An efficient copper(II)-catalyzed synthesis of benzothiazoles through intramolecular coupling-cyclization of N-(2-chlorophenyl)benzothioamides

Article abstract of DOI:10.1016/j.tetlet.2010.07.079

A wide range of 2-aryl or 2-alkyl-substituted benzothiazoles are synthesized through intramolecular C_(aryl)-S bond forming-cyclization using copper(II)-BINAM-catalyzed coupling of less reactive N-(2-chlorophenyl) benzo or alkylthioamide under mild reaction conditions (82 °C).

Full text of DOI:10.1016/j.tetlet.2010.07.079

Tetrahedron Letters 51 (2010) 5009–5012
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient copper(II)-catalyzed synthesis of benzothiazoles through
intramolecular coupling-cyclization of N-(2-chlorophenyl)benzothioamides
*
E. A. Jaseer, D. J. C. Prasad, Arpan Dandapat, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of 2-aryl or 2-alkyl-substituted benzothiazoles are synthesized through intramolecular
C(aryl)-S bond forming-cyclization using copper(II)–BINAM-catalyzed coupling of less reactive N-(2-chlo-
rophenyl)benzo or alkylthioamide under mild reaction conditions (82 °C).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 June 2010
Revised 6 July 2010
Accepted 14 July 2010
Available online 18 July 2010
Keywords:
Copper catalyst
Coupling reaction
Benzothiazole
Diamine ligands
C(aryl)-S bond formation
Benzothiazole moieties are found in a variety of biologically
important natural products1 and they are used as drugs for several
diseases such as tumors, diabetes, Parkinson’s disease, tuberculo-
sis, inflammatory diseases, epilepsy, viral infections, insomnia,
and atherosclerosis (Fig. 1).2 Also, they are inhibitors of several en-
zymes3 and function as antioxidants.4 Due to the importance of
benzothiazole-containing compounds, an efficient synthesis of
benzothiazoles under very mild reaction conditions has become
very important.
OEt
CH3
NH2
4
O
O
2HCl
NH2
P
N
S
F
N
S
OEt
NH
H
antitumour activity 2a
calcium antagonistic activity 2i
N
Cl
Cl
H
S
O
N
N
O
Cl
S
N
O
O
N
N
H
S
The conventional method for the construction of a benzothiazole
moiety is condensation of 2-aminothiophenols with substituted
nitriles, aldehydes, carboxylic acids, acyl chlorides or esters.5 But
synthesis of different substituted benzothiazoles will be difficult be-
cause of the expensive and readily oxidizable nature of substituted
2-aminothiophenols.6 Intramolecular cyclization of N-(2-halophe-
nyl) benzothioamide is one of the attractive methods for the synthe-
sis of benzothiazoles.7 Though highly reactive N-(2-iodophenyl)
benzothioamide yields benzothiazole without any catalyst8 but
N-(2-bromophenyl) benzothioamide needs Pd9 or Cu10 catalyst.
Particularly, N-(2-chlorophenyl) benzothioamide is very less reac-
tive toward intramolecular cyclization and is not much explored.
There are only two reports in the literature for the cyclization of 2-
chlorophenyl benzothioamide to the corresponding benzothiazoles
where the reaction requires more than 140 °C with very limited sub-
strate scope8a,10a or it requires a photochemical condition.11
inhibitor of human hepatic
microsomal 11b-HSD12b
orexin receptor antagonist2h
Figure 1. Biologically active compounds containing benzothiazole skeleton.
Herein for the first time we report BINAM–Cu(II) complex as an
efficient catalyst for the synthesis of benzothiazole through intra-
molecular coupling cyclization from N-(2-chlorophenyl) ben-
zothioamide under mild reaction conditions (Scheme 1).
