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Original article
10 (
2_suppl
); S2750-S2753
doi:
10.1016/j.arabjc.2013.10.021

2,4,6-Trichloro-1,3,5-triazine (TCT) mediated one pot direct synthesis of N-benzoylthioureas from carboxylic acids

,
 Department of Chemistry, Padmashri Vikhe Patil College, Pravaranagar Tal-Rahata, Dist-Ahmednagar, 413713 (MS), India

⁎Corresponding author. ssgholap2002@gmail.com (Somnath Gholap)

Received: , Accepted: ,
© The Author(s) 2013
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

An efficient 2,4,6-trichloro-1,3,5-triazine (TCT) mediated synthesis of N-benzoylthiourea derivatives from carboxylic acid has been described. The reaction of TCT (1), triethyl amine in dichloromethane gives tris-quaternary ammonium salt (A), reacted with carboxylic acid to form activated ester as an intermediate (B). Aroylthiocyanate was formed by the reaction of activated ester ‘B’ and ammonium isothiocyanate followed by aliphatic or aromatic amines affording structurally diverse N-benzoylthiourea derivatives 3. The synthesized compounds were characterized by IR, 1H NMR and mass spectral data.

Keywords

Trichloro-triazine (TCT)
Carboxylic acid
Amines
N-Benzoylthiourea
Aroylthiocyanate
One-pot method
1

1 Introduction

Thiourea derivatives have gained much attention due to their remarkable bioactivities. They are widely used for their antibacterial (Rauf et al., 2009; Nag et al., 2006), anticancer (Yoshida et al., 2005; Manjula et al., 2009; Saeed et al., 2010a,b), antimalarial (Solomon et al., 2010), diuretic (Taylor et al., 1956) and anti-tubercular activities (Saeed et al., 2010a,b). They have been used as organic inhibitors for corrosion activity (Awad, 2004; Quraishi et al., 2002) and in agrochemicals (Gu et al., 2007; Xu et al., 2004). Due to widespread applications of N-benzoylthiourea, numerous methods have been developed. The direct method involves the coupling of amine and carboxylic acid in the presence of Bronsted acid and high temperature. In this process strong acid deactivates amine by the reaction with acid. The commonly used method for the synthesis of titled compounds proceeds from acyl or aroyl isothiocynate (Reeves et al., 1980, 1981; Cainell and Manescalchi, 1979; Smith and Kan, 1964; Lipp et al., 1958; Bai et al., 2002). These reported procedures suffer from some disadvantages such as use of aggressive reagents like SOCl2, expensive catalysts, release of hazardous waste and laborious work-up procedures.

1,3,5-Triazine derivatives were known for a long time due to their widespread application in the field of pharmaceutical, textile, plastic and rubber industries. They have been used in pesticides, dyestuffs, optical bleaches, explosive and surface active agents. The chemistry of this group of compound has been studied extensively (Smoli and Rapapon, 1959; Mur, 1964; Quirke, 1984; Giacomelli et al., 2004). The most important reagent for obtaining these compounds is cyanuric chloride (CC). Cyanuric chloride (CC) is a commercially available, inexpensive reagent and it has been used as a catalyst in various synthetic transformations (Menicagli et al., 2000; David et al., 2000; Barnett et al., 1994; De Luca et al., 2001; Venkataraman and Wagle, 1979; Sandler, 1970; Blonty, 2003; Falchi et al., 2000). Due to reactivity pattern of chlorine atoms in CC with different nucleophiles at various temperature ranges, it has been used as an efficient reagent for the synthesis of pharmacologically active agents (Sharma et al., 2012, 2013; Shariat et al., 2013; Huimin et al., 2001; David et al., 2000).

Though tremendous research work has been done on the catalytic properties of TCT, still there is a need to apply this catalyst for varieties of difficult transformations. To the best of our knowledge there is no report on the TCT mediated synthesis of N-benzoylthiourea derivatives starting from carboxylic acid one-pot.

