Iterative Assembly of Nitrile Oxides and Ynamides: Synthesis of

Subscriber access provided by Chalmers Library

Note

Iterative Assembly of Nitrile Oxides and Ynamides: Synthesis of Isoxazoles and Pyrroles Changwei Chen, and Sunliang Cui J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01430 • Publication Date (Web): 21 Aug 2019 Downloaded from pubs.acs.org on August 25, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Iterative Assembly of Nitrile Oxides and Ynamides: Synthesis of Isoxazoles and Pyrroles Changwei Chen and Sunliang Cui* Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Supporting Information Placeholder

N R

1

OH + Cl

R2 N Ts

Cu(I) free base

N O R1

Ts N R2

O

R4 N Ts

R3

R2 N Ts

R3 R4 N Ts

PPh3AuCl(5 mol %) AgNTf2 (10 mol %)

23 examples 60-99% yield

R1

N H

20 examples 78-99% yield

ABSTRACT: Described is an iterative assembly of nitrile oxides and ynamides for the synthesis of isoxazoles and pyrroles. The nitrile oxides could undergo Cu(I)-free cyclization with terminal ynamides for accessing isoxazoles, which could engage in another cyclization with internal ynamides in the presence of Au(I) catalyst to deliver pyrroles. And the reaction could be carried out in a two-step, one-pot procedure. This process is featured with mild reaction condition and broad substrate scope for the synthesis of heterocycles.

Nitrogen containing heterocycles are an integral part of many biologically active molecules, and there are many marketed drugs hold heterocycles as their core structure.1 Therefore, the synthesis of highly functionalized heterocycles is important and also receives considerable attention in organic synthesis and drug discovery.2 Typically, the cyclization of nitrile oxides represent a distinct approach toward heterocycles, such as isoxazoles, isoxazolines, and oxadiazoles.3 For example, the Cu(I)catalyzed [3+2] cyclization of nitrile oxides with terminal alkynes could deliver isoxazoles smoothly,4 while a Cu(I)-free cyclization method was also established (Scheme 1a).5 Additionally, the regioselectivity could be reversed when [Cp*RuCl(cod)] was used as catalyst (Scheme 1b).6 Meanwhile, the Cu(I)-catalyzed [3+2] cyclization of nitrile oxides with terminal ynamides was investigated for accessing amino isoxazoles (Scheme 1c).7 Despite these advances, the development of divergent reactivity between nitrile oxides and ynamides toward heterocycles with the achievement of structural diversity are interesting and attractive. In continuation of our research in multicomponent reaction for heterocycles synthesis,8 we envisioned that nitrile oxides could undergo differential catalyst-dependent cyclization with ynamides. Herein, we would like to report an iterative assembly of nitrile oxides and ynamides for access to isoxazoles and pyrroles (Scheme 1d). We commenced our study by investigating Nhydroxybenzimidoyl chloride 1a and N-ethynyl-N,4dimethylbenzenesulfonamide 2a as model substrates. The Nhydroxybenzimidoyl chloride 1a could be simply prepared by chlorination of oxime, while 2a was also easily accessible. When the reaction was conducted in DCM at room temperature

Scheme 1. Cyclization of Nitrile Oxides with Alkynes. (a) [3+2] cyclization with terminal alkynes R1

N O

Cu(I) or

R2

+

N

R1

Cu(I) free

O R2

(b) Ru(I)-catalyzed [3+2] cyclization with terminal alkynes R1

N O

[Cp*RuCl(cod)]

R2

+

N

R1 R

O

2

(c) Cu(I)-catalyzed [3+2] cyclization with terminal ynamides R1

N O

R2 N R3

+

Cu(I)

R1

N

O N R3 R2

(d) Iterative assembly with ynamides

R1

R2 N Ts

N O

R1

N

O N Ts R2

Cu(I) free

R4 N Ts

R3

Au(I) catalyst

O R3 R4 N Ts

O Ph Ph

N

O

OMe

O N CYP11B1 inhibitor

NHPh

OH

HO

NH

Atorvastatin

N H O

F OH

R1 NEt2

O

N

F

N H

R2 N Ts

NH Sunitinib

without any bases, a product could be formed in 58% yield (Table 1, entry 1), and the product was identified by standard characterization as the desired amino isoxazole. When TEA was added as base, the yield could be improved significantly to 95% (entry 2). The next survey of solvents showed that THF

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

and dioxane were comparable to DCM, while MeOH, CH3CN and DMF were inferior to give slightly lower yields (entries 37). When the reaction temperature was lowered to 0 °C, the yield of 3a would decrease (entry 8). Raising the reaction temperature to 40 °C would furnish 3a in same yield (entry 9). Meanwhile, the next screening of bases showed that Na2CO3 was also optimal while the utilization of DIPEA, pyridine and DBU would decrease the yields (entries 10-13). In addition, we attempted to conduct the reaction in water using Na2CO3 as base, and found this would give a lower yield probably due to the poor solubility of reactants in water (entry 14). Table 1. Reaction Optimization.a N Ph

OH Cl

+

1a

Entry

Solvent

Me N Ts 2a

Temp. [oC]

N

Ph

3a

Base

Page 2 of 10

Table 2. First Assembly of Nitrile Oxides with Ynamides.a N R1

OH Cl

1

R

CH3 N O

Ts N CH3

N O

Yieldb

R1

N O

N O

N O Br

Ph

N O

Ts Ph

Ts N CH3

N O

Ts N CH3 3r, 60%

N O

Ts

3t, 89%

N

Ts N CH3

3o, 82%

N

Ph

N O

N O

Ts N CH3 Ph

3n, 63%

Ts

Ts N CH3

Cl 3l, 96%

Ts N TBSO CH3 3q, 85%

3s, 87% N O

Cl

N O

Ts N CH3 3p, 82%

Ph

Ts N CH3

3k, 97%

N Boc

N

N O Br

3j, 90%

N O

3m, 84%

N O

Ts N CH3

Ts N R2

3

3i, 81%

Ts N CH3

Me

With the optimized reaction condition in hand, the scope of Cu(I)-free [3+2] cyclization between nitrile oxides and terminal ynamides for the synthesis of isoxazoles was established. As shown in Table 2, various N-hydroxybenzimidoyl chlorides with the para- substitution in the aromatic ring, could well engage in this process with ynamide 2a to deliver the products in excellent yields (3b-3h), and the functional groups such as methyl, methoxy, chloro, trifluoromethyl, cyano, ester and amide were found tolerable. Moreover, the structure of compound 3e was confirmed by X-ray analysis.9 Meanwhile, the ortho- and meta- substituted N-hydroxybenzimidoyl chlorides were applicable to provide the products in excellent yields (3i-3l). The N-hydroxybenzimidoyl chlorides with the scaffold of naphthene and indole could engage in this process smoothly (3m and 3n). Moreover, the styrene containing Nhydroxybenzimidoyl chloride were also compatible in this cyclization process to furnish the isoxazole 3o. In addition, when the aliphatic imidoyl chlorides derived from aliphatic aldehyde including butyl, tert-butyl and protected alcohol moieties were employed, the functionalized isoxazoles could be formed in good yields (3p-3r). On the other hand, various ynamides were prepared and subjected to this process. As shown in Table 2, a variety of functional group including 2bromophenyl, (R)-1-phenylethan-1-yl, furan-2-methyl, silyl

DCM, rt

3b, R= CH3, 98% 3c, R= OCH3, 96% 3d, R= Cl, 99% 3e, R= CF3, 92% Br 3f, R= CN, 61% 3g, R= CO2CH3, 85% F 3h, R= NHCOCH3, 86%

N Ts

N O

Na2CO3

2

N O

O

1 DCM 25 58 2 DCM 25 TEA 95 3 THF 25 TEA 94 4 MeOH 25 TEA 81 5 Dioxane 25 TEA 94 6 CH3CN 25 TEA 88 7 DMF 25 TEA 75 8 DCM 0 TEA 85 9 DCM 40 TEA 95 10 DCM 25 DIPEA 86 11 DCM 25 pyridine 80 12 DCM 25 DBU 87 13 DCM 25 Na2CO3 95 14 H2O 25 Na2CO3 80 a Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol) and base (0.3 mmol) were added to solvent (2 mL) and stirred for 5-8 h. b Yield refers to isolated product.

