Introduction

Organo-medicinal chemists are now paying a lot of attention to green synthesis. One of the most significant functions of green chemistry is the design, creation, and application of chemical reactions while avoiding the use of dangerous solvents [1]. Polyethylene glycol (PEG) is a less toxic, user-friendly, thermally stable, and recyclable medium for specific organic processes as compared to organic solvents [2-4]. In addition, PEG chemistry and its use in medicinal chemistry have been addressed in numerous reviews [5-7]. Due to the hydrophobic nature of the reactants and the sensitivity of many catalysts to aqueous reaction conditions, water, while a safe option, is not always practical to utilise as a solvent medium [8, 9]. These characteristics, together with the network of H-bonds, high polarity, and significant surface tension, make it both cost-effective and ecologically benign, making it an appropriate replacement eco-friendly medium to carry out organic synthesis over volatile and hazardous solvents [10].

Multicomponent reactions (MCRs) have become an effective synthetic method for creating physiologically active molecules [11-14]. Due to the characteristics like atom economy, operational simplicity, easy reaction design, minimum workups, and methods of purification with no by-product, these sorts of reactions are very appealing. From an economic and environmental standpoint, the use of green chemistry with multicomponent reactions is a very appealing methodology that produces a high yield of products in a shorter amount of time [15-19].

Due to their extensive spectrum of biological and pharmacological attributes, dithiocarbamates (DTCs), a type of heterocycles containing sulphur, have drawn a lot of attention [20-26]. DTCs play a ligands role for the complex production of soft metals in a variety of ways described in the literature. These are made by mixing an amine with carbon disulfide, halides, or compounds that are α,β-unsaturated with the desired products [27-34]. Despite the potential usefulness of these procedures, the majority of them have a number of flaws, including demanding conditions for formation of catalyst, the use of costly, dangerous catalysts that can produce side products with low product yields, excessive catalyst loading, corrosiveness, and the use of harmful solvents.

To address these issues, we chose to use a novel catalyst to synthesise DTCs more efficiently and cleanly, with a wide range of potential biological features, including anti-mycobacterial activity (OCT-313) [23], antibacterial [35-38], and antifungal activity [39, 40]. Cerium (IV) ammonium nitrate [(NH₂)₂Ce(NO₃)₆ or CAN] has  emerged as an important catalyst for the construction of various heteroatom and C-C bonds [41]. This is also a powerful catalyst for organic synthesis due to its various benefits, including its high reactivity, low toxicity, easy handling, and great solubility in water. In recent investigations, protocols for mild circumstances, quick conversions, and practical work-up techniques have also been revealed, making ceric (IV) ammonium nitrate as an effective tool in chemistry when employing green and safer methods. In addition, the Lewis acid feature of CAN as well as its electron transfer capacity allows it to catalyse various organic reactions [42-47].

The value of PEG polymers is mostly due to their low toxicity under CAN and PEG-H₂O as a green medium, which is reflected in the rapid rise of published work about PEG with CAN in the medical field. Due to its wide application results in many interesting field, a facile, rapid, and synthetic innovative strategy for the formation of biologically active DTCs with different substituted groups is desirable. On the basis of our best knowledge, we are first time reported a MCRs using an amines, CS₂, and halides with a new catalytic system.

Experimental

Instruments and reagents

All chemicals were purchased from Sigma-Aldrich and were used as follow. All reactions and purity of dithaiocarbamates were monitored by thin-layer chromatography (TLC) using aluminium plates coated with silica gel F 254 plates, (Merck) using 15% ethyl acetate and 85% hexane as an eluent. The spots were detected either under the UV light or by placing in iodine chamber. The melting point of compounds was determined using a Thomas Hoover melting point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FTIR-1710 spectrophotometer using Nujol film or KBr pellet, ¹H-NMR and ¹³C-NMR spectra were recorded on a JEOL JNM-ECX 400P FT NMR system using TMS as an internal standard. ESI-MS mass spectra were recorded on waters LCT Micromass.

