292 Vol. 61, No. 3Chem. Pharm. Bull. 61(3) 292–303 (2013)

© 2013 The Pharmaceutical Society of Japan

A Practical Regioselective Synthesis of Alkylthio- or Arylthioindoles without the Use of Smelly Compounds Such as ThiolsToshihiko Hamashima,a Yoshiaki Mori,a Kazunori Sawada,a Yuko Kasahara,a Daisuke Murayama,a Yuto Kamei,b Hiroaki Okuno,a Yuusaku Yokoyama,a and Hideharu Suzuki*,a

a Faculty of Pharmaceutical Sciences, Toho University; Chiba 274–8510, Japan: and b Coastal Bioenvironment Center, Saga University; Saga 847–0021, Japan.Received October 8, 2012; accepted November 24, 2012; advance publication released online December 6, 2012

A convenient method for the synthesis of 3-methylthioindoles has been established which does not use smelly compounds such as thiol derivatives. The method, which introduces an alkyl- or arylthio-group into the C3-position of the indole skeleton, was extended to the direct introduction of a methylthio or bromo group at the C2-position using 3-methylthioindoles. No dimerization occurred, and the reaction mechanism was confirmed. The products have the partial structure of potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) bromomethylthioindoles (MC 5–8) isolated from marine algae. Furthermore, this reac-tion could be applied to the synthesis of 3,3-diindolyl thioether which is a core structure of Echinosulfone A.

Key words indole;electrophilicaromaticsubstitution;thioether;sulfoxide;trifluoroaceticanhydride

Four bromomethylthioindoles, MC 5–7,1,2) were isolated from the red algae, Laurencia brongniartii. These compounds are the most potent antibacterial substances against methicil-lin-resistant Staphylococcus aureus (MRSA) to be isolated from red algae to date. The antimicrobial activities of these compounds for MRSA are similar to that of vancomycin. Their characteristic common structure is the methylthio group at the C3-position and another methylthio group or bromine atom at the C2-position of 3-methylthioindole. Because of their activity towards MRSA, MC 5–8 are promising lead com-pounds for a new category of antibiotics based on their novel structure.

These natural products are known compounds3–7) and were first isolated by Sun.3) The fundamental characterization of these compounds was described in “Marine Natural Products: Chemical and Biological Perspectives,” by Erickson.4) Fur-thermore, isolations of the same compounds were reported by Higa and colleagues,5) Duh and colleagues,6) and Uchio and colleagues.7) However, the precise structural determination of these natural products has not been published. We started the synthetic studies of these compounds from the viewpoint of confirming their structures.Wewilldescribehere,apracticalregioselective synthesis of alkylthio- or arylthioindoles with-out the use of smelly compounds such as thiols.

Many 3-alkylthio- and 3-arylthioindole derivatives are im-portant biologically active substances (e.g., cyclooxygenase-2 (COX-2) inhibitors,8) 5-lipoxygenase inhibitors,9) anti-human immunodeficiencyvirus (HIV)compounds,10) anti-nociceptive compounds,11) anti-allergy drugs,12) anti-obesity compounds,13) and endothelin antagonists.14) Many methods have been reported15–21) for the synthesis of 3-alkyl- (or aryl-) thioin-dole derivatives, and some studies have utilized alkylsulfenyl chloride15–17) alkyldisulfide,18) or N-alkylthiophthalimide20,21) as umpolung sulfonium cations. However, these reactions are directly substituted by the electron donating alkyl- or aryl-sulfanyl group. Like a Friedel–Crafts alkylation, there is the possibility of over-substitution15) and rearrangement between

the C3- and C2-position on indole ring.22) For the synthetic structural elucidation of MC 5–8, we required reliable, con-trolled functionalization into the C2- and C3-positions of the indole skeleton. Furthermore, earlier approaches used reagents prepared from smelly compounds such as thiols, and thus are not conveniently prepared in laboratories and factories. We focused on using dimethyl sulfoxide (DMSO)-trifluoroaceticanhydride (TFAA) to introduce a strong electron withdraw-ing dimethylsulfonyl group,23–27) to allow reliable electrophilic aromatic substitution into indoles that addresses the above problems. Furthermore, this reagent is a non-smelly MeS+ synthon for methylthiolation and thus can replace smelly thi-ols or sulfides. In this paper, we describe an application ofthe reaction to a practical regioselective synthesis of various indolylthioethers without the use of smelly compounds such as thiols. In a pioneering study usingDMSO,Tomita et al.23) reported the introduction of a dialkylsulfonium group at the C3-position of indole using succinimido-dialkylsulfonium chloridepreparedfromdialkylsulfideandNCSinquantitativeyield. Formed indole-3-dialkylsulfonium chloride was de-al-kylated by heating at 150°Corby refluxing inxylene.Hartkeet al.24) reported the synthesis of indol-3-yldimethylsulfonium salt 4a from unprotected indole using DMSO and TFAA in 58% yield. However, the methyl group on the sulfonium salt 4a easily migrated to the N1-position following addition of K2CO3 in CH2Cl2 via intermolecular rearrangement from ylide 5 to give N-methyl-3-methylthioindole 6, as shown in Fig. 2.

Balenkova and colleagues26,27) reported the introduction of a dimethylsulfonium group at the C3-position of indole using trifluoromethanesulfonylsulfonium triflate (Me2S+SO2CF3· CF3SO3

−) prepared from dimethylsulfide and Tf2O. The

Regular Article

* To whom correspondence should be addressed. e-mail: suzuki@phar.toho-u.ac.jp

Fig. 1. Structures of MC 5–8Theauthorsdeclarenoconflictofinterest.

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dimethylsulfonium salt was de-methylated with Et3N or (NH2)2CS in good to moderate yield (84–45%). However, this trifluoromethanesulfonylsulfonium triflate reagent is only ap-plicable to N-methylated indole or stabilized indoles such as 2,2′-biindole and 2-phenylindole, and not applied to unprotect-ed indole 1a. We believed that trapping the migrating methyl group by nucleophiles from the sulfonium salt prepared by DMSO–TFAA complex24) (4a to 7a) could provide a practi-cally valuable method for the introduction of alkylthio- or ar-ylthio group at the C3-position of unprotected indoles, without

the need to use smelly compounds.The sulfonium perchlorate 4a precipitated as a stable crys-

talline compound upon the addition of saturated aqueous LiClO4, allowing its easy isolationbyfiltration inpurer form.In this experiment, we found that quantitatively precipitationof the perchlorates 4a required few hours. Filtration of the product after stirred for 3 h with excess of saturated aqueous LiClO4 at 0°C gave perchlorate 4a in higher yield (90%) than reported by Hartke et al.24)

Isolated sulfonium salt 4a reacted with various secondary alkylamines as possible sources of nucleophiles for de-methyl-ation. Compound 4a is easily de-methylated in excellent yield to the desired 3-methylthioindole 7abyrefluxingwithsecond-ary alkylamines (Table 1).

Fig. 2. Methyl Group Migration of 4a

Table 1. de-Methylation of the Dimethylsulfonium Salt 4a

R2NH bp (°C) Yield (%)

Bu2NH 159 quant.

106 96

Pr2NH 107 98Et2NH 55 60–98

Table 2. IntroductionofanAlkyl-orArylthioGroupintoVariousIndoles

R1 R2 R3Yield (%)

1 to 4 4 to 7 Total

a H Me Me 90 (58a)) 98 89b 2-SMe Me Me 85 97 82c 5-MeO Me Me 82 92 74d 5-Me Me Me 94 97 91e 5-CN Me Me 96 85 81f 5-NO2 Me Me 89 94 84g 5-F Me Me 87 99 85h 5-Br Me Me 85 99 85i 4-Br Me Me 93 93 87j 2-CO2Et Me Me 91 82 75k 1-Ts Me Me No reaction — —l H n-Bu n-Bu 84 94 79

m H Bn Bn 90 (53a)) 98 88n H Ph Me 96 90 86o H 3-Indolyl Me 81 87 70

a) The yields were reported by Hartke.24)

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Since the overall yield of 7a from 1a was around 90%, we believed this might be a good general method for the introduc-tion of a methylthio group at the C3-position of indole without requiring the use of a smelly thiol compound. We selected dipropylamine (bp 107°C) as a standard nucleophile because triethylamine was lack of reproducibility, and used it in the synthesis of various 3-alkylthioindoles, as shown in Table 2.

The characteristic features of this reaction are as follows. The dimethylsulfonium group is a strong electron-withdraw-ing group, and electrophilic aromatic substitution is inevitably stopped at mono-substitution (as in a Friedel–Crafts acyla-tion). The electron-donating group-substituted indoles (2-SMe, 5-MeO, 5-Me), which are usually unstable to acidic conditions, gave good results in this reaction, likely due to stabilization of the indole ring in the intermediates 4 by the electron-with-drawing dimethylsulfonium group. Furthermore, the dimethyl-sulfonium trifuluoroacetate (3, R2=R3=Me), which possesses high electophilicity, and the electron-withdrawing group-sub-stituted indoles (5-CN, 5-NO2, 5-Br, 4-Br, 5-F, 2-CO2Et), also gave good results. Only 1-tosylindole 1k was found to be not reactive to this reagent. This method could also be expanded to various types of alkylthiolation (R2=R3=Me, n-Bu, Bn) and arylthiolation (R2=Ph, R3=Me), as shown in Table 2, using various dialkyl- or arylalkylsulfoxides.

