Metal-Free Synthesis of 2-Arylbenzothiazoles from Aldehydes, Amines, and Thiocyanate

Article abstract of DOI:10.1021/acs.orglett.9b00245

A highly efficient method for the synthesis of 2-arylbenzothiazoles has been developed using readily available aromatic amines, benzaldehydes, and NH₄SCN as a sulfur source. A library of 2-arylbenzothiazoles with wide functional group compatibility has been synthesized in good yields through iodine-mediated oxidative annulation.

Full text of DOI:10.1021/acs.orglett.9b00245

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Synthesis of 2‑Arylbenzothiazoles from Aldehydes,
Amines, and Thiocyanate
Amrita Dey and Alakananda Hajra*
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
S
* Supporting Information
ABSTRACT: A highly efficient method for the synthesis of 2-arylbenzothiazoles has been developed using readily available
aromatic amines, benzaldehydes, and NH4SCN as a sulfur source. A library of 2-arylbenzothiazoles with wide functional group
compatibility has been synthesized in good yields through iodine-mediated oxidative annulation.
he C−S bond formation has attracted significant interest
from organic chemists owing to the presence of the C−S
continuation of our research on C−S bond formations7 using
ammonium thiocyanate, herein we report an efficient method
for the synthesis of 2-arylbenzothiazoles from readily available
aromatic amines and aldehydes in the presence of iodine
(Scheme 1). The reaction is a fruitful one-pot approach under
mild and facile reaction conditions.
T
bond in many essential biological and pharmaceutical
compounds.1 Benzothiazoles are generally considered to
build fundamental structures of various natural products.2 In
particular, 2-arylbenzothiazole represents an important scaffold
in numerous bioactive compounds such as antiparasitics,
antituberculotics, antitumor agents, and calcium channel
antagonists (Figure 1).3 In addition, 2-arylbenzothiazoles
Scheme 1. Synthesis of 2-Arylbenzothiazoles
To optimize the reaction conditions, 4-methoxybenzalde-
hyde (1a, 0.5 mmol) and p-toluidine (2b, 0.5 mmol) were
taken as the model substrates with ammonium thiocyanate,
different iodide sources, and solvents as summarized in Table
1. Initially, the reaction was performed employing 2.0 equiv of
NH4SCN and 50 mol % of I2 in DMSO under air at 80 °C
temperature. Gratifyingly, 2-(4-methoxyphenyl)-6-
methylbenzo[d]thiazole (3ab) was obtained in 32% yield
after 12 h (Table 1, entry 1). Inspired by this result, the
reaction temperature was increased to 110 °C, but no
significant improvement was observed (Table 1, entry 2).
Pleasingly, the yield of the product was increased to 93% by
increasing the loading of I2 to 1.0 equiv (Table 1, entry 3).
However, no improvement was noticed by increasing the
amount of I2 to 1.5 equiv (Table 1, entry 3). Under these
conditions, a 76% yield of 3ab was obtained at 80 °C (Table 1,
entry 3). A further increase of temperature to 130 °C did not
give any improvement in the yield (Table 1, entry 3). Then the
reaction was performed in different common solvents like
Figure 1. Bioactive compounds containing 2-arylbenzothiazole
moiety.
