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Rhodium-Catalyzed Annulation of #-Imino Carbenes with #,#-Unsaturated Ketones: Construction of Multi-substituted 2,3-Dihydropyrrole/pyrrole Rings Xueji Ma, Li Liu, Jiaying Wang, Xianglin Xi, Xuemei Xie, and Hangxiang Wang J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Nov 2018 Downloaded from http://pubs.acs.org on November 6, 2018

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The Journal of Organic Chemistry

Rhodium-Catalyzed Annulation of α-Imino Carbenes with α,β-Unsaturated Ketones: Construction of Multi-substituted 2,3-Dihydropyrrole/pyrrole Rings

Xueji Ma†, Li Liu†, Jiaying Wang†, Xianglin Xi†, Xuemei Xie†, Hangxiang Wang *‡ † Department

‡

of Chemistry and Chemical Engineering, Xinxiang University, xinxiang 453003, China.

The First Affiliated Hospital; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of

Public Health, Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310003, China. E-mail: [email protected] N N

N Ts

1

R

Rh(II)

+ R3

2

R

R3

R4

O R2

Ts N

O R1

base

R4

2

R

H N

R3

O R1 R4

Novel carbenoid strategy to construct multi-substituted 2,3-dihydropyrroles/pyrroles

ABSTRACT: An efficient annulation of α-imino rhodium carbenes with α,β-unsaturated ketones has been developed to generate multi-substituted 2,3-dihydropyrrole derivatives. Using the optimized catalyst, this approach is compatible with both cyclic and normal linear α,β-unsaturated ketones. Further detosylation in the presence of base could produce multi-substituted pyrroles. The new method has the potential to enable the rapid construction of bioactive molecules containing pyrrole rings.

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INTRODUCTION Multi-substituted 2,3-dihydropyrroles and their pyrrole derivatives are valuable structural motifs in many compounds with biological activity.1 For example, these skeletons are widespread among approved pharmaceuticals, such as sunitinib and atorvastatin, that exhibit promising activities in treating malignancies and hyperlipemia (Figure 1).2 Several effective methods were established for the synthesis of the key structures, such as transition metal-catalyzed C-H activation and metal-catalyzed cyclization (Scheme 1, eq 1 and 2).3-4 In addition, catalytic activation of propargyl alcohols and their derivatives has emerged as a powerful tool.5 However, these methods suffer from some drawbacks such as limited substrate scopes and the employment of expensive catalysts. Therefore, the development of new synthetic protocols for accessing these useful skeletons is highly desirable and would facilitate the exploration of new drug candidates. HO O

H N

HN H 3C F

CH3 H N

CO2H OH H

F N

NEt2

H N

O

Sunitinib

O Atorvastatin

Figure 1. Representative drugs containing multi-substituted pyrrole cores. N-Sulfonyl-1,2,3-triazoles, which can be facilely obtained through Cu(I)-catalyzed cycloadditions of alkynes and sulfonylazides, have become important carbene resource over the past decade.6 This class of compounds can produce α-imino carbenes in the presence of rhodium (II) catalysts.7 These generated α-rhodium imino carbene species can subsequently serve as electrophiles in reactions with heteroatoms bearing lone pairs of electrons such as nitrogen,8 oxygen,9 sulfur,10 and even bromine.11 Aldehydes, 1,3-diketones, epoxides and amides can be used to generate oxonium ylides to enable the efficient construction of heterocyclic compounds and multi-substituted olefins.9,12 α,β-Unsaturated aldehydes and α-imino carbenes were recently exploited to efficiently synthesize disubstituted 2,3-dihydropyrroles.9a ACS Paragon Plus Environment

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Inspired by this finding, we anticipate that α,β-unsaturated ketones, a ubiquitous motif, can be used to construct multi-substituted 2,3-dihydropyrroles, which are useful building blocks for drug development. However, to the best of our knowledge, such reactions have not been explored.

Previous methods: R4

R3 R2

R5 H

R1

N

+

H

R1

Ph

R2

N

O R2 Rh(II)

2

R

R3

Ts N

O R1 base R4

(2)

R1

R3 R4

N Ts

H

base, DMSO

R1

T his method: N N

Cu(OAc)2 , O2

H

HN

R1

R5 (1)

N

COR3

R2

R3

R4

R2

Cu(OAc)2

Ph

H

R3

[CpRuCl2]2 AgSbF6

R2

H N

O R1

R4 R3 R2 = H

Scheme 1. Methods for synthesis of multi-substituted pyrrole rings Indeed, we have explored reactions of α,β-unsaturated ketones with α-imino carbenes but failed to obtain any desired products. The poor reactivity of α-imino carbenes with ketones is in sharp contrast to that of classical α-ester carbenes, which have been widely utilized to generate oxonium ylides using ketones as a reaction partner.13 The reactivity of formamide with α-imino carbenes suggested that the high electron density of nucleophilic oxygen atoms is essential in this reaction.12 Moreover, we previously found that cyclic α,β-unsaturated amide 3-methyleneindolin-2-ones could afford pyrroloindoles, while no products were obtained with linear α,β-unsaturated amides.12c Considering the impact of the electronic effects and structurally rigidity, enhancing the reactivity of α-imino carbenes through tuning the substituents on the α,β-unsaturated ketone derivative may be favorable. Herein we report a feasible protocol for synthesizing multi-substituted 2,3-dihydropyrroles/pyrroles using α,β-unsaturated ketones as substrates (Scheme 1, eq 2). ACS Paragon Plus Environment

