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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2010 September 4.
Published in final edited form as:
PMCID: PMC2735226
NIHMSID: NIHMS137744

Synthesis of 3-Sulfenyl- and 3-Selenylindoles by the Pd/Cu-Catalyzed Coupling of N,N-Dialkyl-2-iodoanilines and Terminal Alkynes, Followed by n-Bu4NI-Induced Electrophilic Cyclization

Abstract

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3-Sulfenyl- and 3-selenylindoles are readily synthesized by a two-step process involving the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-ortho-iodoanilines and terminal alkynes and subsequent electrophilic cyclization of the resulting N,N-dialkyl-ortho-(1-alkynyl)anilines with arylsulfenyl chlorides or arylselenyl chlorides. The presence of a stoichiometric amount of n-Bu4NI is crucial to the success of the electrophilic cyclization. A variety of 3-sulfenyl- and 3-selenylindole derivatives bearing alkyl, vinylic, aryl, and heteroaryl substituents have been prepared in good to excellent yields (up to 99%). By employing N,N-dibenzyl-ortho-iodoanilines, a 3-sulfenyl-N-H-indole has been successfully prepared. In addition, 3-sulfonyl- and 3-sulfinylindoles have also been successfully prepared by facile oxidation of the corresponding 3-sulfenylindoles.

Introduction

The indole ring is present in a wide variety of biologically active compounds and pharmaceutical agents.1 Among the numerous indole derivatives known, 3-thioindoles have recently attracted considerable attention from both industry and academia due to their therapeutic value in a variety of diseases, such as HIV,2 cancer,3 obesity,4 heart disease,5 and allergies.6 For instance, MK-886 is an inhibitor of 5-lipoxygenase and can augment the antitumor activity of celecoxib in human colorectal cancer.7 L-737,126 is known to exhibit potent anti-HIV properties,8 and the 3-(arylsulfenyl)indole 1 is not only an inhibitor of tubulin polymerization, but also capable of inhibiting human breast cancer cell growth.9

Because of their therapeutic potential, there has been growing interest in developing a general and versatile synthetic route to 3-thioindole derivatives. As a consequence, a number of synthetic approaches to 3-sulfenylindoles have been developed in the past few years, including the direct sulfenylation of indoles by disulfides10 or quinone mono-O,S-acetals;11 halide-catalyzed sulfenylation by N-thioalkyl(aryl)phthalimides;12 sulfenylation using thiols activated in situ by N-chlorosuccinimide,13 phenyliodine(III) bis(trifluoroacetate),14 Selectfluor,15 or transition-metal catalysts;16 oxidant-promoted thiocyanation with ammonium thiocyanate;17 and treatment of 3,3’-dithiobisindoles with metalated aromatics or heterocycles.18 In general, all these protocols have focused on direct sulfenylation at the 3-position of the indole nucleus by different sulfenylating agents.

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Recently, our group and others have reported the synthesis of a wide range of carbocyclic and heterocyclic compounds by electrophilic cyclization.19 In the presence of halogen, sulfur and selenium electrophiles, a wide variety of functionally-substituted alkynes undergo electrophilic cyclization to form the corresponding heterocyclic and carbocyclic compounds, including indoles,20 benzofurans,21 benzothiophenes,22 benzoselenophenes,23 benzopyrans,24 furans,25 naphthols,26 naphthalenes,27 isoindolinones,28 coumestans and coumestrols,29 chromones,30 isocoumarins and α-pyrones,31 isochromenes,32 isoquinolines,33 quinolines,34 isoxazoles,35 polycyclic aromatics,36 pyrroles,37 furopyridines,38 furanones,39 and spiro[4,5]trienones.40

Although we had successfully prepared 3-sulfenyl-benzofurans21a and -benzothiophenes22b,c by electrophilic cyclization using arylsulfenyl chlorides as the electrophile, our early attempts to prepare 3-sulfenylindoles using similar methods were unsuccessful. The pharmaceutical interest in 3-sulfenylindoles, however, inspired us to explore this approach further. Our preliminary results have shown that in the presence of one equiv of n-Bu4NI, 3-sulfenylindoles can be successfully prepared under standard electrophilic cyclization conditions.41 Herein, we report our detailed results on the synthesis of 3-sulfenylindoles using this n-Bu4NI-induced electrophilic sulfur cyclization chemistry.

