction mixture was treated with 10 mol% of iodine in toluene under reflux for three hours the expected pyrrole was formed in 88% yield. This is the best result in comparison to other catalysts investigated in the present reaction (Table 2).

Table 1 Optimization of Reaction Parameters for the Synthesis of Pentasubstituted Pyrroles^a,b

Entry	Catalyst	Solvent	Time (h)	Yield (%)c
1	Cu(OTf)2	DCE	12	61
2	Cu(OTf)2	toluene	12	68
3	Cu(OTf)2/AgOAc	toluene	12	70
4	InCl3	toluene	6	77
5	FeCl3	toluene	12	0
6	YbCl3	toluene	12	0
7	BiCl3	toluene	12	0
8	AgOTf	toluene	12	0
9	I2	DCE	6	72
10	I2	MeCN	6	65
11	I2/AgOAc	toluene	6	83d
12	I2/CuOAc	toluene	6	80
13	I2	toluene	6	85
14	I2	toluene	3	88

^a Reaction conditions: aniline (0.5 mmol), dimethyl acetylenedicarboxylate (0.56 mmol), 1,3-diphenylprop-2-yn-1-ol (0.5 mmol), solvent (3 mL), and catalyst (10 mol%) under reflux.

^b The structure of the product was established from their spectral (IR, ¹H and ¹³C NMR, and ESI-MS) data.

^c Isolated yields after purification.

^d AgOAc (5 mol%) along with I₂ (10 mol%) were used.

With the optimized reaction conditions, a series of pentasubstituted pyrroles were subsequently synthesized from various secondary propargylic alcohols containing both terminal alkyne as well as internal alkyne having aryl and alkyl substituents in excellent yields (Table 2). Both aromatics and heteroaromatics containing electron-donating and -withdrawing groups underwent the conversion smoothly. Secondary propargylic alcohols furnished the corresponding pyrroles in good yields. However, when R² = alkyl (Table 2, entries 19, 20) the reaction did not yield the required product probably due to less electron density at the carbon atom attached to the alcohol. On the other hand, amines containing both aromatic and aliphatic substituents underwent the conversion smoothly. The pyrroles were efficiently prepared by using dimethyl and diethyl acetylenedicarboxylates. The conversion was completed only in three hours and the products were formed in high yields (75–88%). The structures of the products were established from their spectral (IR, ¹H and ¹³C NMR, and MS) and analytical data.

Table 2 Pentasubstituted Pyrroles 4 Prepared^a,b

Entry	R1	R2	R3	R4	Product	Yield (%)c
1	Me	Ph	Ph	Ph	4a	88
2	Me	Ph	4-ClC6H4	Ph	4b	83
3	Me	Ph	4-FC6H4	Ph	4c	85
4	Me	4-MeC6H4	4-FC6H4	Ph	4d	78
5	Me	4-MeOC6H4	4-FC6H4	Ph	4e	81
6	Me	4-MeC6H4	4-ClC6H4	Ph	4f	80
7	Me	4-MeOC6H4	4-ClC6H4	Ph	4g	82
8	Me	4-MeC6H4	4-MeOC6H4	Ph	4h	77
9	Me	4-MeC6H4	4-MeC6H4	Ph	4i	75
10	Me	4-MeOC6H4	4-MeC6H4	Ph	4j	82
11	Me	4-MeC6H4	Ph	Ph	4k	85
12	Me	4-ClC6H4	Ph	Ph	4l	86
13	Me	4-FC6H4	Ph	Ph	4m	82
14	Me	PhCH2	4-MeC6H4	Ph	4n	87
15	Me	Ph	Ph	C6H13	4o	82
16	Me	4-MeOC6H4	Ph	C6H13	4p	86
17	Me	4-MeC6H4	Ph	C6H13	4q	79
18	Et	4-MeOC6H4	Ph	Ph	4r	76
19	Me	Ph	furfuryl	Ph	4s	53d
20	Me	4-MeOC6H4	c-C6H11	Ph	4t	0e
21	Me	Ph	c-C6H11	Ph	4u	0e

^a Reaction conditions: amine (0.5 mmol), dialkyl acetylenedicarboxylate (0.56 mmol), propargylic alcohol (0.5 mmol), toluene (3 mL), and I₂ (10 mol%) under reflux.

^b The structures of the products were established from their spectral (IR,¹H and ¹³C NMR, and ESI-MS) data.

^c Isolated yields after purification.

^d Product characterized by GCMS.

^e Reaction carried out for 12 h.