General procedure for the synthesis of dithiocarbamate derivatives 4a-4n and 6a-6l

In a 50 mL round bottom flask, the required amount of carbon disulphide (2.5 mmol) was added dropwise to a stirred mixture of amines (1.2 mmol) in 3 ml PEG-400: H₂O system at 0-5 °C. After 5 min to this stirred mixture, ceric ammonium nitrate (CAN) (5 mol%) and alkyl/aryl halides or Michael acceptors (1 mmol) were added, mixed, and stirred at 50 °C for an appropriate time. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled in dry ice-acetone bath to precipitate the PEG-400 and extracted with diethyl ether (3 x 10 mL) (PEG being insoluble in ether). The upper organic layer was washed with water, brine, and dried over anhydrous sodium sulfate (Na₂SO₄). The solvent was removed under reduced pressure to afford the crude products, which were further purified by column chromatography on silica gel (60-120 mesh size) using ehtyl acetate in hexane (80:20) as eluent to yield pure products (4a-4n & 6a-6l). The structures of all products were established on the basis of their spectral analysis (IR, ¹H-NMR, ¹³C-NMR, and mass spectral data) and melting point determination.

Spectral data of synthesized dithiocarbamates 4a-4n and 6a-6l

Diethyl-1-dithiocarbamic acid-n-phenyl ester (4a)

White solid, M.Pt. 44-46 °C [48]. IR (KBr, ν_max, cm^-1):  2978, 1501, 1421, 1271, 1065, 732, and 686. ¹H-NMR (CDCl₃, 400 MHz): δ 7.24-7.69 (m, 5H), 3.83 (q, J = 6.92 Hz, 2H), 3.71 (q, J = 6.92 Hz, 2H), and 1.22-1.66 (m, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 196.4, 137.3, 130.2, 130.1, 129.4, 129.3, 127.4, 52.3, 52.5, 12.6, and 12.5. m/z (ESI-MS): 226.0679 (M+1, C₁₁H₁₅NS₂ requires 225.0646).

Piperidine-1-carbodithioic acid-n-phenyl ester (4b)

White solid, M.Pt. 116-118 °C [48]. IR (KBr, ν_max, cm^-1): 2918, 1459, 1252, 740, and 650. ¹H-NMR (CDCl₃, 400 MHz): δ 7.05-7.65 (m, 5H), 3.97 (br, 2H), 3.91 (br, 2H), 1.99 (br, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 198.8, 135.2, 129.6, 129.5, 129.2, 129.1, 125.6, 50.7, 50.6, 24.5, 24.4, and 24.1. m/z (ESI-MS): 238.0679 (M+1, C₁₂H₁₅NS₂ requires 237.0646).

Morpholine-1-carbodithioic acid-n-phenyl ester (4c)

White solid, M.Pt. 140-142 °C [49]. IR (KBr, ν_max, cm^-1): 2918, 1466, 1267, 1216, 1113, 756, and 667; ¹H-NMR (CDCl₃, 400 MHz): δ 7.49-6.70 (m, 5H), 3.99 (br, 4H), 3.74-3.88 (m, 4H). ¹³C NMR (CDCl₃, 100 MHz): δ 198.2, 136.3, 131.2, 131.1, 130.6, 130.4, 125.2, 66.5, 66.3, 51.7, and 51.6. m/z (ESI-MS): 240.0472 (M+1, C₁₁H₁₃NOS₂ requires 239.0439).

Pyrrolidine-1-carbodithioic acid-n-phenyl ester (4d)

Colorless oil. IR (Film, ν_max, cm^-1): 2920, 1441, 1217, 756, and 667. ¹H-NMR (CDCl₃, 400 MHz): δ 7.57-7.80 (m, 5H), 3.95 (t, J = 6.8 Hz, 2H), 3.92 (t, J = 6.7 Hz, 2H), 2.55-2.56 (m, 2H), and 1.58-1.83 (m, 2H). ¹³C-NMR (CDCl₃, 100 MHz): δ 197.0, 135.7, 131.85, 129.8, 128.2, 56.9, 50.9, 26.5, and 24.2. m/z (ESI-MS): 224.0523 (M+1, C₁₁H₁₃NS₂ requires 223.0489).

Piperidine-1-carbodithioic acid-4-methyl-phenyl ester (4e)

White solid, M.Pt. 118-120 ° C [48]. IR (KBr, ν_max, cm^-1): 2945, 1480, 1279, 1134, 948, 851, 755, and 666. ¹H NMR (CDCl₃, 400 MHz): δ 7.23-7.48 (m, 4H), 4.10 (br, 2H), 3.29 (br, 2H), 2.38 (s, 3H), and 1.50 (br, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 195.9, 135.2, 131.6, 131.4, 131.3, 129.2, 129.1, 50.5, 50.4, 25.7, 24.3, 24.2, and 22.1; m/z (ESI-MS): 252.0836 (M+1, C₁₃H₁₇NS₂ requires 251.0802).

