Copper-Catalyzed Oxidative Cyclization of Alkynes with

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Copper-catalyzed Oxidative Cyclization of Alkynes with Sulfonylhydrazides Leading to 2-Sulfonated 9H-Pyrrolo[1,2-a]indol-9-ones Xin-Yu Zhu, Ming Li, Ya-Ping Han, Si Chen, Xue-Song Li, and Yong-Min Liang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01497 • Publication Date (Web): 28 Jul 2017 Downloaded from http://pubs.acs.org on July 28, 2017

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The Journal of Organic Chemistry

Copper-catalyzed Oxidative Cyclization of Alkynes with Sulfonylhydrazides Leading to 2-Sulfonated 9H-pyrrolo [1,2-a]indol-9-ones Xin-Yu Zhu, Ming Li, Ya-Ping Han, Si Chen, Xue-Song Li, and Yong-Min Liang*

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China. E-mail: [email protected];

Abstract A copper-catalyzed oxidative cyclization procedure has been developed for the production of 2-sulfonated 9H-pyrrolo[1,2-a]indol-9-ones via the direct sulfonylation of N-propargyl-substituted indoles with sulfonylhydrazides and tert-butyl hydroperoxide (TBHP). This novel protocol, which tolerates a broad range of functional groups, offers a simple, efficient, and atom-economical route to a series of fluorazones in good yields under mild conditions. Derivatives of fluorazone (9H-pyrrolo[1,2-a]indol-9-one) represent an important class of heteroaromatic compounds in pharmaceutical chemistry. They exhibit a wide range of biological activities including antidiabetic, anticancer, and antitubulin.1 Fluorazone acts as the key precursor to fluoranzene which is the basic framework of cytostatic mytomycin family.2 Considering the impressive physiological and chemophysical properties of fluorazone derivatives and their significant role in organic synthesis, the

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development of versatile, convenient, and efficient methods for the synthesis of 9H-Pyrrolo[1,2-a]indol-9-one has recently attracted considerable attention from both the academic and industrial communities. The traditional synthetic approaches to synthesizing substituted and unsubstituted fluorazones have been supplemented via the intramolecular cyclization of N-arylpyrrole.3 However, these methodologies often suffer from long reaction time, low functional group compatibility and large amounts of extra reaction reagents. In recent years, N-propargyl-substituted indoles have come to be used as radical acceptors. By carefully designing the structures of substrates, various multifunctional pyrrolo[1,2-a]indoles can be synthesized in one-pot cascade sequences with radical-triggered cyclization strategy under mild conditions. For example, Zhao et al. and Zhu et al. independently reported a

novel

method

employing

1-(3-phenylprop-2-yn-1-yl)-1H-indole

with

diphenylphosphine oxides to provide 2-phosphorylated pyrrolo[1,2-a]indoles via transition-metal-catalyzed tandem radical cyclization reaction4(Scheme 1, eq 1). Very recently, an effective NaI-catalyzed sulfonylation/cyclization process to form 2-sulfonated 9H-pyrrolo[1,2-a]indoles was disclosed by Zhao and co-workers5 (Scheme 1, eq 2). This series of methods provides a highly efficient route to construct the pyrrolo[1,2-a]indole motif with a wide substrate scope. Nevertheless, to the best of our knowledge, the work involved in the synthesis of fluorazone and its analogues based on the radical addition strategy is underdeveloped and many challenges still remain.


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Scheme 1. Construction of Pyrrolo[1,2-a]indole Derivatives Previous work:

This work

The sulfonyl group is of great importance in agrochemical and material chemistry because of the unique biological and chemical properties of sulfone-containing molecules.6 The development of novel, versatile strategies to construct different useful skeletons bearing sulfonyl groups would be highly significant.7 More recently, a large number of synthetic methods have been extensively researched for the incorporation of sulfonyl radicals generated in situ from sulfonylhydrazides. Many successful alternative methods of radical sulfonylation reactions catalyzed by metal-free catalysts or transition metal catalysts have been reported in the literature.8,9 However, methods for the construction of molecules bearing both a sulfonyl group and a fluorazone motif have only rarely been reported. Based on the significance of the sulfonyl group and our ongoing interest in radical reactions,10 we first developed a copper-catalyzed oxidative cyclization strategy for producing 2-sulfonated 9H-pyrrolo[1,2- a]indol-9-ones from accessible N-propargyl-substituted indoles (Scheme 1, eq 3). The present protocol offers a flexible method to syntheize



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unprecedented

2-sulfonated

fluorazones

in

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functional-group-compatible

fashion using N-S bond cleavage and the formation of sequential C-S, C-C, and C=O bonds formation. In an initial experiment, N-propargyl-substituted indole 1a and tosyl hydrazine 2a were selected as model substrates to optimize the reaction Table 1. Optimization of the Reaction Conditionsa

Entry 1 2 3 4 5 6c 7 8d 9 10 11 12 13 14 15 16 17 18e

Catalyst (20 mol%) CuCl2 Cu(acac)2 CuCl2·2H2O Cu(OAc)2 CuI CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O

Additive (equiv.)

HOAc (1.0) HOAc (0.5) HOAc (0.2) HOAc (0.5) HOAc (0.5) HOAc (0.5) HOAc (0.5) HOAc (0.5) HOAc (0.5) HOAc (0.5)

Solvent

T (°C)

Yieldb (%)

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE MeCN Toluene DCM DCE

80 80 80 80 80 80 80 80 80 80 80 70 90 100 90 90 90 90

44 45 48 28 N.D. 24 20 N.D. 53 63 56 55 70 46 61 35 40 N.D.

a

Unless otherwise noted, all reactions were performed with 1a (0.1 mmol), 2a

(1.5 equiv.), catalyst (20 mol%), TBHP (3.0 equiv., 70 wt% in water), additive in anhydrous solvent (2 mL) under an air atmosphere for 12 h. bYields are given for isolated products. cTBHP (5.5M in decane over molecular sieve 4Å). dThe


