Water-Mediated Synthesis of Benzazole and Thiourea Motifs by Reacting Naturally Occurring Isothiocyanate with Amines

Article abstract of DOI:10.1080/00397911.2015.1062514

An efficient, green, and facile method has been developed for the synthesis of benzazole and thiourea analogues from naturally occurring erucin in moderate to good yields. The reaction was carried out in water without using any metal catalyst or base. The present method tolerated the various functional groups on aromatic rings and also applicable for other isothiocyanates.

Full text of DOI:10.1080/00397911.2015.1062514

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Water-Mediated Synthesis of Benzazole
and Thiourea Motifs by Reacting
Naturally Occurring Isothiocyanate with
Amines
Ritika Sharmaa, Manju Balaab, Praveen Kumar Vermaab & Bikram
Singhab
a Natural Product Chemistry and Process Development Division, CSIR
Institute of Himalayan Bioresource Technology, Palampur, Himachal
Pradesh, India
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b Academy of Scientific and Innovative Research, New Delhi, India
Accepted author version posted online: 15 Jul 2015.Published
online: 15 Jul 2015.
To cite this article: Ritika Sharma, Manju Bala, Praveen Kumar Verma & Bikram Singh (2015) Water-
Mediated Synthesis of Benzazole and Thiourea Motifs by Reacting Naturally Occurring Isothiocyanate
with Amines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 45:18, 2106-2114, DOI: 10.1080/00397911.2015.1062514
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1062514
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Synthetic Communications1, 45: 2106–2114, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1062514
WATER-MEDIATED SYNTHESIS OF BENZAZOLE AND
THIOUREA MOTIFS BY REACTING NATURALLY
OCCURRING ISOTHIOCYANATE WITH AMINES
Ritika Sharma,1 Manju Bala,1,2 Praveen Kumar Verma,1,2 and
Bikram Singh1,2
1Natural Product Chemistry and Process Development Division, CSIR
Institute of Himalayan Bioresource Technology, Palampur, Himachal
Pradesh, India
2Academy of Scientific and Innovative Research, New Delhi, India
GRAPHICAL ABSTRACT
Abstract An efficient, green, and facile method has been developed for the synthesis of
benzazole and thiourea analogues from naturally occurring erucin in moderate to good
yields. The reaction was carried out in water without using any metal catalyst or base.
The present method tolerated the various functional groups on aromatic rings and also
applicable for other isothiocyanates.
Keywords Benzazoles; erucin; isothiocyanates; thiourea; water-mediated synthesis
INTRODUCTION
Erucin (4-methylthiobutylisothiocyanate) (Fig. 1), a natural isothiocyanate, is
abundantly present in the plant Eruca sativa (brassicaceae). This plant is mainly
Received April 28, 2015.
IHBT Communication No. 3792.
Address correspondence to Bikram Singh, Natural Product Chemistry and Process Development
Division, CSIR Institute of Himalayan Bioresource Technology, Palampur, H.P., 176061, India. E-mail:
bikram_npp@rediffmail.com, bikramsingh@ihbt.res.in
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2106

NATURAL PRODUCT ANALOGUES
2107
Figure 1. Structures of erucin, bioactive benzazole, and thiourea-bearing molecules.
known for the presence of glucosinolates,[1] which are hydrolyzed by an enzyme
myrosinase[2] to give isothiocyanates or nitriles. Extracts of Eruca sativa shows
various biological activities[3] such as antibacterial, anticancer, antiphlogistic,
astringent, diuretic, stimulant, laxative, antacid, and anti-inflammatory activities
and also affects blood circulation. Erucin is also known for significant neuroprotec-
tive, antioxidant, and anticancer activities.[4,5] Isothiocyanates constitute a significant
functional class and are widely applicable as moderately reactive chemoselective
electrophiles that are stable toward aqueous reaction conditions.[6]
On the other hand, the benzazole moiety is a privileged scaffold in numerous
bioactive natural products and pharmaceuticals[7] and is also used as a ligand in
important organic transformations.[8] These are oftenly used by medicinal chemists
for synthesis of drugs[9] such as cytotoxic agents, HIV reverse trancriptase inhibitors,
estrogen receptor agonists, orexim-1 receptor antagonists, proton-pump inhibitors,
AT1 receptor antagonists, direct thrombin inhibitors, nonsteroidal anti-inflamma-
tory drugs, and sodium channel blockers (Fig. 1). Much attention has been paid
to the synthesis of azole derivatives due to their diverse applicability. Similarly,
the thiourea backbone also represents a significant structural motif in pharmaceuti-
cal agents[10] having antibacterial, antimalarial, antiviral, and antitumor activities, as
well as organo-catalytic potential (bis-thiourea).[11] Numerous strategies have been
applied earlier for the synthesis of azoles such as via condensation of substituted ani-
lines with isothiocyanates, followed by intramolecular cyclization of the resultant
thiourea with transition-metal catalysts (Pd or Cu).[12] Ding et al. synthesized 2-ami-
nobenzothiazole derivatives using copper(I)-catalyzed tendem addition–cyclization
reaction in toulene[13] and FeCl3 in water with a phase-transfer catalyst, base
(DABCO), and ligand.[14] Li et al. synthesized the same core using FeF3 or CuBr
catalyst.[15] Copper-based catalysts have also been applied for similar transforma-
tions in water.[16] Another effective approach for the synthesis of a benzoxazole core
is the condensation of 2-aminophenol with either carboxylic acid or aldehyde under
high temperature,[17] metal-catalyzed cross coupling,[7b] polymer-supported synthesis
under microwave irradiation,[18] transition metal-free, base-mediated synthesis in the
presence of dimethylsulfoxide (DMSO),[19] and T3P-mediated synthesis via dehydro-
genation under mild conditions.[20]