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RESULTS AND DISCUSSION For this purpose, we initially examined the reaction of N-tosyl-4-phenyl-1,2,3-triazole (1a, 0.4 mmol) with 2-benzylidenebenzofuran-3(2H)-one (2a, 0.2 mmol) in the presence of Rh2(OAc)4 (2.0 mol %) in dichloromethane (DCM) at 100 °C. However, only decomposition of the reactants was observed after 2 h (Table 1, entry 1). To our delight, trans-2,3-dihydro-1H-benzofuro[3,2-b]pyrrole (product 3a) was obtained in 54% yield as the only product using Rh2(Oct)4 as the catalyst (Table 1, entry 2).

9a,12c,14

Rh2(Piv)4 and Rh2(esp)2 exhibited comparable activities, furnishing 3a in moderate yields (entries 3-4). Rh2(TFA)4 did not lead to any products (entry 5). Interestingly, Rh2(S-PTV)4 was highly effective, affording the product in excellent yield (87%, entry 6). A structurally similar catalyst, Rh2(S-PTTL)4, was also active in this reaction and resulted in 83% yield (entry 7). Unfortunately, when catalysts bearing bulky ligands were exploited, the reaction was substantially suppressed (entries 8 and 9). Further optimization of the reaction conditions using Rh2(S-PTV)4 revealed that 110 °C was the optimal temperature (entries 10 and 11).


4

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Table 1. Optimization of Reaction Conditions of 1a and 2a a

N

N

O N Ts

Rh(II)

+ O

Ph 1a

O

Ts N

Ph

CH2Cl2

Ph

Ph

O 3a

2a

entry

Rh2L4

temp (°C)

yield b

1

Rh2(OAc)4

100

0

2

Rh2(Oct)4

100

54

3

Rh2(Piv)4

100

50

4

Rh2(esp)2

100

65

5

Rh2(TFA)4

100

0

6

Rh2(S-PTV)4

100

87

7

Rh2(S-PTTL)4

100

83

8

Rh2(S-NTV)4

100

10

9

Rh2(S-NTTL)4

100

80%). In the case of 5b, the reaction condition was modified slightly to improve the yield, producing 0.96 g product in 63% yield. Therefore, the approach has the potential as a practical tool for synthesizing multi-substituted pyrrole derivatives. Scheme 5. Scale-up synthesis of products 3k and 5b O N

N

N Ts

+

Ts N Rh2(S-PTV)4 (121mg)

O

Ph

1.91 g, 6.4 mmol

N

N

0.81 g, 3.2 mmol

OMe

Ph

1.93 g, 5.5 mmol

+

0.83 g, 3.0 mmol

OMe

3k

1.36 g, 82% yield MeO

Ph

MeO

Ph

O

CH2Cl2 (8 mL), 110 oC, 2 h

O N Ts

O

Ts N

Rh2(S-PTV)4 (139 mg) CH2Cl2 (15 mL), 115-120 oC, 2 h

O Ph

5b

0.96 g, 63% yield

The proposed catalytic cycle for the formation of products 3 and 5 is depicted in Scheme 6 based on the experimental results and literature precedent. First, the triazole generates α-imino rhodium carbene species in the presence of a Rh(II) catalyst. Subsequent nucleophilic attack on the carbene species by the oxygen atom of the α,β-unsaturated ketone leads to the formation of oxonium ylide species A. The nucleophilic attack by the imino group of A on the carbon atom of the carbonyl group followed by ACS Paragon Plus Environment

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1,2-addition forms oxazole compound B. However, B is unstable, and C-O bond cleavage and rearrangement afford the multi-substituted 2,3-dihydropyrrole. On the other hand, A can give seven-membered heterocyclic products through intramolecular ring closure.

9a,12c

However, no

1,4-addition type product was detected during the whole work. We could attribute this excellent selectivity to the high electron-attracting property of carbonyl groups towards amino groups and the preferential generation of five-membered rings rather than seven-membered rings. Scheme 6. Proposed Catalytic Cycle to Generate 3 or 5 R2

O N

N

Rh

Rh(II)

N Ts

- N2

R1

NTs

R2

R1 R2

O

- Rh(II)

R1 R2

path 1 R3 R2

TsN A

O R1

R3 Reported Product

B O

Ts N

R1 Rh

TsN A

R3

N Ts

R3

R3

O

R1 Rh

R2 1,4-addition path 2

O

R1

NTs R3 Undetected Product

CONCLUSIONS In summary, we have described a new and efficient method for the synthesis of multi-substituted 2,3-dihydropyrroles from α-imino rhodium carbenes and α,β-unsaturated ketones in moderate to excellent yields. These products can be facilely converted into multi-substituted pyrroles through an E1cB/prototropy sequence. The protocol outlined here proved the obvious nucleophilicity of α,β-unsaturated ketones towards α-imino rhodium carbenes, which may enable the rapid construction of molecular complexity for generating various bioactive pharmaceuticals.

