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Article

Substituent-Controllable Cascade Regioselective Annulation of β-Enaminones with N-Sulfonyl Triazoles for Modular Access to Imidazoles and Pyrroles

by
Hua Wang
1,
Tongtong Zhou
1,
Mengdi Wu
1,
Qingqing Ye
2,* and
Xinwei He
1,*
1
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials (State Key Laboratory Cultivation Base), College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China
2
Department of Medicine, Chuzhou City Vocation College, Chuzhou 239000, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(11), 4416; https://doi.org/10.3390/molecules28114416
Submission received: 11 May 2023 / Revised: 26 May 2023 / Accepted: 27 May 2023 / Published: 29 May 2023
(This article belongs to the Special Issue Novel Organic Synthetic Route to Heterocyclic Compounds)
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Abstract

:
A controllable synthesis of trisubstituted imidazoles and pyrroles has been developed through rhodium(II)-catalyzed regioselective annulation of N-sulfonyl-1,2,3-trizaoles with β-enaminones. The imidazole ring was formed through a 1,1-insertion of the N-H bond to α-imino rhodium carbene, followed by a subsequent intramolecular 1,4-conjugate addition. This occurred when the α-carbon atom of the amino group was bearing a methyl group. Additionally, the pyrrole ring was constructed by utilizing a phenyl substituent and undergoing intramolecular nucleophilic addition. The mild conditions, good tolerance towards functional groups, gram-scale synthesis capability, and ability to undergo valuable transformations of the products qualify this unique protocol as an efficient tool for the synthesis of N-heterocycles.

1. Introduction

Nitrogen-containing heterocycles are privileged structural motifs in various natural products and bioactive compounds [1,2]. Among them, imidazole and pyrrole frameworks are very common structural units widely distributed in natural products, pharmaceutics, agrochemicals, and other functional materials [3,4]. For this reason, the synthesis of such compounds continues to be a hot topic in modern synthetic chemistry [5,6,7,8]. Consequently, a large number of new reactions have been developed to construct structurally diverse imidazole and pyrrole derivatives, such as multicomponent reactions [9,10]. [3 + 2] cycloaddition [11,12,13,14], as well as both metal-catalyzed intermolecular [15,16] and intramolecular [17,18] cyclization strategies. Despite all the achievements, the development of efficient methods for their synthesis, particularly regiocontrolled synthesis of those containing multiple substituents from readily accessible compounds, is of ever-increasing importance.
In the past decades, 1,2,3-triazoles have emerged as capable precursors for the synthesis of various nitrogen heterocycles [19,20]. Upon treatment with rhodium(II) catalysts, N-sulfonyl-1,2,3-triazoles readily undergo denitrogenation reactions to form α-imino rhodium carbenes, a versatile intermediate that could promote a wide range of transformations [21,22]. In addition to common reactivities such as cyclopropanation [23,24], X-H insertion [25,26,27,28], and ylide formation [29,30,31], α-imino rhodium carbenes can also serve as [1C]- or aza-[3C]-synthons in stepwise cycloadditions, leading to the formation of various N-heterocycles [32,33,34,35]. As a major part of our research efforts in developing new methodologies for the construction of heterocycles [36,37,38,39], we herein describe an efficient strategy for the regioselective synthesis of trisubstituted imidazoles and pyrroles. This strategy involves the cascade N-H insertion to α-imino rhodium carbene, followed by substituent-controllable intramolecular annulation (Scheme 1). In this scheme, the α-imino rhodium carbene acted as [2C] and aza-[3C]-synthons, respectively.