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reaction was conducted without TBHP. eThe reaction was conducted under O2 atmosphere. N.D. = no detected. conditions. The desired sulfonated fluorazone 3a was obtained in 44% yield in the presence of CuCl2 (20 mol%) and TBHP (3.0 equiv., 70 wt% in water) in DCE at 80 °C in an air atmosphere for 12 h (Table 1, entry 1). The structure of 3a was also confirmed by X-ray crystal structure analysis (Supporting Information). A subsequent investigation of copper catalysts revealed the annulation reaction gave a better yield by using CuCl2•2H2O (entries 2–5). No improvement in the yield was observed after the replacement of TBHP (5.5 M in decane) (entry 6). An additional control experiment suggested that the copper catalyst was crucial to this transformation (entry 7), while TBHP was a necessary part of the reaction (entry 8). TBHP acted as both the oxidant and source of oxygen. During subsequent attempts, the addition of acetic acid (0.5 equiv.) proved to be effective, and 63% product of 3a was isolated (entries 9–11). Temperature screening indicated that 90 °C was the most suitable temperature for this protocol (entries 12–14). The reaction was less effective in other solvents, such as MeCN, toluene, and DCM (entries 15–17). Finally, the result replacing air with O2 indicated that the oxygen of the indolone carbonyl did not come from the oxygen gas (entry 18). Ultimately, the optimal reaction conditions were found to be 1a (0.1 mmol) and TsNHNH2 (1.5 equiv.) with CuCl2·2H2O (20 mol%), TBHP (3.0 equiv., 70 wt% in water) and HOAc (0.5 equiv.) in anhydrous DCE (2 mL) at 90 °C for 12 h in the air.



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With the optimized conditions established, the scope of substrates in this Scheme 2. Substrate Scope for Synthesis of 3a,b

a

Unless otherwise noted, all reactions were performed with 1 (0.1 mmol),

TsNHNH2 (1.5 equiv.), CuCl2·2H2O (20 mol%), TBHP (3.0 equiv., 70 wt% in water) and HOAc (0.5 equiv.) in anhydrous DCE (2 mL) at 90 °C for 12 h under air. bYields are given for isolated products. transformation was explored. As summarized in Scheme 2, the substrates bearing electron-donating groups (methoxyl, methyl, and t-butyl) and halo substitutions (fluoro, chloro, and bromo) on the phenyl rings, regardless of the bulky phenyl group, performed well and gave the desired products in moderate to good yields (3a–3j). Strong electron-withdrawing groups (ester group and CF3-group) were investigated and led to the expected products in slightly lower yields

(3k

and

3l).

Subsequently,

the

naphthyl-substituted


and

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thienyl-substituted N-propargyl indoles were suitable for the reaction (3m and 3n). Contrary to expectations, when R1 was an aliphatic chain, no desired product was detected (3o). N-propargyl substrates containing various substituents on the indole ring could also participate in the reaction and furnish the desired products at yields ranging from 42% to 70% (3p–3t). Next, the reactions between various arylsulfonylhydrazides and 1a were also systematically investigated (Scheme 3), the substrates bearing electron-donating

groups

showed

higher

reactivity

than

those

with

electron-withdrawing counterparts (4c vs 4h, 4d vs 4i). Additionally, halo-substituted

sulfonylhydrazides

were

also

well-tolerated

(4e–4g).

Reagents containing naphthyl and thienyl delivered the desired products 4j and 4k in 69% and 52% yields, respectively. The aliphatic sulfonylhydrazide Scheme 3. Substrate Scope for Synthesis of 4a,b



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a

Unless otherwise noted, all reactions were performed with 1a (0.1 mmol), 2

(1.5 equiv.), CuCl2·2H2O (20 mol%), TBHP (3.0 equiv., 70 wt% in water) and HOAc (0.5 equiv.) in anhydrous DCE (2 mL) at 90 °C for 12 h under air. bYields are given for isolated products. was found to be an unreactive substrate, and the desired product 4l was not observed, perhaps due to instability of the sulfonyl radicals generated in situ under the optimized reaction conditions. We designed control experiments to understand the mechanism underlying this transformation (Scheme 4). When the reaction was performed in the presence of a radical scavenger (2.0 equiv.) such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,6-di-tert-butyl-4-methylphenol), the formation of 3a was inhibited to a great extent, indicating that the reaction process might involve radical species (eq 1). No desired product was observed Scheme 4. Verification Experiments

when sodium p-toluenesulfinate or 4-toluenesulfonyl chloride served as the sulfonylating agent instead of p-toluenesulfonyl hydrazide (1.5 equiv.) (eq 2


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and eq 3). When the reaction was carried out in the presence of H218O (13 μL), 55%

16

O-labeled and 45%

18

O-labeled products were observed (Supporting

Information Labeling Experiment Section). The

18

O-labeled experiment meant

that oxygen atoms in the indolone carbonyl come from TBHP or water in the TBHP solution (70 wt% in water) and catalyst.11 On the basis of the results given above and of previous studies11,12, a hypothesized mechanism for this reaction via two possible pathways are shown in Scheme 5. First, TBHP reacts with copper (II) to produce copper (I), tert-butylperoxy (t-BuOO·) and tert-butoxyl radical (t-BuO·). Then these radicals abstract hydrogen atoms from sulfonylhydrazide to generate the sulfonyl radical A. Next, the selective addition of the sulfonyl radical A to the Scheme 5. Proposed Reaction Mechanism

C-C triple bond, gives the vinyl radical B. B undergoes an intramolecular cyclization with the indole ring, generating the intermediate C. Intermediate D is formed by a single-electron transfer (SET) from intermediate C. Then C



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reacts with a tert-butylperoxy free radical to generate intermediate E which decomposes to furnish product 3a. In contrast, product 3a is also afforded via the decomposition of intermediate F, which is formed by water and intermediate D. Conclusions In conclusion, we have developed an unprecedented copper-catalyzed direct oxidative cyclization of alkynes with sulfonylhydrazides to access 2-sulfonated 9H-pyrrolo[1,2-a]indol-9-ones. The tandem reaction enables the one-step construction of C-S, C-C, and C=O bonds, with excellent functional group tolerance and giving the corresponding products in moderate to good yields. Meanwhile, the method to synthesize important functional sulfonylated fluorazone derivatives is expected to extend the potential applications in organic synthetic chemistry.

