Copper-Catalyzed Chemoselective and Enantioselective Friedel

Apr 21, 2017 - A Friedel–Crafts alkylation of pyrrole was developed to afford the β,γ-unsaturated α-hydroxy esters bearing a quaternary stereogen...
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Copper-Catalyzed Chemoselective and Enantioselective Friedel− Crafts 1,2-Addition of Pyrrole with β,γ-Unsaturated α‑Ketoesters Jianan Sun, Yanbin Hu, Yanan Li, Sheng Zhang, Zhenggen Zha, and Zhiyong Wang* Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry & Collaborative Innovation Center of Suzhou Nano Science and Technology, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China S Supporting Information *

ABSTRACT: A Friedel−Crafts alkylation of pyrrole was developed to afford the β,γ-unsaturated α-hydroxy esters bearing a quaternary stereogenic center with good enantioselectivities and yields. This protocol represents the first report of 1,2-addition of Friedel−Crafts alkylation of pyrrole to β,γ-unsaturated α-ketoesters.

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INTRODUCTION

Scheme 1. Study on the Chemoselective Addition of Pyrrole to β,γ-Unsaturated α-Ketoesters

The quaternary stereogenic centers are ubiquitous in both natural products and active pharmaceutical ingredients.1 Despite rapid development in asymmetric catalysis, the construction of the quaternary stereogenic center motifs has been a challenging task for synthetic chemists. Among the catalytic asymmetric methods, the Friedel−Crafts reaction has been an attractive approach to the synthetic chemists, especially to our group.2 Many bioactive molecules with anticancer and antiphlogosis activities contain pyrrole and the corresponding tetrasubstituted chiral center moieties.3 Since the pyrroles contain electron-rich aromatic rings, they could be readily utilized to react with various electrophilic reagents bearing prochiral centers to give enantiomerically enriched pyrrole derivatives. Therefore, developing Friedel−Crafts alkylation of pyrrole to assembly stereogenic quaternary centers should be of great importance in both academic and pharmaceutical settings.4 Until now, most of the available Friedel−Crafts reactions of pyrroles with α,β-unsaturated carbonyl compounds were limited to 1,4-addition.5 Our group also developed a highly enantioselective copper catalyst system for this transformation, and we, like other groups,6 observed that the 1,4-addition reaction proceeded with high efficiency and a very fast reaction rate.7 To the best of our knowledge, the asymmetric Friedel−Crafts 1,2-addition reaction of pyrrole with α,βunsaturated carbonyl compounds has not been reported yet. To this end, we report our recent efforts in developing a chemoselective and enantioselective 1,2-addition of Friedel− Crafts alkylation of pyrrole to β,γ-unsaturated α-ketoesters (Scheme 1). © 2017 American Chemical Society

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RESULTS AND DISCUSSION Our investigation began with the reaction of pyrrole 1 and (E)-isopropyl 2-oxo-4-phenylbut-3-enoate 2a in the presence of a variety of metal catalysts (Table 1). At first, tridentate ligands A and B were examined. However, only poor yields and enantioselectivities were obtained (entries 1 and 2). Then Shiff base ligands C and D were tested, and the results showed that the target product 3a was obtained in 38% yield with 50% ee when the ligand C/CuBr2 was employed as the catalyst; however, when ligand D/CuBr2 was employed as the catalyst, the desired product 3a was obtained with only 11% yield and 21% ee (entries 3 and 4). The employment of ligand E/CuBr2 as the catalyst led to the formation of product 3a in 15% yield with 9% ee (entry 5). Afterward, another N,O ligand F/CuBr2 was examined in the reaction. The desired product 3a was not obtained, and only raw material was recovered (entry 6). Then different types of commonly used catalysts were examined. When the C2-symmetric Schiff base ligand G coordinated with scandium salt was examined, the Received: February 6, 2017 Published: April 21, 2017 5102

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

Article

The Journal of Organic Chemistry Table 1. Optimization of the Ligands of the Reactiona

entry

metal

ligand

1 2 3 4 5 6 7 8 9 10 11 12

CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 Sc(OTf)3 Co(OAc)2·4H2O CrCl3·6H2O Ni(OTf)2 Ti(Oi-Pr)4 CuBr2

A B C D E F G H H I J C

base piperidine piperidine piperidine piperidine piperidine piperidine piperidine piperidine piperidine

(0.1 (0.1 (0.1 (0.1 (0.1 (0.1 (0.1 (0.2 (0.2

equiv) equiv) equiv) equiv) equiv) equiv) equiv) equiv) equiv)

piperidine (0.2 equiv)

yield of 3ab (%)

ee of 3ac (%)

yield of 4ab (%)

16 13 38 11 15 trace nd trace nd nd trace 47

−60 14 50 21 9

17 26 21 n.d. 20 trace 15 trace 54 72 37 19

61

a

Unless otherwise noted, all reactions were performed with 1 (0.2 mmol), 2a (0.1 mmol), ligand (10 mol %), metal (10 mol %), and base (0, 10 mol % or 20 mol %) in toluene (1.0 mL) at rt. bIsolated yield. cDetermined by chiral HPLC analysis. Tf = trifluoromethanesulfonyl.

