Palladium-Catalyzed Synthesis of 3-Haloindol-2-amines from 3

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Palladium-Catalyzed Synthesis of 3-Haloindol-2amines from 3-Diazoindolin-2-imines and Alkyl Halides Yuxuan Zhou, Zhenmin Li, Fanghui Ma, Chang Zhao, Ping Lu, and Yanguang Wang J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019 Downloaded from http://pubs.acs.org on March 26, 2019

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The Journal of Organic Chemistry

Palladium-Catalyzed Synthesis of 3-Haloindol-2-amines from 3Diazoindolin-2-imines and Alkyl Halides Yuxuan Zhou, Zhenmin Li, Fanghui Ma, Chang Zhao, Ping Lu* and Yanguang Wang* Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China

ABSTRACT: Synthetically valuable 3-haloindol-2-amines were prepared from readily available 3-diazoindolin-2-imines and a variety of alkyl halides through palladium-catalyzed reaction. Broad substrate scope of both diazo compounds and alkyl halides, mild reaction conditions and high efficiency are the main characters of this method. The synthesized 3-haloindol-2-amines can be conveniently transformed to more complex indole derivatives. KEYWORDS: indoles, halonium ylides, diazo compounds, palladium catalysis

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INTRODUCTION The indole ring system is a structural component of a vast number of biologically active natural and unnatural compounds. Consequently, the construction and functionalization of indole ring has been the object of research and a variety of well-established methodologies have been reported and applied in both synthetic chemistry and industry. Among various indole derivatives, 2aminoindoles1 and 3-haloindoles2 are the key synthetic intermediates towards many biologically active natural products, clinically used drugs and pharmaceutically valuable compounds. In the last decade, the transition-metal-catalyzed X-H insertion, migratory insertion, cyclopropenation, formal cycloaddition, ylide formation, and cross-coupling reactions through metal carbene intermediates in situ generated from diazo compounds as well as their precursors have attracted synthetic chemists’ interest.3 A variety of transition-metal catalysts (e.g. Rh(II),4 Cu(I)/Cu(II),5 Ag(I),6 Pd(II)7 and Fe(II)/Fe(III) catalysts8) have been explored for these important transformations. However, there are limited examples involving the formation of halonium ylide intermediates from metal carbenes.9 A recent work on bromonium ylide formation from rhodium carbnene through rhodium-catalyzed intramolecular reaction of 4-(2-(bromomethyl)phenyl)-1sulfonyl-1,2,3-triazoles, a class of precousors of -diazo imines, was reported by Li and coworkers.10 We previously developed convenient approaches to 3-diazoindolin-2-imines11 and demonstrated that this class of diazo compounds could be utilized as precursors of metal carbenes for a variety of synthetically valuable transformations.11,12 As continuation of our studies on diazo compound chemistry and inspired by Li’s work,10 we envisioned that the halonium ylide would be


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formed from diazoindolin-2-imines and alkyl halides using suitable transition metal catalyst and this reactive intermediate would undergo further transformation to provide 3-haloindol-2-amines. The halogenated products should be versatile building blocks for the synthesis of 3-functionalized indol-2-amines. In this paper, we report the results of this work. RESULTS AND DISCUSSION With the reaction between 3-diazoindolin-2-imine 1a and allylic bromide (2a) as the model reaction, we initially screened the catalyst (Table 1). When Pd(OAc)2 (0.1 equiv) was used as catalyst and K2CO3 was used as base, the reaction occurred in acetonitrile at 80 oC to furnish 3bromoindol-2-amine 3a in 67% yield (Table 1, entry 1). Several other palladium catalysts (Table 1, entries 2-8) as well as Rh(II) (Table 1, entries 9 and 10), Cu(I)/Cu(II) (Table 1, entries 11-13), Ag(I) (Table 1, entry 14) and Fe(II) catalysts (Table 1, entry 5) were screened and only tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) gave satisfactory yield (Table 1, entry 5). Then, we fixed Pd2(dba)3 as the catalyst to examine other solvents, such as 1,2-dichloroethane (DCE), toluene, THF and 1,4-dioxane. However, only trace of 3a was observed or no reaction took place in these cases (Table 1, entries 16-19). Changing the base from K2CO3 to Na2CO3, Cs2CO3 and KOAc resulted in decreased yields (Table 1, entries 20-22), whereas Et3N and DBU gave trace of desired product (Table 1, entries 23 and 24). Without any base, no reaction took place (Table 1, entry 25). The amount of allylic bromide could be decreased to 1.5 equivalent (Table 1, entry 26), but further decrease led to a lower yield (Table 1, entry 27). Either increasing or decreasing the reaction temperature led to a decrease in the yield (Table 1, entries 28 and 29).



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Table 1. Optimization of Reaction Conditionsa

entry

catalyst

solvent

base

equiv of 2a

temp (oC) yield (%)b

1

Pd(OAc)2

CH3CN

K2CO3

2

80

67

2

Pd(TFA)2

CH3CN

K2CO3

2

80

26

3

Pd(PPh3) 2Cl2

CH3CN

K2CO3

2

80

41

4

Pd(dba)2

CH3CN

K2CO3

2

80

17

5

Pd2(dba)3

CH3CN

K2CO3

2

80

93

6

PdCl2

CH3CN

K2CO3

2

80

trace

7

Pd(CH3CN) 2Cl2

CH3CN

K2CO3

2

80

trace

8

Pd(PPh3)4

CH3CN

K2CO3

2

80

trace

9

Rh2(Oct)4

CH3CN

K2CO3

2

80

trace

10

Rh2(HFB)4

CH3CN

K2CO3

2

80

trace

11

Cu(OTf) 2

CH3CN

K2CO3

2

80

NR

12

CuOTf·1/2Ph

CH3CN

K2CO3

2

80

NR

13

CuBr

CH3CN

K2CO3

2

80

NR

14

AgOTf

CH3CN

K2CO3

2

80

NR

15

Fe(OTf)2

CH3CN

K2CO3

2

80

9

16

Pd2(dba)3

DCE

K2CO3

2

80

NR


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17

Pd2(dba)3

toluene

K2CO3

2

80

trace

18

Pd2(dba)3

THF

K2CO3

2

80

trace

19

Pd2(dba)3

1,4-dioxane

K2CO3

2

80

NR

20

Pd2(dba)3

CH3CN

Na2CO3

2

80

33

21

Pd2(dba)3

CH3CN

Cs2CO3

2

80

29

22

Pd2(dba)3

CH3CN

KOAc

2

80

31

23

Pd2(dba)3

CH3CN

Et3N

2

80

trace

24

Pd2(dba)3

CH3CN

DBU

2

80

trace

25

Pd2(dba)3

CH3CN

−

2

80

NR

26

Pd2(dba)3

CH3CN

K2CO3

1.5

80

93

27

Pd2(dba)3

CH3CN

K2CO3

1.2

80

86

28

Pd2(dba)3

CH3CN

K2CO3

1.5

90

84

29

Pd2(dba)3

CH3CN

K2CO3

1.5

70

81

a

Reaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol), solvent (2 mL), base (0.3 mmol), 12 h.

b

Isolated yields.

With optimal reaction conditions in hand, we next investigated the substrate scope of 3-diazo compounds (Scheme 1). We were pleased to find that the reaction of a wide range of diazoindolin2-imines (1a-m) with 2a proceeded smoothly to provide the corresponding products 3a-m. In most cases, good to excellent yields (71-96%) were obtained (products 3a-h and 3j-m). Only compound 3i was isolated in lower yield (49%) because the electron-rich nature of p-methoxyphenyl in sulfonyl moiety might lead to the yield of some complex by-products. It is noteworthy that the reaction could be scale up as demonstrated by the synthesis of high yield (90%) of 3j in gram scale.



Scheme 1. Scope of 3-Diazoindolin-2-imines 1a

a

Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd2(dba)3 (0.01 mmol), CH3CN (2 mL),

K2CO3 (0.3 mmol), 80 oC, 12 h; aIsolated yield. bGram scale reaction was conducted with 1 (3 mmol), 2a (4.5 mmol), Pd2(dba)3 (0.3 mmol), and K2CO3 (9 mmol) in CH3CN (60 mL), and 1.092 g (90% yield) of 3j was isolated.

The scope of the allylic bromide component in this ylide formation protocol was further examined (Scheme 2). Phenyl-, methyl- and bromo-substituted allylic bromides 2b-e reacted with diazo compound 1j under standard conditions to give the corresponding products 3n-q in good to excellent yields (68-93%). The structure of 3p was unambiguously characterized by its single crystal X-ray analysis.13


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Scheme 2. Scope of Allylic Bromides 2a

a

Reaction conditions: 1j (0.1 mmol), 2 (0.15 mmol), Pd2(dba)3 (0.01 mmol), CH3CN (2 mL),

K2CO3 (0.3 mmol), 80 oC, 12 h.; Isolated yield. When allylic chloride (4a) was subjected to this reaction under the established conditions, however, no desired product was obtained. After careful screened the reaction conditions, we found that the addition of suitable ligand and increasing the amount of allylic chloride could improve the reaction and give satisfactory yield (see Supporting Information, Table S1). The highest yield of 5a (88% yield) was obtained when the Pd(OAc)2-catalyzed reaction was carried out at 100 oC in the presence of bathocuproine (BCP) as ligand. Under the modified reaction conditions, the chlorinated products 5a-h were synthesized in 39-91% yields (Scheme 3).



Scheme 3. Scope of Allylic Chlorides 4a

a

Reaction conditions: 1 (0.1 mmol), 4 (0.7 mL), Pd(OAc)2 (0.01 mmol), BCP = bathocuproine

(0.02 mmol), CH3CN (0.3 mL), K2CO3 (0.3 mmol), 100 oC, 12 h; Isolated yield. Allylic iodide (6a) could also participate in this transformation by a similar procedure. Under modified reaction conditions (see Supporting Information, Table S2), the reactions of diazo compounds 1 and 6a were carried out at lower temperature (40 oC) to produce the corresponding iodinated products 7a-e (Scheme 4). The highest yield (91%) was obtained when the sulfonyl was benzenesulfonyl (product 7b), while the lowest yield (23%) was observed when the sulfonyl was methanesulfonyl (product 7e). Increasing the reaction time to 18 h led to the isolation of improved yield (41%) of 7e along with 1-methylindoline-2,3-dione as by-product.


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Scheme 4. Reaction of 1 with Alkyl Iodidesa

a

Reaction conditions: 1 (0.1 mmol), 6 (0.2 mL), Pd(OAc)2 (0.01 mmol), BCP = bathocuproine

(0.02 mmol), CH3CN (0.8 mL), K2CO3 (0.3 mmol), 40 oC, 12 h; Isolated yield. bReaction time: 18 h. c6 (0.3 mL). We next investigated the possibility for other type of halides to take part in this transformation. As shown in Scheme 5, benzyl bromide (8a) could react with diazo compound smoothly under the standard conditions to provide brominated product 9a in 70% yield. The substituent on the phenyl ring of benzyl bromide could be alkyl, phenyl, bromo, iodo, fluoro, nitro, or trifluoromethyl (products 9b-l, 38-77% yields). 2-(Bromomethyl)naphthalene gave a much lower yield (36%) of the desired product 9m. The sulfonyl could be methanesulfonyl (product 9n, 45% yield) or 4-



methylbenzenesulfonyl (products 9o and 9p, 54% and 49% yields, respectively). 3(bromomethyl)-5-chlorobenzo[b]thio- phene (8o) was also examined for this transformation and the desired product 9q was obtained in 50% yield. Scheme 5. Reaction of 1 with Benzyl Bromides 8a


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a

Reaction conditions: 1 (0.1 mmol), 8 (0.15 mmol), Pd(OAc)2 (0.01 mmol), CH3CN (2 mL),

K2CO3 (0.3 mmol), 12 h.; Isolated yield.

Based on our work mechanism, -bromo ketones and -bromo carboxylic esters would be similar to allyl and benzyl bromides in their reactivity. Consequently, we examined the reaction of a variety of -bromo ketones and -bromo carboxylic esters with 3-diazoindolin-2-imines under the established conditions. As shown in Scheme 6, both aromatic (products 11a-h) and aliphatic -bromo ketones (products 11i-k) reacted with the diazo compound to provide the corresponding products. The structure of 11a was characterized by its single crystal X-ray analysis.13 In the cases where 1-bromo-3,3-dimethylbutan-2-one or 2-bromo-1-cyclopropylethanone was used as one of reaction component, poor yield of the desired products 11j (28%) and 11k (34%) were isolated, respectively. However, when bathocuproine was added as ligand in the catalytic system, a remarkable improvement was observed for 11j (52%) and 11k (85%), respectively. Moreover, it was found that the reaction could be conducted with ethyl 2-bromoacetate. Thus, the desired products 11l (40% yield) and 11m (39% yield) were obtained in relatively lower yields that could be improved as demonstrated by the formation of 11l (51% yield) and 11m (76% yield) using bathocuproine as ligand.