Iodine, used as a catalyst here, is less expensive and easily available. It acts as a Lewis acid in the tandem reaction of amines, dialkyl acetylenedicarboxylates, and propargylic alcohols. The plausible mechanism of the present conversion involves the initial formation of the intermediate, alkenylamine A catalyzed by iodine (Scheme [2]). Subsequent nucleophilic attack of intermediate A to the propargylic alcohol gives the γ-alkynylamine B. Coordination of iodine to the alkyne enhances the electrophilicity of the alkyne and nuclophilic attack of the amino group to the alkyne led to the intermediate C, which undergoes cycloisomerization to furnish the pyrrole derivative (Scheme [2]).

In conclusion, we have developed a simple and efficient iodine-catalyzed method for the synthesis of fully substituted pyrroles directly from amines, dialkyl acetylenedicarboxylates, and propargylic alcohols in excellent yields. High functional-group tolerance, operational simplicity, minimal waste generation (only water was generated as by-product), and use of cheap catalyst are the main advantages of this method.

Silica gel F₂₅₄ plates were used for TLC; the spots were examined under UV light and then developed by I₂ vapor. Column chromatography was performed with silica gel (BDH 100–200 mesh). Solvents were purified according to standard procedures. The spectra were recorded with the following instruments; IR: PerkinElmer RX FT-IR spectrophotometer; NMR: Varian Gemini 200 MHz (¹H) and 50 MHz (¹³C) spectrometer; MS (ESI): VG-Autospec micromass.

Pentasubstituted Pyrroles 4; General Procedure

To a stirred solution of respective amine 2 (0.5 mmol), dialkylacetylene dicarboxylate 1 (0.56 mmol), and propargylic alcohol 3 (0.5 mmol) in toluene (3 mL) was added I₂ (10 mol%). The reaction mixture was heated slowly to reflux for 3 h. After completion of the reaction as monitored by TLC (hexane–EtOAc, 5:1), the mixture was cooled to r.t. and diluted with EtOAc (10 mL). The EtOAc layer was washed with sat. aq Na₂S₂O₃ (2 × 2 mL), followed by H₂O (5 mL) and brine (5 mL). The residue was dried (Na₂SO₄), concentrated under reduced pressure, and subjected to column chromatography (hexane–EtOAc, 10:1) to afford the corresponding pentasubstituted pyrroles 4 (Table 2).

Dimethyl 5-Benzyl-1,4-diphenyl-1H-pyrrole-2,3-dicarboxylate (4a)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4a (185 mg, 88%) as a brownish oil.

IR (neat): 1731, 1692, 1590, 1452 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.41–7.29 (m, 5 H), 7.29–7.21 (m, 4 H), 7.05 (d, J = 7.0 Hz, 2 H), 6.98 (m, 2 H), 6.66–6.59 (m, 2 H), 3.75 (s, 2 H), 3.70 (s, 3 H), 3.61 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 167.0, 160.2, 138.5, 138.0, 135.3, 133.5, 129.7, 129.1, 129.0, 129.9, 128.8, 127.0, 126.1, 123.7, 122.5, 122.0, 114.2, 52.1, 51.8, 30.8.

MS (ESI): m/z = 426 [M + H]⁺, 448 [M + Na]⁺.

HRMS: m/z calcd for C₂₇H₂₃NO₄ + Na: 448.149; found: 448.151.

Anal. Calcd for C₂₇H₂₃NO₄: C, 64.96; H, 4.36; N, 3.79. Found: C, 64.89; H, 4.39; N, 3.82.

Dimethyl 5-Benzyl-4-(4-chlorophenyl)-1-phenyl-1H-pyrrole-2,3-dicarboxylate (4b)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4b (190 mg, 83%) as a yellowish oil.

IR (neat): 1731, 1699, 1592, 1451 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.40–7.35 (m, 4 H), 7.23 (d, J = 8.30 Hz, 1 H), 7.12–7.05 (m, 6 H), 6.90 (d, J = 9.06 Hz, 1 H), 6.68–6.63 (m, 2 H), 3.80 (s, 3 H), 3.75 (s, 5 H), 3.65 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.5, 160.0, 138.1, 136.2, 135.5, 134.5, 133.1, 129.5, 129.3, 128.7, 128.3, 128.2, 129.9, 127.3, 126.2, 123.9, 122.2, 122.0, 114.1, 52.1, 51.6, 29.9.

MS (ESI): m/z = 460 [M + H]⁺, 482 [M + Na]⁺.

Anal. Calcd for C₂₇H₂₂ClNO₄: C, 70.51; H, 4.82; N, 3.05. Found: C, 70.55; H, 4.79; N, 3.09.

Dimethyl 5-Benzyl-4-(4-fluorophenyl)-1-phenyl-1H-pyrrole-2,3-dicarboxylate (4c)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4c (188 mg, 85%) as a dark brownish oil.