EXPERIMENTAL SECTION 1H

NMR spectra were recorded in deuterated solvents on a Bruker 400 (400 MHz) spectrometer and

calibrated to the residual solvent peak or tetramethylsilane (δ = 0 ppm). CDCl3 or d6-DMSO was used ACS Paragon Plus Environment

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as solvent. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, br = broad. J-values are in Hz. HRMS was measured by a Finnigan MA+ mass spectrometer or a GCT Premier (7000FWHM). Organic solvents used were dried by standard methods when necessary. Commercially obtained reagents were used without further purification. All reactions were monitored by TLC with Huanghai GF254 silica gel coated plates. Organocatalysts were synthesized according to the literatures. Flash column chromatography was carried

out

using

200-300

mesh

silica

gel

at

increased

pressure.

Starting

materials

N-tosyl-4-phenyl-1,2,3-triazole 1,15 2-benzylidenebenzofuran-3(2H)-one 2, 16 and Chalcone deriviatives 4 17were prepared according to literatures. General procedure for the synthesis of products 3, 5 and 6a. A 15 mL tube was filled with N2 before it was charged with a solution of N- Sulfonyl-1,2,3-triazole 1 (0.40 mmol), 2-Methylenebenzofuran-3(2H)-one 2 (0.20 mmol) and Rh2(S-PTV)4 (8.0 μmol ) in dry DCM (1.0 mL). The tube was sealed, and the reaction mixture was stirred at 110 °C in an oil bath. The reaction was monitored by TLC, and generally finished in 2 h. After completion and the removal of solvent, the resulting product 3 was isolated by column chromatography on silica gel using ethyl acetate-petroleum ether mixture as eluent. The preparation of 5 and 6a is of generally the same method as above. The reaction was conducted in DCM at 130 °C. Phenyl(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3a):

petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 175 °C-177 °C; yield: 82 mg, 83%; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H),7.56 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.37-7.42 (m, 2H), 7.33-7.37 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.04 (t, J = 7.8 Hz, 2H), 6.34 (d, J = 7.2 Hz, 2H), 5.36 (d, J = 5.4 Hz, 1H), 4.41 (d, J = 5.4 Hz, 1H), 2.44 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 193.4, 160.0, 149.4,

144.5, 138.3, 134.2, 133.9, 131.5, 130.1, 129.2, 128.9, 128.8, 128.5, 128.4, 128.0, 127.4, 125.0, 124.0, 120.7, 120.2, 112.5, 79.2, 48.3, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H24NO4S 494.1426; Found 494.1442. (4-Ethylphenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3b):

petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 202 °C- 204 °C yield: 88 mg, 84%; 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.32-7.43 (m, 3H), 7.18-7.27 (m, 5H), 7.04 (t, J = 7.6 Hz, 2H), 6.34 (d, J = 7.2 Hz, 2H), 5.34 (d, J = 5.2 Hz, 1H), 4.41 (d, J = 5.2 Hz, 1H), 2.71 (q, J = 7.6 Hz, 2H), 2.45 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H), ; 13C {1H} NMR (100 MHz, CDCl3): δ = 188.1, 155.2, 146.4, 144.7, 139.8, 133.6, 126.9, 126.7, 125.4, 124.7, ACS Paragon Plus Environment

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124.1, 123.7, 123.6, 123.5, 123.2, 122.7, 120.2, 119.2, 115.9, 115.4, 107.8, 74.3, 43.6, 24.3, 16.9, 10.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H28NO4S 522.1733; Found 522.1740. (4-Methoxyphenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3c):

petroleum ether:ethyl acetate = 3:1; white solid; mp = 204 °C-206 °C; yield: 96 mg, 92%; 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.33-7.44 (m, 3H), 7.17-7.26 (m, 3H), 7.05 (t, J = 7.6 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.34 (d, J = 7.6 Hz, 2H), 5.31 (d, J = 5.2 Hz, 1H), 4.41 (d, J = 5.2 Hz, 1H), 3.87 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 191.8, 164.3, 160.0, 149.6, 144.6, 138.5, 131.7, 131.4, 130.1, 128.8, 128.5, 128.4, 128.0, 127.5, 126.9, 124.9, 123.9, 120.7, 120.3, 114.1, 112.5, 78.9, 55.6, 48.5, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H26NO5S 524.1532; Found 524.1529. (4-Fluorophenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3d):

petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 178 °C-180 °C; yield: 62 mg, 61%; 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 1H), 7.86 (dd, J = 8.4 Hz, 5.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.32-7.44 (m, 3H), 7.17-7.26 (m, 3H), 7.11 (t, J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz, 2H), 6.34 (d, J = 7.6 Hz, 2H), 5.28 (d, J = 5.2 Hz, 1H), 4.42 (d, J = 5.2 Hz, 1H), 2.45 (s, 3H);

