A straightforward sequence to alkyl 1H-pyrrole-2,5-dicarboxylates starting from acylhydrazono esters and alkyl 2-aroyl-1-chlorocyclopropanecarboxylates

Abstract

A highly regioselective domino reaction was developed between alkyl 2-aroyl-1-chlorocyclopropanecarboxylates 1 and acylhydrazono esters 2 in the presence of Cs₂CO₃ under mild basic conditions, which directly afforded 2,3,5-trifunctionalized pyrroles in good to excellent yields with the extrusion of benzamide. A plausible pathway was proposed involving 1,2-elimination, regioselective nucleophilic addition, the intramolecular Mannich reaction, and the removal of benzamide to rationalize the formation of the aromatic pyrrole system.

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Introduction

Polysubstituted pyrrole as a core structure widely exists in many natural products,¹ pharmaceuticals,² and various functional materials.³ Among the pyrrole derivatives, 1H-pyrrole-2,5-dicarboxylates have many applications in various fields of medicinal and bioorganic chemistry, photochemistry, and materials science. For example, bis(oxazolinyl)pyrroles prepared easily from pyrrole-2,5-dicarboxylate were employed as bidentate ligands for Heck-type reactions.⁴ Some representative examples with this core structure are illustrated in Scheme 1. Chromopyrrolic acid (CPA) with the pyrrole-2,5-dicarboxylate core has been identified as a common intermediate in the biosynthesis of the antitumor indolocarbazoles rebeccamycin and staurosporine.⁵ Ningalin A and storniamide A, found in some marine natural products are the precursors of cytotoxic antitumor agents.^6a Lycogarubin C, isolated from Lycogala epidendrum, was first identified as natural products in 1994.^6b In addition, some amides and thioamides derived from 1H-pyrrole-2,5-dicarboxylates with unique complexation property were investigated as neutral anion receptors.⁷ Methyl 5-benzoyl-1H-pyrrole-2-carboxylate was recently employed to construct pyrrolyldipyrrin motif, which exists in several naturally occurring prodigiosin pigments.⁸

Scheme 1 The important role of 1H-pyrrole-2,5-dicarboxylates.

As for the growing applications of 1H-pyrrole-2,5-dicarboxylates, several synthetic approaches have been established.⁹ Simple 1H-pyrrole-2,5-dicarboxylates without any substituents at C-3 and C-4 sites are usually prepared directly from pyrrole in multistep processes.¹⁰ Formation of N-substituted pyrrole-2,5-dicarboxylates was achieved through Paal–Knorr reaction of anilines with diethyl 2,5-dihydroxyhexa-2,4-dienedioate.¹¹ Symmetric pyrrole-2,5-dicarboxylate derivatives can be synthesized via a titanium(IV)-mediated oxidative dimerization of 2-azidocarboxylic esters at low temperature.¹² 3,4-Disubstituted pyrrole-2,5-dicarboxylates were synthesized via reductive ring contraction of 1,2-diazines generated in azadiene Diels–Alder reactions.^6b The mentioned approaches, however, still have limitations as for the tedious steps, low efficiency, use of transition metal or extreme conditions.

Our recent research interest focused on the chemistry of reactive cyclopropene derived from simple 1,2-elimination of 1-halocyclopropane. Rubin et al. has previously reported the formal substitution of halocyclopropanes with N-centered¹³ and O-centered¹⁴ nucleophiles through a cyclopropene pathway. In addition, Khlebnikov et al. has also reported the reaction of 2H-azirines with 1,2,4-tricarbonyl compounds to produce 2,3-dicarbonyl-pyrrole derivatives which can be used in synthesis of heterocyclyl pyrroles or pyrroles fused with heterocycles via metal catalyzed.¹⁵ In our lab, a kind of versatile reagents, alkyl 2-aroyl-1-chlorocyclopropane-carboxylates 1, prepared directly from alkyl dichloroacetates and enones in the presence of Cs₂CO₃,¹⁶ were proven to be useful in the synthesis of cyclic compounds. Their reactions with various donor–acceptor reagents like salicylaldimines, salicylic aldehydes, and 1,3-dicarbonyl compounds provided efficient routes to construct chroman and functionalized fulvene skeletons, respectively.¹⁷ The reagents 1 also underwent smoothly transformation into 2-pyranones after treatment with N-centered nucleophiles like aliphatic amines.¹⁸ Inspired by the above observations, we anticipated that the reagents 1 could be employed to react with acylhydrazones, commonly useful 1,3-dipoles,¹⁹ to yield fused stained pyrazolidines. In fact, when the reaction of 1 with acylhydrazone 2 derived from ethyl glyoxylate was performed in the presence of base, the predominant formation of an unexpected dialkyl 3-aroyl-1H-pyrrole-2,5-dicarboxylate and benzamide were observed during the reaction. To our best knowledge, this is the first example concerned with direct synthesis of 1H-pyrrole-2,5-dicarboxylates starting from halocyclopropanes. The details for this work are described as follows.

