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Efficient synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chains
Tetrahedron xxx (2016) 1e5
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Efficient synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chains Bowen Li, Shuo Zhou, Shucheng Wang, Xingyi Sun, Zemei Ge *, Runtao Li * State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 March 2016 Received in revised form 1 May 2016 Accepted 3 May 2016 Available online xxx
An efficient method for the synthesis of organic sulfonic acid potassiums containing dithiocarbamate side chains was developed through the reaction of amines, carbon disulfide and sultones in the presence of K3PO4 in water at room temperature. The organic sulfonic acid potassium derivatives are easily transformed into the corresponding organic sulfonic acids, which were further reacted with amines to afford the important organic sulfonamides containing dithiocarbamate side chains. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Dithiocarbamate Sulfonic acid potassium Sulfonic acid Sulfonamide
1. Introduction Sulfonic acid and sulfonic amide are two kinds of important functional groups in medicinal chemistry,1,2 which widely present in biologically active natural products and medicinally valuable compounds.3,4 Therefore, the introduction of both kinds of groups is one of the most commonly used strategies for the lead optimization process in order to improve the desired biological and physical properties of a potential compounds.5 Recent years, dithiocarbamate derivatives have been received considerable attentions because of its important biological activities, such as anesthetic,6 anti-HIV,7 mono glyceride lipase inhibitors,8 anti-tumor agents.9 Therefore, many kinds of dithiocarbamate derivatives have been synthesized.10 However, to the best of our knowledge, it is no report on the direct synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chain. Our group has developed several efficient methodologies for the synthesis of different kinds of dithiocarbamate esters,11 from which some potent anticancer compounds were discovered.12 As the requirement of our work, we urgently hope to develop an efficient method for the synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chains. Recently, Varma et al. have reported an efficient one-pot methodology for the synthesis of unnatural a-amino acids containing the dithiocarbamate side chains through the nucleophilic
* Corresponding authors. Tel.: þ86 10 82801504; e-mail addresses: zmge@bjmu. edu.cn (Z. Ge), [email protected] (R. Li).
ring opening of sulfamidates by in situ generated dithiocarbamate anion (Scheme 1, a).13 Inspired by their work, we envisioned that if replacing the sulfamidates with sultones, the organic sulfonic acid salts containing dithiocarbamate side chains should be formed in one-pot, from which the corresponding sulfonic acid derivatives, such as sulfonic acids, sulfonamides should be easily obtained (Scheme 1, b).
Scheme 1. Synthetic strategy toward sulfonic acid derivatives containing dithiocarbamate side chains.
2. Results and discussion In order to examine the possibility, we initially carried out the reaction of benzylamine (1a), carbon disulfide with g-sultone (2a) in the presence of Al2O3 at room temperature under solvent free conditions.14 To our delight, the desired product (3a) was obtained in 38% yield (Table 1, entry 1). Encouraged by this result, various solvents and bases were screened to optimize the reaction
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Table 1 Optimization of the reaction conditions for the formation of 3aa
Entry
Base
Solvent
Yield(%)b
1c,d 2c 3c 4 5 6 7 8 9 10
d d d NaHCO3 NaHCO3 K3PO4 K2CO3 K2CO3 K3PO4 TEA
d EtOAc MeOH MeOH EtOH Acetone Acetone H2O H2O H2O
38 35 58 75 70 80 83 89 95 85
bond, hydroxyl, alkoxyl, ester and heterocycle, were all well tolerated in this reaction conditions. Then, replacing the g-sultone (2a) with dsultone (2b) to react with carbon disulfide and different amines and the excepted products (3me3o) were also obtained in 73e98% yields. It is important to note that the organic sulfonic acid salts containing dithiocarbamate side chains (3) could be easily transformed into corresponding organic sulfonic acids. Such as compound 3m was treated with 1 equiv HCl (aq, 1M) at room temperature to afford the corresponding sulfonic acid 4m in quantitative yield (Scheme 2).
Scheme 2. Synthesis of compound 4m from 3m.
a
Reaction conditions: 1a (5 mmol, 1 equiv), K3PO4 (1 equiv), CS2 (1.5 equiv) in water (5 mL) at rt for 10 min, then added 2a (1 equiv). b Isolated yield. c No base participated. d The reaction was performed in the solid phase of Al2O3.
conditions (Table 1). We were excited to find that the product 3a could be obtained with a yield of up to 95%, using K3PO4 as base in water at room temperature (Table 1, entry 9). With the optimized reaction conditions in hand, we set out to examine the substrate scope of this methodology (Table 2). A variety of amines were first allowed to react with carbon disulfide and gsultone (2a) under optimized reaction conditions. All the reactions were performed smoothly to give the desired products in good to excellent yields (3ae3l). Generally, the secondary amines provided the expected products in 92e96% yields (3ge3j). Much to our satisfactory, amines with different functional groups including double Table 2 Substrate scope for the reaction of amines, CS2 and sultonesa,b
To further extend the application of this method, we next selected compound 4m to react with various amines and hope to afford the more important organic sulfonamides containing dithiocarbamate side chains 5. After screening the reaction conditions (See Supplementary data, Table 1), it was found that the reaction performed smoothly in the presence of 2,4,6trichloro-1,3,5-triazine (TCT) using acetonitrile as solvent and triethylamine as base at 60 C for 24 h. As shown in Table 3, the optimized reaction conditions were suitable for the different kinds of amines, including primary amines, secondary amines, ammonia, high steric hindrance t-butylamine and low reactively imidazole, to afford the desired products 5ae5j in moderate to good yields.
Table 3 Synthesis of organic sulfonamides containing dithiocarbamate side chains 5.a,b
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Based on relevant reports in the literature11,13 and our observation in the present work, a plausible reaction mechanism for the synthesis of organic sulfonic acid potassiums containing dithiocarbamate side chains has been proposed in Scheme 3. First, amine 1 reacts with CS2 to form intermediate A in the presence of K3PO4, which then goes through intermolecular nucleophilic substitution-ring opening reaction onto 2 to produce the desired product 3.
Scheme 3. Proposed mechanism for the synthesis of 3.
3. Conclusion In conclusion, we have developed an efficient procedure for the synthesis of organic sulfonic acid potassiums containing dithiocarbamate side chains from the reaction of amines, carbon disulfide with sultones using K3PO4 as base in water at room temperature in good to excellent yields. The organic sulfonic acid potassiums containing dithiocarbamate side chains are easily transformed into the corresponding sulfonic acids derivatives, which reacted with amines to afford the important organic sulfonamides containing dithiocarbamate side chains.