Furthermore, the sulfonium reagent 3o was obtained from 3-methylthioindole 7a via sulfoxide 2o by oxidation with Oxone® according to reference28) in 73% yield. Consequently, bis-indol-3-ylthioether 7o was synthesized by applying this reaction to the indole 1a, as shown in Chart 1. The results showed that this reaction could be expanded to a general

synthetic method for unsymmetrical diarylthioether 7n and symmetrical bis-arylthioether 7o. Based on this result, now the total synthesis of anti-bacterial marine natural product echinosulfone A29) is in progress.

Consequently, we succeeded in application of the reaction to a practical regioselective synthesis of various indolylthio-ethers without the use of smelly compounds such as thiols. The experimental procedure is very simple; the sulfonium intermediates 4 were easily purified by filtration of the pre-cipitates from the work-up mixture, or extracted from the water layer by nitromethane as stable perchlorates. Thus, a convenient and high-yield method for the synthesis of 3-me-thylthioindoles without the need to use smelly compounds has been established.

Next, we examined the introduction of the second methyl-thio group at the C2-position of the 3-methylthioindoles 7. 3-Methylthioindole 7a was treated with dimethylsulfonium trifuluoroacetate (3, R2=R3=Me), resulting in the production of both symmetrical 2,2-dimer 89) and unsymmetrical one 9 (Chart2). Incontrast to7a, when 5-nitro-3-methylthioindol 7f was used as a stable electron with-drawing group substituted indole substrate, C2-selective introduction of the dimethyl-sulfonium group provided the desired C2-dimethylsulfonium compound 10f in 76% yield. The structure of 10f was con-firmedbytheNOE,asshowninChart2.

The 2-dimethysulfonium compound 10f was de-methylated to 5-nitro-2,3-bis(methylthio) indole 11f in the same manner as with the C3-dimethylsulfonium salt 4, in 77% yield.

Therefore we introduced tosyl group into the N1-position of the 3-methylthioindole 7a as an electron-withdrawing

Chart 1 SynthesisofBis(indol-3-yl)sulfide7o by the Described Reaction

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protecting group. The reaction of 1-tosyl compound 7k with dimethylsulfonium trifluoroacetate (3, R2= R3=Me) occurred at the C2-position to give the desired C2-dimethylsulfonium compound 10k, but the yields were not satisfactory (23%). We examined in situ de-methylation of the intermediate 10k by adding aqueous NaHCO3 to the reaction mixture, because the methyl group on the sulfonio group of N1-tosyl compound 10k could not rearrange to the protected N1-position. In thismethod, the de-methylated 3-methylthio compound 11k is ob-tained directly in 65% yield from 7k and the 1-tosyl group is de-protected to 7b in 84% yield.

Hamel6) reported that 3-phenylthioindole 7n reacted with 1 mol eq. of benzenelsulfenyl chloride to form 2,3-bis-(phenylthio) indole 19. However, the second sulfenylation occurs not by direct introduction at the C2-position, but via an indolenium 3,3-bis-sulfide intermediate 18 followed by migration to the C2-position (Chart 3). This mechanism was confirmedby the isolationof the intermediate18 and by sub-sequent rearrangement to 2,3-diphenylthioindole 19 from the intermediate. To confirm whether or not the introduction ofthe second thiomethylation at the C2-position of indole (7f or 7k) proceeded via Hamel’s mechanism, we used a deuterated dimethylsulfonium reagent 12 prepared from DMSO-d6 and TFAA. Comparison of the 1H-NMR spectra of the deuterated product with the original compound 10f showed the absence

of one singlet signal (3.42 ppm, 6H) and the presence of a new singlet signal (2.50 ppm, 3H). Hence, the structure of the deu-teratedcompoundwasconfirmedtobe13 and not 17. Incon-clusion, the introduction of a second dimethylsulfonium group does not occur by a methylthio group migration mechanism via C3-electrophilic substitution (route b), but rather occurs as a C2-direct electrophilic substitution activated by the C3-methylthio group (route a).

We next tried bromination of 7a, 7f, and 7k using N-bromosuccinimide (NBS) as a brominating reagent (Chart 4). From unprotected indole 7a, unstable dimeric mono-bromide (M+=402) was obtained. The use of pyridinium bromide per-bromide as the brominating agent in pyridine resulted in production of C2-nucleophilic-substituted30) pyridinium com-pound 20. In contrast, bromination with NBS of the 5-nitrocompound 7f and the 1-tosyl compound 7k resulted in C2-selective bromination to give the desired compounds 21f and 21k. We attempted the hydrolysis of the compound 21k to de-protection. However de-protected 2-bromo-3-methylthioindole 21a could not isolate by instability of the compound.

These results are similar to those obtained by the reaction of the 3-methylthioindoles 7 with the dimethylsulfonium salt 3. We succeeded in C2-selective electrophilic substitution of 5-nitroindole 7f and 1-tosyl-3-methylthioindole 7k, although 3-methylthioindole 7a resulted in dimerization. Our results

Chart 2. Reaction of 3-Methylthioindoles 7 with Reagent 3

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show that the 1-tosyl group is a good protecting group for C2-selective electrophilic substitution of the 3-methylthioindoles. It is possible that the different reactivities of 3-methylthioin-dole 7a, the 5-nitro compound 7f, and the 1-tosyl compound 7k, derive from the reduced nucleophilicity of the indolic nitrogen of the compounds (7f, 7k) by the 5-nitro group or 1-tosyl group (Chart 5).Incontrasttotheaboveresult,C3-electrophilic substitutions

were occurred from the compound 7a by ipso attack of elec-trophiles, followed by C2-nucleophilic addition of pyridine or 3-methylthioindole 7a to form the intermediate 23 or 25. Elimination of dimethylsulfide from intermediate 23 would form symmetrical dimer 8, whereas elimination of methylthio group from 23 would form asymmetrical dimer 9 (Chart 5).

We therefore developed the C2-selective electrophilic sub-stitution of 3-methylthioindoles (7f, 7k). All the products (11f,

Chart 3. Two Possible Routes for the Formation of 13 and 17

Chart 4. Bromination of 3-Methylthioindoles 7

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11k, 21f, 21k) should be good intermediates for the total syn-thesis of MC 5–8.

ConclusionA described methodology for the C3-selective introduction

of the dimethylsulfonio group followed by a de-methylation reaction is a reliable synthetic approach for 3-methylthioin-doles and could be expanded to the alkylthiolation or aryl-thiolation of various indoles. Furthermore, these thiolation processes do not require the use of smelly compounds such as thiols, oriented to the green chemistry. In addition,we foundthat C2-selective substitutions of 5-nitro-3-methylthioindole 7f and 1-tosyl-3-methylthioindole 7k occurred upon the introduc-tion of the dimethylsulfonio group and bromination, whereas 3-methylthioindole 7a caused dimerization. The reaction mechanism was confirmed as being aC2-direct electrophilic aromatic substitution. Thus, we have developed a methodology for the selective functionalization of the C2- and C3-positions and shown its applicability for the total synthesis of a natural product. The total synthesis of MC 5–8 is in progress, as are further applications of this reaction as a general synthesis method for various diarylthioethers, and the total synthesis of anti-bacterial 3,3-bisindolylthioether natural product echino-sulfone A.11)

ExperimentalAll melting points were determined on a micro melting

point hot stage apparatus (Yanagimoto) and are uncorrected. IR spectra were recorded on a JASCO FT/IR-300 spectro-photometer. 1H-NMR (400 MHz) and 13C-NMR (100 MHz)

spectra were recorded on a JEOL AL-400 spectrometers with tetramethylsilane as an internal reference or solvents (CHCl3, acetone, DMSO) peak. Mass spectra (MS) were measured on JEOL Automass System II, JMS D-300 and DX-303 (FAB)spectrometers with a direct inlet system. For column chroma-tography, Silica gel 60N (spherical, neutral, Cica) was used. For TLC, Silica gel 60F254 (Merck) was used. The abbre-viations used are as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet; br, broad; BP, base peak.

