DMSO-mediated palladium-catalyzed cyclization of two isothiocyanates: Via C-H sulfurization: A new route to 2-aminobenzothiazoles

Article abstract of DOI:10.1039/c8ra09784d

DMSO was found to activate arylisothiocyanates for self-nucleophilic addition. A subsequent intramolecular C-H sulfurization catalyzed by PdBr₂ enables access to a wide range of 2-aminobenzothiazole derivatives in moderate to good yields. This is the first example of a DMSO-mediated Pd-catalyzed synthesis of 2-aminobenzothiazoles through cyclization/C-H sulfurization of two isothiocyanates.

Full text of DOI:10.1039/c8ra09784d

RSC Advances
View Article Online
View Journal | View Issue
PAPER
DMSO-mediated palladium-catalyzed cyclization
of two isothiocyanates via C–H sulfurization: a new
route to 2-aminobenzothiazoles†
Cite this: RSC Adv., 2019, 9, 3403
Guangkai Yao,ac Bing-Feng Wang,ab Shuai Yang,ac Zhi-Xiang Zhang,ac
ac
ab
*
*
Han-Hong Xu
and Ri-Yuan Tang
Received 28th November 2018
Accepted 20th January 2019
DMSO was found to activate arylisothiocyanates for self-nucleophilic addition. A subsequent intramolecular
C–H sulfurization catalyzed by PdBr2 enables access to a wide range of 2-aminobenzothiazole derivatives
in moderate to good yields. This is the first example of a DMSO-mediated Pd-catalyzed synthesis of 2-
aminobenzothiazoles through cyclization/C–H sulfurization of two isothiocyanates.
DOI: 10.1039/c8ra09784d
rsc.li/rsc-advances
2-Aminobenzothiazole derivatives are privileged scaffolds examples of Pd-catalyzed protocols have been reported (Scheme
which have been widely used in medicine and agricultural 1b).3b,c,e Therefore, the development of novel palladium-
chemicals (Scheme 1a).1 Signicant effort has been devoted to catalyzed C–H sulfurization reaction is of great interest. As
the development of synthetic methodologies for the preparation a continuation of our interest in sulfur chemistry and C–H
of such species.2 Thioureas,3,4 isothiocyanates,5,6 and benzo- sulfurization,9 we attempted to transform isothiocyanates into
thiazoles7 are effective reaction partners for the synthesis of 2- sulfur-containing compounds.10 Unexpectedly, a newly formed
aminobenzothiazole derivatives via cross-coupling reactions or 2-aminobenzothiazole was observed for the reaction of a phe-
C–H functionalization. Intramolecular C–H sulfurization of N- nylisothiocyanate. Encouraged by this discovery, we developed
arylthioureas is an effective strategy for the synthesis of 2-ami- a new, facile and efficient DMSO-mediated palladium-catalyzed
nobenzothiazoles. Such a transformation can be achieved C–H sulfurization/cyclization of two isothiocyanates for the
through metal-catalyzed C–H activation3 or via radical reac- synthesis of 2-aminobenzothiazoles (Scheme 1c).