2. Results and Discussion

The optimization of a one-pot procedure for the formation of imidazole 3a from triazole 1a and β-enaminone 2a was undertaken (Table 1). Screening of various transition-metal catalysts revealed that dirhodium catalysts Rh2(OAc)4 and Rh2(oct)4 were demonstrated to be more efficient than other metal catalysts for this reaction (Table 1, entries 1–6). Further investigation showed that a lower catalytic loading (2 mol%) had a positive effect on the reaction (Table 1, entries 7–10). Other solvents, including toluene and chlorobenzene, could better promote this transformation and then utilize chlorobenzene for further optimization (Table 1, entries 11–16). A further variation of reaction temperatures revealed that 80 °C was the optimal condition (Table 1, entries 17–19). The reaction time extension did not benefit the product yield (Table 1, entries 20–22). Thus, the optimal reaction conditions were Rh2(oct)4 in chlorobenzene at 90 °C for 12 h (Table 1, entry 13).
With the optimal conditions in hand, we explored the scope and generality of this [3 + 2] annulation with a combination of various substituted N-sulfonyl-1,2,3-triazoles 1 and β-enamino ketones 2 (Scheme 2). We first evaluated the effect of substituents in the R1 group on the phenyl of N-sulfonyl-1,2,3-triazoles. The results indicated that the introduction of electron-neutral (-Me, -Et), electron-rich (-OMe), and electron-deficient (-F, -Cl, -Br) substituents at the para-positions was tolerated in this transformation. The desired imidazoles (products 3b–3g) were obtained in yields ranging from 91% to 96%. Notably, the presence of bulky tert-butyl or strong electron-withdrawing trifluoromethyl groups at the para-position of benzene ring triazoles 1 led to a smooth reaction process. This resulted in the formation of the corresponding products 3h and 3i, with yields of 93% and 75%, respectively. Moreover, the extended π structure did not show an influence, and the desired product 3j was successfully obtained with an 80% yield. Additionally, substituent variations on the meta- and ortho-positions could work well to produce the corresponding products 3k–3n in 79–95% yields. Furthermore, the N-arylsulfonyl groups of the triazole substrates were also examined. The reactions of fluoro- and bromo-substituted phenylsulfonyl triazoles proceeded well, giving the desired products 3o and 3p in 91% and 76% yields, respectively. In addition, (Z)-3-amino-1-phenylpent-2-en-1-one was also a viable substrate for the transformation, generating the product 3q in 56% yield.
Subsequently, an unexpected pyrrole product 5a was obtained in 91% yield under standard conditions when the phenyl group (4a) replaced the methyl group of β-enaminones. We further evaluated the feasibility by using the 1,3-diaryl β-enaminones as starting materials (Scheme 3). As expected, a wide range of electronically different substituents, including alkyl, methoxy, halogen, and bulky tert-butyl groups, were successfully installed into the products 5a–5h. Moreover, an extended π-system was implemented on the pyrrole structure (product 5i). Particularly noteworthy is that the halogen groups (e.g., -F, -Cl, and -Br) remained intact during the course of the reaction, which makes this transformation particularly attractive in terms of increasing the molecular complexity via transition metal-catalyzed coupling reactions (5e–5g and 5k–5m). Additionally, we turned our attention to investigating the suitability of the substrate 1,3-diaryl β-enaminones 4, and the desired products 5n–5q were successfully obtained in 76–92% yields. It was gratifying that the introduction of a naphthyl and thienyl group also proceeded smoothly to produce the desired products 5o and 5p in yields of 92% and 90%, respectively. Likewise, changing the phenyl group to a bulky isopropyl was also tolerated in the reaction to give the desired product 5q in an 86% yield.
Based on the above results, we hypothesize that the reaction of N-sulfonyl-1,2,3-triazoles and β-enaminones might be controlled by the steric hindrance of the substituent on the α-position of amino. Under standard conditions, when a moderate steric group such as n-propyl or n-butyl was present at the amino α-position of β-enaminones, the reaction resulted in the formation of the corresponding products, namely imidazoles (3r and 3s) and pyrroles (5s and 5t), as depicted in Scheme 4a. In the synthesis of pyrroles, the presence of a methyl p-tolyl on the amino group resulted in a satisfactory yield of compounds 7a and 7b (72% and 85%, respectively; Scheme 4b).
Notably, the reaction could be easily scaled up. As shown in Scheme 5, imidazole 3a could be obtained with a satisfactory yield of 77% (1.44 g) when the scale of the reaction was increased to 5 mmol. Additionally, the 3,5-disubstituted pyrrole 5a was obtained in a 75% yield (1.21 g) on the same scale. Subsequently, several transformations were performed to demonstrate the utility of the target products. The desulfonation of imidazole 3a afforded the unprotected imidazole 8 in 96% yield (Scheme 5a). In addition, treating pyrrole 5a with hydroxylamine hydrochloride and iodomethane successfully realized the formation of pyrrolyl oxime 9 in 94% yield (Scheme 5b). In the presence of sodium hydride, N-methylation between compound 5a and iodomethane easily generated N-methylpyrrole derivative 10 in 95% yield (Scheme 5c). This highlights the synthetic utility of the current protocol.
The mechanism of this reaction was proposed as shown in Scheme 6 based on the above experimental results and previous reports [40,41,42]. α-Diazo imino intermediate A, which was generated from the ring-chain tautomerization of triazole 1a, could be efficiently decomposed by the rhodium(II) catalyst to form α-imino rhodium carbene intermediate B along with the release of nitrogen gas. β-Enaminones (2a or 4a) attacked the electrophilic carbene center of intermediate B, and 1,1-insertion occurred to convert intermediate D with the rhodium(II) catalyst regeneration. In the case where R was a methyl group, an imino–enamine tautomerization could be triggered, leading to the formation of a more stable intermediate E. This intermediate E then underwent an intramolecular 1,4-conjugate addition, resulting in the formation of intermediate F. The elimination of the intermediate F results in the desired product 3a. In the case of 4a, the phenyl group was bulky enough to form the intermediate D’. Therefore, after the subsequent intramolecular nucleophilic addition and elimination processes, the corresponding product 5a was obtained.

3. Materials and Methods

Unless otherwise specified, all reagents and starting materials were purchased from commercial sources and used as received. The solvents were purified and dried using standard procedures. The chromatography solvents were technical grade and distilled prior to use. The NMR spectra were recorded with a Bruker Avance 500 spectrometer (500 MHz for 1H and 125 MHz for 13C) with CDCl3 as a solvent and tetramethylsilane (TMS) as the internal standard at room temperature. Chemical shifts are given in δ relative to TMS, and the coupling constants J are given in Hz (Supplementary Materials: 1H NMR and 13C NMR). HRMS spectra were obtained with an Agilent 6200 using a quadrupole time-of-flight mass spectrometer equipped with an ESI source. The melting points were measured using the SGWX-4 melting point apparatus and were not corrected. The X-ray source used for the single crystal X-ray diffraction analysis of compounds 3a and 5a was Mo Kα (λ = 0.71073 Å), and the thermal ellipsoid was drawn at the 30% probability level (Supplementary Materials: X-ray crystal data).

3.1. General Procedure for the Synthesis of Trisubstituted Imidazoles 3 and Pyrroles 5

N-Sulfonyl-1H-1,2,3-triazoles 1 (0.2 mmol), β-enaminones 2 (0.2 mmol), and Rh2(oct)4 (2 mol%) were successively added to a Schlenk reaction tube. The reaction set was evacuated and backfilled with argon three times. Then, chlorobenzene (2.0 mL) was added to the reaction tube through a syringe. The reaction mixture was stirred vigorously in an oil bath preheated to 90 °C for 12 h. After the reaction was complete, the reaction mixture was cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na2SO4, and then evaporated under a vacuum. The residue was purified by flash column chromatography on silica gel (200–300 mesh) using ethyl acetate and petroleum ether (1:8, v/v) as the elution solvents to give desired products 3 or 5.