Results and Discussion

The required starting material, N,N-dialkyl-2-(1-alkynyl)anilines (3), are readily prepared by the Sonogashira coupling42 of N,N-dialkyl-ortho-iodoanilines (2)43 and terminal alkynes. The results of this palladium/copper-catalyzed coupling process are summarized in Table 1. In general, this coupling reaction takes place smoothly between a variety of functionalized N,N-dialkyl-ortho-iodoanilines and terminal alkynes, affording high to excellent yields. A longer reaction time was required when electron-deficient 4-ethynylbenzonitrile was employed (Table 1, entries 11 and 12). Although it was found that the reaction rate in these cases could be significantly accelerated by means of either heating or adding a polar solvent, such as DMF, it is preferred that these reactions be carried out in Et3N at room temperature to avoid the generation of cyclized indole by-products.

TABLE 1
Preparation of N,N-Dialkyl-2-(1-alkynyl)anilines by Sonogashira Couplinga

Alkyne 3u was prepared from N,N-dimethyl-2-iodoaniline (2a) by a three-step reaction sequence, namely Sonogashira coupling, removal of the TMS group, and a second Sonogashira coupling (Scheme 1).

SCHEME 1
Preparation of Intermediate Alkyne 3u

Our initial results indicated that under common electrophilic cyclization conditions, the reaction between N,N-dimethyl-(2-phenylethynyl)aniline (3a) and 4-nitrobenzenesulfenyl chloride leads exclusively to the simple triple bond addition products 4 (Scheme 2).44 Our previous experience on the electrophilic cyclization chemistry of functionally-substituted alkynes suggested that the successful cyclization reactions generally proceed by a stepwise mechanism involving electrophilic activation of the alkyne C-C triple bond, intramolecular nucleophilic attack on the cationic intermediate and subsequent dealkylation by the in situ generated halide anion.45 Based on this assumption and careful mechanism analysis, we envisioned that the failure in this electrophilic sulfur cyclization chemistry could be attributed to the relatively weak nucleophilicity of the in situ generated chloride anion, which should play a significant role in removal of the alkyl group after the intramolecular nucleophilic cyclization step had taken place. Thus, the nature of the halide might seriously impact indole ring construction. It is known that iodide anion is a better nucleophile than chloride anion due to its greater polarizability. For this reason, one equiv of n-Bu4NI was added to the reaction of 3a and p-O2NC6H4SCl as an external source of nucleophile. To our delight, in the presence of one equiv of n-Bu4NI, the triple bond addition reaction was completely shut down and the reaction slowly produced solely the desired cyclization product 5aa (Table 2, entry 1).

SCHEME 2
Reaction between 3a and 4-Nitrobenzenesulfenyl Chloride under Standard Electrophilic Cyclization Conditions
TABLE 2
n-Bu4NI-Induced Electrophilic Cyclization of N,N-Dimethyl-(2-phenylethynyl)aniline with 4-Nitrobenzenesulfenyl Chloridea

Our further study has revealed that this cyclization reaction can be substantially accelerated at an elevated temperature. Therefore, several higher boiling solvents were examined. When the reaction is run at 70 °C in dichloroethane (DCE), instead of room temperature in dichloromethane (DCM), a 90% yield of the desired 3-(arylsulfenyl)indole 5aa was obtained in 5 h (Table 2, entry 2). An 81% yield was obtained when CH3CN was employed (Table 2, entry 3). On the other hand, only a 13% yield of the desired indole product was obtained when the cyclization was carried out in toluene at 70 °C (Table 2, entry 4).