received major attention for their potential applications in
organic luminescent materials, industrial dyes, and agro-
chemical compounds.4 Thus, continuous efforts have been
devoted to develop new synthetic methodologies for synthesiz-
ing 2-arylbenzothiazole derivatives.5 The reported routes to 2-
arylbenzothiazoles mostly depend on the condensation of 2-
aminothiophenols with aldehydes6a−e or ketones6f or carbox-
ylic acid derivatives.6g−j Oxidative intramolecular cyclization of
thiobenzanilides is also effective for their construction.6k−o
However, these methods need prefunctionalized reactants like
2-aminothiophenols and thiobenzanilides which are costly and
not easily available. From the synthetic and medicinal
chemistry perspective, development of an efficient method
for synthesis of 2-arylbenzothiazole derivatives using readily
available starting materials under simple and general reaction
conditions is highly desirable. To the best of our knowledge,
synthesis of 2-arylbenzothiazole moieties exploring ammonium
thiocyanate as the S source has not been revealed until now. In
Received: January 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00245
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope with Variation of Anilines
iodide source
(equiv)
temp
(°C)
entry
solvent
yield (%)
1
2
3
4
5
6
7
8
I2 (50 mol %)
I2 (50 mol %)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
KI (1.0)
NH4I (1.0)
TBAI (1.0)
ZnI2 (20 mol %)
I2 (1.0)
DMSO
DMSO
DMSO
DCB
80
110
110
110
110
110
110
110
110
110
110
110
110
32
50
b
c
d
93, (93, 76, 93 )
65
71
nr
trace
nr
10
20
trace
60
DMF
toluene
PEG-400
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11
12
13
e
f
58, 54
a
Reaction conditions: The reactions were carried out with 1a (0.5
mmol), 2b (0.5 mmol), NH4SCN (2.0 equiv), I2 (1.0 equiv), and
b
c
solvent (2.0 mL) for 12 h under air at 110 °C. 1.5 equiv of I2. At 80
d
e
f
a
°C. At 130 °C. 1.0 equiv of NH4SCN. KSCN (2.0 equiv) was used.
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), NH4SCN (2.0
b
equiv), I2 (1.0 equiv), and DMSO (2.0 mL) for 12 h at 110 °C.
mmol scale.
5
DCB, DMF, toluene, PEG-400, and 1,4-dioxane (Table 1,
entries 4−8). However, no improvement in yield was observed
compared to DMSO. Thereafter, other iodide sources like KI,
NH4I, TBAI, and ZnI2 were checked, but these were not as
effective as I2 (Table 1, entries 9−12). Significantly, the yield
was decreased on using 1.0 equiv of NH4SCN and KSCN (2.0
equiv) as the sulfur source (Table 1, entry 13). Thus, the
optimized yield of the product was obtained with 2.0 equiv of
NH4SCN in the presence of 1.0 equiv I2 in DMSO at 110 °C
(Table 1, entry 3).
thiazole (3ab) was obtained without a significant decrease in
yield (90%).
To illustrate the general applicability of the current protocol,
the substrate scope with various substituted benzaldehydes was
investigated (Scheme 3). Delightfully, benzaldehyde bearing
electron-donating groups such as −Me and −OMe at different
positions reacted well with toluidine, affording the correspond-
ing products (3bb−eb) in excellent yields. Halogen-containing
benzaldehydes such as 4-F, 2-F, 2-Cl, 4-Br, and 2-Br afforded
the desired products (3fb−jb) in excellent yields. Interestingly,
4-(dimethylamino)benzaldehyde also reacted well with
toluidine and 4-chloroaniline under the present protocol to
provide the products (3kb and 3kg) with good yields. 4-
(Methylthio)benzaldehyde underwent this reaction smoothly
to afford an excellent yield of the product (3lb). Pleasingly,
benzaldehyde with an electron-withdrawing substituent (4-
NO2, 3-NO2, 4-CN, and 2-CHO) also successfully gave the
desired products (3mb−pb) in excellent yields. 2-Naphthalde-
hyde also reacted efficiently to give 91% yield of the desired
product (3qb). However, heteroaryl aldehydes (indole-3-
carboxaldehyde, furan-2-carboxaldehyde, and thiophene-2-
carboxaldehyde), aliphatic aldehydes (2-phenylacetaldehyde,
cyclohexane carboxaldehyde, butyraldehyde, and paraformal-
dehyde), cinnamaldehyde, and crotonaldehyde did not afford
the desired products under the present reaction conditions.
To predict the mechanistic path of this reaction, a few
control experiments were carried out as shown in Scheme 4.