As part of our ongoing research toward copper-catalyzed oxida-
tion chemistry,12 very recently we reported copper complex to be
an efficient catalyst for the synthesis of ethers, sulfides, N-arylated
indoles, arylated alkynes, benzoxazines, and benzothiazines
Cl
S
S
Cu catalyst
º
< 100 C
N
H
N
R
R
* Corresponding author. Tel.: +91 44 2257 4229; fax: +91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.079

5010
E. A. Jaseer et al. / Tetrahedron Letters 51 (2010) 5009–5012
OH
cyclization of N-(2-chlorophenyl)benzothioamide using Cs2CO3 as
OH
a base in acetonitrile solvent at 82 °C. After 72 h the coupling reac-
tion provided 19% isolated yield of 2-phenylbenzothiazole (Table 1,
entry 1). When we replaced the L1 with ethylene glycol L2, the
yield was slightly increased to 30% (entry 2). When replacing the
ligand L2 by diamine ligands L3 or L4, the yield decreased (entries
3 and 4). To our surprise, when we used 1,1’-binaphthyl-2,2’-dia-
mine (BINAM) L5 as a ligand the yield for the synthesis of 2-phen-
ylbenzothiazole was increased to 71% at 82 °C (entry 5). Replacing
BINAM by other N-substituted derivatives such as L6–L8 reduced
the yield drastically to 21–24% (entries 6–8). Then the reaction
was screened with several other copper salts and CuCl2 turned
out to be the best choice with ligand L5, which provided 78% iso-
lated yield for the coupling cyclization (entry 12). When the intra-
molecular cyclization was carried out without the ligand, in the
presence of CuCl2 it provided only 28% yield for benzothiazole for-
mation, suggesting the mandatory presence of the ligand in this
reaction (entry 15).
NH2
NH2
NH2
OH
NR1R2
NR1R2
OH
NH2
L5: R1 = R2 = H L7: R1 = H; R2 = Me
L6: R1 = R2 = Me L8: R1 = H; R2 = Bn
L1
L2
L3
L4
Figure 2. Ligands screened for copper catalyzed 2-phenylbenzothiazole synthesis.
through C(aryl)–O, C(aryl)–S, C(aryl)–N and C(aryl)–C bond forming-Ull-
mann type/Sonogashira coupling.13 In this Letter, we report a sim-
ple procedure for the synthesis of benzothiazoles from very less
reactive N-(2-chlorophenyl)benzo or alkylthioamide under mild
reaction conditions (82 °C) using BINAM–Cu(II) catalyst.
In preliminary studies, we used 10 mol % of trans-( )-diol L114
as a ligand (Fig. 2) with 5 mol % of Cu(OTf)2 for the intramolecular
The reaction was then screened with several solvents, bases,
and different ratios of the catalyst to increase the efficiency of
Table 1
Effect of different ligands and copper salts for the synthesis of 2-phenyl benzothiaz-
oles
Table 3
Cu salt (5 mol%)
Cl
S
N
ligand (10 mol%)
Synthesis of benzothiazoles via copper(II)-catalyzed coupling of various N-(2-
S
chlorophenyl)benzothioamides15
Cs2CO3 (2 equiv.)
N
H
CH3CN, 82 ºC, 72 h
Cl
CuCl2 (5 mol%)
S
S
BINAM (10 mol%)
N
Entry
Ligand
Cu salt
Yielda (%)
Cs2CO3 (2 equiv.)
acetonitrile, 82 ºC
N
H
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
L1
L2
L3
L4
L5
L6
L7
L8
L5
L5
L5
L5
L5
L5
—
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu2O
CuSO4
Cu(OAC)2
CuCl2
CuBr
CuI
19
30
23
27
71
21
21
24
30
25
42
78
42
48
28
R
Entry Benzothioamide
Benzothiazole16
Time
(h)
Yielda
(%)
Cl
S
S
N
1
72
96
78
50
N
H
Cl
S
S
N
OMe
Br
2
3
4
N
H
OMe
Br
Cl
S
N
CuCl2
S
S
81b
50
a
48
96
Isolated yield.