IR (neat): 1730, 1798, 1601, 1450 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.32 (dd, J = 7.80, 5.50 Hz, 2 H), 7.10–7.05 (m, 6 H), 7.05– 7.01 (t, J = 8.80 Hz, 2 H), 6.90 (d, J = 7.80 Hz, 2 H), 6.66–6.60 (m, 2 H), 3.74 (s, 5 H), 3.64 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.3, 163.5, 160.2, 138.5, 138.3, 135.2, 131.3, 130.0, 129.3, 129.1, 128.2, 128.1, 127.8, 127.6, 126.1, 115.3, 115.0, 52.1, 51.8, 30.4.

MS (ESI): m/z = 444 [M + H] ⁺, 466 [M + Na]⁺.

Anal. Calcd C₂₇H₂₂FNO₄: C, 73.13; H, 5.00; N, 3.16. Found: C, 73.21; H, 4.96; N, 3.21.

Dimethyl 5-Benzyl-4-(4-fluorophenyl)-1-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4d)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4d (176 mg, 78%) as a brownish oil.

IR (neat): 1739, 1695, 1605, 1451 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.33 (dd, J = 7.70, 5.52 Hz, 2 H), 7.11–7.06 (m, 5 H), 7.05–7.01 (t, J = 8.80 Hz, 2 H), 6.90 (d, J = 7.70 Hz, 2 H), 6.68–6.63 (m, 2 H), 3.75 (s, 5 H), 3.65 (s, 3 H), 2.36 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.4, 162.2 (d, J = 285.96 Hz), 160.0, 138.6, 138.3, 135.3, 131.3, 130.0, 129.5, 129.1, 128.2, 128.0, 127.9, 127.6, 126.1, 115.3, 115.0, 52.0, 51.7, 29.9, 21.1.

MS (ESI): m/z = 458 [M + H]⁺, 480 [M + Na]⁺.

Anal. Calcd for C₂₈H₂₄FNO₄: C, 73.51; H, 5.29; N, 3.06. Found: C, 73.66; H, 5.22; N, 2.11.

Dimethyl 5-Benzyl-4-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrrole-2,3-dicarboxylate (4e)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 12:1) to give 4e (191 mg, 81%) as a light yellowish oil.

IR (neat): 1735, 1709, 1602, 1463 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.37–7.31 (m, 3 H), 7.11–7.07 (m, 2 H), 7.03 (t, J = 8.80 Hz, 2 H), 6.92 (d, J = 8.83 Hz, 2 H), 6.78 (d, J = 8.80 Hz, 2 H), 6.69–6.65 (m, 2 H), 3.80 (s, 3 H), 3.75 (s, 5 H), 3.65 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.2, 163.5, 160.3, 159.5, 138.4, 135.4, 131.4, 131.2, 130.1, 129.5, 128.9, 128.1, 127.9, 129.1, 124.4, 123.9, 119.0, 115.3, 115.08, 114.0, 113.6, 55.3, 52.1, 51.7, 29.6.

MS (ESI): m/z = 474 [M + H]⁺, 496 [M + Na]⁺.

Anal. Calcd for C₂₈H₂₄FNO₄: C, 71.03; H, 5.11; N, 2.96. Found: C, 71.13; H, 5.07; N, 2.99.

Dimethyl 5-Benzyl-4-(4-chlorophenyl)-1-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4f)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 9:1) to give 4f (186 mg, 80%) as a yellowish oil.

IR (neat): 1731, 1591, 1499, 1452 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.32 (d, J = 7.0, 4.0 Hz, 4 H), 7.13–7.08 (m, 5 H), 6.9 (d, J = 7.0 Hz, 2 H), 6.70–6.65 (m, 2 H), 3.78 (s, 5 H), 3.65 (s, 3 H), 2.48 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.5, 160.5, 139.0, 138.5, 135.3, 135.0, 133.2, 132.3, 131.1, 129.4, 128.9, 128.7, 128.5, 126.2, 123.3, 122.5, 121.4, 52.0, 51.8, 30.0, 21.1.

MS (ESI): m/z = 474 [M + H]⁺, 496 [M + Na]⁺.

Anal. Calcd for C₂₈H₂₄ClNO₄: C, 70.96; H, 5.10; N, 2.96. Found: C, 70.99; H, 5.01; N, 2.83.

Dimethyl 5-Benzyl-4-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrrole-2,3-dicarboxylate (4g)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 15:1) to give 4g (198 mg, 82%) as a yellowish oil.