2108
R. SHARMA ET AL.
The thiourea core was synthesized by reacting amines with isothiocyanates
under solvent or solvent-free conditions and sodium or ammonium thiocyanate in
the presence of strong acids [triflouroacetic acid (TFA) or concentrated HCl].[21–23]
N-Allylthioureas were synthesized from allylic bromide by using the KSCN=SiO2-
RNH2OAc=Al2O3 catalytic system.[24] Moreover, to the best of our knowledge direct
synthesis of benzazole and thiourea moieties by directly reacting amines with isothio-
cyanates without using any catalyst or base is not reported. In continuation of our
work on the synthesis of azole scaffolds,[25] herein, we describe an environmentally
benign approach for the synthesis of benzazole and thiourea scaffolds from a
naturally occurring molecule, erucin, by employing water as solvent and catalyst.
RESULTS AND DISCUSSION
Initially, to optimize the best reaction conditions, the reaction of 2-aminothio-
phenol was carried out with erucin under different conditions (Table 1). The model
reaction in ethanol afforded the desired product up to 68% at rt; however, the yield
of the reaction was enhanced up to 95% at elevated temperature (Table 1, entries
1–3). The reaction yields were decreased in the mixture of EtOH=H2O (1:1) even at
high temperature (Table 1, entries 4 and 5). Poor yields were observed in cases of
isopropanol and toluene at rt (Table 1, entries 6 and 8); however, increase in yields
were observed at high temperature (Table 1, entries 7 and 9). To our delight, in the
case of water, the increase in reaction temperature up to 120 °C afforded the desired
product in excellent yield (95%) in 48 h (Table 1, entry 12).
After optimization of the reaction conditions, the scope of the method was
explored for the synthesis of various benzazole- and thiourea-containing analogues
of erucin. Different o-substituted (-SH, -OH) anilines were tested for the synthesis
of benzazole analogues. The reaction of 2-aminothiophenol and 4-chloro-2-
aminothiophenol with erucin afforded the corresponding thioazole analogues in 88
Table 1. Solvent screening for synthesis of benzothiazole analogues of erucina
Entry
Solvent
C2H5OH
C2H5OH
C2H5OH
C2H5OH=H2O (1: 1)
C2H5OH=H2O (1: 1)
CH3CH(OH)CH3
CH3CH(OH)CH3
C6H5CH3
Temperature (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
rt
rt
120
rt
120
rt
120
rt
48
72
48
48
48
48
48
48
48
48
48
67
68
90
61
75
39
72
1
C6H5CH3
H2O
H2O
120
rt
120
70
19
95
10
11
aReaction conditions: 2-aminothiophenol (1 mmol), erucin (1 mmol), solvent (5 mL).
bGC yields.

NATURAL PRODUCT ANALOGUES
2109
Table 2. Synthesis of benzothiazole and benzoxazole analogues of erucina,b
aReaction conditions: o-substituted anilines (1 mmol), erucin (1 mmol), H2O (5 mL) at 120 °C for 48 h.
bIsolated yields.
and 60% yields, respectively (Table 2, entries 3a and 3b). The reactions of substituted
aminophenols with erucin were accomplished with moderate to good yields (Table 2,
entries 3c–3 g), tolerating -Cl, -Me, and -NO2 groups. To broaden the scope of the
Table 3. Synthesis of benzazole analogues of different isothiocyanatesa,b
aReaction conditions: o-substitutedanilines (1 mmol), isothiocyanates (1 mmol), H2O (5 mL) at 120 °C
for 48 h.
bIsolated yields.