Experimental Section General Remarks: Column chromatography was carried out on silica gel. 1H NMR spectra were recorded on 400 MHz in CDCl3. 13C NMR spectra were recorded on 100 MHz in CDCl3. Chemical shifts (ppm) were recorded with tetramethylsilane (TMS) as the internal reference standard. Multiplicities are given as: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), q (quartet) or m (multiplet). Copies of their 1H NMR and 13C NMR spectra are provided in the Supporting Information. High-resolution mass spectra were measured on


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Orbitrap Elite with electrospray ionization mode (ESI+). Solvents were dried under standard method. Commercially available reagents were used with further purification. DCE was distilled immediately before use from CaH. General Procedures for the synthesis of N-propargyl-substituted indoles (1a-1t)13 (1) Sodium hydride (15 mmol) was added to a solution of the appropriate (un)substituted indole (10 mmol) in DMF (25 mL) at 0 °C. After 1h stirring at rt the solution was cooled at 0 °C and propargyl bromide (15 mmol) was added. The reaction was stirred at rt until disappearance of the starting material (TLC). Then water (20 mL) was added, before being extracted with dichloromethane (3 X 30 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue using ethyl acetate/hexanes mixtures gave analytically pure (un)substituted 1-(prop-2-yn-1-yl)-1H-indole.

(2) Under

a

nitrogen

atmosphere,

a

solution

of

(un)substituted

1-(prop-2-yn-1-yl)-1H-indole (5.0 mmol), the appropriate aryl halide (6 mmol), potassium carbonate (3.5 g, 25 mmol), CuI (38.1 mg, 0.2 mmol) and tetrakis(triphenylphosphine)-palladium (0) (115.6 mg, 0.1 mmol) in dry DMF (25 mL) was stirred at 60 °C until no more starting material was detectable by TLC analysis. Then, the reaction mixture was diluted with HCl 0.1 M solution (25 mL) and extracted with ethyl acetate (3 X 30 mL).



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The organic layer, dried over sodium sulfate, was evaporated to dryness and the crude purified by flash chromatography over a silica gel cilumn. General Procedures for the synthesis of arylsulfonylhydrazides (2a-2k)14

Substrates 2 were prepared according to the previous literatures.

General

Procedure

for

the

Synthesis

of

2-Sulfonated

9H-pyrrolo[1,2-a]indol-9-ones (3a-3t, 4a-4l) The reaction of N-propargyl-substituted indoles (1, 0.1 mmol, 1.0 eq.), arylsulfonylhydrazides (2, 0.15 mmol, 1.5 eq.), CuCl2·2H2O (3.4 mg, 0.02 mmol, 20 mol%), TBHP (27.0 mg, 0.3 mmol, 3.0 eq.) and HOAc (3.0 mg, 0.05 mmol, 0.5 eq.) in anhydrous DCE (2.0 mL) was conducted at 90 °C under an air atmosphere. The reaction was completed within 12.0 h by TLC monitoring. The resulting mixture was cooled down to room temperature. The reaction mixture was then diluted with ethyl acetate (2×15 mL), washed with a saturated aqueous solution of brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was further purified by chromatography on silica gel (petroleum ether/ethyl acetate, 4:1) to afford 3. Characterization data of 1p-1t, 3a–4k

6-chloro-1-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-1H-indole (1p):

The resultant residue was purified by flash silica gel column chromatography to afford 1p as a brown liquid; 1H NMR (400 MHz, CDCl3): 7.52 (d, J = 8.4 Hz,


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1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 3.2 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 3.1 Hz, 1H), 4.99 (s, 2H), 3.77 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ159.9, 136.2, 133.2, 128.1, 127.8, 127.4, 121.8, 120.4, 114.1, 114.0, 109.6, 101.9, 85.5, 81.1, 55.2, 36.8. IR (KBr) 2964, 2930, 1880, 1606, 1509, 1455, 1278, 1210, 1029, 907, 829, 811, 734, 724, 600, 536, 424 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C18H15ClNO 296.0837; found 296.0840.

6-fluoro-1-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-1H-indole (1q):

The resultant residue was purified by flash silica gel column chromatography to afford 1q as a brown liquid; 1H NMR (400 MHz, CDCl3): 7.54-7.50 (m, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 3.2 Hz, 1H), 7.15 (dd, J = 9.8 Hz, 2.0 Hz, 1H), 6.92-6.87 (m, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.50-6.49 (m, 1H), 4.97 (s, 2H), 3.76 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ160.4 (d, J = 109 Hz),

158.6, 135.9 (d, J = 12 Hz), 133.2, 127.8 (d, J = 4 Hz), 125.3, 124.5, 121.7 (d, J = 10 Hz), 121.3 (d, J = 10 Hz), 114.1 (d, J = 24 Hz), 108.4 (d, J = 24 Hz), 102.6, 101.9, 96.0 (d, J = 27 Hz), 85.4, 81.2, 55.2, 36.9. IR (KBr) 3432, 2934, 2838, 1606, 1511, 1488, 1466, 1329, 1293, 1250, 1172, 1031, 947, 831, 802, 715, 615, 537 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C18H15FNO 280.1132; found 280.1135.

1-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-6-methyl-1H-indole (1r):



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The resultant residue was purified by flash silica gel column chromatography to afford 1r as a brown liquid; 1H NMR (400 MHz, CDCl3): 7.51 (d, J = 7.8 Hz, 1H), 7.35-7.33 (m, 2H), 7.24-7.19 (m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.6 Hz, 2H), 6.47 (s, 1H), 5.00 (s, 2H), 3.75 (s, 3H), 2.50 (s, 3H).

13

C{H} NMR

(100 MHz, CDCl3): δ159.8, 136.3, 133.2, 131.5, 126.7, 126.7, 121.5, 120.6, 114.4, 113.9, 109.4, 101.5, 85.0, 81.8, 55.2, 36.5, 21.9. IR (KBr) 3415, 2916, 2837, 2244, 1606, 1509, 1465, 1292, 1248, 1173, 1032, 832, 803, 716, 606, 537, 427 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO 276.1383; found 276.1385.