IR (neat): 1729, 1590, 1496, 1447 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.33–7.29 (m, 4 H), 7.13–7.08 (m, 3 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.77 (d, J = 8.30 Hz, 2 H), 6.66 (m, 2 H), 3.81 (s, 2 H), 3.76 (s, 3 H), 3.64 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 167.2, 159.5, 136.4, 135.5, 133.6, 131.0, 130.1, 129.9, 128.5, 128.4, 128.0, 127.9, 127.8, 126.5, 126.1, 121.4, 113.6, 55.5, 52.1, 51.6, 30.5.

MS (ESI): m/z = 490 [M + H]⁺, 513 [M + Na]⁺.

Anal. Calcd for C₂₈H₂₄ClNO₅: C, 68.64; H, 4.94; N, 2.86. Found: C, 68.71; H, 4.89; N, 2.89.

Dimethyl 5-Benzyl-4-(4-methoxyphenyl)-1-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4h)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 8:1) to give 4h (153 mg, 77%) as a brownish oil.

IR (neat): 1724, 1592, 1497, 1446 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.30–7.28 (m, 4 H), 7.10–7.07 (m, 3 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.71 (d, J = 8.3 Hz, 2 H), 6.61–6.65 (m, 2 H), 3.79 (s, 2 H), 3.73 (s, 3 H), 3.61 (s, 3 H), 2.47 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.7, 160.3, 138.6, 136.7, 135.7, 130.5, 130.3, 129.3, 129.0, 128.9, 128.0, 125.9, 123.3, 122.0, 113.5, 55.2, 52.1, 51.6, 30.2, 21.1.

MS (ESI): m/z = 470 [M + H]⁺, 492 [M + Na]⁺.

Anal. Calcd for C₂₉H₂₇NO₅: C, 74.18; H, 5.80; N, 2.98. Found: C, 74.22; H, 5.77; N, 3.01.

Dimethyl 5-Benzyl-1,4-di-p-tolyl-1H-pyrrole-2,3-dicarboxylate(4i)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 8:1) to give 4i (165 mg, 75%) as a colorless oil.

IR (neat): 1732, 1598, 1501, 1450 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.41–7.20 (m, 6 H), 7.08–7.01 (m, 3 H), 6.91–6.82 (m, 2 H), 6.69–6.64 (m, 2 H), 3.77 (s, 2 H), 3.70 (s, 3 H), 3.62 (s, 3 H), 2.36 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 167.2, 160.7, 138.7, 136.8, 135.9, 130.6, 130.4, 128.8, 128.5, 128.2, 127.9, 125.6, 123.3, 122.0, 52.0, 51.5, 30.4, 21.1, 21.1.

MS (ESI): m/z = 454 [M + H]⁺, 475 [M + Na]⁺.

Anal. Calcd for C₂₉H₂₇NO₄: C, 76.80; H, 6.00; N, 3.09. Found: C, 76.89; H, 5.99; N, 3.11.

Dimethyl 5-Benzyl-1-(4-methoxyphenyl)-4-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate(4j)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 15:1) to give 4j (187 mg, 82%) as a yellowish oil.

IR (neat): 1724, 1592, 1497, 1446 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.31–7.27 (m, 4 H), 7.10–7.06 (m, 3 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.71 (d, J = 8.3 Hz, 2 H), 6.61–6.65 (m, 2 H), 3.79 (s, 2 H), 3.73 (s, 3 H), 3.61 (s, 3 H), 2.47 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.7, 160.3, 138.6, 136.7, 135.7, 130.5, 130.3, 129.3, 129.0, 128.9, 128.0, 125.9, 123.3, 122.0, 113.5, 55.2, 52.1, 51.6, 30.5, 21.1.

MS (ESI): m/z = 470 [M + H]⁺, 492 [M + Na]⁺.

Anal. Calcd for C₂₉H₂₇NO₅: C, 74.18; H, 5.80; N, 2.98. Found: C, 74.22; H, 5.77; N, 3.01.

Dimethyl 5-Benzyl-4-phenyl-1-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4k)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 8:1) to give 4k (175 mg, 85%) as a brownish oil.

IR (neat): 1737, 1624, 1530, 1453 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.40–7.21 (m, 6 H), 7.09–7.01 (m, 3 H), 6.92–6.82 (m, 2 H), 6.70–6.62 (m, 2 H), 3.77 (s, 2 H), 3.70 (s, 3 H), 3.61 (s, 3 H), 2.36 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.5, 160.2, 138.4, 137.9, 131.6, 129.5, 129.1, 128.6, 128.4, 128.3, 128.22, 128.1, 128.0, 127.9, 127.8, 127.6, 127.0, 125.9, 30.5, 21.1.

MS (ESI): m/z = 440 [M + H]⁺, 462 [M + Na]⁺.

Anal. Calcd C₂₈H₂₅NO₄: C, 76.52; H, 5.73; N, 3.19. Found: C, 76.55; H, 5.69; N, 3.21.

