Bridging homogeneous and heterogeneous catalysis with CAN·SiO₂ as a solid catalyst for four-component reactions for the synthesis of tetrasubstituted pyrroles

Abstract

An efficient and expeditious method has been developed for the synthesis of tetrasubstituted pyrroles via a four component, one-pot cyclocondensation reaction of amines, aldehydes, dialkyl acetylenedicarboxylates and nitroalkanes using silica supported ceric ammonium nitrate as a heterogeneous catalyst for the first time. Reusable silica supported ceric ammonium nitrate was found to be a highly efficient and renewable heterogeneous catalyst for the rapid and convenient synthesis of tetrasubstituted pyrrole derivatives. The advantageous features of this novel methodology are high atom-economy, operational simplicity, shorter reaction times, convergence, and facile automation.

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1. Introduction

Polysubstituted pyrroles represent some of the most important classes of heterocyclic molecules found in numerous natural and biologically active compounds.¹ Polysubstituted pyrroles have received considerable attention in the field of synthetic organic chemistry due to their numerous applications in the pharmaceutical industry.² Functionalized pyrroles have shown interesting biological properties such as antibacterial,³ antiinflammatory,⁴ antioxidant,⁵ antitumor, antifungal⁶ and immune suppressant activities.⁷ Highly functionalized pyrroles are subunits of heme, chlorophyll, bile pigments, vitamin B12 and pyrrole alkaloids isolated from the marine source.⁸ Furthermore, substituted pyrroles are widely used as synthetic building blocks, pharmacophores, and various kinds of functional materials.⁹ These compounds have many applications as chemosensors, for laser manufacture, and image diagnosis.¹⁰

The importance of chemical and pharmacological properties of pyrrole derivatives and the development of synthetic methods, which enable a facile access to these heterocyclic compounds, are desirable. Recently, many efforts have been devoted to develop novel and highly efficient synthetic protocols for the synthesis of functionalized pyrroles such as multicomponent coupling,¹¹ tandem reactions, transition-metal-catalyzed cyclization,¹² and catalytic C–H bond functionalization strategies have been developed and drawn extensive and enduring attention.¹³ In the midst of them, multicomponent processes have received great attention from the chemical community because they address fundamental principles of synthetic efficiency and reaction processing.¹⁴ Multicomponent coupling reactions (MCRs) are known as powerful tools for the construction of novel and structurally complex molecules in a single pot ensuring high atom economy, good overall yields and high selectivity, lower costs, shorter reaction times, minimizing waste, labor, energy, and avoidance of expensive purification processes.¹⁵

Recently, a four-component reaction of amines, aldehydes, dialkyl acetylenedicarboxylates and nitroalkanes is reported to give diversity oriented pyrroles by using iodine as a catalyst.¹⁶ But unfortunately, they used homogenous catalysts and are not recyclable. The use of homogeneous catalysts has received little attention as alternatives in alleviating some of the limitations. Thus, the search for an inexpensive, readily available, and convenient catalyst is desirable. The use of heterogeneous catalysts¹⁷ has received considerable importance in organic synthesis because of their ease of handling, enhanced reaction rates, greater selectivity, simple work-up, and recoverability of catalysts. Among the various heterogeneous catalysts, particularly, silica gel-supported ceric ammonium nitrate¹⁸ has the advantages of low cost, ease of preparation and catalyst recycling. It is evident from the previous literature that silica gel supported ceric ammonium nitrate has invoked enormous interest as a green and a potential acid catalyst to construct carbon–carbon and carbon–heteroatom bonds in various organic transformations.¹⁹

As part of our ongoing research program for the development of new environmentally benign methodology for the synthesis of a useful precursor in the field of biology, industry, and a key intermediate for the multistep synthesis,^20–23 we decided to investigate the efficiency of a silica gel supported ceric ammonium nitrate catalyst for the synthesis of functionalized pyrroles. The reaction is easy to perform and allows synthesizing various multi functionalized derivatives. These reaction workup procedures are simple and we can isolate products with high purity and yields. So herein, we wish to report a tandem synthesis of tetrasubstituted pyrrole derivatives by using CAN·SiO₂ as an expeditious reusable catalyst in an excellent yield (Scheme 1).

Scheme 1 Synthesis of fully substituted tetrasubstituted pyrrole functionalities catalyzed by CAN·SiO₂.

2. Results and discussion

To identify the suitable conditions for the four-component annulation process, a series of catalysts and solvents were screened (Table 1). Initially, in search of the best catalytic system for this one-pot synthesis, optimization of various reaction parameters like different metal Lewis acid catalysts, temperature, and solvents was carried out (Table 1) with the standard reaction of benzaldehyde, aniline, dimethyl acetylenedicarboxylates, and nitromethane. In order to establish the real effectiveness of the catalyst for the synthesis of tetra substituted pyrroles, a test reaction was performed without catalysts using the model reaction under reflux conditions. It was found that only a trace amount of product was obtained in the absence of a catalyst even after 24 h (Table 1, entry 1).