2110
R. SHARMA ET AL.
method, apart from erucin, reaction with different isothiocyanate was carried out and
various benzoxazoles and benzothiazoles were prepared (Table 3). The reaction of
2-amino 3-methyl phenol and 2-aminothiol with m-tollyl isothiocyanate afforded
the corrosponding benzazoles in 58 and 30% yields respectively (Table 3, entries 6b
and 6f). The reaction of 2-amino 3-methyl phenol and 2-aminothiol with 3-chlorophe-
nyl isothiocyanate afforded corrosponding benzazoles in 30% and 76% yields
(Table 3, entries 6d and 6 h). The reaction of 2-amino 3-methyl phenol and 2-
aminothiol with phenylisothiocyanate provided moderate yields of 65% and 53%
(Table 3, entries 6c and 6 g) while aliphatic substituents afforded the product in mod-
erate to good yields of 82%, 87%, and 56% (Table 3, entries 6a, 6e, and 6i). The reac-
tion of erucin was carried out with different primary amines to prepare the thiourea
analogues. Aniline and 2,3-dimethylaniline afforded the desired product in fair yields
(Table 4, entries 8a and 8b). The reaction of 2-aminobenzothiazole with erucin
afforded the thiourea backbone bearing analogues in good yields (Table 4, entry 8c).
In addition to anilines, the reaction of erucin was also carried out with aliphatic
amines. The reaction of various derivatives of phenylethyl amines and benzyl amine
afforded the corresponding thiourea analogues tolerating -F, -Br, -OH, and -OMe
groups in the aromatic ring (Table 4, entries 8d–8i). The present protocol for the
synthesis of thiourea analogues was also applicable to the secondary amines.
The reaction of piperazine, 1-(4-nitrophenyl)piperazine, pyrrolidine, morpholine,
Table 4. Synthesis of thiourea analogues of erucin by reaction with primary aminesa,b
aReaction conditions: amines (1 mmol), erucin (1 mmol), H2O (5 mL) at 120 °C for 48 h.
bIsolated yields.

NATURAL PRODUCT ANALOGUES
2111
Table 5. Synthesis of thiourea analogues of erucin by reaction with secondary aminesa,b
aReaction conditions: amines (1 mmol), erucin (1 mmol), H2O (5 mL) at 120 °C for 48 h.
bIsolated yields.
4-hydroxypiperidine, and 4-methylpiperidine with erucin gave the corresponding
thiourea analogues in moderate to good yields (Table 5, entries 10a–10f). In the case
of piperazine, double functionalized product was obtained (Table 5, entry 10a). The
thiourea and urea analogues of piperazine have been reported as highly potent
antiglycating agents.[26]
Furthermore, the biological evaluation of erucin as well as its analogues for the
anticancer potential is under progress in our laboratory.
The mechanism of water-catalyzed azole synthesis is well established.[27] Water
acts as a dual activation catalyst for the synthesis of benzazoles via electrophilic as
well as nucleophilic activation steps from aldehydes and o-substituted anilines. On
the basis of earlier reports,[17,26] it has been postulated that the nucleophilic attack
of amine group on the isothiocyanate moiety of erucin results in the formation of
Figure 2. Plausible reaction pathway.

2112
R. SHARMA ET AL.
thiourea derivative (a). The ambifilic activation of thiol and thiocarbonyl groups
of thiourea derivative (a) by water leads to its cyclization via intermediate (b) for
the formation of azole scaffolds (Fig. 2).
CONCLUSION
A new, green, metal-free method has been developed for the synthesis of
various benzazoles (benzothiazole and benzoxazole) and thiourea analogues of an
abundantly available natural molecule, erucin, in water. The present protocol
tolerated the various sensitive functional groups and was also applicable to other
isothiocyanate compounds instead of erucin. The present work provides diverse
azoles and thiourea-backbone-bearing molecules, which constitute effective pharma-
cophores in modern drug discovery.
EXPERIMENTAL
General Experimental Procedure for the Synthesis of Benzazole
Analogues of Isothiocyanates
The stirred suspension of isothiocyanates (1 mmol) and o-substituted anilines
(1 mmol) in H2O (5 mL) was refluxed at 120 °C for 48h. After completion, the reaction
mixture was extracted with ethyl acetate, filtered, passed through anhydrous Na2SO4,
and dried under vacuum. The crude product was purified by column chromatography
over silica gel (60–120 mesh) with an appropriate mixture of n-hexane and ethyl acetate.
General Experimental Procedure for the Synthesis of Thiourea
Analogues of Erucin
The stirred suspension of erucin (1 mmol) and amines (1 mmol) in H2O (5 mL)
was refluxed at 120 °C for 48 h. After completion, the reaction mixture was extracted
with ethyl acetate, filtered, passed through anhydrous Na2SO4, and dried under
vacuum. The crude product was purified by column chromatography over silica
gel (60–120 mesh) with an appropriate mixture of n-hexane and ethyl acetate.
ACKNOWLEDGMENT
The authors are grateful to the director of the institute for providing the
necessary facilities.
FUNDING
P. K. V. is thankful to the Council of Scientific and Industrial Research for a
senior research fellowship. We are also thankful to the Department of Science and
Technology for the financial assistance.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.