Dimethyl 5-Benzyl-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate(4l)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4l (193 mg, 86%) as a colorless oil.

IR (neat): 1728, 1612, 1522, 1443, 1254 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.40–7.35 (m, 4 H), 7.23 (d, J = 8.30 Hz, 1 H), 7.12–7.05 (m, 6 H), 6.90 (d, J = 9.06 Hz, 1 H), 6.68–6.63 (m, 2 H), 3.80 (s, 3 H), 3.75 (s, 5 H), 3.65 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.5, 160.0, 138.1, 136.9, 135.5, 134.5, 133.1, 129.4, 129.2, 128.6, 128.3, 128.1, 129.9, 127.2, 126.2, 123.8, 122.7, 116.1, 52.4, 51.6, 29.5.

MS (ESI): m/z = 460 [M + H]⁺, 482 [M + Na]⁺.

Anal. Calcd for C₂₇H₂₂ClNO₄: C, 70.51; H, 4.82; N, 3.05. Found: C, 70.66; H, 4.76; N, 3.11.

Dimethyl 5-Benzyl-1-(4-fluorophenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate (4m)

Following the general procedure the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4m (180 mg, 82%) as a dark brownish oil.

IR (neat): 1725, 1582, 1490, 1438 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.43–7.28 (m, 5 H), 7.11–7.07 (m, 3 H), 6.94 (d, J = 6.0 Hz, 4 H), 6.68–6.64 (m, 2 H), 3.79 (s, 2 H), 3.76 (s, 3 H), 3.64 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 166.6, 162.2 (d, J = 285.96 Hz), 160.0, 138.1, 135.6, 133.6, 133.2, 129.7, 128.9, 128.8, 129.6, 129.6, 128.3, 128.1, 127.8, 127.2, 126.1, 115.5, 115.2, 52.1, 51.6, 30.5.

MS (ESI): m/z = 444 [M + H]⁺, 466 [M + Na]⁺.

Anal. Calcd for C₂₇H₂₂FNO₄: C, 73.13; H, 5.00; N, 3.16. Found: C, 73.19; H, 5.18; N, 3.21.

Dimethyl 1,5-Dibenzyl-4-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4n)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4n (195 mg, 87%) as a colorless oil.

IR (neat): 1740, 1630, 1604, 1441 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.31–7.18 (m, 8 H), 7.12 (d, J = 8.22 Hz, 2 H), 7.00 (d, J = 7.40 Hz, 2 H), 6.91 (d, J = 8.22 Hz, 2 H), 5.35 (s, 2 H), 3.87 (s, 2 H), 3.76 (s, 6 H), 2.33 (s, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 167.0, 160.7, 138.0, 137.3, 136.7, 134.4, 130.3, 129.2, 129.0, 128.7, 128.6, 127.6, 127.1, 126.5, 125.7, 124.1, 122.9, 120.5, 52.1, 51.6, 48.7, 30.2, 21.1.

MS (ESI): m/z = 454 [M + H]⁺, 476 [M + Na]⁺.

Anal. Calcd for C₂₉H₂₇NO₄: C, 76.80; H, 6.00; N, 3.09. Found: C, 76.85; H, 5.96; N, 3.11.

Dimethyl 5-Heptyl-1,4-diphenyl-1H-pyrrole-2,3-dicarboxylate (4o)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 9:1) to give 4o (175 mg, 82%) as a colorless oil.

IR (neat): 1717, 1565, 1491, 1449, 1296 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.52–7.42 (m, 4 H), 7.40–7.22 (m, 6 H), 3.73 (s, 3 H), 3.63 (s, 3 H), 2.42–2.30 (m, 2 H), 1.18–1.03 (m, 3 H), 1.01–0.83 (m, 5 H), 0.79 (t, J = 6.6 Hz, 3 H).

¹³C NMR (200 MHz, CDCl₃): δ = 166.8, 160.2, 137.9, 133.8, 129.1, 129.5, 128.1, 128.7, 128.0, 126.9, 122.6, 122.2, 120.6, 111.4, 52.1, 51.4, 31.2, 29.5, 29.0, 28.7, 28.2, 24.3, 22.4, 13.9.

MS (ESI): m/z = 434 [M + H]⁺, 456 [M + Na]⁺.

Anal. Calcd for C₂₇H₃₁NO₄: C, 74.80; H, 7.21; N, 3.23. Found: C, 74.85; H, 7.16; N, 3.27.

Dimethyl 5-Heptyl-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate (4p)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 15:1) to give 4p (197 mg, 86%) as a yellowish oil.