The role of the additive, n-Bu4NI, was then investigated. None of the desired indole product was observed when either one equiv of n-Bu4NCl or n-Bu4NBr was employed (Table 2, entries 5 and 6) Indole 5aa was generated only in trace amounts when n-Bu4NI was replaced by LiI (Table 2, entry 7), possibly due to the extremely low solubility of the latter in DCE. An equimolar amount of n-Bu4NI is found necessary for exclusive formation of the cyclization product. When 0.5 equiv of n-Bu4NI is used, a mixture of both indole 5aa and the triple bond addition products 4 is obtained in approximately a 1:1 ratio (Table 2, entry 8). An incomplete reaction was observed after 5 h when the electrophile 4-nitrobenzenesulfenyl chloride was reduced from 2.0 to 1.5 equiv (Table 2, entry 9).

The reaction scope was then explored under the optimal reaction conditions (Table 2, entry 2). This cyclization has proved to be a very general route to a variety of 3-sulfenylindoles (Table 3). Besides 4-nitrobenzenesulfenyl chloride, several other arylsulfenyl chlorides have also been successfully employed as electrophiles in this cyclization. When electron-deficient pentafluorobenzenesulfenyl chloride was employed, an 87% isolated yield of the corresponding indole was obtained (Table 3, entry 2). The more electron-rich arylsulfenyl chlorides phenylsulfenyl chloride and p-toluenesulfenyl chloride afforded similar high yields (Table 3, entries 3 and 4). When the more sterically demanding 2-nitrobenzenesulfenyl chloride was used, the yield of the cyclization product 5ae decreased to 52% (Table 3, entry 5), although the starting material 3a was completely consumed. Products of simple addition of the 2-nitrobenzenesulfenyl chloride to the triple bond of 3a were also observed. Besides arylsulfenyl chlorides, an alkylsulfenyl chloride, trichloromethylsulfenyl chloride, has also been employed in this cyclization. However, this reagent only afforded a complex reaction mixture using our current optimized reaction conditions.

TABLE 3
Preparation of 3-Sulfenyl- and 3-Selenylindoles by n-Bu4NI-Induced Electrophilic Cyclizationa

Despite our previous lack of success with the synthesis of 3-selenylindoles via analogous electrophilic cyclization chemistry,20a the cyclization of aniline 3a by PhSeCl plus n-Bu4NI was investigated. We were quite pleased to find that our current reaction conditions were equally suitable for the synthesis of 3-selenylindoles (Table 3, entry 6).

The electronic effect of the substituents on the aniline moiety in this electrophilic cyclization process has also been investigated. It turns out that this process is not particularly sensitive to the electronic effects of the aniline moiety, which is in good agreement with our previous experience with this type of electrophilic cyclization reaction, although the presence of a strong electron-withdrawing group on the aniline ring can significantly reduce the nucleophilicity of the dialkylamino group.20a,b Thus, this cyclization proceeds nicely in the presence of either electron-withdrawing or electron-releasing groups (Table 3, entries 7–11). In all cases examined, high yields have been obtained with reaction times similar to those of the parent system 3a.

Besides 2-(phenylethynyl)anilines, other 2-(alkynyl)anilines have also been successfully employed in this process (Table 3, entries 12–32). In contrast to the effect of substituents on the aniline moiety, the substituents on the 2-alkynyl moiety display a significant electronic effect on this cyclization process. In general, the reaction is accelerated by the presence of electron-rich groups situated at the distal end of the 2-alkynyl triple bond, such as a 4-(N,N-dimethylamino)phenyl group (Table 3, entries 18 and 19), a thiophene ring (Table 3, entries 23–25), and a 4-methoxyphenyl group (Table 3, entries 31 and 32). The same high reaction rate was observed, when a vinylic moiety, such as a 1-cyclohexenyl group, was present on the distal end of the triple bond (Table 3, entry 26). In this case, no product of addition of the 4-nitrobenzenesulfenyl chloride to the carbon-carbon double bond of the 1-cyclohexenyl moiety was observed, although such an addition reaction has previously been reported.46 The same alkyne substrate 3o also undergoes cyclization smoothly in the presence of a selenium electrophile leading to the corresponding 3-selenylindole in a 76% yield (Table 3, entry 27). The cyclization process was, however, significantly slowed by the presence of electron-withdrawing groups. When an ethoxycarbonyl group is situated at the para-position of the aryl group on the distal end of the alkyne triple bond, the cyclization takes as long as 18 h (Table 3, entry 20) affording product 5at in a 66% yield. The effect is even more pronounced when the stronger electron-withdrawing cyano group is present (Table 3, entries 21 and 22). These cyclizations take more than 50 h and only afford modest yields (<50%) of the desired indole products. In both cases, a significant amount of the simple triple bond addition products are obtained.