NATURAL PRODUCT ANALOGUES
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REFERENCES
1. Vaughn, S. F.; Berhow, M. A. Indus. Crop. Prod. 2005, 21, 193.
2. VanEtten, C. H.; Tookey, H. L. Glucosinolates. In Naturally Occurring Food Toxicants;
M. Rechcigl (Ed.); CRC Press: Boca Raton, FL, 1983; p. 15.
3. (a) Gulfraz, M.; Sadiq, A.; Tariq, H.; Imran, M.; Qureshi, R.; Zeenat, A. Pak. J. Bot. 2011,
43, 1351; (b) Bennett, R. N.; Rosa, E. A. S.; Mellon, F. A.; Kroon, P. A. J. Agric. Food
Chem. 2006, 54, 4005; (c) Zhang, Y.; Talalay, P. Cancer Res. (Suppl.), 1994, 54, 1976.
4. Miyazawa, M.; Maehara, T.; Kurose, K. Flav. Fragr. J. 2002, 17, 187.
5. (a) Tarozzi, A.; Morroni, F.; Bolondi, C.; Sita, G.; Hrelia, P.; Djemil, A.; Cantelli-Forti,
G. Int. J. Mol. Sci. 2012, 13, 10899; (b) Zhang, Y.; Talalay, P.; Cho, C. Proc. Natl. Acad.
Sci. USA 1992, 89, 2399.
6. Fernández, J. M. G.; Mellet, C. O.; Blanco, J. L. J.; Mota, J. F.; Gadelle, A.; Coste
Sarguet, A.; Defaye, J. Carbohydr. Res. 1995, 268, 71.
7. (a) Takuzo, H.; Masataka, I.; Konosuke, T.; Masanobu, T. Chem. Pharm. Bull. 1982, 30,
2996; (b) Lijun, G.; Cheng, J.; Junming, G.; Lizhu, Z.; Wei, W. Chem. Commun. 2013, 49,
10968; (c) Weekes, A. A.; Westwell, A. D. Curr. Med. Chem. 2009, 16, 2430; (d) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (e) Kuhler, T. C.;
Swanson, M.; Shcherbuchin, V.; Larsson, H.; Mellgard, B.; Sjostrom, J. E. J. Med. Chem.
1998, 41, 1777.
8. Drew, M. G. B.; Hill, C.; Hudson, M. J.; Iveson, P. B.; Madic, C.; Vaillant, L.; Youngs,
T. G. A. New J. Chem. 2004, 28, 462.
9. (a) Don, M. J.; Shen, C. C.; Lin, Y. L.; Syu Jr., W.; Ding, Y. H.; Sun, C. M. J. Nat. Prod.
2005, 68, 1066; (b) Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486; (c)
Grobler, J. A.; Dornadula, G.; Rice, R. M.; Simcoe, A. L.; Hazuda, D. J.; Miller, M. D.
J. Biol. Chem. 2007, 282, 8005; (d) Rasmussen, K.; Hsu, M. A.; Yang, Y. Neuropsychophar-
macology 2007, 32, 786; (e) Mortimer, C. G.; Wells, G.; Crochard, J. P.; Stone, E. L.;
Bradshaw, T. D.; Stevens, M. F.; Westwell, A. D. J. Med. Chem. 2006, 49, 179.
10. (a) Daele, I. V.; Munier-Lehmann, H.; Froeyen, M.; Balzarini, J.; Calenbergh, S. V. J.
Med. Chem. 2007, 50, 5281; (b) Krajacic, M. B.; Novak, P.; Dumic, M.; Cindric, M.;
Paljetak, H. C.; Kujundzic, N. Eur. J. Med. Chem. 2009, 44, 3459; (c) Krajacic, M. B.;
Peric, M.; Smith, K. S.; Schonfeld, Z. I.; Ziher, D.; Fajdetic, A.; Kujundzic, N.; Schonfeld,
W.; Landek, G.; Padovan, J.; Jelic, D.; Ager, A.; Milhous, W. K.; Ellis, W.; Spaventi, R.;
Ohrt, C. J. Med. Chem. 2011, 54, 3595; (d) Sharma, S. K.; Wu, Y.; Steinbergs, N.; Crowley,
M. L.; Hanson, A. S.; Casero, R. A.; Woster, P. M. J. Med. Chem. 2010, 53, 5197.
11. (a) Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.; Nagasawa, K. Tetrahedron
2008, 64, 9423; (b) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron
Lett. 2004, 45, 5589.
12. (a) Joyce, L. L.; Evindar, G.; Batey, R. A. Chem. Commun. 2004, 446; (b) Evindar, G.;
Batey, R. A. J. Org. Chem. 2006, 71, 1802; (c) Wang, J.; Peng, F.; Jiang, J.; Lu, Z.; Wang,
L.; Bai, J.; Pan, Y. Tetrahedron Lett. 2008, 49, 467; (d) Benedi, C.; Bravo, F.; Uriz, P.;
Fernandez, E.; Claver, C.; Castillon, S. Tetrahedron Lett. 2003, 44, 6073.
13. Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587.
14. Ding, Q.; Cao, B.; Liu, X.; Zong, Z.; Peng, Y. Green Chem. 2010, 12, 1607.
15. (a) Qiu, J. W.; Zhang, X. G.; Tang, R. Y.; Zhong, P.; Li, J. H. Adv. Synth. Catal. 2009,
351, 2319; (b) Guo, Y.; Tang, R. Y.; Zhong, P.; Li, J. H. Tetrahedron Lett. 2010, 51, 649.
16. (a) Saha, P.; Ramanna, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 8719; (b) Khatun, N.; Jamir, L.; Ganesha, M.; Patel, B. K. RSC Adv.
2012, 2, 11557.
17. (a) Boyd, G. V. In Science of Synthesis: Houben-Weyl Methods of Molecular Transforma-
tions; E. Schaumann (Ed.); Thieme, Stuttgart 2001; vol. 11, p. 481; (b) Pottorf, R. S.;