Results and discussion

Initially, we conducted the reaction of ethyl 2-aroyl-1-chlorocyclopropanecarboxylates 1a with benzoylhydrazono esters 2a in presence of two equiv. of Cs₂CO₃ in THF at 80 °C. The reaction proceeded sluggishly to afford a new product in about 35% yield. The product isolated carefully from the mixture on a silica gel column was identified to be diethyl 3-benzoyl-1H-pyrrole-2,5-dicarboxylates 3aa rather than the expected [3 + 2] cycloaddition product pyrazolidine by spectroscopic means (ESI II†).²⁰ This interesting result encouraged us to investigate the reaction process in detail. Thus, the reaction between 1a and 2a was chosen as the model to optimize the reaction conditions including solvent, base and reaction temperature. All the results observed are listed in Table 1. Effect of the solvents on the reaction was first estimated (entries 1–8). Apparently, aprotic polar solvents such as DMF, DMSO and CH₃CN are the appropriate reaction media (entries 3–5). Among them, the highest yield of 3aa was observed in CH₃CN (entry 3). Both chlorinated solvent and nonpolar solvent such as 1,2-dichloroethane (DCE) and toluene are not good choice for the reaction owing to the low yields (entries 6 and 7). In protic solvent like ethanol, only very little amount of 3aa was detected by TLC analysis (entry 8). In view of both the high yield and simple workup, CH₃CN was chosen as the ideal solvent for the following reactions.

Table 1 Optimization of the reaction conditions^a

Entry	Base	Solvent	Time (h)	Conversion (%)	Yield% (3aa)^b
a Reactions were carried out using 0.2 mmol of 1a, 0.2 mmol of 2a, and 0.4 mmol of base in 2.0 mL of dry solvent at 80 °C for the given time; conversion was based on the consumed 1a.b Isolated yield.c Conducted at 25 °C.d Conducted at 50 °C. Reactions were monitored by TLC analysis using silica gel 60 Å F-254 thin layer plates (petroleum ether/ethyl acetate = 4 : 1).
1	Cs2CO3	THF	6	100	35
2	Cs2CO3	1,4-Dioxane	6	100	78
3	Cs2CO3	CH3CN	4	100	87
4	Cs2CO3	DMF	4	100	73
5	Cs2CO3	DMSO	4	100	76
6	Cs2CO3	DCE	6	70	30
7	Cs2CO3	Toluene	24	80	30
8	Cs2CO3	EtOH	24	100	<5
9	tBuOK	CH3CN	4	90	<5
10	NaOH	CH3CN	8	51	23
11	K3PO4	CH3CN	12	79	53
12	K2CO3	CH3CN	8	54	30
13	NaHCO3	CH3CN	12	36	<5
14	DBU	CH3CN	1	100	61
15	DABCO	CH3CN	12	45	24
16^c	Cs2CO3	CH3CN	12	100	30
17^d	Cs2CO3	CH3CN	8	100	61

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Next, the role of various inorganic and organic bases were assessed under the above reaction conditions. The property of inorganic bases has a marked influence both on the reaction rate and on the product yield. Among t-BuOK, NaOH, K₃PO₄, K₂CO₃ and NaHCO₃, K₃PO₄ possessing moderate base strength gave the highest yield, indicating clearly that neither the strong base nor the weak base favored the reaction (entries 9–13). A parallel experiment demonstrated that strong base like t-BuOK caused quick decomposition of substrate 1a within 1 hour, providing unidentifiable oligomers with high polarity. Similar effect of the organic base strength on the reaction was also observed (entries 14 and 15). The stronger base DBU can promote the reaction well, whereas the relatively weaker base DABCO (1,4-diazabicyclo[2.2.2]octane) has a poorer ability to remove a molecule of HCl from 1 and caused the reaction proceed sluggishly, albeit with the extension of reaction time. In view of the product yield, Cs₂CO₃ was still the promising base because of its high reactivity in CH₃CN. In addition, the reaction temperature has also a considerable effect on the reaction. The reaction mentioned above went slowly at room temperature to form a complicated mixture of products, and only about 30% yield of 4aa was isolated by column chromatography (entry 16). When the reaction temperature was elevated to 50 °C, the product yield was improved to a large extent (entry 17), but still lower than that observed at 80 °C.

With the optimized conditions in hand, we examined the scope of substrates and the limitation of this reaction. All the following reactions were performed in presence of 2.0 equiv. of Cs₂CO₃ in CH₃CN at 80 °C under argon atmosphere, and the observed results are listed in Table 2. To our delight, substrates 1a–1k bearing various aroyl groups are adapted for the reaction, giving the products 3aa–3ka in satisfactory yields. Actually, the substrates with electron-donating 4-Me or 4-OMe groups on aromatic ring gave the products 3ba (ref. 21) or 3ca in 89% and 93% yields, respectively, which are slightly higher than that of 3aa (entries 2 and 3). The introduction of electron-withdrawing 4-Cl or 4-Br groups caused a slight decline in the yields of 3da or 3ea in comparison with 3aa (entries 3 and 4). Additionally, substrates 1f–1g with sterically hindered 4-biphenyl or 1-naphthyl groups on the carbonyl were also tolerated in this process, affording products 3fa–3ga in 78% and 88% yields, respectively (Table 2, entries 6 and 7). Similar result was also observed in the case of substrate 1h with a 2-thienyl group (entry 8). Comparing the yields of 3ea and 3ia, we realized that substituent position in benzene ring has little effect on the reaction (entry 5 vs. entry 9). In addition, the size of the ester group of substrates 1 has little effect on the reaction. In fact, both 1j with small methyl group and 1k with bulky t-butyl group afforded the desired products 3ja and 3ka in high yields, respectively, regardless of the big difference in steric hindrance (Table 2, entries 10 and 11).