desired product 3a was not detected (entry 7). When the Co−Salen system was tested as a catalyst system, it did not afford any 1,2-addition or 1,4-addition product (entry 8). When the Cr−Salen system and Ni−PyBox systems were examined as catalyst systems, respectively, only 1,4-addition product was obtained (entries 9 and 10). Moreover, when (S)-BINOL/Ti(O-i-Pr)4 was examined as a catalyst, a trace amount of product 3a was detected (entry 11). Further optimization showed that increasing the amount of piperidine to 20 mol % led to the formation of target product 3a in 47% yield with 61% ee when the ligand C was used in the reaction (entry 12). All of these experimental results indicated that ligand C/CuBr2 was the best catalyst for 1,2-addition, and therefore, it was chosen as the optimal catalyst for further reaction condition optimization. Subsequently, different temperatures and solvent conditions were tested for this reaction (Table 2). First, the reactions were carried out in toluene at different temperatures (entries 1−3). When the temperature was lowered to 5 °C, the enantioselectivity increased to 80% (entry 3). The optimization of the solvents showed that aromatic hydrocarbon solvents favored this reaction (entries 8−13), among which mesitylene gave the best results in terms of both the yield and the enantioselectivity (entry 11).

Afterward, different bases were screened in this reaction (Table 3). The use of pyrrolidine and 3-methylpiperidine gave the best yields, 60% and 62%, respectively. However, the poor ee values (46% and 13%) excluded the employment of these two bases, as shown in entries 7 and 10. Considering the compromise of the yield and the ee value, piperidine gave the best results in this 1,2-addition reaction (entry 1) and, therefore, was still employed as the base in this reaction. To obtain a better result, the substitution conditions of an aromatic ring in the phenylalanine amino alcohol part of ligand C were optimized (Table 4). The results showed that p-methyl gave better enantioselectivity (entry 4). Then the substitutions at the phenol ring of the chiral ligand were optimized, which indicated that 3-trifluoromethyl was still the best choice (entry 4). Considering that the instability of pyrrole and its derivatives, the reductive agent was added to the system (Table 5). When KI, KSCN, and Na2SO3 were added in this reaction system, respectively, the yield and enantioselectivity of the desired product were improved; however, when n-Bu3P was added, the reaction yield was reduced sharply in spite of a small increase of the enantioselectivity (entries 1−4). Then water absorbent was tested as additive. To our delight, 4 Å molecular sieves as the additive could afford the desired 5103

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

Article

The Journal of Organic Chemistry Table 2. Optimization of the Temperature and Solvents of the Reactiona

entry

solvent

temp (°C)

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

toluene toluene toluene toluene MTBE i-PrOH EtOAc ethylbenzene p-xylene benzene mesitylene anisole fluorobenzene

20 10 5 0 5 5 5 5 5 5 5 5 5

47 48 46 23 55 23 14 52 58 56 57 14 31

61 78 80 76 55 70 21 78 80 80 83 71 76

a

Unless otherwise noted, the reaction of 1 (0.3 mmol) and 2a (0.1 mmol) was performed in the presence of C (10 mol %), base (20 mol %), and CuBr2 (10 mol %) in solvent (1.0 mL) at the temperature indicated. bIsolated yield. cDetermined by chiral HPLC analysis. MTBE = methyl tertbutyl ether.

Table 3. Optimization of the Bases of the Reactiona

entry

base

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10 11

piperidine NEt3 DIPEA DBU t-BuOK 4-methylmorpholine pyrrolidine 1-methylpiperidine 2-methylpiperidine 3-methylpiperidine 4-mehtylpiperidine

57 42 48 45 46 57 60 56 32 62 29

83 63 67 57 21 65 46 59 48 13 81

a

Unless otherwise noted, the reaction of 1 (0.3 mmol) and 2a (0.1 mmol) was performed in the presence of C (10 mol %), base (20 mol %) and CuBr2 (10 mol %) in mesitylene (1.0 mL) at 5 °C. bIsolated yield. cDetermined by chiral HPLC analysis.

copper salt, C4 as the chiral ligand, piperidine as the base, mesitylene as the solvent, 4 Å MS as the additive, at 5 °C. With the optimal conditions in hand (Table 5, entry 7), the substrate scope of β,γ-unsaturated α-ketoesters was studied (Table 6). First, the electronic effect of the substrates was investigated by varying the para substituent groups of R1. It was found that the substrates with electron-donating groups on the phenyl ring gave the desired products with slightly higher yields but lower ee values (3a−c) than that of electron-withdrawing groups (3d−f). When the nitro group was installed, however, only the product of 1,4-addition could be obtained (3g). Second, the position of the substituents of

adduct in 64% yield with 86% ee (entry 7). When KI and 4 Å MS were added together, there was no further improvement in yield and enantioselectivity of the desired product (entry 8). Afterward, this reaction was conducted in nitrogen atmosphere. The result of the reaction in nitrogen atmosphere or air atmosphere was almost the same (entry 9). However, the reaction under oxygen atmosphere gave poor yield and low enantioselectivity (entry 10). Therefore, this reaction was conducted under air atmosphere. Correspondingly, under the optimal conditions, the yield of 1,4-addition product was reduced to 9% (entry 7). Finally, the optimal conditions were obtained as described below: CuBr2 was employed as the 5104

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

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The Journal of Organic Chemistry Table 4. Optimization of the Substitutions of Aromatic Ring and Additive of the Reactiona

entry

ligand

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10

57 45 43 58 49 36 49 51 49 55

83 65 48 84 68 71 80 64 57 34

a

Unless otherwise noted, all reactions were performed with 1 (0.3 mmol), 2a (0.1 mmol), ligand (10 mol %), piperidine (20 mol %), and CuBr2 (10 mol %) in mesitylene (1.0 mL) at 5 °C. bIsolated yield. cDetermined by chiral HPLC analysis.