Table 1 Optimization of the formation of tetrasubstituted pyrroles^a

Entry	Catalyst (10 mol%)	Time (h)	Yield^b (%)
a All reactions were carried out using benzaldehyde (1 mmol), aniline (1 mmol), dimethyl acetylenedicarboxylates (1 mmol) and nitromethane (1 mL) under reflux conditions. b Yields obtained after column chromatography.
1	—	24	Traces
2	SiO2	12	24
3	BF3·SiO2	10	48
4	Cu(OTf)2·SiO2	12	51
5	FeCl3·SiO2	8	75
6	TiO2·SiO2	12	52
7	ZnCl2·SiO2	8	60
8	CAN	4	91
9	CAN·SiO2	4	93
10	Zn(OTf)2·SiO2	9	65
11	P2O5·SiO2	12	55
12	FeCl3·SiO2	24	85
13	CAN·SiO2	24	90
14	CAN·SiO2 (5 mol%)	4	85
15	CAN·SiO2 (7 mol%)	4	88
16	CAN·SiO2 (15 mol%)	6	90
17	CAN·SiO2 (20 mol%)	5	89

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In search of an effective, eco-friendly, and efficient reusable catalytic system for this reaction, the same test reaction was performed with different metal Lewis acid catalysts such as SiO₂, BF₃·SiO₂, Cu(OTf)₂·SiO₂, FeCl₃·SiO₂, TiO₂·SiO₂, ZnCl₂·SiO₂, CAN, CAN·SiO₂, Zn(OTf)₂·SiO₂ and P₂O₅·SiO₂ (Table 1). To study the role of SiO₂, the reaction was tested with SiO₂ (100 mg) only, and we observed a good yield as compared to the catalyst free reaction (Table 1, entry 2). Among all screened catalysts CAN and CAN·SiO₂ gave the best results in view of yield and reaction times (Table 1, entries 8 and 9). In contrast, BF₃·SiO₂, Cu(OTf)₂·SiO₂, FeCl₃·SiO₂, TiO₂·SiO₂, ZnCl₂·SiO₂, Zn(OTf)₂·SiO₂ and P₂O₅·SiO₂ did not afford the desired product in good yields (Table 1, entries 3–7, 10 and 11). The supported Lewis acid catalyst, FeCl₃·SiO₂, is effective, but it required more time for the completion of the reaction as compared with a CAN·SiO₂ catalyst to slightly lower the yield (Table 1, entries 5, 9 and 12). The reaction was also studied in various solvents such as tetrahydrofuran, dichloromethane, dichloroethane, and toluene; however, the yield of the desired product was decreased. So, in this reaction nitromethane was used both as a solvent and as one of the reactants as well.

Once we found CAN·SiO₂ as the best catalyst for this system, the optimization of catalyst loading was done (Table 1, entries 14–17). Consequently, the optimum 10 mol% loading of CAN·SiO₂ provided the maximum yield in minimum time (Table 1, entry 9), but while loading a high amount of catalyst, the reaction proceeded quite slowly with a lower yield (Table 2, entries 16 and 17), on the other hand, a decrease in the yield was observed by lowering the amount of catalyst (Table 1, entries 14 and 15). So, 10 mol% of the catalyst were found to be the optimal quantity and sufficient to push the reaction forward.

Table 2 Synthesis of tetrasubstituted pyrroles by four-component coupling reactions using CAN·SiO₂ as a catalyst^a

Entry (compound)	R1	R2	R3	Time (h)	Yield^b (%)
a All reactions were carried out using amines (1 mmol), aldehydes (1 mmol), dialkyl acetylenedicarboxylates (1 mmol) and nitromethane (1 mL) under reflux conditions. b Isolated yield.
1	Ph	Ph	Me	4	93
2	2-CH3C6H4	Ph	Et	5	92
3	4-OCH3C6H4	2-CH3C6H4	Et	5	91
4	3-CH3C6H4	Ph	Et	4	93
5	4-CH3C6H4	Ph	Et	5	90
6	3-OCH3C6H4	Ph	Et	6	89
7	4-CH3C6H4	4-OHC6H4	Me	5	88
8	4-OCH3C6H4	Ph	Et	4	90
9	PhCH2	4-OEtC6H4	Me	4	96
10	2-OCH3C6H4	Ph	Et	6	85
11	4-ClC6H4	Ph	Et	5	87
12	4-BrC6H4	Ph	Et	4	88
13	4-OCH3C6H4	4-FC6H4	Me	5	92
14	3,5-OCH3C6H3	Ph	Et	6	86
15	3,4-CH3C6H3	Ph	Et	5	90
16	PhCH2	4-BrC6H4	Me	4	94
17	PhCH2	3-FC6H4	Me	5	95
18	4-OCH3C6H4	3,4-FC6H3	Me	4	93
19	3,5-CH3C6H3	Ph	Et	5	89
20	2,5-CH3C6H3	Ph	Et	6	86
21	3,4-CH3C6H3	Ph	Me	4	92
22	Ph	Thiophene	Me	6	62
23	PhCH2	4-CH3C6H4	Me	4	95
24	3,4-OCH3C6H3	Ph	Et	4	92
25	PhCH2	3-FC6H4	Et	4	90
26	5-Amino indane	Ph	Me	6	88
27	4-OCH3C6H4	2,3-FC6H3	Me	6	85
28	2,4,6-CH3C6H2	Ph	Et	6	82
29	Ph	CH3CH2	Me	24	Traces
30	H2C=CH–CH2	Ph	Et	4	75
31	PhCH2	4-BrC6H4	Et	5	89
32	5-Amino indane	Ph	Et	4	84