Table 2 The reaction of various 1a–1k with 2a^a

Entry	Substrate 1 (Ar, R)	Substrate 2	Time (h)	Product	Yield^b (%)
a All the reactions were performed with 1 (0.2 mmol), 2 (0.2 mmol), and Cs2CO3 (2.0 equiv.) in 2.0 mL of dry CH3CN at 80 °C.b Isolated yields.
1	1a (Ph, Et)	2a	4	3aa	87
2	1b (4-MeC6H4, Et)	2a	5	3ba	89
3	1c (4-anisyl, Et)	2a	6	3ca	93
4	1d (4-ClC6H4, Et)	2a	6	3da	82
5	1e (4-BrC6H4, Et)	2a	4	3ea	78
6	1f (4-PhC6H4, Et)	2a	4	3fa	78
7	1g (1-Naph, Et)	2a	4	3ga	88
8	1h (2-thienyl, Et)	2a	4	3ha	86
9	1i (2-BrC6H4, Et)	2a	4	3ia	82
10	1j (Ph, Me)	2a	4	3ja	80
11	1k (Ph, t-Bu)	2a	4	3ka	84

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As a continuation of our research, we tried to expand the reagent scope to acylhydrazones derived from substituted phenylglyoxals for constructing other multi-functionalized pyrroles. Under the above optimal reaction conditions, we treated the reagent 2b prepared from phenylglyoxal with the substrate 1a. As a result, the reaction proceeded quickly to give the corresponding product 3ab in good yield within 1 hour (Table 3, entry 1). This finding allowed us to investigate the electronic property of acylhydrazones on the reaction. Several acylhydrazones 2c–2f bearing electron-donating or electron-withdrawing groups were thus prepared and employed to react with the substrate 1a under the reaction conditions. All the reactions proceeded quickly, affording the corresponding pyrroles 3ac–3af with three carbonyl groups at its 2,3,5-positions in high yields (Table 3, entries 2–5). In the reaction with 2b, substituent effect of substrates 1 was also investigated in the same way (Table 3, entries 6–13). Obviously, although somewhat higher yields of the corresponding pyrrole derivatives were obtained in the cases of 1b and 1g, the influence of substituent group on benzene ring on the reaction was rather small.

Table 3 Scope of the reaction between 1a–1j and 2b–2f^a

Entry	Substrate 1 (Ar)	Reagent 2 (R)	Time (h)	Product	Yield^b (%)
a All the reactions were performed with 1 (0.2 mmol), 2 (0.2 mmol), and Cs2CO3 (2.0 equiv.) in 2.0 mL of dry CH3CN at 80 °C. The reaction was monitored by TCL analysis.b Isolated yields.
1	1a (Ph)	2b (H)	2 h	3ab	79
2	1a	2c (4-Me)	2 h	3ac	76
3	1a	2d (4-OMe)	2 h	3ad	82
4	1a	2e (4-Cl)	2 h	3ae	74
5	1a	2f (4-Br)	2 h	3af	73
6	1b (4-MeC6H4)	2b	2 h	3bb	81
7	1c (4-MeOC6H4)	2b	2 h	3cb	76
8	1d (4-ClC6H4)	2b	2 h	3db	76
9	1e (4-BrC6H4)	2b	2 h	3eb	73
10	1f (4-PhC6H4)	2b	2 h	3fb	61
11	1g (1-naphthyl)	2b	2 h	3gb	82
12	1h (2-thienyl)	2b	2 h	3hb	73
13	1i (2-BrC6H4)	2b	2 h	3ib	71

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Based upon the above observations, we proposed a possible pathway to explain the formation of 2,3,5-trisubstituted pyrroles. As shown in Scheme 2, the reaction was initiated by simple 1,2-elimination of hydrogen chloride from the substrate 1, generating the highly reactive cyclopropene intermediate I. Then, a domino reaction pathway was followed through a continuous aza-Michael addition, nucleophilic addition to C=N bond, and protonation to form the bicyclic compound II. The high regioselectivity for this process could be assigned to the preferential nucleophilic attack at alpha-site of cyclopropene I.²⁰ The compound II was chemically unstable under basic conditions, and easily underwent the ring opening reaction to afford the intermediate III. In turn, an intramolecular nucleophilic substitution at nitrogen center would happen, which led to the breaking of N–N bond and the formation of the five-membered compound IV. Finally, one molecule of benzamide was quickly removed, leading to the thermodynamically stable aromatic pyrrole derivative 3. In fact, to confirm the formation of benzamide, the crude products for the reactions of 1a with 2a, 1c with 2a, and 1a with 2b, was carefully isolated by silica gel column chromatography, and the obtained benzamide was further characterized by ¹H and ¹³C NMR (see ESI I†). The yields for benzamide are 78%, 84% and 76% for the above mentioned reactions, respectively.