13C{1H}

NMR (100

MHz, CDCl3): δ =191.9, 160.1, 149.4, 144.7, 138.2, 132.1, 132.0, 131.2, 130.2, 128.9, 128.5, 128.3, 128.1, 127.4, 125.1, 124.1, 120.7, 120.1, 116.2, 116.0, 112.6, 79.3, 48.3, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23FNO4S 512.1332; Found 512.1329. (4-Chlorophenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3e):

petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 180 °C-182 °C; yield: 58 mg, 55%; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.33-7.43 (m, 5H), 7.18-7.25 (m, 3H), 7.06 (t, J = 7.6 Hz, 2H), 6.34 (d, J = 7.6 Hz, 2H), 5.26 (d, J = 5.2 Hz, 1H), 4.43 (d, J = 5.2 Hz, 1H), 2.45 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 192.4, 160.1,

149.3, 144.7, 140.6, 138.2, 132.4, 131.2, 130.6, 130.2, 129.2, 128.9, 128.5, 128.2, 128.1, 127.4, 125.1, 124.1, 120.7, 120.1, 112.6, 79.4, 48.3, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23ClNO4S 528.1036; Found 528.1028. (4-Bromophenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3f):

petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 181°C-183 °C; yield: 66 mg, 58%; 1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.53-7.59 (m, 4H), 7.33-7.43 (m, 3H), 7.19-7.24 (m, 3H), 7.06 (t, J = 7.6 Hz, 2H), 6.36 (d, J = 7.6 Hz, 2H), 5.26 (d, J = 5.2 Hz, 1H), 4.43 (d, J = 5.2 Hz, 1H), 2.44 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 192.7, 160.1, 149.3,

144.7, 138.2, 132.9, 132.2, 131.2, 130.7, 130.2, 129.4, 128.9, 128.5, 128.3, 128.1, 127.4, 125.1, 124.1, ACS Paragon Plus Environment

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120.7, 120.1, 112.6, 79.4, 48.3, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23BrNO4S 572.0531; Found 572.0528. (3-Fluorophenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3g):

petroleum ether:ethyl acetate = 10:1-6:1; white solid; mp = 209 °C-212 °C; yield: 82 mg, 80%; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 1H), 7.53-7.58 (m, 4H), 7.35-7.44 (m, 4H), 7.86 (dt, J = 2.0 Hz, 8.0 Hz, 1H), 7.18-7.26 (m, 3H), 7.06 (t, J = 7.6 Hz, 2H), 6.35 (d, J = 7.6 Hz, 2H), 5.27 (d, J = 5.2 Hz, 1H), 4.42 (d, J = 5.2 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, d6-DMSO): δ = 192.2, 159.6, 150.5, 145.8, 138.4, 136.3, 131.7, 131.1, 131.0, 129.2, 128.6, 128.5, 127.8, 127.3, 125.8, 125.7, 124.9, 121.9, 119.9, 119.8, 115.9, 113.4, 78.8, 55.4, 46.7, 21.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23FNO4S 512.1332; Found 512.1333. (3,5-Dimethylphenyl)(3-phenyl-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)methanone

(3i):

petroleum ether:ethyl acetate = 4:1; white solid; mp = 225 °C-228 °C; yield: 87 mg, 83%; 1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.36-7.41 (m, 3H), 7.35 (s, 2H), 7.19-7.26 (m, 4H), 7.04 (t, J = 7.6 Hz, 2H), 6.34 (d, J = 7.2 Hz, 2H), 5.41 (d, J = 5.2 Hz, 1H), 4.33 (d, J = 5.2 Hz, 1H), 2.46 (s, 3H), 2.26 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ = 193.2, 160.0, 149.4, 144.5, 138.4, 135.6, 134.0, 131.9, 130.1, 128.8, 128.5, 128.4, 128.0, 127.7, 127.1, 124.9, 123.9, 120.8, 120.3, 112.5, 79.2, 48.4, 21.6, 21.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H28NO4S 522.1733, Found 522.1731. Phenyl(3-(p-tolyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3j):

petroleum ether:ethyl acetate = 10:1-6:1; white solid; mp = 181°C-182 °C; yield: 82 mg, 81%;1H NMR (600 MHz, CDCl3): δ = 8.18 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.32-7.42 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 7.6 Hz, 2H), 6.20 (d, J = 7.6 Hz, 2H), 5.34 (d, J = 5.2 Hz, 1H), 4.37 (d, J = 5.2 Hz, 1H), 2.47 (s, 3H), 2.29 (s, 3H) ; 13C{1H} NMR (100 MHz, CDCl3): δ = 193.4, 160.0, 149.6, 144.5, 137.8, 135.3, 134.2, 133.9, 131.6, 130.1, 129.5, 129.2, 128.8, 128.5, 128.1, 127.4, 124.9, 123.9, 120.7, 120.2, 112.5, 79.3, 48.1, 21.6, 21.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H26NO4S 508.1583; Found 508.1580. (3-(4-methoxyphenyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3k):

petroleum ether:ethyl acetate = 4:1; white solid; mp = 180 °C-182 °C; yield: 92 mg, 88%; 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.40-7.45 (m, 3H), 7.27 (d, J = 7.6 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 8.4 Hz, 2H), 5.34 (d, J = 5.2 Hz, 1H), 4.39 (d, J = 5.2 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 193.3, 160.0, 159.2, 149.6, 144.6, 134.1, 134.0, 131.5, ACS Paragon Plus Environment