Piperidine-1-carbodithioic acid-4-methoxy-phenyl ester (4f)

White solid, M.Pt. 102-104 °C [48]. IR (KBr, ν_max, cm^-1): 2960, 1486, 1458, 1286, 913, 819, 744, and 670. ¹H-NMR (CDCl₃, 400 MHz): δ 7.55 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 4.22 (br, 2H), 3.76 (s, 2H), 2.16 (br, 2H), and 1.75 (br, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 196.8, 159.3, 138.3, 138.1, 126.3, 116.3, 116.2, 55.2, 52.5, 52.3, 24.8, 24.5, and 24.0. m/z (ESI-MS): 268.0785 (M+1, C₁₃H₁₇NOS₂ requires 267.0752).

Pyrrolidine-1-carbodithioic acid-4-acetyl-phenyl ester (4g)

White Solid, M.Pt. 78-80 °C [50]. IR (KBr, ν_max, cm^-1): 2953, 2865, 1685, 1438, 1264, 1153, 1009, 955, 820, 748, and 607. ¹H- NMR (CDCl₃, 400 MHz): δ 7.80 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 3.93 (br, 2H), 3.75 (br, 2H), 2.56 (s, 3H), 2.14-2.18 (m, 2H), 1.97-2.01 (m, 2H). ¹³C-NMR (CDCl₃, 100 MHz): δ 197.5, 195.2, 135.8, 131.9, 129.8, 129.7, 128.3, 128.2, 54.2, 52.6, 52.5, 24.6, and 24.2. m/z (ESI-MS): 266.0629 (M+1, C₁₃H₁₅NOS₂ requires 265.0595).

Piperidine-1-carbodithioic acid-benzyl ester (4h)

White solid, M.Pt. 52-54 °C [51]. IR (KBr, ν_max, cm^-1): 2919, 1426, 1292, 1180, 934, 809, and 709. ¹H-NMR (CDCl₃, 400 MHz): δ 7.47-7.60 (m, 5H), 4.55 (s, 2H), 4.16 (br, 2H), 3.65 (br, 2H), and 1.76 (br, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 197.5, 136.4, 130.1, 129.2, 128.4, 127.4, 52.1, 51.5, 43.2, 29.6, 24.7, and 24.1. m/z (ESI-MS): 252.0836 (M+1, C₁₃H₁₇NS₂ requires 251.0802).

Pyrrolidine-1-carbodithioic acid-4-hydroxy-phenyl ester (4i)

Colorless oil. IR (Film, ν_max, cm^-1): 3441, 2953, 1436, 1250, 1154, 1038, 957, 856, 753, and 683. ¹H-NMR (CDCl₃, 400 MHz): δ 8.12 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 4.14 (s, 1H), 3.76 (br, 2H), 3.61 (br, 2H), 1.72-1.79 (m, 2H), and 1.23-1.55 (m, 2H). ¹³C-NMR (CDCl₃, 100 MHz): δ 197.1, 189.5, 136.7, 133.3, 127.2, 123.7, 122.6, 56.9, 50.9, 26.5, and 24.1. m/z (ESI-MS): 240.0473 (M+1, C₁₁H₁₃NOS₂ requires 239.0440).

Piperidine-1-carbodithioic acid-n-ethyl ester (4j)

Colorless oil. IR (Film, ν_max, cm^-1): 2917, 1431, 1243, 1108, 1006, 908, 851, and 731. ¹H-NMR (CDCl₃, 400 MHz): δ 4.21 (br, 2H), 3.85 (br, 2H), 3.14 (q, J = 7.0 Hz, 2H), 1.74 (br, 6H), and 1.22 (t, J = 2.1 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 192.6, 55.7, 52.4, 29.6, 26.6, 25.4, 24.1, and 14.8; m/z (ESI-MS): 190.0679 (M+1, C₈H₁₅NS₂ requires 189.0646).

Pyrrolidine-1-carbodithioic acid-n-ethyl ester (4k)

Colorless oil. IR (Film, ν_max, cm^-1): 2918, 1435, 1251, 1155, 1002, 910, 731, and 646. ¹H-NMR (CDCl₃, 400 MHz): δ 3.97 (br, 2H), 3.61 (t, J = 6.8 Hz, 2H), 3.27 (q, J = 7.3 Hz, 2H), 2.01-2.13 (m, 2H), 1.99-1.95 (m, 2H), and 1.32 (t, J = 9.8 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 192.6, 50.9, 50.4, 30.6, 26.5, 24.1, and 13.9. m/z (ESI-MS): 177.0447 (M+1, C₇H₁₃NS₂ requires 175.0489).