Scheme 2 A proposed mechanism for the reaction between 1 and 2.

Conclusion

In summary, we have developed a direct synthetic strategy for important 3-aroyl-1H-pyrrole-2,5-dicarboxylates. This is a transition-metal free way to prepare the pyrrole derivatives. This highly regioselective reaction starting from easily available alkyl 2-aroyl-1-chlorocyclopropanecarboxylates and benzoylhydrazono esters proceeded through a continuous pathway involving 1,2-elimination, Michael addition, Mannich reaction, intramolecular nucleophilic substitution at nitrogen center, and aromatization via removal of benzamide under mild basic conditions without any expensive catalyst. This protocol provides highly functionalized pyrrole compounds that have potential applications in new material and drug discovery and development.

Experimental section

General information

All the solvents were dried over CaH₂ or sodium and distilled prior to use. Reactions were monitored by TLC analysis using silica gel 60 Å F-254 thin layer plates under UV lamp. Flash column chromatography was performed on silica gel 60 Å, 10–40 μm. ¹H NMR spectra were recorded on a 400 MHz NMR spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl₃, δ = 7.26). Data are reported as follows: chemical shift, multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad), coupling constants (Hz) and integration. ¹³C NMR spectra were recorded at 101 MHz with complete proton decoupling. Chemical shifts are also reported in ppm from the tetramethylsilane with the solvent resonance as internal standard (CDCl₃, δ = 77.0). IR spectra were recorded on an infrared spectrometer. Melting point was recorded on a melting point detector. HRMS was measured on a TOF-Q mass spectrometer equipped with an ESI source.

Typical procedure for the synthesis of diethyl 3-benzoyl-1H-pyrrole-2,5-dicarboxylate (3aa)

Into a solution of 1a (0.2 mmol) and 2a (0.2 mmol) in 2.0 mL of dry CH₃CN was added Cs₂CO₃ (0.4 mmol), and the mixture was stirred at 80 °C. The reaction was followed by thin layer chromatography until all the substrate 1a disappeared. The mixture was concentrated under reduced pressure to remove the solvent, then washed with 1 M HCl, and extracted with CH₂Cl₂ for three times, then the combined organic layer was washed with water for two times. Combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (8 : 1) as the eluent to afford 55 mg of compound 3aa in 87% yield. Unless otherwise specified, all other products 3 were synthesized according to this typical procedure.

Diethyl 3-benzoyl-1H-pyrrole-2,5-dicarboxylate (3aa)

Oil liquid (55 mg, 87% yield); ¹H NMR (400 MHz, CDCl₃) δ 10.24 (s, 1H), 7.88–7.82 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 2.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.9, 160.0, 159.7, 138.2, 133.1, 129.6, 128.4, 128.3, 125.5, 124.7, 116.6, 61.5, 61.4, 14.3, 13.5; IR (KBr): 3259, 3063, 2983, 2933, 1719, 1662, 1560, 1463, 1368, 1266, 1207, 1092, 1021, 920, 722 cm⁻¹. HRMS (ESI) m/z calcd for C₁₇H₁₇NaNO₅ [M + Na]⁺ 338.1005, found 338.0996.

Diethyl 3-(4-methylbenzoyl)-1H-pyrrole-2,5-dicarboxylate (3ba)

Yellow solid (59 mg, 90% yield); mp 121–125 °C. ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 2.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 191.6, 160.1, 159.7, 143.9, 135.7, 129.8, 129.0, 128.7, 125.4, 124.6, 116.5, 61.4, 61.4, 21.7, 14.3, 13.5. IR (KBr): 3240, 3126, 2987, 1724, 1705, 1654, 1465, 1267, 1092, 1020, 787, 755 cm⁻¹. HRMS (ESI) m/z C₁₈H₁₉NaNO₅ [M + Na]⁺ 352.1161, found 352.1157.

Diethyl 3-(4-methoxybenzoyl)-1H-pyrrole-2,5-dicarboxylate (3ca)

Yield solid (64 mg, 93% yield); mp 86–87 °C. ¹H NMR (400 MHz, CDCl₃) δ 10.20 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 2.6 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.38 (dd, J = 7.4, 6.8 Hz, 3H), 1.00 (td, J = 7.1, 1.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 190.6, 163.7, 160.1, 159.7, 131.9, 131.1, 128.9, 125.4, 124.4, 116.3, 113.6, 61.4, 61.4, 55.5, 14.3, 13.6. IR (KBr): 3263, 1719, 1656, 1597, 1265, 1018, 767 cm⁻¹. HRMS (ESI) m/z calcd for C₁₈H₁₉NaNO₆ [M + Na]⁺ 368.1110, found 368.1104.