14

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130.3, 130.2, 129.2, 128.9, 128.6, 128.5, 128.1, 124.9, 124.0, 120.7, 120.2, 114.2, 112.5, 79.4, 55.3, 47.8, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H26NO5S 524.1532; Found 524.1535. (3-(4-Fluorophenyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3l):

petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 197 °C-200 °C; yield: 74 mg, 72%; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.36-7.44 (m, 3H), 7.24 (d, J = 8.4 Hz, 2H), 6.74 (t, J = 8.4 Hz, 2H), 6.26-6.35 (m, 2H), 5.30 (d, J = 5.2 Hz, 1H), 4.41 (d, J = 5.2 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 193.1, 159.7, 150.4, 145.9, 134.8, 134.1, 131.0, 129.8, 129.7, 129.6, 129.4, 128.4, 127.6, 125.8, 124.9, 120.0, 119.9, 116.2, 115.9, 113.5, 78.3, 46.0, 21.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23FNO4S 512.1332; Found 512.1334. (3-(4-Bromophenyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3m):

petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 175 °C-177 °C; yield: 80 mg, 70%; 1H NMR (400 MHz, d6-DMSO): δ = 8.03 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.75 (t, J = 7.2 Hz, 1H), 7.53-7.57 (m, 5H), 7.41-7.50 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.25 (d, J = 8.0 Hz, 2H), 5.53 (d, J = 4.4 Hz, 1H), 4.79 (d, J = 4.4 Hz, 1H), 2.44 (s, 3H);

13C{1H}

NMR (100 MHz,

d6-DMSO): δ = 193.1, 159.7, 150.3, 145.8, 138.1, 134.8, 134.2, 132.1, 131.2, 130.9, 129.7, 129.6, 129.5, 128.4, 127.8, 125.8, 124.9, 121.6, 120.1, 119.9, 113.5, 77.9, 46.1, 21.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23BrNO4S 572.0531; Found 572.0529. (3-(3-Methoxyphenyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3n):

petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 201 °C-212 °C; yield: 86 mg, 82%; 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.34-7.45 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 6.99 (t, J =8.0 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.01 (s, 1H), 5.97 (d, J = 7.6 Hz, 1H), 5.41 (d, J = 5.2 Hz, 1H), 4.71 (d, J = 5.2 Hz, 1H), 3.67 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, d6-DMSO): δ = 193.3, 159.8, 159.7, 150.3, 145.9, 140.0, 134.8, 134.3, 130.9, 130.3, 129.5, 129.4, 128.3, 127.5, 125.7, 124.8, 120.0, 119.9, 119.7, 114.0, 113.5, 113.4, 78.4, 55.5, 47.1, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H26NO5S 524.1532; Found 524.1537. (3-(2-Fluorophenyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3o):

petroleum ether:ethyl acetate = 5:1; white solid; mp = 176 °C-178 °C; yield: 82 mg, 85%; 1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.39-7.47 (m, 3H), 7.38 (t, J = 7.6 Hz, 2H), 7.14-7.20 (m, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.94 (t, J = 8.8 Hz, 1H), 6.89 (t, J = 8.8 Hz, 1H), 5.97 (t, J = 7.6 Hz, 1H), 5.45 (d, J = 4.8 Hz, 1H), 4.88 ACS Paragon Plus Environment

15


(d, J = 4.8 Hz, 1H), 2.39 (s, 3H);

13C{1H}

Page 16 of 24

NMR (100 MHz, CDCl3): δ = 193.6, 159.8, 149.6, 145.8,

134.9, 134.2, 130.9, 130.8, 130.6, 130.5, 129.5, 129.4, 128.7, 128.6, 128.4, 128.2, 125.9, 125.3, 125.2, 124.9, 120.0, 116.2, 115.9, 113.5, 76.6, 21.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23FNO4S 512.1332; Found 512.1332 . (3-(Naphthalen-2-yl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3p):