Table 5. Optimization of the Additive of the Reactiona

entry

additive

yieldb (%)

eec (%)

1 2 3 4 5 6 7d 8 9 10

KI KSCN Na2SO3 n-Bu3P Na2SO4 MgSO4 4 Å MS KI+4 Å MS N2 + 4 Å MS O2 + 4 Å MS

62 61 60 23 47 38 64 65 64 26

85 86 84 85 78 74 86 86 86 56

a Unless otherwise noted, all reactions were performed with 1 (0.1 mmol), 2a (0.2 mmol), C4 (10 mol %), piperidine (20 mol %), and CuBr2 (10 mol %) in mesitylene (1.0 mL) with additive (30 mg) at 5 °C. bIsolated yield. cDetermined by chiral HPLC analysis. dThe 1,4 addition product 4a could be obtained with 9% yield.

R1 was investigated. The yields and enantioselectivities of 3d and 3e bearing meta substituents were slightly higher than those of 3h and 3j bearing para substituents and 3i and 3k bearing ortho substituents. Meanwhile, ortho substituents gave slightly lower yields but higher ee values when compared to para substituents of R1 (3h−k). This implied that hindrance disfavored the reaction yield but favored the stereoselectivity. The substrates bearing a 2-naphthyl group and a 2-thienyl group could also give the corresponding products with good yields and enantioselectivities, as shown in 3l and 3m.

Moreover, the R2 effect on the reaction was investigated. When isopropyl ester was changed into methyl ester, ethyl ester, and benzyl ester, respectively, this variation had little influence on the reaction yields and enantioselectivities (3n− p). When R2 was changed into a tert-butyl group, however, product 3q could be obtained with lower yield and good enantioselectivity after 48 h, perhaps due to the effect from the large hindrance. At last, substrates derived from oxindoles were studied, and much better results were obtained in the 5105

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

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The Journal of Organic Chemistry Table 6. Scope of β,γ-Unsaturated α-Ketoestersa

In order to obtain insight into the reaction mechanism, a control experiment was carried out (Scheme 2). The reaction of N-methylpyrrole with (E)-isopropyl 2-oxo-4-phenylbut-3enoate 2a was carried out under standard conditions. However, there was no reaction. On the basis of the control experiment, our previous mechanism study,9 and the absolute configuration of the product 3l, a plausible structure of the transition state was proposed (Scheme 3). The β,γ-unsaturated α-ketoester was Scheme 3. A Plausible Structure of the Transition State of 1,2 Friedel−Crafts Addition of Isopropyl (E)-4(Naphthalen-2-yl)-2-oxobut-3-enoate with Pyrrole

activated by chelating with a metal center in the catalyst complex, while the NH in pyrrole served as a hydrogen-bonddonating group to direct the alkylation at the Re face of the β,γ-unsaturated α-ketoester. p-NO 2 -phenyl-substituted β,γ-unsaturated α-ketoester (Table 6, entry 7) yielded the 1,4-addition product as a single product, which was contradictory to the rest of this study. According to the plausible structure of the transition state we proposed (Scheme 3), the reason may come from the strong electron-withdrawing effect of the nitro group in the para position. This strong electron-withdrawing effect could reduce the electron density of the two carboxyl oxygens of the β,γ-unsaturated α-ketoester, weaking the coordinate bond and making the coordinate bond longer. 2-C in pyrrole is hard to connect to the carbon in the carbonyl group of the β,γ-unsaturated α-ketoester because of the distance variation and the constraint of the formed hydrogen bond. Therefore, there was no 1,2 addition of Friedel−Crafts alkylation of pyrrole to the β,γ-unsaturated α-ketoester with p-NO2 substitution on the phenyl ring. Only 1,4-addition product, which was a byproduct, could be obtained. Plausible structures of the transition state are proposed in Scheme 4.

a Unless otherwise noted, the reaction of 1 (0.6 mmol) and 2a (0.2 mmol) was performed in the presence of C4 (10 mol %), piperidine (20 mol %), and CuBr2 (10 mol %) in mesitylene (2.0 mL) with 60 mg of powdered 4 Å molecular sieves as additive at 5 °C. bIsolated yield. cDetermined by chiral HPLC analysis.

two reactions (3r,s). What’s more, the absolute configuration of the product 3l was confirmed by X-ray crystal diffraction.8 Scheme 2. Control Experimenta

a

Unless otherwise noted, the reaction of N-methylpyrrole (0.6 mmol) and 2a (0.2 mmol) was performed in the presence of C4 (10 mol %), piperidine (20 mol %), and CuBr2 (10 mol %) in mesitylene (2.0 mL) with 60 mg of powdered 4 Å molecular sieves as additive at 5 °C. 5106

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

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The Journal of Organic Chemistry