3.2. General Procedure for the Synthesis of Compound 8

2-Methyl-4-phenyl-1-tosyl-1H-imidazole 3a (0.15 mmol) and NaOH (2.25 mmol) were successively added to a Schlenk reaction tube. The reaction set was evacuated and backfilled with argon three times. Then, methanol (2.0 mL) was added into the reaction tube through a syringe. The reaction mixture was stirred vigorously in an oil bath preheated to 70 °C for 30 min. After the reaction was complete, the reaction mixture was cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na2SO4, and then evaporated under a vacuum. The residue was purified by flash column chromatography on silica gel (200–300 mesh) using ethyl acetate and petroleum ether (1:3, v/v) as the elution solvents to give the desired product 8 in a 96% yield.

3.3. General Procedure for the Synthesis of Compound 9

A mixture of (2,5-diphenyl-1H-pyrrol-3-yl)(phenyl)methanone 5a (0.2 mmol), hydroxylamine hydrochloride (0.4 mmol), and sodium acetate (0.5 mmol) was added to a round-bottomed flask with a reflux condenser. Ethanol (4 mL) was then added, and the reaction mixture was stirred vigorously at reflux in an oil bath for 12 h. After quenching with water, the residue was extracted twice with ethyl acetate. The combined layer was washed with brine, dried over Na2SO4, and then evaporated under a vacuum. The residue was purified by flash column chromatography on silica gel (200–300 mesh) using ethyl acetate and petroleum ether (1:8, v/v) as the elution solvents to give the desired product 9 in a 94% yield.