Diethyl 3-(4-chlorobenzoyl)-1H-pyrrole-2,5-dicarboxylate (3da)

Yellow solid (57 mg, yield 82%); mp 114–115 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.16 (d, J = 24.1 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 2.7 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.02 (td, J = 7.1, 2.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 190.0, 159.1, 158.7, 136.2, 130.9, 127.2, 124.8, 123.9, 115.8, 60.9, 60.8, 13.6, 12.9. IR (KBr): 3175, 3096, 2985, 1729, 1644, 1587, 1367, 1280, 1202, 1092, 924, 856, 780 cm⁻¹. HRMS (ESI) m/z calcd for C₁₇H₁₆NaClNO₅ [M + Na]⁺ 372.0615, found 372.0611.

Diethyl 3-(4-bromobenzoyl)-1H-pyrrole-2,5-dicarboxylate (3ea)

Yellow solid (61 mg, yield 78%); mp 118–119 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.14 (s, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 2.7 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.14 (d, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 190.8, 159.9, 159.4, 137.0, 131.7, 131.1, 128.3, 127.9, 125.6, 124.6, 116.5, 61.6, 61.5, 14.3, 13.6. IR (KBr): 3249, 3144, 2982, 2933, 1726, 1670, 1586, 1560, 1467, 1370, 1264, 1093, 1017, 848, 785, 754 cm⁻¹; HRMS (ESI) m/z calcd for C₁₇H₁₆NaBrNO₅ [M + Na]⁺ 416.0110, found 416.0132.

Diethyl 3-([1,1′-biphenyl]-3-carbonyl)-1H-pyrrole-2,5-dicarboxylate (3fa)

White solid (63 mg, 81% yield); mp 164–167 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), δ 7.95 (d, J = 8.3 Hz, 2H), δ 7.69 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.3 Hz, 2H), 7.48 (d, J = 7.7 Hz, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.13 (d, J = 2.7 Hz, 1H). 4.42 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.5, 160.1, 159.7, 145.8, 139.9, 136.9, 130.2, 129.0, 128.5, 128.3, 127.3, 127.0, 125.5, 124.8, 116.6, 61.5, 61.5, 14.3, 13.6. IR (KBr): 3264, 3057, 2982, 2925, 1720, 1701, 1654, 1602, 1556, 1469, 1368, 1262, 1194, 1090, 1023, 923, 858, 781, 746 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₃H₂₁NaNO₅ [M + Na]⁺ 414.1318; found 414.1354.

Diethyl 3-(2-naphthoyl)-1H-pyrrole-2,5-dicarboxylate (3ga)

White solid (64 mg, yield 88%); mp 102–104 °C. ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.94–7.90 (m, 1H), 7.67–7.60 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.46–7.39 (m, 1H), 7.23 (d, J = 2.8 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.86 (q, J = 7.1 Hz, 2H), 1.42–1.38 (m, 3H), 0.62 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.9, 158.8, 158.5, 135.5, 132.6, 131.4, 129.6, 129.0, 128.7, 127.0, 126.7, 125.3, 124.7, 124.1, 123.9, 122.9, 116.2, 60.2, 60.2, 13.0, 11.9. ¹³C NMR (101 MHz, CDCl₃) δ 193.2, 136.7, 133.8, 132.7, 130.8, 130.3, 130.0, 128.3, 127.9, 126.5, 126.0, 125.4, 125.2, 124.2, 117.5, 61.5, 14.3, 13.2; IR (KBr): 3284, 3122, 2985, 1722, 1688, 1655, 1554, 1468, 1265, 1019, 875, 780 cm⁻¹; HRMS (ESI) m/z calcd for: C₂₁H₁₉NaNO₅ [M + Na]⁺ 388.1161, found 388.1137.

Diethyl 3-(thiophene-2-carbonyl)-1H-pyrrole-2,5-dicarboxylate (3ha)

Yield liquid (55 mg, yield 86%). ¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H), 7.62 (dd, J = 4.9, 0.9 Hz, 1H), 7.44 (dd, J = 3.7, 1.0 Hz, 1H), 7.02 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 183.5, 183.3, 159.9, 159.6, 144.9, 134.5, 128.3, 128.0, 125.2, 125.0, 124.6, 116.2, 61.5, 14.3, 13.7. IR (KBr): 3254, 3103, 2982, 2931, 1719, 1643, 1561, 1515, 1465, 1412, 1365, 1261, 1205, 1093, 1025, 1021, 858, 813, 749 cm⁻¹. HRMS (ESI) m/z calcd for: C₁₅H₁₅NaNO₅S [M + Na]⁺: 344.0569, found 344.0594.

