Transition-metal-free Coupling Reaction of Dithiocarbamates with

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Transition-metal-free Coupling Reaction of Dithiocarbamates with Indoles: C-S Bond Formation Azim Ziyaei Halimehjani, Sahar Shokrgozar, and Petr Beier J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00206 • Publication Date (Web): 25 Apr 2018 Downloaded from http://pubs.acs.org on April 25, 2018

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The Journal of Organic Chemistry

Transition-metal-free Coupling Reaction of Dithiocarbamates with Indoles: C-S Bond Formation Azim Ziyaei Halimehjani,*,† Sahar Shokrgozar,‡ Petr Beier*,‡

†

Faculty of Chemistry, Kharazmi University, P. O. Box 15719-14911, 49 Mofateh St.,

Tehran, Iran. E-mail: [email protected]; Fax: +98 (21) 88820992; Tel: +98 (21) 88848949. ‡

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic. E-mail: [email protected]

ABSTRACT

A one-pot three-component route for the direct introduction of dithiocarbamates into indoles using a C-H sulfenylation strategy mediated by molecular iodine is disclosed. Various indole derivatives including 1-methylindole, 2-methylindole, 3-methylindole and 5-substituted indoles were applied successfully in this protocol to afford diverse indole-dithiocarbamates containing the dithiocarbamate group on the position two or three in good to high yields. The reactions do not require transition metals or disulfiram, use an environmentally benign solvent and simple commercially available starting materials.

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The formation of C-S bonds is important in synthetic organic chemistry for the construction of various synthetic and natural biologically active compounds.1 Many reports exist for direct the C-H sulfenylation of indoles with thiols or disulfides. Various catalytic systems such as Pd/Al2O3/CuCl2,2 NBS,3 NCS,4 I2/DMSO,5 I2/air,6 NaOH/DMSO,7 K2CO3/DMSO,8 I2/H2O2,9 I2/TBHP,10 (NH4)2S2O8,11 FeF3/I2,12 N-thioalkyl- and N-thioarylphthalimides/MgBr2,13 CpCo(CO)I2/Cu(OAc)2/In(OTf)314 have been developed for the direct C-S bond formation via a C-H thiolation strategy. Notably, most of the reported methods are applicable for 3-sulfenylation of indoles; however, 2-sulfenylation of indoles is rare.10,

15

While numerous methods are

available for direct C-S bond formation via direct C-H sulfenylation of indoles with thiols and disulfides, a C-S bond formation through the direct introduction of dithiocarbamates into indoles has not been reported to date. The chemistry of dithiocarbamates is well known for their widespread applications in agriculture,16 polymer chemistry,17 and coordination chemistry.18 Recently, dithiocarbamates have been used as intermediates in synthetic organic chemistry for the construction of biologically active compounds.19 Various heterocyclic compounds containing dithiocarbamate groups

including

dithiocarbamates,

chromone-dithiocarbamate,

triazole–dithiocarbamates,

benzimidazole-dithiocarbamates,

benzodioxole-

indole-dithiocarbamates,

and

quinazolinone-dithiocarbamate have been introduced as potential anticancer agents.20 For this reason, methods of introduction of dithiocarbamate groups into heterocyclic compounds are useful in the design of novel biologically active compounds. Recently, Jiao et al. reported an efficient protocol for C-H sulfenylation of imidazohetecocycles with disulfiram in the presence of catalytic amount of iodine and FeF3 in dichloroethane at 80 °C (Scheme 1a).21 The chemistry 2 ACS Paragon Plus Environment

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and biological activity of indole-dithiocarbamates have been less investigated, presumably due to the lack of efficient procedures for their synthesis. Brassinin and isobrassinin are the most famous indole-dithiocarbamate compounds.22 Przheval'skii et al. reported the synthesis of S(indolyl-3) diethyl dithiocarmamates via Fischer indol synthesis (Scheme 1b).23 In addition, Krasovskiy et al. reported the synthesis of S-(indolyl-3) dimethyldithiocarbamate using metalated indole (Grignard reagent) and tetramethylthiuram Disulfide (Scheme 1c).24 Due to a widespread application of indoles and dithiocarbamates and their importance in drug discovery, the development of elegant technologies enabling synthesis of compounds containing both the indole and the dithiocarbamate groups in a single structure is in high demand. For this purpose, a direct reaction of an amine, carbon disulfide and an indole in the presence of iodine under transition-metal-free conditions was developed (Scheme 1d).