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To explore the scope of this novel methodology, reactions of several of amines, aldehydes, dialkyl acetylenedicarboxylates and nitromethane in the presence of 10 mol% of CAN·SiO₂ were conducted. The results are summarized in Table 2. Thus, we selected the optimized reaction condition to examine the universality of this catalyst application with different electron rich and deficient substrates. It was gratifying to observe that most of the tested substrates exhibited satisfactory reactivity profiles, in all cases leading to a heterocyclization sequence that readily afforded the target structures (Table 2). But, with an aliphatic aldehyde only a trace amount of product was detected (Table 2, entry 29). On the other hand, in the case of amines, both aromatic and aliphatic substrates underwent the conversion smoothly.

A possible mechanism of this one-pot reaction is expected on the basis of the reported literature.¹⁷ A possible mechanism for the tetrasubstituted pyrrole ring formation of four-component coupling reactions using CAN·SiO₂ as a catalyst is outlined in Scheme 2.

Scheme 2 Plausible mechanism for the formation of substituted pyrrole derivatives.

The reusability of the CAN·SiO₂ catalyst was also examined. The catalyst was reused four times and the results show that silica supported ceric ammonium nitrate can be reused as such without a significant loss in yield (Table 3). The recyclability of the catalyst was checked with the model reaction (Table 3, entries 1–4). Accordingly, after the first fresh run with a 93% yield, the catalyst was removed by filtration. The recovered catalyst was dried under vacuum at 120 °C for 12 h and tested up to three more reaction cycles. Recycling and reuse of the catalyst showed a minimal decrease in yields. The product was obtained in 93%, 93%, 91%, and 90% yields after successive cycles (Table 3, entries 1–4), thus proving the catalyst reusability. The catalyst showed excellent recyclability in all these reactions (Table 3), as the reaction times and yields remained almost the same without having a loss of catalytic activity.

Table 3 Recycling and reuse of CAN·SiO₂

Entry	Reaction cycle	Yield^a (%)
a Isolated yield.
1	First (fresh run)	93
2	Second cycle	93
3	Third cycle	91
4	Fourth cycle	90

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The reported as well as synthesized novel compounds were further characterized by their spectral properties (¹H, ¹³C NMR, and HRMS).

3. Conclusion

In summary, an efficient, expeditious, operationally simple, economical, and environmentally friendly method has been developed for the synthesis of tetra-substituted pyrroles via a four component; one-pot reaction of amines, aldehydes, dialkyl acetylenedicarboxylates, and nitromethane using silica supported ceric ammonium nitrate as a heterogeneous catalyst. The main advantage of this present methodology is the simple work-up, easy recovery of catalysts, no need for anhydrous conditions, and no base or any additional activator required. To the best of our knowledge this is the first report for the synthesis of tetra-substituted pyrroles by using silica supported ceric ammonium nitrate as a heterogeneous catalyst. Shorter reaction times, excellent yields, and more importantly, the recyclability without losing catalytic activity make this protocol good and attractive.

4. Experimental

4.1 Material and methods

Chemicals were purchased from Aldrich and Alfa Aesar chemical companies and used as it is. The NMR spectra were recorded in CDCl₃ on a Jeol JNMECP 400 NMR instrument using TMS as an internal standard. The HRMS was recorded on a Jeol JMS-700 mass spectrometer.