The General Procedure24) for (Indol-3-yl)dimethylsul-fonium Perchlorate 4 To a stirred solution of indole 1 (1.0 mmol) and DMSO (1.05 mmol) in CH2Cl2 (4 mL), TFAA (1.5 mmol) in CH2Cl2 (1 mL) was added dropwise at −78°C (except for 4h, 4l: −30°C) under shaded argon atmosphere, the mixture was additionally stirred at rt for 0.5–3 h (except for 4j: 14 h). Aqueous sat. LiClO4 (6 mL) was poured into the reaction mixture under ice cooling, then the mixture was stirred at rt for 1–3h. The precipitate was collected by filtration, driedunder reduced pressure to give the corresponding sulfonium perchlorate 4 as pure crystals. In the case of 4c, 4d, 4e, 4g, and 4o, the filtrate was extracted with nitromethane, the or-ganic layer was dried over anhydrous Na2SO4, evaporated to dryness in vacuo to give 2nd crop of the compound 4. In thecase of 4l and 4m, perchlorates were not precipitated, so the solution was extracted with CH2Cl2, the organic layer was separated, then added excess of Et2O under ice-cooling to pre-cipitate the perchlorates 4.

The General Procedure for 3-Methylthioindoles 7 A mixture of the sulfonium salt 4 and n-dipropylamine (ca.

Chart 5. Reactivities of 3-Methylthioindoles (7a, 7f, 7k)

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tenfoldexcessinvolume)wasrefluxedundershadedargonat-mosphere with stirring for 1 h. After cooling, n-dipropylamine was evaporated to dryness in vacuo.The residuewaspurifiedby column chromatography (neutralized SiO2: hexane–AcOEt) to give the corresponding methylthioindole 7.

(Indol-3-yl) dimethylsulfonium Perchlorate24) 4a Ac-cording to the general procedure, from (2.3516 g, 20.1 mmol) of indole 1a, 5.0345 g (90.3%) of (indol-3-yl) dimethylsulfonium perchlorate 4a was obtained as colorless prisms. mp 130–133°C (lit.7b: mp 141°C); 1H-NMR (DMSO-d6) δ: 12.48 (1H, br s, NH), 8.37 (1H, d, J=3.2 Hz, C2-H), 8.00 (1H, dd, J=8.2, 1.1 Hz, C4 or 7-H), 7.62 (1H, dd, J=8.2, 1.1 Hz, C4 or 7-H), 7.34 (1H, ddd, J=8.2, 7.1, 1.1 Hz, C5 or 6-H), 7.29 (1H, ddd, J=8.2, 7.1, 1.1 Hz, C5 or 6-H), 3.32 (6H, s, SMe2).

3-Methylthioindole31) 7a According to the general procedure, from 5.0345 g (18.1 mmol) of (indol-3-yl)-dimethylsulfonium perchlorate 4a, 2.9020 g (98.1%) of 3-me-thylthioindole 7a was obtained as brown prisms. mp <30°C (hexane–AcOEt) (lit.31): Yellow liquid); 1H-NMR (CDCl3) δ: 8.16 (1H, br s, NH), 7.76 (1H, d, J=7.3 Hz, C4 or 7-H), 7.37 (1H, d, J=7.3 Hz, C4 or 7-H), 7.30 (1H, d, J=2.2 Hz, C2-H), 7.23 (1H, t, J=7.3 Hz, C5 or 6-H), 7.19 (1H, t, J=7.3 Hz, C5 or 6-H), 2.37 (3H, s, SMe); IR (KBr): 3366cm−1; electron ionization (EI)-MS m/z: 163 (M+, 74%), 148 (BP).

(2-Methylthioindol-3-yl) dimethylsulfonium Perchlorate 4b According to the general procedure, from 93.4 mg (0.57 mmol) of 2-methylthioindole 1b, 158.0 mg (85.3%) of (2-methylthoindol-3-yl) dimethylsulfonium perchlorate 4b was obtained as colorless prisms. mp 131–135°C (dec.); 1H-NMR (acetone-d6) δ: 8.08 (1H, br d, J=7.6 Hz, C4-H or C7-H), 7.67 (1H, br d, J=7.6 Hz, C4-H or C7-H), 7.40 (1H, br dd, J=7.6, 7.6 Hz, C5-H or C6-H), 7.34 (1H, br dd, J=7.6, 7.6 Hz, C5-H or C6-H), 3.61 (6H, s, SMe2), 2.76 (3H, s, SMe); 13C-NMR (ace-tone-d6) δ: 143.9, 139.1, 125.7, 125.2, 123.6, 118.7, 114.0, 94.2, 28.7, 18.2; IR (KBr): 3435cm−1; EI-MS m/z: 209 (M+–CH3), 194, 50 (BP); Elemental analysis Calcd for C11H14ClNO4S2: C, 40.80; H, 4.36; N, 4.33. Found: C, 40.58; H, 4.25; N, 3.99.

2,3-Bis(methylthio) indole 7b According to the general procedure, from 120.7 mg (0.372 mmol) of (2-methylthoindol-3-yl) dimethylsulfonium perchlorate 4b, 75.3 mg (96.5%) of 2,3-bis(methylthio) indole 7b was obtained as colorless oil. 1H-NMR (CDCl3) δ: 8.25 (1H, br s, NH), 7.71 (1H, br d, C4-H or C7-H), 7.33 (1H, br d J=8.4 Hz, C4-H or C7-H), 7.23 (1H, br dd, J=8.0, 8.0 Hz, C5-H or C6-H), 7.19 (1H, br dd, J=8.0, 8.0 Hz, C5-H or C6-H), 2.54 (3H, s, C2-SMe), 2.37 (3H, s, C3-SMe); 13C-NMR (CDCl3) δ: 136.1, 134.6, 130.0, 123.2, 120.7, 119.2,112.2,110.8,19.7,19.3;IR(neat):3390cm−1;EI-MSm/z: 209 (M+, BP), 194 (M+−CH3);Highresolution(HR)-MS(EI):Calcd for C10H11NS2 (M+) 209.0333, Found 209.0336.

(5-Methoxyindol-3-yl) dimethylsulfonium Perchlorate 4c According to the general procedure, from 73.0 mg (0.50 mmol) of 5-methoxyindole 1c, 124.6 mg (81.7%) of (5-methoxyindol-3-yl) dimethylsulfonium perchlorate 4c was obtained as colorless prisms. mp 120–125°C (dec.); 1H-NMR (DMSO-d6) δ: 12.34 (1H, br s, NH), 8.28 (1H, d, J=3.4 Hz, C2-H), 7.51 (1H, d, J=8.8 Hz, C7-H), 7.41 (1H, d, J=2.2 Hz, C4-H), 6.97 (1H, dd, J=8.8, 2.2 Hz, C6-H), 3.84 (3H, s, OMe), 3.31 (6H, s, SMe2); IR (KBr): 3445cm−1; Elemental analysis Calcd for C11H14ClNO5S·1/4H2O: C, 42.31; H, 4.68; N, 4.49. Found: C, 42.47; H, 4.43; N, 4.18; HR-MS (EI): Calcd for C11H13NOS (M−H)+: 207.0718, Found: 207.0718.

5-Methoxy-3-methylthioindole 7c According to the general procedure, from 118.6 mg (0.385 mmol) of (5-methoxy-indol-3-yl) dimethylsulfonium perchlorate 4c, 67.9 mg (91.9%) of 5-methoxy-3-methylthioindole 7c was obtained as colorless prisms. mp 99–101°C (hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.10 (1H, br s, NH), 7.28 (1H, d, J=2.6 Hz, C2-H), 7.26 (1H, d, J=8.9 Hz, C7-H), 7.18 (1H, d, J=2.3 Hz, C4-H), 6.88 (1H, dd, J=8.9, 2.3 Hz, C6-H), 3.88 (3H, s, OMe), 2.35 (3H, s, SMe); 13C-NMR (CDCl3) δ: 154.6, 131.2, 129.3, 128.7, 113.0, 112.3,107.4,100.5,55.8,20.2;IR(KBr)3370,1203,1021cm−1; EI-MSm/z: 193 (M+, 81%), 178 (BP); Elemental analysis Calcd for C10H11NOS: C, 62.15; H, 5.74; N, 7.25. Found: C, 62.06; H, 5.74; N, 6.96.

(5-Methylindol-3-yl) dimethylsulfonium Perchlorate 4d According to the general procedure, from 135.4 mg (1.03 mmol) of 5-methyl indole 1d, 282.0 mg (93.7%) of (5-methyl indol-3-yl) dimethylsulfonium perchlorate 4d was obtained as brown prisms. mp 159–160°C; 1H-NMR (DMSO-d6) δ: 12.35 (1H, br s, NH), 8.29 (1H, s, C2-H), 7.79 (1H, d, J=0.6 Hz, C4-H), 7.50 (1H, d, J=8.4 Hz, C7-H), 7.16 (1H, dd, J=8.4, 0.6 Hz, C6-H), 3.30 (6H, s, SMe2), 2.44 (3H, s, C5-Me); IR (KBr):3408 cm−1; HR-MS (EI): Calcd for C11H13NS (M−H)+: 191.0769, Found 191.0762; Elemental analysis Calcd for C11H14ClNO4S: C, 45.28; H, 4.84; N, 4.80. Found: C, 45.58; H, 4.82; N, 5.04.