We have previously shown that ortho-methoxyaryl alkynes undergo electrophilic cyclization in the presence of an arylsulfenyl chloride, without the addition of n-Bu4NI, to form 3-sulfenylbenzofurans.21a We therefore investigated the reactivity of substrates 3p and 3q under our current cyclization conditions (Table 3, entries 28–30). Note that this alkyne contains an ortho-methoxyphenyl group at one end of the ethynyl functionality and an ortho-(N,N-dimethylamino)phenyl group at the other end. Thus, two cyclization paths are possible, leading to the formation of an indole, a benzofuran or possibly a mixture of both. In practice, the 3-sulfenylindoles 5bb, 5bc, and 5bd were generated exclusively with no benzofuran products being observed.

Substrate 3r containing both a methyl and a phenyl group on the aniline nitrogen was also studied in this cyclization. As expected, the N-phenylindoles 5be and 5bf were produced exclusively in essentially quantitative yields (Table 3, entries 31 and 32).

The bromine atom present on the aniline ring of the starting internal alkynes 3c, 3g, 3i, 3j, 3l, 3n, and 3q (Table 3), has proved to be an ideal handle for further chemical elaborations by palladium-catalyzed coupling processes, after the cyclization, allowing the efficacious synthesis of a wide variety of substituted 3-thioindoles. Besides sulfenyl chlorides, sulfonyl chlorides and sulfinyl chlorides have also been examined in the current cyclization chemistry. However, none of the desired 3-substituted indole products were observed.

In order to prepare free N-H 3-thioindoles, we employed 4-bromo-2-iodoaniline bearing two benzyl groups on the aniline nitrogen in this cyclization (Scheme 3). The dibenzylated compound 2g was converted to the internal alkyne 3v by Sonogashira coupling in the presence of 2 mol % of Pd(PPh3)4 and 2 mol % of CuI.47 Subsequent electrophilic cyclization took place smoothly under our optimal reaction conditions, affording the N-benzylated indole 5bg in a 71% yield. The latter product was readily converted to the corresponding N-H 3-sulfenylindole 6 by employing Deaton-Rewolinski’s debenzylation conditions.48

SCHEME 3
Preparation of an N-H 3-Sulfenylindole

Although our attempts to prepare 3-sulfonyl- and 3-sulfinylindoles by direct sulfonyl chloride and sulfinyl chloride cyclization chemistry were not successful, these compounds were readily synthesized by simply oxidizing the corresponding 3-sulfenylindoles. Thus, 3-sulfonylindole 7 and 3-sulfinylindole 8 have been successfully prepared in 83% and 91% yields, respectively (Scheme 4).