Solvents were purified according to the standard procedures unless otherwise noted. Commercially available pyrrole should be distilled for the use of the reactions. Ligands9a,10 and various β,γ-unsaturated α-ketoesters 211 were prepared according to literature procedures. General Procedure for the Preparation of the Catalyst. To a 10 mL test tube were added chiral ligand C4 (0.02 mmol), CuBr2 (0.02 mmol), piperidine (0.04 mmol), and Et2O (2 mL). The mixture was stirred for 2 h at room temperature until a large amount of white precipitate was formed. The precipitate was removed by centrifugation at about 6000 rpm for 5 min and washed with Et2O twice. The combined blue supernatant was then concentrated under vacuum to yield the catalyst as a blue solid. General Procedures for 1,2-Friedel−Crafts Addition. To a solution of the catalyst (0.02 mmol) in mesitylene (2 mL) were added the corresponding β,γ-unsaturated α-ketoester 2 (0.20 mmol), 60 mg of powdered 4 Å molecular sieves, and pyrrole 1 (40 μL, 0.60 mmol). The solution was stirred at 5 °C. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel to give the pure product 3. Experimental Data of Products. Isopropyl (R,E)-2-Hydroxy-4phenyl-2-(1H-pyrrol-2-yl)but-3-enoate (3a). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 37.1 mg, 65% yield; [α]D20 −11.3 (c = 0.76, EtOAc, 86% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 240 nm, tR = 17.64 min (minor), tR = 19.03 min (major); 1 H NMR (400 MHz, CD3COCD3) δ 9.96 (br s, 1H), 7.47−7.45 (m, 2H), 7.36−7.32 (m, 2H), 7.27−7.23 (m, 1H), 6.88 (d, J = 15.8 Hz, 1H), 6.78−6.73 (m, 2H), 6.15−6.13 (m, 1H), 6.02 (dd, J = 5.6, 2.7 Hz, 1H), 5.09−5.02 (m, 1H), 4.98 (s, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 173.2, 137.7, 132.4, 130.9, 129.8, 129.5, 128.5, 127.6, 118.6, 108.6, 106.7, 76.1, 70.7, 21.9, 21.8; IR (film, ν/cm−1) 3391, 2980, 2931, 1719, 1448, 1387, 1253, 1181, 1102, 1032, 972, 849, 762, 728, 694; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H19NO3Na 308.1263, found 308.1266. Isopropyl (R,E)-2-Hydroxy-2-(1H-pyrrol-2-yl)-4-(p-tolyl)but-3enoate (3b). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 32.2 mg, 54% yield; [α]D20 −1.8 (c = 0.33, EtOAc, 84% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 230 nm, tR = 22.22 min (minor), t R = 23.88 min (major); 1 H NMR (400 MHz, CD3COCD3) δ 9.94 (br s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 15.8 Hz, 1H), 6.74−6.67 (m, 2H), 6.14−6.13 (m, 1H), 6.02 (dd, J = 5.7, 2.9 Hz, 1H), 5.09−5.00 (m, 1H), 4.94 (s, 1H), 2.30 (s, 3H), 1.26 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 173.2, 138.2, 134.9, 132.5, 130.1, 129.9, 129.7, 127.5, 118.5, 108.5, 106.6, 76.0, 70.6, 21.9, 21.7, 21.1; IR (film, ν/cm−1) 2959, 2922, 2852, 1456, 1375, 1258, 1016, 863, 796, 702; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H21NO3Na 322.1419, found 322.1422. Isopropyl (R,E)-2-Hydroxy-4-(4-methoxyphenyl)-2-(1H-pyrrol-2yl)but-3-enoate (3c). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 20.5 mg, 33% yield; [α]D20 −7.5 (c = 0.71, EtOAc, 85% ee); HPLC: Daicel Chiralpak IC, hexane/2propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 230 nm, tR = 13.82 min (minor), tR = 17.51 min (major); 1H NMR (400 MHz, CD3COCD3): δ 9.93 (br s, 1H), 7.41−7.37 (m, 2H), 6.92− 6.88 (m, 2H), 6.81 (d, J = 15.8 Hz, 1H), 6.73−6.72 (m, 1H), 6.60 (d, J = 15.8 Hz, 1H), 6.13 (m, 1H), 6.02 (dd, J = 5.6, 2.7 Hz, 1H), 5.09−5.00 (m, 1H), 4.91 (s, 1H), 3.79 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 173.4, 160.5, 132.6, 130.3, 129.4, 128.8, 128.6, 118.5, 114.9, 108.5, 106.6, 76.0, 70.6, 55.6, 21.9, 21.7; IR (film, ν/cm−1) 3392, 2924,

Scheme 4. Plausible Structures of the Transition State

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CONCLUSIONS In summary, a copper-catalyzed highly chemoselective and enantioselective Friedel−Crafts 1,2-alkylation reaction of pyrrole to β,γ-unsaturated α-ketoesters was developed. The desired 1,2-addition products bearing quaternary stereogenic centers were obtained with good enantioselectivities and yields.

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EXPERIMENTAL SECTION

General Information. 1H NMR and 13C NMR were recorded on a Bruker-400 MHz spectrometer (1H NMR, 400 MHz; 13C NMR, 100 MHz) using TMS as internal reference. The chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively. UV−vis spectrophotometry was carried out on Shimadzu UV-3000. HPLC analysis was carried out on an Agilent 1100 series HPLC with a multiple wavelength detector. Chiralpak IC, OD-H, and AD-H columns were purchased from Daicel Chemical Industries, Ltd. Optical rotations were measured on a PerkinElmer Polarimeter (Model 343). HRMS (ESI) spectra were recorded on a Waters Q-TOF Premier and a Thermo Scientific LTQ Orbitrap XL hybrid ion trap-orbitrap mass spectrometer. Commercially available compounds were used without further purification. 5107