4.2 General procedure for the synthesis of a silica supported ceric ammonium nitrate catalyst

A silica supported ceric ammonium nitrate catalyst was prepared by adopting the literature procedure.²⁴ Neutral silica gel (9.01 g, Merck Kieselgel 60, particle size 0.063–0.200 mm, 70–230 mesh) was mixed with a solution of CAN (1.02 g) in water (2.0 mL). Evaporation of water under reduced pressure gave a dry yellowish powder, which contained 10% (by weight) of CAN. According to Hwu et al., this reagent was found active for at least six months by storing in a well-capped bottle.²⁴

4.3 General procedure for the synthesis of fully substituted pyrrole functionalities. To a mixture of amines (1 mmol), aldehydes (1 mmol), dialkyl acetylenedicarboxylates (1 mmol) and nitromethane (1 mL) was added 10 mol% CAN·SiO₂ and the reaction mixture was kept for refluxing in a heated oil-bath with constant stirring. After completion of the reaction as monitored by TLC, the reaction mixture was brought to room temperature and the excess nitroalkane was removed using a rotary evaporator. Then, the crude residue was dissolved in 10 mL of dichloromethane and the solid particle was removed by filtration. The precipitate was further washed with 2 mL of dichloromethane. The filtrate was washed with water and dried over anhydrous sodium sulfate. The organic extract was concentrated and the crude residue was finally purified through a silica gel column chromatography. The final product was obtained by eluting with an ethyl acetate and hexane mixture.

4.3.1. Dimethyl 4-(phenyl)-1-phenyl-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.48–7.32 (m, 5H), 7.26–7.15 (m, 5H), 7.02 (s, 1H), 3.82 (s, 3H), 3.74 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.52, 160.12, 138.12, 133.20, 129.32, 128.56, 127.66, 127.09, 126.58, 125.45, 121.23, 120.73, 55.23, 53.26; HRMS m/z calcd for C₂₀H₁₇NO₄ [M⁺] 335.1158, found 335.1153.

4.3.2. Diethyl 1-(2-methylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.47–7.45 (m, 2H), 7.36–7.32 (m, 3H), 7.30–7.20 (m, 4H), 6.88 (s, 1H), 4.34–4.32 (m, 2H), 4.11–4.08 (m, 2H), 2.11 (s, 3H), 1.29 (t, J = 12 Hz, 3H), 1.09 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.47, 159.52, 139.11, 135.46, 133.31, 130.42, 128.91, 128.52, 127.58, 127.35, 126.99, 126.30, 125.35, 124.60, 123.29, 121.85, 61.32, 60.55, 17.36, 14.06, 13.80; HRMS m/z calcd for C₂₁H₁₉NO₄ [M⁺] 349.1314, found 349.1315.

4.3.3. Diethyl 1-(4-methoxyphenyl)-4-(2-methyphenyl)-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.27–7.22 (m, 5H), 7.09 (d, J = 4 Hz, 1H), 6.95–6.92 (m, 3H), 4.35–4.29 (m, 2H), 4.19–4.13 (m, 2H), 3.83 (s, 3H), 2.35 (s, 3H), 1.30 (d, J = 12 Hz, 3H), 1.17 (d, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.41, 159.89, 159.48, 138.00, 133.19, 132.55, 128.43, 127.78, 127.45, 126.10, 124.77, 124.48, 123.17, 121.95, 113.90, 61.25, 60.70, 55.50, 21.45, 14.09, 13.95; HRMS m/z calcd for C₂₄H₂₅NO₅ [M⁺] 407.1733, found 407.1736.

4.3.4. Diethyl 1-(3-methylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.44 (d, J = 8 Hz, 2H), 7.29 (t, J = 8 Hz, 2H), 7.22 (t, J = 12 Hz, 2H), 7.15 (d, J = 8 Hz, 1H), 7.09 (t, J = 12 Hz, 2H), 6.90 (s, 1H), 4.29–4.26 (m, 2H), 4.14–4.11 (m, 2H), 2.32 (s, 3H), 1.24 (t, J = 12 Hz, 3H), 1.11 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.01, 159.91, 139.42, 138.77, 133.29, 129.05, 128.58, 128.38, 127.74, 126.95, 126.60, 125.50, 124.66, 123.10, 121.71, 61.09, 60.70, 21.14, 13.99, 13.82; HRMS m/z calcd for C₂₃H₂₃NO₄ [M⁺] 377.1627, found 377.1629.

4.3.5. Diethyl 1-(4-methylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.43 (t, J = 12 Hz, 2H), 7.28–7.19 (m, 3H), 7.12 (t, J = 8 Hz, 4H), 6.87 (s, 1H), 4.2–4.25 (m, 2H), 4.13–4.10 (m, 2H), 2.29 (s, 3H), 1.23 (t, J = 12 Hz, 3H), 1.11 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.03, 159.87, 138.17, 136.99, 133.33, 129.36, 128.39, 127.71, 126.94, 125.80, 125.63, 124.56, 123.58, 121.76, 61.06, 60.67, 20.97, 14.00, 13.84; HRMS m/z calcd for C₂₃H₂₃NO₄ [M⁺] 377.1627, found 377.1629.