3
2.00 (m, 2H); 13C NMR (101 MHz, D2O) d: 198.4, 132.4, 129.6, 115.5, 115.3, 49.7, 49.5, 33.0, 24.3; HRMS (ESI): exact mass calculated for C11H13FKNO3S3 ([MþK]þ): 399.9310, Found: 399.9307. 4.2.3. Potassium 3-(((4-methoxybenzyl)carbamothioyl)thio)propane-1-sulfonate (3c). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 7.09 (d, J¼8.3 Hz, 2H), 6.73 (d, J¼8.3 Hz, 2H), 4.68 (s, 2H), 3.60 (s, 3H), 3.18 (t, J¼7.0 Hz, 2H), 2.92e2.75 (t, 2H), 1.97 dt, J¼14.1, 7.0 Hz, 2H); 13C NMR (101 MHz, D2O) d: 197.8, 158.4, 129.4, 129.1, 114.2, 55.4, 49.8, 33.1, 24.3; HRMS (ESI): exact mass calculated for C12H16KNO4S3 ([MþK]þ): 411.9510, Found: 411.9504. 4.2.4. Potassium-3-(((pyridin-3-ylmethyl)carbamothioyl)thio)propane-1-sulfonate (3d). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 8.42e8.05 (m, 2H), 7.60 (d, J¼7.9 Hz, 1H), 7.22 (dd, J¼7.6, 5.2 Hz, 1H), 4.72 (s, 2H), 3.15 (t, J¼7.1 Hz, 2H), 2.89e2.74 (t, 2H), 1.90 (dt, J¼16.9, 8.4 Hz, 2H); 13C NMR (101 MHz, D2O) d: 199.3, 147.9, 147.7, 137.0, 133.1, 124.4, 49.6, 47.5, 33.0, 24.2; HRMS (ESI): exact mass calculated for C10H13KN2O3S3 ([MþH]þ): 344.9798, Found: 344.9797. 4.2.5. Potassium 3-(((furan-2-ylmethyl)carbamothioyl)thio)propane1-sulfonate (3e). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.36 (s, 1H), 6.31 (m, 2H), 4.68 (s, 2H), 3.23 (t, J¼7.2 Hz, 2H), 2.89 (t, 2H), 1.99 (dt, J¼14.8, 7.3 Hz, 2H); 13C NMR (100 MHz, D2O) d: 98.3, 149.5, 142.9, 110.8, 108.9, 49.8, 43.4, 33.2, 24.2; HRMS (ESI): exact mass calculated for C9H12KNO4S3 ([MþK]þ): 371.9197, Found: 371.9195.
4. Experimental section 4.1. General information Available reagents and solvents were purchased from commercial sources and were used without further purification. Melting points were determined on a melting point apparatus with a microscope and a hot stage and were uncorrected. All the 1H and 13 C NMR were recorded on a Bruke 400 MHz spectrometer and chemical shifts reported in D2O, CDCl3 or DMSO-d6 with tetramethylsilane as an internal standard. High-resolution mass spectra (HRMS) was recorded using a Bruker Apex IV FTMS instrument. Column chromatography was performed with 200e300 mesh silica gel using flash column techniques.
4.2.6. Potassium 3-((allylcarbamothioyl)thio)propane-1-sulfonate (3f). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 5.99e5.57 (m, 1H), 5.31e4.97 (m, 2H), 4.26 (d, J¼3.8 Hz, 2H), 3.29 (t, J¼6.9 Hz, 2H), 2.98e2.90 (m, 2H), 2.06 (dd, J¼14.4, 7.2 Hz, 2H); 13C NMR (101 MHz, D2O) d: 198.1, 131.8, 116.9, 49.6, 48.9, 32.8, 24.2; HRMS (ESI): exact mass calculated for C7H12KNO3S3 ([MþH]þ): 293.9689, Found: 293.9693.
4.2. General procedure for the synthesis of compounds 3aeo
4.2.7. Potassium 3-((diethylcarbamothioyl)thio)propane-1-sulfonate (3g). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 3.94 (q, J¼6.8 Hz, 2H), 3.75 (q, J¼7.0 Hz, 2H), 3.35 (t, J¼7.1 Hz, 2H), 2.95 (t, 2H), 2.08 (m, J¼9.6, 4.8 Hz, 2H), 1.18 (m, 6H); 13C NMR (101 MHz, D2O) d: 195.0, 50.0, 47.6, 35.26, 24.2, 11.9, 11.2; HRMS (ESI): exact mass calculated for C8H16KNO3S3 ([MþH]þ): 310.0002, Found: 310.0002.
To a solution of 1 (5 mmol, 1 equiv) and K3PO4 (5 mmol, 1 equiv) in H2O (5 mL) was slowly added CS2 (7.5 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 10 min. Then 2 (5 mmol, 1 equiv) was added and continued stirring at room temperature for 1e3 h. The solvent was removed under vacuum and the residue was recrystallized from MeOH to give the products 3.
4.2.8. Potassium 3-((piperidine-1-carbonothioyl)thio)propane-1sulfonate (3h). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.20 (s, 2H), 3.91 (s, 2H), 3.38 (t, J¼7.2 Hz, 2H), 3.03e2.90 (m, 2H), 2.15e2.01 (m, 2H), 1.64 (dd, J¼19.3, 4.8 Hz, 6H); 13C NMR (101 MHz, D2O) d: 194.6, 53.7, 52.3, 49.8, 35.2, 25.8, 25.4, 24.2, 23.7; HRMS (ESI): exact mass calculated for C9H16KNO3S3 ([MK]): 282.0286, Found: 282.0288.
4.2.1. Potassium 3-((benzylcarbamothioyl)thio)propane-1-sulfonate (3a). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.10 (m, 5H), 4.69 (s, 2H), 3.15 (t, J¼7.2 Hz, 2H), 2.81 (t, 2H), 1.94 (dt, J¼14.7, 7.3 Hz, 2H); 13C NMR (100 MHz, D2O) d: 198.2, 136.5, 128.8, 127.8, 127.8, 50.3, 49.8, 33.3, 24.3; HRMS (ESI): exact mass calculated for C11H14KNO3S3 ([MþH]þ): 343.9545, Found: 343.9852.
4.2.9. Potassium 3-((4-methylpiperazine-1-carbonothioyl)thio)propane-1-sulfonate (3i). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 4.20 (s, 2H), 3.93 (s, 2H), 3.34 (t, J¼7.1 Hz, 2H), 2.93e2.81 (t, 2H), 2.51 (s, 4H), 2.21 (s, 3H), 2.02 (dt, 2H); 13C NMR (100 MHz, D2O) d: 197.4, 53.2, 49.8, 44.0, 35.2, 24.0; HRMS (ESI): exact mass calculated for C9H17KN2O3S3 ([MþH]þ): 337.0111, Found: 337.0109.
