Mol Divers (2011) 15:157–161 DOI 10.1007/s11030-010-9236-7

FULL-LENGTH PAPER

Toward a practical and waste-free synthesis of thioureas in water Najmedin Azizi · Alireza Khajeh-Amiri · Hossein Ghafuri · Mohammad Bolourtchian

Received: 15 June 2009 / Accepted: 25 January 2010 / Published online: 24 February 2010 © Springer Science+Business Media B.V. 2010

Abstract An operationally simple and entirely green protocol for the synthesis of thiourea derivatives by the reaction of carbon disulfide with primary amines in pure water is developed. This reaction is a highly atom-economic process for production of highly pure, hindered thioureas without any catalyst and tedious work-up. Keywords Amines · Atom economy · Carbon disulfide · Thiourea · Water chemistry · Waste-free Introduction Development of eco-friendly synthetic methodologies, which are environmentally clean, waste-free, with simple work-up, of high purity and, which prevent pollution have received much attention in recent years. In this context, water is a unique solvent in organic synthesis, not only abundant, inexpensive, and environmentally benign but also showing novel reactivity and selectivity for simple synthesis of biologically active compounds in the pharmaceutical or agrochemical industries [1–4]. Thiourea derivatives are being used as neutral receptors for various anions (anion complexation) [5], natural product mimics, and building blocks in the synthesis of heterocycles [6]. Thiocarlide is a pharmacologically important thiourea drug that is used as a therapeutic agent in the treatment of tuberculosis (Fig. 1) [7]. Electronic supplementary material The online version of this article (doi:10.1007/s11030-010-9236-7) contains supplementary material, which is available to authorized users. N. Azizi (B) · A. Khajeh-Amiri · H. Ghafuri · M. Bolourtchian Research and Technology, Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran e-mail: [email protected]

Furthermore, in recent years, chiral thioureas have become increasingly important asymmetric catalysts and ligands in metal-catalyzed reactions in industrial and laboratory processes [8–11]. Thioureas have been traditionally synthesized mainly using dangerous reagents, such as thiophosgene and isothiocyanates [12,13]. An alternative route consists of reacting a primary amine with CS2 in pyridine or ethanol with conventional heating or in the presence of a catalyst [14]. However, the preparation and handling of isothiocyanates are tedious. Moreover, they are hazardous and display poor long-term stability with formation of side products such as urethane in alcoholic medium. Attempts to overcome these limitations have been focused mainly on the development of numerous alternative phosgene-free methodologies for the synthesis of both symmetrical and unsymmetrical thioureas and to avoid the use of isothiocyanates [15–19]. Although some safer methods without the use of isothiocyanate or thiophosgene have been developed recently, they possess drawbacks such as lack of simplicity, generality, tedious work-up, high reaction temperature, and overall poor yields. In an inventive example, Sartori et al. used Al2 O3 /ZnO to catalyze the addition of amines to CS2 at high temperature [15]. The reaction required additional catalyst, large amounts of CS2 , and simple primary amines.

Results and discussion Recently, we became interested in performing organic reactions in water, and we have shown that an aqueous medium can strongly favor reactivity and selectivity, even when they are carried out under heterogeneous conditions [20–23]. Herein, we wish to report the direct synthesis of thioureas using CS2 and a variety of primary amines in pure water with excellent yields and without using any catalyst.

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O

O

S N H

N H

THC Fig. 1 The pharmacologically important thiourea drug (thiocarlide)

Water 2 PhNH2 + CS2

60 oC, 3 h

Ph

H N

97%

H N

Ph

S

Scheme 1 Optimization of the reaction conditions

Treatment of aniline (10 mmol) with carbon disulfide (10 mmol) in water (15 mL) resulted in formation of the thiourea in quantitative yields. The reaction was carried out with a very simple procedure in water at 60 ◦ C without adding any organic solvent or catalyst. As a result, the work-up procedure was very simple under catalyst-free and organic solvent-free conditions. After completion of the reaction, the solids were filtered off, and the product in the filtrate was purified by simple crystallization from ethanol or hot water resulting in excellent yields and high purity. At the end, only an equal molar amount of CS2 was needed according to the stoichiometry of the reaction. It was noticed that an excess of CS2 (2 molar equiv.) led to higher yields, although this was likely because some CS2 escaped from the system during the reaction. However, any further increase in the amount of the added CS2 was not efficient. In order to test the feasibility of a large-scale reaction, aniline (100 mmol) was treated with CS2 (100 mmol) in water (60 mL) at 60 ◦ C, and the product was isolated in 85% yield after 8 h (Scheme 1). The high yield, simple reaction protocol and originality of this efficient process prompted us to explore the reaction for sterically, electronically and functionally diverse amines under the same reaction conditions (Table 1). As shown in Table 1, the yields of the products are affected by the nature of the primary amine. As expected for a typical nucleophilic addition, aliphatic amines are good substrates for this process and show higher reactivity than the aromatic amines. Primary aliphatic amines, such as tert-butylamine, benzylamine, cyclopentylamine, and cyclohexylamine (entry 1–11) reacted with CS2 to give the corresponding thioureas in excellent yields with short reaction times (1 h). In general, the nucleophilic addition of primary aryl amines proceeds sluggishly, owing to their reduced nucleophilicity and needs much longer reaction times to afford the desired products in good yield (Table 1, entries 12–22). In the case of aromatic amines with an electron-donating group, such as 4-isopropyl aniline and 4-methoxyaniline, the corresponding