4.3.6. Diethyl 1-(3-methoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.46–7.44 (m, 2H), 7.37–7.32 (m, 2H), 7.30–7.24 (m, 2H), 6.98 (s, 1H), 9.96–6.92 (m, 2H), 6.89 (t, J = 12 Hz, 1H), 4.33–4.28 (m, 2H), 4.20–4.14 (m, 2H), 3.80 (s, 3H), 1.27 (t, J = 12 Hz, 3H), 1.16 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.09, 159.93, 159.85, 140.58, 133.25, 129.55, 128.45, 127.81, 127.06, 125.51, 124.79, 123.64, 121.76, 118.38, 114.19, 112.03, 61.25, 60.86, 55.44, 14.03, 13.89; HRMS m/z calcd for C₂₃H₂₃NO₅ [M⁺] 393.4324, found 393.4321.

4.3.7. Dimethyl 1-(4-methylphenyl)-4-(4-hydroxyphenyl)-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.24–7.22 (m, 3H), 7.20–7.15 (m, 4H), 6.87 (s, 1H), 6.76 (d, J = 8 Hz, 2H), 3.81 (s, 3H), 3.67 (s, 3H), 2.34 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 167.48, 160.74, 155.72, 138.41, 136.80, 129.48, 128.90, 125.80, 125.71, 124.84, 124.78, 122.93, 121.24, 115.62, 52.50, 51.99, 21.05; HRMS m/z calcd for C₂₁H₁₉NO₅ [M⁺] 365.1263, found 365.1264.

4.3.8. Diethyl 1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.46–7.43 (m, 2H), 7.35 (t, J = 12 Hz, 2H), 7.29–7.24 (m, 3H), 6.96–6.92 (m, 3H), 4.34–4.28 (m, 2H), 4.19–4.14 (m, 2H), 3.83 (s, 3H), 1.28 (t, J = 12 Hz, 3H), 1.17 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.31, 159.92, 159.49, 133.33, 132.49, 128.47, 127.74, 127.42, 127.00, 126.04, 124.46, 123.41, 121.77, 61.26, 60.74, 55.50, 14.05, 13.95; HRMS m/z calcd for C₂₃H₂₃NO₅ [M⁺] 393.4324, found 393.4321.

4.3.9. Dimethyl 1-(benzyl)-4-(4-ethoxyphenyl)-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.30–7.22 (m, 5H), 7.14 (d, J = 8 Hz, 2H), 6.85 (d, J = 12 Hz, 2H), 6.83 (s, 1H), 5.46 (s, 2H), 4.01–3.96 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 1.37 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 167.35, 160.64, 158.12, 137.10, 128.74, 128.53, 127.79, 127.17, 125.62, 125.35, 123.82, 122.07, 120.90, 115.35, 114.59, 63.39, 52.31, 51.71, 14.82; HRMS m/z calcd for C₂₃H₂₃NO₅ [M⁺] 393.4324, found 393.4323.

4.3.10. Diethyl 1-(2-methoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.43 (d, J = 8 Hz, 2H), 7.32–7.27 (m, 3H), 7.21–7.18 (m, 2H), 6.95–6.91 (m, 2H), 6.83 (s, 1H), 4.29–4.26 (m, 2H), 4.10–4.06 (m, 2H), 3.64 (s, 3H), 1.24 (t, J = 12 Hz, 3H), 1.07 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.36, 159.64, 154.42, 133.46, 129.71, 128.79, 128.40, 127.57, 126.81, 125.56, 124.27, 124.00, 121.51, 120.33, 111.56, 61.10, 60.34, 55.48, 14.00, 13.83; HRMS m/z calcd for C₂₃H₂₃NO₅ [M⁺] 393.4324, found 393.4321.

4.3.11. Diethyl 1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.45–7.40 (m, 4H), 7.35 (t, J = 12 Hz, 2H), 7.29–7.24 (m, 3H), 6.95 (s, 1H), 4.34–4.28 (m, 2H), 4.20–4.14 (m, 2H), 1.28 (t, J = 12 Hz, 3H), 1.18 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.11, 159.67, 138.07, 134.37, 132.97, 129.02, 128.54, 127.66, 127.61, 127.19, 125.70, 125.70, 124.94, 122.99, 122.66, 61.38, 60.91, 14.03, 13.91; HRMS m/z calcd for C₂₂H₂₀ClNO₄ [M⁺] 397.8515, found 397.8519.

4.3.12. Diethyl 1-(4-bromophenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.48 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz, 2H), 7.29 (t, J = 12 Hz, 2H), 7.22 (d, J = 8 Hz, 1H), 7.13 (d, J = 12 Hz, 2H), 6.90 (s, 1H), 4.29–4.26 (m, 2H), 4.14–4.10 (m, 2H), 1.25 (t, J = 12 Hz, 3H), 1.14 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 165.92, 159.52, 138.44, 132.88, 131.87, 128.48, 127.80, 127.54, 127.10, 125.56, 124.82, 122.93, 122.63, 122.12, 61.25, 60.82, 13.98, 13.84; HRMS m/z calcd for C₂₂H₂₀BrNO₄ [M⁺] 442.3025, found 442.3028.