1-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-7-methyl-1H-indole (1s):

The resultant residue was purified by flash silica gel column chromatography to afford 1s as a brown liquid; 1H NMR (400 MHz, CDCl3): 7.35 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 3.2 Hz, 1H), 6.89 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 6.65 (d, J = 8.7 Hz, 2H), 6.38 (d, J = 2.9 Hz, 1H), 5.10 (s, 2H), 3.60 (s, 3H), 2.73 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ159.7,

134.7, 133.1, 129.9, 129.0, 124.6, 121.0, 119.9, 119.1, 114.4, 113.9, 102.1, 85.4, 83.4, 55.1, 39.3, 19.4. IR (KBr) 3420, 3049, 2959, 2837, 2243, 1606, 1509, 1442, 1335, 1292, 1248, 1173, 1107, 1031, 832, 784, 723, 537 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO 276.1383; found 276.1387.

5-methoxy-1-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-1H-indole (1t):


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The resultant residue was purified by flash silica gel column chromatography to afford 1t as a brown liquid; 1H NMR (400 MHz, CDCl3): 7.36-7.32 (m, 3H), 7.24-7.22 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.8 Hz, 2.1 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 6.44 (d, J = 2.9 Hz, 1H), 5.01 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ159.8, 154.2, 133.2, 131.2,

129.3, 127.9, 114.4, 113.9, 112.0, 110.2, 102.8, 101.3, 85.1, 81.7, 55.8, 55.2, 36.8. IR (KBr) 3413, 2955, 2838, 1603, 1509, 1484, 1249, 1237, 1220, 1152, 1027, 835, 802, 756, 729, 599, 539, 428 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO2 292.1332; found 292.1335.

1-(4-methoxyphenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3a):

The resultant residue was purified by flash silica gel column chromatography to afford 3a as a yellow solid (30 mg, 70%); m.p. 160-162 °C ; 1H NMR (400 MHz, CDCl3): 7.95 (s, 1H), 7.69-7.63 (m, 3H), 7.56-7.49 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.27-7.24 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H), 2.32 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.6, 160.4,

143.9, 141.9, 138.5, 134.7, 131.5, 130.0, 129.8, 129.7, 129.3, 128.7, 127.2, 126.9, 124.8, 123.5, 121.2, 113.4, 111.3, 55.2, 21.5. IR (KBr) 3162, 2925, 1723, 1695, 1617, 1502, 1460, 1288, 1250, 1145, 1084, 1037, 966, 900, 756, 675cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C25H20NO4S 430.1108; found 430.1115.

1-(o-tolyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3b):



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The resultant residue was purified by flash silica gel column chromatography to afford 3b as a yellow oil (30.6 mg, 74%); 1H NMR (400 MHz, CDCl3): 7.97 (s, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.34-7.27 (m, 3H), 7.24 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 3.4 Hz, 2H), 7.12 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.2 Hz, 2H), 2.35 (s, 3H), 1.79 (s 3H).

13

C{H} NMR (100 MHz, CDCl3):

δ178.8, 143.8, 142.4, 138.1, 137.2, 134.8, 130.9, 130.7, 129.6, 129.5, 129.1, 128.9, 128.2, 127.7 127.5, 126.9, 125.1, 124.9, 121.7, 111.5, 21.5, 19.4. IR (KBr) 3139, 2921, 1714, 1618, 1483, 1306, 1145, 1081, 967, 902, 780, 754, 668, 608, 542cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H19NO3SNa 436.0978; found 436.0982.

1-(m-tolyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3c):

The resultant residue was purified by flash silica gel column chromatography to afford 3c as a yellow oil (29.3 mg, 71%); 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.28-7.23 (m, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 2.34 (s, 3H), 2.33 (s 3H). 13

C{H} NMR (100 MHz, CDCl3): δ178.7, 143.9, 142.1, 138.5, 137.4, 134.7,

130.4, 130.1, 130.0, 129.9, 129.7, 129.2, 128.9, 128.7, 127.9, 127.4, 126.9, 124.9, 123.1, 111.4, 21.5, 21.3. IR (KBr) 3165, 2921, 1724, 1696, 1619, 1504, 1330, 1286, 1146, 1085, 901, 815, 694, 620, 566cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H19NO3SNa 436.0978; found 436.0985.


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1-(p-tolyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3d):

The resultant residue was purified by flash silica gel column chromatography to afford 3d as a yellow oil (24.8 mg, 60%); 1H NMR (400 MHz, CDCl3): 7.95 (s, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.56-7.51 (m, 3H), 7.48 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H).

13


δ178.7, 143.8, 142.0, 139.3, 138.6, 134.7, 130.1, 130.0, 129.8, 129.8, 129.3, 129.2, 128.9, 128.7, 127.3, 126.9, 125.9, 124.8, 123.3, 111.4, 21.5, 21.4. IR (KBr) 3167, 2923, 1697, 1616, 1503, 1300, 1147, 1082, 901, 826, 755, 673, 613, 558, 495cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C25H20NO3S 414.1158; found 414.1163.

1-phenyl-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3e):

The resultant residue was purified by flash silica gel column chromatography to afford 3e as a yellow solid (21.1 mg, 53%); m.p. 170-172 °C; 1H NMR (400 MHz, CDCl3): 7.97 (s, 1H), 7.64–7.62 (m, 3H), 7.55 (t, J = 7.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.38–7.37 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 15.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 2.3 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 178.7, 143.9, 142.1 138.4, 134.8, 130.2, 129.9, 129.7, 129.7, 129.3, 129.2, 128.9, 128.8, 127.9, 127.3, 127.0, 124.9, 123.1, 111.4, 21.5. IR (KBr) 3110, 2923, 1696, 1618, 1532, 1492, 1316, 1148, 1084, 901, 812, 771, 755, 621,



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542cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H18NO3S 400.1002; found 400.1008..

1-(4-(tert-butyl)phenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3f):

The resultant residue was purified by flash silica gel column chromatography to afford 3f as a yellow oil (28.2 mg, 62%); 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.58-7.52 (m, 3H), 7.44 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.25-7.23 (m, 1H), 7.04 (d, J = 8.1 Hz, 2H), 2.3 (s, 3H), 1.35 (s, 9H).