2114
R. SHARMA ET AL.
Chadha, N. K.; Katkevics, M.; Ozola, V.; Suna, E.; Ghane, H.; Regberg, T.; Player, M. R.
Tetrahedron Lett. 2003, 44, 175.
18. Chanda, K.; Maiti, B.; Yellol, G. S.; Chien, M. H.; Kuo, M. L.; Sun, C. M. Org. Biomol.
Chem. 2011, 9, 1917.
19. Peng, J.; Zong, C.; Ye, M.; Chen, T.; Gao, D.; Wang, Y.; Chen, C. Org. Biomol. Chem.
2011, 9, 1225.
20. Raghavendra, G. M.; Ramesha, A. B.; Revanna, C. N.; Nandeesh, K. N.; Mantelingu, K.;
Rangappa, K. S. Tetrahedron Lett. 2011, 52, 5571.
21. Kaupp, G.; Schmeyers, J.; Boy, J. Tetrahedron 2000, 56, 6899.
22. (a) Loev, B.; Bender, P. E.; Bowman, H.; Helt, A.; McLean, R.; Jen, T. J. Med. Chem.
1972, 15, 1024; (b) Kurzer, F. Org. Synth. Coll. 1963, 4, 180.
23. Aoyama, T.; Murata, S.; Nagata, Y.; Takido, T.; Kodomari, M. Tetrahedron Lett. 2005,
46, 4875.
24. (a) Li, C. J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68; (b) Wang, Z.; Cui, Y. T.; Xu, Z. B.;
Qu, J. J. Org. Chem. 2008, 73, 2270.
25. Bala, M.; Verma, P. K.; Sharma, U.; Kumar, N.; Singh, B. Green Chem. 2013, 15, 1687.
26. Vardhan, D. M. S.; Shantharam, C. S.; Suhas, R.; Gowda, D. C. J. Saudi Chem. Soc.
In press. doi:10.1016=j.jscs.2014.02.006.
27. Chakraborti, A. K.; Rudrawar, S.; Jadhav, K. B.; Kaur, G.; Chankeshwara, S. V. Green
Chem. 2007, 9, 1335.