SCHEME 4
Oxidation of a 3-Sulfenylindole

Based on our previous experience with this type of electrophilic cyclization chemistry, we believe that the current process involves an anti addition of the sulfur electrophile and the nitrogen moiety of the aniline to the alkyne triple bond to form a transient 3-sulfenylindolium salt 10 by a thiirenium intermediate 9 (Scheme 5, path b). In the presence of n-Bu4NI, 10 undergoes methyl group removal via SN2 displacement by the external iodide to complete indole ring construction after the loss of one molecule of MeI, which is possibly the driving force to shift the equilibrium from the thiirenium species 9 to the indolium intermediate 10. In the absence of n-Bu4NI, the harder counter ion chloride is less nucleophilic and prefers trans addition to the thiirenium intermediate to form the undesired olefin product (Scheme 5, path a). However, our attempts to detect MeI and the indolium intermediate 1049 by 1H NMR spectroscopy in a reaction between 3a and 4-nitrobenzenesulfenyl chloride have been unsuccessful. These experiments have clearly shown the conversion of the starting materials to the desired 3-sulfenylindole product, but nothing else.50 In addition, we have also prepared 1-[2-(phenylethynyl)phenyl]pyrrolidine and examined its cyclization in the hope of obtaining the corresponding 3-sulfenylindole with a 4-iodobutyl chain attached to the nitrogen atom. Unfortunately, this reaction only afforded a complex reaction mixture with none of the desired indole product detected.

SCHEME 5
Proposed Mechanism and Plausible Effect of n-Bu4NI on the Electrophilic Cyclization

We cannot rule out activation of the arylsulfenyl chloride by n-Bu4NI through halogen exchange to form the corresponding arylsulfenyl iodide (ArSI) as the real electrophile.51 In the presence of the softer counter ion iodide, the intramolecular cyclization (Scheme 5, path b) may take place much faster than addition to the triple bond (Scheme 5, path a), thus leading to the indole product.

The success of this cyclization reaction presumably relies on two factors, the presence of the two organic groups on the aniline nitrogen atom and the one equivalent of n-Bu4NI. In general, delocalization of the lone-pair of electrons on the aniline nitrogen into the aromatic ring π electron system through orbital overlap dramatically decreases its basicity and nucleophilicity. However, the steric bulkiness of the two organic groups on the nitrogen and the ortho-substituted internal triple bond forces rotation of the aromatic C-N bond and reduces this orbital overlap, resulting in considerable enhancement of the nitrogen nucleophilicity. Inductive electron donation by the two organic groups on nitrogen also raises the nitrogen nucleophilicity. This hypothesis has been proved by our experimental data. No cyclization product was obtained when either the free ortho-amino (NH2) containing alkyne or the ortho-N-monomethylamino (MeNH) containing alkyne analogue of 3a was employed. In addition, the Boc-protected ortho-amino (NHBoc) containing alkyne analogue of 3a has also been examined in this cyclization. However, no cyclized product was observed at all. With respect to n-Bu4NI, it presumably provides the highly nucleophilic iodide ions needed to remove the methyl group from the indolium intermediate 10 and thus facilitates construction of the indole nucleus.

Conclusions

A synthetic approach to 3-sulfenylindoles and 3-selenylindoles by the n-Bu4NI-induced electrophilic cyclization of N,N-dialkyl-2-(1-alkynyl)anilines by arylsulfenyl chlorides or arylselenyl chlorides has been described. A wide variety of N,N-dialkyl-2-(1-alkynyl)anilines undergo this cyclization process in good to excellent yields. Free N-H 3-thioindoles have been successfully prepared using the present method and employing benzyl protecting groups. In addition, the 3-sulfenylindoles synthesized are readily converted to the corresponding 3-sulfonyl- and 3-sulfinylindoles by oxidation. A plausible mechanism for this cyclization has been proposed and the role of n-Bu4NI has been discussed. This synthetic approach allows simultaneous construction of the indole ring system and the installation of a sulfenyl or selenyl functionality at the 3-position of the indole nucleus, and is a useful complement to the known literature protocols for preparing 3-sulfenyl- and 3-selenylindoles.

Experimental Section

General procedure for preparation of the N,N-dimethyl-o-iodoanilines

These compounds were prepared according to a procedure reported by Cadogan.52 To a solution of the corresponding o-iodoaniline (2.0 mmol) and iodomethane (0.85 g, 6.0 mmol) in DMF (10 mL) was added K2CO3 (0.55 g, 4.0 mmol). The resulting mixture was stirred at room temperature for 48 h. Water (10 mL) was added to the reaction mixture. The resulting solution was extracted with diethyl ether (3 × 10 mL). The organic layers were combined and washed with water to remove any remaining DMF and dried over anhydrous MgSO4. The solvent was removed under vaccum and the residue was purified by flash column chromatography on silica gel using ethyl acetate/hexanes as the eluent.