N
H
Cl
S
N
Table 2
Effect of various solvents and bases
F
N
H
CuCl2 (5 mol%)
BINAM (10 mol%)
Cl
F
S
N
S
Cl
Me
S
S
S
Me
base (2 equiv.)
solvent, 82 ºC, 72 h
S
N
N
H
5
6
7
72
46
36
52
N
H
Entry
Solvent
Base
Yielda (%)
Cl
OMe
S
N
1
2
3
4
5
6
7
8
9
Toluene
DMF
DMSO
1,4-Dioxane
THF
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Trace
25
42
60b
92b
OMe
Cl
N
H
49
Cl
Cl
12b
78
S
N
S
N
N
H
23
17
Cl
S
S
21
79c
48d
62e
8
9
45
72
70b
60
10
11
12
N
H
Cl
S
N
a
b
c
Isolated yield.
N
H
Reaction was carried out in pressure tube.
10 mol % CuCl2 and 20 mol % BINAM.
5 mol % CuCl2 and 5 mol % BINAM.
10 mol % CuCl2 and 10 mol % BINAM.
a
d
e
Isolated yield.
Reaction was carried out at 110 °C.17
b

E. A. Jaseer et al. / Tetrahedron Letters 51 (2010) 5009–5012
5011
the cyclization (Table 2). Acetonitrile turned out to be the best sol-
vent of choice in view of the isolated yield. Cs2CO3 as the base pro-
vided the best result in comparison with Na2CO3, K2CO3, and
K3PO4. The 1:2 ratio of CuCl2 and ligand L5 (5:10 and 10:20; entries
6 and 10) provided better results than the 1:1 complex (5:5 and
10:10; entries 11 and 12). In the 1:2 complex, both 5:10 and
10:20 ratios of CuCl2 and ligand L5, respectively, provided almost
the same yield for the intramolecular cyclization.
N-(2-bromophenyl)benzothioamide in excellent yields at 82 °C in
acetonitrile (Table 4). In case of bromo substrates, electron-with-
drawing group (entry 3), electron-releasing group (entries 2, 4,
and 7), and sterically hindered-ortho-substituted benzothioamide
(entry 5) are well tolerated and provided an excellent isolated yield
at 82 °C. 2-Ethyl-substituted benzothiazole was also synthesized in
good yield (entry 8). Importantly, substitution on the 2-bromo ani-
line moiety of N-(2-bromophenyl) benzothioamide also provided
excellent yields (entries 6 and 7).
In summary, for the first time we have demonstrated that BI-
NAM–CuCl2 can be used as an efficient catalyst for the synthesis
of 2-substituted benzothiazoles by intramolecular cyclization
through C(aryl)–S bond formation at 82 °C from very less reactive
N-(2-chlorophenyl)benzothioamide or N-(2-bromophenyl)ben-
zothioamide. The N-(2-halophenyl) benzothioamide containing
electron-withdrawing, electron-releasing groups, and sterically
hindered ortho-substituted benzothioamide is well tolerated. Sim-
ilarly, 2-alkyl-substituted benzothiazoles are also synthesized in
good yields. This synthetic method is expected to find valuable
applications in various areas, as the reaction is carried out under
mild reaction conditions. Further investigations using this method-
ology to construct biologically active benzothiazole-containing
molecules are underway.
Using the above mentioned optimized reaction conditions,15 we
initiated our investigations into the scope of the CuCl2–BINAM
complex-catalyzed intramolecular cyclization of various substi-
tuted N-(2-chlorophenyl)benzothioamide and the results are
summarized in Table 3. A wide range of N-(2-chlorophenyl)aryl-
thioamide with both electron-releasing (entries 2 and 6) and
electron-withdrawing groups (entries 3, 4, and 7) produced the
corresponding benzothiazoles in good yields using the optimal
reaction conditions. Interestingly, 2-alkyl-substituted benzothiaz-
oles were also synthesized in good yields (entries 8 and 9).
Similarly, sterically hindered ortho-substituted benzothioamide
also cyclized to give the corresponding benzothiazole in good yield
(entry 5).