Scheme 1. Published and proposed introduction of dithiocarbamates into nitrogen heterocyles.



C-H sulfenylation of indoles with dithiocarbamates was optimized using 1-methylindole, CS2, and diethylamine as a model reaction (Table 1). Initially, we observed that the reaction of diethylamine (2 equiv) with CS2 (3 equiv) in ethanol for 10 min., followed by the addition of 1methylindole (0.5 mmol, 1 equiv) and iodine (25 mol %) and stirring for 24 h at room temperature afforded only a trace amount of 2a (Table 1, entry 1). Performing the same reaction with 50 mol % of iodine gave a similar result (Table 1, entry 3). However, increasing the reaction temperature to reflux, afforded the product 2a in 45% isolated yield (Table 1, entry 6). Under these conditions, various solvents such as methanol, water, acetonitrile, DMF, toluene, THF, and petroleum ether were screened and afforded 2a, albeit in unsatisfactory yield (Table 1, entries 7–13). In addition, a low yield (20%) of 2a was obtained under solvent-free conditions (Table 1, entry 14). We observed that by increasing the amount of iodine to 100 mol % in ethanol, the yield significantly improved to 65% (Table 1, entry 16). Attempts to improve the product yield by using iodine in the presence of various oxidants such as TBHP, H2O2, DMSO gave unsatisfactory results (Table 1, entrie 17–19). Furthermore, performing the reaction under conditions suitable for thiolation of indoles with thiols and disulfide by using NaOH/DMSO,7 K2CO3/DMSO,8 and NBS3 gave no product formation (Table 1, entries 20–22). In summary, stirring diethylamine (2 equiv) and CS2 (3 equiv) at room temperature for 10 min., followed by addition of 1-methylindole (1 equiv) and iodine (1 equiv) and stirring for 24 h at 60 °C was considered as optimal reaction conditions.


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Table 1. Optimization of the reaction conditions.a

Entry

Catalyst

Oxidant

Solvent

t (h)/Temp (°C)

Yield (%)

(x mol %) (y mol %) 1

I2 ( 25)

-

EtOH

24/rt

trace

2

I2 ( 25)

-

EtOH

3/reflux

trace

3

I2 (50)

-

EtOH

24/rt

trace

4

I2 (50)

-

EtOH

24/50

20

5

I2 (50)

-

EtOH

6/reflux

35

6

I2 (50)

-

EtOH

24/reflux

45

7

I2 (50)

-

MeOH

24/reflux

30

8

I2 (50)

-

H2O

24/70

trace

9

I2 (50)

-

CH3CN

24/reflux

20

10

I2 (50)

-

DMF

24/70

25

11

I2 (50)

-

toluene

24/70

10

12

I2 (50)

-

THF

24/reflux

30

13

I2 (50)

24/reflux

10

14

I2 (50)

-

Solvent-free

24/70

20

15

I2 (75)

-

EtOH

24/reflux

45

16

I2 (100)

-

EtOH

24/60

65

17

I2 (50)

TBHP(100)

EtOH

24/reflux

15

-

Petroleum ether

18

I2 (50)

DMSO (100)

EtOH

24/reflux

trace

19

I2 (50)

H2O2 (100)

EtOH

24/70

30

20

NaOH (200)

DMSO

DMSO

24/100

NRb

21

K2CO3 (50)

DMSO

DMSO

6/70

NR

22

NBS(120)

CH2Cl2

3/ice bath

trace

a

-

Reaction conditions: 1-methylindole (0.5 mmol), diethylamine (1 mmol),

CS2 (1.5 mmol), catalyst (x mol %) , oxidant (y mol %), solvent (3 mL); [b] NR = no reaction.