Ts N R2

+

Ph

Ts N

O

3u, 75%

Ts N

OTBS 3v, 84%

3w, 73%

3e

Reaction condition: 1 (0.24 mmol), 2 (0.2 mmol), Na2CO3 (0.3 mmol) were added to DCM (2 mL), and kept at rt for 5-8 h. Yield refers to isolated product. a)

alcohol and cyclohexene were well tolerable. In addition, a gram-scale reaction of 1a and 2a was performed and the desired isoxazole 3a was formed in 86 % yield (See Experimental Section). However, the reaction between nitrile oxides and internal ynamides didn’t afford the expected products. At this stage, we envisioned that the isoxazoles could undergo another cyclization with internal ynamides in the presence of gold catalyst, which is established by Ye and coworkers.10 This would lead to second assembly between nitrile oxides and ynamides. Therefore, we tested this cyclization of amino isoxazoles 3 and ynamides 2 using the reported reaction condition. To our delight, a variety of amino isoxazoles 3 could participate in this [3+2] cyclization smoothly to deliver the corresponding pyrroles in good yields (Table 3). The substitution originated from nitrile oxides, including various functional group in the aromatic rings such as methyl, methoxy, chloro, ester, cyano, trifluoromethyl and amide could be compatible in the process. The functionalized pyrroles (4a-4j) could be furnished in good to excellent yields. Moreover, the butyl substituted isoxazole 3p could be applicable to deliver pyrrole 4k in 92% yield. On the other hand, numerous internal ynamides were also employed in this process to achieve the pyrrole synthesis. A variety of functional groups such as 2chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4fluorophenyl, 4-chlorophenyl, thiophene, styrene, and cyclopropane, were compatible in this process. Moreover, the

2 ACS Paragon Plus Environment

Page 3 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


structure of compound 4p was confirmed by X-ray analysis.11 Given the importance of pyrrole-3-carboxamides, this method offers a distinct approach toward these compounds with ample structural diversity from readily available starting materials. And we also tried a gram-scale reaction using 3a and 2g under standard condition, the product 4a was obtained in 80 % yield (See Experimental Section). Furthermore, we also tried to test the iterative assembly of nitrile oxides and ynamides in one-pot. As shown in Scheme 2, the nitrile oxide precursor 1s were mixed with ynamide 2a in DCM and treated with Na2CO3 to deliver the isoxazole, which was sequentially added with ynamide 2g and gold catalyst. Indeed, the pyrrole 4u could be furnished in a total 56% yield. Table 3. Second Assembly of Nitrile Oxides with Ynamides.a O Ts

N O R1

N + R3 CH2

3

O Tol H 3C

N Ts

Tol H 3C

N Ts

CH3

O H 3C

N Ts

N H

O H 3C

N Ts

O Br

H 3C

N Ts

Ts N CH3

Ts N Cl CH3

H 3C

N Ts

Ph N H 4m, 99%

O H 3C

H 3C

N Ts

N CH3 Ph N H 4n, 93%

N Ts

O H 3C

N Ts

Ph N H 4p, 93% S

H 3C

N Ts

O

Ts N CH3

Ph N H 4r, 95%

Ph H 3C

N Ts

O

Ts N CH3

Ph N H 4s, 93%

H 3C

N Ts

H 3C

N Ts

N H

4u, 56% yield in total

Ts

2 N R

N O R1

R1

Ts

3

2

NHAC Ts N CH3

Ph N H 4l, 87%

Ts N CH3

Ph N H 4o, 80%

Ts N CH3 Ph

N H 4q, 96%

Ts N CH3

Ph N H 4t, 86%

Reaction condition: 3 (0.2 mmol), 2 (0.2 mmol), Ph3PAuCl (5 mol %), AgNTf2 (10 mol %), were added to DCM (2 mL) under argon and kept at rt for 5 h. Yield refers to isolated product.

a

R

R3

O

O N

R1 A

N Ts

Ts N CH3

H 3C

N H

N CH3

Au+L

O

H 3C

N Ts

Na2CO3

Cl

N H

O

Ts N CH3

Ts N 2 2 R

O N

1

Cl

F

1

OH

Ts N CH3

O H 3C

1s

Ts N CH3 Br

Based on these results and literature,10,12,13 a plausible reaction mechanism was proposed in Scheme 3. Initially, the Nhydroxybenzimidoyl chloride would convert to nitrile oxide A upon treatment with Na2CO3. An electrophilic [3+2] cyclization between A and electron rich ynamide 2 would give isoxazole 3. This is the first assembly of nitrile oxides and ynamides. In the presence of Au(I) catalyst, the internal ynamides could be activated and added by nitrogen atom of isoxazoles 3 to give intermediate C, and the following cleavage of N-O bond and isomerization delivered a gold-carbene containing species D. Finally, the intramolecular cyclization would give pyrrole 4 and regenerate Au(I) catalyst. Scheme 3. Reaction Mechanism.

R

MeO Ts

O Ph

Ph3PAuCl (5 mol %) AgNTf2 (10 mol %)

Na2CO3, DCM, rt

CF3

O H 3C

Br

Ts N CH3

Ph 2g

3

Ts N R2

Au+L

N H 4f, 87%

Tol

CH3

O

Ts N CH3

N Ts

Ts N CH3 2a

OH Cl

N Ts N CH3

H 3C

N Ts

Me Cl O

O

N

Cl

4i, 78%

Ts N CH3

N H 4k, 92%

N H 4c, 95%

Tol

N Ts

Cl 4h, 83% O

N Ts

CN

N H

Tol

H C N Boc 3 N Ts

N H 4j, 90%

N H 4e, 85%

Tol

F

4g, 85%

Tol

N Ts

Ts N CH3

H 3C

Ts N CH3

H 3C

R1 4

N H

Tol

OCH3

Tol

CO2Me Ts N CH3

N H 4b, 88% O

Ts N CH3

N H 4d, 95%

Tol

H 3C

N Ts

O

Ts N CH3

Tol N Ts

H 3C

DCM, argon, rt

O

Ts N CH3

N H 4a, 93% O

2

N CH3

Ts N CH3

R3

Ph3PAuCl (5 mol %) AgNTf2 (10 mol %)

Ts

Therefore, this protocol offers a distinct approach to heterocycles synthesis. Scheme 2. Iterative Assembly in One-Pot.

R1 4

R3 B

Ts N CH3

Ts

Ts

L+Au R

Au+L

LAu

N CH3 3

N O R1

D

Ts N R2

R

N CH3 3

N O R1

Ts N R2

C

In summary, we have described an iterative assembly of nitrile oxides and ynamides for access to isoxazoles and pyrroles. The first assembly was achieved by a Cu(I)-free [3+2] cyclization to deliver isoxazoles, and the second assembly relied on Au(I)-catalyzed cyclization to furnish pyrroles. And we also developed an approach to pyrroles synthesis in one-pot approach. Therefore, this method provided a mild and distinct approach toward privileged heterocycles with remarkable structural diversity and brevity.

EXPERIMENTAL SECTION General Information. 1H NMR and 13C NMR spectra were recorded on BRUKER AVANCE III 600 spectrometer and WNMR-I-400 spectrometer. 19F NMR spectra were recorded at 376 MHz with a Brucker spectrometer. CDCl3 and Acetone-d6 were used as solvent. Chemical shifts were referenced relative to residual solvent. The following abbreviations are used to describe peak patterns where appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and coupling constants (J) are reported in Hertz (Hz). The HRMS were performed on Waters GCT Premier Time of Flight Mass Spectrometer (EI). Melting points were measured with micro melting point apparatus. CH2Cl2, ethyl acetate (EA), methanol, petroleum ether (PE) were commercially available. Hydroxybenzimidoyl chloride