However, 2-aminothiophenol was not the intermediate of this
reaction as toluidine (2b) treated with NH4SCN in the
absence of aldehyde could not produce 2-amino-5-methyl-
benzenethiol 4, and the starting material (2b) was recovered
(Scheme 4a). Furthermore, the imine 5ab was generated in a
major amount when the reaction was quenched after 2 h
(Scheme 4b). It was then found that the imine 5ab could
produce the final product (3ab) under the standard conditions
(Scheme 4c). Interestingly, in the absence of I2, addition of
After the reaction conditions were optimized, the substrate
scope of this protocol was explored. At first, various substituted
anilines were coupled with 4-methoxybenzaldehyde under the
optimized reaction conditions, and the results are presented in
Scheme 2. 2-(4-Methoxyphenyl)benzo[d]thiazole (3aa) was
obtained in 68% yield from aniline. Anilines bearing electron-
donating −Me and −OMe substituents at different positions
efficiently reacted with 4-methoxybenzaldehyde to provide the
products with high to excellent yields (3ab, 3ac, 3ad, 3ae, and
3bd). The structure of 6-methoxy-2-(4-methoxyphenyl)benzo-
[d]thiazole (3ad) was further confirmed by single-crystal X-ray
crystallographic analysis. Anilines with different halogen groups
like 4-F, 4-Cl, and 4-Br produced the corresponding products
in good yields (3af−ah). Benzo[d][1,3]dioxol-5-amine par-
ticipated smoothly in this reaction to provide 91% yield (3ai).
Anilines containing electron-withdrawing groups such as
−CHO and −CO2Et were also well tolerated under the
present reaction conditions, providing the desired products
(3aj and 3ak). Although aminobenzaldehyde may compete
with methoxybenzaldehyde, which may cause the decrease in
the yield of 3aj, we were delighted that the self-coupling
product was not obtained. However, 2-aminopyridine and
benzyl amine did not undergo in this reaction. To demonstrate
the practical applicability of the current methodology, the
gram-scale reaction was also performed with the usual
laboratory setup between 4-methoxybenzaldehyde (1a) and
toluidine (2b). 2-(4-Methoxyphenyl)-6-methylbenzo[d]-
B
DOI: 10.1021/acs.orglett.9b00245
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3ab) in the presence of I2 (Scheme 4e), which indicates that
6ab might be the intermediate of this reaction and I2 plays a
major role in the cyclization. Notably, only 32% yield of the
product (3ab) was obtained when the reaction was carried out
under Ar atmosphere (Scheme 4f). It signifies that I2 also
works as an oxidant of thiazoline to thiazole (Scheme 5), and
Scheme 3. Substrate Scopes with Variation of
Benzaldehydes
a
Scheme 5. Plausible Mechanistic Pathway
areal oxygen also plays an important role in this oxidation.
Additionally, the annulation would not proceed through radical
mechanism since the addition of radical scavengers like 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO), 2,6-di-tert-butyl-4-
methyl phenol (BHT), and p-benzoquinone (BQ) did not
inhibit the desired transformation (Scheme 4g).
On the basis of the control experimental results (Scheme 4)
and previous related literature,5f,g,i,8 a plausible reaction
mechanism is proposed for the formation of 2-(4-methox-
yphenyl)-6-methylbenzo[d]thiazole as depicted in Scheme 5.
Initially, imine intermediate 5ab is formed by the condensation
of aldehyde and aniline. Next, NH4SCN attacks the imine
(5ab) to generate the thiacyanato intermediate 6ab. Afterward,
nucliophilic attack of aryl moiety to S atom results the
formation of a cyclized intermediate B by eliminating the CN−
ion. Deprotonation generates dihydrobenzothiazole C, which
likewise forms the final product (3ab) by oxidation. Regarding
the role of the iodide source, it may be considered to activate
the imine and promote the cyclization and the oxidative
aromatization.9
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), NH4SCN (2.0
equiv), I2 (1.0 equiv), and DMSO (2.0 mL) for 12 h at 110 °C.
Scheme 4. Control Experiments
In conclusion, we have demonstrated an I2-mediated
oxidative annulation of arylbenzaldehydes, aromatic amines,
and ammonium thiocyanate. The reaction provides a novel
synthetic route to 2-arylbenzothiazoles from easily accessible
reagents. Simple reaction conditions, tolerance of a wide range
of functional groups, availability of basic chemicals as starting
materials, and use of NH4SCN as sulfur source make this
protocol practically applicable to synthesis a variety of
benzothiazole derivatives. We believe that the present
methodology would achieve much importance in synthetic
organic chemistry, medicinal chemistry, material science, and
also industrial chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00245.
thiocyanate to imine produced N-((4-methoxyphenyl)-
(thiocyanato)methyl)-4-methylaniline, 6ab (Scheme 4d).