Diethyl-1-dithiocarbamic acid-n-butyl ester (4l)

Colorless oil. IR (Film, ν_max, cm^-1): 2932, 1418, 1270, 1143, 1007, 914, 732, and 646. ¹H-NMR (CDCl₃, 400 MHz): δ 4.04 (br, 2H), 3.75 (br, 2H), 3.28 (t, J = 7.3 Hz, 2H), 1.64-1.72 (m, 2H), 1.42-1.48 (m, 2H), 1.27-1.30 (m, 6H), and 0.92 (t, J = 7.4 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 195.9, 51.9, 49.1, 36.8, 30.5, 22.0, 13.6, 11.5, and 11.3. m/z (ESI-MS): 206.0992 (M+1, C₉H₁₉NS₂ requires 205.0959).

Benzylamine-1-carbodithioic acid-n-ethyl ester (4m)

Colorless viscous oil. IR (Film, ν_max, cm^-1): 3263, 2927, 2093, 1638, 1506, 1454, 1383, 1329, 1253, 1073, 1002, 912, 740, 699, and 648. ¹H NMR (CDCl₃, 400 MHz): δ 8.82 (br, 1H, NH), 7.33-7.36 (m, 5H), 4.93 (d, J = 5.1 Hz, 2H, PhCH₂N), 3.26 (q, J = 6.8 Hz, 2H), and 1.22 (t, J = 6.8 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 198.1, 137.4, 128.9, 128.8, 128.2, 127.9, 126.7, 33.5, 26.3, and 14.3. m/z (ESI-MS): 212.0523 (M+1, C₁₀H₁₃NS₂ requires 211.0489).

Benzylamine-1-carbodithioic acid-n-butyl ester (4n)

Colorless viscous oil. IR (Film, ν_max, cm^-1): 3246, 2959, 2093, 1601, 1508, 1455, 1347, 1278, 1127, 1028, 909, 733, 698, and 648. ¹H-NMR (CDCl₃, 400 MHz): δ 7.90 (br, 1H, NH), 7.40-7.55 (m, 5H), 4.21 (d, J = 6.2 Hz, 2H, PhCH₂N), 3.64 (t, J = 6.9 Hz, 2H), 1.98-2.30 (m, 2H), 1.61-1.93 (m, 2H), and 1.24 (t, J = 7.6 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 199.2, 134.0, 128.9, 128.5, 128.4, 122.1, 118.9, 45.1, 38.4, 31.4, 24.1, and 15.4. m/z (ESI-MS): 240.0836 (M+1, C₁₂H₁₇NS₂ requires 239.0802).

3-Diethylthiocarbamoylsulfanyl-propionic acid methyl ester (6a)

Colorless oil. IR (Film, ν_max, cm^-1): 2935, 1735, 1421, 1355, 1202, 1147, 1008, 909, 732, and 648. ¹H-NMR (CDCl₃, 400 MHz): δ 4.0 (br, 2H, CH₂N), 3.68 (br, 2H, CH₂N), 3.65 (s, 3H), 3.53 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), and 1.22-1.45 (m, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 194.6, 172.5, 51.9, 51.7, 49.3, 33.8, 31.5, 12.3, and 11.4. m/z (ESI-MS): 236.0736 (M+1, C₉H₁₇NO₂S₂ requires 235.0702).

3-(Piperidine-1-carbothiosulfanyl)-propionic acid methyl ester (6b)

Colorless oil. IR (Film, ν_max, cm^-1): 2919, 1654, 1439, 1217, 1020, 953, and 709.  ¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (br, 2H), 3.92 (br, 2H), 3.63 (s, 3H), 3.57 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 7.1 Hz, 2H), and 1.61 (br, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 191.9, 172.4, 54.9, 51.9, 50.9, 33.8, 30.9, 26.5, 25.9, and 24.1. m/z (ESI-MS): 248.0734 (M+1, C₁₀H₁₇NO₂S₂ requires 247.0701).

3-(Pyrrolidine-1-carbothiosulfanyl)-propionic acid methyl ester (6c)

White solid, M.Pt. 46-48 °C [52]. IR (KBr, ν_max, cm^-1): 2917, 1735, 1437, 1221, 1156, 1007, 909, 732, and 647. ¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (t, J = 6.8 Hz, 2H, CH₂N), 3.70 (s, 3H), 3.63 (t, J = 7.2 Hz, 2H, CH₂N), 3.57 (t, J = 6.9 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), and 1.96-2.16 (m, 4H). ¹³C-NMR (CDCl₃, 100 MHz): δ 191.9, 172.4, 54.9, 51.7, 50.9, 33.8, 30.9, 26.5, and 24.1. m/z (ESI-MS): 234.0578 (M+1, C₉H₁₅NO₂S₂ requires 233.0544).