(1a-1u) and ynamide (2a-2p) were prepared according to the reported literature. 14,15 Typical Procedure for the Synthesis of Amino Isoxazole 3a. To a vial was added N-hydroxybenzimidoyl chloride 1a (37.3 mg, 0.24 mmol), N-ethynyl-N,4dimethylbenzenesulfonamide 2a (41.8 mg, 0.2 mmol) and Na2CO3 (31.8 mg, 0.3 mmol). The mixture was dissolved in DCM (2 mL) and was stirred at room temperature until the starting material was fully consumed (for about 5-8 h). Then the mixture was concentrated and purified by flash column chromatography on silica gel using petroleum ether/EtOAc (15/1) as eluent to give 3a as a white solid (59 mg, 90 % yield). Procedure for Gram-Scale Synthesis of Amino Isoxazole 3a. To a 50 mL flask was added N-hydroxybenzimidoyl chloride 1a (933.5 mg, 6 mmol), N-ethynyl-N,4dimethylbenzenesulfonamide 2a (1.05 g, 5 mmol) and Na2CO3 (794.9 mg, 7.5 mmol). The mixture was dissolved in DCM (10 mL) and was stirred at room temperature until the starting material was fully consumed. Then the mixture was concentrated and purified by flash column chromatography on silica gel using petroleum ether/EtOAc (15/1) as eluent to give 3a as a white solid (1.41 g, 86 % yield). N,4-dimethyl-N-(3-phenylisoxazol-5-yl)benzenesulfonamide (3a). White solid (59 mg, 90 % yield): mp 110-112 °C; Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.82 – 7.77 (m, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.49 – 7.43 (m, 3H), 7.30 (d, J = 7.8 Hz, 2H), 6.51 (s, 1H), 3.36 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.0, 163.4, 145.3, 133.9, 130.4, 130.2, 129.0 (d), 127.4, 126.8, 89.9, 34.9, 21.7; HRMS (EI) m/z calcd for C17H16N2O3S (M+) 328.0882, found: 328.0887. N,4-dimethyl-N-(3-(p-tolyl)isoxazol-5yl)benzenesulfonamide (3b). White solid (67 mg, 98% yield): mp 113-115 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 2.4 Hz, 2H), 7.67 (d, J = 2.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 6.48 (s, 1H), 3.35 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.9, 163.2, 145.2, 140.6, 133.8, 130.1, 129.7, 127.4, 126.6, 126.1, 89.8, 34.9, 21.7, 21.6; HRMS (EI) m/z calcd for C18H18N2O3S (M+) 342.1038, found: 342.1035. N-(3-(4-methoxyphenyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3c). White solid (69 mg, 96% yield): mp 106-108 °C, Rf = 0.2 (petroleum ether/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 6.45 (s, 1H), 3.85 (s, 3H), 3.34 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.5, 163.1, 161.3, 145.2, 133.8, 130.1, 128.2, 127.4, 121.4, 114.4, 89.7, 55.5, 34.9, 21.7; HRMS (EI) m/z calcd for C18H18N2O4S (M+) 358.0987, found: 358.0989. N-(3-(4-chlorophenyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3d). White solid (72 mg, 99% yield): mp 129-130 °C, Rf = 0.2 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.48 (s, 1H), 3.35 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.7, 163.0, 145.3, 136.4, 133.9,

Page 4 of 10

130.2, 129.3, 128.1, 127.5, 127.4, 89.6, 34.9, 21.7; HRMS (EI) m/z calcd for C17H15ClN2O3S (M+) 362.0492, found: 362.0489. N,4-dimethyl-N-(3-(4-(trifluoromethyl)phenyl)isoxazol-5yl)benzenesulfonamide (3e). White solid (73 mg, 92% yield): mp 134-135 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.54 (s, 1H), 3.37 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.0, 162.8, 145.4, 133.9, 132.5 (d), 132.2 (q, J = 32.4 Hz), 130.2, 127.4, 127.1, 126.0 (q, J = 3.8 Hz), 123.9 (q, J = 271.5 Hz), 89.6, 34.8, 21.7; 19F{1H} NMR (376 MHz, CDCl3) δ -62.9; HRMS (EI) m/z calcd for C18H15F3N2O3S (M+) 396.0755, found: 396.0760. N-(3-(4-cyanophenyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3f). White solid (43 mg, 61% yield): mp 175-177 °C, Rf = 0.3 (petroleum ether/EtOAc = 5/1); 1H NMR (600 MHz, CDCl ) δ 7.90 (d, J = 8.4 Hz, 2H), 7.75 (d, 3 J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.54 (s, 1H), 3.37 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.2, 162.4, 145.5, 133.8, 133.3, 132.8, 130.3, 127.4 (d), 118.4, 114.0, 89.4, 34.8, 21.8; HRMS (EI) m/z calcd for C18H15N3O3S (M+) 353.0834, found: 353.0830. methyl 4-(5-((N,4-dimethylphenyl)sulfonamido)isoxazol-3yl)benzoate (3g). White solid (66 mg, 85% yield): mp 133-134 °C, Rf = 0.3 (petroleum ether/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 6.54 (s, 1H), 3.94 (s, 3H), 3.36 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.6, 163.9, 163.1, 145.4, 133.9, 133.2, 131.7, 130.3, 130.2, 127.4, 126.8, 89.8, 52.5, 34.9, 21.8; HRMS (EI) m/z calcd for C19H18N2O5S (M+) 386.0936, found: 386.0939. N-(4-(5-((N,4-dimethylphenyl)sulfonamido)isoxazol-3yl)phenyl)acetamide (3h). White solid (66 mg, 86% yield): mp 198-199 °C, Rf = 0.3 (petroleum ether/EtOAc = 1/1); 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.30 (d, J = 7.8 Hz, 2H), 6.45 (s, 1H), 3.34 (s, 3H), 2.41 (s, 3H), 2.19 (s, 3H); 13C{1H} NMR (150 MHz, CDCl ) δ 168.6, 163.4 (d), 145.3, 3 139.9, 133.9, 130.2, 127.6, 127.4, 124.7, 119.9, 89.8, 34.9, 24.8, 21.8; HRMS (EI) m/z calcd for C19H19N3O4S (M+) 385.1096, found: 385.1091. N,4-dimethyl-N-(3-(o-tolyl)isoxazol-5yl)benzenesulfonamide (3i). Colorless oil (56 mg, 81% yield): Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.37 – 7.26 (m, 5H), 6.37 (s, 1H), 3.38 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.7, 162.6, 145.2, 136.8, 133.8, 131.1, 130.0, 129.7, 129.4, 128.6, 127.3, 126.0, 92.2, 34.8, 21.6, 21.1; HRMS (EI) m/z calcd for C18H18N2O3S (M+) 342.1038, found: 342.1035. N-(3-(3-bromophenyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3j). Colorless oil (76 mg, 90% yield): Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.93 (t, J = 1.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.58 – 7.56 (m, 1H), 7.34 – 7.29 (m, 1H), 6.48 (s, 1H), 3.36 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.7, 162.7, 145.3, 133.8, 133.3, 131.0, 130.5, 130.2, 129.7, 127.4, 125.3, 123.1, 89.5, 34.8, 21.7;


Page 5 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


HRMS (EI) m/z calcd for C17H15BrN2O3S (M+) 405.9987, found: 405.9986. N-(3-(3-bromo-4-fluorophenyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3k). White solid (83 mg, 97% yield): mp 103-105 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 8.00 (dd, J1 = 6.6 Hz, J2 = 2.4 Hz, 1H), 7.73 – 7.70 (m, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 8.4 Hz, 1H), 6.46 (s, 1H), 3.36 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.9, 162.0, 160.3 (d, J = 250.1 Hz), 145.4, 133.9, 132.1, 130.2, 127.6 (d, J = 7.7 Hz), 127.4, 126.7 (d, J = 3.9 Hz), 117.1 (d, J = 22.8 Hz), 109.9 (d, J = 21.6 Hz), 89.4, 34.8, 21.8; 19F NMR (376 MHz, CDCl3) δ -104.8; HRMS (EI) m/z calcd for C17H14BrFN2O3S (M+) 423.9893, found: 423.9867. N-(3-(2,6-dichlorophenyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3l). White solid (76 mg, 96% yield): mp 118-120 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.34 (dd, J1 = 9.0 Hz, J2 = 7.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 3.39 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl ) δ 163.4, 160.6, 145.4, 135.6, 3 133.6, 131.4, 130.1, 128.3 (d), 127.5, 93.4, 34.7, 21.8; HRMS (EI) m/z calcd for C17H14Cl2N2O3S (M+) 396.0102, found: 396.0105. N,4-dimethyl-N-(3-(naphthalen-1-yl)isoxazol-5yl)benzenesulfonamide (3m). Brown oil (64 mg, 84% yield): Rf = 0.2 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 8.38 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.93 – 7.91 (m, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 6.6 Hz, 1H), 7.59 – 7.53 (m, 3H), 7.33 (d, J = 7.8 Hz, 2H), 6.52 (s, 1H), 3.45 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.3, 162.9, 145.3, 133.9, 130.9, 130.5, 130.1, 128.6, 127.9, 127.5, 127.2, 126.7, 126.4, 125.6, 125.2, 92.8, 34.9, 21.7; HRMS (EI) m/z calcd for C21H18N2O3S (M+) 378.1038, found: 378.1037. tert-butyl 3-(5-((N,4-dimethylphenyl)sulfonamido)isoxazole3-yl)-1H-indole-1-carboxylate (3n). White solid (58 mg, 63% yield): mp 158-159 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.41 – 7.38 (m, 1H), 7.36 – 7.32 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.51 (s, 1H), 3.38 (s, 3H), 2.41 (s, 3H), 1.72 (s, 9H); 13C{1H} NMR (150 MHz, CDCl ) δ 162.7, 159.2, 149.4, 145.3, 3 135.8, 133.9, 130.2, 127.4, 127.3, 126.2, 125.4, 123.8, 122.1, 115.3, 110.6, 90.0, 84.8, 34.9, 28.3, 21.7; HRMS (EI) m/z calcd for C24H25N3O5S (M+) 467.1515, found: 467.1512. N,4-dimethyl-N-(3-styrylisoxazol-5-yl)benzenesulfonamide (3o). White solid (58 mg, 82% yield): mp 129-131 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 16.8 Hz, 1H), 7.01 (d, J = 16.2 Hz, 1H), 6.43 (s, 1H), 3.33 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.4, 162.9, 145.2, 136.6, 135.7, 133.9, 130.2, 129.2, 129.0, 127.4, 127.2, 116.0, 88.9, 34.8, 21.7; HRMS (EI) m/z calcd for C19H18N2O3S (M+) 354.1038, found: 354.1036. N-(3-butylisoxazol-5-yl)-N,4-dimethylbenzenesulfonamide (3p). Colorless oil (51 mg, 82% yield): Rf = 0.3 (petroleum

ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.00 (s, 1H), 3.28 (s, 3H), 2.58 (t, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.66 – 1.58 (m, 2H), 1.40 – 1.32 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.1, 162.5, 145.1, 133.8, 130.0, 127.3, 91.4, 34.8, 30.2, 26.2, 22.3, 21.7, 13.8; HRMS (EI) m/z calcd for C15H20N2O3S (M+) 308.1195, found: 308.1193. N-(3-(tert-butyl)isoxazol-5-yl)-N,4dimethylbenzenesulfonamide (3q). White solid (53 mg, 85% yield): mp 59-61 °C, Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.28 (d, 3 J = 8.4 Hz, 2H), 6.06 (s, 1H), 3.28 (s, 3H), 2.41 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 174.0, 162.5, 145.1, 133.9, 130.0, 127.4, 89.8, 34.9, 32.5, 29.3, 21.7; HRMS (EI) m/z calcd for C15H20N2O3S (M+) 308.1195, found: 308.1192. N-(3-(3-((tert-butyldimethylsilyl)oxy)propyl)isoxazol-5-yl)N,4-dimethylbenzenesulfonamide (3r). Colorless oil (51 mg, 60% yield): Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.02 (s, 1H), 3.67 (t, J = 6.6 Hz, 2H), 3.29 (s, 3H), 2.67 (t, J = 7.8 Hz, 2H), 2.42 (s, 3H), 1.89 – 1.83 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.8, 162.7, 145.1, 134.0, 130.1, 127.4, 91.6, 62.2, 34.9, 31.1, 26.1, 23.2, 21.7, 18.4, -5.2; HRMS (EI) m/z calcd for C20H32N2O4SSi (M+) 424.1852, found: 424.1859. N-(2-bromophenyl)-4-methyl-N-(3-phenylisoxazol-5-yl)benzenesulfonamide (3s). Colorless oil (81 mg, 87% yield): Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.79 – 7.76 (m, 4H), 7.70 – 7.68 (m, 1H), 7.46 – 7.43 (m, 3H), 7.38 – 7.30 (m, 5H), 6.49 (s, 1H), 2.45 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.7, 162.3, 145.5, 136.0, 135.6, 134.3, 132.0, 131.4, 130.4, 130.1, 129.0, 128.9, 128.5, 128.4, 126.8, 125.7, 91.7, 21.8; HRMS (EI) m/z calcd for C22H17BrN2O3S (M+) 468.0143, found: 468.0141. (S)-4-methyl-N-(1-phenylethyl)-N-(3-phenylisoxazol-5yl)benzenesulfonamide (3t). Colorless oil (74 mg, 89% yield): Rf = 0.3 (petroleum ether/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.72 – 7.69 (m, 2H), 7.44 – 7.41 (m, 3H), 7.34 – 7.26 (m, 7H), 6.18 (s, 1H), 5.55 (q, J = 7.2 Hz, 1H), 2.43 (s, 3H), 1.54 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.3, 161.2, 144.5, 139.1, 136.7, 130.3, 129.9, 129.0, 128.8, 128.5, 128.2, 127.7, 127.6, 126.5, 100.1, 59.2, 21.7, 18.7; HRMS (EI) m/z calcd for C24H22N2O3S (M+) 418.1351, found: 418.1353. N-(furan-2-ylmethyl)-4-methyl-N-(3-phenylisoxazol-5yl)benzenesulfonamide (3u). White solid (59 mg, 75% yield): mp 129-130 °C, Rf = 0.2 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.77 – 7.75 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 – 7.43 (m, 3H), 7.31 (dd, J1 = 1.2 Hz, J2 = 0.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.42 (s, 1H), 6.35 (d, J = 3.0 Hz, 1H), 6.27 (dd, J1 = 3.0 Hz, J2 = 1.8 Hz, 1H), 4.98 (s, 2H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.8, 162.5, 148.5, 145.0, 143.0, 135.3, 130.4, 130.0, 129.0, 128.9, 127.6, 126.7, 110.7, 110.5, 92.6, 45.4, 21.7; HRMS (EI) m/z calcd for C21H18N2O4S (M+) 394.0987, found: 394.0982. N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-N-(3phenylisoxazol-5-yl)benzenesulfonamide (3v). White solid (79 mg, 84% yield): mp 81-82 °C, Rf = 0.3 (petroleum ether/EtOAc



= 15/1); 1H NMR (600 MHz, CDCl3) δ 7.79 – 7.76 (m, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.46 – 7.44 (m, 3H), 7.28 (d, J = 8.4 Hz, 2H), 6.49 (s, 1H), 3.92 – 3.89 (m, 2H), 3.88 – 3.85 (m, 2H), 2.40 (s, 3H), 0.84 (s, 9H), 0.03 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.7, 163.0, 144.9, 135.4, 130.3, 130.1, 129.0 (d), 127.3, 126.7, 92.0, 61.8, 50.7, 25.8, 21.7, 18.2, -5.4; HRMS (EI) m/z calcd for C24H32N2O4SSi (M+) 472.1852, found: 472.1856. N-(2-(cyclohex-1-en-1-yl)ethyl)-4-methyl-N-(3phenylisoxazol-5-yl)benzenesulfonamide (3w). Colorless oil (61 mg, 73% yield): Rf = 0.3 (petroleum ether/EtOAc = 15/1); 1H NMR (600 MHz, CDCl ) δ 7.81 – 7.78 (m, 2H), 7.69 (d, J = 3 8.4 Hz, 2H), 7.47 – 7.44 (m, 3H), 7.28 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H), 5.45 (s, 1H), 3.85 – 3.82 (m, 2H), 2.40 (s, 3H), 2.29 (t, J = 7.2 Hz, 2H), 1.94 (d, J = 6.0 Hz, 4H), 1.62 – 1.57 (m, 2H), 1.53 – 1.48 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 163.7, 162.8, 144.8, 135.5, 133.5, 130.3, 130.0, 129.0, 128.9, 127.3, 126.7, 124.6, 92.5, 47.7, 37.6, 28.1, 25.3, 22.8, 22.2, 21.7; HRMS (EI) m/z calcd for C24H26N2O3S (M+) 422.1664, found: 422.1662. Typical Procedure for the Synthesis of Pyrrole 4a. An oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar was charged with Ph3PAuCl (5 mg, 5 mol %) and AgNTf2 (7.8 mg, 10 mol %) and the tube was then evacuated and purged with Argon for three times. DCM (1 mL) was added and the suspension was stirred for 10 min. N,4-dimethyl-N-(3phenylisoxazol-5-yl)benzenesulfonamide 3a (65.6 mg, 0.2 mmol) and N,4-dimethyl-N-(phenylethynyl) benzenesulfonamide 2g (57 mg, 0.2 mmol) in DCM (1 mL) was added via syringe and the reaction mixture was stirred at room temperature for 5 h. Upon completion, the solvent was evaporated and the residue was purified by flash column chromatography on silica gel using petroleum ether/EtOAc (3/1) as eluent to give 4a as a white solid (106 mg, 87 % yield). Procedure for Gram-Scale Synthesis of Pyrrole 4a. An oven-dried 50 mL flask equipped with a magnetic stir bar was charged with Ph3PAuCl (124 mg, 5 mol %) and AgNTf2 (193 mg, 10 mol %) and the flask was then evacuated and purged with Argon for three times. DCM (2 mL) was added and the suspension was stirred for 10 min. N,4-dimethyl-N-(3phenylisoxazol-5-yl)benzenesulfonamide 3a (1.64 g, 5 mmol) and N,4-dimethyl-N-(phenylethynyl) benzenesulfonamide 2g (1.43 g, 5 mmol) in DCM (10 mL) was added via syringe and the reaction mixture was stirred at room temperature for 5 h. Upon completion, the solvent was evaporated and the residue was purified by flash column chromatography on silica gel using petroleum ether/EtOAc (3/1) as eluent to give 4a as a white solid (2.45 g, 80 % yield). 5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-2,4-di-ptolyl-N-tosyl-1H-pyrrole-3-carboxamide (4a). White solid (118 mg, 93% yield): mp 214-215 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.85 (s, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 6.73 (d, J = 7.8 Hz, 2H), 6.27 (d, J = 7.8 Hz, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.45 (s, 6H), 2.35 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.7, 144.5, 144.3, 138.2, 136.8, 135.9, 134.4, 129.9, 129.8, 129.2, 128.9 (t), 128.7, 128.5, 127.7, 127.6, 126.2, 124.6, 119.3, 114.4, 38.2, 34.4, 21.8, 21.7, 21.4, 21.3; HRMS (EI) m/z calcd for C35H35N3O5S2 (M+) 641.2018, found: 641.2017.