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

Article

The Journal of Organic Chemistry

130.2, 127.4, 127.4, 126.3, 125.3, 117.8, 107.7, 105.8, 75.1, 69.8, 21.0, 20.8; IR (film, ν/cm−1) 3750, 3648, 3392, 2980, 2358, 1717, 1593, 1559, 1472, 1418, 1387, 1098, 1031, 904, 778, 722, 682; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H18ClNO3Na 342.0873, found 342.0870. Ethyl (R,E)-4-(2-Chlorophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)but3-enoate (3i). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 32.2 mg, 53% yield; [α]D20 −16.6 (c = 0.42, EtOAc, 82% ee); HPLC Daicel Chiralpak OD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 240 nm, tR = 11.28 min (minor), t R = 12.25 min (major); 1 H NMR (400 MHz, CD3COCD3) δ 10.01 (br s, 1H), 7.72 (dd, J = 7.6, 1.8 Hz, 1H), 7.41 (dd, J = 7.7, 1.5 Hz, 1H), 7.34−7.26 (m, 3H), 6.84 (d, J = 15.8 Hz, 1H), 6.76−6.74 (m, 1H), 6.17−6.16 (m, 1H), 6.04 (dd, J = 5.9, 2.7 Hz, 1H), 5.19 (s, 1H), 4.28−4.23 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, acetone) δ 172.4, 134.6, 133.0, 132.8, 131.1, 129.6, 129.1, 127.3, 124.7, 117.9, 117.7, 107.7, 106.0, 75.3, 61.9, 13.5; IR (film, ν/cm−1) 3393, 2923, 2853, 1723, 1470, 1367, 1231, 1114, 1029, 969, 858, 749, 722; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H16ClNO3Na 328.0716, found 328.0718. Isopropyl (R,E)-4-(3-Bromophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)but-3-enoate (3j). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 45.1 mg, 62% yield; [α]D20 −24.6 (c = 0.66, EtOAc, 86% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 240 nm, tR = 15.00 min (major), tR = 15.59 min (minor); 1H NMR (400 MHz, CD3COCD3) δ 9.97 (br s, 1H), 7.66 (t, J = 1.7 Hz, 1H), 7.47−7.42 (m, 2H), 7.29 (t, J = 7.8 Hz, 1H), 6.86 (s, 2H), 6.74−6.73 (m, 1H), 6.17−6.15 (m, 1H), 6.03 (dd, J = 5.9, 2.6 Hz, 1H), 5.10−5.01 (m, 2H), 1.27 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 172.0, 139.3, 131.8, 131.2, 130.5, 130.4, 129.3, 127.4, 125.7, 122.3, 117.8, 107.7, 105.8, 75.1, 69.8, 21.0, 20.8; IR (film, ν/cm−1) 3392, 2980, 1717, 1387, 1246, 1099, 1031, 994, 914, 884, 800, 775, 723, 681; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H18BrNO3Na 386.0368, found 386.0365. Ethyl (R,E)-4-(2-Bromophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)but3-enoate (3k). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 36.2 mg, 52% yield; [α]D20 −7.9 (c = 0.65, EtOAc, 81% ee); HPLC: Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 240 nm, tR = 17.88 min (major), t R = 19.06 min (minor); 1 H NMR (400 MHz, CD3COCD3) δ 10.00 (br s, 1H), 7.69 (dd, J = 7.9, 1.6 Hz, 1H), 7.59 (dd, J = 8.0, 1.1 Hz, 1H), 7.37−7.33 (m, 1H), 7.27 (d, J = 15.7 Hz, 1H), 7.21−7.17 (m, 1H), 6.80 (d, J = 15.7 Hz, 1H), 6.76 (td, J = 2.7, 1.6 Hz, 1H), 6.18−6.16 (m, 1H), 6.05−6.03 (m, 1H), 5.19 (s, 1H), 4.25 (qd, J = 7.1, 0.7 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 172.4, 136.4, 133.1, 132.9, 131.1, 129.3, 127.9, 127.5, 127.5, 123.4, 118.0, 107.8, 106.0, 75.3, 61.9, 13.6; IR (film, ν/cm−1) 3392, 2980, 2927, 2361, 1728, 1558, 1541, 1437, 1395, 1243, 1148, 1024, 970, 907, 753, 669; HRMS (ESI-TOF) m/z [M + Na]+calcd for C16H16BrNO3Na 372.0211, found 372.0207. Isopropyl (R,E)-2-Hydroxy-4-(naphthalen-2-yl)-2-(1H-pyrrol-2-yl)but-3-enoate (3l). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a brown solid: 40.0 mg, 60% yield; mp = 146−147 °C; [α]D20 −12.3 (c = 0.23, EtOAc, 83% ee); HPLC Daicel Chiralpak IC, hexane/2propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 230 nm, tR = 10.06 min (minor), tR = 12.17 min (major); 1H NMR (400 MHz, CD3COCD3) δ 10.01 (br s, 1H), 7.90−7.86 (m, 4H), 7.72 (dd, J = 8.7, 1.4 Hz, 1H), 7.51−7.45 (m, 2H), 7.05 (d, J = 15.8 Hz, 1H), 6.91 (d, J = 15.8 Hz, 1H), 6.76−6.74 (m, 1H), 6.19−6.17 (m, 1H), 6.04 (dd, J = 5.9, 2.6 Hz, 1H), 5.11−5.05 (m, 2H), 1.28 (d, J = 6.2 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz,