2

2 Result and discussion

In continuation to our ongoing research on the development of novel methods (Gholap, 2012; Gholap et al., 2009, 2012, 2013; Gholap and Gill, 2010), herein we have reported the synthesis of structurally diverse N-benzoylthiourea derivatives directly from carboxylic acid in one-pot using cyanuric chloride as an acid activator (Schemes 1 and 2). During the course of our study, we have observed that aliphatic amines react faster to yield desired N-benzoylthiourea derivatives in good to excellent yield under mild conditions (Table 1). However, for aromatic amines reflux conditions are required. In a typical experimental procedure for aliphatic amines, 2,4,6-trichloro-1,3,5-triazine (3 mmol) was dissolved in dichloromethane (10 ml) at 0 °C. To this solution, triethylamine (9.5 mmol) was added. The white suspension of salt of TCT and Et3N was formed immediately. After 20 min, 4-nitrobenzoic acid (9.5 mmol) was added portionwise then reaction mixture was slowly warmed to room temperature. To the above clear solution, ammonium thiocyanate (9.5 mmol) was added followed by addition of ethylene diamine (9 mmol) and during this reaction stirring was continued for 30 min. After completion of reaction (TLC), reaction mixture was mixed with saturated sodium bicarbonate solution and separated organic layer was dried over anhydrous MgSO4. Dichloromethane was removed under reduced pressure to afford almost pure ethylenediamino-[bis-(N,N-4-nitrobenzoyl)]-thiourea (3a).

Reaction conditions: (a) Et3N, CH2Cl2, 0 °C; (b) 3RCOOH, rt; (c) NH4SCN, CH2Cl2, rt; (d) Aliphatic diamine, rt.
Scheme 1 Reaction conditions: (a) Et3N, CH2Cl2, 0 °C; (b) 3RCOOH, rt; (c) NH4SCN, CH2Cl2, rt; (d) Aliphatic diamine, rt.
Reaction conditions: (a) Et3N, CH2Cl2, 0 °C; (b) 3RCOOH, r.t; (c) NH4SCN, CH2Cl2, r.t; (d) Aromatic diamine, 60 °C.
Scheme 2 Reaction conditions: (a) Et3N, CH2Cl2, 0 °C; (b) 3RCOOH, r.t; (c) NH4SCN, CH2Cl2, r.t; (d) Aromatic diamine, 60 °C.
Table 1 TCT mediated synthesis of bis-(N-benzoyl) thioureas at various temperatures.
Entry RCOOH Amine Products Yield (%) Temp (°C) M.P (°C)
1. 4-NO2,C6H4COOH H2N(CH2)2NH2 3a 94 25 144–145
2. C6H5COOH H2N(CH2)2NH2 3b 87 25 150–151
3. 4-MeO,C6H4COOH H2N(CH2)2NH2 3c 93 25 165–167
4. 3-NO2,C6H4COOH H2N(CH2)2NH2 3d 79 25 225–226
5. 4-OH,C6H4COOH H2N(CH2)2NH2 3e 64 25 200–201
6. 4-Cl,C6H4COOH H2N(CH2)2NH2 3f 91 25 149–150
7. 2,6-Di-Me,C6H3COOH H2N(CH2)2NH2 3g 69 25 257–258
8. H2N(CH2)2NH2 3h 75 25 170–172
9. H2N(CH2)2NH2 3i 82 25 160–162
10. H2N(CH2)2NH2 3j 87 25 135–137
11. C6H5COOH H2NNH2 3k 90 25 209–210
12. 4-Cl,C6H5COOH H2NNH2 3l 94 25 175–177
13. C6H5COOH C6H5NH2 3m 77 25 134–136
14. 4-Me,C6H4COOH C6H5NH2 3n 69 60 131–133
15. 4-MeO,C6H4COOH C6H5NH2 3o 84 60 112–114
16. 2-Cl,C6H4COOH C6H5 NH2 3p 91 60 152–153
17. C6H5CH2COOH 4-Cl,C6H4 NH2 3q 72 60 137–139
18. C6H5CH⚌CHCOOH C6H5 NH2 3r 70 60 162–164
19. C6H5COOH 4-Me,C6H4NH2 3s 75 60 122–124
20. 4-NO2,C6H4COOH 4-Me,C6H4NH2 3t 98 60 156–157
21. 3,4,5-Tri-MeO,C6H2COOH C6H5 NH2 4u 94 60 201–203

∗All products were characterized by IR, 1H NMR, 13C NMR and mass spectral data and by comparison with authentic samples.

It has been found that there is no side product formation such as acid chloride and acid anhydride. The presence of the electron withdrawing group at aromatic amine shows slow reaction whereas, the electron donating group accelerates the rate of reaction to form desired compounds in excellent yields (Table 1).

3

3 Experimental

The melting points were determined on the open capillary tube and were uncorrected. The IR spectra were recorded on Bomen FT-IR MB-104 Spectrophotometer with KBr disc and 1H NMR spectra were recorded on Brucker AC-300 MHz in DMSO-d6.