The new catalytic system was also successfully utilized for the
synthesis of 2-substituted benzothiazoles from the corresponding
Acknowledgments
Table 4
We thank the DST (Project No.: SR/S1/OC-06/2008), New Delhi
for the financial support. E.A.J. thanks the CSIR, New Delhi and
D.J.C Prasad thanks the UGC, New Delhi for SRF. We thank the
DST, New Delhi for funding toward the 400-MHz NMR machine
to the department of Chemistry, IIT-Madras under the IRPHA
Scheme and for funding the ESI-MS facility under the FIST Program
Synthesis of benzothiazoles using copper(II)–BINAM coupling cyclization of N-(2-
bromophenyl) benzothioamide15
Br
S
N
S
CuCl2 (5 mol%)
BINAM (10 mol%)
R
R
N
H
R'
Cs2CO3 (2 equiv.)
acetonitrile, 82 ºC
R'
Entry Benzothioamide
Benzothiazole16
Time Yielda
(h)
(%)
References and notes
Br
S
S
N
1. (a) Bradshaw, T. D.; Westwell, A. D. Curr. Med. Chem. 2004, 11, 1009–1021;
(b) Tale, R. H. Org. Lett. 2002, 4, 1641–1642; (c) Mathis, C. A.; Wang, Y. M.;
Holt, D. P.; Huang, G. F.; Debnath, M. L.; Klunk, W. E. J. Med. Chem. 2003, 46,
2740–2754.
1
28
98
N
H
Br
S
S
N
2. (a) Bradshaw, T. D.; Westwell, A. D. Curr. Med. Chem. 2004, 11, 1241–1253; (b)
Su, X.; Vicker, N.; Ganeshapillai, D.; Smith, A.; Purohit, A.; Reed, M. J.; Potter, B.
V. L. Mol. Cell. Endocrinol. 2006, 248, 214–217; (c) Chakraborti, A. K.; Rudrawar,
S.; Kaur, G.; Sharma, L. Synlett 2004, 1533–1536; (d) Shirke, V. G.; Bobade, A. S.;
Bhamaria, R. P.; Khadse, B. G.; Sengupta, S. R. Indian Drugs 1990, 27, 350–353;
(e) Das, J.; Moquin, R. V.; Liu, C.; Doweyko, A. M.; Defex, H. F.; Fang, Q.; Pang, S.;
Pitt, S.; Shen, D. R.; Schieven, G. L.; Barrish, J. C.; Wityak, J. Bioorg. Med. Chem.
Lett. 2003, 13, 2587–2590; (f) Hays, S. J.; Rice, M. J.; Ortwine, D. F.; Johnson, G.;
Schwarz, R. D.; Boyd, D. K.; Copeland, L. F.; Vartanian, M. G.; Boxer, P. A. J.
Pharm. Sci. 1994, 83, 1425–1432; (g) Paget, C. J.; Kisner, K.; Stone, R. L.; Delong,
D. C. J. Med. Chem. 1969, 12, 1016–1018; (h) Bergman, J. M.; Coleman, P. J.; Cox,
C.; Hartman, G. D.; Lindsley, C.; Mercer, S. P.; Roecker, A. J.; Whitman, D. B. PCT
Int. Appl. WO2006127550, 2006.; (i) Yoshino, K.; Kohno, T.; Uno, T.; Morita, T.;
Tsukamoto, G. J. Med. Chem. 1986, 29, 820–825.
OMe
2
3
28
36
89
90
N
H
OMe
Br
S
N
S
S
F
N
H
F
Br
OMe
S
N
OMe
4
5
6
27
36
29
95
96
99
N
H
3. (a) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.;
Dee, M. F.; Siegel, T. W.; Singleton, D. H. J. Med. Chem. 1991, 34, 108–122; (b)
Sato, G.; Chimoto, T.; Aoki, T.; Hosokawa, S.; Sumigama, S.; Tsukidate, K.;
Sagami, F. J. Toxicol. Sci. 1999, 24, 165–175.