1716, 1606, 1540, 1510, 1456, 1374, 1254, 1099, 1030, 1099, 1030, 830, 796, 725; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H21NO4Na 338.1368, found 338.1371. Isopropyl (R,E)-4-(4-Chlorophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)but-3-enoate (3d). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 41.1 mg, 64% yield; [α]D20 −3.3 (c = 0.25, EtOAc, 78% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 254 nm, tR = 12.36 min (minor), tR = 14.79 min (major); 1H NMR (400 MHz, CD3COCD3) δ 9.97 (br s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 15.8 Hz, 1H), 6.79 (d, J = 15.9 Hz, 1H), 6.74−6.72 (m, 1H), 6.15−6.13 (m, 1H), 6.02 (dd, J = 5.8, 2.6 Hz, 1H), 5.10−5.00 (m, 2H), 1.26 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 172.0, 135.7, 132.7, 131.3, 131.0, 128.6, 128.2, 127.5, 117.8, 107.8, 105.8, 75.1, 69.8, 21.0, 20.8; IR (film, ν/cm−1) 3391, 2922, 2853, 1718, 1490, 1456, 1375, 1272, 1250, 1091, 1012, 972, 830, 760, 722; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H18ClNO3Na 342.0873, found 342.0871. Isopropyl (R,E)-4-(4-Bromophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)but-3-enoate (3e). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 42.4 mg, 58% yield; [α]D20 −24.6 (c = 0.67, EtOAc, 81% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 240 nm, tR = 26.02 min (minor), tR = 31.30 min (major); 1H NMR (400 MHz, CD3COCD3) δ 9.97 (br s, 1H), 7.53−7.50 (m, 2H), 7.44−7.42 (m, 2H), 6.86 (d, J = 15.9 Hz, 1H), 6.81 (d, J = 15.8 Hz, 1H), 6.74− 6.72 (m, 1H), 6.15−6.13 (m, 1H), 6.02 (dd, J = 5.6, 2.8 Hz, 1H), 5.10−5.00 (m, 2H), 1.26 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CD3COCD3) δ 173.0, 137.0, 132.5, 132.1, 132.0, 129.5, 128.5, 121.8, 118.7, 108.6, 106.7, 76.0, 70.7, 21.9, 21.8; IR (film, ν/cm−1) 3391, 2980, 2925, 1717, 1647, 1588, 1507, 1488, 1456, 1399, 1387, 1375, 1250, 1101, 1008, 973, 973, 914, 829, 726; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H18BrNO3Na 386.0368, found 386.0369. Isopropyl (R,E)-2-Hydroxy-2-(1H-pyrrol-2-yl)-4-(4-(trifluoromethyl)phenyl)but-3-enoate (3f). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 47.8 mg, 68% yield; [α]D20 −17.1 (c = 0.44, EtOAc, 75% ee); HPLC Daicel Chiralpak AD-H, hexane: 2propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 254 nm, tR = 18.53 min (minor), tR = 21.51 min (major); 1H NMR (400 MHz, CD3COCD3) δ 9.98 (br s, 1H), 7.71−7.66 (m, 4H), 6.98 (d, J = 15.9 Hz, 1H), 6.94 (d, J = 15.9 Hz, 1H), 6.75−6.74 (m, 1H), 6.17−6.15 (m, 1H), 6.03 (dd, J = 5.9, 2.6 Hz, 1H), 5.11−5.02 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H), 1.25 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CD3COCD3) δ 172.8, 141.7, 134.0, 132.0, 129.9, and 129.6 (2JCF = 31.8 Hz, 1C), 128.3, 128.1, 126.7, and 124.1 (1JCF = 269.4 Hz, 1C), 126.4−126.3 (q, 4JCF = 3.9 Hz, 2C), 118.8, 108.6, 106.8, 76.1, 70.8, 21.8, 21.7; IR (film, ν/cm−1) 3397, 2924, 1717, 1409, 1323, 1256, 1101, 1015, 870, 835, 797, 711, 669; HRMS (ESITOF) m/z [M + Na]+ calcd for C18H18F3NO3Na 376.1136, found 376.1137. Isopropyl (R,E)-4-(3-Chlorophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)but-3-enoate (3h). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 39.2 mg, 61% yield; [α]D20 −20.9 (c = 0.51, EtOAc, 84% ee); HPLC Daicel Chiralpak IC, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 254 nm, tR = 6.72 min (minor), tR = 7.32 min (major); 1H NMR (400 MHz, CD3COCD3) δ 9.99 (br s, 1H), 7.52 (t, J = 1.8 Hz, 1H), 7.44−7.41 (m, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30−7.27 (m, 1H), 6.87 (s, 2H), 6.75−6.73 (m, 1H), 6.17−6.15 (m, 1H), 6.03 (dd, J = 5.6, 2.8 Hz, 1H), 5.10−5.00 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C NMR (101 MHz, CD3COCD3) δ 172.0, 139.0, 134.1, 131.8, 131.2, 5108