3.1

3.1 General procedure for synthesis of bis-N-benzoyl thiourea

In a mixture of 2,4,6-tricho-1,3,5-triazine (3 mmol) in dichloromethane (10 ml), triethyl amine (9.5 mmol) was added at 0 °C for 1 h. To this solution, carboxylic acid (9.5 mmol) was added and reaction mixture was slowly warmed to room temperature. Clear solution was obtained and all the acid was consumed (TLC) then NH4SCN (9.5 mmol) was added portionwise during 10 min time interval with constant stirring for further 1 h. To this stirred solution, aliphatic diamine (9 mmol) was added and stirring was continued for next 30 min. After completion of reaction (TLC), the reaction mixture was mixed with saturated sodium bicarbonate solution and separated organic layer was dried over anhydrous MgSO4. Dichloromethane was removed under reduced pressure to afford crystalline bis-N-benzoylthiourea.

3.2

3.2 General procedure for the synthesis of N-benzoyl thioureas

In a mixture of 2,4,6-tricho-1,3,5-triazine (3 mmol) in dichloromethane (15 ml), triethyl amine (9.5 mmol) was added at 0 °C for 1 h. On addition a white suspension was formed then carboxylic acid (9.5 mmol) was added in one portion and the reaction mixture was slowly warmed to room temperature, clear solution was obtained and all the acid was consumed (TLC). To the clear solution, NH4SCN (9.5 mmol) was added portionwise for 10 min with constant stirring for next 1 h followed by the addition of aromatic amine (9 mmol) and the reaction mixture was refluxed in hot water bath for 20 min. After completion of reaction (TLC), the reaction mixture was washed with saturated sodium bicarbonate solution and separated organic layer was dried over anhydrous MgSO4. Dichloromethane was removed under reduced pressure to afford pure N-benzoylthiourea derivatives (Table 1).

3.2.1

3.2.1 Compound 3a

IR (KBr): 3332, 3310, 2995, 2983, 1588, 1560, 810 cm−1; 1H NMR (DMSO-d6, 300 MHz, in δ ppm): 4.4 (s, 4H), 5.6 (s,1H), 6.9 (s,1H), 7.2 (d,4H), 7.4 (d,4H); 13C: 178, 170, 165, 140, 128, 120, 76; C18H17N7O6S2 (m/z): 483.0 (M+).

3.2.2

3.2.2 Compound 3d

IR (KBr): 3300, 3211, 2950, 1610, 1210, 816 cm−1; 1H NMR (DMSO-d6, 300 MHz, in δ ppm): 4.6 (s, 4H), 5.1 (s,1H), 7.0 (s,1H), 7.5 (d, 4H), 7.3 (d, 4H); 13C NMR: 176, 168, 164, 142, 130, 115, 77, 60; C20H23N5O4S2 (m/z): 413.9 (M+).

3.2.3

3.2.3 Compound 3t

IR (KBr): 3350, 2922, 1598, 790 cm−1; 1H NMR (DMSO-d6, 300 MHz, in δ ppm): 2.3(s, 3H), 5.1 (s,1H), 6.6 (d,2H), 7.1 (d,2H), 7.6 (m,3H), 7.8 (m, 2H); 13C NMR: 178, 134, 130, 125, 26; C15H13N3O3S (m/z): 270.3 (M+).

3.2.4

3.2.4 Compound 3u

IR (KBr): 3410, 3330, 2943, 1560, 1450, 717 cm−1; 1H NMR (DMSO-d6, 300 MHz, in δ ppm): 2.5 (s, 3H), 5.7 (s,1H), 6.0 (s, 1H), 7.5 (d,2H), 7.0 (d, 2H), 7.7 (d, 2H), 8.2 (d, 2H); 13C NMR: 180, 173, 152, 140, 127, 30; C15H14N2OS (m/z): 316.6 (M+).

4

4 Conclusion

In conclusion we have developed a new and expeditious one-pot methodology for N-benzoyl thiourea derivatives directly from carboxylic acid. 2,4,6-Trichloro-1,3,5-triazine (TCT) was found to be inexpensive easily available, easy to handle and dramatic genrality for various aliphatic or aromatic acids and amines undergo smooth N-benzoyl thiourea formation through formation of bezoylisothiocynate in one pot strategy under mild condition.

Acknowledgement

The authors are thankful to BCUD, University of Pune for financial assistance, Dr. S. R. Walunj, Principal, Padmashri Vikhe Patil Collage, Pravaranagar for providing necessary laboratory facilities.

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