4.2.2. Potassium 3-(((4-fluorobenzyl)carbamothioyl)thio)propane-1sulfonate (3b). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.21 (dd, J¼8.3, 5.6 Hz, 2H), 6.98 (t, J¼8.8 Hz, 2H), 4.68 (s, 2H), 3.23 (t, J¼7.2 Hz, 2H), 2.93e2.83 (t, 2H),
4.2.10. Potassium 3-((morpholine-4-carbonothioyl)thio)propane-1sulfonate (3j). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.30 (s, 2H), 4.05 (s, 2H), 3.79 (s, 4H), 3.45 (t, 2H), 3.00 (t, 2H), 2.13 (t, 2H); 13C NMR (101 MHz, D2O) d: 197.7,
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66.0, 50.8, 49.8, 35.0, 24.0; HRMS (ESI): exact mass calculated for C8H14KNO4S3 ([MþK]þ): 361.9354, Found: 361.9355. 4.2.11. Potassium 3-(((2-hydroxyethyl)(methyl)carbamothioyl)thio) propane-1-sulfonate (3k). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.13e4.15 (t, J¼5.6 Hz, 1H), 3.92e3.95 (t, J¼5.4 Hz, 1H), 3.77e3.81 (m, 2H), 3.43 (s, 1H), 3.32e3.36 (m, 3H), 2.96e2.91 (m, 2H), 2.04e2.09 (m, 2H); 13C NMR (101 MHz, D2O) d: 198.3, 58.6, 56.6, 49.8, 41.4, 35.5, 24.0; HRMS (ESI): exact mass calculated for C7H14KNO4S3 ([MþNa]þ): 333.9614, Found: 333.9616. 4.2.12. Potassium 3-(((4-(methoxycarbonyl)benzyl)carbamothioy-l) thio)propane-1-sulfonate (3l). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, DMSO) d: 10.48 (s,1H), 7.92 (d, J¼8.1 Hz, 2H), 7.42 (d, J¼8.1 Hz, 2H), 4.92 (s, 2H), 3.84 (s, 3H), 3.29 (t, J¼7.2 Hz, 2H), 2.55 (t, J¼7.4 Hz, 2H), 2.02e1.83 (m, 2H); 13C NMR (101 MHz, DMSO) d: 197.9, 166.5, 143.6, 129.7, 128.8, 128.2, 52.6, 50.5, 49.4, 33.8, 25.9. 4.2.13. Potassium 4-(((pyridin-3-ylmethyl)carbamothioyl)thio)butane-1-sulfonate (3m). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 8.43e8.26 (m, 2H), 7.67 (d, J¼6.9 Hz, 1H), 7.29 (dd, J¼7.7, 4.4 Hz, 1H), 4.79 (s, 2H), 3.11 (t, J¼6.9 Hz, 2H), 2.91e2.74 (m, 2H), 1.80e1.58 (m, 4H); 13C NMR (101 MHz, D2O) d: 199.4, 148.0, 147.7, 136.9, 133.0, 124.3, 50.5, 47.4, 34.0, 27.4, 23.3; HRMS (ESI): exact mass calculated for C11H15KN2O3S3 ([MK]): 319.0239, Found: 319.0232. 4.2.14. Potassium 4-((piperidine-1-carbonothioyl)thio)butane-1sulfonate (3n). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.17 (s, 2H), 3.87 (s, 2H), 3.24 (t, J¼6.6 Hz, 2H), 2.96e2.76 (m, 2H), 1.74 (d, J¼12.9 Hz, 4H), 1.63 (d, J¼4.5 Hz, 6H); 13C NMR (101 MHz, D2O) d: 195.1, 53.5, 52.1, 50.7, 36.2, 27.6, 25.9, 25.5, 23.8, 23.5; HRMS (ESI): exact mass calculated for C10H18KNO3S3 ([MK]): 296.0454, Found: 296.0445. 4.2.15. Potassium 4-((benzylcarbamothioyl)thio)butane-1-sulfonate (3o). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.24e6.99 (m, 5H), 4.70 (s, 2H), 3.07 (t, J¼7.1 Hz, 2H), 2.81e2.64 (m, 2H), 1.80e1.46 (m, 4H); 13C NMR (101 MHz, D2O) d: 198.5, 136.5, 128.8, 127.8, 127.7, 50.6, 50.2, 34.1, 27.6, 23.5; HRMS (ESI): exact mass calculated for C12H16KNO3S3 ([MK]): 318.0287, Found: 318.0278. 4.3. Synthesis of compound 4m To the solution of 3m (358 mg, 1 mmol) in water (5 mL), 1 N HCl (1 mL) was slowly added. The solution was cooled in ice-bath and then filtered. The filter cake was washed with little cool water and recrystallized from water (5 mL) to afford the pure 4m (313 mg, 97.8%); mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 8.77e8.58 (m, 2H), 8.49 (d, J¼8.1 Hz, 1H), 8.07e7.90 (m, 1H), 5.04 (s, 2H), 3.20 (t, J¼6.3 Hz, 2H), 2.86 (t, J¼7.1 Hz, 2H), 1.88e1.56 (m, 4H); 13 C NMR (101 MHz, D2O) d: 200.7, 146.1, 140.2, 140.0, 137.8, 127.3, 50.5, 46.3, 34.2, 27.4, 23.3; HRMS (ESI): exact mass calculated for C11H16N2O3S3 ([MþH]þ): 321.0396, Found: 321.0384. 4.4. General procedure for the synthesis of compounds 5aej To a flask of 4m (321 mg, 1 mmol) in anhydrous acetonitrile (10 mL) was added TCT (111 mg, 0.6 mmol) and the solution was stirred at 60 C for 24 h. After being cooled to room temperature, the mixture of amine (1.5 mmol) and trimethylamine (152 mg, 1.5 mmol) was slowly added. The mixture was continue stirred at room temperature until the reaction was complete (monitored by TLC). Then the solvent was removed under reduced pressure, the residue was added 15 mL brine and extracted twice with CH2Cl2 (215 mL). The combined organic phase were dried over Na2SO4,
filtered, and evaporated. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the pure compound 5. 4.4.1. 4-(N,N-Dimethylsulfamoyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5a). White solid; mp¼103.1e108.1 C; 1H NMR (400 MHz, CDCl3) d: 8.53 (s, 1H), 8.49 (d, J¼3.9 Hz, 1H), 8.29 (s, 1H), 7.72 (d, J¼7.7 Hz, 1H), 7.29 (dd, J¼7.3, 5.2 Hz, 1H), 4.96 (d, J¼5.4 Hz, 2H), 3.33 (t, J¼6.9 Hz, 2H), 3.03e2.93 (m, 2H), 2.87 (s, 6H), 2.01e1.81 (m, 4H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.0, 136.2, 132.4, 123.7, 48.1, 47.5, 37.5, 34.5, 28.1, 22.1; HRMS (ESI): exact mass calculated for C13H21N3O2S3 ([MþH]þ): 348.0869, Found: 348.0866. 4.4.2. 4-(N-Isobutylsulfamoyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5b). White solid; mp¼120.4e122.8 C; 1H NMR (400 MHz, CDCl3) d: 8.64e8.40 (m, 2H), 8.06 (s, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.35e7.28 (m, 1H), 4.97 (d, J¼5.4 Hz, 2H), 4.69 (s, 1H), 3.33 (t, J¼6.9 Hz, 2H), 3.10e3.03 (m, 2H), 2.94 (t, J¼6.6 Hz, 2H), 2.00e1.83 (m, 4H), 1.81 (t, J¼6.7 Hz, 1H), 0.96 (d, J¼6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.1, 136.1, 132.3, 123.7, 52.0, 50.7, 48.1, 34.6, 29.0, 27.9, 22.8, 19.9; HRMS (ESI): exact mass calculated for C15H25N3O2S3 ([MþH]þ): 376.1182, Found: 376.1169. 