Significantly, 6ab was transferred into the final benzothiazole
Experimental procedures and spectral data (PDF)
C
DOI: 10.1021/acs.orglett.9b00245
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
B.; Ermolenko, L.; Dean, W. A.; Al-Mourabit, A. Org. Lett. 2012, 14,
5948. (h) Li, G.; Jiang, J.; Zhang, F.; Xiao, F.; Deng, G.-J. Org. Biomol.
Chem. 2017, 15, 10024. (i) Dar, A. A.; Shadab, M.; Khan, S.; Ali, N.;
Khan, T. A. J. Org. Chem. 2016, 81, 3149. (j) Sung, G. H.; Lee, I.-H.;
Kim, B. R.; Shin, D.-S.; Kim, J.-J.; Lee, S.-G.; Yoon, Y.-J. Tetrahedron
2013, 69, 3530. (k) Itoh, T.; Mase, T. Org. Lett. 2007, 9, 3687.
(l) Cheng, Y.; Yang, J.; Qu, Y.; Li, P. Org. Lett. 2012, 14, 98.
(m) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.;
Williams, J. M. Org. Lett. 2009, 11, 2039. (n) Inamoto, K.; Hasegawa,
C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. (o) Zhang, G.; Liu,
C.; Yi, H.; Meng, Q.; Bian, C.; Chen, H.; Jian, J.-X.; Wu, L.-Z.; Lei, A.
J. Am. Chem. Soc. 2015, 137, 9273.
(7) (a) Dey, A.; Hajra, A. Adv. Synth. Catal. 2019, 361, 842.
(b) Mitra, S.; Ghosh, M.; Mishra, S.; Hajra, A. J. Org. Chem. 2015, 80,
8275. (c) Mondal, S.; Samanta, S.; Hajra, A. Eur. J. Org. Chem. 2018,
2018, 1060. (d) Samanta, S.; Chatterjee, R.; Santra, S.; Hajra, A.;
Khalymbadzha, I. A.; Zyryanov, G. V.; Majee, A. ACS Omega 2018, 3,
13081. (e) Bagdi, A. K.; Mitra, S.; Ghosh, M.; Hajra, A. Org. Biomol.
Chem. 2015, 13, 3314. (f) Kibriya, G.; Mondal, S.; Hajra, A. Org. Lett.
2018, 20, 7740.
(8) (a) Liu, B.-B.; Cao, W.-B.; Wang, F.; Wang, S.-Y.; Ji, S.-J. J. Org.
Chem. 2018, 83, 11118. (b) Dwivedi, V.; Rajesh, M.; Kumar, R.; Kant,
R.; Reddy, M. S. Chem. Commun. 2017, 53, 11060. (c) Fan, W.; Li,
Q.; Li, Y.; Sun, H.; Jiang, B.; Li, G. Org. Lett. 2016, 18, 1258.
(9) (a) Jiang, H.; Huang, H.; Cao, H.; Qi, C. Org. Lett. 2010, 12,
5561. (b) Xue, W.-J.; Li, Q.; Zhu, Y.-P.; Wang, J.-G.; Wu, A.-X. Chem.
Commun. 2012, 48, 3485. (c) Yagyu, T.; Takemoto, Y.; Yoshimura,
A.; Zhdankin, V. V.; Saito, A. Org. Lett. 2017, 19, 2506.
CCDC 1888103 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alakananda.hajra@visva-bharati.ac.in.
ORCID
Alakananda Hajra: 0000-0001-6141-0343
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A.H. acknowledges financial support from SERB-DST (Grant
No. EMR/2016/001643), New Delhi.
■
REFERENCES
■
(1) (a) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X.
Chem. Soc. Rev. 2015, 44, 291. (b) Castanheiro, T.; Suffert, J.;
Donnard, M.; Gulea, M. Chem. Soc. Rev. 2016, 45, 494.
(2) (a) Bandyopadhyay, P.; Sathe, M.; Ponmariappan, S.; Sharma,
A.; Sharma, P.; Srivastava, A. K.; Kaushik, M. P. Bioorg. Med. Chem.
Lett. 2011, 21, 7306. (b) Wang, X.; Sarris, K.; Kage, K.; Zhang, D.;
Brown, S. P.; Kolasa, T.; Surowy, C.; Kouhen, O. F. E.; Muchmore, S.