Diethyl 3-(2-bromobenzoyl)-1H-pyrrole-2,5-dicarboxylate (3ia)

Colorless liquid (65 mg, yield 82%). ¹H NMR (400 MHz, CDCl₃) δ 10.33 (s, 1H), 7.64 (dd, J = 7.5, 1.2 Hz, 1H), 7.43 (d, J = 7.1 Hz, 1H), 7.34 (dt, J = 7.4, 5.7 Hz, 2H), 7.15 (d, J = 2.8 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 190.5, 159.9, 159.4, 141.0, 133.7, 131.8, 130.4, 128.1, 127.4, 127.0, 125.8, 125.0, 120.4, 118.1, 61.7, 61.5, 14.2, 13.8. IR (KBr): 3263, 2993, 2936, 1727, 1660, 1584, 1558, 1470, 1452, 1369, 1280, 1211, 1090, 1026, 780, 757, 645 cm⁻¹. HRMS (ESI) m/z calcd for: C₁₇H₁₆BrNaNO₅ [M + Na]⁺ 416.0110, found 416.0134.

2-Ethyl 5-methyl 3-benzoyl-1H-pyrrole-2,5-dicarboxylate (3ja)

Colourless liquid (48 mg, yield 80%), ¹H NMR (400 MHz, CDCl₃) δ 10.53 (s, 1H), 7.90–7.79 (m, 2H), 7.55 (dd, J = 10.5, 4.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.08 (d, J = 2.7 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 0.92 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 191.9, 160.5, 159.7, 138.2, 133.0, 129.6, 128.3, 128.3, 125.2, 125.1, 116.8, 61.5, 52.3, 13.4. IR (KBr): 3264, 2985, 2957, 2903, 1723, 1663, 1561, 1456, 1431, 1269, 1211, 1092, 1010, 918, 782, 722, 691. HRMS (ESI) m/z: C₁₆H₁₅NO₅Na [M + Na]⁺ 324.0848, found 324.0827.

5-tert-Butyl 2-ethyl 3-benzoyl-1H-pyrrole-2,5-dicarboxylate (3ka)

Yellow liquid (57 mg, yield 84%). ¹H NMR (600 MHz, CDCl₃) δ 10.45 (s, 1H), 7.84–7.79 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 6.98 (d, J = 2.7 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 1.54 (s, 9H), 0.86 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 192.1, 159.8, 159.3, 138.3, 132.9, 129.5, 128.3, 127.0, 124.3, 116.1, 82.4, 61.3, 28.2, 13.4. IR (KBr): 3270, 2980, 2934, 1719, 1664, 1559, 1457, 1368, 1278, 1210, 1158, 1092, 991, 848, 783, 722, 693 cm⁻¹. HRMS (ESI) m/z: C₁₉H₂₁NO₅Na [M + Na]⁺ 366.1318, found 366.1327.

Ethyl 5-benzoyl-4-(4-methylbenzoyl)-1H-pyrrole-2-carboxylate (3ab)

White solid (54 mg, 79% yield). Mp: 130–132 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.75 (s, 1H), 7.51 (td, J = 8.1, 1.1 Hz, 4H), 7.44–7.35 (m, 2H), 7.28–7.23 (m, 3H), 7.19 (t, J = 7.8 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.3, 187.1, 160.2, 138.7, 137.9, 133.7, 132.8, 132.6, 129.2, 129.1, 128.9, 128.3, 128.2, 125.6, 117.2, 61.6, 14.3. IR (KBr): 3171, 3097, 2970, 2927, 2864, 1708, 1657, 1640, 1596, 1564, 1452, 1284, 1212, 1024, 956, 877, 718 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₁H₁₇NaNO₄ [M + Na]⁺ 370.1056, found 370.1046. Found 370.1058.

Ethyl 4-benzoyl-5-(4-methylbenzoyl)-1H-pyrrole-2-carboxylate (3ac)

Yellow liquid (55 mg, yield 76%) ¹H NMR (600 MHz, CDCl₃) δ 10.65 (s, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 7.2 Hz, 3H), 7.29 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 7.9 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.40 (t, J = 7.1 Hz, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 191.4, 185.8, 163.5, 160.3, 138.7, 134.3, 132.6, 132.3, 131.5, 131.4, 130.7, 130.2, 129.2, 128.9, 128.4, 128.2, 125.2, 117.3, 113.7, 61.5, 55.5, 14.3. IR (KBr): 3252, 3062, 2981, 1716, 1650, 1603, 1556, 1452, 1277, 1201, 1023, 959, 880, 730 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₂H₁₉NaNO₄ [M + Na]⁺ 384.1212, found 384.1230.

Ethyl 4-benzoyl-5-(4-methylbenzoyl)-1H-pyrrole-2-carboxylate (3ad)

Yellow liquid (62 mg, yield 82%); ¹H NMR (400 MHz, CDCl₃) δ 10.49 (s, 1H), 7.57–7.52 (m, 2H), 7.46–7.40 (m, 3H), 7.27 (dd, J = 8.9, 6.6 Hz, 2H), 7.23 (d, J = 2.7 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.34, 186.8, 160.2, 143.8, 138.7, 135.3, 134.0, 132.6, 129.2, 129.1, 129.1, 128.8, 128.1, 125.3, 117.2, 61.5, 21.6, 14.3. IR (KBr): 3174, 2964, 2925, 1708, 1657, 1564, 1452, 1283, 1212, 1025, 718 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₂H₁₉NaNO₅ [M + Na]⁺ 400.1161, found 400.1154.