Scheme 6. Reaction of 1 with -Bromo Ketones and -Bromo Carboxylic Esters 10a

a

Reaction conditions: 1 (0.1 mmol), 10 (0.15 mmol), Pd(OAc)2 (0.01 mmol), CH3CN (2 mL),

K2CO3 (0.3 mmol), 80 oC, 1 h.; Isolated yield. bReaction conditions 1 (0.1 mmol), 10 (0.3 mL), Pd(OAc)2 (0.01 mmol), BCP = bathocuproine (0.02 mmol), CH3CN (0.7 mL), K2CO3 (0.3 mmol), 80 oC, 1 h.


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The substrate scope of halides could be further extended to 2-bromoacetonitrile and other alkyl bromides. As shown in Scheme 7, five different 3-diazoindolin-2-imines were tested for their reaction with 2-bromoacetonitrile (12). The desired products 13a-e were provided in relatively lower yields (29-53%). The addition of ligand (e.g. bathocuproine) led to an increase in the yield of 13a (53%), 13c (56%), 13d (60%) and 13e (36%), but did not improve the yield of 13b. Bromoethane and 1,2-dibromoethane could also react with 1a in the presence of bathocuproine and resulted in the corresponding products 13f (30%) and 13g (55%). Secondary bromides such as (1-bromoethyl)benzene and 3-bromocyclohex-1-ene were examined for this transformation, but no desired product (i.e. 13h and 13i) was obtained with or without the ligand.



Scheme 7. Reaction of 3-Diazoindolin-2-imines with Other Alkyl Bromidesa

a

Reaction conditions: 1 (0.1 mmol), 12a (0.15 mmol), Pd(OAc)2 (0.01 mmol), CH3CN (2 mL),

K2CO3 (0.3 mmol), 80 oC, 12 h; Isolated yield. bReaction conditions 1 (0.1 mmol), 12 (0.1 mL), Pd(OAc)2 (0.01 mmol), BCP = bathocuproine (0.02 mmol), CH3CN (0.9 mL), K2CO3 (0.3 mmol), 80 oC, 12 h; Isolated yield. With the products in hand, we performed further transformations to demonstrate the potential applications of this chemistry. For example, a number of N-allyl-3-iodo-1-methylindol-2-amines 7 were conveniently converted into pyrrolo[2,3-b]indoles 14a-e via a palladium-catalyzed intramolecular Heck reaction (Scheme 8). The synthesized pyrrolo[2,3-b]indoles are a key structural motif found in a wide number of biologically active alkaloids.14


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Scheme 8. Synthesis of Pyrrolo[2,3-b]indoles 14a

a

Reaction conditions: Pd(OAc)2 (10 mmol%), DMA (1 mL), Bu4NCl (1 equiv), NaHCO3 (2.5

equiv), 90 oC, 12 h; Isolated yield.

To have a good insight into the reaction mechanism, crossover reactions of 1a with different alkyl halides (e.g. 2a/4d, 6a/2d, and 6a/4d) were investigated (Scheme 9). When the reaction was performed with the mixture of 2a/4d, we isolated 3a as major product (78%) and compound 15 as minor product (7%) (Scheme 9, eq. (a)). Similarly, a crossover product 16 was obtained when the mixture of 6a/2d were used (Scheme 9, eq.(b)). In the case where the mixture of 6a/4d was used for the reaction, we obtained 7a as sole product (50% yield) without any crossover product 17 (Scheme 9, eq. (c)).



Scheme 9. Crossover Reactions

Based on our observations and the literatures, we propose two plausible mechanisms for our reactions as shown in Scheme 10. First, a palladium carbene intermediate A is generated from diazo compound and palladium catalyst.7 Then, alkyl halide reacts with A to form halonium ylide B,9,10 which subsequently undergos an intramolecular SN2 reaction to give 3 or other final products (path a). Alternatively, the carbene atom of A is initially attacked by halide ion to form intermediate C, which subsequently undergoes an intermolecular SN2 reaction with alkyl halide to furnish 3 along with release of halide ion (phat b). The initial halide ion might be generated from the nucleophilic substitution of alkyl halide with base that is nessessary for this reaction. Formation of crossover products 15 and 16 may be through path b, in which the more nucleophilic halide ion (i.e., Br− or I−) preferentially reacts with electrophilic carbene A and then SN2 with different alkyl halides occurs.


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Scheme 10. Proposed Mechanism

CONCLUSIONS In conclusion, we have demonstrated a palladium-catalyzed reaction of 3-diazoindolin-2-mines with a variety of alky halides, such as allylic bromides/chlorides/iodides, benzyl bromides, bromoketones, -bromocarboxylic esters as well as -bromonitriles. This reaction offers a practical and highly efficient method to synthesize valuable 3-haloindol-2-amine architectures from readily available materials. The substrate scope of both diazo compounds and halides is significant. Moreover, the synthesized 3-iodoindol-2-amines could be conveniently converted to pyrrolo[2,3-b]indoles. EXPERIMENTAL SECTION General Information. 1H NMR spectra were obtained on 400 or 600 MHz in CDCl3. Chemical shifts are expressed in ppm and are referenced to 0 ppm for TMS as internal standard, where multiplicity is defined as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13C NMR spectra were recorded on 100 or 150 MHz in CDCl3. Chemical shifts are expressed in ppm and are



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referenced to the internal solvent signals (77.0 ppm for CDCl3). 13C{1H} for proton-decoupled carbon data was recorded. Coupling constants J are given in Hz. IR spectra were obtained on an FTIR spectrometer. HRMS data were obtained by using ESI or EI ionization. Melting points were measured with micro melting point apparatus. Column chromatography was performed on silica gel (300-400 mesh). TLC was done on silica gel HSGF254. CH3CN and DCE were dried by distillation over CaH2. THF, toluene and dioxane was distilled from Na. All catalysts, bases and halogen compounds were used as received from the commercial sources. 3-Diazoindolin-2-imines 1a-m were prepared according to our published methods.11 General Procedure for the Synthesis of 3. To a sealed tube with a magnetic stirrer were added sequentially 1 (0.1 mmol), 2 (0.15 mmol), Pd2(dba)3 (0.01 mmol), K2CO3 (0.3 mmol) and dry CH3CN (2 mL) under air atmosphere. The reaction mixture was stirred at 80 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 6:1 - 10:1, v/v) to give the product 3. Gram Scale Procedure for the Synthesis of 3j. To a sealed tube with a magnetic stirrer were added sequentially 1j (3 mmol), 2a (4.5 mmol), Pd2(dba)3 (0.3 mmol), K2CO3 (9 mmol) and dry CH3CN (60 mL) under air atmosphere. The reaction mixture was stirred at 80 oC (oil bath) for 12 h. After the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) to give pure product 3j in 1.092 g (90% yield). N-Allyl-N-(3-bromo-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide

(3a).

Colorless

liquid; Yield 93% (39 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.65 (m, 2H), 7.45 (dt, J = 8.0, 0.9 Hz, 1H), 7.34 – 7.27 (m, 4H), 7.19 – 7.15 (m, 1H), 5.86 – 5.76 (m, 1H), 5.14 – 5.00 (m, 2H),


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4.59 – 4.54 (m, 1H), 4.09 (dd, J = 13.7, 8.5 Hz, 1H), 3.79 (s, 3H), 2.45 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.2, 135.9, 134.5, 131.9, 130.9, 129.8, 128.1, 125.3, 123.6, 120.39, 120.36, 119.3, 110.1, 88.2, 53.3, 30.3, 21.6; IR(film): 3059, 2926, 1469, 1354, 1235, 1166, 1090, 1056 cm1

; HRMS (ESI-TOF) calcd for C19H19BrN2NaO2S+([M+Na]+): 441.0243; found: 441.0245. N-Allyl-N-(3-bromo-1-ethyl-1H-indol-2-yl)-4-methylbenzenesulfonamide (3b). Colorless liquid;

Yield 77% (33 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.45 (dd, J = 8.0, 1.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.33 – 7.27 (m, 3H), 7.17 (t, J = 7.5 Hz, 1H), 5.91 – 5.76 (m, 1H), 5.17 – 5.00 (m, 2H), 4.55 (ddd, J = 13.9, 5.6, 1.3 Hz, 1H), 4.42 (dq, J = 14.5, 7.3 Hz, 1H), 4.28 (dq, J = 14.5, 7.2 Hz, 1H), 4.11 (dd, J = 13.8, 8.5 Hz, 1H), 2.45 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 135.6, 133.4, 132.1, 130.3, 129.8, 128.3, 125.5, 123.5, 120.4, 120.3, 119.4, 110.7, 88.2, 53.5, 38.5, 21.7, 14.8; IR(film): 2983, 2937, 1598, 1458, 1355, 1227, 1166, 1090 cm-1; HRMS (ESI-TOF) calcd for C20H21BrN2NaO2S+([M+Na]+): 455.0399; found: 455.0397. N-Allyl-N-(1-benzyl-3-bromo-1H-indol-2-yl)-4-methylbenzenesulfonamide

(3c).

Colorless

liquid; Yield 83% (41 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.67 (m, 2H), 7.47 (dd, J = 7.1, 1.8 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.28 – 7.23 (m, 3H), 7.22 – 7.13 (m, 2H), 7.12 – 7.05 (m, 3H), 5.71 (d, J = 16.9 Hz, 1H), 5.45 – 5.33 (m, 2H), 4.98 (dd, J = 17.1, 1.4 Hz, 1H), 4.83 (d, J = 9.9 Hz, 1H), 4.41 – 4.33 (m, 1H), 4.12 (dd, J = 13.7, 8.4 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.3, 137.1, 135.5, 134.3, 131. 9, 130.9, 129.8, 128.5, 128.3, 127.3, 126.8, 125.5, 123.9, 120. 6, 120.2, 119.4, 111.3, 89.4, 53.5, 47.3, 21. 7; IR(film): 3062, 2924, 1598, 1460, 1352, 1219, 1166, 1090 cm-1; HRMS (ESI-TOF) calcd for C25H23BrN2NaO2S+([M+Na]+): 517.0556; found: 517.0535.



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N-Allyl-N-(1-allyl-3-bromo-1H-indol-2-yl)-4-methylbenzenesulfonamide (3d). Yellowish green liquid; Yield 72% (32 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.31 – 7.27 (m, 3H), 7.20 – 7.14 (m, 1H), 6.01 – 5.91 (m, 1H), 5.85 – 5.75 (m, 1H), 5.26 – 5.14 (m, 2H), 5.10 (dd, J = 17.0, 1.3 Hz, 1H), 5.05 – 4.96 (m, 2H), 4.83 (ddt, J = 16.8, 5.2, 1.8 Hz, 1H), 4.54 (ddt, J = 13.8, 5.5, 1.4 Hz, 1H), 4.13 (dd, J = 13.7, 8.5 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 135.7, 134.1, 133.6, 132.1, 130.4, 129.8, 128.3, 125.5, 123.6, 120.5, 120.3, 119.4, 117.4, 111.3, 88. 9, 53.5, 46.5, 21. 7; IR(film): 3058, 2923, 1598, 1459, 1355, 1220, 1166,1090 cm-1; HRMS (ESI-TOF) calcd for C21H21BrN2NaO2S+([M+Na]+): 467.0399; found: 467.0391. N-Allyl-N-(3-bromo-5-methoxy-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide

(3e).

Colorless liquid; Yield 71% (32 mg); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.9 Hz, 1H), 6.96 (dd, J = 8.9, 2.4 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 5.86 – 5.76 (m, 1H), 5.14 – 5.00 (m, 2H), 4.56 (dd, J = 13.7, 5.5 Hz, 1H), 4.08 (dd, J = 13.7, 8.5 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.8, 144.1, 135.9, 131.9, 130.8, 129.8, 129.6, 128.1, 125.5, 120.3, 114.5, 111.3, 100.1, 87.5 , 55.8, 53.3, 30.4, 21.7; IR(film): 3075, 2940, 1490, 1353, 1290, 1215, 1165, 1090 cm-1; HRMS (ESI-TOF) calcd for C20H21BrN2NaO3S+([M+Na]+): 471.0348; found: 471.0331. N-Allyl-N-(3-bromo-1,5-dimethyl-1H-indol-2-yl)-4-methylbenzenesulfonamide (3f). Colorless liquid; Yield 93% (40 mg); 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.13 (dd, J = 8.4, 1.5 Hz, 1H), 5.87 – 5.74 (m, 1H), 5.15 – 4.98 (m, 2H), 4.56 (dd, J = 14.0, 5.2 Hz, 1H), 4.08 (dd, J = 13.7, 8.5 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 144.1, 135.9, 132.9, 131.9, 130.6, 129.9, 129.8, 128.1, 125.32, 125.30, 120.3, 118.7, 109.9, 87.5, 53.3, 30.3, 21.7, 21.4; IR(film): 3024, 2921, 1597, 1490,


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1354, 1294, 1165, 1091 cm-1; HRMS (ESI-TOF) calcd for C20H21BrN2NaO2S+([M+Na]+): 455.0399; found: 455.0397. N-Allyl-N-(3-bromo-5-chloro-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide

(3g).