3.4. General Procedure for the Synthesis of Compound 10

NaH (60% in mineral oil, 0.5 mmol, 1.7 equiv.) was added to a solution of 5a (0.25 mmol) in DCM (4 mL) at 0 °C in portions. After stirring for 5 min at 0 °C, MeI (0.22 mmol, 1.1 equiv.) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for another 19 h. After quenching with water, the residue was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtrated and concentrated, and purified by column chromatography to afford 10 in 95% yield.
  • 2-Methyl-4-phenyl-1-tosyl-1H-imidazole (3a). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 96% yield (60 mg); mp 122–124 °C; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.0 Hz, 2H), 7.67 (s, 1H), 7.39–7.35 (m, 4H), 7.25 (d, J = 7.5 Hz, 1H), 2.57 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.5, 146.4, 141.0, 135.5, 132.7, 130.8, 129.1, 128.2, 127.8, 125.6, 114.4, 22.1, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H17N2O2S 313.1005; found 313.1006.
  • 2-Methyl-4-(p-tolyl)-1-tosyl-1H-imidazole (3b). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 96% yield (62 mg); mp 60–62 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.4, 146.3, 141.0, 138.0, 135.4, 130.7, 129.9, 129.8, 127.7, 125.5, 113.9, 22.1, 21.7, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O2S 327.1162; found 327.1170.
  • 4-(4-Ethylphenyl)-2-methyl-1-tosyl-1H-imidazole (3c). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 95% yield (64 mg); mp 77–79 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.0 Hz, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.57 (s, 3H), 2.42 (s, 3H), 1.23 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 146.4, 146.3, 144.4, 141.0, 135.4, 130.8, 130.1, 128.6, 127.7, 125.5, 113.9, 29.1, 22.1, 15.9, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H21N2O2S 341.1318; found 341.1319.
  • 4-(4-Methoxyphenyl)-2-methyl-1-tosyl-1H-imidazole (3d). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 91% yield (62 mg); mp 66–68 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 9.0 Hz, 2H), 7.57 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 2.56 (s, 3H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.8, 146.4, 146.3, 140.8, 135.4, 130.7, 127.7, 126.9, 125.5, 114.5, 113.2, 55.7, 22.1, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O3S 343.1111; found 343.1112.
  • 4-(4-Fluorophenyl)-2-methyl-1-tosyl-1H-imidazole (3e). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 94% yield (62 mg); mp 107–109 °C; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.69 (dd, J = 8.5, 5.0 Hz, 2H), 7.61 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 8.5 Hz, 2H), 2.56 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.9 (d, JC-F = 246.3 Hz), 146.6, 146.5, 140.1, 135.3, 130.8, 129.0, 127.8, 127.3 (d, JC-F = 8.0 Hz), 116.0 (d, JC-F = 21.6 Hz), 114.0, 22.1, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16FN2O2S 331.0911; found 331.0909.
  • 4-(4-Chlorophenyl)-2-methyl-1-tosyl-1H-imidazole (3f). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 94% yield (65 mg); mp 107–109 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 2H), 7.66–7.65 (m, 3H), 7.36–7.32 (m, 4H), 2.56 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.6, 146.6, 139.9, 135.2, 133.8, 131.3, 130.8, 129.2, 127.8, 126.8, 114.5, 22.1, 15.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16ClN2O2S 347.0616; found 347.0612.
  • 4-(4-Bromophenyl)-2-methyl-1-tosyl-1H-imidazole (3g). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 93% yield (72 mg); mp 104–106 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 2.56 (s, 3H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.7, 146.6, 139.9, 135.2, 132.2, 131.7, 130.8, 127.8, 127.1, 122.0, 114.6, 22.1, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16BrN2O2S 391.0110; found 391.0109.
  • 4-(4-(tert-Butyl)phenyl)-2-methyl-1-tosyl-1H-imidazole (3h). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 93% yield (68 mg); mp 69–71 °C; 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 7.0 Hz, 2H), 7.69–7.64 (m, 3H), 7.39 (d, J = 7.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H), 2.42 (s, 3H), 1.32 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 151.3, 146.4, 146.4, 141.0, 135.5, 130.7, 129.9, 127.7, 126.0, 125.3, 114.0, 35.0, 31.7, 22.1, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H25N2O2S 369.1631; found 369.1634.
  • 2-Methyl-1-tosyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazole (3i). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 75% yield (57 mg); mp 76–78 °C; 1H NMR (500 MHz, CDCl3) δ 7.84–7.82 (m, 4H), 7.76 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.8, 139.5, 136.2, 135.1, 130.9, 129.9 (q, JC-F = 32.5 Hz), 128.5, 127.9, 126.6, 126.1(q, JC-F = 3.8 Hz), 124.6(q, JC-F = 270.0 Hz), 115.6, 22.1, 15.5; HRMS (ESI-TOF) m/z: [M + H] + Calcd for C18H16F3N2O2S 381.0879; found 381.0878.
  • 2-Methyl-4-(4’-propyl-[1,1’-biphenyl]-4-yl)-1-tosyl-1H-imidazole (3j). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in an 80% yield (69 mg); mp 94–96 °C; 1H NMR (500 MHz, CDCl3) δ 7.83–7.79 (m, 4H), 7.71(s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.59 (s, 3H), 1.72–1.64 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 146.5, 146.5, 142.4, 140.9, 140.7, 138.4, 135.4, 131.4, 130.8, 129.3, 127.8, 127.6, 127.1, 125.9, 114.3, 38.1, 25.0, 22.1, 15.6, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H27N2O2S 431.1788; found 431.1781.
  • 2-Methyl-4-(m-tolyl)-1-tosyl-1H-imidazole (3k). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 95% yield (62 mg); mp 107–109 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.67 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 2.57 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.5, 146.4, 141.0, 138.8, 135.4, 132.5, 130.8, 129.0, 127.8, 126.2, 122.6, 114.3, 22.1, 21.8, 15.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O2S 327.1162; found 327.1163.
  • 4-(3-Chlorophenyl)-2-methyl-1-tosyl-1H-imidazole (3l). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in an 85% yield (59 mg); mp 83–85 °C; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.68 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.7, 139.7, 135.1, 134.6, 130.8, 130.3, 128.1, 127.8, 125.7, 123.6, 115.0, 22.1, 15.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16ClN2O2S 347.0616; found 347.0625.