5-Methyl-3-methylthioindole32) 7d According to the general procedure, from 237.7 mg (0.815 mmol) of (5-methyl-indol-3-yl) dimethylsulfonium perchlorate 4d, 139.5 mg (96.6%) of 5-methyl-3-methylthioindole 7d was obtained as pale brown oil. 1H-NMR (CDCl3) δ: 8.06 (1H, br s, NH), 7.54 (1H, s, C2 or 4-H), 7.26 (1H, d, J=8.3 Hz, C6 or 7-H), 7.26 (1H, s, C2 or 4-H), 7.06 (1H, d, J=8.3 Hz, C6 or 7-H), 2.48 (3H, s, C5-Me or SMe), 2.36 (3H, s, C5-Me or SMe); IR (KBr): 3401cm−1; EI-MSm/z: 177 (M+, 75%), 162 (BP).

(5-Cyanoindol-3-yl) dimethylsulfonium Perchlorate 4e According to the general procedure, from 145.1 mg (1.02 mmol) of 5-cyanoindole 1e, 295.2 mg (95.5%) of (5-cyanoindol-3-yl)-dimethylsulfonium perchlorate 4e was obtained as colorless prisms. mp 230–235°C; 1H-NMR (DMSO-d6) δ: 12.92 (1H, br s, NH), 8.65 (1H, d, J=1.4 Hz, C4-H), 8.56 (1H, s, C2-H), 7.79 (1H, d, J=8.5 Hz, C7-H), 7.71 (1H, dd, J=8.5, 1.4 Hz, C6-H), 3.34 (6H, s, SMe2); IR (KBr): 3446, 2223cm−1, El-emental analysis Calcd for C11H11ClN2O4S·1/2H2O: C, 42.38; H, 3.88; N, 8.99. Found: C, 42.32; H, 3.52; N, 8.76.

5-Cyano-3-methylthioindole 7e According to the general procedure, from 120.9 mg (0.400 mmol) of (5-cyanoindol-3-yl)-dimethylsulfonium perchlorate 4e, 63.6 mg (84.6%) of 5-cya-no-3-methylthoindole 7e was obtained as colorless prisms. mp 106.5–107.5°C (hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.51 (1H, br s, NH), 8.09 (1H, d, J=1.5 Hz, C4-H), 7.46 (1H, dd, J=8.2, 1.5 Hz, C6-H), 7.43 (1H, d, J=8.2 Hz, C7-H), 7.41 (1H, d, J=2.4 Hz, C2-H),2.36(3H,s,SMe);IR(KBr)3283,2224cm−1; HR-MS(EI):CalcdforC10H8N2S: 188.0408, Found: 188.0408; Elemental analysis Calcd for C10H8N2S: C, 63.80; H, 4.28; N, 14.88.Found:C,63.97;H,4.33;N,14.73;EI-MSm/z: 188 (M+, 55%), 173 (BP).

(5-Nitroindol-3-yl) dimethylsulfonium Perchlorate 4f According to the general procedure, from 5.04 g (31.1 mmol) of 5-nitroindole 1f, 8.943 g (89.1%) of (5-nitroindol-3-yl)-dimethylsulfonium perchlorate 4f was obtained as colorless prisms. mp 260–265°C; 1H-NMR (DMSO-d6) δ: 13.07 (1H,

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br s, NH), 8.90 (1H, d, J=2.2 Hz, C4-H), 8.67 (1H, s, C2-H), 8.19 (1H, dd, J=9.0, 2.2 Hz, C6-H), 7.81 (1H, d, J=9.0 Hz, C7-H), 3.36 (6H, s, SMe2); IR (KBr) 3445, 1525, 1348cm−1; HR-MS (EI): Calcd for C10H10N2O2S (M−H)+: 222.0457, Found: 222.0459; Elemental analysis Calcd for C10H11ClN2O6S: C, 37.22; H, 3.44; N, 8.68. Found: C, 37.12; H, 3.43; N, 8.49.

3-Methylthio-5-nitroindole 7f According to the gen-eral procedure, from 8.94 g (27.7 mmol) of (5-nitroindol-3-yl) dimethylsulfonium perchlorate 4f, 5.45 g (94.4%) of 3-methylthio-5-nitroindole 7f was obtained as pale yellow prisms. mp 157–158°C (hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.70 (1H, d, J=2.2 Hz, C4-H), 8.55 (1H, s, NH), 8.14 (1H, dd, J=8.9, 2.2 Hz, C6-H), 7.44 (1H, d, J=2.2 Hz, C2-H), 7.42 (1H, d, J=8.9 Hz, C7-H), 2.40 (3H, s, SMe); 13C-NMR (CDCl3) δ: 142.4, 139.3, 130.4, 128.4, 118.4, 116.6, 111.7, 111.6, 20.2; IR(KBr) 3312, 1326 cm−1; HR-MS (EI): Calcd for C9H8N2O2S: 208.0307, Found: 208.0306; Elemental analysis Calcd for C9H8N2O2S: C, 51.91; H, 3.87; N, 13.45. Found: C, 51.86; H, 3.88;N,13.44;EIMSm/z: 208 (M+, BP).

(5-Fluoroindol-3-yl) dimethylsulfonium Perchlorate 4g According to the general procedure, from 137.5 mg (1.02 mmol) of 5-fluoroindole1g, 260.2mg (86.5%) of (5-fluoroindol-3-yl)-dimethylsulfonium perchlorate 4g was obtained as colorless prisms. mp 184–190°C (dec.); EI-MS m/z: 181 (M+−CH3), 166 (BP, M+−2·CH3); 1H-NMR (DMSO-d6) δ: 12.58 (1H, br s, NH), 8.42 (1H, br s, C2-H), 7.90 (1H, dd, J=9.6, 2.4 Hz, C4-H), 7.64 (1H, dd, J=9.0, 4.6 Hz, C7-H), 7.21 (1H, ddd, J=9.0, 9.0, 2.4 Hz, C6-H), 3.32 (6H, s, SMe2); 13C-NMR (acetone-d6) δ: 159.9 (d, JC–F=237 Hz), 136.2, 134.7, 126.0 (d, JC–F=10.7 Hz), 116.1 (d, JC–F=9.9 Hz), 113.5 (d, JC–F=25.0 Hz), 104.6 (d, JC–F=26.4 Hz), 94.2 (d, JC–F=4.1Hz), 29.7; IR (KBr):3412 cm−1; Elemental analysis Calcd for C10H11ClFNO4S: C, 40.62; H, 3.75; N, 4.74. Found: C, 40.23; H, 3.68; N, 4.40.

5-Fluoro-3-methylthioindole16) 7g According to the general procedure, from 130.0mg (0.440mmol) of (5-fluoro-indol-3-yl) dimethylsulfonium perchlorate 4g, 78.5 mg (98.5%) of 5-fluoro-3-methylthioindole 7g was obtained as colorless oil. 1H-NMR (CDCl3) δ: 8.20 (1H, br s, NH), 7.40 (1H, dd, J=9.2, 2.4 Hz, C4-H), 7.35 (1H, d, J=2.4 Hz, C2-H), 7.30 (1H, dd, J=9.0, 4.2 Hz, C7-H), 6.98 (1H, ddd, J=9.0, 9.0, 2.4 Hz, C6-H), 2.35 (3H, s, SMe); 13C-NMR (CDCl3) δ: 158.4 (d, JC–F=236 Hz), 132.7, 129.7, 129.5 (d, JC–F=9.9 Hz), 112.2 (d, JC–F=9.1 Hz), 111.2 (d, JC–F=26.5 Hz), 108.3 (d, JC–F=5.0 Hz), 104.3 (d, JC–F=24.0Hz), 20.2; IR (KBr): 3462cm−1; HR-MS (EI):CalcdforC9H8FNS (M+) 181.0361, Found 181.0389.

(5-Bromoindol-3-yl) dimethylsulfonium Perchlorate 4h According to the general procedure, from 784.2 mg (4.00 mmol) of 5-bromoindole 1h, 1.218 g (85.4%) of (5-bromoindol-3-yl) dimethylsulfonium perchlorate 4h was ob-tained as colorless prisms. mp 178–181°C; 1H-NMR (acetone-d6) δ: 11.74 (1H, br s, NH), 8.49 (1H, d, J=3.4 Hz, C2-H), 8.21 (1H, br d, J=1.6 Hz,, C4-H), 7.71 (1H, d, J=8.8 Hz, C7-H), 7.521 (1H, dd, J=8.8, 1.6 Hz, C6-H), 3.61 (6H, s, SMe2); 13C-NMR (acetone-d6) δ: 136.8, 135.8, 127.9, 127.2, 121.7, 116.5, 116.2, 94.2, 30.0; IR (KBr): 3428cm−1; EI-MSm/z: 241 (M+−CH3), 226 (BP, M+−2·CH3), 243 (M+−CH3), 228 (BP, M+−2·CH3); Elemental analysis Calcd for C10H11BrClNO4S: C, 33.68; H, 3.11; N, 3.93. Found: C, 33.63; H, 3.16; N, 3.71.