Colorless liquid; Yield 88% (40 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.64 (m, 2H), 7.42 (t, J = 1.3 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.26 – 7.24 (m, 2H), 5.85 – 5.74 (m, 1H), 5.14 – 5.01 (m, 2H), 4.56 (ddt, J = 13.7, 5.5, 1.4 Hz, 1H), 4.07 (dd, J = 13.6, 8.6 Hz, 1H), 3.78 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 135.6, 132.9, 132.0, 131.7, 129.9, 128.1, 126.4, 126.2, 124.1, 120.6, 118.8, 111.4, 87.4, 53.2, 30.5, 21.7; IR(film): 3062, 2925, 1654, 1598, 1472, 1356, 1185, 1091 cm-1; HRMS (ESI-TOF) calcd for C19H18BrClN2NaO2S+([M+Na]+): 474.9853; found: 474.9837. N-Allyl-N-(3-bromo-5-fluoro-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide

(3h).

Colorless liquid; Yield 98% (43 mg); 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.64 (m, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.27 – 7.24 (m, 1H), 7.13 – 7.02 (m, 2H), 5.85 – 5.75 (m, 1H), 5.14 – 5.01 (m, 2H), 4.56 (ddt, J = 13.7, 5.4, 1.4 Hz, 1H), 4.08 (ddt, J = 13.7, 8.5, 0.8 Hz, 1H), 3.78 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.2 (d, JC-F = 235.4 Hz), 144.3, 135.7, 132.1, 131.7, 131.1, 129.9, 128.1, 125.5 (d, JC-F = 10.4 Hz), 120.5, 112.4 (d, JC-F = 26.2 Hz), 111.3 (d, JC-F = 9.4 Hz), 104.3 (d, JC-F = 24.4 Hz), 87.7 (d, JC-F = 4.9 Hz), 53.2, 30.5, 21.7; IR(film): 3065, 2927, 1623, 1489, 1354, 1279, 1164, 1091 cm-1; HRMS (ESI-TOF) calcd for C19H18BrFN2NaO2S+([M+Na]+): 459.0149; found: 459.0135. N-Allyl-N-(3-bromo-1-methyl-1H-indol-2-yl)-4-methoxybenzenesulfonamide (3i). Colorless liquid; Yield 49% (21 mg); 1H NMR (600 MHz, CDCl3) δ 7.75 – 7.68 (m, 2H), 7.48 – 7.42 (m, 1H), 7.34 – 7.28 (m, 2H), 7.19 – 7.16 (m, 1H), 6.97 (d, J = 9.1 Hz, 2H), 5.85 – 5.78 (m, 1H), 5.10 (dt, J = 16.7, 1.4 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H), 4.59 – 4.51 (m, 1H), 4.10 (dd, J = 13.8, 8.5



Page 22 of 53

Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 163.6, 134.6, 132.0, 131.0, 130.5, 130.3, 125.3, 123.6, 120.4, 120.3, 119.3, 114.4, 110.1, 88.0, 55.6, 53.3, 30.2; IR(film): 3054, 2941,

1596,

1497,

1352,

1260,

1161,1093

cm-1;

HRMS

(ESI-TOF)

calcd

for

C19H19BrN2NaO3S+([M+Na]+): 457.0192; found: 457.0187. N-Allyl-N-(3-bromo-1-methyl-1H-indol-2-yl)benzenesulfonamide (3j). Colorless liquid; Yield 94% (38 mg); 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.78 (m, 2H), 7.66 – 7.60 (m, 1H), 7.53 – 7.49 (m, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.20 – 7.16 (m, 1H), 5.87 – 5.77 (m, 1H), 5.15 – 5.02 (m, 2H), 4.65 – 4.55 (m, 1H), 4.10 (dd, J = 13.7, 8.5 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.7, 134.5, 133.3, 131.8, 130.6, 129.2, 128.1, 125.2, 123.7, 120.5, 120.4, 119.3, 110.2, 88.2, 53.4, 30.3; IR(film): 3060, 2942, 1542, 1469, 1356, 1234, 1170, 1091 cm-1; HRMS (ESI-TOF) calcd for C18H17BrN2NaO2S+([M+Na]+): 427.0086; found: 427.0069. N-Allyl-N-(3-bromo-1-methyl-1H-indol-2-yl)-4-chlorobenzenesulfonamide

(3k).

Colorless

liquid; Yield 78% (34 mg); 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.70 (m, 2H), 7.52 – 7.43 (m, 3H), 7.36 – 7.31 (m, 2H), 7.22 – 7.16 (m, 1H), 5.86 – 5.76 (m, 1H), 5.15 – 5.03 (m, 2H), 4.58 (ddt, J = 13.6, 5.4, 1.4 Hz, 1H), 4.15 – 4.06 (m, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.9, 137.3, 134.6, 131.5, 130.3, 129.53, 129.50, 125.2, 123.8, 120.8, 120.6, 119.4, 110.2, 88.3, 53. 6, 30.3; IR(film):3087, 2942, 1586, 1475, 1359, 1235, 1169, 1092 cm-1; IR(film): 3087, 2941, 1586, 1469, 1359, 1169, 1092, 1012 cm-1; HRMS (ESI-TOF) calcd for C18H16BrClN2NaO2S+([M+Na]+): 460.9697; found: 460.9687. N-Allyl-N-(3-bromo-1-methyl-1H-indol-2-yl)-4-nitrobenzenesulfonamide (3l). Yellow liquid; Yield 87% (39 mg); 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.33 (m, 2H), 8.01 – 7.95 (m, 2H), 7.45 (dt, J = 8.1, 1.0 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.24 – 7.17 (m, 1H), 5.88 – 5.78 (m, 1H), 5.18 – 5.07 (m, 2H), 4.63 (ddt, J = 13.8, 5.6, 1.3 Hz, 1H), 4.12 (dd, J = 13.6, 8.6 Hz, 1H), 3.81 (s, 3H);


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C NMR (100 MHz, CDCl3) δ 150.5, 144.5, 134.6, 131.1, 129.7, 129.4, 125.1, 124.4, 124.1, 121.3,

13

120.8, 119.5, 110.3, 88.5, 54.0, 30.4; IR(film): 3104, 2944, 1606, 1531, 1469, 1349, 1170, 1089 cm-1; HRMS (ESI-TOF) calcd for C18H16BrN3NaO4S+([M+Na]+): 471.9937; found: 471.9911. N-Allyl-N-(3-bromo-1-methyl-1H-indol-2-yl)methanesulfonamide (3m). Yellow liquid; Yield 88% (30 mg); 1H NMR (400 MHz, CDCl3) δ 7.55 (dt, J = 8.0, 1.0 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.23 – 7.18 (m, 1H), 5.93 – 5.83 (m, 1H), 5.21 – 5.07 (m, 2H), 4.52 – 4.44 (m, 1H), 4.28 – 4.22 (m, 1H), 3.72 (s, 3H), 3.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 134.6, 131.7, 130.6, 125.2, 124.0, 120.78, 120.75, 119.4, 110.2, 88.1, 53.8, 40.6, 30.2; IR(film): 3058, 2932, 1544, 1469, 1347, 1234, 1160,1060 cm-1; HRMS (ESI-TOF) calcd for C13H15BrN2NaO2S+([M+Na]+): 364.9930; found: 364.9925. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-cinnamylbenzenesulfonamide (3n). Colorless liquid; Yield 92% (44 mg); 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 7.2, 1.4 Hz, 2H), 7.66 – 7.60 (m, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.26 – 7.19 (m, 5H), 7.18 – 7.14 (m, 1H), 6.39 (d, J = 15.8 Hz, 1H), 6.28 – 6.18 (m, 1H), 4.72 (dd, J = 14.0, 5.7 Hz, 1H), 4.25 (dd, J = 14.0, 8.5 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.0, 136.0, 135.0, 134.5, 133.3, 130.8, 129. 2, 128.5, 128.1, 128.0, 126.5, 125.2, 123.7, 123.0, 120. 5, 119.4, 110. 2, 88.3, 53. 5, 30.3; IR(film): 3058, 2941, 1545, 1469, 1356, 1234, 1169, 1090 cm-1; HRMS (ESI-TOF) calcd for C24H21BrN2NaO2S+([M+Na]+): 503.0399; found: 503.0393. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(3-methylbut-2-en-1-yl)benzenesulfonamide

(3o).

Colorless liquid; Yield 83% (36 mg); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.77 (m, 2H), 7.66 – 7.59 (m, 1H), 7.53 – 7.49 (m, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.19 – 7.15 (m, 1H), 5.20 – 5.16 (m, 1H), 4.51 (dd, J = 13.9, 6.5 Hz, 1H), 4.21 (dd, J = 13.9, 8.5 Hz, 1H), 3.77 (s, 3H), 1.58 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.2, 139.0, 134.5, 133.1, 130.9,



Page 24 of 53

129.2, 128.0, 125.3, 123.5, 120.3, 119.3, 117.9, 110.1, 88.1, 48.3, 30.1, 25.7, 17.6; IR(film): 3058, 2936, 1447, 1351, 1234, 1168, 1091, 1035

cm-1;

HRMS

(ESI-TOF) calcd for

C20H21BrN2NaO2S+([M+Na]+): 455.0399; found: 455.0395. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-methylallyl)benzenesulfonamide (3p). White solid; Yield 93% (39 mg); m.p. 24-25 oC ; 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.73 (m, 2H), 7.66 – 7.60 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.44 (dt, J = 8.0, 1.0 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.19 – 7.15 (m, 1H), 4.78 – 4.69 (m, 2H), 4.45 (d, J = 13.2 Hz, 1H), 4.16 (d, J = 13.2 Hz, 1H), 3.81 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.9, 138.5, 134.5, 133.3, 130.6, 129.2, 128.2, 125.4, 123.6, 120.4, 119.3, 117.1, 110.1, 87.6, 56.5, 30.4, 20.4; IR(film): 3060, 2944, 1469, 1447, 1357, 1235, 1171, 1092 cm-1; HRMS (ESI-TOF) calcd for C19H19BrN2NaO2S+([M+Na]+): 441.0243; found: 441.0233. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-bromoallyl)benzenesulfonamide

(3q).

Colorless

liquid; Yield 68% (33 mg); 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.71 (m, 2H), 7.67 – 7.63 (m, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.21 – 7.17 (m, 1H), 5.69 (d, J = 1.5 Hz, 1H), 5.45 (d, J = 1.9 Hz, 1H), 4.78 (d, J = 14.1 Hz, 1H), 4.52 (d, J = 14.1 Hz, 1H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.0, 134.7, 133.6, 129.7, 129.4, 128.2, 126.0, 125.2, 123.8, 123.2, 120.5, 119.3, 110.3, 87.4, 58.3, 31.1; IR(film): 3054, 2942, 1447, 1361, 1235, 1170, 1091, 1063 cm-1; HRMS (ESI-TOF) calcd for C18H16Br2N2NaO2S+([M+Na]+): 504.9191; found: 504.9190. General Procedure for the Synthesis of 5. To a sealed tube with a magnetic stirrers were added sequentially 1 (0.1 mmol), 4 (0.7 mL), Pd(OAc)2 (0.01 mmol), BCP (0.02 mmol), K2CO3 (0.3 mmol) and CH3CN (0.3 mL) under air atmosphere. The reaction mixture was stirred at 100 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The residue was purified


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by column chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1 - 20:1, v/v) to give the product 5. N-Allyl-N-(3-chloro-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide

(5a).