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

Article

The Journal of Organic Chemistry CD3COCD3) δ 172.2, 134.3, 133.8, 133.2, 131.5, 130.6, 128.9, 128.2, 127.9, 127.6, 126.6, 126.3, 125.9, 123.8, 117.7, 107.7, 105.8, 75.3, 69.8, 21.0, 20.9; IR (film, ν/cm−1) 3391, 2923, 2853, 1716, 1540, 1456, 1374, 1246, 1099, 1031, 971, 902, 803, 742; HRMS (ESITOF) m/z [M + Na]+ calcd for C21H21NO3Na 358.1419, found 358.1418. Isopropyl (R,E)-2-Hydroxy-2-(1H-pyrrol-2-yl)-4-(thiophene-2-yl)but-3-enoate (3m). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 32.8 mg, 56% yield; [α]D20 −25.7 (c = 0.64, EtOAc, 86% ee); HPLC Daicel Chiralpak AD-H, hexane/2propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 215 nm, tR = 21.52 min (minor), tR = 22.77 min (major); 1H NMR (400 MHz, CD3COCD3) δ 9.99 (br s, 1H), 7.34 (d, J = 5.1 Hz, 1H), 7.09−7.08 (m, 1H), 7.02−6.98 (m, 2H), 6.75−6.73 (m, 1H), 6.53 (d, J = 15.6 Hz, 1H), 6.12−6.11 (m, 1H), 6.02 (dd, J = 5.9, 2.6 Hz, 1H), 5.10−5.01 (m, 2H), 1.27 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 172.0, 141.6, 131.2, 129.5, 127.5, 126.5, 124.7, 122.3, 117.8, 107.6, 105.8, 74.9, 69.8, 21.0, 20.8; IR (film, ν/cm−1) 3392, 2980, 2931, 2359, 1868, 1771, 1716, 1540, 1489, 1387, 1259, 1101, 854, 797, 725; HRMS (ESI-TOF) m/ z [M + Na]+calcd for C15H17NO3SNa 314.0827, found 314.0829. Methyl (R,E)-2-Hydroxy-4-phenyl-2-(1H-pyrrol-2-yl)but-3-enoate (3n). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to give the product as a light yellow oil: 32.4 mg, 63% yield; [α]D20 −7.7 (c = 0.76, EtOAc, 80% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 254 nm, tR = 19.45 min (minor), tR = 25.10 min (major); 1H NMR (400 MHz, CD3COCD3) δ 10.02 (br s, 1H), 7.49−7.47 (m, 2H), 7.36−7.32 (m, 2H), 7.28−7.24 (m, 1H), 6.88 (d, J = 15.8 Hz, 1H), 6.78 (d, J = 15.9 Hz, 1H), 6.75−6.73 (m, 1H), 6.14−6.12 (m, 1H), 6.02 (dd, J = 5.9, 2.6 Hz, 1H), 5.07 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ 173.2, 136.7, 131.4, 129.8, 129.0, 128.6, 127.7, 126.7, 117.9, 107.6, 106.0, 75.2, 52.3; IR (film, ν/cm−1) 3384, 2958, 2922, 2852, 1731, 1448, 1375, 1258, 1092, 1031, 973, 802, 763, 727, 694; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H15NO3Na 280.0950, found 280.0949. Ethyl (R,E)-2-Hydroxy-4-phenyl-2-(1H-pyrrol-2-yl)but-3-enoate (3o). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 30.7 mg, 57% yield; [α]D20 −9.8 (c = 0.80, EtOAc, 86% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 230 nm, tR = 19.23 min (minor), tR = 21.95 min (major); 1H NMR (400 MHz, CD3COCD3) δ 9.98 (br s, 1H), 7.48−7.46 (m, 2H), 7.36−7.32 (m, 2H), 7.27−7.24 (m, 1H), 6.89 (d, J = 15.8 Hz, 1H), 6.78 (d, J = 15.8 Hz, 1H), 6.75−6.74 (m, 1H), 6.15−6.13 (m, 1H), 6.02 (dd, J = 5.6, 2.7 Hz, 1H), 5.02 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CD3COCD3) δ 178.0, 141.9, 136.7, 135.1, 134.2, 133.8, 132.9, 131.9, 123.0, 112.9, 111.1, 80.4, 67.0, 18.7; IR (film, ν/cm−1) 3392, 2924, 2360, 1722, 1541, 1447, 1367, 1233, 1093, 1026, 971, 906, 726, 692; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H17NO3Na 294.1106, found 294.1105. Benzyl (R,E)-2-Hydroxy-4-phenyl-2-(1H-pyrrol-2-yl)but-3-enoate (3p). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 43.8 mg, 66% yield; [α]D20 −16.0 (c = 0.69, EtOAc, 81% ee); HPLC Daicel Chiralpak AD-H, hexane: 2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 230 nm, tR = 28.08 min (minor), tR = 35.20 min (major); 1H NMR (400 MHz, CD3COCD3) δ 10.02 (br s, 1H), 7.47−7.45 (m, 2H), 7.35−7.31 (m, 7H), 7.27−7.24 (m, 1H), 6.89 (d, J = 15.8 Hz, 1H), 6.82 (d, J = 15.9 Hz, 1H), 6.75−6.73 (m, 1H), 6.15−6.13 (m, 1H), 6.02 (dd, J = 5.9, 2.6 Hz, 1H), 5.26 (s, 2H), 5.15 (s, 1H); 13C NMR (100 MHz, CD3COCD3) δ 173.5, 137.6, 136.9, 132.2, 130.7, 130.2, 129.5, 129.3,