  • 4-(3-Bromophenyl)-2-methyl-1-tosyl-1H-imidazole (3m). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in an 82% yield (64 mg); mp 79–81 °C; 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.67 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.39–7.35 (m, 3H), 7.22 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.7, 146.6, 139.5, 135.2, 134.8, 131.0, 130.8, 130.6, 128.6, 127.8, 124.1, 123.3, 115.0, 22.1, 15.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16BrN2O2S 391.0110; found 391.0119.
  • 4-(2-Fluorophenyl)-2-methyl-1-tosyl-1H-imidazole (3n). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 79% yield (52 mg); mp 57–59 °C; 1H NMR (500 MHz, CDCl3) δ 8.03 (t, J = 7.5 Hz, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.0 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 10 Hz, 1H), 2.58 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.2 (d, JC-F = 247.9 Hz), 146.5, 145.9, 135.4, 134.5, 130.8, 129.1 (d, JC-F = 8.5 Hz), 128.2 (d, JC-F = 3.6 Hz), 127.8, 124.7 (d, JC-F = 3.6 Hz), 120.6 (d, JC-F = 12.5 Hz), 118.4 (d, JC-F = 15.4 Hz), 116.0 (d, JC-F = 21.5 Hz), 22.1, 15.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16FN2O2S 331.0911; found 331.0914.
  • 1-((4-Fluorophenyl)sulfonyl)-2-methyl-4-phenyl-1H-imidazole (3o). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 91% yield (57 mg); mp 107–109 °C; 1H NMR (500 MHz, CDCl3) δ 7.97–7.94 (m, 2H), 7.73 (d, J = 7.5 Hz, 2H), 7.67 (s, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 8.0 Hz, 2H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.6 (d, JC-F = 257.5 Hz), 146.4, 141.3, 134.4 (d, JC-F = 2.8 Hz), 132.5, 130.7 (d, JC-F = 9.8 Hz), 129.1, 128.4, 125.6, 117.7 (d, JC-F = 22.9 Hz), 114.2, 15.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14FN2O2S 317.0755; found 317.0760.
  • 1-((4-Bromophenyl)sulfonyl)-2-methyl-4-phenyl-1H-imidazole (3p). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 76% yield (57 mg); mp 97–99 ℃; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 9.0 Hz, 2H), 7.72 (t, J = 9.0 Hz, 4H), 7.65 (s, 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.5, 141.4, 137.3, 133.6, 132.4, 130.6, 129.1, 129.1, 128.4, 125.6, 114.2, 15.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14BrN2O2S 376.9954; found 376.9952.
  • 2-Ethyl-4-phenyl-1-tosyl-1H-imidazole (3q). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 56% yield (37 mg); mp 49–51 °C; 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 7.0 Hz, 2H), 7.67 (s, 1H), 7.39-7.34 (m, 4H), 7.28 (d, J = 7.5 Hz, 1H), 2.90 (q, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 151.4, 146.4, 140.9, 135.7, 132.9, 130.7, 129.0, 128.1, 127.7, 125.6, 114.3, 22.4, 22.1, 12.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O2S 327.1162; found 327.1163.
  • 4-Phenyl-2-propyl-1-tosyl-1H-imidazole (3r). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a colorless oil in a 45% yield (31 mg); 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 7.0 Hz, 2H), 7.66 (s, 1H), 7.38–7.33 (m, 4H), 7.27 (t, J = 7.5 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.81–1.74 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 150.4, 146.4, 141.0, 135.8, 132.9, 130.7, 129.0, 128.1, 127.6, 125.6, 114.3, 30.8, 22.1, 21.9, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H21N2O2S 341.1318; found 341.1312.
  • 2-Butyl-4-phenyl-1-tosyl-1H-imidazole (3s). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a colorless oil in a 44% yield (31 mg); 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H), 7.67 (s, 1H), 7.38–7.33 (m, 4H), 7.28 (d, J = 7.5 Hz, 1H), 2.87 (t, J = 8 Hz, 2H), 2.43 (s, 3H), 1.72–1.69 (m, 2H), 1.42–1.37 (m, 2H), 0.91 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 150.5, 146.4, 140.9, 135.7, 132.9, 130.7, 129.1, 128.2, 127.7, 125.6, 114.3, 30.5, 28.6, 22.9, 22.1, 14.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23N2O2S 355.1475; found 355.1482.
  • (2,5-Diphenyl-1H-pyrrol-3-yl)(phenyl)methanone (5a). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 91% yield (59 mg); mp 81–83 °C; 1H NMR (500 MHz, CDCl3) δ 8.98 (s, 1H), 7.80 (d, J = 7.0 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.45-7.42 (m, 3H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.29–7.24 (m, 4H), 6.84 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.9, 139.8, 138.3, 132.3, 132.1, 131.8, 130.1, 129.5, 128.9, 128.8, 128.5, 128.3, 127.5, 124.5, 122.3, 110.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H18NO 324.1383; found 324.1382.
  • Phenyl(2-phenyl-5-(p-tolyl)-1H-pyrrol-3-yl)methanone (5b). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 91% yield (61 mg); mp 81–83 °C; 1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.47–7.38 (m, 5H), 7.31 (t, J = 7.7 Hz, 2H), 7.21–7.17 (m, 5H), 6.78 (s, 1H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.1, 139.8, 138.1, 137.3, 132.5, 132.2, 132.1, 130.1, 130.1, 129.1, 128.9, 128.7, 128.4, 128.3, 124.6, 122.2, 110.4, 21.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H20NO 338.1539; found 338.1545.
  • (5-(4-Ethylphenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5c). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 92% yield (64 mg); mp 71–73 °C; 1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 7.80 (d, J = 7.0 Hz, 2H), 7.47-7.42 (m, 5H), 7.32 (t, J = 7.5 Hz, 2H), 7.26–7.22 (m, 5H), 6.81 (d, J = 3.0 Hz, 1H), 2.67 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 193.0, 143.8, 139.8, 138.0, 132.5, 132.2, 132.1, 130.1, 129.3, 128.9, 128.9, 128.7, 128.4, 128.3, 124.6, 122.2, 110.4, 29.0, 15.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H22NO 352.1693; found 352.1689.
  • (5-(4-Methoxyphenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5d). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 92% yield (65 mg); mp 111–113 °C; 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 7.0 Hz, 3H), 7.31 (t, J = 7.5 Hz, 2H), 7.22 (d, J = 7.5 Hz, 3H), 6.92 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.1, 159.3, 139.9, 137.9, 132.4, 132.3, 132.1, 130.1, 128.9, 128.7, 128.3, 128.3, 126.0, 124.8, 122.2, 114.9, 109.8, 55.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H20NO 354.1489; found 354.1489.