Page 6 of 10

5-((N,4-dimethylphenyl)sulfonamido)-2-(4-methoxyphenyl)N-methyl-4-(p-tolyl)-N-tosyl-1H-pyrrole-3-carboxamide (4b). White solid (116 mg, 88% yield): mp 233-234 °C; Rf = 0.2 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.73 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.23 – 7.20 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 7.8 Hz, 2H), 6.25 (d, J = 7.8 Hz, 2H), 3.83 (s, 3H), 2.94 (s, 3H), 2.91 (s, 3H), 2.46 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.7, 159.7, 144.5, 144.3, 136.9, 136.0, 134.3, 129.9, 129.2, 129.0, 128.9, 128.8, 128.5, 127.8, 127.7, 124.4, 123.1, 119.2, 114.7, 114.0, 55.5, 38.2, 34.4, 21.8 (d), 21.3; HRMS (EI) m/z calcd for C35H35N3O6S2 (M+) 657.1967, found: 657.1970. 2-(4-chlorophenyl)-5-((N,4-dimethylphenyl)sulfonamido)N-methyl-4-(p-tolyl)-N-tosyl-1H-pyrrole-3-carboxamide (4c). White solid (126 mg, 95% yield): mp 216-217 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.01 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.26 – 7.18 (m, 8H), 6.75 (d, J = 7.8 Hz, 2H), 6.29 (d, J = 8.4 Hz, 2H), 2.97 (s, 3H), 2.90 (s, 3H), 2.45 (s, 6H), 2.27 (s, 3H); 13C{1H} NMR (150 MHz, CDCl ) δ 167.5, 144.6, 137.1, 135.8, 3 134.3, 134.0, 129.9, 129.3 (d), 129.0, 128.9, 128.7, 128.6, 128.5, 127.7, 127.6, 127.5, 125.2, 119.5, 115.4, 38.3, 34.4, 21.8, 21.3; HRMS (EI) m/z calcd for C34H32ClN3O5S2 (M+) 661.1472, found: 661.1468. methyl 4-(5-((N,4-dimethylphenyl)sulfonamido)-3(methyl(tosyl)carbamoyl)-4-(p-tolyl)-1H-pyrrol-2-yl)benzoate (4d). White solid (130 mg, 95% yield): mp 224-226 °C; Rf = 0.2 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.09 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.29 – 7.21 (m, 6H), 6.77 (d, J = 7.8 Hz, 2H), 6.30 (d, J = 7.8 Hz, 2H), 3.94 (s, 3H), 2.96 (s, 3H), 2.92 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.4, 166.6, 144.7 (d), 137.3, 135.7, 134.5, 134.2, 130.4, 129.9, 129.4, 129.2, 129.0, 128.6, 128.5 (d), 127.7, 126.8, 126.0, 125.7, 119.5, 116.4, 52.3, 38.2, 34.4, 21.8, 21.7, 21.3; HRMS (EI) m/z calcd for C36H35N3O7S2 (M+) 685.1916, found: 685.1921. 2-(4-cyanophenyl)-5-((N,4-dimethylphenyl)sulfonamido)-Nmethyl-4-(p-tolyl)-N-tosyl-1H-pyrrole-3-carboxamide (4e). White solid (110 mg, 85% yield): mp 220-221 °C; Rf = 0.2 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.27 (s, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 7.8 Hz, 2H), 6.27 (d, J = 7.8 Hz, 2H), 2.97 (s, 3H), 2.89 (s, 3H), 2.46 (s, 6H), 2.28 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.3 , 144.8, 137.4, 135.6, 134.6, 134.1, 132.8, 123.0, 129.3, 129.0, 128.6, 128.5, 128.3, 127.7, 126.5, 126.4, 126.0, 119.7, 118.7, 117.1, 111.0, 38.2, 34.3, 21.8 (d), 21.3; HRMS (EI) m/z calcd for C35H32N4O5S2 (M+) 652.1814, found: 652.1816. 5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-4-(p-tolyl)N-tosyl-2-(4-(trifluoromethyl)phenyl)-1H-pyrrole-3carboxamide (4f). White solid (120 mg, 87% yield): mp 197199 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.19 (s, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 7.8 Hz, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.46 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H); 13C{1H} NMR (150


Page 7 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


MHz, CDCl3) δ 167.4, 144.7 (d), 137.2, 135.6, 134.2, 133.7, 129.9, 129.6 (q, J = 32.3 Hz), 129.3, 129.0, 128.6, 128.5 (d), 127.7, 126.6, 126.3, 126.0 (q, J = 3.8 Hz), 125.9, 124.0 (q, J = 270.5 Hz), 119.6, 116.4, 38.3, 34.3, 21.8, 21.7, 21.3; 19F{1H} NMR (376 MHz, CDCl3) δ -62.7; HRMS (EI) m/z calcd for C35H32F3N3O5S2 (M+) 695.1735, found: 695.1731. 2-(3-bromo-4-fluorophenyl)-5-((N,4dimethylphenyl)sulfonamido)-N-methyl-4-(p-tolyl)-N-tosyl1H-pyrrole-3-carboxamide (4g). White solid (124 mg, 85% yield): mp 229-230 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl ) δ 9.07 (s, 1H), 7.62 (d, J = 7.8 Hz, 3 2H), 7.56 – 7.52 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.8 Hz, 3H), 6.97 (t, J = 8.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 2H), 6.32 (d, J = 7.2 Hz, 2H), 3.00 (s, 3H), 2.89 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.3, 158.8 (d, J = 248.4 Hz), 144.6 (d), 137.1, 135.8, 134.3, 131.5, 129.9, 129.4, 129.0, 128.6, 128.5 (d), 128.2 (d, J = 3.9 Hz), 127.7, 127.5 (d, J = 7.2 Hz), 126.6, 125.4, 119.7, 117.1 (d, J = 22.5 Hz), 115.6, 109.8 (d, J = 21.5 Hz), 38.4, 34.4, 21.8 (d), 21.3; 19F{1H} NMR (376 MHz, CDCl3) δ -108.0; HRMS (EI) m/z calcd for C34H31BrFN3O5S2 (M+) 723.0873, found: 723.0879. 2-(2,6-dichlorophenyl)-5-((N,4dimethylphenyl)sulfonamido)-N-methyl-4-(p-tolyl)-N-tosyl1H-pyrrole-3-carboxamide (4h). White solid (115 mg, 83% yield): mp 244-245 °C; Rf = 0.2 (petroleum ether/EtOAc = 5/1); 1H NMR (400 MHz, CDCl ) δ 8.90 (s, 1H), 7.68 (d, J = 8.4 Hz, 3 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.35 – 7.30 (m, 2H), 7.29 – 7.18 (m, 5H), 6.87 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 8.0 Hz, 2H), 3.04 (s, 3H), 2.80 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl ) δ 165.9, 144.6, 144.1, 137.2, 3 136.5, 135.8, 133.9, 130.8, 129.7, 129.1, 129.0 (d), 128.8, 128.7 (d), 128.3, 127.8, 125.5, 124.8, 118.7, 117.3, 38.2, 34.6, 21.7, 21.3; HRMS (EI) m/z calcd for C34H31Cl2N3O5S2 (M+) 695.1082, found: 695.1085. 2-(4-acetamidophenyl)-5-((N,4dimethylphenyl)sulfonamido)-N-methyl-4-(p-tolyl)-N-tosyl1H-pyrrole-3-carboxamide (4i). White solid ( 107 mg, 78 % yield): mp 227-229 °C; Rf = 0.2 (petroleum ether/EtOAc = 1/1); 1H NMR (400 MHz, Acetone-d ) δ 10.70 (s, 1H), 9.23 (s, 1H), 6 7.76 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 – 7.23 (m, 4H), 6.86 (d, J = 7.6 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 3.20 (s, 3H), 3.00 (s, 3H), 2.88 (s, 3H), 2.50 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, Acetone-d ) δ 169.0, 168.4, 145.4, 6 144.6, 140.1, 137.4, 136.9, 136.6, 130.6, 130.3, 130.0, 129.5, 129.4, 129.3, 129.2, 128.5, 127.7, 126.5, 126.0, 121.4, 119.9, 114.8, 39.1, 35.0, 24.3, 21.6, 21.5, 21.2; HRMS (EI) m/z calcd for C36H36N4O6S2 (M+) 684.2076, found: 684.2080. tert-butyl 3-(5-((N,4-dimethylphenyl)sulfonamido)-3(methyl(tosyl)carbamoyl)-4-(p-tolyl)-1H-pyrrol-2-yl)-1Hindole-1-carboxylate (4j). White solid (138 mg, 90 % yield): mp 209-210 °C; Rf = 0.2 (petroleum ether/EtOAc = 5/1); 1H NMR (600 MHz, CDCl3) δ 9.00 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.67 – 7.58 (m, 5H), 7.39 – 7.34 (m, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.27 – 7.23 (m, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 7.8 Hz, 2H), 6.34 (d, J = 7.8 Hz, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 1.69 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.1, 149.4, 144.6, 144.2, 137.1, 136.1, 135.5, 134.3, 130.0, 129.2, 129.0,