13

C{H} NMR (100 MHz, CDCl3): δ178.7,

152.4, 143.8, 142.0, 138.3, 134.7, 130.1, 130.1, 130.0, 129.7, 129.6, 129.1, 128.8, 127.4, 127.3, 126.9, 125.9, 124.9, 124.8, 123.2, 111.4, 34.7, 31.2, 21.4. IR (KBr) 3154, 2955, 2866, 1724, 1695, 1618, 1502, 1299, 1084, 969, 900, 838, 815, 756, 675cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C28H26NO3S 456.1628; found 456.1632.

1-([1,1'-biphenyl]-4-yl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3g):

The resultant residue was purified by flash silica gel column chromatography to afford 3g as a yellow oil (39.9 mg, 84%); 1H NMR (400 MHz, CDCl3): 7.98 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.67-7.61 (m, 4H), 7.56-7.45 (m, 6H), 7.39 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 2.31 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.8, 144.0, 142.0,

141.9, 140.5, 138.4, 134.8, 130.4, 130.1, 129.7, 129.5, 129.4, 129.0, 128.8, 127.8, 127.6, 127.3, 127.1, 126.6, 125.0, 123.3, 111.4, 21.5. IR (KBr) 3117,


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2924, 1706, 1616, 1478, 1317, 1145, 1083, 962, 899, 732, 675, 610, 569, 531cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C30H22NO3S 476.1315; found 476.1324.

1-(4-fluorophenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3h):

The resultant residue was purified by flash silica gel column chromatography to afford 3h as a yellow solid (22.9 mg, 55%); m.p. 158-160 °C; 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.68-7.64 (m, 3H), 7.56 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.34-7.28 (m, 2H), 7.12-7.04 (m, 4H), 2.33 (s, 3H).

13

C{H}

NMR (100 MHz, CDCl3): δ178.7, 163.2 (d, J = 248 Hz), 144.09, 142.0, 138.3, 134.9, 132.1, 132.0, 130.0, 129.6, 129.4, 128.9, 128.6, 127.2, 127.1, 125.0, 124.9, 124.8, 123.2, 115.1 (d, J = 22 Hz), 111.4, 21.5. IR (KBr) 3120, 2923, 1709, 1699, 1619, 1503, 1225, 1160, 1082, 901, 842, 812, 752, 669, 621, 558cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17FNO3S 418.0908; found 418.0912.

1-(4-chlorophenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3i):

The resultant residue was purified by flash silica gel column chromatography to afford 3i as a yellow oil (23.4 mg, 54%); 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.66–7.54 (m, 4H), 7.48 (d, J = 8.2 Hz, 2H), 7.36-7,28 (m, 4H), 7.12(d, J =8.1 Hz, 2H), 2.34 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.7, 144.2,

142.0, 138.3, 135.3, 134.9, 131.3, 130.0, 129.6, 129.5, 129.0, 128.3, 127.3, 127.2, 127.1, 125.0, 123.3, 111.5, 21.5. IR (KBr) 3108, 2924, 1705, 1696,



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1619, 1488, 1146, 1083, 901, 833, 813, 752, 677, 623, 569cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17ClNO3S 434.0612; found 434.0620.

1-(4-bromophenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3j):

The resultant residue was purified by flash silica gel column chromatography to afford 3j as a yellow oil (23.9 mg, 50%); 1H NMR (400 MHz, CDCl3): 7.95 (s, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.57-7.47 (m, 7H), 7.34-7.28 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ178.7, 144.2, 142.0, 138.3, 134.9, 131.6, 131.2, 130.0, 129.6, 129.5, 128.9, 128.3, 127.8, 127.2, 127.2, 125.0, 123.7, 123.2, 111.5, 21.5. IR (KBr) 3167, 2923, 1699, 1617, 1597, 1498, 1486, 1285, 1145, 1084, 900, 812, 756, 676, 609cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17BrNO3S 478.0107; found 478.0117.

methyl 4-(9-oxo-2-tosyl-9H-pyrrolo[1,2-a]indol-1-yl)benzoate (3k):

The resultant residue was purified by flash silica gel column chromatography to afford 3k as a yellow oil (18.3 mg, 40%); 1H NMR (400 MHz, CDCl3): 8.03 (t, J = 8.3 Hz, 3H), 7.72 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 3.95 (s, 3H), 2.32 (s, 3H).

13

C{H} NMR (100

MHz, CDCl3): δ178.7, 166.7, 144.2, 142.1, 138.3, 135.0, 133.5, 130.4, 130.2, 130.0, 129.5, 129.2, 128.1, 127.2, 125.6, 125.0, 123.8, 123.3, 111.6, 52.2, 21.5. IR (KBr) 3167, 2923, 1718, 1701, 1616, 1499, 1278, 1144, 1109, 900,


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813, 756, 697, 609, 544cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C26H19NO5SNa 480.0876; found 480.0886.

2-tosyl-1-(4-(trifluoromethyl)phenyl)-9H-pyrrolo[1,2-a]indol-9-one (3l):

The resultant residue was purified by flash silica gel column chromatography to afford 3l as a yellow solid (19.1 mg, 41%); m.p. 180-182 °C; 1H NMR (400 MHz, CDCl3): 7.97 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.67-7.57 (m, 4H), 7.45 (d, J = 8.0 Hz, 2H), 7.36-7.28 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H). 13

C{H} NMR (100 MHz, CDCl3): δ178.7, 144.3, 142.1, 138.2, 135.1, 132.5,

131.1, 130.4, 129.4, 129.2, 127.5, 127.3, 125.2, 124.9 (d, J = 4 Hz), 123.1, 111.5, 21.5. IR (KBr) 3119, 2926, 1709, 1617, 1481, 1333, 1144, 1069, 970, 902, 848, 814, 752, 668, 599cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H16F3NO3SNa 490.0695; found 490.0703.