petroleum ether:ethyl acetate = 4:1; white solid; mp = 207 °C-208 °C; yield: 78 mg, 75%; 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.77 (d, J = 7.2 Hz, 1H), 7.47-7.63 (m, 4H), 7.37-7.46 (m, 8H), 7.18 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.40 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 5.48 (d, J = 5.2 Hz, 1H), 4.60 (d, J = 5.26 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, d6-DMSO): δ = 193.3, 159.7, 150.5, 145.8, 136.0, 134.9, 134.1, 133.0, 132.7, 131.2, 131.1, 129.5, 129.4, 129.1, 128.5, 128.1, 127.6, 127.1, 127.0, 126.9, 125.8, 125.2, 124.9, 120.0, 119.9, 113.5, 78.2, 47.2, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C34H26NO4S+ 544.1583; Found 544.1581. Phenyl(3-(4-(4-phenyl-1-tosyl-1H-imidazol-2-yl)phenyl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrro l-2-yl) methanone (3q): petroleum ether:ethyl acetate = 10:1-2:1; white solid; mp = 217 °C-219 °C; yield: 70 mg, 44%;1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.37-7.50 (m, 7H), 7.33 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.22-7.25 (m, 2H), 7.14-7.19 (m, 4H), 6.37 (d, J = 8.0 Hz, 2H), 5.32 (d, J = 5.2 Hz, 1H), 4.53 (d, J = 5.2 Hz, 1H), 2.45 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ =193.3, 160.1, 148.8, 147.7, 146.2, 145.2, 142.2, 141.1, 140.3, 134.3, 134.2, 134.0, 132.5, 132.0, 131.2, 131.1, 130.3, 129.9, 129.2, 129.0, 128.8, 128.4, 128.2, 127.7, 127.5, 126.9, 125.3, 124.2, 120.9, 120.1, 115.6, 112.6, 79.4, 48.1, 21.8, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C46H36N3O6S2 790.2046; Found 790.2049. (3-(5-Methylfuran-2-yl)-1-tosyl-2,3-dihydro-1H-benzofuro[3,2-b]pyrrol-2-yl)(phenyl)methanone

(3s):

petroleum ether:ethyl acetate = 10:1-6:1; white solid; mp = 214 °C-217 °C; yield: 82 mg, 82%;1H NMR (400 MHz, d6-DMSO): δ = 8.01 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.74 (t, J = 7.6 Hz, 1H), 7.55-7.63 (m, 5H), 7.41-7.48 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 5.89 (d, J = 2.0 Hz, 1H), 5.72 (d, J = 5.2 Hz, 1H), 5.66 (d, J = 3.5 Hz, 1H), 4.86 (d, J = 5.2 Hz, 1H), 3.37 (s, 3H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 192.3, 158.9, 152.2, 148.0, 147.1, 144.8, 134.3, 133.5, 131.0, 130.2, 129.0, 128.9, 127.8, 126.7, 125.3, 124.3, 119.5, 119.4, 112.9, 109.2, 106.6, 74.7, 40.4, 21.0, 13.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H24NO5S 498.1375; Found 498.1374. (5-(2,4-Dimethoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(phenyl)methanone

(5a):

petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 153 °C-154 °C; yield: 78 mg, 72%; 1H NMR ACS Paragon Plus Environment

16

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(400 MHz, CDCl3): δ = 8.04 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.35-7.40 (m, 3H), 7.15-7.24 (m, 5H), 6.83 (d, J = 7.2 Hz, 2H), 6.47 (dd, J = 8.4 Hz, 2.0 Hz, 2H), 6.37 (s, 1H), 5.40 (d, J = 5.2 Hz, 1H), 5.16 (d, J = 2.4 Hz, 1H), 3.96-3.98 (m, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 2.44 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 195.6, 161.8, 159.0, 143.5, 142.0, 141.3, 134.9,

134.5, 133.4, 132.6, 129.4, 129.2, 128.7, 128.6, 128.4, 127.7, 127.3, 114.8, 113.2, 103.7, 98.2, 73.7, 55.4, 55.3, 50.9, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C32H30NO5S 540.1839; Found 540.1827. (5-(4-Methoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(phenyl)methanone

(5b):

petroleum ether:ethyl acetate = 10:1-6:1; white solid; mp = 163 °C-164 °C; yield: 75 mg, 74%; 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.46-7.53 (m, 4H), 7.41 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 7.6 Hz, 2H), 5.50 (d, J = 4.4 Hz, 1H), 5.13 (d, J = 3.6 Hz, 1H), 3.87 (t, J = 3.6 Hz, 1H), 3.85 (s, 3H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 195.5, 160.3, 145.4, 143.9, 141.5, 134.6, 134.4, 133.6, 130.2, 129.6, 129.1, 128.8, 128.7, 128.2, 127.6, 127.3, 124.2, 114.1, 113.2, 73.5, 55.3, 50.8, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H28NO4S 510.1733; Found 510.1720. (5-(4-Iodophenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(phenyl)methanone

(5d):

petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 166 °C-168 °C; yield: 67 mg, 53%; 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 5.51 (d, J = 4.0 Hz, 1H), 5.18 (d, J = 3.2 Hz, 1H), 3.81 (t, J = 4.0 Hz, 1H), 3.80 (s, 3H), 2.49 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 195.1, 158.9, 144.4,

144.2, 136.9, 134.7, 134.2, 133.7, 133.0, 131.5, 130.4, 129.7, 129.1, 128.8, 128.7, 128.2, 116.2, 114.1, 94.9, 73.2, 55.3, 50.4, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H27INO4S 636.0699; Found 636.0702. (3-(2-Fluorophenyl)-(5-(4-methoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)methanone (5f): petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 113 °C-115 °C; yield: 47 mg, 45%; 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.4 Hz, 2H), 7.60-7.65 (m, 1H), 7.48-7.52 (m, 4H), 7.40 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.80-6.87 (m, 4H), 6.65 (dd, J = 8.4, 5.2 Hz, 2H), 5.45 (d, J = 4.4 Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H), 3.86 (t, J = 4.4 Hz, 1H), 3.85 (s, 3H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 195.5, 160.3, 145.7, 144.0, 137.4, 137.2, 134.7, 134.4, 133.7, 130.1, 129.6, 129.2, 129.1, 129.0, 128.8, 128.2, 124.0, 115.6, 115.4, 113.8, 113.2, 73.4, 55.3, 49.9, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H27FNO4S 528.1645; Found 528.1641. ACS Paragon Plus Environment