Colorless

liquid; Yield 88% (33 mg); 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.65 (m, 2H), 7.50 (dt, J = 8.0, 1.1 Hz, 1H), 7.35 – 7.27 (m, 4H), 7.18 – 7.14 (m, 1H), 5.84 – 5.74 (m, 1H), 5.14 – 4.99 (m, 2H), 4.56 (ddt, J = 13.7, 5.3, 1.4 Hz, 1H), 4.04 (dd, J = 13.7, 8.6 Hz, 1H), 3.78 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 135.7, 133.8, 131.8, 129.7, 129.1, 128.0, 123.6, 123.5, 120.4, 120.2, 118.3, 110.1, 101.9, 53.1, 30.0, 21.6; IR(film): 3060, 2927, 1470, 1354, 1237, 1167, 1091, 1057 cm-1; HRMS (ESI-TOF) calcd for C19H19ClN2NaO2S+([M+Na]+): 397.0748; found: 397.0758. N-Allyl-N-(3-chloro-1-methyl-1H-indol-2-yl)methanesulfonamide (5b). Colorless liquid; Yield 81% (24 mg); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.22 – 7.18 (m, 1H), 5.92 – 5.82 (m, 1H), 5.21 – 5.08 (m, 2H), 4.48 (ddt, J = 13.9, 5.5, 1.3 Hz, 1H), 4.23 (dd, J = 13.9, 8.6 Hz, 1H), 3.71 (s, 3H), 3.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 133.8, 131.8, 128.9, 123.9, 123.5, 120.7, 120.5, 118.4, 110.2, 101.5, 53.7, 40.1, 29.9; IR(film): 3054, 2933, 1551, 1470, 1347, 1236, 1160, 1061 cm-1; HRMS (ESI-TOF) calcd for C13H15ClN2NaO2S+([M+Na]+): 321.0435; found: 321.0426. N-Allyl-N-(3-chloro-1-methyl-1H-indol-2-yl)benzenesulfonamide (5c). Colorless liquid; Yield 89% (32 mg); 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.75 (m, 2H), 7.66 – 7.60 (m, 1H), 7.54 – 7.47 (m, 3H), 7.36 – 7.28 (m, 2H), 7.18 – 7.13 (m, 1H), 5.85 – 5.75 (m, 1H), 5.13 – 5.01 (m, 2H), 4.58 (ddt, J = 13.7, 5.5, 1.4 Hz, 1H), 4.05 (dd, J = 13.7, 8.5 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.6, 133.8, 133.3, 131.7, 129.2, 128.9, 128.0, 123.6, 123.6, 120.5, 120.3, 118.3, 110.1,



Page 26 of 53

102.0, 53.3, 30.0; IR(film): 3061, 2941, 1551, 1470, 1356, 1237, 1171, 1091 cm-1; HRMS (ESITOF) calcd for C18H17ClN2NaO2S+([M+Na]+): 383.0591; found: 383.0589. N-Allyl-N-(3-chloro-1,5-dimethyl-1H-indol-2-yl)-4-methylbenzenesulfonamide (5d). Colorless liquid; Yield 88% (34 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.64 (m, 2H), 7.32 – 7.26 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 8.4, 1.6 Hz, 1H), 5.83 – 5.73 (m, 1H), 5.11 – 5.00 (m, 2H), 4.55 (ddt, J = 13.7, 5.4, 1.4 Hz, 1H), 4.03 (dd, J = 13.6, 8.5 Hz, 1H), 3.74 (s, 3H), 2.44 (d, J = 1.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 144.1, 135.7, 132.2, 131.8, 129.7, 128.9, 128.0, 127.6, 125.3, 123.7, 120.3, 117.7, 109.9, 101.2, 53.1, 30.0, 21.6, 21.4; IR(film): 3024, 2921, 1598, 1492, 1354, 1296, 1166, 1091 cm-1; HRMS (ESI-TOF) calcd for C20H21ClN2NaO2S+([M+Na]+): 411.0904; found: 411.0918. N-Allyl-N-(3-chloro-5-fluoro-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide (5e). Pale yellow liquid; Yield 82% (32 mg); 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.28 – 7.22 (m, 1H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 7.05 (td, J = 9.1, 2.6 Hz, 1H), 5.84 – 5.73 (m, 1H), 5.09 (d, J = 17.2 Hz, 1H), 5.04 (d, J = 10.0 Hz, 1H), 4.57 – 4.52 (m, 1H), 4.03 (dd, J = 13.6, 8.6 Hz, 1H), 3.77 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1 (d, JC-F = 235.4 Hz), 144.3, 135.6, 131.7, 130.4 (d, JC-F = 7.0 Hz), 129.8, 128.0, 123.8 (d, JC-F = 10.4 Hz), 120.5, 112.4, (d, JC-F = 26.3 Hz), 111.3, (d, JC-F = 9.4 Hz), 103.3 (d, JC-F = 24.7 Hz), 101.8, 101.7, 53.1, 30.2, 21.6; IR(film): 3067, 2927, 1490, 1354, 1281, 1165, 1091, 1055 cm-1; HRMS (ESI-TOF) calcd for C19H18ClFN2NaO2S+([M+Na]+): 415.0654; found: 415.0650. N-(3-Chloro-1-methyl-1H-indol-2-yl)-N-(2-methylallyl)benzenesulfonamide

(5f).

Colorless

liquid; Yield 83% (31 mg); 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.74 (m, 2H), 7.66 – 7.60 (m, 1H), 7.54 – 7.46 (m, 3H), 7.35 – 7.28 (m, 2H), 7.18 – 7.14 (m, 1H), 4.76 – 4.69 (m, 2H), 4.44 (d, J = 13.1 Hz, 1H), 4.09 (d, J = 13.2 Hz, 1H), 3.79 (s, 3H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3)


Page 27 of 53 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


δ 138.9, 138.4, 133.9, 133.3, 129.2, 129.0, 128.1, 123.7, 123.6, 120.2, 118.3, 117.0, 110.1, 101.5, 56.4, 30.1, 20.3; IR(film): 3061, 2944, 1547, 1447, 1357, 1237, 1171, 1092 cm-1; HRMS (ESITOF) calcd for C19H19ClN2NaO2S+([M+Na]+): 397.0748; found: 397.0748. N-(3-Chloro-1-methyl-1H-indol-2-yl)-N-(3-methylbut-2-en-1-yl)benzenesulfonamide

(5g).

Colorless liquid; Yield 39% (15 mg); 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.78 (m, 2H), 7.65 – 7.59 (m, 1H), 7.54 – 7.47 (m, 3H), 7.36 – 7.28 (m, 2H), 7.18 – 7.14 (m, 1H), 5.19 – 5.14 (m, 1H), 4.53 – 4.45 (m, 1H), 4.16 (dd, J = 13.7, 8.6 Hz, 1H), 3.75 (s, 3H), 1.58 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.11, 139.07, 133.8, 133.1, 129.2, 129.1, 127.9, 123.7, 123.5, 120.2, 118.3, 117.7, 110.1, 101.9, 48.1, 29.8, 25.7, 17.6; IR(film): 3062, 2934, 1550, 1447, 1352, 1237, 1168, 1091 cm-1; HRMS (ESI-TOF) calcd for C20H21ClN2NaO2S+([M+Na]+): 411.0904; found: 411.0920. N-(3-Chloro-1-methyl-1H-indol-2-yl)-N-(2-chloroallyl)benzenesulfonamide (5h). Colorless liquid; Yield 91% (36 mg); 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.72 (m, 2H), 7.68 – 7.61 (m, 1H), 7.55 – 7.45 (m, 3H), 7.38 – 7.30 (m, 2H), 7.19 – 7.15 (m, 1H), 5.25 – 5.18 (m, 2H), 4.71 (dd, J = 13.9, 1.1 Hz, 1H), 4.33 (d, J = 13.9 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.0, 135.5, 134.0, 133.5, 129.3, 128.2, 128.0, 123.8, 123.5, 120.3, 118.5, 118.3, 110.3, 101.4, 56.3, 30.4; IR(film): 3061, 2941, 1636, 1448, 1362, 1238, 1170, 1091 cm-1; HRMS (ESI-TOF) calcd for C18H16Cl2N2NaO2S+([M+Na]+): 417.0202; found: 417.0199. General Procedure for the Synthesis of 7. To a sealed tube with a magnetic stirrers were added sequentially 1 (0.1 mmol), 6a (0.2 mL), Pd(OAc)2 (0.01 mmol) , BCP (0.02 mmol) , K2CO3 (0.3 mmol) and CH3CN (0.8 mL) under air atmosphere. The reaction mixture was stirred at 40 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The residue was purified



Page 28 of 53

by column chromatography on silica gel (first petroleum ether then petroleum ether/ ethyl acetate = 6:1, v/v) to give the product 7. N-Allyl-N-(3-iodo-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide (7a). Colorless liquid; Yield 75% (35 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.66 (m, 2H), 7.36 – 7.28 (m, 5H), 7.20 – 7.16 (m, 1H), 5.89 – 5.79 (m, 1H), 5.15 – 5.01 (m, 2H), 4.59 (ddt, J = 13.9, 5.5, 1.4 Hz, 1H), 4.15 (dd, J = 13.9, 8.5 Hz, 1H), 3.82 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 136.2, 135.5, 134.3, 132.0, 130.0, 128.6, 128.3, 123.7, 121.4, 120.6, 120.4, 110.2, 55.9, 53.8, 30.6, 21.7; IR(film): 3057, 2925, 1468, 1353, 1233, 1165, 1091, 1055 cm-1; HRMS (ESI-TOF) calcd for C19H19IN2NaO2S+([M+Na]+): 489.0104; found: 489.0097. N-Allyl-N-(3-iodo-1-methyl-1H-indol-2-yl)benzenesulfonamide (7b). Colorless liquid; Yield 91% (41 mg); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.78 (m, 2H), 7.66 – 7.60 (m, 1H), 7.53 – 7.49 (m, 2H), 7.37 – 7.27 (m, 3H), 7.20 – 7.16 (m, 1H), 5.79 – 5.90 (m, 1H), 5.14 – 5.02 (m, 2H), 4.61 (ddt, J = 13.9, 5.5, 1.4 Hz, 1H), 4.16 (dd, J = 13.8, 8.5 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.0, 135.5, 134.2, 133.3, 131.9, 129.4, 128.5, 128.3, 123.7, 121.4, 120.6, 120.5, 110.2, 55.9, 54.0, 30.6; IR(film): 3059, 2946, 1447, 1354, 1232, 1169, 1090, 1055 cm-1; HRMS (ESITOF) calcd for C18H17IN2NaO2S+([M+Na]+): 474.9948; found: 474.9940. N-Allyl-N-(3-iodo-1,5-dimethyl-1H-indol-2-yl)-4-methylbenzenesulfonamide (7c). Colorless liquid; Yield 65% (31 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.63 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.16 – 7.09 (m, 2H), 5.88 – 5.78 (m, 1H), 5.15 – 4.99 (m, 2H), 4.58 (ddt, J = 13.8, 5.5, 1.3 Hz, 1H), 4.14 (dd, J = 13.8, 8.5 Hz, 1H), 3.79 (s, 3H), 2.45 (d, J = 3.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 144.2, 136.2, 134.1, 133.8, 132.1, 130.1, 129.9, 128.6, 128.3, 125.4, 120.8, 120.3, 110.0, 55.3, 53.8, 30.6, 21.7, 21.4; IR(film): 3024, 2920, 1487, 1353,


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1234, 1165, 1090, 1054 cm-1; HRMS (ESI-TOF) calcd for C20H21IN2NaO2S+([M+Na]+): 503.0261; found: 503.0245. N-Allyl-N-(5-chloro-3-iodo-1-methyl-1H-indol-2-yl)-4-methylbenzenesulfonamide

(7d).