1-(naphthalen-1-yl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3m):

The resultant residue was purified by flash silica gel column chromatography to afford 3m as a yellow oil (29.2 mg, 65%); 1H NMR (400 MHz, CDCl3): 8.05 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.59-7.53 (m, 2H), 7.49-7.45 (m, 2H), 7.37-7.34 (m, 2H), 7.25-7.23 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.10, (d, J = 7.7 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.67 (d, J = 8.1 Hz, 2H), 2.10 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.5, 143.5, 142.5, 137.3,

134.9, 133.1, 132.1, 131.3, 130.3, 129.5, 129.3, 128.8, 128.7, 128.0, 127.3, 127.0, 126.2, 126.2, 125.9, 125.5, 125.0, 124.8, 124.8, 121.6, 111.5, 21.2. IR



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(KBr) 3111, 2921, 1698, 1617, 1481, 1328, 1314, 1147, 1156, 1082, 897, 765, 663, 606, 550cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C28H20NO3S 450.1158; found 450.1166.

1-(thiophen-2-yl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3n):

The resultant residue was purified by flash silica gel column chromatography to afford 3n as a yellow solid (32.4 mg, 80%); m.p. 156-158 °C; 1H NMR (400 MHz, CDCl3): 8.02 (s, 1H), 8.00-7.99 (m, 1H), 7.68-7.65 (m, 3H), 7.57-7.53 (m, 1H), 7.42 (dd, J = 5.1 Hz, 1.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.10-7.07 (m, 1H), 2.34 (s, 3H) 13C{H} NMR (100 MHz, CDCl3): δ178.0, 144.1, 141.5, 138.2, 134.7, 131.7, 129.5, 129.5, 128.7, 128.6, 127.3, 127.2, 127.0, 124.9, 124.3, 122.6, 111.4, 21.5. IR (KBr) 3132, 2921, 1719, 1683, 1616, 1503, 1304, 1146, 1083, 898, 813, 753, 718, 704, 537cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C22H16NO3S2 406.0566; found 406.0574.

6-chloro-1-(4-methoxyphenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3p):

The resultant residue was purified by flash silica gel column chromatography to afford 3p as a yellow solid (27.8 mg, 60%); m.p. 174-176 °C; 1H NMR (400 MHz, CDCl3): 7.91 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 1.3 Hz, 1H), 7.24 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 2.33 (s, 3H). 13

C{H} NMR (100 MHz, CDCl3): δ177.3, 160.6, 144.1, 142.7, 140.9, 138.4,


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131.5, 130.6, 130.5, 129.4, 129.0, 128.3, 127.3, 127.0, 125.7, 123.6, 121.0, 113.5, 112.3, 55.3, 21.5. IR (KBr) 3122, 2924, 1701, 1610, 1499, 1302, 1264, 1182, 1147, 914, 836, 803, 677, 621, 561cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C25H19ClNO4S 464.0718; found 464.0722.

6-fluoro-1-(4-methoxyphenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3q):

The resultant residue was purified by flash silica gel column chromatography to afford 3q as a yellow oil (31.3 mg, 70%); 1H NMR (400 MHz, CDCl3): 7.94 (s, 1H), 7.67-7.61 (m, 3H), 7.49 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.05 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 6.96-6.89 (m, 3H), 3.85 (s, 3H), 2.32 (s, 3H). 13

C{H} NMR (100 MHz, CDCl3): δ177.3, 166.8 (d, J = 255 Hz), 160.5, 144.0,

143.7, 143.6, 138.3, 131.5, 130.4, 130.2, 129.9, 129.4, 129.2, 127.3, 126.8, 126.7, 125.9, 123.6, 120.9, 113.7, 113.5, 100.5 (d, J = 28 Hz), 55.3, 21.5. IR (KBr) 3157, 2922, 1694, 1617, 1503, 1303, 1247, 1152, 1035, 939, 839, 797, 677, 617, 562cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C25H19FNO4S 448.1013; found 448.1019.

1-(4-methoxyphenyl)-6-methyl-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3r):

The resultant residue was purified by flash silica gel column chromatography to afford 3r as a yellow oil (27.0 mg, 61%); 1H NMR (400 MHz, CDCl3): 7.91 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.52-7.48 (m, 3H), 7.12-7.09 (m, 3H), 7.05 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.45 (s, 3H). 2.32 (s, 3H). 13

C{H} NMR (100 MHz, CDCl3): δ178.6, 160.3, 146.4, 143.8, 142.3, 138.6,



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131.5, 129.6, 129.4, 129.3, 129.1, 127.5, 127.4, 127.2, 124.7, 123.2, 121.3, 113.4, 112.0, 55.2, 22.3, 21.5. IR (KBr) 3123, 2919, 1698, 1614, 1503, 1303, 1261, 1183, 1150, 1082, 928, 837, 707, 613, 562cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C26H22NO4S 444.1264; found 444.1270.

1-(4-methoxyphenyl)-5-methyl-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3s):

The resultant residue was purified by flash silica gel column chromatography to afford 3s as a yellow oil (25.3 mg, 57%); 1H NMR (400 MHz, CDCl3): 8.00 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.52-7.48 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H), 2.60 (s, 3H), 2.32 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.9, 160.4,

143.8, 140.5, 138.6, 137.2, 131.5, 130.1, 129.6, 129.3, 128.4, 127.2, 126.8, 125.8, 123.3, 122.6, 121.1, 113.4, 55.3, 21.5, 17.8. IR (KBr) 3156, 2924, 1731, 1689, 1598, 1504, 1362, 1298, 1255, 1146, 1083, 925, 870, 762, 686, 578cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C26H22NO4S 444.1264; found 444.1269.

7-methoxy-1-(4-methoxyphenyl)-2-tosyl-9H-pyrrolo[1,2-a]indol-9-one (3t):

The resultant residue was purified by flash silica gel column chromatography to afford 3t as a yellow oil (19.3 mg, 42%); 1H NMR (400 MHz, CDCl3): 7.86 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 7.03 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.32 (s, 3H).