128.9, 128.7, 128.5, 128.1, 127.7, 125.5, 125.1, 124.5, 123.9, 123.6, 119.1 (d), 115.8, 115.2, 110.5, 84.3, 38.1, 34.6, 28.3, 21.8, 21.7, 21.3; HRMS (EI) m/z calcd for C41H42N4O7S2 (M+) 766.2495, found: 766.2498. 2-butyl-5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-4(p-tolyl)-N-tosyl-1H-pyrrole-3-carboxamide (4k). White solid (112 mg, 92% yield): mp 202-203 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 7.8 Hz, 2H), 6.31 (d, J = 7.8 Hz, 2H), 2.94 (s, 3H), 2.74 (s, 3H), 2.60 (t, J = 7.8 Hz, 2H), 2.43 (s, 6H), 2.29 (s, 3H), 1.52 – 1.46 (m, 2H), 1.31 – 1.24 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.6, 144.4 (d), 136.8, 136.0, 134.7, 134.5, 129.7, 129.4, 129.2, 128.9, 128.8, 128.5, 127.6, 122.5, 118.5, 113.8, 38.3, 34.5, 31.7, 25.9, 22.3, 21.8, 21.7, 21.3, 13.8; HRMS (EI) m/z calcd for C32H37N3O5S2 (M+) 607.2175, found: 607.2173. 5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-2,4diphenyl-N-tosyl-1H-pyrrole-3-carboxamide (4l). White solid (106 mg, 87% yield): mp 210-211 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.98 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.28 (s, 6H), 7.24 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.95 (t, J = 7.8 Hz, 2H), 6.43 (d, J = 7.2 Hz, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 2.44 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.5, 144.5, 144.4, 135.8, 134.2, 131.8, 130.3, 129.9, 129.3, 129.2, 128.8, 128.7, 128.6, 128.2 (d), 127.7, 127.2, 126.3, 125.1, 119.6, 114.8, 38.4, 34.3, 21.8, 21.7; HRMS (EI) m/z calcd for C33H31N3O5S2 (M+) 613.1705, found: 613.1711. 4-(2-chlorophenyl)-5-((N,4-dimethylphenyl)sulfonamido)N-methyl-2-phenyl-N-tosyl-1H-pyrrole-3-carboxamide (4m). White solid (130 mg, 99% yield): mp 192-194 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.04 (s, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.38 (s, 5H), 7.27 (d, J = 6.6 Hz, 3H), 7.18 (d, J = 7.2 Hz, 2H), 7.11 – 7.05 (m, 2H), 6.72 (s, 1H), 5.96 (d, J = 6.6 Hz, 1H), 2.92 (s, 3H), 2.90 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.2, 144.4, 144.1, 135.8, 134.0, 132.4, 131.2, 130.5, 130.0, 129.6, 129.4, 129.1 (d), 129.0, 128.8, 128.6, 127.8, 127.00, 126.5, 126.2, 115.0, 37.8, 34.8, 21.7; HRMS (EI) m/z calcd for C33H30ClN3O5S2 (M+) 647.1315, found: 647.1319. 5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-2-phenyl-4(p-tolyl)-N-tosyl-1H-pyrrole-3-carboxamide (4n). White solid (116 mg, 93% yield): mp 225-227 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.95 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.30 – 7.23 (m, 7H), 7.21 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 7.8 Hz, 2H), 6.29 (d, J = 7.8 Hz, 2H), 2.98 – 2.96 (m, 3H), 2.91 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.6, 144.5, 144.4, 136.9, 135.8, 134.3, 130.4, 129.8, 129.2 (d), 128.9, 128.8, 128.7, 128.6, 128.5, 128.2, 127.7, 126.3, 125.0, 119.4, 114.9, 38.3, 34.4, 21.8 (d), 21.3; HRMS (EI) m/z calcd for C34H33N3O5S2 (M+) 627.1862, found: 627.1864. 5-((N,4-dimethylphenyl)sulfonamido)-4-(4-methoxyphenyl)N-methyl-2-phenyl-N-tosyl-1H-pyrrole-3-carboxamide (4o).



White solid (104 mg, 80% yield): mp 200-201 °C; Rf = 0.2 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.91 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.30 – 7.24 (m, 7H), 7.21 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 3.77 (s, 3H), 2.98 (s, 3H), 2.92 (s, 3H), 2.44 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.6, 158.9, 144.5, 144.4, 135.8, 134.4, 130.4, 129.9 (d), 129.3, 129.2, 128.6, 128.5, 128.2, 127.7, 126.2, 124.9, 124.1, 119.2, 114.9, 113.6, 55.2, 38.3, 34.4, 21.8, 21.7; HRMS (EI) m/z calcd for C34H33N3O6S2 (M+) 643.1811, found: 643.1810. 5-((N,4-dimethylphenyl)sulfonamido)-4-(4-fluorophenyl)-Nmethyl-2-phenyl-N-tosyl-1H-pyrrole-3-carboxamide (4p). White solid (118 mg, 93% yield): mp 210-211 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.96 (s, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.33 – 7.22 (m, 7H), 7.20 (d, J = 7.8 Hz, 2H), 6.63 (t, J = 8.4 Hz, 2H), 6.45 – 6.40 (m, 2H), 3.00 (s, 3H), 2.91 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.4, 162.1 (d, J = 245.6 Hz), 144.6 (d), 135.7, 134.4, 130.5 (d, J = 8.0 Hz), 130.3, 129.9, 129.3, 129.2, 128.7, 128.6, 128.4, 127.9 (d, J = 3.3 Hz), 127.7, 126.3, 125.3, 118.7, 115.1 (d, J = 21.2 Hz), 114.9, 38.5, 34.3, 21.7 (d); 19F{1H} NMR (376 MHz, CDCl3) δ -115.2; HRMS (EI) m/z calcd for C33H30FN3O5S2 (M+) 631.1611, found: 631.1615. 4-(4-chlorophenyl)-5-((N,4-dimethylphenyl)sulfonamido)N-methyl-2-phenyl-N-tosyl-1H-pyrrole-3-carboxamide (4q). White solid (124 mg, 96% yield): mp 224-225 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.03 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.32 – 7.28 (m, 5H), 7.22 (dd, J1 = 12.0 Hz, J2 = 8.4 Hz, 4H), 6.87 (d, J = 8.4 Hz, 2H), 6.37 (d, J = 8.4 Hz, 2H), 3.03 (s, 3H), 2.92 (s, 3H), 2.45 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.4, 144.7 (d), 135.6, 134.4, 133.2, 130.4, 130.2, 130.0, 129.9, 129.3, 129.2, 128.9, 128.6, 128.4, 128.3, 127.6, 126.3, 125.3, 118.6, 114.8, 38.6, 34.4, 21.8, 21.7; HRMS (EI) m/z calcd for C33H30ClN3O5S2 (M+) 647.1315, found: 647.1318. 5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-2-phenyl-4(thiophen-2-yl)-N-tosyl-1H-pyrrole-3-carboxamide (4r). Yellow solid (118 mg, 95% yield): mp 168-170 °C; Rf = 0.2 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.11 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.34 – 7.23 (m, 10H), 7.07 (d, J = 4.8 Hz, 1H), 6.72 (dd, J1 = 5.2 Hz, J2 = 4.0 Hz, 1H), 6.20 (d, J = 3.6 Hz, 1H), 3.18 (s, 3H), 3.03 (s, 3H), 2.48 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.3, 144.5 (d), 135.7, 134.5, 132.2, 130.1, 129.8, 129.3, 129.2, 128.7, 128.6, 128.4, 127.8, 126.9, 126.4, 126.2, 125.5, 125.4, 114.8, 112.8, 38.2, 34.3, 21.8, 21.7; HRMS (EI) m/z calcd for C31H29N3O5S3 (M+) 619.1269, found: 619.1275. 5-((N,4-dimethylphenyl)sulfonamido)-N-methyl-2-phenyl-4styryl-N-tosyl-1H-pyrrole-3-carboxamide (4s). Yellow solid (118 mg, 93% yield): mp 217-218 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 8.93 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.30 – 7.14 (m, 12H), 6.83 (d, J = 6.6 Hz, 2H), 6.20 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 16.8 Hz, 1H), 3.31 (s, 3H), 3.12 (s, 3H), 2.43 (s, 3H), 2.23 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.3, 144.9, 144.7, 137.2, 136.1, 134.7, 130.1, 130.0, 129.5, 129.3, 129.1, 128.7, 128.4, 128.3, 127.8, 127.4, 126.8, 126.1 (d),