5-Bromo-3-methylthioindole16) 7h According to the gen-eral procedure, from 200.0 mg (0.561 mmol) of (5-bromoindol- 3-yl) dimethylsulfonium perchlorate 4h, 134.4 mg (84.5%) of

5-bromo-3-methylthioindole 7h was obtained as pale colorless needles. mp 76–78°C (hexane–benzene); 1H-NMR (CDCl3) δ: 8.21 (1H, br s, NH), 7.89 (1H, br d, J=1.6 Hz, C4-H), 7.32 (1H, dd, J=8.6, 1.6 Hz, C6-H), 7.30 (1H, d, J=2.6 Hz, C2-H), 7.24 (1H, d, J=8.6 Hz, C7-H), 2.35 (3H, s, SMe); 13C-NMR (CDCl3) δ: 134.9, 130.6, 129.0, 125.7, 122.0, 113.9, 112.9, 108.2, 20.3;IR(KBr):3410cm−1;HR-MS(EI):CalcdforC9H8NS79Br (M+): 240.9561. Found: 240.9566; Elemental analysis Calcd for C9H8BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.59; H, 3.32; N, 5.53.

(4-Bromoindol-3-yl) dimethylsulfonium Perchlorate 4i According to the general procedure, from 454.9 mg (2.32 mmol) of 4-bromoindole 1i, 772.7 mg (93.4%) of (4-bromoindol-3-yl)-dimethylsulfonium perchlorate 4i was obtained as colorless prisms. mp 130–135°C (dec.); 1H-NMR (DMSO-d6) δ: 12.88 (1H, br s, NH), 8.50 (1H, d, J=0.9 Hz, C2-H), 7.64 (1H, d, J=8.0 Hz, C5 or 7-H), 7.49 (1H, d, J=8.0 Hz, C6-H), 7.25 (1H, t, J=8.0 Hz, C5 or 7-H), 3.34 (6H, s, SMe2); IR (KBr): 3420cm−1; Elemental analysis Calcd for C10H11BrClNO4S: C, 33.68; H, 3.11; N, 3.93. Found: C, 33.46; H, 3.04; N, 3.57.

4-Bromo-3-methylthioindole 7i According to the gen-eral procedure, from 772.7 mg (2.17 mmol) of (4-bromoindol-3-yl) dimethylsulfonium perchlorate 4i, 488.4 mg (93.1%) of 4-bromo-3-methylthioindole 7i was obtained as pale brown prisms. mp 54.5–56°C (hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.23 (1H, br s, NH), 7.33 (1H, dd, J=7.9, 0.7 Hz, C5 or 7-H), 7.31 (1H, dd, J=7.9, 0.7 Hz, C5 or 7-H), 7.30 (1H, d, J=0.7 Hz, C2-H), 7.03 (1H, t, J=7.9 Hz, C6-H), 2.43 (3H, s, SMe); 13C-NMR (100 MHz, CDCl3) δ 137.6, 128.9, 126.0, 125.0, 123.5, 114.3, 110.9, 109.5, 22.0; IR (KBr): 3248cm−1; HR-MS (EI): Calcdfor C9H8NS79Br (M+) 240.9561, Found 240.9568; Elemental analysis Calcd for C9H8BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.71; H, 3.30; N, 5.48.

(2-Carboethoxyindol-3-yl) dimethylsulfonium Perchlo-rate 4j According to the general procedure, from 573.2 mg (3.03 mmol) of ethyl indole-2-carboxylate 1j, 964.8 mg (91.1%) of (2-carboethoxyindol-3-yl) dimethylsulfonium perchlorate 4j was obtained as colorless prisms. mp 211–219°C (dec.); 1H-NMR (DMSO-d6) δ: 13.34 (1H, br s, NH), 8.19 (1H, d, J=8.2 Hz, C4 or 7-H), 7.69 (1H, d, J=8.2 Hz, C4 or 7-H), 7.50 (1H, t, J=8.2 Hz, C5 or 6-H), 7.38 (1H, t, J=8.2 Hz, C5 or 6-H), 4.46 (2H, q, J=7.1 Hz, CH2CH3), 3.43 (6H, s, SMe2), 1.41 (3H, t, J=7.1 Hz, CH2CH3); 13C-NMR (100 MHz, DMSO-d6) δ: 159.1, 136.4, 131.7, 126.4, 124.8, 123.3, 120.2, 114.6, 97.4, 62.4, 27.8, 14.1; IR (KBr): 3421, 1715cm−1;HR-MS (EI): Calcd forC13H15NO2S (M−H)+: 249.0818, Found: 249.0823; Elemental analysis Calcd for C13H16ClNO6S: C, 44.64; H, 4.61; N, 4.00. Found: C, 44.80; H, 4.54; N, 3.95.

Ethyl 3-Methylthioindole-2-carboxylate33) 7j Accord-ing to the general procedure, from 536.5 mg (1.53 mmol) of (2-carboethoxyindol-3-yl) dimethylsulfonium perchlorate 4j, 295.5 mg (81.9%) of ethyl 3-methylthioindole-2-carboxylate 7j was obtained as colorless prisms. mp 116–118°C (hex-ane–AcOEt) (lit.33): mp 114–116°C); 1H-NMR (CDCl3) δ: 8.96 (1H, br s, NH), 7.87 (1H, dd, J=8.2, 1.2 Hz, C4 or 7-H), 7.39 (1H, dd, J=8.2, 1.2 Hz, C4 or 7-H), 7.34 (1H, ddd, J=8.2, 7.0, 1.2 Hz, C5 or 6-H), 7.20 (1H, ddd, J=8.2, 7.0, 1.2 Hz, C5 or 6-H), 4.46 (2H, q, J=7.1 Hz, CH2CH3), 2.48 (3H, s, SMe), 1.44 (3H, t, J=7.1 Hz, CH2CH3); IR (KBr): 3306, 1665cm−1; EI-MSm/z: 235 (M+, 42%), 146 (BP); Elemental analysis Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95. Found: C, 61.48; H,

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5.54; N, 5.90.(Indol-3-yl) Di-n-butylsulfonium Perchlorate 4l Ac-

cording to the general procedure, 728.3 mg (84.2%) of (indol-3-yl) di-n-butylsulfonium perchlorate 4l was obtained as colorless prisms, from 279.9 mg (2.39 mmol) of indole 1a, 388.8 mg (2.40 mmol) of di-n-buthylsulfoxide, and 500 µL (3.59 mmol) of TFAA. mp 93–95°C; 1H-NMR (acetone-d6) δ: 11.74 (1H, br s, NH), 8.51 (1H, d, J=3.2 Hz, C2-H), 8.05 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.79 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.43 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H), 7.36 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H), 4.05–4.12 (2H, m, CH2), 3.89–3.96 (2H, m, CH2), 1.62–1.80 (4H, m, CH2×2), 1.41–1.59 (4H, m, CH2×2), 0.87 (6H, t, J=7.4 Hz, CH2CH3×2); 13C-NMR (acetone-d6) δ: 138.5, 136.9, 125.9, 125.3, 123.6, 119.0, 114.9, 88.7, 43.8, 27.3, 21.8, 13.6; IR (KBr): 3423cm−1; EI-MS m/z: 205 (M+−nBu), 149 (BP), 148 (M+−2·nBu); El-emental analysis Calcd for C16H24ClNO4S: C, 53.10; H, 6.68; N, 3.87. Found: C, 53.08; H, 6.52; N, 3.65.

3-n-Butylthioindole8) 7l According to the general proce-dure, from 301.0 mg (0.831 mmol) of (indol-3-yl)-di-n-butylsul-fonium perchlorate 4l, 162.4 mg (93.7%) of 3-n-butylthioindole 7l was obtained as colorless oil. 1H-NMR (CDCl3) δ: 8.20 (1H, br s, NH), 7.78 (1H, br d, J=8.0 Hz, C4-H or C7-H), 7.38 (1H, br d, J=8.0 Hz, C4-H or C7-H), 7.31 (1H, d, J=2.4 Hz, C2-H), 7.24 (1H, br dd, J=8.0, 8.0 Hz, C5-H or C6-H), 7.20 (1H, br dd, J=8.0, 8.0 Hz, C5-H or C6-H), 2.70 (2H, t, J=7.2 Hz, SCH2), 1.54 (2H, quintet, J=8.0, CH2–CH2–CH2), 1.40 (2H, 6th, J=8.0, CH2–CH2–CH3), 0.87 (3H, t, J=8.0 Hz, CH2CH3); 13C-NMR (CDCl3) δ: 136.3, 129.5, 129.2, 122.6, 120.4, 119.4, 111.4, 106.3, 36.1, 32.0, 21.7, 13.7; IR (KBr): 3407cm−1; HR-MS (electrospray ionization (ESI)): Calcd for C12H15NS: 205.0925. Found: 205.0928.