tions.6 For example, Doi and coworkers reported a Pd-catalyzed
Our study began with the reaction of phenyl isothiocyanate
intramolecular C–H sulfurization of arylthiourea using O2 as an (1a) with PdCl2 in different solvents (Table 1). Solvents
oxidant.3c Metal-free iodine-catalyzed intramolecular C–H sul- including toluene, chlorobenzene, DCE, CH3CN, DMF, NMP (N-
furization also provides an effective pathway to 2-amino- methyl-2-pyrrolidinone), and DMSO, were examined (Table 1,
benzothiazoles.6e Zhu et al. developed an efficient oxidative entries 1–7). Only highly polar solvents, such as DMF, NMP, and
radical strategy for the synthesis of 2-aminobenzothiazoles via DMSO were suitable for this reaction; however, DMF and NMP
an aminyl radical addition to aryl isothiocyanates followed by
C–H sulfurization in the presence of n-Bu4NI and TBHP.6c
Interestingly, Lei et al. reported a “green” synthesis of 2-ami-
nobenzothiazoles by employing electro-catalysis technology for
an external oxidant-free intramolecular C–H sulfurization.6d In
terms of metal-catalyzed C–H sulfurization,8 palladium-
catalyzed C–H sulfurization has not been widely reported
because thioureas are oen strong metal-chelating species that
may lead to poisoning of palladium catalysts. Thus, only a few
aKey Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education,
South China Agricultural University, Guangzhou 510642, China. E-mail: hhxu@
scau.edu.cn; rytang@scau.edu.cn
bDepartment of Applied Chemistry, College of Materials and Energy, South China
Agricultural University, Guangzhou 510642, China
cState Key Laboratory for Conservation and Utilization of Subtropical Agro-
Bioresources, South China Agricultural University, Guangzhou 510642, China
† Electronic supplementary information (ESI) available. See DOI:
Scheme
1 Biological application and synthetic methods for the
10.1039/c8ra09784d
preparation of 2-aminobenzothiazoles.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 3403–3406 | 3403

View Article Online
RSC Advances
Paper
Table 1 Screening of reaction conditionsa
Table 2 The scope of 2-aminobenzothiazolesa
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdBr2
Pd(OAc)2
Pd(PPh3)2Cl2
PdBr2
—
Toluene
Chlorobenzene
DCE
CH3CN
DMF
NMP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
0
0
0
12
16
72
32
58
82
Trace
Trace
70
0
8c
9d
10
11
12
13e
14
15f
16g
17h
18i
DMSO
PdBr2
PdBr2
PdBr2
PdBr2
DMSO/CH3CN
DMSO/CH3CN
DMSO/H2O
DMSO/H2O
55
23
61
75
a
Reaction conditions: 1a (0.4 mmol), [Pd] (10 mol%), stirred at 80 ꢀC in
solvent (2 mL) for 24 h. b Isolated yield. c At 100 ꢀC. d At 60 ꢀC. e PdBr2
(5 mol%). f DMSO/CH3CN ¼ 1 : 1. g DMSO/CH3CN ¼ 1 : 4. h DMSO/H2O
i
¼ 10 : 1. DMSO/H2O ¼ 20 : 1.
gave low yields of the desired product (entries 5 and 6). DMSO
was found to be the preferable solvent for the reaction giving the
desired product 2 in 72% yield in the presence of 10 mol%
PdCl2 at 80 ꢀC over 24 hours (entry 7). Increasing or decreasing
the reaction temperature led to lower yields (e.g. 32% at 100 ꢀC
and 58% at 60 ꢀC) (entries 8 and 9). Next, other palladium
catalysts, such as PdBr2, Pd(OAc)2, and Pd(PPh3)2Cl2, were
evaluated (entries 10–12). Compared with PdCl2, PdBr2 was
more effective affording product 2 in 82% yield (entry 10).
However, Pd(OAc)2 and Pd(PPh3)2Cl2 were not suitable catalysts
for this reaction (entries 11 and 12). The yield of the desired
product decreased to 70% when the reaction was conducted in
the presence of 5 mol% PdBr2 (entry 13). The reaction did not
proceed in the absence of PdBr2 (entry 14). When the reaction
was carried out in a mixed DMSO/CH3CN solvent system, lower
yields of product were obtained (entries 15 and 16). The inu-
ence of water was also examined. The addition of water facili-
tated the formation of thiourea, but reduced the yield of target
product (entries 17 and 18).
With the optimized reaction conditions in hand, the reaction
scope was investigated (Table 2). Initially, 4-substituted aryli-
sothiocyanates were subjected to the reaction conditions.
Substituents, including methyl, ethyl, butyl, t-butyl, methoxy,
ethoxyl, bromo, and iodo groups, were all tolerated. Electron-
donating substituents promoted the reaction, affording their
corresponding products 2–8 in moderate to good yields.
Although both the C–Br and C–I bonds are reactive units for
cross-coupling reactions, the C–H sulfurization was selectively
carried out to afford products 9 and 10 in 38% and 34% yields,
a
Reaction conditions: 1 (0.4 mmol), PdBr2 (10 mol%), stirred at 80 ꢀC in
DMSO (2 mL) for 24 h.
respectively. However, the electron-withdrawing cyano group
was not amenable to the reaction conditions (products 11). This
suggests that the reaction may involve an electrophilic cyclo-
palladation process and the electron-withdrawing group would
thus decrease the reactivity.