IR (neat): 1732, 1628, 1531, 1450 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.40–7.29 (m, 5 H), 7.21 (d, J = 9.06 Hz, 2 H), 6.98 (d, J = 8.30 Hz, 2 H), 3.87 (s, 3 H), 3.73 (s, 3 H), 3.65 (s, 3 H), 2.37 (t, J = 8.30 Hz, 2 H), 1.22–1.07 (m, 3 H), 1.05–0.89 (m, 5 H), 0.79 (t, J = 7.55 Hz, 3 H).

¹³C NMR (200 MHz, CDCl₃): δ = 166.8, 160.3, 159.9, 138.3, 133.9, 130.6, 129.5, 129.0, 128.5, 128.1, 126.8, 122.4, 122.1, 121.4, 113.8, 55.3, 52.0, 51.5, 31.3, 29.6, 29.1, 28.8, 28.2, 24.3, 22.4, 13.9.

MS (ESI): m/z = 464 [M + H]⁺, 476 [M + Na]⁺.

Anal. Calcd for C₂₈H₃₃NO₅: C, 72.55; H, 7.18; N, 3.02. Found: C, 72.59; H, 7.11; N, 3.07.

Dimethyl 5-Heptyl-4-phenyl-1-(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4q)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4q (174 mg, 79%) as a brownish oil.

IR (neat): 1725, 1621, 1527, 1442 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.40–7.31 (m, 5 H), 7.30–7.22 (m, 2 H), 7.17 (d, J = 8.30 Hz, 2 H), 3.73 (s, 3 H), 3.64 (s, 3 H), 2.43 (s, 3 H), 2.37 (t, J = 7.55 Hz, 2 H), 1.22–1.05 (m, 3 H), 1.03–0.89 (m, 5 H), 0.79 (t, J = 6.79 Hz, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 167.8, 160.3, 138.6, 138.0, 135.4, 134.0, 129.5, 129.4, 128.9, 128.1, 127.7, 126.9, 122.5, 52.1, 51.5, 31.3, 29.6, 29.1, 28.7, 28.2, 24.3, 22.3, 22.4, 21.2, 13.9.

MS (ESI): m/z = 448 [M + H]⁺, 470 [M + Na]⁺.

Anal. Calcd for C₂₈H₃₃NO₄: C, 75.14; H, 7.43; N, 3.13. Found: C, 75.19; H, 7.34; N, 3.21.

Diethyl 5-Benzyl-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate (4r)

Following the general procedure, the crude residue was subjected to column chromatography (hexane–EtOAc, 10:1) to give 4r (179 mg, 76%) as a yellowish oil.

IR (neat): 1728, 1612, 1522, 1443 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 7.44–7.27 (m, 5 H), 7.10–7.03 (m, 3 H), 6.91 (d, J = 8.83 Hz, 2 H), 6.77 (d, J = 8.83 Hz, 2 H), 6.70–6.64 (m, 2 H), 4.21 (q, J = 7.75 Hz, 2 H), 4.09 (q, J = 7.75 Hz, 2 H), 3.80 (s, 3 H), 3.78 (s, 2 H), 1.17 (t, J = 7.72 Hz, 3 H), 1.12 (t, J = 7.72 Hz, 3 H).

¹³C NMR (50 MHz, CDCl₃): δ = 164.5, 159.4, 138.6, 135.5, 133.3, 132.0, 131.6, 130.5, 129.6, 129.0, 128.2, 128.0, 127.5, 127.8, 127.3, 127.0, 126.0, 113.6, 63.0, 61.0, 60.4, 55.3, 29.6, 14.1, 14.0.

MS (ESI): m/z = 484 [M + H]⁺, 503 [M + Na]⁺.

Anal. Calcd for C₃₀H₂₉NO₅: C, 74.52; H, 6.04; N, 2.90. Found: C, 74.56; H, 6.01; N, 2.95.

Acknowledgment

The authors thank CSIR, New Delhi for financial assistance.