13

C{H}

NMR (100 MHz, CDCl3): δ178.5, 160.4, 158.9, 143.8, 138.7, 135.5, 131.5,


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131.2, 130.3, 129.3, 129.1, 128.9, 127.2, 123.4, 121.3, 120.2, 113.4, 112.2, 109.5, 56.0, 55.3, 21.5. IR (KBr) 3155, 2921, 1681, 1607, 1506, 1296, 1257, 1182, 1147, 1013, 970, 832, 801, 680, 553cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C26H21NO5SNa 482.1033; found 482.1037.

1-(4-methoxyphenyl)-2-(phenylsulfonyl)-9H-pyrrolo[1,2-a]indol-9-one (4a):

The resultant residue was purified by flash silica gel column chromatography to afford 4a as a yellow oil (23.7 mg, 57%); 1H NMR (400 MHz, CDCl3): 7.99 (s, 1H), 7.65-7.61 (m, 5H), 7.54 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.33-7.24 (m, 4H), 6.90 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H),

13

C{H} NMR (100

MHz, CDCl3): δ178.6, 160.4, 141.9, 141.3, 134.7, 132.9, 131.4, 130.0, 129.8, 129.2, 128.7, 127.2, 127.0, 124.8, 123.6, 121.1, 113.4, 111.4, 55.2. IR (KBr) 3125, 2934, 1698, 1617, 1504, 1307, 1253, 1148, 1083, 964, 899, 840, 762, 738, 617, 554cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H18NO4S 416.0951; found 416.0957.

1-(4-methoxyphenyl)-2-(o-tolylsulfonyl)-9H-pyrrolo[1,2-a]indol-9-one (4b):

The resultant residue was purified by flash silica gel column chromatography to afford 4b as a yellow oil (28.7 mg, 67%); 1H NMR (400 MHz, CDCl3): 7.99 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.55-7.52 (m, 3H), 7.35-7.32 (m, 1H), 7.30 (d, J = 4.2 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.13 (d, J



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= 7.5 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 2.49 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.6, 160.3, 141.9, 138.5,

137.2, 134.7, 133.2, 132.2, 131.2, 130.0, 129.8, 129.7, 129.1, 128.5, 128.5, 126.9, 125.8, 124.9, 123.9, 120.9, 113.3, 111.4, 55.2, 20.0. IR (KBr) 3117, 2930, 1698, 1619, 1502, 1301, 1251, 1180, 1149, 967, 899, 835, 733, 621, 556cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H19NO4SNa 452.0927; found 452.0930.

1-(4-methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)-9H-pyrrolo[1,2-a]ind ol-9-one (4c):

The resultant residue was purified by flash silica gel column chromatography to afford 4c as a yellow solid (30.7 mg, 69%); m.p. 156-158 °C; 1H NMR (400 MHz, CDCl3): 7.93 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 7.4 Hz, 1H), 7.55-7.51 (m, 3H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 3.77 (s, 3H).

13

C{H} NMR

(100 MHz, CDCl3): δ178.7, 163.1, 160.4, 141.9, 134.6, 133.0, 131.5, 130.1, 129.9, 129.8, 129.5, 128.7, 126.8, 124.8, 123.2, 121.3, 113.9, 113.4, 111.3, 55.5, 55.2. IR (KBr) 3150, 2838, 1691, 1619, 1597, 1504, 1337, 1296, 1180, 1024, 966, 900, 837, 757, 676, 620, 559cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H19NO5SNa 468.0876; found 468.0884.

2-((4-isopropylphenyl)sulfonyl)-1-(4-methoxyphenyl)-9H-pyrrolo[1,2-a]in dol-9-one (4d):


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The resultant residue was purified by flash silica gel column chromatography to afford 4d as a yellow oil (26.0 mg, 57%); 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.66-7.62 (m, 3H), 7.54-7.51 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.90-2.83 (m, 1H), 1.17 (d, J = 6.9 Hz, 6H).

13


δ178.6, 160.4, 154.5, 141.9, 138.7, 134.6, 131.5, 130.0, 129.8, 129.8, 128.7, 127.4, 126.8, 126.8, 124.8, 123.4, 121.2, 113.4, 111.3, 55.2, 34.0, 23.5. IR (KBr) 3118, 2961, 1698, 1619, 1502, 1306, 1250, 1149, 1084, 900, 833, 733, 659, 610, 564cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C27H24NO4S 458.1421; found 458.1429.

2-((4-fluorophenyl)sulfonyl)-1-(4-methoxyphenyl)-9H-pyrrolo[1,2-a]indol9-one (4e):

The resultant residue was purified by flash silica gel column chromatography to afford 4e as a yellow oil (22.1 mg, 51%); 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.66-7.53 (m, 6H), 7.34-7.25 (m, 2H), 6.96 (t, J = 8.5 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ178.6, 165.2 (d, J = 254 Hz), 160.5, 141.9, 137.4, 137.3, 134.7, 131.4, 130.1, 130.0, 129.8, 129.8, 129.3, 128.8, 127.0, 124.9, 123.3, 121.0, 116.0, 115.8, 113.5, 111.4, 55.3. IR (KBr) 3122, 2926, 1708, 1619, 1590, 1504, 1289, 1269, 1145, 1081, 900, 830, 731, 678, 620, 539cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17FNO4S 434.0857; found 434.0863.



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2-((4-chlorophenyl)sulfonyl)-1-(4-methoxyphenyl)-9H-pyrrolo[1,2-a]indol9-one (4f):

The resultant residue was purified by flash silica gel column chromatography to afford 4f as a yellow solid (32.3 mg, 72%); m.p. 176-178 °C; 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.66-7.63 (m, 3H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.31 (t, J = 7.8 Hz, 3H), 7.26 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 13C{H} NMR (100 MHz, CDCl3): δ178.6, 160.5, 141.9, 139.9, 139.6, 134.7, 131.5, 129.9, 129.8, 129.0, 128.8, 128.7, 127.1, 124.9, 123.5, 120.9, 113.5, 111.4, 55.3. IR (KBr) 3120, 2928, 1700, 1619, 1503, 1307, 1251, 1147, 1085, 900, 833, 759, 643, 556, 476cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17ClNO4S 450.0561; found 450.0568.