Page 8 of 10

116.8, 112.8, 39.2, 34.4, 21.8, 21.5; HRMS (EI) m/z calcd for C35H33N3O5S2 (M+) 639.1862, found: 639.1864. 4-cyclopropyl-5-((N,4-dimethylphenyl)sulfonamido)-Nmethyl-2-phenyl-N-tosyl-1H-pyrrole-3-carboxamide (4t). White solid (98 mg, 86% yield): mp 201-202 °C; Rf = 0.2 (petroleum ether/EtOAc = 5/1); 1H NMR (600 MHz, CDCl3) δ 8.74 (s, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.28 – 7.24 (m, 4H), 7.23 – 7.17 (m, 3H), 7.12 – 7.09 (m, 2H), 3.32 (s, 3H), 3.05 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 0.89 – 0.82 (m, 1H), 0.30 – 0.25 (m, 2H), -0.01 – -0.04 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.1, 144.6, 144.3, 135.7, 134.9, 130.5, 129.8, 129.3, 129.0, 128.7, 127.9, 127.7, 127.5, 126.7, 125.9, 119.9, 115.2, 38.5, 34.4, 21.8, 21.7, 5.7; HRMS (EI) m/z calcd for C30H31N3O5S2 (M+) 577.1705, found: 577.1708. Procedure for One-Pot Synthesis of 4u. To a vial was added 4-bromo-N-hydroxybenzimidoyl chloride 1s (56.2 mg, 0.24 mmol), N-ethynyl-N,4-dimethylbenzenesulfonamide 2a (41.8 mg, 0.2 mmol) and Na2CO3 (31.8 mg, 0.3 mmol). The mixture was dissolved in DCM (2 mL) and stirred at room temperature for 5h. Then the solution was filtered and the filtrate was used directly later. An oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar was charged with N,4-dimethyl-N(phenylethynyl)benzenesulfonamide 2g (57 mg, 0.2 mmol), Ph3PAuCl (5 mg, 5 mol %) and AgNTf2 (7.8 mg, 10 mol %). The tube was then evacuated and purged with Argon for three times. DCM (1 mL) was added and the suspension was stirred for 10 min. The filtrate was added via syringe and the reaction mixture was stirred at room temperature for 5 h. Upon completion, the solvent was evaporated and the residue was purified by flash column chromatography on silica gel using petroleum ether/EtOAc (3/1) as eluent to give 4u as a white solid (76 mg, 56 % yield). 2-(4-bromophenyl)-5-((N,4-dimethylphenyl)sulfonamido)N-methyl-4-phenyl-N-tosyl-1H-pyrrole-3-carboxamide (4u). White solid (76 mg, 56% yield): mp 220-221 °C; Rf = 0.3 (petroleum ether/EtOAc = 3/1); 1H NMR (600 MHz, CDCl3) δ 9.00 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 3H), 6.97 (t, J = 7.8 Hz, 2H), 6.43 (d, J = 7.8 Hz, 2H), 2.97 (s, 3H), 2.89 (s, 3H), 2.45 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.4, 144.7, 144.6, 135.7, 134.2, 132.3, 131.7, 129.9, 129.3 (d), 128.7, 128.6, 128.3, 127.9, 127.7, 127.6, 127.4, 125.4, 122.3, 119.6, 115.5, 38.3, 34.3, 21.8 (d); HRMS (EI) m/z calcd for C33H30BrN3O5S2 (M+) 691.0810, found: 691.0811.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/. Copies of all 1H and 13C NMR spectra (PDF) and crystallographic data for 3e (CIF) and 4p (CIF).

AUTHOR INFORMATION Corresponding Author [email protected] Notes The authors declare no competing financial interest.


Page 9 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ACKNOWLEDGMENT We are grateful for the financial support from Key R & D Plan of Zhejiang Province (2019C03082).

REFERENCES (1) (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. The Current Status of Heterocyclic Combinatorial Libraries. Chem. Rev. 1997, 97, 449-472. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 1025710274. (2) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Solvent-Free Heterocyclic Synthesis. Chem. Rev. 2009, 109, 4140-4182. (b) Majumdar, P.; Pati, A.; Patra, M.; Behera, R. K.; Behera, A. K. Acid Hydrazides, Potent Reagents for Synthesis of Oxygen-, Nitrogen-, and/or SulfurContaining Heterocyclic Rings. Chem. Rev. 2014, 114, 29422977. (c) Zhang, W. Fluorous Synthesis of Heterocyclic Systems. Chem. Rev. 2004, 104, 2531-2556. (d) Nakamura, I.; Yamamoto, Y. Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis. Chem. Rev. 2004, 104, 2127-2198. (e) Krchňák, V.; Holladay, M. W. Solid Phase Heterocyclic Chemistry. Chem. Rev. 2002, 102, 61-92. (f) Li, C.-L.; Liu, R.-S. Synthesis of Heterocyclic and Carbocyclic Compounds via Alkynyl, Allyl, and Propargyl Organometallics of Cyclopentadienyl Iron, Molybdenum, and Tungsten Complexes. Chem. Rev. 2000, 100, 3127-3162. (3) (a) Roscales, S.; Plumet, J. Metal-catalyzed 1,3-dipolar cycloaddition reactions of nitrile oxides. Org. Biomol. Chem. 2018, 16, 8446-8461. (b) Hu, F.; Szostak, M. Recent Developments in the Synthesis and Reactivity of Isoxazoles: Metal Catalysis and Beyond. Adv. Synth. Catal. 2015, 357, 2583-2614. (c) Heaney, F. Nitrile Oxide/Alkyne Cycloadditions - A Credible Platform for Synthesis of Bioinspired Molecules by Metal-Free Molecular Clicking. Eur. J. Org. Chem. 2012, 2012, 3043-3058. (d) Digamber, R.; Mukund, S. Recent Advances in Nitrile Oxide Cycloadditions. Synthesis of Isoxazolines. Curr. Org. Syn. 2011, 8, 616-627. (e) Browder, C. C. Recent Advances in Intramolecular Nitrile Oxide Cycloadditions in the Synthesis of 2-Isoxazolines. Curr. Org. Syn. 2011, 8, 628-644. (f) Savage, G. P. Spiro Isoxazolines via Nitrile Oxide 1,3-Dipolar Cycloaddition Reactions. Curr. Org. Chem. 2010, 14, 1478-1499. (g) Gallo, J. K.; Koumbis, A. E. 1,3-Dipolar Cycloadditions in the Synthesis of Carbohydrate Mimics. Part 1: Nitrile Oxides and Nitronates. Curr. Org. Chem. 2003, 7, 397-426. (4) (a) Meena, D. R.; Maiti, B.; Chanda, K. Cu(I) catalyzed microwave assisted telescopic synthesis of 3,5-disubstituted isoxazoles in green media. Tetrahedron Lett. 2016, 57, 55145517. (b) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. Copper(I)Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127, 210-216. (c) Hansen, T. V.; Wu, P.; Fokin, V. V. One-Pot Copper(I)-Catalyzed Synthesis of 3,5-Disubstituted Isoxazoles. J. Org. Chem. 2005, 70, 7761-7764. (5) (a) Kesornpun, C.; Aree, T.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles. Angew. Chem., Int. Ed. 2016, 55, 3997-4001. (b) Mohammed, S.; Vishwakarma, R. A.;