(Indol-3-yl) Bis(phenylmethyl) sulfonium Perchlorate24) 4m According to the general procedure, 1161.8 mg (89.7%) of (indol-3-yl) bis(phenylmethyl) sulfonium perchlorate 4m was obtained as colorless prisms from 353.0 mg (3.01 mmol) of indole 1a, 693.9 mg (3.01 mmol) of dibezylsulfoxide, and 640 µL (4.60 mmol) of TFAA. mp 142–144°C; (lit.24): mp 166°C); 1H-NMR (acetone-d6) δ: 11.62 (1H, br s, NH), 8.14 (1H, d, J=3.4 Hz, C2-H), 8.03 (1H, br d, J=8.0 Hz, C4-H or C7-H), 7.71 (1H, br d, J=8.0 Hz, C4-H or C7-H), 7.41 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H), 7.34 (1H, br d, J=7.8 Hz), 7.34–7.14 (10H, m, Ar-H), 5.44 and 5.40 (each 2H, d, J=19 Hz, CH2Ph); 13C-NMR (acetone-d6) δ: 138.3, 137.7, 131.4, 130.5, 130.0, 129.7, 126.2, 125.3, 123.7, 119.2, 114.8, 87.5, 49.1. IR (KBr) 3437cm−1; EI-MS m/z: 239 (M+−Bn), 149 (BP), 148 (M+−2·Bn), 91 (BP, Bn); Elemental analysis Calcd for C22H20ClNO4S: C, 61.46; H, 4.69; N, 3.26. Found: C, 61.39; H, 4.67; N, 3.10.

3-(Phenylmethylthio) indole 7m According to the gen-eral procedure, from 300.4 mg (0.699 mmol) of (indol-3-yl) bis(phenylmethyl) sulfonium perchlorate 4m, 163.8 mg (98.0%) of 3-(phenylmethylthio) indole 7m was obtained as colorless prisms. mp 85–86°C (hexane); 1H-NMR (CDCl3) δ: 8.10 (1H, br s, NH), 7.70 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.35 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.16–7.25 (5H, m, Ar-H), 7.07 (1H, d, J=7.6 Hz, Ar-H), 7.07 (1H, d, J=7.6 Hz, Ar-H), 6.99 (1H, d, J=2.4 Hz, C2-H), 3.86 (2H, s, SCH2Ph); 13C-NMR (CDCl3) δ: 139.0, 136.2, 129.8, 129.2, 129.0, 128.2, 126.7, 122.6, 120.5, 119.3, 111.4, 105.3, 40.9; IR (KBr): 3404cm−1; HR-MS (ESI): Calcd for C15H13NS (M+): 239.0769. Found:

239.0771; Elemental analysis Calcd for C15H13NS: C, 75.27; H, 5.47; N, 5.85. Found: C, 74.93; H, 5.55; N, 5.45.

(Indol-3-yl) methylphenylsulfonium Perchlorate 4n Ac-cording to the general procedure, 976.8 mg (95.7%) of (indol-3-yl) methylphenylsulfonium perchlorate 4n was obtained as col-orless prisms from 351.9 mg (3.00 mmol) of indole 1a, 427.1 mg (3.05 mmol) of methylphenylsulfoxide, and 650 µL (4.67 mmol) of TFAA. mp 81–86°C (dec.); 1H-NMR (acetone-d6) δ: 11.79 (1H, br s, NH), 8.63 (1H, d, J=3.4 Hz, C2-H), 8.03–8.07 (2H, m, Ar-H), 7.69–7.78 (4H, m, Ar-H), 7.66 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.38 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H), 7.25 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H), 3.98 (3H, s, SCH3); 13C-NMR (acetone-d6) δ: 138.5, 136.0, 133.9, 131.7, 129.4, 129.3, 125.3, 125.0, 123.5, 119.0, 114.8, 92.8, 29.1; IR(KBr): 3443 cm−1; Elemental analysis Calcd for C15H14ClNO4S · H2O: C, 50.35; H, 4.51; N, 3.91. Found: C, 50.40; H, 4.13; N, 3.74.

3-Phenylthioindole 7n According to the general proce-dure, from 202.5 mg (0.596 mmol) of (indol-3-yl) methylphe-nylsulfonium perchlorate 4n, 121.0 mg (90.1%) of 3-phenylthi-oindole 7n was obtained as colorless needles. mp 151–152°C (hexane–benzene); 1H-NMR (CDCl3) δ: 8.56 (1H, br s, NH), 7.61 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.46 (1H, d, J=2.6 Hz, C2-H), 7.42 (1H, br d, J=7.8 Hz, C4-H or C7-H), 7.26 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H), 7.08–7.17 (5H, m, Ar-H), 7.04 (1H, br dd, J=7.8, 7.8 Hz, C5-H or C6-H); 13C-NMR (CDCl3) δ: 139.3, 136.6, 130.9, 129.1, 128.7, 125.8, 124.7, 122.9, 120.8, 119.6, 111.7, 102.4; IR (KBr): 3411cm−1;HR-MS (ESI):Calcd for C14H11NS (M+): 225.0612. Found: 225.0614; Elemen-tal analysis Calcd for C14H11NS: C, 74.63; H, 4.92; N, 6.22. Found: C, 74.94; H, 5.01; N, 6.14.

Bis(indol-3-yl) methylsulfonium Perchlorate 4o Ac-cording to the general procedure, 549.4 mg (80.6%) of bis(indol-3-yl) methylsulfonium perchlorate 4o was obtained as pale-green prisms from 210.7 mg (1.80 mmol) of indole 1a, 323.3mg (1.80mmol) of 3-methylsulfinylindole28) 2o, and 380 µL (2.71 mmol) of TFAA. mp 130–135°C (dec.); 1H-NMR (acetone-d6) δ: 11.46 (2H, br s, NH), 8.45 (2H, d, J=3.3 Hz, C2-H), 7.70 (2H, dt, J=8.2, 1.0 Hz, C4-H or C7-H), 7.53 (2H, dt, J=8.2, 1.0 Hz, C4-H or C7-H), 7.17 (2H, ddd, J=8.2, 7.2, 1.0 Hz, C5-H or C6-H), 7.07 (2H, ddd, J=8.2, 7.2, 1.0 Hz, C5-H or C6-H), 3.88 (3H, s, SCH3),IR(KBr):3446cm−1

Bis(indol-3-yl) Sulfide34,35) 7o According to the gen-eral procedure, from 518.4 mg (1.37 mmol) of bis(indol-3-yl) methylsulfonium perchlorate 4o, 315.9 mg (87.3%) of bis (indol-3-yl) sulfide 7o was obtained as colorless prisms. mp 207–209°C (hexane–AcOEt) (lit.34) 227.5–229°C, lit.35) 232°C); 1H-NMR (acetone-d6) δ: 10.34 (2H, br s, NH), 7.79 (2H, dd, J=8.1, 1.2 Hz, C4-H or C7-H), 7.57 (2H, d, J=2.6 Hz, C2-H), 7.36 (2H, dd, J=8.1, 1.2 Hz, C4-H or C7-H), 7.08 (2H, ddd, J=8.1, 6.9, 1.2 Hz, C5-H or C6-H), 7.03 (2H, ddd, J=8.1, 6.9, 1.2 Hz, C5-H or C6-H); 1H-NMR (DMSO-d6) δ: 11.27 (2H, br s, NH), 7.73 (2H, d, J=8.1 Hz, C4-H or C7-H), 7.65 (2H, d, J=2.6 Hz, C2-H), 7.35 (2H, br d, J=8.1 Hz, C4-H or C7-H), 7.08 (2H, br d, J=8.1 Hz, C5-H or C6-H), 7.03 (2H, br t, J=8.1 Hz, C5-H or C6-H); 13C-NMR (DMSO-d6) δ: 136.2, 129.7, 128.5, 121.6, 119.4, 118.6, 111.9, 105.3 ; IR (KBr): 3411cm−1; EI-MSm/z: 264 (M+, BP).

3-(Methylthio)-2-[3-(methylthio)-1H-indol-2-yl]-1H- indole26) 8 To a stirred solution of 3-methylthioindole 7a (99.4 mg, 0.609 mmol) and DMSO (48 µL, 0.676 mmol) in

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CH2Cl2 (3 mL), TFAA (140 µL, 1.0 mmol) in CH2Cl2 (1 mL) was added dropwise at −78°C under argon atmosphere, the mixture was additionally stirred at rt for 1 h. Aqueous sat. LiClO4 (4 mL) was poured into the reaction mixture under ice cooling, then the mixture was stirred at rt for 2 h. The mixture was extracted with nitromethane, the organic layer was dried over Na2SO4, solvent was removed in vacuo. The residue was subjected to column chromatography (neutralized SiO2) to sep-arate Fr-A (hexane–AcOEt= 10 : 1) and Fr-B (CHCl3–MeOH= 7 : 1). The solvents were removed from Fr-A to give 33.3 mg (33.7%) of the symmetrical dimer 8 as colorless prisms. mp 220–230°C (hexane–AcOEt) (lit.26): mp 222–224°C); 1H-NMR (DMSO-d6) δ: 11.65 (2H, br s, NH), 7.69 (2H, d, J=7.5 Hz, C4 or 7-H), 7.48 (2H, d, J=7.5 Hz, C4 or 7-H), 7.23 (2H, t, J=7.5 Hz, C5 or 6-H), 7.15 (2H, t, J=7.5 Hz, C5 or 6-H), 2.24 (6H, s,SMe);IR(KBr):3303cm−1;EI-MSm/z: 324 (M+, 60%), 262 (BP).

