Copper-catalyzed tandem reactions of 2-halobenzenamines with isothiocyanates under ligand- and base-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.11.086

A ligand-free copper-catalyzed reaction of 2-halobenzenamines with isothiocyanates has been developed for the synthesis of 2-aminobenzothiazoles. In the presence of CuBr and TBAB (tetra-n-butyl ammonium bromide, additive), a variety of 2-halobenzenamines underwent the reaction with isothiocyanates at 40 °C, affording 2-aminobenzothiazoles in moderate to excellent yields. It is noteworthy that the reaction is conducted under mild, relatively low catalyst loading, and ligand- and base-free conditions.

Full text of DOI:10.1016/j.tetlet.2009.11.086

Tetrahedron Letters 51 (2010) 649–652
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed tandem reactions of 2-halobenzenamines
with isothiocyanates under ligand- and base-free conditions
Yan-Jin Guo a, Ri-Yuan Tang a, Ping Zhong a, Jin-Heng Li a,b,
*
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, China
b Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University, Changsha 410081, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2009
Revised 18 November 2009
Accepted 20 November 2009
Available online 26 November 2009
A ligand-free copper-catalyzed reaction of 2-halobenzenamines with isothiocyanates has been developed
for the synthesis of 2-aminobenzothiazoles. In the presence of CuBr and TBAB (tetra-n-butyl ammonium
bromide, additive), a variety of 2-halobenzenamines underwent the reaction with isothiocyanates at
40 °C, affording 2-aminobenzothiazoles in moderate to excellent yields. It is noteworthy that the reaction
is conducted under mild, relatively low catalyst loading, and ligand- and base-free conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Tandem reaction
2-Halobenzenamine
Isothiocyanate
2-Aminobenzothiazole
Synthesis of 2-aminobenzothiazoles is a continuing hot topic
because the 2-aminobenzothiazole moieties are privileged pharma-
cophores as well as valuable reactive intermediates.1–7 The majority
of efficient methods include transition metal-catalyzed cyclization
of 2-bromobenzothioureas (often Pd or Cu catalysts, Eq. 1 in Scheme
1).5–7 However, both a ligand and a base are required to promote the
reaction, and the substrates are not readily available. For example,
Pd-catalyzed cyclization of 2-bromophenylthioamides reported by
Castillón and co-workers required o-biphenylP(t-Bu)2 (ligand) and
Cs2CO3 (base).6a Very recently, Wu and co-workers developed a
new copper-catalyzed tandem route to the construction of 2-amino-
benzothiazole cores (Eq. 2).7 In the presence of CuI, 1,10-phenan-
throline, and DABCO, 2-iodobenzenamines underwent the reaction
with isothiocyanates in moderate to excellent yields. Although the
R1
R1
N
H
Pd or Cu
ligand, base
N
N
R2
N
(1)
(2)
R2
S
S
R
Br
R
R
CuI (10 mol %)
N
S
NH2
I
NHR1
1,10-phenanthroline (20 mol%)
+
R1NCS
R1NCS
DABCO (2 equiv)
toluene, 50 oC
R
CuBr (1 mol %)
TBAB (1 equiv)
NH2
X
N
S
NHR1
(3)
+
DMSO, 40 o
C
R
R
X = I, Br, Cl
Scheme 1.
* Corresponding author. Tel./fax: +86 577 8836 8607.
E-mail address: jhli@hunnu.edu.cn (J.-H. Li).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.086

650
Y.-J. Guo et al. / Tetrahedron Letters 51 (2010) 649–652
Table 1
reaction partners, 2-iodobenzenamines and isothiocyanates, are
Screening optimal conditionsa
commercially available, both ligand and base are still necessary.
Moreover, the scope is limited to 2-iodobenzenamines. To overcome
these drawbacks, herein we report a ligand- and base-free copper-
catalyzed reaction of 2-halobenzenamines with isothiocyanates
using TBAB as the promoter8 (Eq. 3).9,10 Moreover, the reaction
was conducted smoothly at 1 mol % loading of CuBr under mild con-
ditions (Scheme 1).