4.4.3. 4-(N-(tert-Butyl)sulfamoyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5c). White solid; mp¼140.2e142.7 C; 1H NMR (400 MHz, DMSO-d6) d: 10.45 (t, J¼5.5 Hz, 1H), 8.54e8.45 (m, 2H), 7.69 (d, J¼7.8 Hz, 1H), 7.37 (dd, J¼7.8, 4.8 Hz, 1H), 4.85 (d, J¼5.6 Hz, 2H), 3.23 (t, J¼6.7 Hz, 2H), 3.09e2.89 (m, 2H), 1.83e1.60 (m, 4H), 1.25 (s, 9H); 13C NMR (101 MHz, DMSO-d6) d: 197.7, 149.5, 148.9, 135.9, 133.4, 124.0, 55.0, 53.5, 47.5, 34.1, 30.5, 27.9, 23.3; HRMS (ESI): exact mass calculated for C15H25N3O2S3 ([MþH]þ): 376.1182, Found: 376.1174. 4.4.4. 4-(N-(3-Methoxypropyl)sulfamoyl)butyl (pyridin-3-ylmethyl) carbamodithioate (5d). Pale green solid; mp¼96.7e97.3 C; 1H NMR (400 MHz, CDCl3) d: 8.59e8.45 (m, 2H), 8.38 (s, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.38e7.24 (m, 1H), 5.19 (t, J¼5.7 Hz, 1H), 4.95 (d, J¼5.4 Hz, 2H), 3.50 (t, J¼5.7 Hz, 2H), 3.43e3.26 (m, 5H), 3.22 (q, J¼6.1 Hz, 2H), 3.10e2.97 (m, 2H), 1.97e1.74 (m, 6H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.3, 148.9, 136.2, 132.5, 123.7, 71.2, 58.9, 51.7, 48.0, 41.9, 34.6, 29.7, 27.9, 22.7; HRMS (ESI): exact mass calculated for C15H25N3O3S3 ([MþH]þ): 392.1131, Found: 392.1132. 4.4.5. 4-(Pyrrolidin-1-ylsulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5e). White solid; mp¼123.9e124.6 C; 1H NMR (400 MHz, CDCl3) d: 8.62e8.42 (m, 2H), 8.29 (s, 1H), 7.72 (d, J¼7.7 Hz, 1H), 7.29 (d, J¼12.4 Hz, 1H), 4.87 (t, J¼57.2 Hz, 2H), 3.46e3.24 (m, 6H), 3.09e2.86 (m, 2H), 1.98e1.83 (m, 8H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.0, 136.2, 132.4, 123.7, 48.7, 48.1, 47.8, 34.6, 28.1, 25.9, 22.3; HRMS (ESI): exact mass calculated for C15H23N3O2S3 ([MþH]þ): 374.1025, Found: 374.1020. 4.4.6. 4-(Piperidin-1-ylsulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5f). Pale yellow solid; mp¼109.2e113.4 C; 1H NMR (400 MHz, CDCl3) d: 8.52 (s, 1H), 8.48 (d, J¼3.9 Hz, 1H), 8.38 (s, 1H), 7.72 (d, J¼7.6 Hz, 1H), 7.28 (t, J¼6.0 Hz, 1H), 4.95 (d, J¼5.1 Hz, 2H), 3.32 (t, J¼6.8 Hz, 2H), 3.22 (d, J¼5.2 Hz, 4H), 2.99e2.86 (m, 2H), 1.89 (ddd, J¼20.9, 14.4, 7.3 Hz, 4H), 1.61 (dd, J¼26.4, 4.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.0, 136.2, 132.5, 123.7, 48.5, 48.0, 46.7, 34.5, 28.1, 25.7, 23.8, 22.2; HRMS (ESI): exact mass calculated for C16H25N3O2S3 ([MþH]þ): 388.1182, Found: 388.1187. 4.4.7. 4-(Morpholinosulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5g). White solid; mp¼107.9e109.5 C; 1H NMR (400 MHz, CDCl3) d: 8.73e8.38 (m, 2H), 8.22 (s, 1H), 7.71 (d, J¼7.6 Hz, 1H), 7.29
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(d, J¼8.6 Hz, 1H), 4.96 (d, J¼5.0 Hz, 2H), 3.82e3.71 (m, 4H), 3.34 (t, J¼6.8 Hz, 2H), 3.30e3.19 (m, 4H), 3.04e2.90 (m, 2H), 1.91 (ddd, J¼20.5, 14.5, 7.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.1, 136.1, 132.4, 123.7, 66.6, 48.2, 48.1, 45.8, 34.5, 28.1, 22.0; HRMS (ESI): exact mass calculated for C15H23N3O3S3 ([MþH]þ): 390.0974, Found: 390.0964. 4.4.8. 4-((4-Phenylpiperazin-1-yl)sulfonyl)butyl (pyridin-3-ylmethyl) carbamodithioate (5h). Pale yellow solid; mp¼124.3e125.6 C; 1H NMR (400 MHz, CDCl3) d: 8.51 (d, J¼13.7 Hz, 2H), 8.27 (s, 1H), 7.71 (d, J¼7.4 Hz, 1H), 7.43e7.14 (m, 3H), 6.94 (t, J¼7.0 Hz, 3H), 4.95 (d, J¼4.7 Hz, 2H), 3.37 (dd, J¼24.1, 17.4 Hz, 6H), 3.25 (s, 4H), 3.07e2.92 (m, 2H), 2.04e1.80 (m, 4H); 13C NMR (101 MHz, CDCl3) d: 198.6, 150.8, 149.4, 149.0, 136.2, 132.4, 129.3, 123.7, 120.9, 117.0, 49.7, 48.6, 48.1, 45.8, 34.5, 28.1, 22.1; HRMS (ESI): exact mass calculated for C21H28N4O2S3 ([MþH]þ): 465.1447, Found: 465.1445. 4.4.9. 4-((1H-Imidazol-1-yl)sulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5i). White solid; mp¼111.4e117.8 C; 1H NMR (400 MHz, CDCl3) d: 8.53 (d, J¼9.3 Hz, 2H), 8.30 (s, 1H), 7.94 (s, 1H), 7.72 (d, J¼7.6 Hz, 1H), 7.30 (d, J¼10.6 Hz, 2H), 7.15 (s, 1H), 4.96 (d, J¼5.1 Hz, 2H), 3.48e3.23 (m, 4H), 1.84 (s, 4H); 13C NMR (101 MHz, CDCl3) d: 198.1, 149.4, 149.2, 137.0, 136.2, 132.2, 131.4, 123.7, 117.8, 55.5, 48.3, 34.1, 27.5, 22.1; HRMS (ESI): exact mass calculated for C14H18N4O2S3 ([MþH]þ): 371.0665, Found: 371.0659. 4.4.10. 4-Sulfamoylbutyl (pyridin-3-ylmethyl)carbamodithioate (5j). White solid; mp¼127.7e130.6 C; 1H NMR (400 MHz, DMSOd6) d: 10.46 (t, J¼5.5 Hz, 1H), 8.62e8.36 (m, 2H), 7.69 (d, J¼7.8 Hz, 1H), 7.37 (dd, J¼7.7, 4.8 Hz, 1H), 6.77 (s, 2H), 4.98e4.14 (m, 2H), 3.23 (t, J¼6.9 Hz, 2H), 3.09e2.91 (m, 2H), 1.74 (dt, J¼12.9, 7.9 Hz, 4H); 13C NMR (101 MHz, DMSO-d6) d: 197.7, 149.5, 148.9, 136.0, 133.4, 124.0, 54.4, 47.5, 34.1, 28.0, 23.3; HRMS (ESI): exact mass calculated for C11H17N3O2S3 ([MþH]þ): 320.0556, Found: 320.0554.
Acknowledgements The authors thank the National Natural Science Foundation of China (No. 21372019) for financial support.
Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2016.05.011. These data include MOL files and InChiKeys of the most important compounds described in this article.