• References

• 1 Part 234 in the series Studies on Novel Synthetic Methodologies.
• 2a O’Hagan D. Nat. Prod. Rep. 2000; 17: 435
  CrossrefSearch in Google Scholar
• 2b Walsh CT, Gameau-Tsodikova S, Howard-Jones AR. Nat. Prod. Rep. 2006; 23: 517
  CrossrefPubMedSearch in Google Scholar
• 2c Reisser M, Maas G. J. Org. Chem. 2008; 69: 4913
  Search in Google Scholar
• 3a Denny WA, Rewcastle GW, Baguley BC. J. Med. Chem. 1990; 33: 814
  CrossrefPubMedSearch in Google Scholar
• 3b Daidone G, Maggis B, Schillari D. Pharmazie 1990; 45: 441
  Search in Google Scholar
• 3c Davis FA, Bowen KA, Xu H, Velvadapu V. Tetrahedron 2008; 64: 4174
  CrossrefPubMedSearch in Google Scholar
• 4a Estévez V, Villacampa M, Menéndez JC. Chem. Soc. Rev. 2010; 39: 4402
  CrossrefSearch in Google Scholar
• 4b Steven EN, Stephen JN, Ilke SD, Peter L, Joel SR. JAMA, J. Am. Med. Assoc. 2006; 295: 1556
  CrossrefSearch in Google Scholar
• 5a Boger DL, Boyce CW, Labrilli MA, Sehon CA, Jin Q. J. Am. Chem. Soc. 1999; 121: 54
  CrossrefSearch in Google Scholar
• 5b Abid M, Landge SM, Torok B. Org. Prep. Proced. Int. 2006; 38: 495
  CrossrefSearch in Google Scholar
• 6a Ramanavicius A, Ramanaviciene A, Malinauskas A. Electrochem. Acta 2006; 51: 6025
  CrossrefSearch in Google Scholar
• 6b Pu S, Liu G, Shen L, Xu J. Org. Lett. 2007; 9: 2139
  CrossrefSearch in Google Scholar

Some recent examples:
• 7a Shiner CM, Taner TD. Tetrahedron 2005; 61: 11628
  CrossrefSearch in Google Scholar
• 7b Minetto G, Raveglia LF, Sega A, Taddei M. Eur. J. Org. Chem. 2005; 34: 5277
  Search in Google Scholar
• 7c Larionov OV, de Meijire A. Angew. Chem. Int. Ed. 2005; 44: 5664
  CrossrefPubMedSearch in Google Scholar
• 7d Istrate FM, Gagosz F. Org. Lett. 2007; 9: 318
  Search in Google Scholar
• 7e Hwang SJ, Cho SH, Chang S. J. Am. Chem. Soc. 2008; 130: 16158
  CrossrefPubMedSearch in Google Scholar
• 7f La YD, Arndtsen BA. Angew. Chem. Int. Ed. 2008; 47: 5430
  CrossrefSearch in Google Scholar
• 7g Plaskon AS, Ryabukhin SV, Volochnyuk DM, Shivanyuk AN, Tolmachev AA. Tetrahedron 2008; 64: 5933
  CrossrefSearch in Google Scholar
• 7h Brichacek M, Njardarson JT. Org. Biomol. Chem. 2009; 7: 1760
  Search in Google Scholar
• 7i Lu Y, Fu X, Chen H, Du X, Jia X, Liu Y. Adv. Synth. Catal. 2009; 351: 129
  CrossrefSearch in Google Scholar
• 7j Wang J-Y, Wang X-P, Yu Z-S, Yu W. Adv. Synth. Catal. 2009; 351: 2063
  CrossrefSearch in Google Scholar
• 8a Maity S, Biswas S, Jana U. J. Org. Chem. 2010; 75: 1674
  CrossrefSearch in Google Scholar
• 8b Dieter RK, Yu H. Org. Lett. 2001; 3: 3855
  CrossrefPubMedSearch in Google Scholar
• 8c Grigg R, Savic V. Chem. Commun. 2000; 873
• 8d Gabriele B, Salerno G, Fazio A. J. Org. Chem. 2003; 68: 7853
  Search in Google Scholar
• 9 Das B, Bhunia N, Lingaiah M. Synthesis 2011; 347
  Thieme Connect
• 10a Das B, Ramu R, Reddy MR, Mahender G. Synthesis 2005; 250
  Thieme Connect
• 10b Das B, Krishnaiah M, Venkateswarlu K. Tetrahedron Lett. 2006; 47: 4457
  CrossrefSearch in Google Scholar
• 10c Das B, Damodar K, Bhunia N. J. Org. Chem. 2009; 74: 5607
  CrossrefPubMedSearch in Google Scholar
• 10d Das B, Reddy GC, Balasubramanyam P, Veeranjaneyulu B. Synthesis 2010; 1625
  Thieme Connect
• 10e Reddy GC, Balasubramanyam P, Salvanna N, Das B. Eur. J. Org. Chem. 2012; 471
• 10f Das B, Reddy GC, Balasubramanyam P, Salvanna N. Tetrahedron 2012; 68: 300
  CrossrefSearch in Google Scholar