3-(4-Phenylpiperazine-1-carbothiosulfanyl)-propionic acid methyl ester (6d)

Colorless oil. IR (Film, ν_max, cm^-1): 3017, 2917, 2850, 1734, 1599, 1492, 1420, 1215, 1145, 1015, 925, 755, and 667. ¹H-NMR (CDCl₃, 400 MHz): δ 7.24-7.29 (m, 2H), 6.84-6.93 (m, 3H), 4.54 (br, 2H), 4.45 (br, 2H), 3.38 (s, 3H), 3.18 (t, J = 6.5 Hz, 2H), 3.09-3.10 (m, 4H), and 2.85 (t, J = 6.5 Hz, 2H). ¹³C-NMR (CDCl₃, 100 MHz): δ 193.4, 172.5, 151.1, 129.3, 129.1, 120.3, 116.2, 52.4, 51.3, 49.1, 45.2, 31.8, and 29.6. m/z (ESI-MS):325.1245 (M+1, C₁₅H₂₀N₂O₂S₂ requires 324.0976).

3-Diethylcarbamodithioic acid-3-amino-3-oxopropyl ester (6e)

White solid, M.Pt. 104-106 °C [53]. IR (KBr, ν_max, cm^-1): 3411, 2920, 1667, 1271, 1202, 1147, 1006, 908, 733, and 649. ¹H-NMR (CDCl₃, 400 MHz): δ 5.70 and 5.34 (together, br, 2H, NH₂), 4.06 (br, 2H, CH₂N), 3.72 (q, J = 7.3 Hz, 2H, CH₂N), 3.56 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H), and 0.85 (t, J = 7.3 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 196.2, 172.1, 53.8, 52.3, 34.1, 33.5, 13.6, and 12.8; m/z (ESI-MS): 221.0738 (M+1, C₈H₁₆N₂OS₂ requires 220.0704).

3-(Piperidine-1-carbodithioic acid)-3-amino-3-oxopropyl ester (6f)

White solid, M.Pt. 115-117 °C [53]. IR (KBr, ν_max, cm^-1): 3340, 2917, 1645, 1208, 1154, 1042, 913, and 744. ¹H-NMR (CDCl₃, 400 MHz): δ 7.23 (br, 2H, NH₂), 4.21 (br, 2H, CH₂N), 3.75 (br, 2H, CH₂N), 3.58 (t, J = 7.1 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), and 0.85-1.73 (m, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 194.3, 173.5, 52.6, 52.2, 34.7, 33.2, 24.3, 24.1, and 21.3. m/z (ESI-MS): 233.0738 (M+1, C₉H₁₆N₂OS₂ requires 232.0704).

3-(Pyrrolidine-1-carbodithioic acid)-3-amino-3-oxopropyl ester (6g)

White solid, M.Pt. 76-78 °C [51]. IR (KBr, ν_max, cm^-1): 3431, 2979, 1647, 1442, 1216, 1154, 1038, 955, 757, and 667. ¹H- NMR (CDCl₃, 400 MHz): δ 4.13 and 4.11 (together, br, 2H, NH₂), 3.93 (t, J = 6.8 Hz, 2H, CH₂N), 3.63 (t, J = 6.9 Hz, 2H, CH₂N), 3.54 (t, J = 6.6 Hz, 2H), 2.13 (t, J = 6.6 Hz, 2H), and 1.98-2.03 (m, 4H). ¹³C-NMR (CDCl₃, 100 MHz): δ 206.5, 189.1, 56.9, 50.9, 32.1, 30.9, 26.5, and 24.2. m/z (ESI-MS): 219.0581 (M+1, C₈H₁₄N₂OS₂ requires 218.0548).

Diethyl-1-carbamodithioic acid-3-oxo-1,3-diphenylpropyl ester (6h)

Colorless oil. IR (Film, ν_max, cm^-1): 3017, 2981, 1663, 1578, 1450, 1216, 1178, 1018, 916, 754, and 689. ¹H-NMR (CDCl₃, 400 MHz): δ 8.00-8.03 (m, 2H), 7.40-7.55 (m, 8H), 4.89 (dd, J = 4.4, 4.4 Hz, 1H), 3.57-4.09 (m, 6H), and 1.25-1.45 (m, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 192.3, 190.2, 144.6, 137.9, 134.6, 132.6, 130.4, 129.6, 129.1, 128.8, 128.4, 128.3, 128.2, 52.1, 47.2, 29.5, 13.2, and 11.2. m/z (ESI-MS): 358.1255 (M+1, C₂₀H₂₃NOS₂ requires  357.1221).