The scope of the reaction under optimized reaction conditions was examined using various commercially available secondary amines and indoles. As shown in Table 2, all tested acyclic and cyclic secondary amines such as dimethylamine, diethylamine, dipropylamine, pyrrolidine, piperidine, azepane, and morpholine afforded the corresponding products 2 in high yields. Indole, 1-methylindole, 2-methylindole, 5-bromoindole and 5-methoxyindole were applied successfully in this protocol to afford products containing the dithiocarbamate group substituted in the position three. The presence of an electron-withdrawing group on the carbon atom at the position five in the indole, decreased the yield significantly (Table 2, compound 2p). Interestingly, by performing the reaction with 3-methylindole, the dithiocarbamate group was substituted on the carbon at the position two. It was also observed that primary amines were not suitable starting materials for this reaction and gave a mixture of isothiocyanate, starting materials and other unidentified side-products. A proposed mechanism for this transformation is depicted in Scheme 2. Initially, the reaction of an amine with CS2 provides the intermediate dithiocarbamic acid A, which reacts with molecular iodine to produce the intermediate B. The intermediate B may directly undergo electrophilic substitution reaction with 1a to afford the intermediate D or react with another equivalent of A to provide disulfiram C. Disulfiram C can furnish the intermediate B by the reaction with molecular iodine or HI. Finally, removal of HI from D affords the product 2a. The proposed mechanism also explains why one equivalent of iodine is needed for this transformation. A control experiment without using indole afforded the corresponding disulfiram C in good yield. By using disulfiram in this protocol, a similar result was obtained in the presence of 0.5 equivalent of iodine. For 3-substituted indoles, the reaction took place on the position two, via a similar mechanism. 6 ACS Paragon Plus Environment

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Scheme 2. Proposed mechanism for C-H functionalization of indoles with dithiocarbamates. In conclusion, an efficient and environmetally benign protocol for the synthesis of indole-dithiocarbamates is reported for the first time via iodine-mediated one-pot threecomponent reaction of secondary amines, CS2 and indoles. This metal-free method proceeds in environmetally benign solvent and allows for efficient introduction of the dithiocarbamate group by C-H sulfenylation of indoles at positions two or three.



Table 2. Diversity in the synthesis of indole-dithiocarbamates 2

a

Isolated yield. Reaction conditions: amine (2 mmol), CS2 (3 mmol)

indole (1 mmol), iodine (1 mmol), EtOH (6 mL), 24 h at 60 °C under N2 or Ar. 8 ACS Paragon Plus Environment

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EXPERIMENTAL SECTION General. All chemicals and solvents were obtained from commercial sources and used as received. The 1H and 13C NMR spectra of products were recorded on a Bruker AMX 300 and 400 MHz spectrometers referenced to internal Me4Si at 0.00 ppm. Reaction monitoring was carried out by thin-layer chromatography using TLC silica gel 60 F254 plates. IR spectra were recorded on an FTIR instrument using a film technique or KBr disc and wave numbers are reported in cm-1. Elemental analyses were conducted with a Perkin-Elmer 2004 Series II CHN analyzer. High-resolution mass spectra (HRMS) were recorded on an Agilent 7890A gas chromatograph coupled with a Waters GCT Premier orthogonal acceleration time-of-flight detector using electron impact (EI) ionization. General procedure for synthesis of indole-dithiocarbamates 2a-u: In a Schlenk flask under Ar or N2 atmosphere, EtOH (6 mL), a secondary amine (2 mmol, 2 equiv) and CS2 (3 mmol, 0.18 mL, 3 equiv.) were added respectively. After stirring for 10 min at room temperature, an indole (1 mmol, 1 equiv) and I2 (1 mmol, 0.254 g, 1 equiv) was added and the reaction mixture was further stirred at 60 °C for 24 h. Aqueous NaHSO3 solution was added and the product was extracted into EtOAc (3 × 10 mL). The organic extracts were combined, washed with water (2 × 10 mL), dried with anhydrous Na2SO4 or MgSO4, and evaporated to give crude products. Chromatography on silica gel, elution with EtOAc /petroleum ether (1:15) afforded pure products. 1-Methyl-1H-indol-3-yl diethylcarbamodithioate (2a). Yellow solid; Yield 181 mg (65%); mp 117-118°C; IR (KBr) ν 1508, 1482, 1458, 1267, 1203 ,740 cm-1; 1H NMR (300 MHz, DMSOd6) δ 7.63 (s, 1H, H-Ar), 7.52 (td, J = 8.2, 0.9 Hz, 1H, H-Ar), 7.35 (td, J = 7.8, 1.0 Hz, 1H, HAr), 7.21 (m, 1H, H-Ar), 7.10 (m, 1H, H-Ar), 3.97–3.88 (m, 4H), 3.84 (s, 3H), 1.37 (t, J = 7.0 9 ACS Paragon Plus Environment


Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 196.3, 137.6, 137.0, 129.8, 121.8, 120.1, 118.7, 110.4, 99.1, 49.8, 46.9, 32.8, 12.8, 11.4 ppm; Anal. Calcd (%) for C14H18N2S2 (MW = 278.44): C, 60.39; H, 6.52; N, 10.06; Found: C, 60.34; H, 6.24; N, 9.88. 1-Methyl-1H-indol-3-yl pyrrolidine-1-carbodithioate (2b). Cream solid; Yield: 218 mg (79%); mp 163-164 °C; IR (KBr) ν 1511, 1460, 1425, 1266, 1228, 1109, 1030, 959 ,734 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.59 (s, 1H, , H-Ar), 7.51 (dd, 1H, J = 8.3, 1.1 Hz, H-Ar), 7.39 (dd, 1H, J = 7.9, 1.1 Hz, H-Ar), 7.21 (m, 1H, H-Ar), 7.09 (m, 1H, H-Ar), 3.86–3.82 (m, 5H), 3.74 (t, 2H, J = 7.0 Hz), 2.13–2.03 (m, 2H), 1.96–1.87 (m, 2H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 192.3, 137.4, 137.0, 129.7, 121.8, 120.1, 118.8, 110.5, 98.9, 55.4, 50.7, 32.9, 26.0, 23.8 ppm; Anal. Calcd. (%) for C14H16N2S2 (MW = 276.4): C, 60.83; H, 5.83; N, 10.13; Found: C, 60.95; H, 5.98; N, 10.50. 1-Methyl-1H-indol-3-yl piperidine-1-carbodithioate (2c). Cream solid; Yield: 162 mg (56%); mp 176-177 °C; IR (KBr) ν 2093, 1513, 1431, 1238, 1134, 1113, 1005, 968, 732 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.51 (d, 1H, J = 8.3Hz, H-Ar), 7.36 (td, 1H, J = 7.1, 1.2 Hz, H-Ar), 7.21 (m, 1H, H-Ar), 7.10 (m, 1H, H-Ar), 4.17-4.98 (brs, 4H), 3.84 (s, 3H), 1.68-1.59 (brs, 6H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 195.3, 137.6, 137.1, 129.8, 121.8, 120.1, 118.7, 110.4, 99.1, 53.1, 52.9, 32.8, 26.0, 25.3, 23.6 ppm; Anal. Calcd. (%) for C15H18N2S2 (MW= 290.4): C, 62.03; H, 6.25; N, 9.64; Found: C, 61.75; H, 6.36; N, 9.36. 1-Methyl-1H-indol-3-yl morpholine-4-carbodithioate (2d). Cream solid; Yield: 184 mg (63%); mp 176-177 °C; IR (KBr) ν 1509, 1462, 1427, 1372, 1342, 1116, 1005, 989 ,737 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.52 (d, 1H, J = 8.2 Hz, H-Ar), 7.37 (d, 1H, J = 7.8 Hz, H-Ar), 7.25–7.19 (m, 1H, H-Ar), 7.10 (t, 1H, J = 7.4 Hz, H-Ar), 4.17 (brs, 4H), 3.85 (s, 3H), 3.72 (t, 4H, J = 7.8 Hz) ppm;

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C NMR (75 MHz, DMSO-d6) δ 197.1, 137.6, 137.1, 129.7, 10 ACS Paragon Plus Environment

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121.9, 120.2, 118.7, 110.5, 98.4, 65.7 (2C), 51.9, 51.1, 32.9 ppm; Anal. Calcd (%) for C14H16N2OS2 (MW = 292.4): C, 57.50; H, 5.52; N, 9.58; Found: C, 57.38; H, 5.69; N, 9.40. 1-Methyl-1H-indol-3-yl azepane-1-carbodithioate (2e). Cream crystal; Yield: 198 mg (65%); mp 149-150 °C; IR (KBr) ν 2915, 1510, 1446, 1409, 1270, 1197, 1116, 945, 734 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.21 (m, 1H, H-Ar), 7.10 (m, 1H, H-Ar), 4.10–4.06 (m, 4H), 3.84 (s, 3H), 1.96–1.88 (m, 2H), 1.79– 1.71 (m, 2H), 1.59–1.52 (m, 4H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 196.1, 137.6, 137.1, 129.7, 121.8, 120.1, 118.7, 110.5, 99.2, 55.7, 52.7, 32.8, 27.1, 26.1, 25.9, 25.4 ppm; Anal. Calcd (%) for C16H20N2S2 (MW= 304.47): C, 63.12; H, 6.62; N, 9.20; Found: C, 62.78; H, 6.64; N, 9.09. 2-Methyl-1H-indol-3-yl diethylcarbamodithioate (2f). White yellow solid; Yield 181 mg (65%); mp 119-120 °C; IR (KBr) ν 3232 (NH), 1490, 1454, 1416, 1267, 1203, 980, 747 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H, N-H), 7.34 (m, 1H, H-Ar), 7.24 (m, 1H, H-Ar), 7.09– 6.97 (m, 2H, H-Ar), 3.97–3.90 (m, 4H), 2.32 (s, 3H), 1.39 (t, 3H, J= 7.0 Hz), 1.17 (t, 3H, J= 6.9 Hz) ppm; 13C NMR (75 MHz, DMSO-d6) δ 195.1, 143.9, 135.4, 130.3, 120.9, 119.7, 117.6, 111.1, 97.5, 49.7, 46.7,12.8, 12.0, 11.4 ppm; Anal. Calcd (%) for C14H18N2S2 (MW = 278.44): C, 60.39; H, 6.52; N, 10.06; Found: C, 60.54; H, 6.54; N, 9.98. 2-Methyl-1H-indol-3-yl azepane-1-carbodithioate (2g). White yellow solid; Yield 198 mg (65%); mp 79-80 °C; IR (KBr) ν 3228 (NH), 1453, 1417, 1363, 1291, 1202, 854 ,746 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H, N-H), 7.32 (m, 1H, H-Ar), 7.24 (m, 1H, H-Ar), 7.07–6.93 (m, 2H, H-Ar), 4.12–4.06 (m, 4H), 2.32 (s, 3H), 1.98–1.90 (m, 2H), 1.79–1.71 (m, 2H), 1.62–1.45 (m, 4H) ppm;

13

C NMR (75 MHz, DMSO-d6) δ 195.9, 143.9, 135.4, 130.3,



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120.9, 119.7, 117.5, 111.1, 97.6, 55.8, 52.7, 27.1, 26.1, 25.8, 25.3, 11.9 ppm; Anal. Calcd (%) for C16H20N2S2 (MW = 304.47): C, 63.12; H, 6.62; N, 9.20; Found: C, 62.79; H, 6.89; N, 8.90. 2-Methyl-1H-indol-3-yl dimethylcarbamodithioate (2h). White solid; Yield: 188 mg (75%); mp 180-182 °C; IR (KBr) ν 3391 (NH), 3275 (NH), 1500, 1453, 1377, 1248, 1228, 1148, 973, 750 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H, N-H), 7.51 (m, 1H, H-Ar), 7.28 (m, 1H, HAr), 7.19-7.15 (m, 2H), 3.63 (s, 3H), 3.61 (s, 3H), 2.39 (s, 3H) ppm;

13

C NMR (101 MHz,

CDCl3) δ 198.2, 143.2, 135.2, 130.3, 121.9, 120.8, 118.4, 111.0, 99.9, 46.1, 41.8, 12.4 ppm; HRMS Calcd for C12H14N2NaS2 (M+Na)+: 273.0496; Found: 273.0491. 2-Methyl-1H-indol-3-yl pyrrolidine-1-carbodithioate (2i). White solid; Yield: 190 mg (69%); mp 178-180 °C; IR (KBr) ν 3388 (NH), 3226 (NH), 1437, 1157, 1001, 951, 741 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H, N-H), 7.53 (m, 1H, H-Ar), 7.29 (m, 1H, H-Ar), 7.18-7.14 (m, 2H), 4.00–3.95 (m, 4H), 2.42 (s, 3H), 2.22–2.17 (2H, m), 2.06–2.02 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 193.8, 143.1, 135.2, 130.3, 121.9, 120.8, 118.4, 111.1, 99.3, 55.5, 50.9, 26.5, 24.4, 12.5 ppm; HRMS Calcd for C14H17N2S2 (M+H)+: 277.0833; Found: 277.0828. 2-Methyl-1H-indol-3-yl dipropylcarbamodithioate (2j). Viscous yellow oil; Yield: 230 mg (75%); IR (film) ν 3388 (NH), 3285 (NH), 2964, 2930, 2873, 1483, 1455, 1414, 1238, 988, 741 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H, N-H), 7.49 (m, 1H, H-Ar), 7.29 (m, 1H, HAr), 7.17–7.15 (m, 2H, H-Ar), 3.97–3.88 (m, 4H), 2.40 (s, 3H), 2.02–1.94 (m, 2H), 1.88–1.80 (m, 2H), 1.11 (t, 3H, J = 7.4 Hz), 0.97 (t, 3H, J = 7.4 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ 197.1, 143.2, 135.2, 130.4, 121.9, 120.7, 118.5, 111.0, 99.99, 57.5, 54.6, 21.2, 19.8, 12.5, 11.3, 11.2 ppm; HRMS Calcd for C16H23N2S2 [M+H]+ :307.1303; Found: 307.1298. 2-Methyl-1H-indol-3-yl dibenzylcarbamodithioate (2k). Yellow solid; Yield 298 mg (74%); mp 130-133 °C; IR (KBr) ν 3407 (NH), 2923, 1619, 1454, 1414, 1352, 1212, 1142, 957, 739, 698 12 ACS Paragon Plus Environment

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cm-1; 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H, N-H), 7.55-7.19 (m, 14H, H-Ar), 5.39 (brs, 2H), 5.19 (brs, 2H), 2.48 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 200.6, 143.3, 135.8 (2C), 135.2, 130.3, 129.0, 128.9, 128.1, 127.9, 127.4, 127.3, 122.1, 120.9, 118.5, 111.0, 100.0, 57.0, 54.2, 12.6 ppm; HRMS Calcd for C24H22N2NaS2 (M+Na)+: 425.1122; Found: 425.1117. 1H-Indol-3-yl pyrrolidine-1-carbodithioate (2l). Yellow solid; Yield 178 mg (68%); mp 162165 °C; IR (film) ν 3393 (NH), 3257 (NH), 1437, 11559, 1000, 953, 741 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H, N-H), 7.63 (m, 1H, H-Ar), 7.37–7.32 (m, 2H, H-Ar), 7.25–7.19 (m, 2H, H-Ar), 4.02–3.93 (m, 4H), 2.23–2.16 (m, 2H), 2.08–2.01 (m, 2H) ppm;

13

C NMR (101

MHz, CDCl3) δ 194.4, 136.2, 132.6, 129.2, 122.8, 120.9, 119.3, 112.0, 102.1, 55.6, 51.0, 26.5, 24.4 ppm; HRMS Calcd for C13H14N2NaS2 (M+Na)+: 285.0496; Found: 285.0492. 1H-Indol-3-yl dimethylcarbamodithioate (2m). Cream solid; Yield: 154 mg (65%); mp 181-183 °C; IR (KBr) ν 3402 (NH), 3326 (NH), 1505, 1457, 1411, 1371, 1252, 1239, 1147, 972, 738 cm; H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H, N-H), 7.60 (m, 1H, H-Ar), 7.39 (m, 1H, H-Ar),

1 1

7.35 (d, 1H, J = 2.7 Hz, H-Ar), 7.27–7.20 (m, 2H, H-Ar), 3.62 (s, 6H) ppm;

13

C NMR (101

MHz, CDCl3) δ 198.8, 136.2, 132.6, 129.2, 122.9, 121.0, 119.3, 111.9, 102.8, 46.1, 41.9 ppm; HRMS calcd for C11H13N2S2 [M+H]+, 237.0520; Found 237.0514. 1H-Indol-3-yl azepane-1-carbodithioate (2n). White yellow solid; Yield 160 mg (55%); mp 162-163 °C; IR (film) ν 3253 (NH), 2934, 1487, 1418, 1269, 1197, 735 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H, N-H), 7.60 (dd, J= 7.7, 1.4, 1H, H-Ar), 7.41–7.38 (m, 2H, H-Ar), 7.27–7.19 (m, 2H, H-Ar), 4.24 (t, 2H, J = 6.0 Hz), 4.16 (t, 2H, J = 6.2 Hz), 2.08–2.02 (m, 2H), 1.96–1.90 (m, 2H), 1.75-1.67 (m, 4H) ppm; 13C NMR (101 MHz, CDCl3) δ 197.7, 136.2, 132.7, 129.3, 122.8, 121.0, 119.3, 111.9, 102.9, 56.5, 53.2, 27.8, 26.8, 26.7, 26.2 ppm; HRMS Calcd for C15H19N2S2 (M+H)+: 291.0990; Found: 291.0984. 13 ACS Paragon Plus Environment


1H-Indol-3-yl diethylcarbamodithioate (2o). Cream solid; yield: 172 mg (65%); mp 187-188 °C; IR (KBr) ν 3368 (NH), 1495, 1421, 1335, 1272, 1199, 974 ,756 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.66 (s, 1H, N-H), 7.6 (d, 1H, J = 2.7 Hz, H-Ar), 7.44 (d, 1H, J = 8.0 Hz, H-Ar), 7.34 (d, 1H, J = 7.7 Hz, H-Ar), 7.12 (m, 1H, H-Ar), 7.02 (m, 1H, H-Ar), 3.96–3.89 (m, 4H), 1.37 (t, 3H, J = 7.0 Hz), 1.17 (t, 3H, J = 7.1 Hz) ppm; 13C NMR (75 MHz, DMSO-d6) δ 195.5, 136.4, 134.1, 129.4, 121.7, 119.9, 118.5, 112.1, 100.2, 49.6, 46.7, 12.8, 11.4 ppm; Anal. Calcd (%) for C13H16N2S2 (MW: 264.41) C, 59.05; H, 6.10; N, 10.59; Found C, 58.88; H, 6.02; N, 10.37. 5-Bromo-1H-indol-3-yl morpholine-4-carbodithioate (2p). White solid; Yield: 161 mg (45%); mp: decomposed at >170 °C; IR (film) ν 3196 (NH), 3163 (NH), 2916, 2856, 1455, 1421, 1267, 1231, 1112, 1029 cm-1; 1H NMR (400 MHz, DMSO-d6+CDCl3) δ 11.27 (s, 1H, N-H), 7.49 (m, 1H, H-Ar), 7.35-7.28 (m, 2H, H-Ar), 7.180 (m, 1H, H-Ar), 4.18 (brs, 4H), 3.76 (brs, 4H) ppm; C NMR (101 MHz, DMSO-d6 + CDCl3) δ 198.6, 135.5, 134.8, 131.3, 125.0, 121.5, 113.9,

13

113.8, 100.2, 66.2 (2C), 52.0, 50.9 ppm; HRMS Calcd for C13H14BrN2OS2 (M+H)+: 356.9731; Found: 356.9727. 5-Methoxy-1H-indol-3-yl pyrrolidine-1-carbodithioate (2q). White solid; Yield: 248 mg (85%); mp 134-137 °C; IR (KBr) ν 3365 (NH), 3241 (NH), 1622, 1584, 1485, 1437, 1288, 1206, 1169, 1037, 1004, 955 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H, N-H), 7.24-7.19 (m, 2H, HAr), 7.05 (d, 1H, J =2.4 Hz, H-Ar), 6.86 (dd, 1H, J = 8.8, 2.5 Hz, H-Ar), 4.00 (t, 2H, J = 7.0 Hz), 3.95 (t, 2H, J = 6.9 Hz), 3.88 (s, 3H), 2.23-2.16 (m, 2H), 2.08-2.01 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 194.6, 155.1, 133.3, 131.3, 129.9, 113.2, 112.9, 101.2, 100.6, 55.8, 55.7, 51.0, 26.5, 24.4 ppm; HRMS Calcd for C14H16N2NaOS2 [M+Na]+: 315.0602; Found: 315.0597.