• References

• 1 Part 234 in the series Studies on Novel Synthetic Methodologies.
• 2a O’Hagan D. Nat. Prod. Rep. 2000; 17: 435
  CrossrefSearch in Google Scholar
• 2b Walsh CT, Gameau-Tsodikova S, Howard-Jones AR. Nat. Prod. Rep. 2006; 23: 517
  CrossrefPubMedSearch in Google Scholar
• 2c Reisser M, Maas G. J. Org. Chem. 2008; 69: 4913
  Search in Google Scholar
• 3a Denny WA, Rewcastle GW, Baguley BC. J. Med. Chem. 1990; 33: 814
  CrossrefPubMedSearch in Google Scholar
• 3b Daidone G, Maggis B, Schillari D. Pharmazie 1990; 45: 441
  Search in Google Scholar
• 3c Davis FA, Bowen KA, Xu H, Velvadapu V. Tetrahedron 2008; 64: 4174
  CrossrefPubMedSearch in Google Scholar
• 4a Estévez V, Villacampa M, Menéndez JC. Chem. Soc. Rev. 2010; 39: 4402
  CrossrefSearch in Google Scholar
• 4b Steven EN, Stephen JN, Ilke SD, Peter L, Joel SR. JAMA, J. Am. Med. Assoc. 2006; 295: 1556
  CrossrefSearch in Google Scholar
• 5a Boger DL, Boyce CW, Labrilli MA, Sehon CA, Jin Q. J. Am. Chem. Soc. 1999; 121: 54
  CrossrefSearch in Google Scholar
• 5b Abid M, Landge SM, Torok B. Org. Prep. Proced. Int. 2006; 38: 495
  CrossrefSearch in Google Scholar
• 6a Ramanavicius A, Ramanaviciene A, Malinauskas A. Electrochem. Acta 2006; 51: 6025
  CrossrefSearch in Google Scholar
• 6b Pu S, Liu G, Shen L, Xu J. Org. Lett. 2007; 9: 2139
  CrossrefSearch in Google Scholar

Some recent examples:
• 7a Shiner CM, Taner TD. Tetrahedron 2005; 61: 11628
  CrossrefSearch in Google Scholar
• 7b Minetto G, Raveglia LF, Sega A, Taddei M. Eur. J. Org. Chem. 2005; 34: 5277
  Search in Google Scholar
• 7c Larionov OV, de Meijire A. Angew. Chem. Int. Ed. 2005; 44: 5664
  CrossrefPubMedSearch in Google Scholar
• 7d Istrate FM, Gagosz F. Org. Lett. 2007; 9: 318
  Search in Google Scholar
• 7e Hwang SJ, Cho SH, Chang S. J. Am. Chem. Soc. 2008; 130: 16158
  CrossrefPubMedSearch in Google Scholar
• 7f La YD, Arndtsen BA. Angew. Chem. Int. Ed. 2008; 47: 5430
  CrossrefSearch in Google Scholar
• 7g Plaskon AS, Ryabukhin SV, Volochnyuk DM, Shivanyuk AN, Tolmachev AA. Tetrahedron 2008; 64: 5933
  CrossrefSearch in Google Scholar
• 7h Brichacek M, Njardarson JT. Org. Biomol. Chem. 2009; 7: 1760
  Search in Google Scholar
• 7i Lu Y, Fu X, Chen H, Du X, Jia X, Liu Y. Adv. Synth. Catal. 2009; 351: 129
  CrossrefSearch in Google Scholar
• 7j Wang J-Y, Wang X-P, Yu Z-S, Yu W. Adv. Synth. Catal. 2009; 351: 2063
  CrossrefSearch in Google Scholar
• 8a Maity S, Biswas S, Jana U. J. Org. Chem. 2010; 75: 1674
  CrossrefSearch in Google Scholar
• 8b Dieter RK, Yu H. Org. Lett. 2001; 3: 3855
  CrossrefPubMedSearch in Google Scholar
• 8c Grigg R, Savic V. Chem. Commun. 2000; 873
• 8d Gabriele B, Salerno G, Fazio A. J. Org. Chem. 2003; 68: 7853
  Search in Google Scholar
• 9 Das B, Bhunia N, Lingaiah M. Synthesis 2011; 347
  Thieme Connect
• 10a Das B, Ramu R, Reddy MR, Mahender G. Synthesis 2005; 250
  Thieme Connect
• 10b Das B, Krishnaiah M, Venkateswarlu K. Tetrahedron Lett. 2006; 47: 4457
  CrossrefSearch in Google Scholar
• 10c Das B, Damodar K, Bhunia N. J. Org. Chem. 2009; 74: 5607
  CrossrefPubMedSearch in Google Scholar
• 10d Das B, Reddy GC, Balasubramanyam P, Veeranjaneyulu B. Synthesis 2010; 1625
  Thieme Connect
• 10e Reddy GC, Balasubramanyam P, Salvanna N, Das B. Eur. J. Org. Chem. 2012; 471
• 10f Das B, Reddy GC, Balasubramanyam P, Salvanna N. Tetrahedron 2012; 68: 300
  CrossrefSearch in Google Scholar

• Supplementary Material