Ortho-substituents, such as methyl, methoxy, methylthio,
and phenyl, which increase steric hindrance, still performed
well to give their corresponding products in moderate to good
yields (products 12–20). For reactions involving ortho-
Scheme
isothiocyanates.
2 PdBr2-catalyzed cross-reaction of two different
3404 | RSC Adv., 2019, 9, 3403–3406
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
substituted substrates, a small amount of brominated by-
product similar to compound 19 was observed; however, the
majority of these by-products were obtained in far lower yield
than 19. To our delight, a naphthyl isothiocyanate also under-
went reaction smoothly to give product 22 in 77% yield. 3-Iso-
thiocyanatopyridine was also subjected to the reaction
conditions. However, no cyclization/C–H sulfurization
occurred; the electron-decient pyridine ring is not reactive
enough for C–H sulfurization. The reaction of meta-substituted
methyl phenylisothiocyanates provided two isomers which
could not be easily puried.
To prove the feasibility of the cyclization of two different aryl
isothiocyanates,
a
cross-reaction
between
4-methyl-
phenylisothiocyanate and 4-nitro-phenyliso-thiocyanate was
conducted. The cross-reaction product 23, was obtained in 27%
yield with compound 3 being formed as the main product in
52% yield (Scheme 2). The strong electron-withdrawing nitro
group greatly reduces the electron density of the benzene ring,
thus C–H sulfurization is disfavored; C–H sulfurization only
occurred on the methyl-substituted benzene ring.
To gain insight into the reaction mechanism, control
experiments were conducted, as shown in Scheme 3. In the
absence of PdBr2, thiourea 24 was obtained in 35% yield for the
reaction of 4-methyl phenylisothiocyanate in DMSO at 80 ꢀC
over 24 hours (Scheme 3, eqn (1)). This suggested that the
thiourea may be the reaction intermediate; however, when
thiourea 24 was subjected to reaction with PdBr2, product 3 was
obtained in only 16% yield (Scheme 3, eqn (2)). Aryl iso-
thiocyanate may decompose to aniline, and react with iso-
thiocyanate for C–H sulfurization. However, only a trace
amount of product 25 was observed in the reaction between 4-
methylphenyl isothiocyanate and aniline (Scheme 3, eqn (3)).
None of the target product 26 was observed for the reaction of
benzothiazole with 4-methyl phenylisothiocyanate, suggesting
Scheme 4 A possible mechanism.
that benzothiazole is not a reaction intermediate (Scheme 3,
eqn (4)). To our delight, a mass peak corresponding to inter-
mediate 27 was observed with real-time ESI-MS when phenyl-
isothiocyanate was stirred in DMSO at 60 ꢀC (Scheme 3, eqn (5))
(see the ESI, Fig. S1†). Based on theoretical calculations,11 the
dipole moment of the DMSO molecule is 3.9274 debye (gas) or
5.1281 debye in solvent form. Natural bond orbital analysis
shows the differences in the charge distribution on the O and S
atoms. Obviously, the polarity of the S–O bond increases and
a greater distribution of the negative charge on the O atom leads
to an improvement in its nucleophilic character. The oxygen
atom attacks the carbon atom with the most positive NBO
charge in PhNCS (see the ESI, Fig. S2 and S3†). These results
indicate that DMSO acts as a nucleophilic agent for the activa-
tion of arylisothiocyanates for C–H sulfurization.
Based on the above results and previous work,3 a possible
reaction mechanism has been proposed and is shown in
Scheme 4. Firstly, the polarized DMSO undergoes a nucleophilic
addition with phenylisothiocyanate to afford the active inter-
mediate A, which then reacts with another equivalent of phe-
nylisothiocyanate to produce an intermediate B. Intermediate B
chelates with PdBr2 to form an intermediate C. Subsequent
elimination of HBr leads to the formation of intermediate D,
which undergoes reductive elimination to afford the desired
product 2. The Pd(0) is oxidized by DMSO to PdBr2 for the next
catalytic cycle.