2-((4-bromophenyl)sulfonyl)-1-(4-methoxyphenyl)-9H-pyrrolo[1,2-a]indol9-one (4g):

The resultant residue was purified by flash silica gel column chromatography to afford 4g as a yellow oil (31.0 mg, 63%); 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.65-7.63 (m, 3H), 7.55 (t, J = 7.6 Hz, 1H), 7.43 (s, 4H), 7.32 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 15 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H).

13

C{H}

NMR (100 MHz, CDCl3): δ178.6, 160.5, 141.8, 140.4, 134.7, 131.9, 131.4, 129.9, 129.8, 128.8, 128.8, 128.7, 128.1, 127.0, 124.9, 123.5, 120.9, 113.5, 111.4, 55.3. IR (KBr) 3119, 2928, 1708, 1619, 1503, 1305, 1251, 1144, 1080,


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1008, 900, 749, 637, 619, 555cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17BrNO4S 494.0056; found 494.0061.

1-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)sulfonyl)-9H-pyrrolo[1, 2-a]indol-9-one (4h):

The resultant residue was purified by flash silica gel column chromatography to afford 4h as a yellow solid (27.0 mg, 56%); m.p. 158-160 °C; 1H NMR (400 MHz, CDCl3): 7.99 (s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.0 Hz, 3H), 7.34 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H),

13

C{H} NMR (100

MHz, CDCl3): δ178.5, 160.6, 144.9, 141.8, 134.8, 134.7, 134.3, 131.5, 129.9, 129.8, 128.9, 128.3, 128.1, 127.7, 127.2, 125.8 (d, J = 4 Hz), 125.0, 123.7, 121.7, 120.8, 113.6, 111.5, 55.3. IR (KBr) 3127, 2926, 1709, 1619, 1504, 1322, 1147, 1062, 900, 837, 733, 639, 622, 552, 421cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C25H17F3NO4S 484.0825; found 484.0834.

1-(4-methoxyphenyl)-2-((4-nitrophenyl)sulfonyl)-9H-pyrrolo[1,2-a]indol-9one (4i):

The resultant residue was purified by flash silica gel column chromatography to afford 4i as a yellow oil (16.1 mg, 35%); 1H NMR (400 MHz, CDCl3): 8.12 (d, J = 8.8 Hz, 2H), 8.00 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.4 Hz, 1H), 7.63-7.57 (m, 3H), 7.36 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ178.5, 160.7, 150.1,



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

147.0, 141.8, 134.9, 131.5, 129.9, 129.8, 129.0, 128.5, 127.8, 127.4, 125.1, 123.9, 123.8, 120.6, 113.7, 111.5, 55.3. IR (KBr) 3112, 2923, 1722, 1702, 1605, 1512, 1351, 1301, 1253, 1146, 1083, 899, 747, 683, 639cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C24H17N2O6S 461.0802; found 461.0805.

1-(4-methoxyphenyl)-2-(naphthalen-2-ylsulfonyl)-9H-pyrrolo[1,2-a]indol-9 -one (4j):

The resultant residue was purified by flash silica gel column chromatography to afford 4j as a yellow solid (32.1 mg, 69%); m.p. 158-160 °C; 1H NMR (400 MHz, CDCl3): 8.11 (s, 1H), 8.01 (s, 1H), 7.79-7.70 (m, 3H), 7.62-7.57 (m, 5H), 7.55-7.49 (m, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.6, 160.4,

141.9, 138.0, 134.8, 134.7, 131.8, 131.4, 130.0, 129.8, 129.5, 129.2, 129.1, 129.0, 128.9, 128.7, 127.7, 127.3, 126.9, 124.8, 123.5, 122.1, 121.1, 113.4, 111.4, 55.2. IR (KBr) 3121, 2926, 1688, 1619, 1504, 1300, 1253, 1145, 1119, 1089, 901, 815, 756, 671, 557cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C28H20NO4S 466.1108; found 466.1119.

1-(4-methoxyphenyl)-2-(thiophen-2-ylsulfonyl)-9H-pyrrolo[1,2-a]indol-9-o ne (4k):

The resultant residue was purified by flash silica gel column chromatography to afford 4k as a yellow oil (21.9 mg, 52%); 1H NMR (400 MHz, CDCl3): 7.95 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.60-7.51 (m, 2H), 7.49


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(dd, J = 5.0 Hz, 1.2 Hz, 1H), 7.33-7.28 (m, 3H), 6.96-6.93 (m, 2H), 6.89-6.87 (m, 1H), 3.87 (s, 3H).

13

C{H} NMR (100 MHz, CDCl3): δ178.7, 160.5, 142.8,

141.9, 134.7, 133.3, 133.1, 131.6, 130.0, 129.9, 128.7, 127.2, 127.0, 124.9, 123.2, 121.1, 113.5, 111.4, 55.3. IR (KBr) 3126, 2923, 1708, 1617, 1551, 1488, 1306, 1250, 1145, 1041, 899, 828, 677, 622, 568cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C22H16NO4S2 422.0515; found 422.0519.

Supporting Information X-ray single crystal diffraction data of 3a, Labeling experiment, 1H and

13

C

NMR spectra of the products, and a CIF file. This material is available free of charge via the Internet at http://pubs.acs.org Acknowledgements We thank the National Science Foundation (NSF 21472073 and 21532001). We also thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript. Notes and references (1) (a) Diana, P.; Stagno, A.; Barraja, P.; Montalbano, A.; Carbone, A.; Parrino, B.; Cirrincione, G. Tetrahedron 2011, 67, 3374. (b) Grande, F.; Yamada, R.; Cao, X.; Aiello, F.; Garofalo, A.; Neamati, N. Expert Opin. Investig. Drug 2009, 18, 555. (c) Lisowski, V.; Léonce, S.; Kraus-Berthier, L.; Sopková-de Oliveira Santos, J.; Pierré, A.; Atassi, G.; Caignard, D.-H.; Renard, P.; Rault, S. J. Med. Chem. 2004, 47, 1448. (d)Sugihara, H.; Matsumoto, N.; Hamuro, Y.; Kawamatsu, Y. Arzneim.-Forsch. 1974, 24, 1560.



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