4.3.13. Dimethyl 1-(4-methoxyphenyl)-4-(4-fluorophenyl)-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.05 (d, J = 8 Hz, 1H), 7.46–7.61 (m, 2H), 7.47–7.44 (m, 1H), 7.36 (d, J = 4 Hz, 1H), 7.17–7.02 (m, 3H), 6.95–6.91 (m, 1H), 4.02 (s, 3H), 3.93 (m, 3H), 3.72 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 168.25, 166.59, 159.26, 152.73, 144.71, 136.93, 131.40, 130.36, 130.27, 127.22, 124.89, 124.62, 123.45, 115.59, 115.36, 114.03, 55.66, 53.17, 52.78; HRMS m/z calcd for C₂₁H₁₈FNO₅ [M⁺] 383.1669, found 383.1167.

4.3.14. Diethyl 1-(3,5-dimethoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.44 (d, J = 8 Hz, 2H), 7.33 (t, J = 12 Hz, 2H), 7.28–7.23 (m, 1H), 6.97 (s, 1H), 6.50 (s, 3H), 4.32–4.27 (m, 2H), 4.21–4.16 (m, 2H), 3.75 (s, 6H), 1.26 (t, J = 12 Hz, 3H), 1.18 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 165.94, 160.74, 159.99, 141.05, 133.26, 128.42, 127.86, 127.05, 125.29, 124.82, 123.91, 121.45, 104.60, 100.46, 61.19, 60.91, 55.49, 14.02, 13.92; HRMS m/z calcd for C₂₄H₂₅NO₆ [M⁺] 423.4584, found 423.4582.

4.3.15. Diethyl 1-(3,4-dimethylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.44 (d, J = 8 Hz, 2H), 7.28 (t, J = 12 Hz, 2H), 7.21–7.17 (m, 1H), 7.10–7.05 (m, 2H), 7.00 (d, J = 8 Hz, 1H), 6.89 (s, 1H), 4.28–4.26 (m, 2H), 4.16–4.11 (m, 2H), 2.21 (s, 6H), 1.23 (t, J = 12 Hz, 3H), 1.15 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.04, 159.98, 137.21, 137.16, 136.83, 133.39, 129.83, 128.37, 127.75, 126.94, 125.60, 124.55, 123.26, 121.50, 61.03, 60.68, 19.65, 19.33, 14.01, 13.87; HRMS m/z calcd for C₂₄H₂₅NO₄ [M⁺] 391.4596, found 391.4595.

4.3.16. Dimethyl 1-(benzyl)-4-(4-bromophenyl)-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.40–7.37 (m, 2H), 7.27–7.19 (m, 5H), 7.11 (d, J = 8 Hz, 2H), 6.88 (s, 1H), 5.40 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.82, 160.41, 136.84, 132.21, 131.56, 128.92, 128.70, 127.80, 127.05, 125.57, 122.68, 121.83, 121.52, 120.80, 52.27, 51.74; HRMS m/z calcd for C₂₁H₁₈BrNO₄ [M⁺] 427.0419, found 427.0416.

4.3.17. Dimethyl 1-(benzyl)-4-(3-fluorophenyl)-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.32–7.22 (m, 5H), 7.16–7.12 (m, 3H), 7.09–7.06 (m, 1H), 6.93 (s, 1H), 5.47 (s, 2H), 3.81 (s, 3H), 3.76 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.96, 164.11, 161.67, 160.53, 136.82, 135.51, 130.12, 130.04, 128.82, 127.93, 127.22, 125.77, 122.99, 122.76, 122.13, 121.46, 114.29, 114.07, 113.84, 113.63, 52.43, 51.84; HRMS m/z calcd for C₂₁H₁₈FNO₄ [M⁺] 367.3703, found 367.3705.

4.3.18. Dimethyl 1-(4-methoxyphenyl)-4-(3,4-difluorophenyl)-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.06 (d, J = 8 Hz, 1H), 7.56–7.47 (m, 3H), 7.37–7.32 (m, 2H), 7.27–7.21 (m, 2H), 4.03 (s, 3H), 3.95 (s, 3H), 3.76 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 167.99, 166.47, 159.52, 151.47, 144.69, 137.10, 131.45, 124.89, 124.69, 123.69, 117.96, 117.76, 117.36, 117.19, 102.69, 55.72, 53.22, 52.90; HRMS m/z calcd for C₂₁H₁₇F₂NO₅ [M⁺] 401.3601, found 401.3603.