W.; Brioni, J. D.; Stewart, A. O. J. Med. Chem. 2009, 52, 170.
(c) Mortimer, C. G.; Wells, G.; Crochard, J.-P.; Stone, E. L.;
Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem.
2006, 49, 179. (d) Facchinetti, V.; Reis, R. R.; Gomes, C. R. B.;
Vasconcelos, T. R. A. Mini-Rev. Org. Chem. 2012, 9, 44.
(3) (a) Gupta, V.; Kant, V. Sci. Int. 2013, 1, 253. (b) Prajapati, N. P.;
Vekariya, R. H.; Borad, M. A.; Patel, H. D. RSC Adv. 2014, 4, 60176.
(c) Noel, S.; Cadet, S.; Gras, E.; Hureau, C. Chem. Soc. Rev. 2013, 42,
7747. (d) Chakraborty, M.; Jin, K. J.; Novak, M.; Glover, S. A. J. Org.
Chem. 2010, 75, 5296. (e) Sun, Q.; Wu, R.; Cai, S.; Peterson, B. R.;
Llewlyn, S.; Kaori, S.; Lin, Y.; He, B. J. Med. Chem. 2011, 54, 1126.
(4) (a) Hrobarikova, V.; Hrobarik, P.; Gajdos, P.; Fitilis, I.; Fakis,
M.; Persephonis, P.; Zahradnık, P. J. Org. Chem. 2010, 75, 3053.
(b) Serdons, K.; Bormans, G.; Verbruggen, A.; Terwinghe, C.;
Vermaelen, P.; Laere, K. V.; Mortelmans, L.; Kung, H. J. Med. Chem.
2009, 52, 1428.
(5) (a) Liu, Y.; Yuan, X.; Guo, X.; Zhang, X.; Chen, B. Tetrahedron
2018, 74, 6057. (b) Natarajan, P.; Manjeet, M.; Brar, N. K.; Kaur, J.
Org. Chem. Front. 2018, 5, 1527. (c) Bakthadoss, M.; Selvakumar, R. J.
Org. Chem. 2016, 81, 3391. (d) Wang, X.; Qiu, X.; Wei, J.; Liu, J.;
Song, S.; Wang, W.; Jiao, N. Org. Lett. 2018, 20, 2632. (e) Huang, Y.;
Zhou, P.; Wu, W.; Jiang, H. J. Org. Chem. 2018, 83, 2460. (f) Huang,
H.; Xu, Z.; Ji, X.; Li, B.; Deng, G.-J. Org. Lett. 2018, 20, 4917.
(g) Zhu, X.; Yang, Y.; Xiao, G.; Song, J.; Liang, Y.; Deng, G. Chem.
Commun. 2017, 53, 11917. (h) Ding, Q.; Huang, X.-G.; Wu, J. J.
Comb. Chem. 2009, 11, 1047. (i) Che, X.; Jiang, J.; Xiao, F.; Huang,
H.; Deng, G.-J. Org. Lett. 2017, 19, 4576. (j) Deng, H.; Li, Z.; Ke, F.;
Zhou, X. Chem. - Eur. J. 2012, 18, 4840. (k) Xing, Q.; Ma, Y.; Xie, H.;
Xiao, F.; Zhang, F.; Deng, G.-J. J. Org. Chem. 2019, 84, 1238.
(6) (a) Pereira Araujo, D. P.; Santos Morais, V. S. S.; de Fatima, A.;
Modolo, L. V. RSC Adv. 2015, 5, 28814. (b) Bahrami, K.; Khodaei,
M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835. (c) Cho, Y. H.; Lee, C.-
Y.; Ha, D.-C.; Cheon, C.-H. Adv. Synth. Catal. 2012, 354, 2992.
(d) Chen, Y.-X.; Qian, L.-F.; Zhang, W.; Han, B. Angew. Chem., Int.
Ed. 2008, 47, 9330. (e) Kumar, A.; Sharma, S.; Maurya, R. A.
Tetrahedron Lett. 2010, 51, 6224. (f) Liao, Y.; Qi, H.; Chen, S.; Jiang,
P.; Zhou, W.; Deng, G.-J. Org. Lett. 2012, 14, 6004. (g) Nguyen, T.
D
DOI: 10.1021/acs.orglett.9b00245
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