5
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chains Bowen Li, Shuo Zhou, Shucheng Wang, Xingyi Sun, Zemei Ge *, Runtao Li * State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 March 2016 Received in revised form 1 May 2016 Accepted 3 May 2016 Available online xxx
An efficient method for the synthesis of organic sulfonic acid potassiums containing dithiocarbamate side chains was developed through the reaction of amines, carbon disulfide and sultones in the presence of K3PO4 in water at room temperature. The organic sulfonic acid potassium derivatives are easily transformed into the corresponding organic sulfonic acids, which were further reacted with amines to afford the important organic sulfonamides containing dithiocarbamate side chains. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Dithiocarbamate Sulfonic acid potassium Sulfonic acid Sulfonamide
1. Introduction Sulfonic acid and sulfonic amide are two kinds of important functional groups in medicinal chemistry,1,2 which widely present in biologically active natural products and medicinally valuable compounds.3,4 Therefore, the introduction of both kinds of groups is one of the most commonly used strategies for the lead optimization process in order to improve the desired biological and physical properties of a potential compounds.5 Recent years, dithiocarbamate derivatives have been received considerable attentions because of its important biological activities, such as anesthetic,6 anti-HIV,7 mono glyceride lipase inhibitors,8 anti-tumor agents.9 Therefore, many kinds of dithiocarbamate derivatives have been synthesized.10 However, to the best of our knowledge, it is no report on the direct synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chain. Our group has developed several efficient methodologies for the synthesis of different kinds of dithiocarbamate esters,11 from which some potent anticancer compounds were discovered.12 As the requirement of our work, we urgently hope to develop an efficient method for the synthesis of organic sulfonic acid derivatives containing dithiocarbamate side chains. Recently, Varma et al. have reported an efficient one-pot methodology for the synthesis of unnatural a-amino acids containing the dithiocarbamate side chains through the nucleophilic
* Corresponding authors. Tel.: þ86 10 82801504; e-mail addresses: zmge@bjmu. edu.cn (Z. Ge), [email protected] (R. Li).
ring opening of sulfamidates by in situ generated dithiocarbamate anion (Scheme 1, a).13 Inspired by their work, we envisioned that if replacing the sulfamidates with sultones, the organic sulfonic acid salts containing dithiocarbamate side chains should be formed in one-pot, from which the corresponding sulfonic acid derivatives, such as sulfonic acids, sulfonamides should be easily obtained (Scheme 1, b).
Scheme 1. Synthetic strategy toward sulfonic acid derivatives containing dithiocarbamate side chains.
2. Results and discussion In order to examine the possibility, we initially carried out the reaction of benzylamine (1a), carbon disulfide with g-sultone (2a) in the presence of Al2O3 at room temperature under solvent free conditions.14 To our delight, the desired product (3a) was obtained in 38% yield (Table 1, entry 1). Encouraged by this result, various solvents and bases were screened to optimize the reaction
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Table 1 Optimization of the reaction conditions for the formation of 3aa
Entry
Base
Solvent
Yield(%)b
1c,d 2c 3c 4 5 6 7 8 9 10
d d d NaHCO3 NaHCO3 K3PO4 K2CO3 K2CO3 K3PO4 TEA
d EtOAc MeOH MeOH EtOH Acetone Acetone H2O H2O H2O
38 35 58 75 70 80 83 89 95 85
bond, hydroxyl, alkoxyl, ester and heterocycle, were all well tolerated in this reaction conditions. Then, replacing the g-sultone (2a) with dsultone (2b) to react with carbon disulfide and different amines and the excepted products (3me3o) were also obtained in 73e98% yields. It is important to note that the organic sulfonic acid salts containing dithiocarbamate side chains (3) could be easily transformed into corresponding organic sulfonic acids. Such as compound 3m was treated with 1 equiv HCl (aq, 1M) at room temperature to afford the corresponding sulfonic acid 4m in quantitative yield (Scheme 2).
Scheme 2. Synthesis of compound 4m from 3m.
a
Reaction conditions: 1a (5 mmol, 1 equiv), K3PO4 (1 equiv), CS2 (1.5 equiv) in water (5 mL) at rt for 10 min, then added 2a (1 equiv). b Isolated yield. c No base participated. d The reaction was performed in the solid phase of Al2O3.
conditions (Table 1). We were excited to find that the product 3a could be obtained with a yield of up to 95%, using K3PO4 as base in water at room temperature (Table 1, entry 9). With the optimized reaction conditions in hand, we set out to examine the substrate scope of this methodology (Table 2). A variety of amines were first allowed to react with carbon disulfide and gsultone (2a) under optimized reaction conditions. All the reactions were performed smoothly to give the desired products in good to excellent yields (3ae3l). Generally, the secondary amines provided the expected products in 92e96% yields (3ge3j). Much to our satisfactory, amines with different functional groups including double Table 2 Substrate scope for the reaction of amines, CS2 and sultonesa,b
To further extend the application of this method, we next selected compound 4m to react with various amines and hope to afford the more important organic sulfonamides containing dithiocarbamate side chains 5. After screening the reaction conditions (See Supplementary data, Table 1), it was found that the reaction performed smoothly in the presence of 2,4,6trichloro-1,3,5-triazine (TCT) using acetonitrile as solvent and triethylamine as base at 60 C for 24 h. As shown in Table 3, the optimized reaction conditions were suitable for the different kinds of amines, including primary amines, secondary amines, ammonia, high steric hindrance t-butylamine and low reactively imidazole, to afford the desired products 5ae5j in moderate to good yields.
Table 3 Synthesis of organic sulfonamides containing dithiocarbamate side chains 5.a,b
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Based on relevant reports in the literature11,13 and our observation in the present work, a plausible reaction mechanism for the synthesis of organic sulfonic acid potassiums containing dithiocarbamate side chains has been proposed in Scheme 3. First, amine 1 reacts with CS2 to form intermediate A in the presence of K3PO4, which then goes through intermolecular nucleophilic substitution-ring opening reaction onto 2 to produce the desired product 3.
Scheme 3. Proposed mechanism for the synthesis of 3.
3. Conclusion In conclusion, we have developed an efficient procedure for the synthesis of organic sulfonic acid potassiums containing dithiocarbamate side chains from the reaction of amines, carbon disulfide with sultones using K3PO4 as base in water at room temperature in good to excellent yields. The organic sulfonic acid potassiums containing dithiocarbamate side chains are easily transformed into the corresponding sulfonic acids derivatives, which reacted with amines to afford the important organic sulfonamides containing dithiocarbamate side chains.