Br
Me
S
Me
S
N
N
H
4. Ivanov, S. K.; Yuritsyn, V. S. Neftekhimiya 1971, 11, 99–107.
5. (a) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1997, 38, 6395–
6396; (b) Seijas, J. A.; Vazquez-Tato, M. P.; Carballido-Reboredo, M. R.;
Crecente-Campo, J.; Romar-Lopez, L. Synlett 2007, 313–317.
Br
S
S
S
N
N
H
6. Ranu, B. C.; Jana, R.; Dey, S. S. Chem. Lett. 2004, 33, 274–275.
7. The C–H functionalized-cyclization of thiobenzanilide using various oxidants
like K3Fe(CN)6, DDQ, Mn(OAc)3, and Dess–Martin periodinane is an alternative
for the intramolecular cyclization of N-(2-halophenyl)benzothioamide. But this
C–H functionalized cyclization generally leads to regioisomers, and only few
benzothiazoles synthesis is reported particularly from the substrates which are
not yielding regioisomers. (a) Jacobson, P. Chem. Ber. 1886, 19, 1067; (b) Bose,
D. S.; Idrees, M. Tetrahedron Lett. 2007, 48, 669–672; (c) Mu, X.; Zou, J.; Zeng, R.;
Wu, J. Tetrahedron Lett. 2005, 46, 4345–4347; (d) Bose, D. S.; Idrees, M. J. Org.
Chem. 2006, 71, 8261–8263.
Br
S
N
OMe
7
8
33
28
83
71
N
H
OMe
Br
S
N
S
N
H
8. (a) Bernardi, D.; Ba, L. A.; Kirsch, G. Synlett 2007, 2121–2123; (b) 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, 179–185.
a
Isolated yield.

5012
E. A. Jaseer et al. / Tetrahedron Letters 51 (2010) 5009–5012
9. (a) Benedı, C.; Bravo, F.; Uriz, P.; Fernandez, E.; Claver, C.; Castillon, S.
Tetrahedron Lett. 2003, 44, 6073–6077; (b) Vera, M. D.; Pelletier, J. C. J. Comb.
Chem. 2007, 9, 569–570.
10. (a) Ma, H. C.; Jiang, X. Z. Synlett 2008, 1335–1340; (b) Evindar, G.; Batey, R. A. J.
Org. Chem. 2006, 71, 1802–1808.
15. Typical experimental procedure: Anhydrous CuCl2 (3.36 mg, 0.025 mmol), ( )-
BINAM (14.2 mg, 0.05 mmol), Cs2CO3 (325.8 mg, 1 mmol), and N-(2-
chlorophenyl)benzothioamide (123.9 mg, 0.5 mmol) were taken in a 10 ml
reaction tube equipped with a septum. The reaction tube was evacuated and
back-filled with nitrogen. Acetonitrile (2 mL) was added to the reaction
mixture at room temperature. The reaction tube was sealed with a glass
stopper and the reaction mixture was heated for 72 h at 82 °C. After the
complete disappearance of starting material (the progress of the reaction was
followed by TLC), the reaction mixture was allowed to cool to room
temperature and the crude reaction mixture was directly purified by column
chromatography on silica gel using ethyl acetate/hexanes as the eluents to
afford 2-phenylbenzothiazole 82.4 mg (78%) as a white solid (Table 3, entry 1).
Mp 112 °C (lit. 110–111 °C)10b, Rf 0.48 (5% ethyl acetate: hexanes); IR (neat):
11. Jayanthi, G.; Muthusamy, S.; Paramasivam, R.; Ramakrishnan, V. T.; Ramasamy,
N. K.; Ramamurthy, P. J. Org. Chem. 1997, 62, 5766–5770.
12. (a) Mannam, S.; Kumar, S. A.; Sekar, G. Adv. Synth. Catal. 2007, 349, 2253–2258;
(b) Kumar, S. A.; Mannam, S.; Muthupandi, P.; Sekar, G. Chem. Eur. J. 2009, 15,
1086–1090; (c) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 1083–1086;
(d) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 2457–2460.
13. (a) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009, 74, 3675–3679; (b)
Prasad, D. J. C.; