Synthesis of Polysubstituted Pyrroles through a Formal [4 + 1

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Synthesis of Polysubstituted Pyrroles through a Formal [4 + 1] Cycloaddition/E1cb Elimination/Aromatization Sequence of Sulfur Ylides and α,β-Unsaturated Imines Bei-Yi Cheng,† Ya-Ni Wang,† Tian-Ren Li,† Liang-Qiu Lu,*,† and Wen-Jing Xiao*,†,‡ †

Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China ‡ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China S Supporting Information *

ABSTRACT: A reaction sequence comprising a formal [4 + 1] cycloaddition, an E1cb elimination, and an aromatization process is described in this work. By doing so, polysubstituted pyrroles were achieved from easily available chemicals, sulfur ylides, and α,β-unsaturated imines. This protocol features mild conditions, high efficiency, and wide substrate scopes.

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stable and easily available sulfur ylides,10 herein we plan to develop a novel and efficient approach to polysubstituted pyrroles through a sequential reactions of sulfur ylides and 2ester-substituted α,β-unsaturated imines.11 As illustrated in Scheme 1, we propose that sulfur ylides could first participate in a formal [4 + 1] cycloaddition (a Michael addition/intramolecular N-substitution sequence). The afforded pyrroline intermediates would proceed through a base-promoted E1cb elimination/aromatization sequence to give the final polysubstituted pyrrole.

INTRODUCTION Polysubstituted pyrroles form a significant family of Ncontaining five-membered heterocycles, which are widespread in natural products, functional materials, and pharmaceuticals.1 Numerous attention has been attracted from chemists along with many strategies in the construction of pyrrole framework.2 Among them, transition-metal-catalyzed or -mediated formal [4 + 1] cycloadditions have been well developed with the purpose of pyrrole synthesis.3 For example, Iwasawa and co-workers used a rhodium(I) catalyst to realize a formal [4 + 1] cycloaddition of β-TMS-substituted α,β-unsaturated imines with terminal alkynes (TMS: trimethylsilyl).4 Danks’ group reported a formal [4 + 1] cycloaddition for pyrrole synthesis with α,β-unsaturated imines and prepared chromium carbenes as feedstocks.5 Despite these significant advancements, invention of efficient and practical methods that avoid metal catalyst or reagent are still highly desirable for the synthesis of functionalized pyrroles. Sulfur ylides are known as a family of versatile reagents that are extensively used in the heterocycle synthesis.6 Beyond their application in the classic Johnson−Corey−Chaykovsky reaction,7 sulfur ylides have already demonstrated their powerful capacities as C1 synthons for constructing structurally diverse carbo- and heterocyclic systems.8 For example, in 2008 the group of Tang reported a formal [4 + 1] cycloaddition of αylidene-β-diketones and sulfur ylides, affording enantioenriched dihydrofurans in good reaction efficiency and stereocontrol.9c After this significant work, many formal [4 + 1] cycloaddition reactions were developed by Tang, Zhou, Huang as well as many other groups9 and ours.10 In 2012, we disclosed a formal [4 + 1] cycloaddition of stabilized sulfur ylides with 1-estersubstituted α,β-unsaturated imines, producing polysubstituted pyrrolines in generally good yields and enantioselectivities.10f In the theme of divergent synthesis of heterocycles using bench© 2017 American Chemical Society

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RESULTS

To examine the above idea, we initially performed the sequential reaction with stabilized sulfur ylide 1a and α,βunsaturated imine 2a as model substrates in CHCl3 with Cs2CO3 as base (Table 1, entry 1). Gratifyingly, the designed scenario did occur and the desired product 3aa was isolated in 20% yield. Then solvent effects were examined to improve the reaction efficiency (Table 1, entries 1−4). The protic solvent MeOH was proven better than other solvents such as CHCl3 and xylenes (entries 1−3). Replacing MeOH with CF3CH2OH further improved the reaction efficiency and product 3aa was isolated in 84% yield (Table 1, entry 4). Subsequently, a variety of bases were screened in order to increase the efficiency of E1cb elimination step (Table 1, entries 5−9). Inorganic bases tBuONa, tBuOK and CH3CH2ONa gave comparable results (Table 1, entries 7−9, 92−94% yields) but other bases, such as TMG and tBuOLi, gave inferior results (Table 1, entries 5−6). Furthermore, the ratio of 1a to 2a was examined. Using a lightly excess of sulfur ylide 1a gave the product 3aa in best yield. The Received: August 1, 2017 Published: October 31, 2017 12134

DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140

Article

The Journal of Organic Chemistry Scheme 1. Reaction Design

Table 1. Optimization of Reaction Conditionsa

entry

equiv (1a:2a)

solvent

base

yield (%)b

1 2 3 4 5 6 7 8 9 10 11

1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1:1 1.5:1

CHCl3 xylenes CH3OH CF3CH2OH CF3CH2OH CF3CH2OH CF3CH2OH CF3CH2OH CF3CH2OH CF3CH2OH CF3CH2OH

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 TMG tBuOLi tBuONa tBuOK CH3CH2ONa CH3CH2ONa CH3CH2ONa

20 16 66 84 61 71 92 92 94 82 94

amenable to this transformation pyrrole 3sa was produced in 70% yield. To demonstrate the praticality of reaciton methodology, a gram-scale experiment with substrates 1b and 2a were performed and pyrrole 3ba was achieved in a comparable reaction yield (eq 1). A limitation of this protocol is that active and semistable sulfur ylides failed to participate in this sequential reaction at current stage.

Following, we turned our attention to exploring the scope of α,β-unsaturated imines in this sequential reaction. As highlighted in Table 3, variations of electronic character and substitution position on the benzene ring of α,β-unsaturated imines were tolerated. Correspondingly, a series of structurally varied pyrrole products 3ab−3ag were obtained in moderate to good efficiency (57−89% yields). Additionally, the substrate scope could be expanded to heteroaryl substituted α,βunsaturated imines. Substrates bearing 2-furanyl and 2-thienyl groups were converted to products 3ah and 3ai in 98% and 81% yield, respectively. Moreover, variation of the ester group did not affect the reactivity very much, even the sterically hindered tert-butyl ester. Products 3aj-3al with benzyl, tertbutyl and ethyl ester functional groups were obtained in good to excellent yields (78−98% yields). However, when α,βunsaturated imines with alphatic groups (i.e., 2m: R2 = Me, R3 = tBu) were subjected the standard conditions, no reaction occurs with both sulfur ylide 1a and imine 2m untoched.

a

Reaction conditions: 1a (0.24−0.30 mmol), 2a (0.2 mmol), base (1.2 mmol), solvent (2.0 mL), Ar, 10 h, rt to 40 °C. bIsolated yield. TMG = 1,1,3,3-Tetramethylguanidine. rt: room temperature. Ts: 4-Methylbenzenesulfonyl.

use of 6.0 equiv of CH3CH2ONa was found necessary to maintain the reaction efficiency (see Table 1). Having determined the optimized reaction conditions, we started to probe the generality of present sequential reaction. With respect to sulfur ylide, generally good to excellent reaction efficiencies were observed and these results are summarized in Table 2. For example, a variety of sulfur ylides with electrondonating groups (i.e., Me and MeO) at the para-position of the benzene ring showed good reactivity and the corresponding products 3ba and 3ca were obtained in 97% yield and 85% yield, respectively. Sulfur ylides bearing electron-withdrawing groups (i.e., NO2, CN) and halogen groups (i.e., F, Cl and Br) were transformed into products 3da−3ha in 71−97% yields. The variation of the substituted position on the aromatic ring of sulfur ylides was evaluated, producing pyrroles 3ia−3ka in 62− 93% yields. Furthermore, the reactions performed with heteroaryl- and 2-naphthyl-substituted sulfur ylides proceeded well under the standard conditions, affording products 3ia−3na in 62−94% yields. Notably, the success of this sequential reaction could be significantly extended to aliphatic acyl sulfur ylides. For example, acyl sulfur ylides with isobutyl, isopropyl, cyclopropyl and cyclohexyl groups were well-tolerated and the corresponding products 3oa−3ra were delivered in 52−98% yields. Notably, an ethyl ester-substituted sulfur ylide was also

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CONCLUSION In conclusion, a sequential reaction of stabilized sulfur ylides and α,β-unsaturated imines has been developed. This protocol allows the synthesis of polysubstituted pyrroles in generally good to excellent yields. The features of simple operation, mild and metal-free conditions, and readily available feedstock will attract the research interests from synthetic chemists and pharmacologists.

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EXPERIMENTAL SECTION

General Information. Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. All the solvents were treated according to general methods. Flash column chromatography was performed using 200− 300 mesh silica gel. 1H NMR spectra were recorded on 400/600 MHz 12135

DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140

Article

The Journal of Organic Chemistry Table 2. Synthesis of Pyrroles from Various Sulfur Ylidesa,b

a

Unless noted otherwise, reactions were performed under the condition as described in Table 1, entry 9 at 0.4 mmol scale. bIsolated yield. cRection conditions: 1s (0.24 mmol), 2a (0.2 mmol), CHCl3 (2.0 mL), Ar, 13 h, rt; then Cs2CO3 (1.2 mmol), toluene (2.0 mL), 80 °C. equiv) was added into the reaction mixture. After heated to 40 °C, the reaction was allowed to further stir at this temperature for t2 (8−18 h). The solvent was removed under vacuum and the crude product was purified by column chromatography on silicon gel (petroleum ether/ ethyl acetate = 12:1) to give the pure product 3. The diastereomer ratio was determined by 1H NMR analysis of the reaction mixture. General Procedure for 2-Ethyl-4-methyl-5-phenyl-1H-pyrrole-2,4-dicarboxylate Synthesis. Sulfur ylide 1s (0.24 mmol) and unsaturated imine 2a (0.2 mmol), were dissolved in CHCl3 (2.0 mL). Then, the resulting mixture was stirred under argon atmosphere and the solution was stirred for 5 h at room temperature, Then, removed CHCl3 and the system was dissolved in toluene (2 mL) and then CsCO3 (1.2 mmol) was added in the system and stirred for 14 h in 80 °C. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 12:1) directly to give the desired product 3sa in 70% yield.

spectrophotometers. Chemical shifts are reported in delta (δ) units in parts per million (ppm) relative to the singlet (0 ppm) for tetramethylsilane (TMS). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet), coupling constants (Hz) and integration. 13C NMR spectra were recorded on Varian Mercury 400 (100 MHz) with complete proton decoupling spectrophotometers (CDCl3: 77.0 ppm or DMSO: 39.0 ppm). HRMS was recorded on Bruker ultrafleXtreme MALDITOF/TOF mass spectrometer. Sulfur ylide 1 and unsaturated imine 2 are known compounds which were parepared according previous methods.10b−f,11g General Procedure for Polysubstituted Pyrroles Synthesis. Sulfur ylide 1 (0.48 mmol, 1.2 equiv) and unsaturated imine 2 (0.4 mmol, 1.0 equiv) were dissolved into CF3CH2OH (4 mL) in a 15 mL Schlenk flask. The resulting mixture was stirred under room temperature until substrate 2 completely disappeared (monitored by TLC, t1 = 10 min to 5 h). After that, CH3CH2ONa (2.4 mmol, 6.0 12136

DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140

Article

The Journal of Organic Chemistry Table 3. Synthesis of Pyrroles from Various α,β-Unsaturated Iminesa,b

a

Unless noted otherwise, reactions were performed under the condition as described in Table 1, entry 9 at 0.4 mmol scale. bIsolated yield. Methyl-5-(4-nitrobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3da). Reaction time = 20 min + 15 h, 99 mg, yield: 71%; yellow solid, mp 258−260 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.95 (s, 1 H), 8.38 (d, J = 8.1 Hz, 2 H), 8.04 (d, J = 8.1 Hz, 2 H), 7.70 (s, 2 H), 7.49 (s, 3 H), 7.37 (s, 1 H), 3.78 (s, 3 H). 13C NMR (100 MHz, DMSO) δ (ppm) 182.0, 163.0, 148.8, 143.1, 142.7, 129.4, 129.4, 129.4, 129.3, 128.6, 127.2, 123.3, 122.3, 113.0, 50.6. IR (in KBr) 3261, 1637, 1386, 840, 780 cm−1. HRMS (ESI) calcd for C19H15N2O5 [M + H]+: 351.0975, found 351.0965. Methyl-5-(4-cyanobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ea). Reaction time = 20 min + 15 h, 123 mg, yield: 93%; yellow solid, mp 265−267 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.20 (s, 1 H), 7.94 (d, J = 7.8 Hz, 2 H), 7.81 (d, J = 7.9 Hz, 2 H), 7.69 (d, J = 6.8 Hz, 2 H), 7.47 (d, J = 7.1 Hz, 3 H), 7.36 (s, 1 H), 3.78 (s, 3 H). 13 C NMR (100 MHz, DMSO) δ (ppm) 182.3, 163.0, 143.0, 141.2, 132.2, 129.4, 129.4, 129.2, 128.7, 128.6, 127.2, 122.1, 117.8, 113.7, 113.0, 50.6. IR (in KBr) 3301, 1629, 1386, 779 cm−1. HRMS (ESI) calcd for C20H14N2NaO3 [M + Na]+: 353.0897, found 353.0892. Methyl-5-(4-fluorobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3fa). Reaction time = 2 h + 13 h, 125 mg, yield: 97%; white solid, mp 216−217 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.01 (s, 1 H), 7.98−7.90 (m, 2 H), 7.69 (dd, J = 6.6, 2.9 Hz, 2 H), 7.51−7.45 (m, 3 H), 7.37 (d, J = 2.7 Hz, 1 H), 7.20 (t, J = 8.6 Hz, 2 H), 3.78 (s, 3 H). 13 C NMR (100 MHz, CDCl3) δ (ppm) 183.4, 165.4 (d, J = 252.0 Hz), 164.3, 142.9, 133.6 (d, J = 3.1 Hz), 131.6 (d, J = 9.1 Hz), 130.3, 129.7, 129.4, 128.8 (d, J = 111.2 Hz), 126.4, 122.2, 115.6 (d, J = 21.8 Hz), 114.4, 51.3. 19F NMR (376 MHz, CDCl3) δ (ppm) −106.40. IR (in KBr) 3267, 1629, 1388, 781, 548 cm−1. HRMS (ESI) calcd for C19H14FNNaO3 [M + Na]+: 346.0850, found 346.0841. Methyl-5-(4-chlorobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ga). Reaction time = 20 min + 11 h, 129 mg, yield: 95%; white solid,

All the unsaturated imines and sulfur ylides were prepared according to the known procedure. Methyl-5-benzoyl-2-phenyl-1H-pyrrole-3-carboxylate (3aa). Reaction time = 10 min + 10 h, 115 mg, yield: 94%; white solid, mp 188−190 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.87 (s, 1 H), 7.85 (d, J = 8.1 Hz, 2 H), 7.75−7.71 (m, 2 H), 7.62 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.44 (dd, J = 7.5, 2.4 Hz, 4 H), 3.79 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 184.9, 164.4, 142.8, 137.4, 132.4, 130.4, 129.9, 129.3, 129.3, 129.0, 128.4, 128.2, 122.3, 114.2, 51.3. IR (in KBr) 3255, 1719, 1618, 761 cm−1. HRMS (ESI) calcd for C19H16NO3 [M + H]+: 306.1125, found 306.1124. Methyl-5-(4-methylbenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ba). Reaction time = 20 min + 11 h, 114 mg, yield: 85%; white solid, mp 215−218 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.80 (s, 1 H), 7.84 (d, J = 7.4 Hz, 2 H), 7.68 (s, 2 H), 7.47 (d, J = 6.8 Hz, 3 H), 7.39 (s, 1 H), 7.33 (d, J = 7.5 Hz, 2 H), 3.78 (s, 3 H), 2.46 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 184.7, 164.4, 143.1, 142.6, 134.7, 130.4, 130.0, 129.3, 129.2, 129.1, 128.1, 122.0, 114.1, 51.2, 21.6. IR (in KBr) 3293, 1697, 1601, 1388, 763 cm−1. HRMS (ESI) calcd for C20H18NO3 [M + H]+: 320.1281, found 320.1274. Methyl-5-(4-methoxybenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ca). Reaction time = 20 min + 11 h, 114 mg, yield: 71%; white solid, mp 215−216 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.96 (s, 1 H), 7.94 (d, J = 8.6 Hz, 2 H), 7.73−7.65 (m, 2 H), 7.46 (dd, J = 5.2, 2.0 Hz, 3 H), 7.39 (d, J = 2.6 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 2 H), 3.91 (s, 3 H), 3.78 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 183.5, 164.5, 163.2, 142.1, 131.3, 130.5, 130.0, 130.0, 129.3, 129.2, 128.2, 121.3, 114.0, 113.8, 55.5, 51.3. IR (in KBr) 3290, 1628, 1388, 762 cm−1. HRMS (ESI) calcd for C20H18NO4 [M + H]+: 336.1230, found 336.1220. 12137

DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140

Article

The Journal of Organic Chemistry mp 234−236 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.37 (s, 1 H), 7.80 (d, J = 7.9, 2 H), 7.68 (d, J = 6.5, 2 H), 7.46 (m, 5 H), 7.40− 7.35 (m, 1 H), 3.77 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 183.4, 164.2, 142.8, 138.8, 135.7, 130.4, 130.3, 129.6, 129.5, 129.2, 128.9, 128.3, 122.0, 114.4, 51.4. IR (in KBr) 3262, 1695, 1623, 1389, 770, 584 cm−1. HRMS (ESI) calcd for C19H15ClNO3 [M + H]+: 340.0735, found 340.0730. Methyl-5-(4-bromobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ha). Reaction time = 20 min + 11 h, 131 mg, yield: 85%; white solid, mp 114−116 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.02 (s, 1 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.70−7.64 (m, 4 H), 7.47 (t, J = 3.3 Hz, 3 H), 7.37 (d, J = 2.6 Hz, 1 H), 3.78 (s, 3 H). 13C NMR (100 MHz, DMSO) δ (ppm) 182.4, 163.1, 142.4, 136.3, 131.2, 130.1, 129.5, 129.4, 129.3, 128.4, 127.1, 125.5, 121.3, 112.7, 50.5. IR (in KBr) 3277, 1627, 1387, 782 cm−1. HRMS (ESI) calcd for C19H15BrNO3 [M + H]+: 384.0230, found 384.0226. Methyl-5-(3-bromobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ia). Reaction time = 2 h + 8 h, 131 mg, yield: 85%; white solid, mp 200−202 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.11 (s, 1 H), 7.99 (s, 1 H), 7.82 (d, J = 7.7 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H,), 7.69 (m, 2 H), 7.51−7.43 (m, 3 H), 7.39 (d, J = 9.4 Hz, 2 H), 3.78 (s, 3 H). 13 C NMR (100 MHz, CDCl3) δ (ppm) 183.2, 164.2, 143.2, 139.2, 135.3, 131.8, 130.2, 130.0, 129.7, 129.4, 129.2, 128.3, 127.6, 122.8, 122.5, 114.5, 51.4. IR (in KBr) 3274, 1629, 1387, 1104, 687 cm−1. HRMS (ESI) calcd for C19H14BrNNaO3 [M + Na]+: 406.0049, found 406.0039. Methyl-5-(2-fluorobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ja). Reaction time = 2 h + 13 h, 120 mg, yield: 93%; white solid, mp 224−227 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.69 (s, 1 H), 7.71−7.67 (m, 2 H), 7.64 (t, J = 6.9 Hz, 1 H,), 7.55 (q, J = 7.3 Hz, 1 H), 7.50−7.45 (m, 3 H), 7.31−7.27 (m, 2 H), 7.22 (t, J = 9.4, 1 H), 3.76 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 181.5, 164.2, 159.8 (d, J = 253.3), 143.0, 130.4 (d, J = 2.8), 130.4 (d, J = 36), 133.0 (d, J = 8.2), 129.7, 129.6, 129.1, 128.3, 126.3 (d, J = 31.3) 124.1 (d, J = 3.7), 122.8 (d, J = 3.4), 116.5 (d, J = 21.8), 114.5, 51.3. 19F NMR (376 MHz, CDCl3) δ(ppm) −113.15. IR (in KBr) 3291, 2310, 1631, 1387, 789 cm−1. HRMS (ESI) calcd for C19H14FNNaO3 [M + Na]+: 346.0850, found 346.0842. Methyl-5-(2,4-dichlorobenzoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ka). Reaction time = 2 h + 10 h, 93 mg, yield: 62%; white solid, mp 261−263 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.63 (s, 1 H), 7.68 (d, J = 5.5 Hz, 2 H), 7.53 (s, 1 H), 7.51−7.44 (m, 4 H), 7.38 (d, J = 8.2 Hz, 1 H), 7.08 (s, 1 H), 3.75 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 182.2, 164.0, 148.2, 144.0, 138.7, 134.6, 129.9, 129.7, 129.3, 129.1, 128.2, 126.6, 123.8, 123.0, 114.9, 51.4, 14.3 IR (in KBr) 3244, 1636, 1387, 780, 616 cm−1 . HRMS (ESI) calcd for C19H14Cl2NO3 [M + H]+: 374.0345, found 374.0338. Methyl-2-phenyl-5-(thiophene-2-carbonyl)-1H-pyrrole-3-carboxylate (3la). Reaction time = 20 min + 11 h, 96 mg, yield: 77%; white solid, mp 143−145 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.68 (s, 1 H), 7.99 (d, J = 3.8 Hz, 1 H,), 7.71 (d, J = 5.0 Hz, 1 H,), 7.68 (d, J = 6.7 Hz, 2 H,), 7.65 (d, J = 2.8 Hz, 1 H,), 7.48 (d, J = 6.9 Hz, 3 H,), 7.22 (t, J = 4.4 Hz, 1 H,), 3.80 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 175.7, 164.3, 142.6, 141.8, 133.1, 132.7, 130.3, 129.5, 129.3, 129.2, 128.2, 128.0, 120.4, 114.2, 51.3. IR (in KBr) 3267, 1629, 1388, 781, 548 cm−1. HRMS (ESI) calcd for C17H14NO3S [M + H]+: 312.0689, found 312.0681. Methyl-5-(furan-2-carbonyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ma). Reaction time = 2 h + 13 h, 105 mg, yield: 89%; white solid, mp 191−193 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 9.84 (s, 1 H), 7.93 (d, J = 2.6 Hz, 1 H), 7.75 (s, 1 H), 7.74−7.70 (m, 2 H), 7.50 (dd, J = 5.2, 2.0 Hz, 3 H,), 7.42 (d, J = 3.6 Hz, 1 H,), 6.66 (dd, J = 3.6, 1.7 Hz, 1 H,), 3.85 (s, 3 H). 13C NMR (100 MHz, DMSO) δ (ppm) 169.3, 163.2, 151.3, 147.1, 141.9, 129.6, 129.4, 128.7, 128.3, 127.1, 119.7, 117.8, 112.9, 112.1, 50.5. IR (in KBr) 3293, 1600, 1412, 782, 584 cm−1. HRMS (ESI) calcd for C17H13NNaO4 [M + Na]+: 318.0737, found 318.0732. Methyl-5-(2-naphthoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3na). Reaction time = 2 h + 13 h, 134 mg, yield: 94%; white solid, mp 220−222 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.34 (s, 1 H),

8.44 (s, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 1 H), 7.94−7.88 (m, 2 H), 7.75−7.70 (m, 2 H), 7.61 (dt, J = 21.1, 7.2 Hz, 2 H), 7.47 (dd, J = 16.7, 3.8 Hz, 4 H), 3.78 (s, 3 H). 13C NMR (100 MHz, DMSO) δ (ppm) 183.6, 163.2, 142.2, 134.7, 134.1, 131.5, 129.8, 129.7, 129.6, 129.4, 129.1, 128.9, 128.4, 127.8, 127.7, 127.2, 126.5, 124.5, 121.4, 112.7, 50.5. IR (in KBr) 3281, 1634, 1376, 992, 752 cm−1. HRMS (ESI) calcd for C23H17NNaO3 [M + Na]+: 378.1101, found 378.1097. Methyl-5-(3-methylbutanoyl)-2-phenyl-1H-pyrrole-3-carboxylate (3oa). Reaction time = 3 h + 12 h, 112 mg, yield: 98%; white solid, mp 141−143 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.75 (s, 1 H), 7.68−7.60 (m, 2 H), 7.49−7.41 (m, 3 H), 7.39 (d, J = 2.7 Hz, 1 H), 3.77 (s, 3 H), 2.64 (d, J = 7.2 Hz, 2 H), 2.22 (dt, J = 13.5, 6.7 Hz, 1 H), 0.97 (d, J = 6.7 Hz, 6 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 191.3, 164.4, 142.3, 131.4, 130.5, 129.3, 129.2, 128.0, 119.5, 113.8, 51.3, 46.8, 25.9, 22.7. IR (in KBr) 3280, 1642, 1372, 767 cm−1. HRMS (ESI) calcd for C17H20NO3 [M + H]+: 286.1438, found 286.1433. Methyl-5-isobutyryl-2-phenyl-1H-pyrrole-3-carboxylate (3pa). Reaction time = 1 h + 12 h, 56 mg, yield: 52%; white solid, mp 171−173 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.61 (s, 1 H), 7.63 (d, J = 6.0 Hz, 2 H), 7.45 (d, J = 6.6 Hz, 3 H), 7.43 (d, J = 3.0 Hz, 1 H,), 3.78 (s, 3 H), 3.31 (1 H, p, J = 6.9), 1.22 (6 H, d, J = 6.9). 13C NMR (100 MHz, CDCl3) δ (ppm) 195.5, 164.4, 142.2, 130.5, 129.8, 129.2, 128.1, 118.9, 118.9, 113.8, 51.2, 35.7, 19.4. IR (in KBr) 3249, 2980, 1633, 1374, 696 cm−1. HRMS (ESI) calcd for C16H18NO3 [M + H]+: 272.1281, found 272.1275. Methyl-5-(cyclopropanecarbonyl)-2-phenyl-1H-pyrrole-3-carboxylate (3qa). Reaction time = 1 h + 12 h, 75 mg, yield: 70%; white solid, mp 163−164 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.58 (1 H), 7.62 (dd, J = 6.8, 2.8 Hz, 2 H), 7.56 (d, J = 2.6, 1 H), 7.48−7.37 (m, 3 H), 3.77 (s, 3 H), 2.47−2.39 (m, 1 H), 1.01−0.89 (m, 4 H) 13C NMR (100 MHz, CDCl3) δ (ppm) 191.0, 164.5, 142.2, 131.4, 130.6, 129.4, 129.1, 128.0, 119.4, 113.9, 51.2, 17.1, 11.1. IR (in KBr) 3253, 1629, 1387, 764 cm−1. HRMS (ESI) calcd for C16H16NO3 [M + H]+: 270.1125, found 270.1119. Methyl-5-(cyclohexanecarbonyl)-2-phenyl-1H-pyrrole-3-carboxylate (3ra). Reaction time = 1 h + 12 h, 92 mg, yield: 74%; white solid, mp 171−173 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.84 (s, 1 H), 7.63 (d, J = 5.7 Hz, 2 H), 7.50−7.37 (m, 4 H), 3.78 (s, 3 H), 3.01 (t, J = 11.6 Hz, 1 H,), 1.83 (d, J = 11.3 Hz, 4 H), 1.73 (d, J = 13.5 Hz, 1 H), 1.45 (q, J = 12.7 Hz, 2 H,), 1.40−1.33 (m, 2 H), 1.24 (q, J = 13.0 Hz, 1 H,). 13C NMR (100 MHz, CDCl3) δ (ppm) 194.8, 164.4, 142.2, 130.6, 130.0, 129.2, 129.2, 128.2, 118.7, 113.7, 51.2, 46.0, 29.5, 25.7, 25.7. IR (in KBr) 3253, 1635,1421, 1387, 780 cm−1. HRMS (ESI) calcd for C19H22NO3 [M + H]+: 312.1594, found 312.1598. 2-Ethyl-4-methyl 5-phenyl-1H-pyrrole-2,4-dicarboxylate (3sa). Reaction time = 1 h + 12 h, 77 mg, yield: 70%; white solid, mp 159−161 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.35 (1 H, s), 7.63 (2 H, d, J = 7.1), 7.45 (3 H, q, J = 7.3), 7.40 (1 H, d, J = 2.7), 4.32 (2 H, q, J = 7.0), 3.77 (3 H, s), 1.41−1.33 (3 H, m). 13C NMR (100 MHz, CDCl3) δ (ppm) 64.5, 161.2, 141.0, 130.8, 129.3, 129.1, 128.1, 122.3, 118.4, 113.7, 60.9, 51.2, 14.3. IR (in KBr) 3302, 1701, 1678, 1387, 770 cm−1. HRMS (ESI) calcd for C15H16NO4 [M + H]+: 274.1074, found 274.1073. Methyl-5-benzoyl-2-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (3ab). Reaction time = 1 h + 18 h, 93 mg, yield: 72%; white solid, mp 228−230 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.03 (s, 1 H), 7.89 (d, J = 7.6 Hz, 2 H), 7.69 (dd, J = 8.6, 5.3 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.53 (t, J = 7.6 Hz, 2 H,), 7.39 (d, J = 2.8 Hz, 1 H), 7.15 (t, J = 8.5 Hz, 2 H), 3.78 (s, 3 H). 13C NMR (100 MHz, DMSO) δ (ppm) 183.6, 161.97 (d, J = 246.4), 163.1, 141.1, 137.3, 131.71 (d, J = 8.6), 129.6, 128.7, 128.07 (d, J = 3.7), 126.0, 125.99 (d, J = 3.2), 121.0, 114.05 (d, J = 21.6), 112.6, 50.5. 19F NMR (376 MHz, CDCl3) δ(ppm) −111.34. IR (in KBr) 3268, 1627, 1388, 781 cm−1. HRMS (ESI) calcd for C19H15FNO3 [M + H]+: 324.1030, found 324.1038. Methyl-5-benzoyl-2-(4-chlorophenyl)-1H-pyrrole-3-carboxylate (3ac). Reaction time = 2 h + 11 h, 84 mg, yield: 62%; white solid, mp 236−238 °C. 1H NMR (400 MHz, DMSO) δ (ppm) 12.88 (s, 1 H), 7.88 (d, J = 7.5 Hz, 2 H), 7.70 (d, J = 8.0 Hz, 3 H), 7.61 (t, J = 7.5 Hz, 2 H), 7.54 (d, J = 8.2 Hz, 2 H), 7.17 (s, 1 H), 3.69 (s, 3 H). 13C NMR 12138

DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140

Article

The Journal of Organic Chemistry

KBr) 3307, 1628, 1387, 780 cm−1. HRMS (ESI) calcd for C20H17NNaO3 [M + Na]+: 342.1101, found 342.1093. Benzyl-5-benzoyl-2-phenyl-1H-pyrrole-3-carboxylate (3ak). Reaction time = 1 h + 9 h, 150 mg, yield: 98%; white solid, mp197−199 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.76 (s, 1 H), 7.92 (d, J = 7.8 Hz, 2 H), 7.71−7.64 (m, 2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.49−7.38 (m, 4 H), 7.37−7.27 (m, 5 H), 5.25 (s, 2 H) 13 C NMR (100 MHz, CDCl3) δ (ppm) 184.9, 163.7, 142.8, 137.4, 136.1, 132.4, 130.5, 129.9, 129.3, 129.0, 128.5, 128.4, 128.2, 128.1, 128.0, 122.1, 114.4, 65.9. IR (in KBr) 3271, 1718, 1626, 1387, 781 cm−1. HRMS (ESI) calcd for C25H20NO3 [M + H]+: 382.1438, found 382.1443. tert-Butyl-5-benzoyl-2-phenyl-1H-pyrrole-3-carboxylate (3al). Reaction time = 1 h + 18 h, 108 mg, yield: 78%; white solid, mp200−202 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.71 (s, 1 H), 7.93 (d, J = 7.3 Hz, 2 H), 7.67−7.59 (m, 3 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.46 (d, J = 6.3 Hz, 3 H), 7.35 (d, J = 2.9 Hz, 1 H), 1.44 (s, 9 H). 13 C NMR (100 MHz, CDCl3) δ (ppm) 184.9, 163.4, 142.1, 137.5, 132.3, 131.0, 129.7, 129.4, 129.1, 129.1, 128.4, 128.1, 122.4, 116.6, 80.6, 28.2. IR (in KBr) 3269,1713, 1387, 778 cm−1. HRMS (ESI) calcd for C22H21NNaO3 [M + Na]+: 370.1414, found 370.1409. Methyl-5-benzoyl-2-phenyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-carboxylate (4aa). Reaction time = 10 min, 84 mg, yield: 91%; white solid, mp 151−153 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.03 (d, J = 8.0 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.59−7.50 (m, 2H), 7.32 (d, J = 8.6 Hz, 3H), 7.19 (d, J = 6.8 Hz, 4H), 7.10 (d, J = 8.0 Hz, 2H), 6.12 (dd, J = 12.3, 4.9 Hz, 1H), 3.44 (s, 3H), 3.44 (m, 1H) 2.87 (dd, J = 16.2, 4.9 Hz, 1H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 194.7, 164.4, 152.8, 144.1, 136.4, 133.9, 133.8, 130.1, 129.6, 129.3, 129.2, 129.0, 128.9, 128.1, 127.1, 111.8, 63.9, 51.2, 33.6, 21.6. IR (in KBr) 1637, 1346, 701, 623 cm−1. HRMS (ESI) calcd for C26H24NO5S [M + H]+: 462.1370, found 462.1358. Methyl (Z)-4,4-dimethyl-2-methylene-3-(tosylimino)pentanoate (2m). White solid, mp 94−95 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.81 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.55 (s, 1H), 5.68 (s, 1H), 3.81 (s, 3H), 2.43 (s, 3H), 1.18 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) 189.0, 163.3, 143.7, 137.6, 137.4, 129.4, 127.7, 127.4, 52.4, 42.5, 27.6, 21.6. IR (in KBr) 1603, 1325, 997, 742, 675 cm−1. HRMS (ESI) calcd for C16H22NO4S [M + H]+: 324.1264, found 324.1235.