As shown in Table 1, the reaction of 2-iodobenzenamine (1a)
with 1-isothiocyanatobenzene (2a) was investigated to optimize
the reaction conditions. The results demonstrated that 2-iodoben-
zenamine (1a) could undergo the reaction with 1-isothiocyanato-
benzene (2a) and CuBr smoothly, affording the target product 3
in a 60% yield without the aid of both ligands and additives (entry
1). After a series of failures, we found that TBAB could improve the
reaction, and the yield was enhanced by increasing the amount of
TBAB (entries 2–4). For example, 88% yield of 3 was obtained using
0.1 equiv of TBAB (entry 2) and 98% yield in the presence of 1 equiv
of TBAB (entry 4). Encouraged by these results, three other Cu salts,
including CuI, CuCl, and Cu2O, were subsequently evaluated (en-
tries 5–7). Results identical to those of CuBr were obtained using
CuCl (entry 6). However, both CuI and Cu2O were less effective (en-
tries 5 and 7). Among the effects of solvents and the reaction tem-
NCS
NH2
+
S
N
[Cu]
H
N
I
2a
1a
Entry
3
[Cu] (mol %)
TBAB (equiv)
Solvent
t (oC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuI (5)
CuCl (5)
Cu2O (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (1)
CuCl (1)
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Toluene
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
80
80
80
80
40
25
40
40
60
88
92
98
90
98
90
73
40
98
70
98
89
0.1
0.5
1
1
1
1
1
1
1
1
1
1
a
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), [Cu], TBAB (n-Bu4NBr), and
solvent (2 mL) for 20 h.
b
Isolated yield.
Table 2
TBAB-promoted copper-catalyzed reactions of 2-halobenzenamines (1) with isothiocyanates (2)a
NH2
S
N
CuBr, TBAB
H
R1NCS
N
R1
+
DMSO, 40 o
C
X
2
R
R
1
Entry
1
Substrate 1
Isothiocyanate 2
Time (h)
20
Yieldb (%)
NH2
NCS
91 (4)
2b
I
1a
1a
1a
1a
1a
1a
NH2
NCS
2
3
20
20
20
20
20
92 (5)
95 (6)
98 (7)
98 (8)
96 (9)
2c
I
NH2
NCS
I
MeO
Cl
2d
NH2
NCS
c
4
I
2e
NH2
NCS
c
5
I
Cl
2f
NCS
NH2
6
I
O2N
2g
NH2
NCS
7
8
9
20
48
24
70 (10)
57 (11)
96 (12)
2h
I
1a
1a
NH2
MeNCS 2i
I
NH2
NCS
2a
I
1b

Y.-J. Guo et al. / Tetrahedron Letters 51 (2010) 649–652
651
Table 2 (continued)
Entry
Substrate 1
Isothiocyanate 2
Time (h)
24
Yieldb (%)
NH2
NCS
10
11
98 (13)
90 (14)
66 (3)
68 (3)
63 (3)
62 (5)
68 (9)
2a
Cl
F
I
1c
NCS
NH2
24
24
24
16
20
20
2a
I
1d
NCS
NH2
12
2a
Br
1e
NH2
NCS
13c
14d
15
2a
Br
1e
1e
1e
1e
1e
NCS
NH2
2a
Br
NCS
NH2
2c
Br
NH2
NCS
16
O2N
Br
2g
NH2
17
18
19
20
MeNCS 2i
48
24
24
36
45 (11)
70 (12)
trace (15)
67 (3)
Br
NH2
NCS
2a
Br
1f
NH2
NCS
N
Br
2a
1g
1h
1h
1i
NCS
NH2
2a
Cl
NH2
21
MeNCS 2i
48
24
41 (11)
76 (3)
Cl
NH2
NCS
22
2a
SH
a
Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), CuBr (1 mol %), TBABr (1 equiv), and DMSO (2 mL) at 40 °C.
b
c
Isolated yield.
CuBr (10 mol %).
At 80 °C.
d
perature examination (entries 8–11), it turned out that DMSO com-
To our delight, the standard conditions were also compatible with
aliphatic isothiocyanates 2h and 2i (entries 7 and 8). Subsequently,
a variety of 2-halobenzenamines 1b–1i were examined for the
reaction with isothiocyanates 2 (entries 9–22). The results demon-
strated that 2-iodobenzenamines 1b–1d, bearing methyl, chloro,
or fluoro groups, displayed high activity (entries 9–11). 2-Iodo-4-
methylbenzenamine (1b), for instance, reacted with 1-isothiocy-
anatobenzene, affording the target product 12 in 96% yield (entry
9). Gratifyingly, the standard conditions were successfully applied
in the reactions of both 2-bromobenzenamines and 2-chloroben-
zenamine (entries 12–18 and 20–21). For example, 2-bromoben-
zenamine (1e) underwent the reactions with isothiocyanates 2a,
2c, 2g, or 2i; CuBr; and TBAB smoothly in 66%, 62%, 68%, and 45%
yields, respectively (entries 12 and 15–17). We found that increas-
ing either CuBr loading or reaction temperature affected the yield
slightly (entries 13 and 14). However, an attempt to cyclize sub-
bined with 40 °C afforded the best results (entry 10). It is notewor-
thy that excellent yield is still achieved using 1 mol % of CuBr
(entry 12), but 1 mol % of CuCl reduces the yield to some extent
(entry 13).
