Copper-catalyzed tandem reaction of 2-haloanilines with thiocarbamoyl chloride: Synthesis of 2-aminobenzothiazoles

Article abstract of DOI:10.1080/00397911.2017.1324033

A simple and efficient protocol for the synthesis of 2-aminobenzothiazoles by a ligand-free copper-catalyzed tandem reaction has been developed. In the presence of CuBr and t-BuOK, a variety of 2-haloanilines (halogen = Br, I) underwent the reaction with thiocarbamoyl chloride efficiently to afford the corresponding 2-aminobenzothiazoles in good yields (83–94%). The features of this method include good yield, cheap catalyst, mild reaction conditions, and broad substrate scope, which make the protocol practical and attractive in the preparation of some potential pharmaceutically active compounds.

Full text of DOI:10.1080/00397911.2017.1324033

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper-Catalyzed Tandem Reaction of 2-
Haloanilines with Thiocarbamoyl Chloride:
Synthesis of 2-Aminobenzothiazoles
Cai-Zhu Chang, Wan Xu, Meng-Tian Zeng, Min Liu, Xing Liu, Hui Zhu & Zhi-
Bing Dong
To cite this article: Cai-Zhu Chang, Wan Xu, Meng-Tian Zeng, Min Liu, Xing Liu, Hui
Zhu & Zhi-Bing Dong (2017): Copper-Catalyzed Tandem Reaction of 2-Haloanilines with
Thiocarbamoyl Chloride: Synthesis of 2-Aminobenzothiazoles, Synthetic Communications, DOI:
10.1080/00397911.2017.1324033
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1324033
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Date: 05 May 2017, At: 19:33

Copper-Catalyzed Tandem Reaction of 2-Haloanilines with Thiocarbamoyl Chloride:
Synthesis of 2-Aminobenzothiazoles
Cai-Zhu Chang1, Wan Xu1, Meng-Tian Zeng1, Min Liu1, Xing Liu1, Hui Zhu1, Zhi-Bing
Dong1,2
1School of Chemistry and Environmental Engineering, Wuhan Institute of Technology,
Wuhan, China, 2Key Laboratory of Green Chemical Process, Ministry of Education,
Wuhan Institute of Technology, Wuhan, China
Corresponding Author: Zhi-Bing Dong, Email: dzb04982@wit.edu.cn
Abstract
A simple and efficient protocol for the synthesis of 2-aminobenzothiazoles by a ligand free
copper-catalyzed tandem reaction has been developed. In the presence of CuBr and
t-BuOK, a variety of 2-haloanilines (halogen=Br, I) underwent the reaction with
thiocarbamoyl chloride efficiently to afford the corresponding 2-aminobenzothiazoles in
good yields (83-94%). The features of this method includes good yield, cheap catalyst,
mild reaction conditions and broad substrate scope, which make the protocol practical and
attractive in the preparation of some potential pharmaceutically active compounds.
Graphical Abstract:
S
NH2
N
CuBr, t-BuOK
R
+
R
N
Cl
N
60 C, 4 h
S
X
X= Br, I
R= F, Cl, Br, CN, H, OMe, Me
11 examples
83%-94% yield
1

KEYWORDS: copper, tandem reaction, 2-haloanilines, thiocarbamoyl chloride,
2-aminobenzothiazoles
INTRODUCTION
The development of the formation of C-S bonds has drawn great attention since sulfur
atom is ubiquitous in bioactive molecules.[1-2] To speak of these sulfur-containing
compounds, the scaffold of 2-aminobenzothiazoles bearing C-S bonds has emerged in
various pharmaceutical and agrochemical compounds.[3-4] All sorts of pharmacophores
possessing this unit have shown great potential in the development of novel therapeutics.
For instance, the treatment of amyotrophic lateral sclerosis (1),[5-6] the antiparasitic
tioxidazole (2),[7] the immunosuppressive drug frentizole (3)[8] and anti-inflammatory drug
(4)[9] (Figure 1). Due to the potential of the 2-aminobenzothiazoles, it has led to them being
encountered through the development of various synthetic protocols. Despite great
achievements in this area, the development of novel approaches towards
2-aminobenzothiazoles is still of importance.
In the last decades, classical synthesis of 2-aminobenzothiazoles involves: (a)
intramolecular aromatic electrophilic substitution of thiobenzanilides using various
oxidants, including Jacobson’s and Hugerschoff’s methods;[10-13] (b) transition
metal-catalyzed intramolecular cyclisation of 2-halobenzothioureas;[14-16] (c) base
promoted substitution reaction of 2-halobenzothiozoles or transition-metal-catalyzed
2

oxidative coupling of 2-unsubstituted benzothiazoles with amines;[17-18] (d) tandem
condensation and cyclization of 2-haloanilines with isothiocyanates under transition-metal
catalysis.[19-20] Rencently, it is reported that n-Bu4NI was applied to form
2-aminobenzothiazoles[21-22] and 2-aminobenzothiazoles via a water mediated tandem
reaction of 2-haloarylisothiocyanates with various amines.[23] These methods are
commonly efficient, however, they also have many limitations such as highly toxic
reagents, expensive catalysts or restricted substrates. Herein, we describe a new procedure
for the formation of 2-aminobenzothiazoles by reacting 2-haloanilines (halogen=Br, I)
with thiocarbamoyl chloride catalyzed by copper.
RESULTS AND DISCUSSIONS
We began our investigations by using 2-iodoaniline (1a) and N,N-dimethylthiocarbamoyl
chloride (2a) as model substrates (Table 1). Among the different catalysts examined, CuO
afforded the expected products in low yield (Table 1, entry 1). Whereas other catalysts,
such as CuCl, Cu(OTf)2, Cu(OAc)2, CuSO4, CuI and CuCl2 resulted in good yields (Table 1,
entries 2-7). Gratifyingly, the product was obtained in maximum yield when CuBr was
served as catalyst (Table 1, entry 8). Subsequently, the effect of bases was evaluated (Table
1, entries 8-15), and the results indicated that NaOH, KOH, Cs2CO3, Na2CO3, K2CO3, NEt3
and NaH were inferior to t-BuOK. A study of the solvent effect revealed that THF is the
most suitable solvent (Table 1, entries 8 and 16-20). The control experiments revealed that
the reaction did not proceed at room temperature (Table 1, entry 22) and the reaction was
3

sluggish at 40oC (Table 1, entry 21). Decreasing the amount of t-BuOK from 3.0 to 2.0
equiv led to a further decrease of the yield to 41% (Table 1, entry 23) and no reaction was
observed when the loading of t-BuOK was 1.0 equiv (Table 1, entry 24).
Under the optimized experimental conditions (Table 1, entry 8), we started to explore the
generality and scope of the substrates (Scheme 1). The reaction of 2-haloaniline derivatives
with thiocarbamoyl chloride produced the desired products in good yields. The results
demonstrated that the standard conditions were consistent with a number of functional
groups, such as cyano, fluoro, chloro, bromo, methoxyl and methyl group on the aryl
moiety of 2-haloaniline derivatives (3b-i). For example, 2-iodoaniline derivatives with the
electron-withdrawing fluoro group or an electron-donating methoxyl group underwent the
tandem reaction with thiocarbamoyl chloride smoothly in 87% and 92% yields (3d and 3f),
respectively. Meanwhile, it was delightful to observe that the optimized condition could be
equally applicable to the substituted 2-bromoaniline. The electron-withdrawing bromo or
cholo groups and electron-donating methyl substituent could be readily incorporated, and
excellent yields of the desired products were obtained (3c and 3g-i). It was found that the
electronic nature of the 2-haloanilines play either little or no effect on the reaction, which
revealed the versatility of this protocol.
Though 2-iodoanilines and 2-bromoanilines could react with thiocarbamoyl chloride with
a tandem manner to afford the product with nice yield, the protocol could not be applied to
2-chloroanilines successfully. The target molecular (benzothiazole) could be detected in
4

trace, and the intermediate N-(2-chloro)arylthiourea was obtained with an isolation yield of
88% (Scheme 2).
CONCLUSION
In conclusion, we demonstrated a novel protocol for the synthesis of
2-aminobenzothiazoles via a ligand free copper-catalyzed tandem reaction. The plausible
mechanism for the reaction was proposed. The first step is the formation of aryl thioureas
promoted by base, then subsequently transformed to aryl-isothioureas. The second step is
the copper catalyzed intra-molecular cross-coupling reaction which let aryl-isothioureas
afford 2-aminobenzothiazoles smoothly. This method enables the use of a wide range of
2-haloanilines (halogen=Br, I) and thiocarbamoyl chloride to assemble various products in
good yields (83-94%). In this regard, this approach would be practical and attractive for
library synthesis in drug discovery efforts.
EXPERIMENTAL
All starting materials were purchased from commercial suppliers and used without further
purification unless otherwise stated. DMSO was dried with molecular sieves. NMR spectra
were recorded on a Bruker AM400 NMR instrument in CDCl3. All melting points were
determined on a RY-1G melting point instrument without correction. High-resolution mass
spectra (HRMS) were recorded on a Finnigan MAT 95Q or Finnigan 90 mass instrument
(ESI). TLC was performed using aluminum plates coated with SiO2 (Merck 60, F-254) and
5

visualized with UV light at 254 nm. Column chromatography was performed on silica gel
with PE–EtOAc as the eluent.
General Procedure For Synthesis Of 2-Aminobenzothiazoles Derivatives (3a-I)
A mixture of 2-iodoanilines (1.0 mmol), THF (3 mL), and t-BuOK (3 mmol) was stirred in
a 10 mL sealed Schlenk tube for 5 minutes, and then dimethylthiocarbamoyl chloride (1.2
mmol) and CuBr (10 mol%) were added. The reaction mixture was heated at 60oC until
completion as indicated by TLC. Then the mixture was cooled down to room temperature
and quenched with sat. NH4Cl solution (5 mL). The aqueous phase was extracted with
EtOAc (3×10 mL). The combined organic phases were dried (Na2SO4), and the solvent
was removed under reduced pressure. The obtained crude product was purified by flash
column chromatography.
N,N-Dimethybenzo[D]Thiazol-2-Amine (3a)[24]
Brown solid; m.p.: 83-85 oC; 1H NMR (400 MHz, CDCl3): δ= 7.57 (d, J = 8 Hz, 2H), 7.28
(t, J = 8.0 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 3.21 (s, 6H); 13C NMR (100 MHz, CDCl3): δ=
168.3, 152.7, 130.4, 125.7, 120.7, 120.4, 118.5, 39.8; HRMS (ESI): calcd for C9H10N2S:
178.0565; found: 178.0557.
ACKNOWLEDGMENT
6

We thank the foundation support from National Natural Science Foundation of China
(21302150), Hubei Provincial Department of Education (D20131501), Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State Education Ministry
[2012]1707.
SUPPORTING INFORMATION
The supporting material contains the spectral characterization data and copy of 1H and 13C
NMR spectra. This material can be found via the “Supplementary Content” section of this
article’s webpage.
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9

Table 1 Optimization of the Reaction Conditionsa
S
NH2
[Cu]
N
S
N
+
Cl
N
base, sol.
I
1a
2a
3a
Yieldb
(%)
21
Entry
Catalyst
Base(equiv)
Solvent
Temp (oC)
1
CuO
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
2
CuCl
75
3
Cu(OTf)2
Cu(OAc)2
CuSO4
CuI
74
4
76
5
79
6
80
7
CuCl2
CuBr
CuBr
78
8
83
9
46
10
11
12
13
14
15
CuBr
KOH
57
CuBr
Cs2CO3
Na2CO3
K2CO3
NEt3
67
CuBr
15
CuBr
43
CuBr
28
CuBr
NaH
70
10

16
17
18
19
20
21
22
23c
24d
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
toluene
MeCN
DMSO
DMF
DMAC
THF
60
60
60
60
60
40
r.t
46
trace
61
21
16
63
0
THF
THF
60
60
41
0
THF
a Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), catalyst (10 mol%), base (3 equiv),
solvent (3 mL), 4 h; b Isolated yield based on 1a; c base (2 equiv); d base (1 equiv).
11

Scheme 1
Scope of the reaction
S
NH2
CuBr (10 mol%)
t-BuOK (3.0 equiv)
N
S
+
R
R
N
Cl
N
X
THF, 60 C, 4 h
1
2a
3
-----------------------------------------------------------------------------------------------------------------------------------
Cl
N
N
N
S
N
N
N
S
S
Br
3c
X=I: 86%
X=Br: 84%
3a
X=I: 83%
X=Br: 84%
3b
X=I: 84%
H3CO
N
S
N
N
S
N
N
N
S
NC
F
3f
3e
X=I: 82%
3d
X=I: 87%
X=I: 92%
N
S
N
S
N
N
N
N
Cl
S
3h
3g
3i
X=Br: 94%
X=Br: 91%
X=Br: 87%
12

Scheme 2
The reaction limitation for 2-chloroaniline
H
S
NH2
+
CuBr (10 mol%)
t-BuOK (3.0 equiv)
N
N
Cl
N
THF, 60 C, 4 h
S
Cl
Cl
yield: 88%
13

Figure 1 Structures of bioactive 2-N-substituted benzothiazoles
O
F3CO
S
N
O
N
S
NH2
NH
O
(1)
(2)
S
N
O
HN
N
S
O
Cl
N
H
O
N
F
(4)
(3)
14