Conclusions
In summary, a DMSO-mediated PdBr2-catalyzed synthesis of 2-
aminobenzothiozoles via the cyclization/C–H sulfurization of
two aryl isothiocyanates has been developed for the rst time. In
the presence of DMSO and PdBr2, a variety of aryl iso-
thiocyanates underwent reaction to afford the corresponding 2-
aminobenzothiozoles in moderate to good yields. In this
tandem reaction, DMSO acts as a key initiator for the activation
of aryl isothiocyanates, although the exact role of DMSO is
unclear.
Scheme 3 Control experiments.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 3403–3406 | 3405

View Article Online
RSC Advances
Paper
G. Xiao, W. Liu and Y. Liang, Org. Biomol. Chem., 2016, 14,
11088–11091; (f) W. Zeng, P. Dang, X. Zhang, Y. Liang and
C. Peng, RSC Adv., 2014, 4, 31003–31006.
Conflicts of interest
There are no conicts to declare.
5 Metal-catalyzed tandem reaction of isothiocyanates with
amines, see: (a) Q. Ding, X. He and J. Wu, J. Comb. Chem.,
2009, 11, 587–591; (b) Y.-J. Guo, R.-Y. Tang, P. Zhong and
J.-H. Li, Tetrahedron Lett., 2010, 51, 649–652; (c) N. Khatun,
L. Jamir, M. Ganesh and B. K. Patel, RSC Adv., 2012, 2,
11557–11565; (d) L. Chen, B. Huang, Q. Nie and M. Cai,
Appl. Organomet. Chem., 2016, 30, 446–450; (e) N. Zhao,
L. Liu, F. Wang, J. Li and W. Zhang, Adv. Synth. Catal.,
2014, 356, 2575–2579; (f) Q. Ding, B. Cao, X. Liu, Z. Zong
and Y.-Y. Peng, Green Chem., 2010, 12, 1607–1610.
6 Metal-free conditions: (a) Z.-G. Le, J.-P. Xu, H.-Y. Rao and
M. Ying, J. Heterocycl. Chem., 2006, 43, 1123–1124; (b)
W. Zhang, Y. Yue, D. Yu, L. Song, Y.-Y. Xu, Y.-J. Tian and
Y.-J. Guo, Adv. Synth. Catal., 2012, 354, 2283–2287; (c)
Y. He, J. Li, S. Luo, J. Huang and Q. Zhu, Chem. Commun.,
2016, 52, 8444–8447; (d) P. Wang, S. Tang and A. Lei, Green
Chem., 2017, 19, 2092–2095; (e) Y. Xu, B. Li, X. Zhang and
X. Fan, J. Org. Chem., 2017, 82, 9637–9646.
7 (a) S. Toulot, T. Heinrich and F. R. Leroux, Adv. Synth. Catal.,
2013, 355, 3263–3272; (b) A. Armstrong and J. C. Collins,
Angew. Chem., Int. Ed., 2010, 49, 2282–2285; (c) S. Mitsuda,
T. Fujiwara, K. Kimigafukuro, D. Monguchi and A. Mori,
Tetrahedron, 2012, 68, 3585–3590; (d) D. Monguchi,
T. Fujiwara, H. Furukawa and A. Mori, Org. Lett., 2009, 11,
1607–1610.
8 (a) C. Shen, P. Zhang, Q. Sun, S. Bai, T. S. A. Hor and X. Liu,
Chem. Soc. Rev., 2015, 44, 291–314; (b) F.-J. Chen, G. Liao,
X. Li, J. Wu and B.-F. Shi, Org. Lett., 2014, 16, 5644–5647.
9 (a) J.-R. Zhang, L.-Z. Zhan, L. Wei, Y.-Y. Ning, X.-L. Zhong,
J.-X. Lai, L. Xu and R.-Y. Tang, Adv. Synth. Catal., 2018, 360,
533–543; (b) J.-C. Deng, J.-H. Chen, J.-R. Zhang, T.-T. Lu
and R.-Y. Tang, Adv. Synth. Catal., 2018, 360, 4795–4806; (c)
J.-R. Zhang, Y.-Y. Liao, J.-C. Deng, K.-Y. Feng, M. Zhang,
Y.-Y. Ning, Z.-W. Lin and R.-Y. Tang, Chem. Commun.,
2017, 53, 7784–7787; (d) J.-C. Deng, S.-B. Zhuang, Q.-Z. Liu,
Z.-W. Lin, Y.-L. Su, J.-H. Chen and R.-Y. Tang, RSC Adv.,
2017, 7, 54013–54016; (e) J. Jiao, L. Wei, X.-M. Ji, M.-L. Hu
and R.-Y. Tang, Adv. Synth. Catal., 2016, 358, 268–275; (f)
X.-M. Ji, S.-J. Zhou, F. Chen, X.-G. Zhang and R.-Y. Tang,
Synthesis, 2015, 47, 659–671.
Acknowledgements
We are grateful for nancial support from the Science Tech-
nology Program Project of Guangdong Province (No.
2016B020204005), Natural Science Foundation of Guangdong
Province (Grant 2016A030313387), and China Postdoctoral
Science Foundation (Grant 2018M643105).
Notes and references
1 (a) P. C. Sharma, K. K. Bansal, A. Deep and M. Pathak, Curr.
Top. Med. Chem., 2017, 17, 208–237; (b) J. B. Sweeney,
M. Rattray, V. Pugh and L. A. Powell, ACS Med. Chem. Lett.,
2018, 9, 552–556; (c) L. Hroch, P. Guest, O. Benek,
O. Soukup, J. Janockova, R. Dolezal, K. Kuca, L. Aitken,
T. K. Smith, F. Gunn-Moore, D. Zala, R. R. Ramsay and
K. Musilek, Bioorg. Med. Chem., 2017, 25, 1143–1152; (d)
Z. Ji, F. Zhou and S. Wei, Bioorg. Med. Chem. Lett., 2015, 25,
4065–4068.
2 For reviews, see: (a) T. L. Dadmal, S. D. Katre,
M. C. Mandewale and R. M. Kumbhare, New J. Chem.,
2018, 42, 776–797; (b) N. P. Prajapati, R. H. Vekariya,
M. A. Borad and H. D. Patel, RSC Adv., 2014, 4, 60176–60208.
3 Synthesis of benzothiazoles via C–H sulfurization, see: (a)
A. D. Jordan, C. Luo and A. B. Reitz, J. Org. Chem., 2003,
68, 8693–8696; (b) L. L. Joyce and R. A. Batey, Org. Lett.,
2009, 11, 2792–2795; (c) K. Inamoto, C. Hasegawa,
J. Kawasaki, K. Hiroya and T. Doi, Adv. Synth. Catal., 2010,
352, 2643–2655; (d) H. Wang, L. Wang, J. Shang, X. Li,
H. Wang, J. Gui and A. Lei, Chem. Commun., 2012, 48, 76–
78; (e) S. K. Sahoo, A. Banerjee, S. Chakraborty and
B. K. Patel, ACS Catal., 2012, 2, 544–551; (f) J. Wang,
Y. Zong, X. Zhang, Y. Gao, Z. Li, G. Yue, Z. Quan and
X. Wang, Synlett, 2014, 25, 2143–2148; (g) S. Sharma,
R. S. Pathare, A. K. Maurya, K. Gopal, T. K. Roy,
D. M. Sawant and R. T. Pardasani, Org. Lett., 2016, 18, 356–
359.
4 Synthesis of benzothiazoles via cross-coupling reaction of
ortho-halothiourea, see: (a) C. Benedi, F. Bravo, P. Uriz,
´
´
E. Fernandez, C. Claver and S. Castillon, Tetrahedron Lett.,
2003, 44, 6073–6077; (b) L. L. Joyce, G. Evindar and
R. A. Batey, Chem. Commun., 2004, 446–447; (c) R. Wang,
W.-J. Yang, L. Yue, W. Pan and H.-Y. Zeng, Synlett, 2012,
23, 1643–1648; (d) S. K. Rout, S. Guin, J. Nath and
B. K. Patel, Green Chem., 2012, 14, 2491–2498; (e) H. Min,
10 Y.-Y. Liao, J.-C. Deng, Y.-P. Ke, X.-L. Zhong, L. Xu, R.-Y. Tang
and W. Zheng, Chem. Commun., 2017, 53, 6073–6076.
11 M. J. Frisch, G. W. Trucks and H. B. Schlegel, et al., Gaussian
09, rev. D. 01, Gaussian, Inc., Wallingford, CT2009.
3406 | RSC Adv., 2019, 9, 3403–3406
This journal is © The Royal Society of Chemistry 2019