Colorless liquid; Yield 86% (43 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.64 (m, 2H), 7.35 – 7.29 (m, 3H), 7.27 – 7.18 (m, 2H), 5.87 – 5.77 (m, 1H), 5.14 – 5.02 (m, 2H), 4.58 (ddt, J = 13.9, 5.5, 1.4 Hz, 1H), 4.13 (dd, J = 13.8, 8.6 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 136.0, 135.5, 133.9, 131.8, 130.0, 129.5, 128.3, 126.5, 124.1, 120.8, 120.6, 111.5, 54.9, 53.7, 30. 8, 21.7, 21.5; IR(film): 3075, 2916, 1598, 1470, 1355, 1228, 1166, 1090 cm-1; HRMS (ESI-TOF) calcd for C19H18ClIN2NaO2S+([M+Na]+): 522.9714; found: 522.9714. N-Allyl-N-(3-iodo-1-methyl-1H-indol-2-yl)methanesulfonamide (7e). Colorless liquid; Yield 23% (9 mg); 1H NMR (400 MHz, CDCl3) δ 7.43 (dt, J = 7.9, 1.0 Hz, 1H), 7.35 – 7.31 (m, 1H), 7.28 (dt, J = 8.4, 1.1 Hz, 1H), 7.24 – 7.20 (m, 1H), 5.96 – 5.86 (m, 1H), 5.21 – 5.08 (m, 2H), 4.48 (ddt, J = 14.0, 5.5, 1.3 Hz, 1H), 4.28 (ddt, J = 14.0, 8.6, 0.8 Hz, 1H), 3.76 (s, 3H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.7, 134.2, 132.0, 128.4, 124.0, 121.4, 120.9, 120.8, 110.4, 56.6, 54.2, 41.7, 30.6; IR(film): 3058, 2925, 1528, 1467, 1344, 1231, 1158, 1057 cm-1; HRMS (ESI-TOF) calcd for C13H15IN2NaO2S+([M+Na]+): 412.9791; found: 412.9803. N-(3-Iodo-1-methyl-1H-indol-2-yl)-N,4-dimethylbenzenesulfonamide (7f). Colorless liquid; Yield 64% (28 mg); 1H NMR (600 MHz, CDCl3) δ 7.73 – 7.68 (m, 2H), 7.36 – 7.28 (m, 5H), 7.20 – 7.17 (m, 1H), 3.85 (s, 3H), 3.39 (s, 3H), 2.45 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.2, 136.5, 135. 5, 135.4, 129.9, 128.6, 128.4, 123.8, 121.4, 120.7, 110.2, 54.6, 38.5, 30.6, 21. 7; IR(film): 3058, 2941, 1532, 1468, 1350, 1226, 1158, 1089 cm-1; HRMS (EI-TOF) calcd for C17H17IN2O2S [M]+: 440.0055; found: 440.0052.



N-(3-Iodo-1-methyl-1H-indol-2-yl)-N-methylbenzenesulfonamide (7g). Colorless liquid; Yield 61% (26 mg); 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.80 (m, 2H), 7.68 – 7.62 (m, 1H), 7.57 – 7.50 (m, 2H), 7.37 – 7.28 (m, 3H), 7.21 – 7.17 (m, 1H), 3.86 (s, 3H), 3.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.3, 136.3, 135.4, 133.4, 129.4, 128. 6, 128.4, 123.9, 121.4, 120.7, 110.2, 54.6, 38.6, 30.6; IR(film): 3054, 2938, 1529, 1467, 1351, 1229, 1160, 1088 cm-1; HRMS (EI-TOF) calcd for C16H15IN2O2S [M]+: 425.9899; found: 425.9898. N-Ethyl-N-(3-iodo-1-methyl-1H-indol-2-yl)benzenesulfonamide (7h). Colorless liquid; Yield 32% (14 mg); 1H NMR (600 MHz, CDCl3) δ 7.82 – 7.80 (m, 2H), 7.65 – 7.59 (m, 1H), 7.52 – 7.50 (m, 2H), 7.37 – 7.30 (m, 3H), 7.21 – 7.17 (m, 1H), 4.08 – 4.01 (m, 1H), 3.86 (s, 3H), 3.73 – 3.65 (m, 1H), 1.13 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 139.1, 135.6, 134.1, 133.2, 129.3, 128.7, 128.3, 123. 8, 121.4, 120.7, 110.2, 55.7, 46.3, 30.6, 14.5; IR (film): 3054, 2933, 1528, 1467, 1349, 1232, 1172, 1087 cm-1; HRMS (EI-TOF) calcd for C17H17IN2O2S [M]+: 440.0055; found: 440.0057. General Procedure for the Synthesis of 9. To a sealed tube with a magnetic stirrers were added sequentially 1 (0.1 mmol), 8 (0.15 mmol), Pd(OAc)2 (0.01 mmol), K2CO3 (0.3 mmol) and dry CH3CN (2 mL) under air atmosphere. The reaction mixture was stirred at 80 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1 – 20:1, v/v) to give the product 9. N-Benzyl-N-(3-bromo-1-methyl-1H-indol-2-yl)benzenesulfonamide (9a). Colorless liquid; Yield 70% (32 mg); 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.82 (m, 2H), 7.69 – 7.62 (m, 1H), 7.56 – 7.52 (m, 2H), 7.47 – 7.44 (m, 1H), 7.28 – 7.19 (m, 6H), 7.17 – 7.13 (m, 2H), 5.22 (d, J = 13.3 Hz, 1H), 4.55 (d, J = 13.3 Hz, 1H), 3.27 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 139.2, 135.2,


Page 30 of 53

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134.4, 133.3, 130.3, 129.4, 129.3, 128.6, 128.3, 128.1, 125.2, 123.5, 120.3, 119.3, 110.1, 88.0, 54.3, 29.7; IR(film): 3060, 2929, 1447, 1352, 1235, 1168, 1091, 1047 cm-1; HRMS (ESI-TOF) calcd for C22H19BrN2NaO2S+([M+Na]+): 477.0243; found: 477.0246. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(4-methylbenzyl)benzenesulfonamide (9b). Colorless liquid; Yield 58% (27 mg); 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.82 (m, 2H), 7.67 – 7.61 (m, 1H), 7.56 – 7.49 (m, 2H), 7.44 (dt, J = 8.0, 1.0 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.19 – 7.12 (m, 2H), 7.11 – 7.06 (m, 2H), 6.99 (d, J = 7.8 Hz, 2H), 5.18 (d, J = 13.3 Hz, 1H), 4.52 (d, J = 13.3 Hz, 1H), 3.30 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.3, 138.0, 134.4, 133.2, 132.1, 130.4, 129.29, 129.27, 129.2, 128.0, 125.3, 123.4, 120.3, 119.2, 110.1, 87.9, 53.9, 29.8, 21.1; IR(film): 3058, 2941, 1447, 1352, 1234, 1169, 1090, 1048 cm-1; HRMS (ESI-TOF) calcd for C23H21BrN2NaO2S+([M+Na]+): 491.0399; found: 491.0395. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(4-(tert-butyl)benzyl)benzenesulfonamide

(9c).

Colorless liquid; Yield 49% (25 mg); 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.81 (m, 2H), 7.67 – 7.61 (m, 1H), 7.56 – 7.50 (m, 2H), 7.45 (dt, J = 7.9, 1.0 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.23 – 7.19 (m, 2H), 7.18 – 7.15 (m, 2H), 7.14 – 7.11 (m, 2H), 5.18 (d, J = 13.4 Hz, 1H), 4.52 (d, J = 13.4 Hz, 1H), 3.26 (s, 3H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 151.4, 139.4, 134.4, 133.2, 132.3, 130.5, 129.3, 129.0, 128.0, 125.4, 125.3, 123.5, 120.3, 119.3, 110.1, 88.0, 54.0, 34.5, 31.2, 29.7; IR(film): 3059, 2963, 1469, 1357, 1234, 1169, 1090, 1049 cm-1; HRMS (ESI-TOF) calcd for C26H27BrN2NaO2S+([M+Na]+): 533.0869; found: 533.0865. N-(3-bromo-1-methyl-1H-indol-2-yl)-N-(4-bromobenzyl)benzenesulfonamide (9d). Colorless liquid; Yield 55% (29 mg); 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.80 (m, 2H), 7.70 – 7.62 (m, 1H), 7.56 – 7.52 (m, 2H), 7.44 (dt, J = 7.9, 1.0 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.28 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.22 – 7.13 (m, 2H), 7.13 – 7.07 (m, 2H), 5.15 (d, J = 13.5 Hz, 1H), 4.52 (d, J =



Page 32 of 53

13.4 Hz, 1H), 3.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.9, 134.4, 134.3, 133.4, 131.7, 131.1, 130.0, 129.4, 128.1, 125.2, 123.7, 122.5, 120.5, 119.3, 110.2, 88.0, 53.5, 29.9; IR(film): 3054, 2938, 1447, 1353, 1234, 1168, 1090, 1012

cm-1;

HRMS

(ESI-TOF) calcd for

C22H18Br2N2NaO2S+([M+Na]+): 554.9348; found: 554.9348. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(4-iodobenzyl)benzenesulfonamide

(9e).

Colorless

liquid; Yield 60% (35 mg); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.80 (m, 2H), 7.68 – 7.62 (m, 1H), 7.57 – 7.50 (m, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.22 – 7.14 (m, 2H), 7.00 – 6.94 (m, 2H), 5.13 (d, J = 13.5 Hz, 1H), 4.50 (d, J = 13.5 Hz, 1H), 3.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.9, 137.7, 134.9, 134.4, 133.4, 131.2, 130.1, 129.3, 128.1, 125.2, 123.7, 120.5, 119.3, 110.2, 94.3, 87.9, 53.7, 29.9; IR(film): 3059, 2941, 1447, 1353, 1235, 1168, 1090, 1008 cm1

; HRMS (ESI-TOF) calcd for C22H18BrIN2NaO2S+([M+Na]+): 602.9209; found: 602.9206. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(4-nitrobenzyl)benzenesulfonamide (9f). Orange liquid;

Yield 64% (32 mg); 1H NMR (400 MHz, CDCl3) δ 8.13 – 8.05 (m, 2H), 7.88 – 7.80 (m, 2H), 7.73 – 7.65 (m, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.48 – 7.40 (m, 3H), 7.31 – 7.26 (m, 1H), 7.22 – 7.14 (m, 2H), 5.26 (d, J = 13.8 Hz, 1H), 4.69 (d, J = 13.7 Hz, 1H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.8, 142.5, 138.4, 134.4, 133.7, 130.2, 129.8, 129.5, 128.1, 125.1, 124.0, 123.8, 120.7, 119.3, 110.2, 88.0, 53.4, 30.0; IR(film): 3061, 2945, 1608, 1524, 1348, 1169, 1090, 1055 cm-1; HRMS (ESI-TOF) calcd for C22H18BrN3NaO4S+([M+Na]+): 522.0094; found: 522.0094. N-([1,1'-Biphenyl]-4-ylmethyl)-N-(3-bromo-1-methyl-1H-indol-2-yl)benzenesulfonamide (9g). White solid; Yield 77% (41 mg); m.p. 79-80 oC ; 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.82 (m, 2H), 7.69 – 7.62 (m, 1H), 7.58 – 7.49 (m, 4H), 7.47 – 7.43 (m, 3H), 7.42 – 7.38 (m, 2H), 7.35 – 7.22 (m, 4H), 7.19 – 7.13 (m, 2H), 5.25 (d, J = 13.4 Hz, 1H), 4.60 (d, J = 13.4 Hz, 1H), 3.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.0, 140.2, 139.2, 134.4, 134.2, 133.3, 130.3, 129.8, 129.3,


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128.8, 128.1, 127.5, 127.2, 126.9, 125.2, 123.6, 120.4, 119.3, 110.2, 88.0, 54.0, 29.8; IR(film): 3058, 2933, 1447, 1352, 1234, 1168, 1090, 1049 cm-1; HRMS (ESI-TOF) calcd for C28H23BrN2NaO2S+([M+Na]+): 553.0556; found: 553.0551. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(3,5-dimethylbenzyl)benzenesulfonamide

(9h).

Colorless liquid; Yield 54% (26 mg); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.82 (m, 2H), 7.68 – 7.61 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.20 – 7.11 (m, 2H), 6.83 (d, J = 6.3 Hz, 3H), 5.14 (d, J = 13.4 Hz, 1H), 4.48 (d, J = 13.4 Hz, 1H), 3.34 (s, 3H), 2.16 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 139.3, 138.0, 135.1, 134.4, 133.2, 130.6, 129.8, 129.3, 128.1, 127.0, 125.3, 123.5, 120.3, 119.2, 110.1, 87.9, 54.3, 29.8, 21.1; IR(film): 3054, 2941, 1469,

1351,

1234,

1169,

1091,

1055

cm-1;

HRMS

(ESI-TOF)

calcd

for

C24H23BrN2NaO2S+([M+Na]+): 505.0556; found: 505.0546. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(3,5-difluorobenzyl)benzenesulfonamide (9i). White solid; Yield 59% (29 mg); m.p. 178-179 oC ; 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.78 (m, 2H), 7.70 – 7.63 (m, 1H), 7.56 – 7.52 (m, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.32 – 7.28 (m, 1H), 7.23 (dt, J = 8.4, 0.9 Hz, 1H), 7.19 – 7.15 (m, 1H), 6.88 – 6.79 (m, 2H), 6.69 (tt, J = 8.9, 2.4 Hz, 1H), 5.15 (d, J = 13.8 Hz, 1H), 4.54 (d, J = 13.8 Hz, 1H), 3.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, JC-F = 248.6 Hz), 162.8 (d, JC-F = 248.3 Hz), 139.3 (d, JC-F = 9.0 Hz), 139.2 (d, JC-F = 8.7 Hz), 138.6, 134.5, 133.6, 130.0, 129.4, 128.1, 125.2, 123.9, 120.6, 119.4, 112.13 (d, JC-F = 21.6 Hz), 112.13 (d, JC-F = 11.5 Hz), 110.2, 104.0 (d, JC-F = 25.0 Hz), 103.8 (d, JC-F = 25.0 Hz), 87.9, 53.6, 30.0; IR(film): 3054, 2938, 1598, 1466, 1355, 1234, 1169, 1120 cm-1; HRMS (ESI-TOF) calcd for C22H17BrF2N2NaO2S+([M+Na]+): 513.0054; found: 513.0033. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-bromobenzyl)benzenesulfonamide (9j). Colorless liquid; Yield 38% (20 mg); 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.81 (m, 2H), 7.70 – 7.63 (m,



Page 34 of 53

1H), 7.56 – 7.52 (m, 2H), 7.48 – 7.37 (m, 3H), 7.28 – 7.24 (m, 1H), 7.20 – 7.14 (m, 2H), 7.12 (dd, J = 7.4, 1.4 Hz, 1H), 7.07 (td, J = 7.6, 1.9 Hz, 1H), 5.33 (d, J = 13.5 Hz, 1H), 4.87 (d, J = 13.5 Hz, 1H), 3.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.8, 134.6, 134.4, 133.4, 133.0, 132.2, 130.04, 129.96, 129.3, 128.2, 127.6, 125.2, 124.6, 123.6, 120.3, 119.3, 110.1, 88.9, 53.6, 29.8; IR(film): 3060, 2942, 1537, 1469, 1353, 1234, 1169, 1090 cm-1; HRMS (ESI-TOF) calcd for C22H18Br2N2NaO2S+([M+Na]+): 554.9348; found: 554.9340. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-iodobenzyl)benzenesulfonamide

(9k).