  • (5-(4-Fluorophenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5e). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 85% yield (58 mg); mp 104–106 °C; 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 7.78 (d, J = 7.0 Hz, 2H), 7.50 (dd, J = 9.0, 5.0 Hz, 2H), 7.45–7.41 (m, 3H), 7.31 (t, J = 7.5 Hz, 2H), 7.24–7.22 (m, 3H), 7.08 (t, J = 8.5 Hz, 2H), 6.76 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.9, 162.4 (d, JC-F = 245.0 Hz), 139.7, 138.3, 132.2, 132.1, 131.5, 130.1, 128.8 (d, JC-F = 6.3 Hz), 128.6, 128.3, 128.2, 126.4, 126.3, 122.4, 116.5 (d, JC-F = 22.5 Hz), 110.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17FNO 342.1289; found 342.1287.
  • (5-(4-Chlorophenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5f). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 84% yield (60 mg); mp 112–114 ℃; 1H NMR (500 MHz, CDCl3) δ 9.04 (s, 1H), 7.77 (d, J = 7.0Hz, 2H), 7.46–7.42 (m, 3H), 7.39 (dd, J = 6.5, 3.0 Hz, 2H), 7.35–7.30 (m, 4H), 7.23–7.19 (m, 3H), 6.79 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.9, 139.6, 138.6, 133.1, 132.2, 131.9, 131.3, 130.4, 130.1, 129.6, 128.9, 128.8, 128.6, 128.3, 125.8, 122.4, 111.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17ClNO 358.0993; found 358.1002.
  • (5-(4-Bromophenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5g). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 84% yield (67 mg); mp 127–129 °C; 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.46–7.43 (m, 3H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.29-7.27 (m, 3H), 6.85 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 193.0, 139.6, 138.7, 132.5, 132.3, 131.9, 131.3, 130.8, 130.1, 128.9, 128.7, 128.6, 128.3, 126.1, 122.4, 121.1, 111.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17BrNO 402.0488; found 402.0489.
  • (5-(4-(tert-Butyl)phenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5h). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 93% yield (70 mg); mp 98–100 °C; 1H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.49–7.40 (m, 7H), 7.32 (t, J = 8.0 Hz, 2H), 7.28–7.23 (m, 3H), 6.82 (s, 1H), 1.34 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 192.9, 150.7, 139.8, 138.0, 132.4, 132.3, 132.1, 130.1, 129.1, 128.9, 128.8, 128.4, 128.3, 126.4, 124.3, 122.3, 110.5, 35.0, 31.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H26NO 380.2009; found 380.2008.
  • Phenyl(2-phenyl-5-(4’-propyl-[1,1’-biphenyl]-4-yl)-1H-pyrrol-3-yl)methanone (5i). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 85% yield (72 mg); mp 149–151 °C; 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 7.80 (d, J = 7.5 Hz, 2H), 7.59 (s, 4H), 7.52 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.41–7.36 (m, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.20–7.15 (m, 3H), 6.85 (d, J = 3.0 Hz, 1H), 2.64 (d, J = 8.0 Hz, 2H), 1.69 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 193.3, 142.5, 140.0, 139.8, 138.7, 138.2, 132.3, 132.2, 132.1, 130.5, 130.2, 129.4, 129.0, 128.7, 128.4, 128.3, 127.8, 127.1, 125.0, 122.3, 110.9, 38.1, 25.0, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H28NO 442.2165; found 442.2170.
  • Phenyl(2-phenyl-5-(m-tolyl)-1H-pyrrol-3-yl)methanone (5j). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 86% yield (58 mg); mp 118–120 °C; 1H NMR (500 MHz, CDCl3) δ 9.08 (s, 1H), 7.80 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 6.0 Hz, 3H), 7.37–7.31 (m, 4H), 7.27 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 6.0 Hz, 3H), 7.08 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.1, 139.8, 139.0, 138.4, 132.5, 132.2, 132.1, 131.8, 130.1, 129.3, 128.9, 128.7, 128.4, 128.3, 125.4, 122.2, 121.7, 110.8, 21.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H20NO 338.1539; found 338.1531.
  • (5-(3-Chlorophenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5k). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 85% yield (60 mg); mp 83–85 °C; 1H NMR (500 MHz, CDCl3) δ 9.19 (s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.51 (s, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.41–7.38 (m, 3H), 7.34–7.27 (m, 3H), 7.23–7.18 (m, 4H), 6.80 (d, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 193.0, 139.6, 138.9, 135.4, 133.6, 132.3, 131.8, 130.9, 130.6, 130.1, 128.9, 128.7, 128.6, 128.4, 127.3, 124.6, 122.6, 122.3, 111.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17ClNO 358.0993; found 358.0992.
  • (5-(3-Bromophenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5l). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 87% yield (69 mg); mp 99–101 °C; 1H NMR (500 MHz, CDCl3) δ 9.10 (s, 1H), 7.78 (d, J = 7.0 Hz, 2H), 7.67 (s, 1H), 7.46–7.40 (m, 4H), 7.37 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.25–7.21 (m, 4H), 6.81 (d, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.9, 139.6, 138.9, 133.9, 132.3, 131.8, 130.9, 130.7, 130.2, 130.1, 128.9, 128.8, 128.7, 128.4, 127.4, 123.6, 123.1, 122.4, 111.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17BrNO 402.0488; found 402.0489.
  • (5-(2-Fluorophenyl)-2-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (5m). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 79% yield (54 mg); mp 77–79 °C; 1H NMR (500 MHz, CDCl3) δ 9.39 (s, 1H), 7.81 (d, J = 7.0 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.48–7.44 (m, 3H), 7.34 (t, J = 8.0 Hz, 2H), 7.29–7.26 (m, 3H), 7.23–7.13 (m, 3H), 6.98 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ192.8, 159.2 (d, JC-F = 124.1 Hz), 139.7, 138.3, 132.2, 132.0, 130.1, 128.8, 128.6, 128.57 (d, JC-F = 8.5 Hz), 128.4, 127.3 (d, JC-F = 4.0 Hz), 127.1, 125.3 (d, JC-F = 3.0 Hz), 121.7, 119.4, 119.3, 116.8 (d, JC-F = 23.8 Hz), 112.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17FNO 342.1289; found 342.1281.
  • (4-Chlorophenyl)(2-(4-chlorophenyl)-5-phenyl-1H-pyrrol-3-yl) methanone (5n). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 75% yield (58 mg); mp 94–96 °C; 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 7.0 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.34 (m, 4H), 6.80 (d, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 191.2, 138.7, 138.0, 136.8, 134.8, 132.7, 131.4, 130.5, 130.0, 129.6, 129.2, 128.8, 127.9, 124.6, 122.3, 110.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H16Cl2NO 392.0603; found 392.0612.
  • (2,5-Diphenyl-1H-pyrrol-3-yl) (naphthalen-2-yl) methanone (5o). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 92% yield (68 mg); mp 107–109 °C; 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H), 8.34 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.0 Hz, 3H), 7.60–7.52 (m, 5H), 7.49 (d, J = 7.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.31–7.26 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.7, 138.1, 137.0, 135.4, 132.7, 132.3, 132.2, 131.8, 131.7, 129.7, 129.5, 128.9, 128.8, 128.6, 128.2, 128.2, 128.1, 127.6, 126.8, 126.1, 124.5, 122.6, 111.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H20NO 374.1539; found 374.1537.
  • (2,5-Diphenyl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone (5p). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 90% yield (59 mg); mp 86–88 °C; 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 7.66 (d, J = 3.5 Hz, 1H), 7.60–7.54 (m, 5H), 7.42 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 7.0 Hz, 2H), 7.33–7.28 (m, 2H), 7.04 (dd, J = 5.0, 4.0 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 184.1, 145.9, 137.4, 134.1, 133.2, 132.4, 132.1, 131.8, 129.5, 129.0, 128.7, 128.6, 128.0, 127.6, 124.6, 122.3, 110.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H16NOS 330.0947; found 330.0955.
  • (2-Isopropyl-5-phenyl-1H-pyrrol-3-yl) (phenyl)methanone (5q). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 86% yield (50 mg); mp 85–87 °C; 1H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 7.84 (d, J = 7.0 Hz, 2H), 7.53 (t, J = 7.0 Hz, 1H), 7.48–7.44 (m, 4H), 7.36 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 3.0 Hz, 1H), 3.87 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 192.8, 147.8, 141.1, 132.2, 131.6, 129.8, 129.5, 129.4, 128.5, 127.2, 124.3, 120.2, 110.1, 26.8, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20NO 290.1539; found 290.1530.
  • Phenyl(5-phenyl-2-propyl-1H-pyrrol-3-yl) methanone (5r). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 42% yield (24 mg); mp 74–76 °C; 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.87–7.82 (m, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.49–7.44 (m, 4H), 7.39–7.34 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 3.0 Hz, 1H), 3.02 (t, J = 7.5 Hz, 2H), 1.76 (m, 2H), 1.60 (s, 3H), 1.01 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 192.7, 142.4, 141.0, 132.1, 131.6, 130.0, 129.5, 129.4, 128.5, 127.1, 124.2, 121.2, 109.8, 30.1, 23.1, 14.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20NO 290.1539; found 290.1542.
  • (2-Butyl-5-phenyl-1H-pyrrol-3-yl) (phenyl)methanone (5s). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in a 49% yield (30 mg); mp 74–76 °C; 1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.55–7.45 (m, 5H), 7.34 (t, J = 7.0 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 6.67 (s, 1H), 3.01 (t, J = 7.5 Hz, 2H), 1.7–1.64 (m, 2H), 1.39–1.32 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 192.7, 142.7, 140.7, 131.8, 131.3, 129.8, 129.1, 129.0, 128.1, 126.6, 123.9, 120.6, 109.4, 31.7, 27.5, 22.6, 14.0, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H22NO 304.1696; found 304.1702.
  • (1,2-Dimethyl-5-phenyl-1H-pyrrol-3-yl) (phenyl)methanone (7a). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 72% yield (40 mg); mp 96–98 °C; 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 7.0 Hz, 2H), 7.26 (t, J = 7.5Hz, 1H), 7.14 (t, J = 7.5 Hz, 2H), 7.04 (q, J = 8.0 Hz, 4H), 6.98 (d, J = 6.5 Hz, 1H), 6.64 (s, 1H), 3.62 (s, 3H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.4, 140.0, 135.8, 135.6, 131.9, 130.2, 128.8, 128.2, 128.0, 126.2, 125.9, 120.2, 120.1, 34.2, 11.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H18NO 276.1383; found 276.1388.
  • 1-(2-Methyl-5-phenyl-1-(p-tolyl)-1H-pyrrol-3-yl) ethan-1-one (7b). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a yellow solid in an 85% yield (49 mg); mp 66–68 °C; 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 4.0 Hz, 4H), 7.32–7.27 (m, 3H), 7.21 (d, J = 8.5 Hz, 2H), 6.64 (s, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 2.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.1, 138.5, 136.6, 136.5, 135.8, 130.3, 129.7, 128.7, 127.2, 126.6, 126.4, 122.8, 121.1, 31.5, 21.5, 13.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20NO 290.1539; found 290.1538.
  • 2-Methyl-4-phenyl-1H-imidazole (8). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:3) to afford a white solid in a 96% yield (30 mg); mp 57–59 °C; 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.0 Hz, 2H), 7.37 (s, 1H), 7.30 (t, J = 7.5Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 3.39 (brs, 1H), 2.29 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 145.7, 138.2, 133.2, 129.1, 127.2, 125.1, 115.6, 14.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H11N2 159.0917; found 159.091.
  • (E)-(2,5-Diphenyl-1H-pyrrol-3-yl) (phenyl)methanone oxime (9). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a white solid in a 94% yield (63 mg); mp 95–97 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.44 (s, 1H), 11.19 (s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.49 (d, J = 7.5 Hz, 4H), 7.37 (t, J = 8.0 Hz, 2H), 7.26–7.23 (m, 5H), 7.19 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 153.7, 137.7, 133.2, 132.8, 131.6, 129.6, 129.5, 129.1, 129.0, 128.8, 127.4, 127.2, 127.0, 126.5, 124.8, 115.1, 109.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H19N2O 339.1492; found 339.1496.
  • (1-Methyl-2,5-diphenyl-1H-pyrrol-3-yl) (phenyl)methanone (10). This compound was purified by column chromatography (ethyl acetate/petroleum ether = 1:8) to afford a colorless oil in a 98% yield (66 mg); 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.40–7.35 (m, 5H), 7.34 (s, 1H), 7.32–7.27 (m, 3H), 6.67 (s, 1H), 3.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.3, 140.8, 140.1, 135.7, 132.9, 132.3, 131.6, 131.2, 129.8, 129.4, 129.0, 128.6, 128.5, 128.1, 128.1, 122.3, 112.3, 34.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H20NO 338.1539; found 338.1544.