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products were obtained in good to high yields (Table 1, entry 16–19). Especially, with a sterically hindered amine, such as 2,6-dimethylaniline and 2,4,6-trimethylaniline, the corresponding adducts were produced in good yields (Table 1, entry 20–22). Aromatic amines with an electron-withdrawing group, such as 4-nitroaniline, are not good substrates for this reaction and give the corresponding products in very low yields. Cyclic thioureas such as oxazolidine-2-thiones, 1-mercaptobenzothiazole, and benzolidine-2-thione are very useful compounds, and there is a possibility to manipulate these functional groups for the synthesis of heterocyclic compounds containing sulfur- and nitrogen-building blocks, or they can be readily elaborated to introduce other functional groups. Thus, in light of these promising results, we then focused our attention on the use of amines containing additional nucleophilic groups, such as o-phenylenediamine and ethylenediamine (Table 1, entry 23–25) as the amine source. Under optimized reaction conditions, o-phenylenediamine and ethylenediamine (5 mmol), and CS2 (5 mmol) were mixed in water, and corresponding cyclic thioureas were isolated in high yields. In a similar manner, we also studied the reaction of secondary amines, such as diethyl amine with CS2 , under the same reaction conditions. Thus, the treatment of 10 mmol of diethyl amine with 10 mmol of CS2 in water (15 mL) at 60 ◦ C afforded the dithiocarbamates 3 in high yield (Scheme 2) [24]. Although no detailed mechanistic studies have been carried out, we believe that the reaction of CS2 with primary amines proceeds with the formation of the intermediate isothiocyanates, which adds to the amine to form the thiourea. This mechanism is supported by the observation that secondary amines, such as diethyl amine, failed to give the desired thiourea by the reaction with a CS2 under the same procedure.

Conclusion In summary, we have developed a mild and practical procedure for the synthesis of various thioureas with excellent yields in water. This simple procedure is faster with high yield, and less laborious in isolation and purification procedures than those with isothiocyanates. Furthermore, the reaction is carried out in very mild condition by just mixing of the reactants in water, followed by a simple purification method, as it involves filtration, washing with water, and recrystallization from ethanol or diethyl ether in some cases. Moreover, it reduces the use of organic solvents, minimizes the formation of waste, and improves energy consumption. Further studies to improve the applicability of CS2 in water for the preparation of other biologically important substances are in progress in our laboratories.

Mol Divers (2011) 15:157–161

159 S

Water

Table 1 Synthesis of various thioureas in water

RNH2

+

CS2

60 oC, 1-12 h

Products

Entry

R

N H

N H

R

Yields (%)a time (h) Entry

S

CH3 N H

N H

1 2

X

X

3 4 5

X

N H S

6

84 5 80 5

20

CH3

N H

CH3

H N

22 H3C

90 3

N H

24 76

HN

N H

N H

N H

70

8

70

8

a

H N

H N

12

82

12

82

12

00

12

97 75 80 76 95 95 95 95

8 12 12 12 7 7 7 7

5

12

H N S

H N

X

X=H X = Cl X = Br X=I X= CH3 X = n-Bu X = OMe X = Me2CH

N H

O2N H N

27 O2N

H N S

NO2

NMR yields

S

Water, 60 oC + CS2

N H

S

X

82

N H

NH

26

S N H

10

25

11 12 13 14 15 16 17 18 19

S H N S

S

8

S

10

80 CH3

H N N H

N H

10

90 3

S

9

82 CH3

S CH3 H3C

23 N H

10

CH3 H N

S 8

82

CH3

S

S

7

H N

21

82 10

N H

CH3

H N

H N

H3C

N H

N H

H N S

X X=H 80 7 78 7 X = Cl X = OMe 75 10

S N H

X=H X = Cl

Yields (%)a Time (h)

Products

N 60 min 90%

+H S

H N

mercial suppliers and used without further purification. Water and other solvents were distilled before use.