3
2.00 (m, 2H); 13C NMR (101 MHz, D2O) d: 198.4, 132.4, 129.6, 115.5, 115.3, 49.7, 49.5, 33.0, 24.3; HRMS (ESI): exact mass calculated for C11H13FKNO3S3 ([MþK]þ): 399.9310, Found: 399.9307. 4.2.3. Potassium 3-(((4-methoxybenzyl)carbamothioyl)thio)propane-1-sulfonate (3c). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 7.09 (d, J¼8.3 Hz, 2H), 6.73 (d, J¼8.3 Hz, 2H), 4.68 (s, 2H), 3.60 (s, 3H), 3.18 (t, J¼7.0 Hz, 2H), 2.92e2.75 (t, 2H), 1.97 dt, J¼14.1, 7.0 Hz, 2H); 13C NMR (101 MHz, D2O) d: 197.8, 158.4, 129.4, 129.1, 114.2, 55.4, 49.8, 33.1, 24.3; HRMS (ESI): exact mass calculated for C12H16KNO4S3 ([MþK]þ): 411.9510, Found: 411.9504. 4.2.4. Potassium-3-(((pyridin-3-ylmethyl)carbamothioyl)thio)propane-1-sulfonate (3d). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 8.42e8.05 (m, 2H), 7.60 (d, J¼7.9 Hz, 1H), 7.22 (dd, J¼7.6, 5.2 Hz, 1H), 4.72 (s, 2H), 3.15 (t, J¼7.1 Hz, 2H), 2.89e2.74 (t, 2H), 1.90 (dt, J¼16.9, 8.4 Hz, 2H); 13C NMR (101 MHz, D2O) d: 199.3, 147.9, 147.7, 137.0, 133.1, 124.4, 49.6, 47.5, 33.0, 24.2; HRMS (ESI): exact mass calculated for C10H13KN2O3S3 ([MþH]þ): 344.9798, Found: 344.9797. 4.2.5. Potassium 3-(((furan-2-ylmethyl)carbamothioyl)thio)propane1-sulfonate (3e). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.36 (s, 1H), 6.31 (m, 2H), 4.68 (s, 2H), 3.23 (t, J¼7.2 Hz, 2H), 2.89 (t, 2H), 1.99 (dt, J¼14.8, 7.3 Hz, 2H); 13C NMR (100 MHz, D2O) d: 98.3, 149.5, 142.9, 110.8, 108.9, 49.8, 43.4, 33.2, 24.2; HRMS (ESI): exact mass calculated for C9H12KNO4S3 ([MþK]þ): 371.9197, Found: 371.9195.
4. Experimental section 4.1. General information Available reagents and solvents were purchased from commercial sources and were used without further purification. Melting points were determined on a melting point apparatus with a microscope and a hot stage and were uncorrected. All the 1H and 13 C NMR were recorded on a Bruke 400 MHz spectrometer and chemical shifts reported in D2O, CDCl3 or DMSO-d6 with tetramethylsilane as an internal standard. High-resolution mass spectra (HRMS) was recorded using a Bruker Apex IV FTMS instrument. Column chromatography was performed with 200e300 mesh silica gel using flash column techniques.
4.2.6. Potassium 3-((allylcarbamothioyl)thio)propane-1-sulfonate (3f). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 5.99e5.57 (m, 1H), 5.31e4.97 (m, 2H), 4.26 (d, J¼3.8 Hz, 2H), 3.29 (t, J¼6.9 Hz, 2H), 2.98e2.90 (m, 2H), 2.06 (dd, J¼14.4, 7.2 Hz, 2H); 13C NMR (101 MHz, D2O) d: 198.1, 131.8, 116.9, 49.6, 48.9, 32.8, 24.2; HRMS (ESI): exact mass calculated for C7H12KNO3S3 ([MþH]þ): 293.9689, Found: 293.9693.
4.2. General procedure for the synthesis of compounds 3aeo
4.2.7. Potassium 3-((diethylcarbamothioyl)thio)propane-1-sulfonate (3g). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 3.94 (q, J¼6.8 Hz, 2H), 3.75 (q, J¼7.0 Hz, 2H), 3.35 (t, J¼7.1 Hz, 2H), 2.95 (t, 2H), 2.08 (m, J¼9.6, 4.8 Hz, 2H), 1.18 (m, 6H); 13C NMR (101 MHz, D2O) d: 195.0, 50.0, 47.6, 35.26, 24.2, 11.9, 11.2; HRMS (ESI): exact mass calculated for C8H16KNO3S3 ([MþH]þ): 310.0002, Found: 310.0002.
To a solution of 1 (5 mmol, 1 equiv) and K3PO4 (5 mmol, 1 equiv) in H2O (5 mL) was slowly added CS2 (7.5 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 10 min. Then 2 (5 mmol, 1 equiv) was added and continued stirring at room temperature for 1e3 h. The solvent was removed under vacuum and the residue was recrystallized from MeOH to give the products 3.
4.2.8. Potassium 3-((piperidine-1-carbonothioyl)thio)propane-1sulfonate (3h). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.20 (s, 2H), 3.91 (s, 2H), 3.38 (t, J¼7.2 Hz, 2H), 3.03e2.90 (m, 2H), 2.15e2.01 (m, 2H), 1.64 (dd, J¼19.3, 4.8 Hz, 6H); 13C NMR (101 MHz, D2O) d: 194.6, 53.7, 52.3, 49.8, 35.2, 25.8, 25.4, 24.2, 23.7; HRMS (ESI): exact mass calculated for C9H16KNO3S3 ([MK]): 282.0286, Found: 282.0288.
4.2.1. Potassium 3-((benzylcarbamothioyl)thio)propane-1-sulfonate (3a). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.10 (m, 5H), 4.69 (s, 2H), 3.15 (t, J¼7.2 Hz, 2H), 2.81 (t, 2H), 1.94 (dt, J¼14.7, 7.3 Hz, 2H); 13C NMR (100 MHz, D2O) d: 198.2, 136.5, 128.8, 127.8, 127.8, 50.3, 49.8, 33.3, 24.3; HRMS (ESI): exact mass calculated for C11H14KNO3S3 ([MþH]þ): 343.9545, Found: 343.9852.
4.2.9. Potassium 3-((4-methylpiperazine-1-carbonothioyl)thio)propane-1-sulfonate (3i). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 4.20 (s, 2H), 3.93 (s, 2H), 3.34 (t, J¼7.1 Hz, 2H), 2.93e2.81 (t, 2H), 2.51 (s, 4H), 2.21 (s, 3H), 2.02 (dt, 2H); 13C NMR (100 MHz, D2O) d: 197.4, 53.2, 49.8, 44.0, 35.2, 24.0; HRMS (ESI): exact mass calculated for C9H17KN2O3S3 ([MþH]þ): 337.0111, Found: 337.0109.