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5-Methoxy-1H-indol-3-yl morpholine-4-carbodithioate (2r). Cream solid; Yield: 203 mg (66%); mp 163-166 °C; IR (KBr) ν 3405 (NH), 3298 (NH), 1623, 1583, 1485, 1462, 1428, 1266, 1232, 1211, 1172, 1107, 1030, 990, 805 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H, N-H), 7.30-7.24 (m, 2H, H-Ar), 7.02 (dd, J = 3.0, 0.7 Hz, 1H, H-Ar), 6.90 (dd, 1H, J= 8.8, 2.5 Hz, HAr), 4.31(brs, 4H), 3.89-3.84 (m, 7H) ppm; 13C NMR (101 MHz, CDCl3) δ 199.2, 155.2, 133.4, 131.2, 130.0, 113.4, 112.8, 101.1, 100.8, 66.4 (2C), 55.8, 52.5, 51.3 ppm; HRMS Calcd for C14H17N2O2S2 [M+H]+: 309.0731; Found: 309.0727. 3-Methyl-1H-indol-2-yl pyrrolidine-1-carbodithioate (2s). White solid; Yield: 174 mg (63%); mp 163-165 °C; IR (KBr) ν 3423 (NH), 3301 (NH), 1628, 1442, 1332, 1159, 1002, 954 cm-1; 1

H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H, N-H), 7.63 (m, 1H, H-Ar), 7.38 (td, 1H, J = 8.2, 1.0

Hz, H-Ar), 7.27 (m, 1H, H-Ar), 7.15 (m, 1H, H-Ar), 3.98-3.94 (m, 2H), 3.90-3.86 (m, 2H), 2.40 (s, 3H), 2.22-2.15 (m, 2H), 2.08-2.01 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 191.1, 137.7, 128.3, 123.9, 121.9, 120.2, 119.8, 119.6, 111.2, 55.3, 51.3, 26.5, 24.4, 9.60 ppm; HRMS Calcd for C14H16N2NaS2 [M+Na]+: 299.0653; Found: 299.0647. 3-Methyl-1H-indol-2-yl morpholine-4-carbodithioate (2t). White solid; Yield: 205 mg (70%); mp 193-196 °C; IR (KBr) ν 3279 (NH), 1406, 1271, 1231, 1113, 1037, 991, 871, 746 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H, N-H), 7.65 (d, 1H, J = 8.0 Hz, H-Ar), 7.38 (d, 1H, J = 8.2 Hz, H-Ar), 7.31-7.27 (m, 1H, H-Ar), 7.17 (t, 1H, J = 7.5 Hz, H-Ar), 4.33-4.13 (brs, 4H), 3.85 (t, J = 5.0 Hz, 4H), 2.40 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 195.7, 137.9, 128.3, 124.1, 122.6, 119.8, 119.7, 119.4, 111.2, 66.3, 66.2, 51.6, 51.3, 9.8 ppm; HRMS Calcd for C14H17N2OS2 [M+H]+: 293.0782; Found: 293.0777. 3-Methyl-1H-indol-2-yl azepane-1-carbodithioate (2u). Yellow solid; Yield: 167 mg (55%); mp 131-134 °C; IR (KBr) ν 3395 (NH), 2930, 2852, 1617, 1445, 1415, 1352, 1268, 1165, 946, 738 15 ACS Paragon Plus Environment


cm-1; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H, N-H), 7.63 (m, 1H, H-Ar), 7.38 (td, 1H, J = 8.2, 1.0 Hz, H-Ar), 7.27 (m, 1H, H-Ar), 7.15 (m, 1H, H-Ar), 4.20 (t, J = 6.1 Hz, 2H), 4.07 (t, J = 6.0 Hz , 2H), 2.39 (s, 3H), 2.04-1.95 (m, 2H), 1.95-1.89 (m, 2H), 1.70-1.47 (m, 4H) ppm; 13C NMR (101 MHz, CDCl3) δ 194.7, 137.8, 128.4, 123.8, 122.1, 120.6, 119.8, 119.5, 111.2, 56.1, 53.5, 27.8, 26.7, 26.6, 26.1, 9.6 ppm; HRMS Calcd for C16H20N2NaS2 [M+Na]+: 327.0966; Found: 327.0961.

ASSOCIATED CONTENT Supporting Information Copies of 1H and 13C NMR spectra for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * Email: [email protected] * Email: [email protected]

ACKNOWLEDGMENTS We are grateful to the research council of Kharazmi University for supporting this work. This work was also supported by the Academy of Sciences of the Czech Republic (RVO: 61388963). REFERENCES 16 ACS Paragon Plus Environment

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Transition-metal-free Coupling Reaction of Dithiocarbamates with

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