Ethyl 4-benzoyl-5-(4-chlorobenzoyl)-1H-pyrrole-2-carboxylate (3ae)

White solid (54 mg, yield 71%); mp 138–139 °C. ¹H NMR (600 MHz, CDCl₃) δ 10.70 (s, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.47 (t, J = 7.9 Hz, 3H), 7.32 (t, J = 7.7 Hz, 2H), 7.25 (d, J = 2.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 191.1, 185.9, 160.1, 139.3, 138.5, 136.2, 133.4, 132.8, 130.2, 129.2, 129.1, 128.7, 128.3, 125.9, 117.3, 61.6, 14.3. IR (KBr): 3127, 3091, 1993, 1716, 1646, 1591, 1566, 1453, 1281, 1215, 1020, 958, 878, 733 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₁H₁₆ClNaNO₄ [M + Na]⁺ 404.0666, found 404.0670.

Ethyl 4-benzoyl-5-(4-bromobenzoyl)-1H-pyrrole-2-carboxylate (3af)

Yellow solid (60 mg, yield 71%); mp 119–121 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 1H), 7.58–7.53 (m, 2H), 7.48 (t, J = 7.4 Hz, 3H), 7.37 (d, J = 2.2 Hz, 3H), 7.33 (t, J = 7.7 Hz, 2H), 7.25 (d, J = 2.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.2, 186.0, 160.0, 138.5, 136.6, 133.1, 132.9, 131.6, 130.2, 129.2, 128.3, 128.0, 125.9, 117.3, 61.7, 14.3. IR (KBr): 3125, 2995, 1716, 1645, 1585, 1564, 1453, 1279, 1216, 1068, 1021, 957, 851, 731 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₁H₁₆BrNaNO₄ [M + Na]⁺ 448.0161, found 448.0172.

Ethyl 5-benzoyl-4-(4-methybenzoyl)-1H-pyrrole-2-carboxylate (3bb)

White solid (52 mg, yield 81%); mp 120–125 °C; ¹H NMR (600 MHz, CDCl₃) δ 10.63 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.25–7.19 (m, 3H), 7.08 (d, J = 8.0 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 190.0, 187.1, 160.2, 143.5, 137.9, 136.1, 133.6, 132.8, 129.4, 129.4, 128.9, 128.9, 128.2, 125.5, 117.1, 61.5, 21.6, 14.3. IR (KBr): 3246, 3061, 2984, 1716, 1642, 1603, 1550, 1450, 1346, 1281, 1202, 1029, 769 cm⁻¹. HRMS calcd for: C₂₂H₁₉NaNO₄ [M + Na]⁺ 384.1212, found 384.1225.

Ethyl 5-benzoyl-4-(4-methoxybenzoyl)-1H-pyrrole-2-carboxylate (3cb)

Yellow liquid (54 mg, yield 73%). ¹H NMR (600 MHz, CDCl₃) δ 10.63 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.24–7.19 (m, 3H), 7.07 (d, J = 8.0 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 190.0, 187.1, 163.3, 160.2, 137.9, 133.3, 132.8, 131.6, 131.6, 129.6, 128.8, 128.2, 125.6, 117.0, 113.5, 61.5, 55.5, 14.3. IR (KBr): 3249, 3065, 2962, 2931, 2843, 1715, 1645, 1598, 1501, 1449, 1256, 1021, 1171, 1115, 1025, 960, 881, 735 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₂H₁₉NaNO₄ [M + Na]⁺ 400.1161, found 400.1120.

Ethyl 5-benzoyl-4-(4-chlorobenzoyl)-1H-pyrrole-2-carboxylate (3db)

White solid (58 mg, yield 76%); mp 163–165 °C. ¹H NMR (600 MHz, CDCl₃) δ 10.76 (s, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.24 (dd, J = 12.6, 4.9 Hz, 5H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 190.1, 187.0, 160.2, 139.0, 137.9, 137.1, 133.7, 133.0, 130.4, 128.9, 128.6, 128.5, 128.4, 125.9, 117.1, 61.6, 14.3. IR (KBr): 3242, 3066, 2985, 1717, 1644, 1589, 1553, 1449, 1281, 1204, 878, 768 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₁H₁₆ClNaNO₄ [M + Na]⁺ 404.0666, found 404.0623.