4.2.2. Potassium 3-(((4-fluorobenzyl)carbamothioyl)thio)propane-1sulfonate (3b). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.21 (dd, J¼8.3, 5.6 Hz, 2H), 6.98 (t, J¼8.8 Hz, 2H), 4.68 (s, 2H), 3.23 (t, J¼7.2 Hz, 2H), 2.93e2.83 (t, 2H),
4.2.10. Potassium 3-((morpholine-4-carbonothioyl)thio)propane-1sulfonate (3j). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.30 (s, 2H), 4.05 (s, 2H), 3.79 (s, 4H), 3.45 (t, 2H), 3.00 (t, 2H), 2.13 (t, 2H); 13C NMR (101 MHz, D2O) d: 197.7,
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66.0, 50.8, 49.8, 35.0, 24.0; HRMS (ESI): exact mass calculated for C8H14KNO4S3 ([MþK]þ): 361.9354, Found: 361.9355. 4.2.11. Potassium 3-(((2-hydroxyethyl)(methyl)carbamothioyl)thio) propane-1-sulfonate (3k). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.13e4.15 (t, J¼5.6 Hz, 1H), 3.92e3.95 (t, J¼5.4 Hz, 1H), 3.77e3.81 (m, 2H), 3.43 (s, 1H), 3.32e3.36 (m, 3H), 2.96e2.91 (m, 2H), 2.04e2.09 (m, 2H); 13C NMR (101 MHz, D2O) d: 198.3, 58.6, 56.6, 49.8, 41.4, 35.5, 24.0; HRMS (ESI): exact mass calculated for C7H14KNO4S3 ([MþNa]þ): 333.9614, Found: 333.9616. 4.2.12. Potassium 3-(((4-(methoxycarbonyl)benzyl)carbamothioy-l) thio)propane-1-sulfonate (3l). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, DMSO) d: 10.48 (s,1H), 7.92 (d, J¼8.1 Hz, 2H), 7.42 (d, J¼8.1 Hz, 2H), 4.92 (s, 2H), 3.84 (s, 3H), 3.29 (t, J¼7.2 Hz, 2H), 2.55 (t, J¼7.4 Hz, 2H), 2.02e1.83 (m, 2H); 13C NMR (101 MHz, DMSO) d: 197.9, 166.5, 143.6, 129.7, 128.8, 128.2, 52.6, 50.5, 49.4, 33.8, 25.9. 4.2.13. Potassium 4-(((pyridin-3-ylmethyl)carbamothioyl)thio)butane-1-sulfonate (3m). White solid; mp: decomposed over 200 C; 1 H NMR (400 MHz, D2O) d: 8.43e8.26 (m, 2H), 7.67 (d, J¼6.9 Hz, 1H), 7.29 (dd, J¼7.7, 4.4 Hz, 1H), 4.79 (s, 2H), 3.11 (t, J¼6.9 Hz, 2H), 2.91e2.74 (m, 2H), 1.80e1.58 (m, 4H); 13C NMR (101 MHz, D2O) d: 199.4, 148.0, 147.7, 136.9, 133.0, 124.3, 50.5, 47.4, 34.0, 27.4, 23.3; HRMS (ESI): exact mass calculated for C11H15KN2O3S3 ([MK]): 319.0239, Found: 319.0232. 4.2.14. Potassium 4-((piperidine-1-carbonothioyl)thio)butane-1sulfonate (3n). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 4.17 (s, 2H), 3.87 (s, 2H), 3.24 (t, J¼6.6 Hz, 2H), 2.96e2.76 (m, 2H), 1.74 (d, J¼12.9 Hz, 4H), 1.63 (d, J¼4.5 Hz, 6H); 13C NMR (101 MHz, D2O) d: 195.1, 53.5, 52.1, 50.7, 36.2, 27.6, 25.9, 25.5, 23.8, 23.5; HRMS (ESI): exact mass calculated for C10H18KNO3S3 ([MK]): 296.0454, Found: 296.0445. 4.2.15. Potassium 4-((benzylcarbamothioyl)thio)butane-1-sulfonate (3o). White solid; mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 7.24e6.99 (m, 5H), 4.70 (s, 2H), 3.07 (t, J¼7.1 Hz, 2H), 2.81e2.64 (m, 2H), 1.80e1.46 (m, 4H); 13C NMR (101 MHz, D2O) d: 198.5, 136.5, 128.8, 127.8, 127.7, 50.6, 50.2, 34.1, 27.6, 23.5; HRMS (ESI): exact mass calculated for C12H16KNO3S3 ([MK]): 318.0287, Found: 318.0278. 4.3. Synthesis of compound 4m To the solution of 3m (358 mg, 1 mmol) in water (5 mL), 1 N HCl (1 mL) was slowly added. The solution was cooled in ice-bath and then filtered. The filter cake was washed with little cool water and recrystallized from water (5 mL) to afford the pure 4m (313 mg, 97.8%); mp: decomposed over 200 C; 1H NMR (400 MHz, D2O) d: 8.77e8.58 (m, 2H), 8.49 (d, J¼8.1 Hz, 1H), 8.07e7.90 (m, 1H), 5.04 (s, 2H), 3.20 (t, J¼6.3 Hz, 2H), 2.86 (t, J¼7.1 Hz, 2H), 1.88e1.56 (m, 4H); 13 C NMR (101 MHz, D2O) d: 200.7, 146.1, 140.2, 140.0, 137.8, 127.3, 50.5, 46.3, 34.2, 27.4, 23.3; HRMS (ESI): exact mass calculated for C11H16N2O3S3 ([MþH]þ): 321.0396, Found: 321.0384. 4.4. General procedure for the synthesis of compounds 5aej To a flask of 4m (321 mg, 1 mmol) in anhydrous acetonitrile (10 mL) was added TCT (111 mg, 0.6 mmol) and the solution was stirred at 60 C for 24 h. After being cooled to room temperature, the mixture of amine (1.5 mmol) and trimethylamine (152 mg, 1.5 mmol) was slowly added. The mixture was continue stirred at room temperature until the reaction was complete (monitored by TLC). Then the solvent was removed under reduced pressure, the residue was added 15 mL brine and extracted twice with CH2Cl2 (215 mL). The combined organic phase were dried over Na2SO4,
filtered, and evaporated. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the pure compound 5. 4.4.1. 4-(N,N-Dimethylsulfamoyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5a). White solid; mp¼103.1e108.1 C; 1H NMR (400 MHz, CDCl3) d: 8.53 (s, 1H), 8.49 (d, J¼3.9 Hz, 1H), 8.29 (s, 1H), 7.72 (d, J¼7.7 Hz, 1H), 7.29 (dd, J¼7.3, 5.2 Hz, 1H), 4.96 (d, J¼5.4 Hz, 2H), 3.33 (t, J¼6.9 Hz, 2H), 3.03e2.93 (m, 2H), 2.87 (s, 6H), 2.01e1.81 (m, 4H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.0, 136.2, 132.4, 123.7, 48.1, 47.5, 37.5, 34.5, 28.1, 22.1; HRMS (ESI): exact mass calculated for C13H21N3O2S3 ([MþH]þ): 348.0869, Found: 348.0866. 4.4.2. 4-(N-Isobutylsulfamoyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5b). White solid; mp¼120.4e122.8 C; 1H NMR (400 MHz, CDCl3) d: 8.64e8.40 (m, 2H), 8.06 (s, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.35e7.28 (m, 1H), 4.97 (d, J¼5.4 Hz, 2H), 4.69 (s, 1H), 3.33 (t, J¼6.9 Hz, 2H), 3.10e3.03 (m, 2H), 2.94 (t, J¼6.6 Hz, 2H), 2.00e1.83 (m, 4H), 1.81 (t, J¼6.7 Hz, 1H), 0.96 (d, J¼6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.1, 136.1, 132.3, 123.7, 52.0, 50.7, 48.1, 34.6, 29.0, 27.9, 22.8, 19.9; HRMS (ESI): exact mass calculated for C15H25N3O2S3 ([MþH]þ): 376.1182, Found: 376.1169. 