17


Page 18 of 24

(3-(4-Methoxylphenyl)-(5-(4-methoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)methanone (5g): petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 125 °C-127 °C; yield: 76 mg, 70%; 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.46-7.51 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 5.46 (d, J = 4.4 Hz, 1H), 5.10 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H), 3.82 (t, J = 4.0 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 195.4, 160.2, 158.8, 145.1, 143.9,

134.8, 134.4, 133.6, 130.2, 129.6, 129.1, 128.8, 128.7, 128.3, 124.2, 114.4, 114.0, 113.2, 73.7, 55.3, 55.2, 50.2, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H30NO5S 540.1839; Found 540.1833. (5-(4-Methoxyphenyl)-3-(naphthalene-2-yl)-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(phenyl)methanone (5h): petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 127 °C-129 °C; yield: 72 mg, 64%; 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.2 Hz, 2H), 7.96 (dd, J = 6.0 Hz, 3.6 Hz, 1H), 7.61-7.65 (m, 2H), 7.55-7.59 (m, 3H), 7.48-7.51 (m, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.84 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 5.58 (d, J = 4.0 Hz, 1H), 5.23 (d, J = 3.2 Hz, 1H), 4.05-4.07 (m, 1H), 3.86 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 195.8, 160.3, 145.7, 144.0, 139.0, 134.6, 134.5, 133.6, 133.2, 132.6, 130.2, 129.6, 129.1, 128.8, 128.6, 128.2, 127.9, 127.7, 126.3, 126.2, 126.1, 125.4, 124.2, 113.9, 113.2, 73.4, 55.3, 50.8, 21.6; HRMS (ESI-TOF) m/z:

[M+H]+

Calcd

for

C35H30NO4S

560.1896;

Found

560.1894.

(5-(4-methoxyphenyl)-3-(5-methylfuran-2-yl)-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(phenyl)methanone (5i): petroleum ether:ethyl acetate = 10:1-6:1; white solid; mp = 103 °C-105 °C; yield: 69 mg, 67%; 1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.50-7.55 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.78 (d, J = 3.2 Hz, 1H), 5.71 (d, J = 1.6 Hz, 1H), 5.39 (d, J = 2.4 Hz, 1H), 5.14 (d, J = 3.6 Hz, 1H), 3.90-3.93 (m, 1H), 3.85 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 194.3, 160.3, 151.6，151.5, 146.0, 143.5, 134.8, 134.0, 133.6, 130.1, 129.3, 129.2, 128.8, 127.9, 124.2, 113.2, 111.1, 107.4, 106.3, 70.8, 55.3, 43.9, 21.6, 13.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H28NO5S 514.1688; Found 514.1689. (5-(2,4-Dimethoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(4-flurophenyl)methanone (5j): petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 122 °C-124 °C; yield: 62 mg, 56%; 1H NMR (400 MHz, CDCl3): δ = 8.11 (dd, J = 8.0 Hz, 5.6 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.13-7.25 (m, 7H), 6.79 (d, J = 7.2 Hz, 2H), 6.48 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.39 (s, 1H), 5.25-5.30 (m, 1H), 5.16 (d, J = 2.4 Hz, 1H), 3.96-3.99 (m, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 2.45 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3): δ = 194.2, 161.9, 159.1, 143.6, 141.9, 134.5, 132.5, 132.2, 132.1,

130.8, 129.2, 128.8, 128.4, 127.6, 127.4, 115.9, 115.6, 114.7, 113.1, 103.8, 98.3, 77.3, 74.1, 55.4, 51.0, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H29FNO5S 558.1744; Found 558.1739. ACS Paragon Plus Environment

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(5-(2,4-Dimethoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(4-chlorophenyl)methanone (5k): petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 179 °C-180 °C; yield: 61 mg, 53%; 1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.16-7.20 (m, 4H), 6.79 (d, J = 6.8 Hz, 2H), 6.48 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.25 (d, J = 5.6 Hz, 1H), 5.16 (d, J = 2.8 Hz, 1H), 3.97 (dd, J = 5.2 Hz, 2.8 Hz, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 2.45 (s, 3H);

13C{1H}

NMR (100 MHz,

CDCl3): δ = 194.6, 161.9, 159.1, 143.7, 141.9, 141.5, 139.9, 134.4, 132.8, 132.5, 130.9, 129.2, 128.9, 128.8, 128.4, 127.6, 127.5, 114.7, 113.0, 103.7, 98.2, 74.2, 55.5, 55.4, 51.0, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H29ClNO5S 574.1449; Found 574.1448. (5-(2,4-Dimethoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(3-flurophenyl)methanone (5l): petroleum ether:ethyl acetate = 10:1-5:1; white solid; mp = 159 °C-160 °C; yield: 46 mg, 41%; 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 7.2 Hz, 2H), 7.46-7.50 (m, 1H), 7.31-7.39 (m, 4H), 7.23 (d, J = 7.6 Hz, 1H), 7.13-7.22 (m, 4H), 6.79 (d, J = 7.2 Hz, 2H), 6.48 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.21 (d, J = 5.2 Hz, 1H), 5.16 (d, J = 2.8 Hz, 1H), 3.98-4.00 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 2.46 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 194.5, 161.9, 159.2, 143.7, 141.8, 136.5,