Ethyl 5-benzoyl-4-(4-bromobenzoyl)-1H-pyrrole-2-carboxylate (3eb)

White solid (62 mg, yield 73%); mp 163–165 °C. ¹H NMR (600 MHz, CDCl₃) δ 10.74 (s, 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.45–7.36 (m, 4H), 7.25 (dd, J = 9.2, 6.2 Hz, 3H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 190.3, 187.0, 160.2, 137.9, 137.5, 133.7, 133.0, 131.5, 130.5, 130.2, 128.9, 128.6, 128.4, 128.4, 127.8, 125.8, 117.1, 61.7, 14.3. IR (KBr): 3252, 3065, 2983, 1716, 1643, 1583, 1552, 1450, 1282, 1203, 1029, 877, 768 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₁H₁₆BrNaNO₄ [M + Na]⁺ 448.0161, found 448.0182.

Ethyl 4-([1,1′-biphenyl]-3-carbonyl)-5-benzoyl-1H-pyrrole-2-carboxylate (3fb)

White solid (52 mg, yield 61%); mp 161–165 °C. ¹H NMR (600 MHz, CDCl₃) δ 10.50 (s, 1H), 7.59 (dd, J = 14.6, 7.8 Hz, 4H), 7.53 (d, J = 7.3 Hz, 2H), 7.51–7.47 (m, 4H), 7.41 (dd, J = 15.0, 7.4 Hz, 2H), 7.31 (d, J = 2.7 Hz, 1H), 7.23 (t, J = 7.8 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 190.9, 187.1, 160.2, 145.3, 139.9, 138.0, 137.5, 133.6, 132.8, 129.8, 129.2, 129.0, 128.9, 128.3, 128.2, 127.2, 126.9, 125.7, 117.2, 61.6, 14.4. IR (KBr): 3251, 3062, 2982, 1717, 1641, 1600, 1553, 1450, 1279, 1203, 1026, 881, 752 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₇H₂₁NaNO₄ [M + Na]⁺ 446.1369, found 446.1375.

Ethyl 4-(2-naphthoyl)-5-benzoyl-1H-pyrrole-2-carboxylate (3gb)

White solid (65 mg, yield 82%); mp 164–169 °C. ¹H NMR (400 MHz, CDCl₃) δ 10.89 (s, 1H), 8.33–8.26 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.71–7.66 (m, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.45–7.39 (m, 3H), 7.38–7.33 (m, 2H), 7.32–7.26 (m, 1H), 6.94–6.90 (m, 2H), 4.41 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 191.8, 187.7, 160.4, 137.7, 136.9, 134.8, 133.6, 132.7, 132.1, 130.4, 129.7, 128.7, 128.2, 128.1, 128.0, 127.9, 127.3, 126.4, 125.9, 125.4, 123.9, 117.7, 61.5, 14.3. IR (KBr): 3245, 3059, 2974, 1714, 1644, 1595, 1555, 1449, 1274, 1205, 1022, 944, 886, 766, 694 cm⁻¹. HRMS (ESI) m/z calcd for: C₂₅H₁₉NaNO₄ [M + Na]⁺ 420.1212, found 420.1204.

Ethyl 5-benzoyl-4-(thiophene-2-carbonyl)-1H-pyrrole-2-carboxylate (3hb)

White solid (52 mg, yield 73%); mp 138–141 °C. ¹H NMR (600 MHz, CDCl₃) δ 10.58 (s, 1H), 7.63–7.60 (m, 2H), 7.55 (d, J = 4.9 Hz, 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.29–7.25 (m, 2H), δ 7.02–6.99 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 187.0, 182.7, 160.1, 145.2, 137.7, 134.6, 134.1, 133.2, 132.9, 129.1, 128.9, 128.4, 127.9, 125.7, 116.5, 61.6, 14.4. IR (KBr): 3249, 3103, 2972, 1718, 1638, 1553, 1451, 1282, 1190, 1027, 818, 768, 728 cm⁻¹. HRMS (ESI) m/z calcd for: C₁₉H₁₅SNaNO₄ [M + Na]⁺ 376.0620, found 376.0627.

Ethyl 5-benzoyl-4-(2-bromobenzoyl)-1H-pyrrole-2-carboxylate (3ib)

Yellow liquid (60 mg, yield 71%) ¹H NMR (400 MHz, CDCl₃) δ 10.74 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.54–7.44 (m, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.23 (ddd, J = 10.5, 5.9, 3.0 Hz, 3H), 7.14 (d, J = 2.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 189.6, 187.6, 160.2, 140.3, 137.4, 134.9, 133.7, 133.3, 131.7, 130.2, 129.1, 128.5, 127.7, 127.1, 125.2, 120.1, 118.0, 61.6, 14.3. IR (KBr): 3243, 3102, 2993, 2936, 1724, 1634, 1584, 1548, 1470, 1454, 1366, 1280, 1211, 1090, 1026, 783, 756, cm⁻¹ HRMS (ESI) m/z calcd for: C₂₁H₁₆BrNaNO₄ [M + Na]⁺ 448.0161, found 448.0157.

Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (no. 21472053, 21172082). The Analysis and Testing Centre of Huazhong University of Science and Technology is acknowledged for characterization of the new compounds.

Notes and references

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21. The single crystal X-ray data see CCDC 1406166†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1406166. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra01829g

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