Piperidine-1-carbodithioic acid-3-oxo-1,3-diphenylpropyl ester (6i)

Colorless oil. IR (Film, ν_max, cm^-1): 3060, 2940, 1664, 1606, 1576, 1449, 1216, 1134, 1016, 748, and 689. ¹H-NMR (CDCl₃, 400 MHz): δ 8.00-8.02 (m, 4H), 7.39-7.54 (m, 8H), 4.65 (dd, J = 4.4 Hz, 4.4 Hz, 1H), 4.21 (br, 2H, CH₂N), 3.85 (br, 2H, CH₂N), 3.57-3.60 (m, 2H), and 1.23-2.15 (m, 6H). ¹³C-NMR (CDCl₃, 100 MHz): δ 202.4, 198.9, 144.8, 134.8, 132.7, 130.5, 128.9, 128.6, 128.5, 128.4, 128.3, 128.0, 127.8, 127.6, 48.2, 43.5, 38.7, 25.3, 24.8, and 24.9. m/z (ESI-MS): 370.1255 (M+1, C₂₁H₂₃NOS₂ requires 369.1221).

Pyrrolidine-1-carbodithioic acid-3-oxo-1,3-diphenylpropyl ester (6j)

White solid, M.Pt. 117-119 °C [54]. IR (KBr, ^νmax, cm^-1): 3062, 2923, 1664, 1577, 1440, 1215, 1178, 1017, 909, 753, and 689. ¹H-NMR (CDCl₃, 400 MHz): δ 7.26 -8.03 (m, 10H), 5.75 (dd, J = 4.5, 4.5 Hz, 1H), 3.59-4.15 (m, 6H), and 2.01-2.17 (m, 4H). ¹³C-NMR (CDCl₃, 100 MHz): δ 197.2, 190.3, 137.6, 134.6, 130.4, 128.8, 128.6, 128.4 128.3, 128.2, 128.1, 126.5, 126.3, 126.1, 52.9, 52.8, 48.5, 38.7, 26.3, and 24.1. m/z (ESI-MS): 356.1098 (M+1, C₂₀H₂₁NOS₂ requires 355.1065).

Benzyl-1-carbamodithioic acid-3-oxo-1,3-diphenylpropyl ester (6k)

Colorless oil. IR (Film, ν_max, cm^-1): 3018, 2918, 2850, 1638, 1664, 1605, 1450, 1336, 1215, 1177, 1016, and 747. ¹H-NMR (CDCl₃, 400 MHz): δ 8.02 (d, J = 7.3 Hz, 2H), 7.82-7.91 (m, 3H), 7.22-7.65 (m, 10H), 6.20 (br, 1H, NH), 4.86 (dd, J = 5.8, 5.8 Hz, 1H), 4.70 (s, 2H), and 3.74-3.86 (m, 2H). ¹³C-NMR (CDCl₃, 100 MHz): δ 196.2, 190.1, 144.8, 138.0, 134.7, 133.7, 132.7, 130.5, 128.9, 128.8, 128.5, 128.4, 128.2, 128.0, 121.9, 50.9, 50.1, 48.5, 43.6, 42.5, 37.8, and 29.6. m/z (ESI-MS): 392.1099 (M+1, C₂₃H₂₁NOS₂ requires 391.1067).

Butyl-1-carbamodithioic acid-3-oxo-1,3-diphenylpropyl ester (6l)

Colorless oil. IR (Film, ν_max, cm^-1): 3065, 2918, 2850, 1663, 1605, 1577, 1450, 1336, 1216, 1178, 1017, and 908; ¹H-NMR (CDCl₃, 400 MHz): δ 8.0 (d, J = 7.3 Hz, 2H), 7.30-7.37 (m, 8H), 4.70 (dd, J = 6.6, 6.6 Hz, 1H), 4.45 (br, 1H, NH), 3.17-3.46 (m, 2H), 3.17 (t, J = 6.8 Hz, 2H), 1.41-1.58 (m, 2H), 1.23-1.39 (m, 2H), and 0.92 (t, J = 7.3 Hz, 3H). ¹³C-NMR (CDCl₃, 100 MHz): δ 202.0, 198.9, 138.1, 134.8, 128.9, 128.6, 128.4, 126.8, 48.6, 39.1, 38.1, 35.2, 31.8, 31.3, 30.8, 30.1, 23.5, 21.6, and 13.3; m/z (ESI-MS): 357.7302 (M+1, C₂₀H₂₃NOS₂ requires 357.1221).