Bharate, S. B. Metal-free DBU promoted regioselective synthesis of isoxazoles and isoxazolines. RSC Adv. 2015, 5, 3470-3473. (c) Jawalekar, A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; van Delft, F. L. Synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes. Chem. Commun. 2011, 47, 3198-3200. (d) Perez, V.; Fadel, A.; Rabasso, N. Synthesis of N-Sulfonyl Ynamido-Phosphonates: Valuable Partners for Cycloadditions. Synthesis. 2017, 49, 4035-4044. (6) Grecian, S.; Fokin, V. V. Ruthenium-Catalyzed Cycloaddition of Nitrile Oxides and Alkynes: Practical Synthesis of Isoxazoles. Angew. Chem., Int. Ed. 2008, 47, 82858287. (7) Li, H.; You, L.; Zhang, X.; Johnson, W. L.; Figueroa, R.; Hsung, R. P. Synthesis of Amide-Substituted Isoxazoles and Pyrazoles via Regioselective [3+2] Cycloadditions of Terminally Unsubstituted Ynamides. Heterocycles. 2007, 74, 553-568. (8) (a). Huang, B.; Zeng, L.; Shen, Y.; Cui, S. One-Pot Multicomponent Synthesis of β‐Amino Amides. Angew. Chem., Int. Ed. 2017, 56, 4565-4568. (b). Shen, Y.; Huang, B.; Zeng, L.; Cui, S. Single Reactant Replacement Approach of Passerini Reaction: One-Pot Synthesis of β-Acyloxyamides and Phthalides. Org. Lett. 2017, 19, 4616-4619. (c). Chen, R.; Zeng, L.; Huang, B.; Shen, Y.; Cui, S. Decarbonylative Coupling of α-Keto Acids and Ynamides for Synthesis of β-Keto Imides. Org. Lett. 2018, 20, 3377-3380. (d). Chen, R.; Liu, Y.; Cui, S. 1,4-Conjugate addition/esterification of ortho-quinone methides in a multicomponent reaction. Chem. Commun. 2018, 54, 11753-11756. (e). Zeng, L.; Huang, B.; Shen, Y.; Cui, S. Multicomponent Synthesis of Tetrahydroisoquinolines. Org. Lett. 2018, 20, 3460-3464. (9) CCDC 1883881. (10) (a) Zhou, A.-H.; He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.; Zhao, T.; Zhang, W.; Lu, X.; Ye, L.-W. Atom-economic generation of gold carbenes: gold-catalyzed formal [3+2] cycloaddition between ynamides and isoxazoles. Chem. Sci. 2015, 6, 12651271. (b) Xiao, X.-Y.; Zhou, A.-H.; Shu, C.; Pan, F.; Li, T.; Ye, L.-W. Atom-Economic Synthesis of Fully Substituted 2Aminopyrroles via Gold-Catalyzed Formal [3+2] Cycloaddition between Ynamides and Isoxazoles. Chem. Asian J. 2015, 10, 1854-1858. (c) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold-Catalyzed C-H Annulation of Anthranils with Alkynes: A Facile, Flexible, and Atom-Economical Synthesis of Unprotected 7-Acylindoles. Angew. Chem., Int. Ed. 2016, 55, 794-797. (d) Jin, H.; Tian, B.; Song, X.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold-Catalyzed Synthesis of Quinolines from Propargyl Silyl Ethers and Anthranils through the Umpolung of a Gold Carbene Carbon. Angew. Chem., Int. Ed. 2016, 55, 12688-12692. (e) Shen, W.-B.; Xiao, X.-Y.; Sun, Q.; Zhou, B.; Zhu, X.-Q.; Yan, J.-Z.; Lu, X.; Ye, L.-W. Highly Site Selective Formal [5+2] and [4+2] Annulations of Isoxazoles with Heterosubstituted Alkynes by Platinum Catalysis: Rapid Access to Functionalized 1,3-Oxazepines and 2,5-Dihydropyridines. Angew. Chem., Int. Ed. 2017, 56, 605-609. (f) Zhu, X.-Q.; Sun, Q.; Zhang, Z.-X.; Zhou, B.; Xie, P.-X.; Shen, W.-B.; Lu, X.; Zhou, J.-M.; Ye, L.W. Zinc-catalyzed reaction of isoxazoles with thioynol ethers involving an unprecedented 1,2-sulfur migration. Chem. Commun. 2018, 54, 7435-7438. (g) Zhu, X.-Q.; Yuan, H.; Sun, Q.; Zhou, B.; Han, X.-Q.; Zhang, Z.-X.; Lu, X.; Ye, L.-W. Benign catalysis with zinc: atom-economical and divergent synthesis of nitrogen heterocycles by formal [3 + 2] annulation



Page 10 of 10

of isoxazoles with ynol ethers. Green Chem. 2018, 20, 42874291. (h) Tsai, M.-H.; Wang, C.-Y.; Kulandai Raj, A. S.; Liu, R.-S. Gold-catalyzed annulations of N-aryl ynamides with benzisoxazoles to construct 6H-indolo[2,3-b]quinoline cores. Chem. Commun. 2018, 54, 10866-10869. (i) Kardile, R. D.; Kale, B. S.; Sharma, P.; Liu, R. S. Gold-Catalyzed [4 + 1]Annulation Reactions between 1,4-Diyn-3-ols and Isoxazoles To Construct a Pyrrole Core. Org. Lett. 2018, 20, 3806-3809. (11) CCDC 1902539. (12) (a) Gan, H. K.; Seruga, B.; Knox, J. J. Sunitinib in solid tumors. Expert. Opin. Investig. Drugs. 2009, 18, 821-834. (b) Nawrocki, J. W.; Weiss, S. R.; Davidson, M. H.; Sprecher, D. L.; Schwartz, S. L.; Lupien, P.-J.; Jones, P. H.; Haber, H. E.; Black, D. M. Reduction of LDL Cholesterol by 25% to 60% in Patients With Primary Hypercholesterolemia by Atorvastatin, a New HMG-CoA Reductase Inhibitor. Arterioscleriosis, Thrombosis, Vascular Biology. 1995, 15, 678-682. (13) Zeng, Z.; Jin, H.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold(III)-Catalyzed Site-Selective and Divergent Synthesis of 2-Aminopyrroles and Quinoline-Based Polyazaheterocycles. Angew. Chem., Int. Ed. 2018, 57, 1654916553. (14) (a) Jiang, K. M.; Luesakul, U.; Zhao, S. Y.; An, K.; Muangsin, N.; Neamati, N.; Jin, Y.; Lin, J. TautomericDependent Lactam Cycloaddition with Nitrile Oxide: Facile Synthesis of 1,2,4-Oxadiazole[4,5-a]indolone Derivatives. ACS Omega 2017, 2, 3123-3134. (b) Mo, X.; Morgan, T. D. R.; Ang, H. T.; Hall, D. G. Scope and Mechanism of a True Organocatalytic Beckmann Rearrangement with a Boronic Acid/Perfluoropinacol System under Ambient Conditions. J. Am. Chem. Soc. 2018, 140, 5264-5271. (15) (a) Chen, X. Y.; Wang, L.; Frings, M.; Bolm, C. CopperCatalyzed N-Alkynylations of Sulfoximines with Bromoacetylenes. Org. Lett. 2014, 16, 3796-3799. (b) Mansfield, S. J.; Campbell, C. D.; Jones, M. W.; Anderson, E. A. A robust and modular synthesis of ynamides. Chem. Commun. 2015, 51, 3316-3319. (c) Zhao, X.; Song, X.; Jin, H.; Zeng, Z.; Wang, Q.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2018, 360, 2720-2726.


Iterative Assembly of Nitrile Oxides and Ynamides: Synthesis of

Recommend Documents