Colorless

liquid; Yield 57% (33 mg); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz, 2H), 7.72 (dd, J = 7.9, 1.3 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.57 – 7.49 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.23 – 7.11 (m, 3H), 6.90 (td, J = 7.6, 1.7 Hz, 1H), 5.30 (d, J = 13.8 Hz, 1H), 4.84 (d, J = 13.8 Hz, 1H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.8, 138.8, 138.2, 134.5, 133.4, 131.6, 130.03, 129.97, 129.3, 128.5, 128.3, 125.3, 123.7, 120.3, 119.4, 110.1, 99.7, 89.3, 58.1, 30.0; IR(film): 3058, 2946, 1469, 1447, 1352, 1234, 1168, 1090 cm-1; HRMS (ESI-TOF) calcd for C22H18BrIN2NaO2S+([M+Na]+): 602.9209; found: 602.9205. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-fluoro-6-(trifluoromethyl)benzyl) benzenesulfonamide (9l). Colorless liquid; Yield 39% (21 mg); 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.78 (m, 2H), 7.67 – 7.60 (m, 1H), 7.52 – 7.48 (m, 2H), 7.42 – 7.33 (m, 3H), 7.30 – 7.26 (m, 1H), 7.22 (dt, J = 8.4, 0.9 Hz, 1H), 7.18 – 7.11 (m, 2H), 5.36 (d, J = 14.4, 1H), 5.15 (d, J = 14.4 Hz, 1H), 3.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6 (d, JC-F = 250.7 Hz), 138.7, 134.6, 133.4, 130.4 (d, JC-F = 9.2 Hz), 129.6, 129.1, 128.5, 125.2, 123.8, 122.1(q, JC-CF3 = 3.7 Hz), 121.4 (d, JC-F = 15.8 Hz), 120.3, 119.6, 119.5 (d, JC-F = 22.8 Hz), 110.0, 90.8, 44.9, 29.8; IR(film): 3062, 2950,

1468,

1354,1318,

1252,

1169,

1128

cm-1;

C23H17BrF4N2NaO2S+([M+Na]+): 563.0022; found: 563.0023.


HRMS

(ESI-TOF)

calcd

for

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N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(naphthalen-2-ylmethyl)benzenesulfonamide （ 9m ） . Colorless liquid; Yield 36% (18 mg); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.86 (m, 2H), 7.79 – 7.71 (m, 2H), 7.70 – 7.64 (m, 2H), 7.61 – 7.52 (m, 3H), 7.50 – 7.37 (m, 4H), 7.24 – 7.19 (m, 1H), 7.15 – 7.11 (m, 1H), 7.09 (dt, J = 8.3, 0.9 Hz, 1H), 5.39 (d, J = 13.4 Hz, 1H), 4.73 (d, J = 13.5 Hz, 1H), 3.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.1, 134.4, 133.3, 133.1, 133.0, 132.7, 130.3, 129.3, 128.5, 128.4, 128.1, 128.0, 127.6, 126.9, 126.3, 126.2, 125.2, 123.5, 120.3, 119.2, 110.2, 87.9, 54.5, 29.9; IR(film): 3058, 2933, 1447, 1352, 1234, 1168, 1090, 1054 cm-1; HRMS (ESITOF) calcd for C26H21BrN2NaO2S+([M+Na]+): 527.0399; found: 527.0408. N-([1,1'-Biphenyl]-4-ylmethyl)-N-(3-bromo-1-methyl-1H-indol-2-yl)methanesulfonamide (9n). Yellow liquid; Yield 45% (21 mg); 1H NMR (400 MHz, CDCl3) δ 7.58 (dt, J = 7.8, 1.0 Hz, 1H), 7.55 – 7.51 (m, 2H), 7.49 – 7.44 (m, 2H), 7.44 – 7.38 (m, 2H), 7.36 – 7.31 (m, 1H), 7.31 – 7.25 (m, 3H), 7.22 – 7.18 (m, 1H), 7.15 (dt, J = 8.3, 0.9 Hz, 1H), 5.15 (d, J = 13.5 Hz, 1H), 4.74 (d, J = 13.5 Hz, 1H), 3.25 (s, 3H), 3.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.2, 140.2, 134.5, 134.3, 130.3, 129.9, 128.8, 127.5, 127.2, 127.0, 125.1, 123.8, 120.7, 119.3, 110.3, 87.8, 54.3, 40.9, 29.7; IR(film): 3028, 2929, 1488, 1469, 1347, 1234, 1157, 1052 cm-1; HRMS (ESI-TOF) calcd for C23H21BrN2NaO2S+([M+Na]+): 491.0399; found: 491.0396. N-([1,1'-Biphenyl]-4-ylmethyl)-N-(3-bromo-5-chloro-1-methyl-1H-indol-2-yl)-4-methyl benzenesulfonamide (9o). White solid; Yield 54% (31 mg); m.p. 82-83 oC ; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 6.8 Hz, 2H), 7.54 – 7.49 (m, 2H), 7.47 – 7.37 (m, 5H), 7.35 – 7.30 (m, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 8.8, 2.0 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.21 (d, J = 13.3 Hz, 1H), 4.57 (d, J = 13.3 Hz, 1H), 3.31 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 141.1, 140.2, 136.1, 134.1, 132.7, 131.6, 130.0, 129.8, 128.8, 128.1, 127.5, 127.2, 126.9, 126.3, 126.1, 124.0, 118.7, 111.4, 87.3, 53.7, 30.0, 21.7; IR(film): 3030, 2943, 1598, 1472, 1357, 1165,



Page 36 of 53

1090, 1048 cm-1; HRMS (ESI-TOF) calcd for C29H24BrClN2NaO2S+([M+Na]+): 601.0323; found: 601.0316. N-([1,1'-Biphenyl]-4-ylmethyl)-N-(3-bromo-5-methoxy-1-methyl-1H-indol-2-yl)-4-methyl benzenesulfonamide (9p). White solid; Yield 49% (28 mg); m.p. 73-74 oC ; 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.71 (m, 2H), 7.54 – 7.49 (m, 2H), 7.47 – 7.37 (m, 4H), 7.36 – 7.30 (m, 3H), 7.30 – 7.26 (m, 2H), 7.06 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.9, 2.5 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 5.21 (d, J = 13.4 Hz, 1H), 4.58 (d, J = 13.4 Hz, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.7, 144.1, 141.0, 140.3, 136.4, 134.4, 130.5, 129.9, 129.8, 129.6, 128.8, 128.1, 127.5, 127.1, 127.0, 125.5, 114.5, 111.3, 100.1, 87.3, 55.7, 53.8, 29.9, 21.7; IR(film): 3024, 2938, 1489, 1353, 1215, 1164, 1090, 1049 cm-1; HRMS (ESI-TOF) calcd for C30H27BrN2NaO3S+([M+Na]+): 597.0818; found: 597.0814. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-((5-chlorobenzo[b]thiophen-3-yl)methyl) benzenesulfonamide（9q）. White solid; Yield 50% (27 mg); m.p. 150-151 oC ; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 1.9 Hz, 1H), 7.89 – 7.87 (m, 2H), 7.71 – 7.66 (m, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.18 – 7.12 (m, 1H), 7.11 – 7.06 (m, 2H), 5.44 (d, J = 13.6 Hz, 1H), 4.88 (d, J = 13.6 Hz, 1H), 3.09 (s, 3H); C NMR (100 MHz, CDCl3) δ 139.0, 138.7, 138.2, 134.5, 133.5, 131.1, 129.7, 129.5, 129.4, 129.0,

13

128.1, 125.2, 125.2, 123.7, 123.7, 121.8, 120.5, 119.3, 110.1, 88.0, 46.8, 29.6; IR(film): 3054, 2938, 1469, 1350, 1234, 1168, 1090, 1042

cm-1;

HRMS

(ESI-TOF) calcd for

C24H18BrClN2NaO2S2+([M+Na]+): 566.9574; found: 566.9571. General Procedure for the Synthesis of 11. To a sealed tube with a magnetic stirrers were added sequentially 1 (0.1 mmol), 10 (0.15 mmol), Pd(OAc)2 (0.01 mmol) , K2CO3 (0.3 mmol) and dry CH3CN (2 mL) under air atmosphere. The reaction mixture was stirred at 80 OC (oil bath) for


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1 h. Upon completion, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 6:1 - 10:1, v/v) to give the product 11. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-oxo-2-phenylethyl)benzenesulfonamide

(11a).

White solid; Yield 64% (31 mg); m.p. 169-170 oC ; 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.85 (m, 2H), 7.81 – 7.75 (m, 2H), 7.70 – 7.63 (m, 1H), 7.61 – 7.56 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.48 – 7.44 (m, 2H), 7.42 – 7.36 (m, 2H), 7.35 – 7.30 (m, 1H), 7.19 – 7.13 (m, 1H), 5.46 (d, J = 17.9 Hz, 1H), 5.04 (d, J = 17.9 Hz, 1H), 4.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.5, 138.2, 134.7, 133.8, 133. 6, 131.3, 129.4, 128.8, 128.1, 127.9, 124.9, 123.8, 120.5, 119.1, 110.4, 86.8, 56.4, 31.1; IR(film): 3054, 2942, 1705, 1448, 1356, 1226, 1169, 1090 cm-1; HRMS (ESI-TOF) calcd for C23H19BrN2NaO3S+([M+Na]+): 505.0192; found: 505.0197. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-(4-methoxyphenyl)-2-oxoethyl) benzenesulfonamide (11b). Yellow liquid; Yield 63% (32 mg); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.84 (m, 2H), 7.82 – 7.75 (m, 2H), 7.69 – 7.62 (m, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.43 – 7.35 (m, 2H), 7.33 – 7.29 (m, 1H), 7.17 – 7.13 (m, 1H), 6.95 – 6.88 (m, 2H), 5.41 (d, J = 17.7 Hz, 1H), 4.99 (d, J = 17.6 Hz, 1H), 4.08 (s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.9, 164.0, 138.3, 134.7, 133.5, 131.3, 130.2, 129.4, 128.1, 127.7, 124.9, 123.7, 120.4, 119.1, 114.0, 110.4, 86.8, 55.9, 55.5, 31.1; IR(film): 3058, 2936, 1694, 1600, 1355, 1237, 1170, 1091 cm-1; HRMS (ESITOF) calcd for C24H21BrN2NaO4S+([M+Na]+): 535.0298; found: 535.0306. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-(4-bromophenyl)-2-oxoethyl)benzenesulfonamide

（11c）. Yellow liquid; Yield 50% (28 mg); 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.72 (m, 4H), 7.70 – 7.64 (m, 1H), 7.63 – 7.58 (m, 2H), 7.56 – 7.50 (m, 2H), 7.41 – 7.37 (m, 2H), 7.35 – 7.31 (m, 1H), 7.19 – 7.15 (m, 1H), 5.41 (d, J = 17.9 Hz, 1H), 4.98 (d, J = 17.9 Hz, 1H), 4.07 (s, 3H);