4.4.3. 4-(N-(tert-Butyl)sulfamoyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5c). White solid; mp¼140.2e142.7 C; 1H NMR (400 MHz, DMSO-d6) d: 10.45 (t, J¼5.5 Hz, 1H), 8.54e8.45 (m, 2H), 7.69 (d, J¼7.8 Hz, 1H), 7.37 (dd, J¼7.8, 4.8 Hz, 1H), 4.85 (d, J¼5.6 Hz, 2H), 3.23 (t, J¼6.7 Hz, 2H), 3.09e2.89 (m, 2H), 1.83e1.60 (m, 4H), 1.25 (s, 9H); 13C NMR (101 MHz, DMSO-d6) d: 197.7, 149.5, 148.9, 135.9, 133.4, 124.0, 55.0, 53.5, 47.5, 34.1, 30.5, 27.9, 23.3; HRMS (ESI): exact mass calculated for C15H25N3O2S3 ([MþH]þ): 376.1182, Found: 376.1174. 4.4.4. 4-(N-(3-Methoxypropyl)sulfamoyl)butyl (pyridin-3-ylmethyl) carbamodithioate (5d). Pale green solid; mp¼96.7e97.3 C; 1H NMR (400 MHz, CDCl3) d: 8.59e8.45 (m, 2H), 8.38 (s, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.38e7.24 (m, 1H), 5.19 (t, J¼5.7 Hz, 1H), 4.95 (d, J¼5.4 Hz, 2H), 3.50 (t, J¼5.7 Hz, 2H), 3.43e3.26 (m, 5H), 3.22 (q, J¼6.1 Hz, 2H), 3.10e2.97 (m, 2H), 1.97e1.74 (m, 6H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.3, 148.9, 136.2, 132.5, 123.7, 71.2, 58.9, 51.7, 48.0, 41.9, 34.6, 29.7, 27.9, 22.7; HRMS (ESI): exact mass calculated for C15H25N3O3S3 ([MþH]þ): 392.1131, Found: 392.1132. 4.4.5. 4-(Pyrrolidin-1-ylsulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5e). White solid; mp¼123.9e124.6 C; 1H NMR (400 MHz, CDCl3) d: 8.62e8.42 (m, 2H), 8.29 (s, 1H), 7.72 (d, J¼7.7 Hz, 1H), 7.29 (d, J¼12.4 Hz, 1H), 4.87 (t, J¼57.2 Hz, 2H), 3.46e3.24 (m, 6H), 3.09e2.86 (m, 2H), 1.98e1.83 (m, 8H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.0, 136.2, 132.4, 123.7, 48.7, 48.1, 47.8, 34.6, 28.1, 25.9, 22.3; HRMS (ESI): exact mass calculated for C15H23N3O2S3 ([MþH]þ): 374.1025, Found: 374.1020. 4.4.6. 4-(Piperidin-1-ylsulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5f). Pale yellow solid; mp¼109.2e113.4 C; 1H NMR (400 MHz, CDCl3) d: 8.52 (s, 1H), 8.48 (d, J¼3.9 Hz, 1H), 8.38 (s, 1H), 7.72 (d, J¼7.6 Hz, 1H), 7.28 (t, J¼6.0 Hz, 1H), 4.95 (d, J¼5.1 Hz, 2H), 3.32 (t, J¼6.8 Hz, 2H), 3.22 (d, J¼5.2 Hz, 4H), 2.99e2.86 (m, 2H), 1.89 (ddd, J¼20.9, 14.4, 7.3 Hz, 4H), 1.61 (dd, J¼26.4, 4.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.0, 136.2, 132.5, 123.7, 48.5, 48.0, 46.7, 34.5, 28.1, 25.7, 23.8, 22.2; HRMS (ESI): exact mass calculated for C16H25N3O2S3 ([MþH]þ): 388.1182, Found: 388.1187. 4.4.7. 4-(Morpholinosulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5g). White solid; mp¼107.9e109.5 C; 1H NMR (400 MHz, CDCl3) d: 8.73e8.38 (m, 2H), 8.22 (s, 1H), 7.71 (d, J¼7.6 Hz, 1H), 7.29
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(d, J¼8.6 Hz, 1H), 4.96 (d, J¼5.0 Hz, 2H), 3.82e3.71 (m, 4H), 3.34 (t, J¼6.8 Hz, 2H), 3.30e3.19 (m, 4H), 3.04e2.90 (m, 2H), 1.91 (ddd, J¼20.5, 14.5, 7.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) d: 198.6, 149.4, 149.1, 136.1, 132.4, 123.7, 66.6, 48.2, 48.1, 45.8, 34.5, 28.1, 22.0; HRMS (ESI): exact mass calculated for C15H23N3O3S3 ([MþH]þ): 390.0974, Found: 390.0964. 4.4.8. 4-((4-Phenylpiperazin-1-yl)sulfonyl)butyl (pyridin-3-ylmethyl) carbamodithioate (5h). Pale yellow solid; mp¼124.3e125.6 C; 1H NMR (400 MHz, CDCl3) d: 8.51 (d, J¼13.7 Hz, 2H), 8.27 (s, 1H), 7.71 (d, J¼7.4 Hz, 1H), 7.43e7.14 (m, 3H), 6.94 (t, J¼7.0 Hz, 3H), 4.95 (d, J¼4.7 Hz, 2H), 3.37 (dd, J¼24.1, 17.4 Hz, 6H), 3.25 (s, 4H), 3.07e2.92 (m, 2H), 2.04e1.80 (m, 4H); 13C NMR (101 MHz, CDCl3) d: 198.6, 150.8, 149.4, 149.0, 136.2, 132.4, 129.3, 123.7, 120.9, 117.0, 49.7, 48.6, 48.1, 45.8, 34.5, 28.1, 22.1; HRMS (ESI): exact mass calculated for C21H28N4O2S3 ([MþH]þ): 465.1447, Found: 465.1445. 4.4.9. 4-((1H-Imidazol-1-yl)sulfonyl)butyl (pyridin-3-ylmethyl)carbamodithioate (5i). White solid; mp¼111.4e117.8 C; 1H NMR (400 MHz, CDCl3) d: 8.53 (d, J¼9.3 Hz, 2H), 8.30 (s, 1H), 7.94 (s, 1H), 7.72 (d, J¼7.6 Hz, 1H), 7.30 (d, J¼10.6 Hz, 2H), 7.15 (s, 1H), 4.96 (d, J¼5.1 Hz, 2H), 3.48e3.23 (m, 4H), 1.84 (s, 4H); 13C NMR (101 MHz, CDCl3) d: 198.1, 149.4, 149.2, 137.0, 136.2, 132.2, 131.4, 123.7, 117.8, 55.5, 48.3, 34.1, 27.5, 22.1; HRMS (ESI): exact mass calculated for C14H18N4O2S3 ([MþH]þ): 371.0665, Found: 371.0659. 4.4.10. 4-Sulfamoylbutyl (pyridin-3-ylmethyl)carbamodithioate (5j). White solid; mp¼127.7e130.6 C; 1H NMR (400 MHz, DMSOd6) d: 10.46 (t, J¼5.5 Hz, 1H), 8.62e8.36 (m, 2H), 7.69 (d, J¼7.8 Hz, 1H), 7.37 (dd, J¼7.7, 4.8 Hz, 1H), 6.77 (s, 2H), 4.98e4.14 (m, 2H), 3.23 (t, J¼6.9 Hz, 2H), 3.09e2.91 (m, 2H), 1.74 (dt, J¼12.9, 7.9 Hz, 4H); 13C NMR (101 MHz, DMSO-d6) d: 197.7, 149.5, 148.9, 136.0, 133.4, 124.0, 54.4, 47.5, 34.1, 28.0, 23.3; HRMS (ESI): exact mass calculated for C11H17N3O2S3 ([MþH]þ): 320.0556, Found: 320.0554.
Acknowledgements The authors thank the National Natural Science Foundation of China (No. 21372019) for financial support.
Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2016.05.011. These data include MOL files and InChiKeys of the most important compounds described in this article.
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