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

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.


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.
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 R 1 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 metaand 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. 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][12][13][14][15][16]. A further variation of reaction temperatures revealed that 80 °C was the optimal condition (Table 1, entries [17][18][19]. The reaction time extension did not benefit the product yield (Table 1, entries [20][21][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 R 1 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 metalcatalyzed 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. 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).
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 Rh 2 (oct) 4 (2 mol%) in PhCl (2 mL) at 90 • C for 12 h under an argon atmosphere. Isolated yields were reported. Based on the above results, we hypothesize that the reaction of N-sulfonyl-1,2,3triazoles 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).
Molecules 2023, 28 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 Nmethylpyrrole 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.  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. 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 Nmethylpyrrole 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. 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 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.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 16 nucleophilic addition and elimination processes, the corresponding product 5a was obtained.

Scheme 6.
Proposed mechanism for the formation of trisubstituted imidazoles and pyrroles.

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 1 H and 125 MHz for 13 C) 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: 1 H NMR and 13 C NMR). HRMS spectra were obtained with an Agilent 6200 using a quadrupole time-offlight 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).

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 hours. 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. Scheme 6. Proposed mechanism for the formation of trisubstituted imidazoles and pyrroles.

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 1 H and 125 MHz for 13 C) with CDCl 3 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: 1 H NMR and 13 C 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).

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 Rh 2 (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 CH 2 Cl 2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na 2 SO 4 , 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.

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 CH 2 Cl 2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na 2 SO 4 , 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.

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 Na 2 SO 4 , 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.

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 Na 2 SO 4 , filtrated and concentrated, and purified by column chromatography to afford 10 in 95% yield.  +   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.