N,N-Dimethyl-4-bromo-2-iodoaniline (2c)

This compound was obtained as a light red oil in an 81% yield: 1H NMR (400 MHz, CDCl3) δ 2.72 (s, 6H), 6.92 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.5, 2.4 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 45.0, 97.6, 116.4, 121.5, 132.0, 142.0, 154.3; HRMS (EI) calcd for C8H9BrIN 324.8963, found 324.8969.

General procedure for preparation of the N,N-dialkyl-2-(1-alkynyl)anilines

To a 4-dram oven-dried vial was added PdCl2(PPh3)2 (18.3 mg, 0.026 mmol), CuI (3.8 mg, 0.020 mmol), 2.0 mmol of the N,N-dialkyl-o-iodoaniline, 2.2 mmol of the terminal acetylene and 6 mL of Et3N. The resulting mixture was flushed with Ar and stirred at room temperature for the desired time. The reaction mixture was diluted with 15 mL of diethyl ether and washed with brine (15 mL). The aqueous phase was then extracted with diethyl ether (2 × 10 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to afford the crude product, which was purified by flash column chromatography on silica gel using ethyl acetate/hexanes as the eluent.

N,N-Dimethyl-4-bromo-2-(phenylethynyl)aniline (3c)

This compound was obtained as a light yellow oil in a 76% yield: 1H NMR (400 MHz, CDCl3) δ 2.98 (s, 6H), 6.78 (d, J = 8.8 Hz, 1H), 7.31–7.37 (m, 4H), 7.51–7.54 (m, 2H), 7.59 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 43.4, 87.7, 95.9, 112.1, 116.7, 118.5, 123.4, 128.4, 128.5, 131.4, 132.0, 136.4, 153.7; HRMS (EI) calcd for C16H14BrN 299.0310, found 299.0314.

General procedure for preparation of the 3-sulfenyl- and 3-selenylindoles

To a solution of 0.50 mmol of the N,N-dialkyl-2-(1-alkynyl)aniline, 0.50 mmol of n-Bu4NI and 3 mL of 1,2-dichloroethane (DCE) was gradually added a solution of 1.00 mmol of arylsulfenyl or arylselenyl chloride in 2 mL of DCE. The resulting mixture was stirred at room temperature for 5 min and then heated to 70 °C for the desired time. The reaction mixture was cooled to room temperature and diluted with 5 mL of dichloromethane (DCM). The mixture was then washed with 10 mL of satd aq NH4Cl. The aqueous phase was extracted with diethyl ether (2 × 5 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to yield the crude product, which was purified by flash column chromatography on silica gel using either ethyl acetate/hexanes or chloroform/hexanes as the eluent.

1-Benzyl-5-bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)indole (5bg)

This product was obtained as a white solid in a 71% yield: mp 161–163 °C; 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 5.34 (s, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 7.0 Hz, 2H), 7.04–7.12 (m, 4H), 7.19 (t, J = 7.4 Hz, 2H), 7.25–7.30 (m, 6H), 7.80 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 48.7, 55.5, 99.9, 112.5, 114.1, 114.8, 122.1, 122.4, 124.8, 125.6, 125.96, 126.04, 127.7, 129.0, 129.1, 131.8, 132.1, 135.9, 137.3, 139.6, 147.5, 160.4; HRMS (EI) calcd for C28H22BrNOS 499.0605, found 499.0616.