129.0, 128.7, 128.6, 127.6, 118.8, 108.6, 107.0, 76.3, 68.0; IR (film, ν/cm−1) 3750, 3689, 3675, 3648, 3420, 2921, 2852, 2359, 1868, 1844, 1771, 1732, 1456, 1374, 1221, 1089, 1028, 970, 800, 725, 691; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H19NO3Na 356.1263, found 356.1264. tert-Butyl (R,E)-2-Hydroxy-4-phenyl-2-(1H-pyrrol-2-yl)but-3enoate (3q). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 6:1) to give the product as a light yellow oil: 27.9 mg, 47% yield; [α]D20 −18.2 (c = 0.64, EtOAc, 85% ee); HPLC: Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 240 nm, tR = 14.29 min (minor), t R = 18.87 min (major); 1 H NMR (400 MHz, CD3COCD3) δ 9.93 (br s, 1H), 7.47−7.45 (m, 2H), 7.35−7.32 (m, 2H), 7.27−7.23 (m, 1H), 6.87 (d, J = 15.8 Hz, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.17−6.15 (m, 1H), 6.02 (dd, J = 5.9, 2.6 Hz, 1H), 4.85 (s, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CD3COCD3) δ 172.0, 136.9, 131.7, 130.3, 128.6, 128.5, 127.6, 126.6, 117.5, 107.7, 105.6, 82.4, 75.3, 27.2; IR (film, ν/cm−1) 3392, 2978, 2930, 2361, 1716, 1541, 1473, 1394, 1369, 1253, 1119, 1031, 971, 800, 725, 693; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H21NO3Na 322.1419, found 322.1421. Ethyl (R,E)-2-Hydroxy-3-(1-methyl-2-oxoindolin-3-ylidene)-2-(1Hpyrrol-2-yl)propanoate (3r). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to give the product as a yellow solid: 50.4 mg, 77% yield; mp = 122−123 °C; [α]D20 +12.9 (c = 0.88, EtOAc, 90% ee); HPLC Daicel Chiralpak AD-H, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, T = 30 °C, UV = 254 nm, tR = 44.40 min (minor), tR = 47.10 min (major); 1 H NMR (400 MHz, CD3COCD3) δ 10.20 (br s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.42 (s, 1H), 7.26 (t, J = 7.7 Hz, 1H), 6.91−6.88 (m, 1H), 6.77−6.77 (m, 2H), 6.17 (s, 1H), 6.03 (dd, J = 5.6, 2.7 Hz, 1H), 5.68 (s, 1H), 4.30−4.19 (m, 2H), 3.18 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 171.8, 167.5, 144.9, 137.6, 130.2, 129.9, 129.8, 128.3, 121.6, 120.2, 118.6, 107.9, 107.8, 106.5, 74.9, 62.2, 25.3, 13.5; IR (film, ν/cm−1) 3377, 2924, 2860, 1736, 1608, 1464, 1383, 1232, 1093, 1043, 926, 876, 800, 752; HRMS (ESI-TOF) m/z [M + Na]+calcd for C18H18N2O4Na 349.1164, found 349.1179. Ethyl (R,E)-3-(1-Benzyl-2-oxoindolin-3-ylidene)-2-hydroxy-2-(1Hpyrrol-2-yl)propanoate (3s). The title compound was prepared according to the general working procedure and purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to give the product as a yellow solid: 62.3 mg, 77% yield; mp = 56−57 °C; [α]D20 +8.4 (c = 0.86, EtOAc, 88% ee); HPLC Daicel Chiralpak ADH, hexane/2-propanol = 70:30, flow rate = 0.8 mL/min, T = 30 °C, UV = 230 nm, tR = 21.06 min (minor), tR = 22.50 min (major); 1H NMR (400 MHz, CD3COCD3) δ 10.22 (br s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.37−7.31 (m, 4H), 7.27−7.24 (m, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.78−6.77 (m, 1H), 6.21−6.19 (m, 1H), 6.04 (dd, J = 5.6, 2.7 Hz, 1H), 5.70 (s, 1H), 4.98 (s, 2H), 4.29−4.23 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CD3COCD3) δ 171.7, 167.7, 143.9, 138.2, 136.8, 130.1, 129.8, 129.5, 128.6, 128.5, 127.4, 127.3, 121.7, 120.4, 118.7, 108.6, 107.2, 106.6, 75.0, 62.2, 43.0, 13.5; IR (film, ν/cm−1) 3440, 2924, 2854, 1732, 1697, 1608, 1468, 1381, 1259, 1134, 1026, 916, 864, 802, 752; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C24H22N2O4Na 425.1477, found 425.1481.

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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.7b00159. 1 H NMR and 13C NMR spectra for all products; HPLC profiles and crystallographic data of compound 3l (PDF) X-ray data for compound 3l (CIF) 5109

DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110

Article

The Journal of Organic Chemistry

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crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (9) (a) Guo, F.; Chang, D.; Lai, G.; Zhu, T.; Xiong, S.; Wang, Z. Chem. - Eur. J. 2011, 17, 11127. (b) Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192. (10) (a) Brunner, H.; Chuard, T. Monatsh. Chem. 1994, 125, 1293. (b) Zheng, H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng, J.-G.; Lin, W.-Q.; Yuan, W.-C.; Zhang, X.-M. Chem. - Eur. J. 2008, 14, 9864. (c) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Wang, R. Angew. Chem., Int. Ed. 2015, 54, 2185. (11) (a) Srivastava, B.; Joharapurkar, A.; Raval, S.; et al. J. Med. Chem. 2007, 50, 5951. (b) Meng, Q.; Zhu, L.; Zhang, Z. J. Org. Chem. 2008, 73, 7209. (c) Yang, C.; Chen, X.; Tang, T.; He, Z. Org. Lett. 2016, 18, 1486.

AUTHOR INFORMATION

Corresponding Author

*Fax: 86-551-3631760. E-mail: [email protected]. ORCID

Zhiyong Wang: 0000-0002-3400-2851 Author Contributions

J.S. and Y.H. contributed equally. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Nature Science Foundation of China (21432009, 21472177, 21672200) is greatly acknowledged. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDB20000000.

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REFERENCES

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DOI: 10.1021/acs.joc.7b00159 J. Org. Chem. 2017, 82, 5102−5110