Page 38 of 53

C NMR (100 MHz, CDCl3) δ 191.6, 138.0, 134.7, 133.6, 133.4, 132.2, 131.1, 129.43, 129.37,

13

129.1, 128.1, 124.9, 123.9, 120.5, 119.2, 110.4, 86.9, 56.3, 31.1; IR(film): 3058, 2933, 1705, 1585, 1471, 1356, 1168, 1090 cm-1; HRMS (ESI-TOF) calcd for C23H18Br2N2NaO3S+([M+Na]+): 582.9297; found: 582.9301. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-(4-cyanophenyl)-2-oxoethyl)benzenesulfonamide (11d). Yellow and white solid; Yield 53% (27 mg); m.p. 96-97 oC ; 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.95 (m, 2H), 7.80 – 7.74 (m, 4H), 7.71 – 7.65 (m, 1H), 7.55 – 7.51 (m, 2H), 7.42 – 7.37 (m, 2H), 7.36 – 7.32 (m, 1H), 7.19 – 7.15 (m, 1H), 5.45 (d, J = 18.1 Hz, 1H), 5.01 (d, J = 18.1 Hz, 1H), 4.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.6, 137.8, 137.7, 134.7, 133.8, 132.7, 130.9, 129.5, 128.4, 128.1, 124.9, 124.0, 120.6, 119.2, 117.6, 117.1, 110.4, 87.0, 56.6, 31.0; IR(film): 3062, 2946, 1711, 1448, 1356, 1222, 1169, 1091 cm-1; HRMS (ESI-TOF) calcd for C24H18BrN3NaO3S+([M+Na]+): 530.0144; found: 530.0142. N-(3-Bromo-1-methyl-1H-indol-2-yl)-4-methyl-N-(2-oxo-2-phenylethyl)benzenesulfonamide (11e). White solid; Yield 50% (25 mg); m.p. 204-205 oC ; 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.85 (m, 2H), 7.69 – 7.64 (m, 2H), 7.61 – 7.55 (m, 1H), 7.47 – 7.43 (m, 2H), 7.39 (dd, J = 11.4, 8.2 Hz, 2H), 7.35 – 7.29 (m, 3H), 7.18 – 7.14 (m, 1H), 5.43 (d, J = 17.9 Hz, 1H), 5.04 (d, J = 17.9 Hz, 1H), 4.07 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.6, 144.5, 135.3, 134.8, 134.7, 133.8, 131.4, 130.0, 128.8, 128.2, 127.9, 125.0, 123.7, 120.4, 119.1, 110.4, 86.7, 56.3, 31.0, 21.7; IR(film): 3058, 2922, 1705, 1597, 1355, 1226, 1166, 1090 cm-1; HRMS (ESI-TOF) calcd for C24H21BrN2NaO3S+([M+Na]+): 519.0348; found: 519.0342. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-oxo-2-phenylethyl)methanesulfonamide

(11f).

Yellow liquid; Yield 60% (25 mg); 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.87 (m, 2H), 7.62 – 7.56 (m, 1H), 7.52 (dt, J = 7.9, 1.0 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.39 – 7.30 (m, 2H), 7.22 – 7.18 (m,


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1H), 5.39 (d, J = 18.0 Hz, 1H), 5.20 (d, J = 18.0 Hz, 1H), 4.02 (s, 3H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.5, 134.8, 134.5, 133.9, 131.2, 128.9, 127.9, 124.9, 124.0, 120.8, 119.2, 110.5, 87.0, 56.8, 40.3, 31.0; IR(film): 3058, 2925, 1706, 1472, 1349, 1227, 1158, 1108 cm-1; HRMS (ESI-TOF) calcd for C18H17BrN2NaO3S+([M+Na]+): 443.0035; found: 443.0031. N-(3-bromo-5-chloro-1-methyl-1H-indol-2-yl)-4-methyl-N-(2-oxo-2-phenylethyl) benzenesulfonamide (11g). Colorless liquid; Yield 45% (24 mg); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.85 (m, 2H), 7.68 – 7.62 (m, 2H), 7.62 – 7.56 (m, 1H), 7.48 – 7.44 (m, 2H), 7.38 (d, J = 1.9 Hz, 1H), 7.35 – 7.28 (m, 3H), 7.25 (dd, J = 7.1, 1.8 Hz, 1H), 5.43 (d, J = 17.9 Hz, 1H), 5.02 (d, J = 17.9 Hz, 1H), 4.07 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.5, 144.7, 135.1, 134.7, 133.9, 133.1, 132.6, 130.1, 128.9, 128.1, 127.9, 126.4, 125.9, 124.2, 118.6, 111.7, 86.0, 56.0, 31.3, 21.7; IR(film): 3062, 2924, 1705, 1473, 1355, 1227, 1166, 1090 cm-1; HRMS (ESITOF) calcd for C24H20BrClN2NaO3S+([M+Na]+): 552.9959; found: 552.9958. N-(3-Bromo-1,5-dimethyl-1H-indol-2-yl)-4-methyl-N-(2-oxo-2-phenylethyl) benzenesulfonamide (11h). Orange liquid; Yield 39% (20 mg); 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.84 (m, 2H), 7.69 – 7.63 (m, 2H), 7.61 – 7.55 (m, 1H), 7.47 – 7.43 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.14 (dd, J = 8.4, 1.6 Hz, 1H), 5.42 (d, J = 17.9 Hz, 1H), 5.02 (d, J = 17.9 Hz, 1H), 4.03 (s, 3H), 2.46 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.7, 144.5, 135.3, 134.8, 133.7, 133.1, 131.3, 129.9, 128.8, 128.2, 127.9, 125.4, 125.1, 118.5, 110.2, 86.1, 56.3, 31.0, 21.7, 21.4; IR(film): 3067, 2921, 1705, 1490, 1355, 1226, 1166, 1090 cm1

; HRMS (ESI-TOF) calcd for C25H23BrN2NaO3S+([M+Na]+): 533.0505; found: 533.0493 N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-oxopropyl)benzenesulfonamide （ 11i ） . Colorless

liquid; Yield 52% (22 mg); 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.69 (m, 2H), 7.68 – 7.61 (m, 1H), 7.54 – 7.47 (m, 2H), 7.41 – 7.36 (m, 2H), 7.35 – 7.31 (m, 1H), 7.19 – 7.15 (m, 1H), 4.82 (d,



J = 18.5 Hz, 1H), 4.36 (d, J = 18.4 Hz, 1H), 4.05 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.8, 137.9, 134.7, 133.6, 131.3, 129.4, 128.1, 124.9, 123.8, 120.5, 119.1, 110.4, 86.8, 59.5, 31.0, 27.1; IR(film): 3059, 2938, 1689, 1611, 1512, 1447, 1169, 1089 cm-1; HRMS (ESI-TOF) calcd for C18H17BrN2NaO3S+([M+Na]+): 443.0035; found: 443.0025. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(3,3-dimethyl-2-oxobutyl)benzenesulfonamide（11j）. Yellow liquid; Yield 28% (13 mg) 52%b (24 mg); 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 8.6 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 4.99 (d, J = 18.2 Hz, 1H), 4.59 (d, J = 18.2 Hz, 1H), 4.08 (s, 3H), 1.13 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 207.8, 138.3, 134.8, 133.4, 131.4, 129.4, 128.1, 125.0, 123.7, 120.4, 119.1, 110.4, 86.4, 54.5, 43.5, 31.1, 26.2; IR(film): 3058, 2968, 1726, 1472, 1356, 1235, 1169, 1056 cm-1; HRMS (ESI-TOF) calcd for C21H23BrN2NaO3S+([M+Na]+): 485.0505; found: 485.0506. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-cyclopropyl-2-oxoethyl)benzenesulfonamide (11k). Yellow and white solid; Yield 34% (15 mg) 85%b (38 mg); m.p. 185-186 oC ; 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.72 (m, 2H), 7.68 – 7.62 (m, 1H), 7.53 – 7.49 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.34 – 7.30 (m, 1H), 7.19 – 7.15 (m, 1H), 5.01 (d, J = 18.2 Hz, 1H), 4.54 (d, J = 18.2 Hz, 1H), 4.04 (s, 3H), 1.96 – 1.88 (m, 1H), 1.15 – 1.10 (m, 1H), 1.02 – 0.95 (m, 2H), 0.93 – 0.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 203.2, 138.1, 134.7, 133.5, 131.3, 129.3, 128.1, 124.9, 123.8, 120.5, 119.1, 110.4, 86.8, 59.5, 31.0, 18.2, 11.6, 11.5; IR(film): 3062, 2946, 1717, 1538, 1448, 1356, 1169, 1062 cm-1; HRMS (ESI-TOF) calcd for C20H19BrN2NaO3S+([M+Na]+): 469.0192; found: 469.0178. Ethyl 2-(N-(3-bromo-1-methyl-1H-indol-2-yl)phenylsulfonamido)acetate （ 11l ） . Yellow liquid; Yield 40% a (18 mg) 51%b (23 mg); 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.72 (m, 2H),


Page 40 of 53

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7.68 – 7.62 (m, 1H), 7.55 – 7.47 (m, 2H), 7.43 (dt, J = 8.0, 0.9 Hz, 1H), 7.38 (dt, J = 8.4, 1.0 Hz, 1H), 7.36 – 7.32 (m, 1H), 7.20 – 7.16 (m, 1H), 4.73 (d, J = 17.8 Hz, 1H), 4.27 – 4.12 (m, 3H), 4.04 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 138.0, 134.7, 133.6, 131.4, 129.4, 128.1, 125.0, 123.9, 120.5, 119.3, 110.4, 87.0, 61.7, 52.2, 30.9, 14.1; IR(film): 3054, 2982, 1754,

1448,

1359,

1200,

1170,

1091

cm-1;

HRMS

(ESI-TOF)

calcd

for

C19H19BrN2NaO4S+([M+Na]+): 473.0141; found: 473.0133. Methyl 2-(N-(3-bromo-1-methyl-1H-indol-2-yl)phenylsulfonamido)acetate (11m). Colorless liquid; Yield 39% a (17 mg) 76%b (33 mg); 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.72 (m, 2H), 7.68 – 7.62 (m, 1H), 7.53 – 7.49 (m, 2H), 7.43 (dt, J = 8.0, 1.0 Hz, 1H), 7.40 – 7.37 (m, 1H), 7.36 – 7.32 (m, 1H), 7.20 – 7.16 (m, 1H), 4.74 (d, J = 17.9 Hz, 1H), 4.25 (d, J = 17.9 Hz, 1H), 4.04 (s, 3H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 138.0, 134.7, 133.6, 131.3, 129.4, 128.1, 125.0, 123.9, 120.6, 119.3, 110.4, 87.1, 52.5, 52.0, 30.9; IR(film): 3058, 2951, 1758, 1448, 1357, 1206, 1170, 1091 cm-1; HRMS (ESI-TOF) calcd for C18H17BrN2NaO4S+([M+Na]+): 458.9985; found: 458.9971. General Procedure for the Synthesis of 13. To a sealed tube with a magnetic stirrers were added sequentially 1 (0.1 mmol), 12a (0.15 mmol), Pd(OAc)2 (0.01 mmol) , K2CO3 (0.3 mmol) and dry CH3CN (2 mL) under air atmosphere. The reaction mixture was stirred at 80 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 6:1, v/v) to give the product 13. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(cyanomethyl)-4-methylbenzenesulfonamide

(13a).

Colorless liquid; Yield 36%a (15 mg) 53%b (22 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m, 2H), 7.47 (dt, J = 8.1, 1.0 Hz, 1H), 7.40 – 7.37 (m, 2H), 7.35 – 7.30 (m, 2H), 7.24 – 7.20 (m,



Page 42 of 53

1H), 4.86 (d, J = 17.5 Hz, 1H), 4.41 (d, J = 17.5 Hz, 1H), 3.89 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.4, 134.9, 134.6, 130.2, 129.4, 128.2, 125.0, 124.6, 121.0, 119.7, 114.7, 110.5, 89.0, 39.3, 30.5, 21.7; IR(film): 3054, 2942, 1597, 1468, 1361, 1236, 1167, 1090 cm-1; HRMS (ESI-TOF) calcd for C18H16BrN3NaO2S+([M+Na]+): 440.0039; found: 440.0033. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(cyanomethyl)benzenesulfonamide (13b). Colorless liquid; Yield 50% a (20 mg) 47%b (19 mg); 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.77 (m, 2H), 7.72 – 7.66 (m, 1H), 7.56 – 7.52 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 4.0 Hz, 2H), 7.24 – 7.20 (m, 1H), 4.89 (d, J = 17.5 Hz, 1H), 4.42 (d, J = 17.5 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.5, 134.9, 134.2, 129.6, 129.2, 128.1, 124.9, 124.7, 121.0, 119.7, 114.6, 110.5, 89.1, 39.4, 30.5; IR(film): 3062, 2942, 1545, 1448, 1362, 1236, 1170, 1091 cm-1; HRMS (ESITOF) calcd for C17H14BrN3NaO2S+([M+Na]+): 425.9882; found: 425.9883. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(cyanomethyl)methanesulfonamide

(13c).