134.3, 132.4, 130.2, 129.3, 128.8, 128.5, 127.6, 127.5, 125.2, 120.6, 120.3, 116.4, 116.1, 114.7, 113.0, 103.7, 98.2, 74.5, 55.4, 55.3, 50.9, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H29FNO5S 558.1744; Found 558.1742. (5-(2,4-Dimethoxyphenyl)-3-phenyl-1-tosyl-2,3-dihydro-1H-pyrrol-2-yl)(3-Methoxylphenyl)methanone (5m): petroleum ether:ethyl acetate = 10:1-4:1; white solid; mp = 164 °C-166 °C; yield: 51 mg, 45%; 1H NMR (400 MHz, CDCl3): δ = 7.56 (dd, J = 8.0, 2.4 Hz, 2H), 7.35-7.40 (m, 4H), 7.15-7.24 (m, 6H), 6.85 (d, J = 7.2 Hz, 2H), 6.46 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.42 (d, J = 4.8 Hz, 1H), 5.15 (d, J = 3.2 Hz, 1H), 3.96 (dd, J = 4.8 Hz, 3.2 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 195.3, 161.8, 159.8, 159.0, 143.5, 142.0, 141.2, 135.8, 135.0, 132.6, 129.6, 129.1, 128.7, 128.4, 127.7, 127.3, 121.9, 120.5, 114.7, 113.2, 113.1, 103.7, 98.2, 73.6, 55.5, 55.4, 55.3, 51.0, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C33H32NO6S 570.1944; Found 570.1939. (5-(4-methoxylphenyl)-3-naphthalen-2-yl)-1H-pyrrol-2-yl)(phenyl)methanone

(6a):

petroleum ether:ethyl acetate = 10:1-4:1; light yellow solid; mp = 157 °C-159 °C; yield: 44 mg, 55%; 1H

NMR (400 MHz, d6-DMSO): δ = 12.11 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.75-7.78 (m, 1H), 7.70 (s,

1H), 7.69 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.39-7.42 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.01-7.08 (m, 4H), 6.90 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H); ACS Paragon Plus Environment

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13C{1H}

Page 20 of 24

NMR (100 MHz, CDCl3): δ = 186.3, 159.5, 139.2, 137.6, 134.1, 133.5, 133.1, 131.9, 131.7,

129.5, 128.2, 128.1, 128.0, 127.8, 127.5, 127.2, 126.3, 126.1, 124.1, 114.7, 109.7, 55.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H22NO2 404.1651; Found 404.1653. Procedure for the synthesis of product 6b. A 15 mL tube was filled with a solution of 5h (0.20 mmol) in dry DCM (1.0 mL). DBU (0.20 mmol) was added, and then the reaction mixture was stirred at 80 °C in an oil bath. The reaction was monitored by TLC, and finished in 1h. After completion and the removal of solvent, the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to afford the desired product 6b. (5-(2,4-dimethoxylphenyl)-3-phenyl-1H-pyrrol-2-yl)(4-pentylphenyl)methanone

(6b):

light

yellow

solid; mp = 146 °C-148 °C; yield: 103 mg, 92%; 1H NMR (400 MHz, CDCl3): δ = 10.54 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.11-7.14 (m, 2H), 7.04-7.06 (m, 3H), 6.87 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 2.8 Hz, 1H), 6.59-6.61 (m, 1H), 6.58 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 2.49 (t, J = 7.2 Hz, 2H), 1.47-1.55 (m, 2H), 1.27-1.35 (m, 2H), 1.18-1.25 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ = 186.0, 160.7, 157.3, 146.3, 136.0, 135.9, 135.0, 134.1, 129.7, 129.4, 128.7, 127.6, 127.5, 126.6, 126.3, 112.2, 109.6, 105.7, 99.1, 55.9, 55.5, 35.8, 31.2, 30.9, 22.5, 14.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H32NO3 454.2376; Found 454.2376. ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author *‡ E-mail: [email protected] Notes The authors declare no competing ﬁnancial interest.

S Supporting Information ○

Details of NMR spectra of the compounds prepared. This material is available free of charge via the Internet at http://pubs.acs.org. ACKNOWLEDGMENT.


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The authors thank the financial support from the National Natural Science Foundation of China (Nos. 21702176, 81773193, and 81571799) and the Key Scientific Research Project of Henan Province (17A150046).

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Ts R2

O

N

H2 R3

H1

B

A

(15) (a) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. Rhodium-catalyzed enantioselective cyclopropanation of olefins with N-sulfonyl-1,2,3-triazoles. J. Am. Chem.Soc. 2009, ACS Paragon Plus Environment

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