4.3.19. Diethyl 1-(3,5-dimethylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.43 (d, J = 8 Hz, 2H), 7.27 (t, J = 12 Hz, 2H), 7.18 (t, J = 12 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 8 Hz, 3H), 4.28–4.23 (m, 2H), 4.15–4.10 (m, 2H), 2.26 (s, 6H), 1.22 (t, J = 12 Hz, 3H), 1.17 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 165.92, 160.01, 139.36, 138.52, 133.40, 129.91, 128.36, 127.80, 126.91, 125.37, 124.65, 123.68, 121.45, 60.99, 60.68, 21.03, 13.99, 13.84; HRMS m/z calcd for C₂₄H₂₅NO₄ [M⁺] 391.4596, found 391.4597.

4.3.20. Diethyl 1-(2,5-dimethylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.44 (d, J = 8 Hz, 2H), 7.27 (t, J = 12 Hz, 2H), 7.17 (t, J = 12 Hz, 1H), 7.08 (s, 2H), 6.96 (s, 1H), 6.77 (s, 1H), 4.30–4.25 (m, 2H), 4.08–4.03 (m, 2H), 2.26 (s, 3H), 2.00 (s, 3H), 1.23 (t, J = 12 Hz, 3H), 1.04 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.26, 159.43, 138.88, 135.94, 133.37, 132.09, 130.47, 130.17, 129.56, 128.45, 127.82, 127.53, 126.89, 125.30, 124.46, 123.53, 121.71, 61.09, 60.41, 20.59, 16.75, 14.00, 13.75; HRMS m/z calcd for C₂₄H₂₅NO₄ [M⁺] 391.1718, found 391.1786.

4.3.21. Dimethyl 1-(3,4-dimethylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.41 (d, J = 8 Hz, 2H), 7.29 (t, J = 8 Hz, 2H), 7.22–7.19 (m, 1H), 7.11 (d, J = 8 Hz, 1H), 7.06 (s, 1H), 7.00 (d, J = 8 Hz, 1H), 6.90 (s, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 2.23 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.54, 160.45, 137.29, 137.06, 136.96, 133.24, 129.88, 128.46, 127.65, 126.99, 126.80, 125.85, 124.62, 123.45, 123.19, 121.22, 52.12, 51.78, 19.69, 19.36; HRMS m/z calcd for C₂₄H₂₅NO₄ [M⁺] 391.4596, found 391.4598.

4.3.22. Dimethyl 1-(phenyl)-4-(thiophene)-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.42–7.32 (m, 4H), 7.26–7.15 (m, 4H), 6.99 (s, 1H), 3.75 (s, 3H), 3.67 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 165.42, 161.34, 139.54, 136.21, 129.57, 129.19, 128.71, 127.93, 126.44, 125.86, 124.56, 124.21, 52.89, 52.21; HRMS m/z calcd for C₁₈H₁₅NO₄S [M⁺] 341.3810, found 341.3812.

4.3.23. Dimethyl 1-(benzyl)-4-(4-methylphenyl)-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.27–7.17 (m, 5H), 7.14–7.09 (m, 4H), 6.86 (s, 1H), 5.41 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 2.28 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 167.30, 160.56, 137.11, 136.55, 130.33, 129.28, 128.68, 127.73, 127.16, 127.08, 125.60, 123.90, 122.19, 120.93, 52.24, 51.64, 21.03; HRMS m/z calcd for C₂₂H₂₁NO₄ [M⁺] 363.4064, found 363.4066.

4.3.24. Diethyl 1-(3,4-dimethoxyphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.45 (d, J = 8 Hz, 2H), 7.34 (t, J = 12 Hz, 2H), 7.27 (t, J = 8 Hz, 1H), 6.97 (s, 1H), 6.92–6.86 (m, 3H),4.33–4.28 (m, 2H), 4.19–4.14 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 1.28 (t, J = 12 Hz, 3H), 1.18 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.03, 159.82, 148.95, 148.69, 133.13, 132.41, 128.30, 127.60, 126.87, 125.80, 124.35, 123.56, 121.39, 118.14, 110.49, 110.00, 61.09, 60.66, 55.88, 13.89, 13.82; HRMS m/z calcd for C₂₂H₂₁NO₆ [M⁺] 395.4052, found 395.4055.

4.3.25. Diethyl 1-(benzyl)-4-(3-fluorophenyl)-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.30–7.20 (m, 5H), 7.16–1.09 (m, 4H), 6.92 (s, 1H), 5.46 (s, 2H), 4.30–4.21 (m, 4H), 1.29–1.21 (m, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.51, 164.08, 161.64, 160.14, 137.01, 130.05, 129.96, 128.75, 127.22, 125.66, 123.09, 122.44, 121.51, 114.34, 113.50, 61.35, 60.77, 52.31, 14.01, 13.99; HRMS m/z calcd for C₂₃H₂₂FNO₄ [M⁺] 395.4235, found 395.4237.