5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)indole (6)

This compound was prepared according to a procedure reported by Deaton-Rewolinski.48 A solution of 5bg (220 mg, 0.44 mmol) and KO-t-Bu (345 mg, 3.08 mmol) in DMSO (5 mL) was purged with O2 at room temperature for 20 min. The reaction mixture was vigorous stirred at 80 °C for 8 h. The resulting mixture was diluted with EtOAc (10 mL) and washed with water (15 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to afford the crude product, which was purified by flash column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the corresponding product 6 in an 84% yield as a yellow oil, which solidified to a yellow solid upon standing: mp 154–155 °C; 1H NMR (400 MHz, CDCl3) δ 3.81 (s, 3H), 6.94 (d, J = 8.8 Hz, 2H), 7.02–7.09 (m, 3H), 7.14–7.21 (m, 2H), 7.23–7.34 (m, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H), 8.50 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.6, 98.3, 112.7, 114.5, 114.7, 122.4, 123.5, 125.0, 125.6, 126.2, 129.1, 129.6, 133.5, 134.5, 139.1, 143.6, 160.4; HRMS (EI) calcd for C21H16BrNOS 409.0136, found 409.0148.

5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfonyl)indole (7)

This compound was prepared according to a procedure reported by Shaabani.53 5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)indole (6) (0.195 mmol, 80 mg) were dissolved in CH2Cl2 (1.0 mL) and CH3CN (1.0 mL). To the reaction mixture was added finely ground KMnO4/MnO2 (0.40 g) in portions over a period of 10 min. The mixture was stirred vigorously at room temperature, while the progress of the reaction was monitored by TLC. Upon completion of the reaction, the product was filtered through a sintered glass funnel to remove the solid precipitate. The product (in solution) was then filtered through a celite pad and the solid residue was washed with CH2Cl2 (2 × 3 mL). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the corresponding product 7 as a brown oil in an 83% yield: 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 6.48 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.8 Hz, 2H), 6.93 (t, J = 7.6 Hz, 2H), 7.02–7.14 (m, 4H), 7.79 (d, J = 8.8 Hz, 2H), 8.32 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.6, 112.7, 118.6, 121.29, 121.31, 126.2, 128.2, 128.7, 129.8, 130.6, 131.0, 132.1, 136.1, 139.3, 152.4, 161.4, 175.1; HRMS (EI) calcd for C21H16BrNO3S 441.0034, found 441.0044.

5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfinyl)indole (8)

This compound was prepared according to a modification of a procedure reported by Xu.54 To a solution of 5-bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)indole (6) (80 mg, 0.195 mmol) and phenol (183.5 mg, 1.95 mmol) in HFIP (2.0 mL) was added 30% H2O2 (0.05 mL, 0.4 mmol). The reaction mixture was stirred at room temperature for 5 h. After complete disappearance of the reactant as monitored by TLC, the excess H2O2 was quenched with satd aq Na2SO3. Phenol was neutralized with 10% aq NaOH. The aqueous layer was extracted with EtOAc (2 × 3 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to afford the crude product, which was purified by flash column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the corresponding product 8 as a yellow oil in a 91% yield, which solidified to a yellow solid upon standing: mp 112–114 °C; 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 6.42 (d, J = 8.6 Hz, 2H), 6.92–7.05 (m, 2H), 7.03 (d, J = 8.6 Hz, 2H), 7.45–7.55 (m, 3H), 7.63–7.72 (m, 2H), 11.22 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.6, 109.6, 114.0, 114.4, 114.5, 121.4, 122.2, 125.5, 126.1, 126.5, 129.4, 130.5, 130.6, 135.4, 142.9, 146.5, 160.9; HRMS (EI) calcd for C21H16BrNO2S 425.0085, found 425.0089.

Supplementary Material

1_si_001

Acknowledgment

We thank the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Center of Excellence for Chemical Methodologies and Library Development (P50 GM069663) for financial support of this project. We also thank Johnson Matthey, Inc. and Kawaken Fine Chemicals Co., Ltd. for donations of palladium catalysts.

Footnotes

Supporting Information Available: Experimental procedures, characterization data for the new compounds and copies of 1H, 13C, and 19F NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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