(100 MHz, DMSO) δ (ppm) 183.6, 163.0, 140.7, 137.2, 133.2, 131.7, 131.2, 129.8, 128.4, 128.1, 128.0, 127.1, 121.0, 112.8, 50.5. IR (in KBr) 3267, 1696, 1337, 699 cm−1. HRMS (ESI) calcd for C19H14ClNNaO3 [M + Na]+: 362.0554, found 362.0546. Methyl-5-benzoyl-2-(4-bromophenyl)-1H-pyrrole-3-carboxylate (3ad). Reaction time = 20 min + 12 h, 88 mg, yield: 57%; white solid, mp 239−241 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.35 (s, 1 H), 7.85 (d, J = 7.6 Hz, 2 H), 7.63 (t, J = 7.3 Hz, 1 H), 7.58 (s, 4 H), 7.53 (t, J = 7.5 Hz, 2 H), 7.39 (d, J = 2.9, 1 H), 3.78 (s, 3 H). 13C NMR (100 MHz, DMSO) δ (ppm) 183.6, 163.0, 140.8, 137.2, 131.7, 131.4, 130.1, 129.8, 128.7, 128.1, 128.1, 122.0, 121.0, 112.8, 50.5. IR (in KBr) 3244, 1717, 1388, 786 cm−1. HRMS (ESI) calcd for C19H14BrNNaO3 [M + Na]+: 406.0049, found 406.0058. Methyl-5-benzoyl-2-(p-tolyl)-1H-pyrrole-3-carboxylate (3ae). Reaction time = 1 h + 18 h, 114 mg, yield: 89%; white solid, mp 203−205 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.93 (s, 1 H), 7.93−7.87 (2m, H), 7.63−7.57 (m, 3 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.38 (d, J = 2.6 Hz, 1 H), 7.27 (s, 1 H), 7.26 (s, 1 H), 3.77 (s, 3 H), 2.42 (s, 3 H) 13C NMR (100 MHz, CDCl3) δ (ppm) 184.8, 164.4, 143.0, 139.5, 137.5, 132.3, 129.8, 129.1, 129.1, 128.9, 128.4, 127.5, 122.3, 114.1, 51.2, 21.4. IR (in KBr) 3244, 1613, 1388, 786 cm−1. HRMS (ESI) calcd for C20H18NO3 [M + H]+: 320.1281, found 320.1279. Methyl-5-benzoyl-2-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (3af). Reaction time = 1 h + 18 h, 110 mg, yield: 82%; white solid, mp 235−237 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.93 (s, 1 H), 7.90 (d, J = 7.6 Hz, 2 H), 7.66 (d, J = 8.2 Hz, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 0.6, 2 H), 7.38 (d, J = 2.8 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 2 H,), 3.87 (s, 3 H), 3.78 (s, 3 H). 13C NMR (150 MHz, DMSO) δ (ppm) 184.4, 164.2, 160.4, 143.3, 138.5, 132.5, 131.8, 130.3, 129.1, 129.0, 122.8, 122.4, 113.6, 113.1, 55.7, 51.4. IR (in KBr) 3275, 1629, 1388, 780 cm−1. HRMS (ESI) calcd for C20H17NNaO4 [M + Na]+: 358.1050, found 358.1048. Methyl-5-benzoyl-2-(3-chlorophenyl)-1H-pyrrole-3-carboxylate (3ag). Reaction time = 20 min + 12 h, 84 mg, yield: 62%; white solid, mp 203−205 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.29 (s, 1 H), 7.88 (d, J = 7.6 Hz, 2 H), 7.70 (s, 1 H), 7.62 (t, J = 7.5 Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.40−7.36 (m, 2 H), 3.78 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 185.0, 164.1, 140.8, 137.3, 134.2, 132.6, 132.1, 130.2, 129.5, 129.4, 129.4, 129.1, 128.5, 127.6, 122.1, 114.8, 51.4. IR (in KBr) 3286, 1628, 1387, 624 cm−1. HRMS (ESI) calcd for C19H15ClNO3 [M + H]+: 340.0735, found 340.0736. Methyl-5-benzoyl-2-(furan-2-yl)-1H-pyrrole-3-carboxylate (3ah). Reaction time = 20 min + 12 h, 116 mg, yield: 98%; white solid, mp 169−171 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 10.03 (1 H, s), 7.92 (2 H, d, J = 7.6), 7.73 (1 H, s), 7.68−7.50 (4 H, m), 7.33 (1 H, s), 6.57 (1 H, s), 3.87 (3 H, s). 13C NMR (100 MHz, CDCl3) δ (ppm) 184.3, 163.9, 144.5, 143.1, 137.5, 132.3, 132.0, 129.3, 128.8, 128.5, 121.8, 114.1, 112.6, 112.5, 51.4. IR (in KBr) 3245, 1710, 1391, 793 cm−1. HRMS (ESI) calcd for C17H13NNaO4 [M + Na]+: 318.0737, found 318.0729. Methyl-5-benzoyl-2-(thiophen-2-yl)-1H-pyrrole-3-carboxylate (3ai). Reaction time = 2 h + 12 h, 101 mg, yield: 81%; white solid, mp 192−193 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.85 (s, 1 H), 7.92 (d, J = 7.7 Hz, 2 H), 7.78 (s, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 2 H), 7.48 (d, J = 5.2 Hz, 1 H), 7.37 (s, 1 H), 7.14 (t, J = 4.2 Hz, 1 H), 3.85 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 184.8, 164.2, 137.3, 135.9, 132.4, 131.1, 129.7, 129.4, 129.0, 128.5, 128.2, 127.3, 122.5, 114.0, 51.4. IR (in KBr) 3293, 1623, 1387, 778 cm−1. HRMS (ESI) calcd for C17H13NNaO3S [M + Na]+: 334.0508, found 334.0500. Ethyl-5-benzoyl-2-phenyl-1H-pyrrole-3-carboxylate (3aj). Reaction time = 1 h + 18 h, 115 mg, yield: 90%; white solid, mp 171− 173 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.93 (s, 1 H), 7.95− 7.88 (m, 2 H), 7.69 (dt, J = 5.5, 3.4 Hz, 2 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.46 (q, J = 3.3 Hz, 3 H), 7.40 (d, J = 2.9 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 185.0, 164.0, 142.8, 137.4, 132.3, 130.5, 129.9, 129.4, 129.2, 129.1, 128.4, 128.0, 122.4, 114.7, 60.1, 14.2. IR (in

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01931. Details for condition optimization, copies of 1H and 13 NMR spectra for all new compounds, and primary mechanism investigation (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Liang-Qiu Lu: 0000-0003-2177-4729 Wen-Jing Xiao: 0000-0002-9318-6021 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21472057, 21572074, 21772052, and 21772053), the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) and other 12139

DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140

Article

The Journal of Organic Chemistry

L.-P.; Zhang, P.-P.; Zhong, Y.; Wang, R. Angew. Chem., Int. Ed. 2013, 52, 11329. (f) Zhang, Q.-M.; Fang, T.; Tong, X.-F. Tetrahedron 2011, 66, 8095. (g) Liu, H.-M.; Zhang, Q.-M.; Wang, L.-M.; Tong, X.-F. Chem. - Eur. J. 2010, 16, 1968. (h) Liu, H.-M.; Zhang, Q.-M.; Wang, L.-M.; Tong, X.-F. Chem. Commun. 2010, 46, 312.

foundations (Nos. 201422, CCNU15A02007, 2015CFA033, and 2017AH047) for their support of this research.

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REFERENCES

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DOI: 10.1021/acs.joc.7b01931 J. Org. Chem. 2017, 82, 12134−12140