Yellow

liquid; Yield 47% a (16 mg) 56%b (19 mg); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 1H), 7.43 – 7.35 (m, 2H), 7.28 – 7.24 (m, 1H), 4.75 (d, J = 17.6 Hz, 1H), 4.56 (d, J = 17.7 Hz, 1H), 3.84 (s, 3H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.0, 129.0, 124.9, 124.8, 121.3, 119.7, 114.6, 110.6, 89.2, 41.1, 39.5, 30.5; IR(film): 3054, 2932, 1546, 1469, 1354, 1236, 1161, 1087 cm1

; HRMS (ESI-TOF) calcd for C12H12BrN3NaO2S+([M+Na]+): 363.9726; found: 363.9715. N-(3-Bromo-5-chloro-1-methyl-1H-indol-2-yl)-N-(cyanomethyl)-4-methyl benzenesulfonamide

(13d). Yellow liquid; Yield 35% a (16 mg) 60%b (27 mg); 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.61 (m, 2H), 7.45 – 7.44 (m, 1H), 7.36 – 7.28 (m, 4H), 4.85 (d, J = 17.5 Hz, 1H), 4.40 (d, J = 17.4 Hz, 1H), 3.88 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.6, 134.4, 133.3, 130.5, 130.3, 128.1, 127.0, 125.8, 125.2, 119.1, 114.5, 111.8, 88.3, 39.2, 30.7, 21.8; IR(film): 3058, 2946,


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1597,

1472,

1362,

1267,

1167,

1090

cm-1;

HRMS

(ESI-TOF)

calcd

for

C18H15BrClN3NaO2S+([M+Na]+): 473.9649; found: 473.9628. N-(3-Bromo-5-methoxy-1-methyl-1H-indol-2-yl)-N-(cyanomethyl)-4-methyl benzenesulfonamide (13e). Yellow liquid; Yield 29% a (13 mg) 36%b (16 mg); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 9.2 Hz, 1H), 7.03 (dd, J = 9.0, 2.5 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 4.85 (d, J = 17.5 Hz, 1H), 4.40 (d, J = 17.5 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1, 145.3, 134.7, 130.2, 130.0, 129.3, 128.2, 125.2, 115.8, 114.7, 111.7, 100.2, 88.3, 55.8, 39.3, 30.6, 21.7; IR(film): 2948, 2830, 1491,

1361,

1291,

1217,

1166,

1090

cm-1;

HRMS

(ESI-TOF)

calcd

for

C19H18BrN3NaO3S+([M+Na]+): 470.0144; found: 470.0128. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-ethyl-4-methylbenzenesulfonamide (13f). White solid; Yield 30% (12 mg); m.p. 170-171 oC ; 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.65 (m, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.21 – 7.17 (m, 1H), 4.04 – 3.95 (m, 1H), 3.82 (s, 3H), 3.66 – 3.58 (m, 1H), 2.45 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 136.0, 134.6, 130.7, 129.7, 128.1, 125.4, 123.6, 120.5, 119.3, 110.1, 88.0, 45.6, 30.2, 21.6, 14.3; IR(film): 3058, 2972, 1542, 1468, 1349, 1234, 1170, 1087 cm-1; HRMS (EITOF) calcd for C18H19BrN2O2S [M]+: 406.0351; found: 406.0354. N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-bromoethyl)-4-methylbenzenesulfonamide

(13g).

Yellow solid; Yield 55% (27 mg); m.p. 55-56 oC; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.22 – 7.18 (m, 1H), 4.28 – 4.21 (m, 1H), 3.96 – 3.89 (m, 1H), 3.88 (s, 3H), 3.51 – 3.41 (m, 2H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 135.0, 134.7, 130.7, 129.9, 128.2, 125.2, 124.0, 120.7, 119.4,



110.3, 87.8, 52.6, 30.8, 29.1, 21.7; IR(film): 3058, 2924, 1597, 1470, 1354, 1235, 1163, 1090 cm1

; HRMS (EI-TOF) calcd for C18H18Br2N2O2S [M]+: 483.9456; found: 483.9459. General Procedure for the Synthesis of 14. To a sealed tube with a magnetic stirrers were

added sequentially 7, Pd(OAc)2 (10 mmol%) , Bu4NCl (1 equiv), NaHCO3 (2.5 equiv) and DMA (1 mL) under air atmosphere. The reaction mixture was stirred at 90 OC (oil bath) for 12 h. Upon completion, the resulting mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1 – 20:1, v/v) to give the product 14. 3,8-dimethyl-1-Tosyl-1,8-dihydropyrrolo[2,3-b]indole (14a). Colorless liquid; Yield 91% (19 mg); 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.58 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.27 – 7.21 (m, 2H), 7.20 – 7.11 (m, 3H), 6.78 (q, J = 1.4 Hz, 1H), 4.05 (s, 3H), 2.32 (d, J = 1.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 144.7, 140.9, 137.6, 135.3, 129.8, 126.6, 121.5, 120.1, 119.8, 119.4, 119.2, 118.6, 113.7, 110.0, 32.3, 21.5, 11.7; IR(film): 3058, 2920, 1516, 1446, 1365, 1214, 1172, 1090 cm-1; HRMS (ESI-TOF) calcd for C19H18N2NaO2S+([M+Na]+): 361.0981; found: 361.0977. 3,8-dimethyl-1-(Phenylsulfonyl)-1,8-dihydropyrrolo[2,3-b]indole (14b). Colorless liquid; Yield 49% (14 mg); 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.71 (m, 2H), 7.65 (dt, J = 7.7, 1.0 Hz, 1H), 7.54 – 7.47 (m, 1H), 7.41 – 7.37 (m, 2H), 7.33 (dt, J = 8.3, 0.9 Hz, 1H), 7.28 – 7.22 (m, 2H), 7.17 – 7.13 (m, 1H), 6.79 (q, J = 1.3 Hz, 1H), 4.05 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.9, 138.3, 137.6, 133.6, 129.2, 126.5, 121.6, 120.1, 119.9, 119.7, 119.2, 118.6, 113.8, 110.0, 32.3, 11.7; IR(film): 3058, 2912, 1518, 1447, 1365, 1215, 1174, 1090 cm-1; HRMS (ESI-TOF) calcd for C18H16N2NaO2S+([M+Na]+): 347.0825; found: 347.0818.


Page 44 of 53

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3,8-dimethyl-1-(Methylsulfonyl)-1,8-dihydropyrrolo[2,3-b]indole (14c). Colorless liquid; Yield 68% (11 mg); 1H NMR (400 MHz, CDCl3) δ 7.73 (dt, J = 7.7, 1.0 Hz, 1H), 7.38 (dt, J = 8.3, 0.9 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.23 – 7.19 (m, 1H), 6.68 (q, J = 1.4 Hz, 1H), 4.02 (s, 3H), 2.97 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.1, 137.6, 121.8, 120.14, 120.12, 120.10, 119.1, 118.7, 113.6, 110.2, 40.3, 32. 5, 11.7; IR(film): 3011, 2925, 1521, 1446, 1360, 1215, 1170, 1101 cm-1; HRMS (ESI-TOF) calcd for C13H15N2O2S+([M+H]+): 263.0849; found: 263.0841. 3,5,8-trimethyl-1-Tosyl-1,8-dihydropyrrolo[2,3-b]indole (14d). Colorless liquid; Yield 70% (16 mg); 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.57 (m, 2H), 7.43 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.06 (dd, J = 8.4, 1.6 Hz, 1H), 6.74 (q, J = 1.3 Hz, 1H), 4.01 (s, 3H), 2.44 (s, 3H), 2.31 (d, J = 1.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 144.6, 139.3, 137.8, 135.3, 129.7, 129.2, 126.6, 122.8, 120.2, 119.6, 119.0, 118.6, 113.3, 109.7, 32.3, 21.5, 21.4, 11.7; IR(film): 2919, 2860, 1520, 1445, 1364, 1312, 1171, 1091

cm-1;

HRMS

(ESI-TOF) calcd for

C20H20N2NaO2S+([M+Na]+): 375.1138; found: 375.1132. 5-Chloro-3,8-dimethyl-1-tosyl-1,8-dihydropyrrolo[2,3-b]indole (14e). Colorless liquid; Yield 46% (17 mg); 1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.24 – 7.16 (m, 4H), 6.79 (q, J = 1.4 Hz, 1H), 4.03 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.9, 139.2, 138.2, 135.2, 129.9, 126.6, 125.5, 121.5, 120.9, 119.6, 119.0, 118.2, 113.0, 111.0, 32.5, 21.6, 11.6; IR(film): 2946, 2916, 1520, 1433, 1365, 1309, 1171, 1090 cm-1; HRMS (ESI-TOF) calcd for C19H17ClN2NaO2S+([M+Na]+): 395.0591; found: 395.0596. Procedure for the Synthesis of 15. To a sealed tube with a magnetic stirrers were added sequentially 1a (0.2 mmol), 2a (0.7 mL), 4h (0.7 mL), Pd(OAc)2 (0.02 mmol) , BCP (0.04 mmol) , K2CO3 (0.6 mmol) and CH3CN (0.6 mL) under air atmosphere. The reaction mixture was stirred at 80 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The resulted



Page 46 of 53

mixture was seperated by column chromatography on silica gel (petroleum ether/ ethyl acetate = 30:1, v/v) to give pure 3a (78% yield) and 15 (7% yield).

N-(3-Bromo-1-methyl-1H-indol-2-yl)-N-(2-chloroallyl)-4-methylbenzenesulfonamide

(15).

Colorless liquid; Yield 7% (6 mg); 1H NMR (600 MHz, CDCl3) δ 7.65 – 7.60 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 – 7.27 (m, 4H), 7.17 – 7.20 (m, 1H), 5.26 (s, 1H), 5.20 (s, 1H), 4.69 (d, J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.89 (s, 3H), 2.45 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.5, 135.7, 135.3, 134.7, 130.0, 129.9, 128.2, 125.2, 123.7, 120.5, 119.3, 118.4, 110.3, 107.3, 87.5, 56.4, 30.7, 21.7; IR(film): 3058, 2920, 1467, 1359, 1236, 1167, 1089, 1064 cm-1; HRMS (EITOF) calcd for C19H18BrClN2O2S [M]+: 451.9961; found: 451.9964. Procedure for the Synthesis of 16. To a sealed tube with a magnetic stirrers were added sequentially 1a (0.2 mmol), 2d (0.3 mL), 6a (0.3 mL), Pd(OAc)2 (0.02 mmol) , BCP (0.04 mmol) , K2CO3 (0.6 mmol) and CH3CN (1.4 mL) under air atmosphere. The reaction mixture was stirred at 50 OC (oil bath) for 12 h. Upon completion, the solvent was evaporated in vacuum. The resulted mixture was seperated by column chromatography on silica gel (petroleum ether/ ethyl acetate = 50:1, v/v) to give pure 7a (21% yield) and 16 (13% yield). N-(3-Iodo-1-methyl-1H-indol-2-yl)-4-methyl-N-(2-methylallyl)benzenesulfonamide

(16).

Colorless liquid; Yield 13% (12 mg); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.62 (m, 2H), 7.36 – 7.28 (m, 5H), 7.20 – 7.16 (m, 1H), 4.76 (t, J = 1.5 Hz, 1H), 4.72 (s, 1H), 4.44 (d, J = 13.4 Hz, 1H), 4.24 (d, J = 13.4 Hz, 1H), 3.84 (s, 3H), 2.45 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.3, 139.2, 135.9, 135.5, 134.2, 130.0, 128.7, 128.5, 123.6, 121.4, 120.6, 117.2, 110.2, 56.9, 55.0, 30.7, 21.7, 20. 6; IR(film): 3054, 2942, 1517, 1468, 1349, 1232, 1165, 1091 cm-1; HRMS (EI-TOF) calcd for C20H21IN2O2S [M]+: 480.0368; found: 480.0365.


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ASSOCIATED CONTENT Supporting Information The supporting information is available free of charge on the ACS Publications website at DOI: 1

H NMR and 13C NMR spectra for all new compounds. (PDF)

X-ray crystallography of 3p and 11a. (CIF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; *E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was financially supported by NSFC (Grant Nos. 21632003 and 21772169).

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