3

General procedure

Scheme 2 Reaction of secondary amine with carbon disulfide

General procedure for the green reaction of amines and CS2 in water Experimental General Melting points were measured on a Buchi Melting Point B-545 apparatus and are uncorrected. NMR spectra were recorded on a Bruker ACF 500 using CDCl3 /CCl4 or CDCl3 / DMSO-d6 as solvent. All chemicals were obtained from com-

Carbon disulfide (10 mmol for aromatic amines; 7 mmol for aliphatic amines) and an amine (10 mmol) were added in water (15 mL), and the reaction mixture was stirred at 60 ◦ C for 1–12 h. When the reaction was completed, the water insoluble solid product was filtered, washed with water, and then recrystallized from hot water, ethanol, or diethyl ether. All products were characterized by NMR (1 H, and 13 C) and high resolution mass spectrometry.

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Selected spectroscopic data

N , N  -Di-( p-methoxyphenyl)thiourea (Table 1, entry 18)

N , N  -Di-(R)-1-phenylethyl)thiourea (Table 1, entry 7)

95% White crystal; m.p. 182 ◦ C; 1 H NMR (500 MHz, DMSO−d6 ) : δ9.41 (brs, 2H, NH), 7.31 (d, J = 8.8 Hz, 4H), 6.89 (d, J = 8.8 Hz, 4H), 3.74 (s, 6H); 13 C NMR (125.1 MHz, DMSO−d6 )δ181.0, 157.3, 133.1, 126.9, 114.5, 56.0, MS (m/z, %) : 288(M+ ), 165, 122, 108.

90% White crystal; m.p. 193.5 ◦ C, 1 H NMR, 500 MHz (CDCl3 + DMSO-d6 )δ7.02 (brs, 2H, NH), 6.67–6.75 (m, 10H), 4.98 (q, J = 6.2 Hz, 2H), 0.99 (d, J = 6.1 Hz, 6H); 13 C NMR (125 MHz, CDCl3 /DMSO-d6 )δ180.5, 145.1, 129.3, 127.5, 126.7, 53.2, 23.2. MS (m/z, %) : 284(M+ ), 103 (100), 120(79). N , N  -Di-tert-butylthiourea (Table 1, entry 11) 70% White crystal; m.p. 155.5 ◦ C;1 H NMR (500 MHz, CDCl3 + DMSOd6 )δ6.86 (brs, 2H, NH), 1.36 (s, 18H); 13 C NMR (125.1 MHz, CDCl3 + DMSOd6 )δ181.7, 52.9, 29.8. MS (m/z, %) : 188(M+), 57 (80), 28 (100).

N , N  -Di-( p-isopropylphenyl)thiourea (Table 1, entry 19) 95% white crystal; 1 H NMR (500 MHz, DMSO−d6 ) : δ9.14 (brs, 2H, NH), 7.36 (d, J = 8.2 Hz, 4H), 7.18 (d, J = 8.2 Hz, 4H), 2.88 (hept, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz 12H);13 C NMR (100.4 MHz, DMSO−d6 )δ180.4, 146.3, 136.9, 127.1, 125.0, 34.0, 24.6; MS (m/z, %) : 312(M+ ), 278, 263, 120 (100). N , N  -Di-(o-methylphenyl)thiourea (Table 1, entry 20)

N , N  -Diphenylthiourea (Table 1, Entry 12) 97% White solid; mp 151–152 ◦ C; 1 H NMR (500 MHz, DMSO−d6 ) : 9.42 (brs, 2H, NH), 7.57–7.12 (m, 10H); 13 C NMR (125 MHz, DMSO− ) : 179.62, 138.77, 128.10, d6 124.54, 123.69; MS (m/z, %) : 228(M+ ), 93 (100), 77 (79). N , N  -Di-( p-chlorophenyl)thiourea (Table 1, entry 13) 75% White crystal; m.p. 171.4 ◦ C; 1 H NMR (500 MHz, DMSO−d6 ) : δ9.92 (brs, 2H, NH), 7.51 (d, J = 8.7 Hz, 4H), 7.38 (d, J = 8.7 Hz, 4H); 13 C NMR (125. 1 MHz, DMSO−d6 )δ180.6, 139.1, 129.3, 129.2, 126.2.