The scopes of both 2-halobenzenamines and isothiocyanates
were explored under the optimized conditions, and the results
are summarized in Table 2.11 Our initial investigation was focused
on the scope of isothiocyanates (entries 1–8). It was found that sev-
eral functional groups, including methyl, methoxy, chloro, and ni-
tro groups, on the aryl moiety were tolerated (entries 1–6). For
example, methyl-substituted aryl isothiocyanates 2b and 2c re-
acted with 1a, CuBr, and TBAB, furnishing benzothiazoles 4 and 5
in 91% and 92% yields, respectively (entries 1 and 2). Substrates
2e–2g, bearing a chloro group or a nitro group, were also suitable
for the reaction with 1a under the same conditions (entries 4–6).

652
Y.-J. Guo et al. / Tetrahedron Letters 51 (2010) 649–652
NH2
X
NCS
H
N
H
N
H
N
X
N
+
S
SH
R
R'
X
R'
1
R'
R
R
2
B
A
CuBr/TBAB
H
N
N
S
N
H
N
S
Cu
X
R'
R
R
R'
C
Scheme 2. A possible mechanism.
Riemer, C. PCT Int. Appl. WO 2001097786, 2001 (Chem Abstr. 2001, 134,
252353); (c) Yoshida, M.; Hayakawa, I.; Hayashi, N.; Agatsuma, T.; Oda, Y.;
Tanzawa, F.; Iwasaki, S.; Koyama, K.; Furukawa, H.; Kurakatad, S.; Suganob, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 3328; (d) Toya, Y.; Takagi, M.; Kondo, T.;
Nakata, H.; Isobe, M.; Goto, T. Bull. Soc. Chem. Jpn. 1992, 65, 2604; (e) Zamora, I.;
Oprea, T.; Cruciani, G.; Pastor, M.; Ungell, A.-L. J. Med. Chem. 2009, 52, 1744.
2. Suter, H.; Zutter, H. Helv. Chim. Acta 1967, 50, 1084.
3. Hays, S. J.; Rice, M. J.; Ortwine, D. F.; Johnson, G.; Schwartz, R. D.; Boyd, D. K.;
Copeland, L. F.; Vartanian, M. G.; Boxer, P. A. J. Pharm. Sci. 1994, 83, 1425.
4. Shirke, V. G.; Bobade, A. S.; Bhamaria, R. P.; Khadse, B. G.; Sengupta, S. R. Indian
Drugs 1990, 27, 350.
5. (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, Structure, Reactions,
Syntheses, and Applications, 2nd ed.; Wiley-VCH: Weinheim, 2003; (b) Victor, J.
C.; Nicholas, S. D. Tetrahedron Lett. 2006, 47, 3747; (c) Inamoto, K.; Hasegawa,
C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147.
6. Pd: (a) Benedí, C.; Bravo, F.; Uriz, P.; Fernández, E.; Claver, C.; Castillón, S.
Tetrahedron Lett. 2003, 44, 6073; Pd or Cu: (b) Joyce, L. L.; Evindar, G.; Batey, R.
A. Chem. Commun. 2004, 446; Cu: (c) Wang, J.-K.; Peng, F.; Jiang, J.-L.; Lu, Z.-J.;
Wang, L.-Y.; Bai, J.-F.; Pan, Y. Tetrahedron Lett. 2008, 49, 467; (d) Ma, D.; Xie, S.;
Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009, 48, 4222.
7. Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587.
8. For selected example of TBAB-promoted the cross-coupling reactions, see: (a)
Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031; (b) Yang, D.; Chen,
Y.-C.; Zhu, N.-Y. Org. Lett. 2004, 6, 1557. and references therein; (c) Li, J.-H.; Liu,
W.-J.; Xie, Y.-X. J. Org. Chem. 2005, 80, 5409; (d) Li, J.-H.; Li, J.-L.; Xie, Y.-X.
Synthesis 2007, 984; (e) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559;
(f) Liu, W.-J.; Xie, Y.-X.; Liang, Y.; Li, J.-H. Synthesis 2006, 860; (g) Bedford, R. B.;
Blake, M. E.; Butts, C. P.; Holder, D. Chem. Commun. 2003, 466.
9. For selected reviews, see: (a) Kondo, T.; Mitsudo, T.-A. Chem. Rev. 2000, 100,
3205; (b) Steven, V. L.; Andrew, W. T. Angew. Chem., Int. Ed. 2003, 42, 5400.