Results and Discussion

The review of literature indicated that there are no studies on the use of CAN as a catalyst for the three-component synthesis of dithiocarbamate derivatives without the use of any harmful solvents. This approach uses CAN as a Lewis acid catalyst in PEG to combine the reactions of amines, carbon disulfide, and alkyl/aryl halides in a single reaction vessel. Amines are a key ingredient in the reaction that creates antibacterial and anti-cancer medications. In the intended products, this agent provided the C-N bond while the alkyl/aryl halides provided the C-S bond. The dithiocarbamate formation is stabilised by the inductive impact of the alkyl group, which also alters the polarity of the S-H bond by increasing the electron density on the nitrogen atom.

Diethylamine 1a, carbon disulfide 2, and iodobenzene 3a were used in combination with varied amounts of the catalyst and temperatures to optimise the reaction conditions to increase yield (Scheme 1). Table 1 provides a summary of the findings.

The ideal CAN dosage was assessed. The catalyst concentration of 5 mol% produced the maximum yield. Motivated by this outcome, we continued to investigate the optimal reaction conditions using CAN at varying concentrations from 2 to 5 mol%, which not only reduced the reaction time from 4 to 2 h, but also boosted the product yield from 90% to 94%. This demonstrated that a key factor in the optimization of product yields is the catalyst concentration. Although using 10 mol% of CAN allowed for a 1-hour reaction time reduction, the yield surprisingly dropped to 86%. When an excessive amount (10 mol%) of CAN was employed in the reaction, it is likely that the starting material or product was destroyed during the reaction, which might account for the low product yield. A reaction of diethyamine, carbon disulphide, and iodobenzene was carried out at 50 ^oC in PEG-400:H₂O without any catalyst to determine the catalyst's genuine efficacy. After 5 hours of heating, it turned out that just a little amount of dithiocarbamate was produced (Table 1, Entry 3).

Scheme 1. Synthesis of diethyl-1-dithiocarbamic acid-n-phenyl ester as a model reaction

Table 1. One-pot synthesis of the modal reaction: temperature and CAN quantity screening^a

In the majority of MCRs, solvent selection is significant. Different solvents, including non-polar solvents like n-hexane, protic solvents like water, ethanol, and ethanol: H₂O, polyethylene glycol (PEG), and PEG-400: H₂O, as well as aprotic polar solvents like acetonitrile, were examined to compare the solvent efficiency. The outcomes shown in Table 2 show that solvents had an impact on the catalyst's effectiveness. Acetonitrile and n-hexane had lower yields (Table 2, Entries 6 and 7). Due to the lack of strong interactions between the starting components, the yield was low (30%) when the reaction was carried out without the use of a solvent. However, after only 2 hours of stirring the combination at 50 ^oC, a non-toxic, recyclable, and thermally stable PEG-400 was discovered to deliver the good product yield increase of up to 86% (Table 2, Entry 9). We were encouraged by these encouraging results and used various PEG-400:H2O solvent system ratios to optimize the reaction conditions. The product yield increased from 87% to 95% when PEG-400 was reduced from 100% to 50% (Table 2, Entries 10–14). However, a further reduction in the PEG-400 ratio reduced the product yield, which is attributable to the loss of the reactants' water solubility. The best solvent, PEG 400: H₂O, is thought to have the best catalytic activity because "PEG-400 is a prominent solvent that may increase the solubility of substrates and other reagents with water." PEG also has the ability to remove the hydrogen atom from amine. This might be because the oxygen in the PEG hydroxyl group and hydrogen in diethyl amine (C₂H₅)₂NH are attracted to one another. By weakening the N-H bond, this increases the carbon's nucleophilicity. To complete the synthesis of desired dithiocarbamate products, we can therefore anticipate that PEG-400: H₂O can provide a better reaction medium. As a result, this solvent system can significantly contribute to the achievement of green chemistry's objectives.