[2-(3′-Methylthio-1H-indol-2′-yl)-1H-indol-3-yl] Dimeth-ylsulfonium Perchlorate 9 The solvents were removed from Fr-B to give 30.9 mg (23.1%) of the dimeric-dimethylsulfoni-um perchlorate 9 as colorless prisms. mp 130–140°C (dec.) (hexane–AcOEt); 1H-NMR (DMSO-d6) δ: 12.93 (1H, br s, NH), 12.16 (1H, br s, NH), 8.29 (1H, d, J=8.0 Hz, C4 or 7-H), 7.78 (1H, d, J=8.0 Hz, C4 or 7-H), 7.68 (1H, d, J=8.0 Hz, C4 or 7-H), 7.54 (1H, d, J=8.0 Hz, C4 or 7-H), 7.45 (1H, t, J=8.0 Hz, C5 or 6-H), 7.38 (1H, t, J=8.0 Hz, C5 or 6-H), 7.33 (1H, t, J=8.0 Hz, C5 or 6-H), 7.24 (1H, t, J=8.0 Hz, C5 or 6-H), 3.44 (6H, s, SMe2),2.33 (3H,s,SMe); IR (KBr):3567cm−1;EI-MSm/z: 324 (M+−15, 31%), 83 (BP).

(3-Methylthio-5-nitroindol-2-yl) dimethylsulfonium Per-chlorate 10f To a stirred solution of 5-nitro-3-methyl-thioindole 7f (106.0 mg, 0.51 mmol) and DMSO (36 µL, 0.53 mmol) in CH2Cl2 (2 mL), TFAA (105 µL, 0.75 mmol) in CH2Cl2 (0.5 mL) was added dropwise at −78°C under argon atmosphere, the mixture was additionally stirred at rt for 1 h. The reaction mixture was poured into sat. LiClO4 aq. (3 mL) under ice cooling, then the mixture was stirred at rt for 2 h. The precipitates were collected by filtration, dried underreduced pressure to give 142.9 mg (76%) of the compound 10f. mp 180–190°C (dec.); 1H-NMR (acetone-d6) δ: 12.30 (1H, br s, NH), 8.73 (1H, d, J=2.2 Hz, C4-H), 8.34 (1H, dd, J=9.1, 2.2 Hz, C6-H), 7.89 (1H, d, J=9.1 Hz, C7-H), 3.72 (6H, s, SMe2), 2.58 (3H, s, SMe); 13C-NMR (acetone-d6) δ: 144.3, 142.6, 128.6, 124.5, 123.4, 122.3, 118.1, 115.3, 20.4; IR (KBr):3446, 1522, 1337 cm−1; HR-MS (EI): Calcd for C11H12N2O2S2 (M-H)+: 268.0335, Found: 268.0343; Elemental analysis Calcd for C11H13ClN2O6S2: C, 35.82; H, 3.55; N, 7.60. Found: C, 35.83; H, 3.52; N, 7.31.

2,3-Bis(methylthio)-5-nitroindole 11f A mixture of the (3-methylthio-5-nitroindol-2-yl) dimethylsulfonium per-chlorate 10f (251.9 mg, 0.683 mmol) and dipropylamine (5mL, 36.5mmol) was refluxed under argon atmospherewith stirring for 2 h. After the reaction, dipropylamine was removed in vacuo, the residue was purified by column chro-matography (neutralized SiO2: hexane–AcOEt= 2 : 1) to give 133.6 mg (76.9%) of 2,3-bis(methylthio)-5-nitroindole 11f as orange needles. mp 157–160°C (hexane–AcOEt); 1H-NMR (DMSO-d6) δ: 12.18 (1H, br s, NH), 8.35 (1H, dd, J=2.3, 0.5 Hz, C4-H), 8.00 (1H, dd, J=8.9, 2.3 Hz, C6-H), 7.50 (1H, dd, J=8.9, 0.5 Hz, C7-H), 2.64 (3H, s, C2-SMe), 2.30 (3H, s, C3-SMe); 13C-NMR (acetone-d6) δ: 143.2, 142.3, 140.8, 130.7,

118.1, 115.2, 112.3, 110.8, 19.5, 16.8; HR-MS (EI): Calcd forC10H10N2O2S2: 254.0184, Found: 254.0184; Elemental analysis Calcd for C10H10N2O2S2: C, 47.22; H, 3.96; N, 11.01. Found: C, 47.40;H, 4.04;N, 10.79; IR (KBr): 3367, 1508, 1323cm−1; EI-MSm/z: 254 (M+, 87%), 69 (BP).

(3-Methylthio-5-nitroindol-2-yl) bis(trideuteriomethyl)-sulfonium Perchlorate 13 According to the method described above, from 101.7 mg (0.488 mmol) of 5-nitro-3-methylthioindole 7f and 36 µL (0.507 mmol) of DMSO-d6, 73.6 mg (40.2%) of (3-methylthio-5-nitroindol-2-yl)-bis(trideuteriomethyl) sulfonium perchlorate 13 was obtained as yellow prisms. mp 175–180°C; 1H-NMR (acetone-d6) δ: 12.41 (1H, br s, NH), 8.73 (1H, dd, J=2.2, 0.6 Hz, C4-H), 8.34 (1H, dd, J=9.1, 2.2 Hz, C6-H), 7.89 (1H, dd, J=9.1, 0.6 Hz, C7-H), 2.58 (s, 3H, SMe); HR-MS (EI): Calcd forC11H6D6N2O2S2 (M−H)+:247.0717,Found:274.0716,IR(KBr):3365 cm−1.

3-Methylthio-1-tosylindole 7k To a stirred suspension of NaH 46.7 mg (1.17 mmol) in DMF (1 mL), a solution of 3-methylthioindole 7a (88.2 mg (0.540 mmol) in DMF (2 mL) was added dropwise at 0°C under argon atmosphere, the mixture was additionally stirred at rt for 1 h. To the mix-ture, a solution of tosyl chloride 126.6 mg (0.664 mmol) in DMF (1 mL) was added dropwise at rt, then the mixture was heated at 80°C with stirring for 1.5 h. The reaction mixture was poured into ice-water, then extracted with AcOEt, the organic layer was washed with sat. NaHCO3 aq. and ‘brine,’ dried over anhydrous Na2SO4, evaporated to dryness in vacuo. The residual solid was subjected to column-chromatography (hexane–AcOEt= 8 : 1) to separate Fr-A and Fr-B. The solvent was removed from Fr-A to give 112.9 mg (65.8%) of the 3-me-thylthio-1-tosylindole 7k as colorless prisms. Additionally, the solvent was removed from Fr-B to give 24.7 mg (28.0%) of the starting material 7a recovery. mp 108.5–109.5°C (hex-ane–AcOEt); 1H-NMR (CDCl3) δ: 7.96 (1H, dd, J=8.0, 1.0 Hz, C4 or 7-H), 7.74 (2H, d, J=8.6 Hz, C2′,6′-H), 7.55 (1H, dd, J=8.0, 1.0 Hz, C4 or 7-H), 7.45 (1H, s, C2-H), 7.33 (1H, td, J=8.0, 1.0 Hz, C5 or 6-H), 7.25 (1H, td, J=8.0, 1.0 Hz, C5 or 6-H), 7.20 (2H, d, J=8.6 Hz, C3′,5′-H), 2.42 (3H, s, Ts-Me or SMe), 2.32 (3H, s, Ts-Me or SMe); 13C-NMR (CDCl3) δ: 145.1, 135.2, 135.0, 130.6, 129.9, 126.8, 125.2, 124.9, 123.4, 119.8, 117.5, 113.8,21.5,17.7;IR(KBr)3462,1370,1173cm−1;HR-MS(EI):Calcd for C16H15NO2S2: 317.0544, Found: 317.0543; Elemental analysis Calcd for C16H15NO2S2: C, 60.54; H, 4.76; N, 4.41. Found: C, 60.50; H, 4.70; N, 4.15.