85% White solid; m.p. 152.1 ◦ C; 1 H NMR (500 MHz, DMSO−d6 ) : δ9.13 (brs, 2H, NH), 7.15-7.24 (m, 8H), 2.24 (s, 6H); 13 C NMR (125 MHz, DMSO−d6 )δ182.0, 138.6, 135.9, 131.1, 129.1, 127.4, 126.9, 18.6; MS (m/z, %) : 256(M+ ), 241, 91, 106 (100). N , N  -Di-(2,6 dimethylphenyl)thiourea (Table 1, entry 21) 80% White solid; m.p. 213.8 ◦ C; 1 H NMR (500 MHz, DMSO−d6 ) : δ9.32−8.07 (brs, 2H, NH), 7.01-7.16 (m, 6H), 2.31 (s, 6H), 2.15 (s, 3H), 2.08 (s, 3H);13 C NMR (100.4 MHz, DMSO−d6 )δ180.8, 138.8, 137.7, 137.4, 137.1, 135.7, 129.2, 128.6, 128.3, 127.3, 19.1, 18.7; MS (m/z, %) : 284(M+ ), 269, 91, 77(100).

N , N  -Di-( p-iodophenyl)thiourea (Table 1, entry 15) 176.7 ◦ C: 1 H

76% white crystal; m.p. NMR (500 MHz, DMSO−d6 )δ9.79 (brs, 2H, NH), 7.62 (d, J = 9.1 Hz, 4H), 7.30 (d, J = 9.1 Hz, 4H); 13 C NMR (125 MHz, DMSO−d6 )δ180.3, 140.1, 138.0, 126.4, 89.5, MS (m/z, %) : 261, 219, 127. N , N  -Di-( p-n-butylphenyl)thiourea (Table 1, entry 17) 95% White crystal; 1 H NMR (500 MHz, DMSO−d6 )δ9.24 (brs, 2H, NH), 7.35 (d, J = 8.3 Hz, 4H), 7.11 (d, J = 8.3 Hz, 4H), 2.55 (t, J = 7.4 Hz 4H), 1.52-1.57 (m, 4H), 1.31-1.36 (m, 4H), 0.91 (t, J = 7.2 Hz 6H); 13 C NMR (125.1 MHz, DMSO−d6 )δ180.4, 140.1, 137.1, 129.0, 124.9, 35.4, 34.0, 22.7, 14.5. MS (m/z, %) : 341(M+ ), 263, 191, 148 (100), 106, 77, 39, 27.

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N , N  -Di-(2,4,6-trimethylphenyl)thiourea (Table 1, entry 22) 80% White solid; m.p. 175 ◦ C; 1 H NMR (500 MHz, DMSO−d6 ) : δ8.03 (brs, 1H, NH), 7.30 (s, 2H), 6.98 (s, 2H), 5.98 (brs, 1H, NH), 2.44 (s, 6H), 2.38 (s, 6H), 2.16 (s, 6H); 13 C NMR (100.4 MHz, DMSO−d6 )δ181.2, 137.7, 137.3, 137.0, 136.8, 136.2, 133.1, 129.8, 129.2, 128.9, 21.4, 18.9, 18.5 MS (m/z, %) : 312(M+ ), 298, 134 (100), 91. 2(1H)benzoimidazolinethione (Table 1, entry 23) 80% White solid; m.p. 304 ◦ C;1 H NMR (500 MHz, DMSO−d6 ) : δ12.5 (brs, 2H, NH), 7.11 (s, 4H); 13 C13 C NMR (125 MHz, DMSO−d6 )δ169.0, 133.1, 123.1, 110.3; MS (m/z, %) : 150(M+ ), 118, 59.

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Imidazolidine-2-thione (Table 1, entry 24) 75% White solid; m.p. 197 ◦ C;1 H NMR (500 MHz, DMSO− d6) : δ7.95 (brs, 2H, NH), 7.19 (t, J=7.8 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 3.48 (s, 4H); 13 C NMR (125 MHz, DMSO−d6 )δ184.3, 44.9; MS (m/z, %) : 102(M+ ), 28 (100). 1,8-diaminonaphtaline-2-thione (Table 1, entry 25) 84% Brownish solid; 1 H NMR (500 MHz, DMSO − d6 ) : δ11.27 (brs, 2H, NH), 7.18 (t, J = 7.8 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 6.59 (d, J = 7.2 Hz, 2H); 13 C NMR (125 MHz, DMSO−d6 )δ182.0, 136.1, 134.8, 129.1, 119.8, 116.9, 105.4, MS (m/z, %) : 200(M+ ), 166, 70, 59 (100), 28. Diethylamine-1-dithiocarboxylicacid diethylammonium salts (Scheme 2) 85% White solid; 1 H NMR (500 MHz, D2 O) : δ3.91 (q, J = 7.0 Hz, 4H), 2.95 (q, J = 7.3 Hz, 4H), 1.15 (t, J = 7.3 Hz, 6H), 1.10 (t, J = 7.0 Hz, 6 H); 13 C NMR (100.4 MHz, D2 O)δ206.2, 49.1, 42.7, 11.8, 11.0. Acknowledgements Financial support of this study provided by Chemistry and Chemical Research Center of Iran is gratefully appreciated.

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