4. Conclusions

In conclusion, we have demonstrated that the Rh(II)-catalyzed substituent-controllable regioselective annulations provide a new synthetic strategy for trisubstituted imidazoles and pyrroles. The highlight of the current reaction is the substituent-dependent product selectivity. The imidazole skeleton was formed via N-H insertion to α-imino rhodium carbene, followed by intramolecular 1,4-conjugate addition when α-carbon atom of the amino group bore with methyl. Switching the methyl to phenyl group, the pyrrole framework was generated through N-H insertion and the intramolecular nucleophilic addition process. The large-scale reactions and transformations of the products further demonstrated the potential synthetic value of this strategy.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114416/s1, Characterization data for products 3 5, 7, 8, 9, and 10 including 1H- and 13C-NMR spectroscopies, are available online. CCDC 2260879 and 2260880 contain supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033.

Author Contributions

Conceptualization, X.H. and Q.Y.; methodology, H.W. and T.Z.; formal analysis, T.Z.; data curation, H.W. and M.W.; writing—original draft preparation, H.W. and Q.Y.; writing—review and editing, X.H. and Q.Y.; supervision, Q.Y. and X.H.; project administration, X.H. All authors have read and agreed to the published version of the manuscript.

Funding

We thank the Natural Scientific Research Foundations of Anhui Provincial Universities (2022AH050210), the Excellent Scientific Research and Innovation Team of Anhui Provincial Universities (No. 2022AH010011), the University Synergy Innovation Program of Anhui Province (No. GXXT-2020-074), and the Excellent Young Talents Support Program of the Education Administration of Anhui Province (No. gxyq2022233) for financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 28 04416 sch001 550
Scheme 1. Substituent-controllable cascade strategy for the synthesis of trisubstituted imidazoles and pyrroles.
Scheme 1. Substituent-controllable cascade strategy for the synthesis of trisubstituted imidazoles and pyrroles.
Molecules 28 04416 sch001
Molecules 28 04416 sch002 550
Scheme 2. Substrate scope of N-sulfonyl-1,2,3-triazoles and β-enaminones for the synthesis of trisubstituted imidazoles. Reaction conditions: N-sulfonyl-1,2,3-triazoles 1 (0.2 mmol), β-enaminones 2 (0.2 mmol), and Rh2(oct)4 (2 mol%) in PhCl (2 mL) at 90 °C for 12 h under an argon atmosphere. Isolated yields were reported.
Scheme 2. Substrate scope of N-sulfonyl-1,2,3-triazoles and β-enaminones for the synthesis of trisubstituted imidazoles. Reaction conditions: N-sulfonyl-1,2,3-triazoles 1 (0.2 mmol), β-enaminones 2 (0.2 mmol), and Rh2(oct)4 (2 mol%) in PhCl (2 mL) at 90 °C for 12 h under an argon atmosphere. Isolated yields were reported.
Molecules 28 04416 sch002
Molecules 28 04416 sch003 550
Scheme 3. Substrate scope of N-sulfonyl-1,2,3-triazoles and β-enaminones for the synthesis of trisubstituted pyrroles. Reaction conditions: N-sulfonyl-1,2,3-triazoles 1 (0.2 mmol), β-enaminones 2 (0.2 mmol), and Rh2(oct)4 (2 mol%) in PhCl (2 mL) at 90 °C for 12 h under an argon atmosphere. Isolated yields were reported.
Scheme 3. Substrate scope of N-sulfonyl-1,2,3-triazoles and β-enaminones for the synthesis of trisubstituted pyrroles. Reaction conditions: N-sulfonyl-1,2,3-triazoles 1 (0.2 mmol), β-enaminones 2 (0.2 mmol), and Rh2(oct)4 (2 mol%) in PhCl (2 mL) at 90 °C for 12 h under an argon atmosphere. Isolated yields were reported.
Molecules 28 04416 sch003
Molecules 28 04416 sch004 550
Scheme 4. Further studies.
Scheme 4. Further studies.
Molecules 28 04416 sch004
Molecules 28 04416 sch005 550
Scheme 5. Gram-scale synthesis and further synthetic transformations.
Scheme 5. Gram-scale synthesis and further synthetic transformations.
Molecules 28 04416 sch005
Molecules 28 04416 sch006 550
Scheme 6. Proposed mechanism for the formation of trisubstituted imidazoles and pyrroles.
Scheme 6. Proposed mechanism for the formation of trisubstituted imidazoles and pyrroles.
Molecules 28 04416 sch006
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 28 04416 i001
EntryCatalyst (x mol%)SolventYield (%) b
1Rh2(OAc)4 (4)DCM56
2Rh2(oct)4 (4)DCM58
3CuI (4)DCM44
4Sc(OTf)3 (4)DCMtrace
5Co2(CO)8 (4)DCMnr
6Ni(acac)2 (4)DCMnr
7Rh2(oct)4 (3)DCM73
8Rh2(oct)4 (2)DCM79
9Rh2(oct)4 (1)DCM41
10/DCMnr
11Rh2(oct)4 (2)DCE55
12Rh2(oct)4 (2)toluene84
13Rh2(oct)4 (2)PhCl96
14Rh2(oct)4 (2)CH3OHtrace
15Rh2(oct)4 (2)CH3NO2trace
16Rh2(oct)4 (2)DMFnr
17 cRh2(oct)4 (2)PhClnr
18 dRh2(oct)4 (2)PhCl87
19 eRh2(oct)4 (2)PhCl94
20 fRh2(oct)4 (2)PhCl56
21 gRh2(oct)4 (2)PhCl78
22 hRh2(oct)4 (2)PhCl96
a Reaction conditions: 4-phenyl-1-tosyl-1H-1,2,3-triazole 1a (0.2 mmol), 3-amino-1-phenylbut-2-en-1-one 2a (0.2 mmol), and catalyst in solvent (2 mL) at 90 °C for 12 h under an argon atmosphere. b Isolated yields. c At 60 °C. d At 80 °C. e At 100 °C. f For 2 h. g For 6 h. h For 18 h. nr = no reaction.
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Wang, H.; Zhou, T.; Wu, M.; Ye, Q.; He, X. Substituent-Controllable Cascade Regioselective Annulation of β-Enaminones with N-Sulfonyl Triazoles for Modular Access to Imidazoles and Pyrroles. Molecules 2023, 28, 4416. https://doi.org/10.3390/molecules28114416

AMA Style

Wang H, Zhou T, Wu M, Ye Q, He X. Substituent-Controllable Cascade Regioselective Annulation of β-Enaminones with N-Sulfonyl Triazoles for Modular Access to Imidazoles and Pyrroles. Molecules. 2023; 28(11):4416. https://doi.org/10.3390/molecules28114416

Chicago/Turabian Style

Wang, Hua, Tongtong Zhou, Mengdi Wu, Qingqing Ye, and Xinwei He. 2023. "Substituent-Controllable Cascade Regioselective Annulation of β-Enaminones with N-Sulfonyl Triazoles for Modular Access to Imidazoles and Pyrroles" Molecules 28, no. 11: 4416. https://doi.org/10.3390/molecules28114416

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