Table 2. Solvent effects^a

We tested the generality of this protocol after refining the reaction conditions by coupling alkyl or aryl halides (iodide and bromide groups) with the dithiocarbamate anion, which was produced in situ by the reaction of carbon disulfide and a number of amines to produce the corresponding dithiocarbamate derivatives (Scheme 2). Table 1 provides a summary of the findings. We used various primary and secondary amines when dealing with amines. Due to the strong reactivity of 2^o-amines (Table 3, Entries 13 and 14), the secondary amines such diethyl amine, piperidine, morpholine, and pyrrolidine typically delivered larger yields of products in shorter reaction times as compared to primary amines (Table 3, Entries 1–12). There is no discernible difference between alkyl iodides and bromides in terms of reaction time and product yields. In general, all of the syntheses were carried out using standard reaction conditions, including speedier reaction durations, high selectivity, and no by-products.

Scheme 2. Ceric ammonium nitrate (CAN) catalyze synthesis of dithiocarbamates

The viability of using the existing method for the other new one-pot three-component coupling was then evaluated, and we looked at various amines and Michael acceptors under the same reaction circumstances (Scheme 2). A wide variety of amines with different structural characteristics, including the primary and secondary amines, were utilised in this technique with great success. This procedure is also quite generic. In general, the secondary amines like piperidine, pyrrolidine, and diethylamine have better yields than primary amines. Michael acceptors are effectively added to primary amines like benzylamine and n-butylamine to produce the corresponding dithiocarbamate with great outcomes. Michael acceptors were produced in high to outstanding yields by reactions that went smoothly with electron-deficient olefins including methyl acrylate, acrylamide, and chalcone (Table 4). In addition, we discovered that using 1-phenylpiperazine produced the equivalent Michael adducts in high quantities as well. (Table 4, Entry 18).

Table 3. Dithiocarbamate anions are coupled to alkyl/aryl halides via CAN^a

Table 4. Dithiocarbamate anions' nucleophilic addition to the Michael acceptor under CAN catalysis^a

Recovery of the Solvent

After the reaction is finished, polyethylene glycol (PEG) should be easily recycled with little loss and degradation to demonstrate that using it as a reusable solvent is also feasible. Diethyl ether and PEG-400 are immiscible. Therefore, the desired product can be extracted using it while the PEG-400 phase is still present. Although there was a clean start to the reaction and consistent results up to three cycles, there was a 5% mechanical loss in the weight of PEG-400 from cycle to cycle (Figure 1).

Figure 1. Recyclable ability of green solvent

The proposed mechanism for this formation of dithiocarbamate is depicted in Scheme 3 under the Lewis acidic nature of CAN, carbon disulfide (CS₂) 2 become actively participated in nucleophilic addition reaction with diethyl amine (C₂H₅)₂NH 1 to give dithiocarbamic acid (in situ) I. Furthermore, the properly activated in situ produced intermediate I quickly goes through, a) A nucleophilic substitution reaction with iodobenzene 3 to form dithiocarbamate 4, b) Immediately Michael-type addition with conjugated alkene 5 to give the adduct 6. We believe that Lewis acid catalyst (CAN) and formation of dithiocarbamic acid is essential for the progress of the reaction in forward direction. The plausible mechanism is cited in the article.

Scheme 3. Intriguing pathway for the formation of dithiocarbamate using CAN as a catalyst

Conclusion

In conclusion, using ceric ammonium nitrate (CAN) as an Lewis acid catalyst in a PEG-400: H₂O green solvent system, we have devised a simple, efficient, and unique synthesis of bioactive dithiocarbamates using carbon disulfide, amines, and halides. The novel points of the proposed protocol include an eco-friendly nature, cost-effectiveness, simple purification, recovery of solvent, high yields of desired products, and an easy procedure. In addition, minimum loading of catalyst, clean reaction, and less chemical waste generation gives promising opportunities for generating a diversity-oriented library of molecules related to dithiocarbamates and green chemistry.

Orcids

Anwar Jahan: https://orcid.org/0000-0002-4141-1557

Acknowledgements

The authors gratefully acknowledge the University Science and Instrument Centre (USIC), Department of Chemistry, Ramjas College, and University of Delhi, for providing necessary instrumentation facilities to characterize the compounds and library facility for literature.

Conflict of interest

The authors declare no potential conflict of interest.

Citation: M. Kidwai, P. Dwivedi, A. Jahan*‎. An Environmentally Friendly Strategy for One-pot Synthesis of Dithiocarbamates Using Ceric Ammonium Nitrate (CAN) and PEG: H₂O Solvent System.‎ J. Appl. Organomet. Chem., 2023, 3(3), 156-168.