4.3.26. Dimethyl 1-(5-indane)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.41 (d, J = 8 Hz, 2H), 7.29 (t, J = 12 Hz, 2H), 7.22–7.16 (m, 2H), 7.11 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.91 (s, 1H), 3.77 (s, 3H), 3.66 (s, 3H), 2.87 (t, J = 12 Hz, 4H), 2.08–2.03 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.53, 160.44, 145.06, 144.55, 137.49, 133.23, 128.39, 127.62, 126.96, 125.96, 124.55, 124.37, 123.82, 121.85, 121.18, 119.13, 52.11, 51.77, 32.74, 32.48, 25.52; HRMS m/z calcd for C₂₃H₂₁NO₄ [M⁺] 375.4171, found 375.4173.

4.3.27. Dimethyl 1-(4-methoxyphenyl)-4-(2,3-fluorophenyl)-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.07 (d, J = 8 Hz, 1H), 7.50–7.47 (m, 1H), 7.40 (t, J = 12 Hz, 1H), 7.28–7.16 (m, 5H), 4.04 (s, 3H), 3.94 (s, 3H), 3.77 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.83, 166.76, 159.62, 144.96, 138.31, 131.50, 125.94, 125.07, 124.36, 123.97, 117.83, 117.67, 102.72, 55.73, 53.19, 52.84; HRMS m/z calcd for C₂₁H₁₇F₂NO₅ [M⁺] 401.3602, found 401.3605.

4.3.28. Diethyl 1-(2,4,6-trimethylphenyl)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.45 (d, J = 8 Hz, 2H), 7.33 (t, J = 12 Hz, 2H), 7.25 (d, J = 8 Hz, 1H), 6.92 (s, 2H), 6.76 (s, 1H), 4.34–4.28 (m, 2H), 4.13–4.08 (m, 2H), 2.30 (s, 3H), 2.00 (s, 6H), 1.27 (t, J = 12 Hz, 3H), 1.10 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.37, 159.60, 138.31, 135.91, 135.25, 134.63, 133.47, 129.49, 128.58, 128.43, 127.64, 126.88, 125.03, 124.52, 123.20, 121.30, 61.16, 60.50, 20.89, 17.41, 14.04, 13.79; HRMS m/z calcd for C₂₅H₂₇NO₄ [M⁺] 405.4862, found 405.4865.

4.3.29. Dimethyl 1-allyl-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Brown sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.43 (d, J = 8 Hz, 2H), 7.25 (t, J = 12 Hz, 2H), 7.20 (d, J = 8Hz, 1H), 6.91 (s, 1H), 6.02 (m, 1H), 5.22 (d, J = 10 Hz, 1H), 5.13 (d, J = 16 Hz, 1H), 5.01 (d, J = 5 Hz, 2H), 3.82 (s, 3H), 3.76 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.32, 160.51, 133.74, 126.56, 127.21, 126.85, 125.32, 123.87, 122.12, 120.85, 118.75, 53.21, 51.36, 51.01; HRMS m/z calcd for C₁₇H₁₇NO₄ [M⁺] 299.3212, found 299.3215.

4.3.30. Diethyl 1-(benzyl)-4-(4-bromophenyl)-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.50 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz, 1H), 7.34 (m, 4H), 7.15 (d, J = 4 Hz, 2H), 6.90 (s, 1H), 5.47 (s, 2H), 4.30–4.21 (m, 4H), 1.30–1.22 (m, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.44, 160.11, 137.62, 137.45, 136.91, 132.53, 131.50, 130.43, 129.01, 128.71, 127.80, 127.19, 126.54, 125.34, 122.58, 122.12, 121.57, 120.76, 61.29, 60.75, 52.27, 14.03, 13.98; HRMS m/z calcd for C₂₃H₂₂BrNO₄ [M⁺] 456.3291, found 456.3292.

4.3.31. Diethyl 1-(5-indane)-4-phenyl-1H-pyrrole-2,3-dicarboxylate. Yellow sticky liquid; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 4 Hz, 2H), 7.28 (t, J = 12 Hz, 2H), 7.21–7.15 (m, 2H), 7.11 (s, 1H), 7.03–7.00 (m, 1H), 6.91 (s, 1H), 4.30–4.25 (m, 2H), 4.17–4.11 (m, 2H), 2.86 (t, J = 12 Hz, 4H), 2.07–2.01 (m, 2H), 1.24 (t, J = 12 Hz, 3H), 1.13 (t, J = 12 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ (ppm) 166.04, 159.97, 144.94, 144.43, 137.65, 133.39, 128.46, 128.36, 128.21, 127.71, 126.88, 125.72, 124.30, 123.90, 121.99, 121.48, 119.07, 61.02, 60.66, 32.73, 32.47, 25.56, 14.00, 13.86; HRMS m/z calcd for C₂₅H₂₅NO₄ [M⁺] 403.4703, found 403.4706.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nj01234h

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