10. For selected papers on transition metal-catalyzed cross-coupling of aryl halides
with sulfur nucleophiles, see: Pd: (a) Fernández-Rodríguez, M. A.; Shen, Q.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180; (b) Fernández-Rodríguez, M. A.;
Hartwig, J. F. J. Org. Chem. 2009, 74, 1663; (c) Li, G. Y. Angew. Chem., Int. Ed.
2001, 40, 1513; Cu: (d) Prudencio, S. H.; Kathleen, A. P.; Kiplin, R. G. Org. Lett.
2000, 2, 2019; (e) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609; (f) Kwong, F.
Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517; (g) Wong, Y.-C.; Jayanth, T. T.; Cheng,
C.-H. Org. Lett. 2006, 8, 5613; (h) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew.
Chem., Int. Ed. 2007, 46, 5583; (i) Verma, A. K.; Singh, J.; Chaudhary, R.
Tetrahedron Lett. 2007, 49, 7199; (j) Herrero, M. T.; SanMartin; Domínguez, R.
Tetrahedron 2009, 65, 1500; (k) She, J.; Jiang, Z.; Wang, Y. Tetrahedron Lett.
2009, 50, 593; Fe/Cu: (l) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed.
2008, 47, 2880; (m) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5586; (n) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348.
strate 1g, a heteroarylamine, with isothiocyanate 2a failed (entry
19). We were pleased to disclose that moderate yields were still
achieved from the reaction of 2-chlorobenzenamine (1i) with
isothiocyanates 2a or 2i under the optimized conditions (entries
20 and 21). Notably, 2-aminobenzenethiol (1i) was a suitable sub-
strate, affording the target product 3 in 76% yield (entry 22).
A possible mechanism was proposed as outlined in Scheme 2 on
the basis of the earlier proposed mechanism.6–10 Intermediate A
can be generated readily in situ from the reaction between 2-halo-
benzenamines 1 and isothiocyanates 2,6b followed by cross-cou-
pling to afford the target product with the aid of CuBr and
TBAB.6–10 Among the process, 2-halobenzenamines, 2-amin-
obenzothiazoles, and DMSO (a Lewis base) may play the role as
bases. We also deduced that TBAB might play two roles in the pres-
ent reaction: (i) a promoter or/and a ligand to activate and stabilize
the active Cu species; and (ii) phase-transfer catalyst for the inor-
ganic catalyst/solvent/substrate/product phases.8 Study on the de-
tailed mechanism is in progress.
In summary, a mild and efficient tandem method for the syn-
thesis of 2-aminobenzothiazoles has been demonstrated. The re-
sults showed that TBAB could improve the reaction. In the
presence of CuBr and TBAB, a variety of 2-halobenzenamines
underwent the tandem reaction with isothiocyanates smoothly in
moderate to excellent yields. It is noteworthy that the reaction is
conducted under mild, relatively low catalyst loading, and ligand-
and base-free conditions. Further application of the present system
in organic synthesis and study of the detailed mechanism are
underway.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (No. 20872112), the Zhejiang Provincial Natural Science
Foundation of China (Nos. Y407116, Y4080169, and Y4080027),
and the Foundation of Wenzhou University (2007L004) for finan-
cial support.
11. Typical procedure:
A
mixture of 2-halobenzenamine
1
(0.3 mmol),
isothiocyanates 2 (0.3 mmol), CuBr (1 mol %), and TBABr (1 equiv) was stirred
in DMSO (2 mL) at 40 °C for the indicated time (Tables 1 and 2) until the
complete consumption of starting material as monitored by TLC. After the
reaction was complete, the mixture was washed with saturated brine and
extracted with diethyl ether. The organic layers were dried with Na2SO4 and
evaporated under vacuum, the residue was purified by flash column
chromatography (hexane/ethyl acetate) to afford the pure product. N-
Phenylbenzo[d]thiazol-2-amine (3): White solid, mp 158.1–159.3 °C (lit.12 mp
157.2–159.4 °C); 1H NMR (300 MHz, DMSO-d6) d: 10.47 (s, 1H), 7.82–7.78 (m,
3H), 7.59 (s, 1H), 7.39–7.33 (m, 3H), 7.16 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 7.9 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) d: 161.9, 152.4, 141.0, 130.3, 129.3, 126.2,
122.6, 122.4, 121.3, 119.5, 118.1; LRMS (EI, 70 eV) m/z (%): 226 (M+, 74), 225
(100), 96 (13).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.086.
References and notes
1. For selected examples, see: (a) Brade, A. R.; Khadse, H. B.; Bobade, A. S. Indian
Drugs 1998, 35, 554; (b) Alanine, A.; Flohr, A.; Miller, A. K.; Norcross, R. D.;
12. Fajkusova, D.; Pazdera, P. Synthesis 2008, 1297.