2,3-Bis(Methylthio)-1-tosylindole 11k To a stirred solu-tion of 3-methylthio-1-tosylindole 7k (103.5 mg, 0.326 mmol) and DMSO (50 µL, 0.706 mmol) in CH2Cl2 (2 mL), TFAA (140 µL, 1.0 mmol) in CH2Cl2 (0.5 mL) was added dropwise at −78°C under argon atmosphere, the mixture was addition-ally stirred at rt for 1 h. The reaction mixture was re-cooled to −78°C, DMSO (50 µL, 0.706 mmol) in CH2Cl2 (2 mL), then TFAA (140 µL, 1.0 mmol) in CH2Cl2 (0.5 mL) was added drop-wise, the mixture was additionally stirred at rt for 30 min. The reaction mixture was neutralized (pH= 9) with sat. NaHCO3 aq, extracted with CH2Cl2, dried over anhydrous Na2SO4, evaporated to dryness in vacuo.The residurewas purifiedbycolumn chromatography (neutralized SiO2: hexane–AcOEt= 19 : 1) to give 77.0 mg (65.0%) of the title compound 11k as colorless prisms. mp 102.5–104.5°C (hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.34 (1H, ddd, J=8.6, 1.0, 0.7 Hz,

302 Vol. 61, No. 3

C4 or 7-H), 7.78 (2H, d, J=8.3 Hz, C2′,6′-H), 7.65 (1H, ddd, J=8.2, 1.4, 0.7 Hz, C4 or 7-H), 7.39 (1H, ddd, J=8.6, 7.2, 1.4 Hz, C5 or 6-H), 7.31 (1H, ddd, J=8.2, 7.2, 1.0 Hz, C5 or 6-H), 7.18 (2H, d, J=8.3 Hz, C3′,5′-H), 2.43 (3H, s, Ts-Me or SMe), 2.34 (3H,s,Ts-MeorSMe),2.34(3H,s,Ts-MeorSMe); IR(KBr)3448, 1368 cm−1; EI-MSm/z: 363 (M+, 4%), 83 (BP); HR-MS (EI): Calcd for C17H17NO2S3: 363.0421, Found: 363.0423; El-emental analysis Calcd for C17H17NO2S3: C, 56.17; H, 4.71; N, 3.85. Found: C, 55.93; H, 4.66; N, 3.79.

2,3-Bis(methylthio)indole 7b To a stirred solution of 2,3-bis(methylthio)-1-tosylindole 11k (51.7 mg, 0.142 mmol) in EtOH (7 mL) KOH 231.9 mg (4.13 mmol) in EtOH (2 mL) was added at rt under argon atmosphere, The mixture was stirred at rt for 72 h. Excess of water was added to the reaction mix-ture, then the mixture was extracted with AcOEt, washed with brine, dried over anhydrous Na2SO4, evaporated to dryness in vacuo. The residue was subjected to column-chromatography (neutralized SiO2: hexane–AcOEt= 8 : 1) to give 25.1 mg (84.2%) of the title compound 7b as colorless oil. This sample was identical with the same compound 7b prepared from 2-methylthioindole 1b.

N-(3-Methylthioindol-2-yl)pyridinium Bromide 20 To the solution of 3-methylthioindole 7a (156.4 mg, 0.958 mmol) in pyridine (1.0 mL) was added pyridinium bromide perbro-mide 312.9 mg (0.978 mmol) in pyridine (3.0 mL) dropwise at rt under argon atomosphere, then the mixture was stirred additionally for 30 min at rt. The precipitates were col-lected by filtration to give 196.0mg (64.0%) of pure N-(3-methylthioindol-2-yl) pyridinium bromide 20. Additionaly, the solventwasremovedfromthefiltratetodryness in vacuo, the residue was purified by column chromatography (neutralizedSiO2: CHCl3–MeOH= 10 : 1) to give 33.4 mg (10.9%) of the 2nd crop. Totally 229.6 mg (74.9%) of the compound 20 was obtained as yellow prisms. mp 240–250°C (dec.); 1H-NMR (DMSO-d6) δ: 12.98 (1H, br s, NH), 9.40 (2H, dd, J=6.6, 1.0 Hz, C2′,6′-H), 8.90 (1H, td, J=7.8, 1.0 Hz, C4′-H), 8.44 (2H, dd, J=7.8, 6.6 Hz, C3′,5′-H), 7.83 (1H, d, J=7.9 Hz, C4 or 7-H), 7.63 (1H, d, J=8.2 Hz, C4 or 7-H), 7.43 (1H, dd, J=8.2, 7.2 Hz, C5 or 6-H), 7.33 (1H, dd, J=7.9, 7.2 Hz, C5 or 6-H), 2.33 (3H, s, SMe); 13C-NMR (CD3OD) δ: 149.0, 147.2, 137.3, 135.9, 129.4, 128.8, 126.8, 123.2, 121.4, 113.8, 104.9, 19.4; IR (KBr):3446 cm−1;EI-MSm/z: 241 (M+,13%),225(BP);HR-MS(EI):Calcd for C14H12N2S (M−H)+: 240.0721 Found: 240.0727; Ele-mental analysis Calcd for C14H13BrN2Swith1/3H2O: C, 51.38; H, 4.21; N, 8.56. Found: C, 51.45; H, 4.06; N, 8.30.

2-Bromo-3-methylthio-5-nitroindole 21f To a solu-tion of 3-methylthio-5-nitroindole 7f (104.1 mg, 0.500 mmol) in AcOEt (2.0 mL), NBS 90.9 mg (0.511 mmol) was added at −25°C under shading argon atmosphere, then the mixture was stirred at rt for 15 min. After the reaction, NaBH4CN (1 mg) was added, stirred additionally for 25 min, then the mixture was poured into ice-water, extracted with AcOEt, dried over anhydrous Na2SO4, evaporated in vacuo to dryness. The residue was purified by column chromatography (neutralizedSiO2: hexane–AcOEt) to give 114.9 mg (80.1%) of the com-pound 21f as yellow prisms. mp 190–195°C (dec., hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.74 (1H, br s, NH), 8.66 (1H, d, J=2.0 Hz, C4-H), 8.14 (1H, dd, J=8.8, 2.0 Hz, C6-H), 7.38 (1H, d, J=8.8 Hz, C7-H), 2.36 (3H, s, SMe); 13C-NMR (acetone-d6) δ: 143.4, 140.5, 129.8, 121.3, 118.7, 115.7, 112.7, 111.3, 19.3; EI-MS m/z: 286 (M+, 95%), 288 (M++2, BP); HR-MS (EI):

Calcd for C9H779Br N2O2S (M+): 285.9412 Found: 285.9420;

Calcd for C9H781Br N2O2S (M++2): 287.9391 Found: 287.9383.

Elemental analysis Calcd for C9H7BrN2O2S: C, 37.65; H, 2.46; N, 9.76. Found: C, 38.03; H, 2.61; N, 9.34.

2-Bromo-3-methylthio-1-tosylindole 21k To a solution of 3-methylthio-1-tosylindole 7k (99.0 mg, 0.311 mmol) in CHCl3 (2.0 mL), NBS (92.4 mg, 0.519 mmol) was added at 0°C under shading argon atmosphere, then the mixture was stirred at rt for 25 min, NBS (18.9 mg, 0.106 mmol) was additionally added, then the mixture was stirred for 35 min. After the reac-tion, solution of Na2S2O3 (153.1 mg, 0.617 mmol) in H2O (2 mL) was added to the mixture, then stirred for 25 min. The mix-ture was extracted with CHCl3, dried over anhydrous Na2SO4, evaporated in vacuo to dryness. The residue was purified bycolumn chromatography (neutralized SiO2: hexane–benzene= 1 : 1) to give 64.1 mg (54.9%) of the compound 21k as colorless prisms. mp 91.5–93°C (hexane–AcOEt); 1H-NMR (CDCl3) δ: 8.29 (1H, dd, J=8.4, 1.1 Hz, C4 or 7-H), 7.76 (2H, d, J=8.3 Hz, C2′,6′-H), 7.62 (1H, dd, J=7.2, 1.2 Hz, C4 or 7-H), 7.35 (1H, ddd, J=8.4, 7.2, 1.2 Hz, C5 or 6-H), 7.30 (1H, td, J=7.2, 1.1 Hz, C5 or 6-H), 7.21 (2H, d, J=8.3 Hz, C3′,5′-H), 2.34 (3H, s, Ts-Me or SMe), 2.27 (3H, s, Ts-Me or SMe); 13C-NMR (CDCl3) δ: 145.5, 137.3, 135.2, 130.4, 129.8, 127.2, 125.4, 124.2, 119.7, 119.4, 116.6, 115.4, 21.6, 17.9; IR (KBr) 3447, 1389cm−1; El-emental analysis Calcd for C16H14BrNO2S2: C, 48.49; H, 3.56; N, 3.53. Found: C, 48.46; H, 3.60; N, 3.18; EI-MS m/z: 395 (M+, 5%), 397 (M++2, 6%), 57 (BP).

Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Min-istry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by the “Foundation of Encouragement for Joint Research” from Toho University.

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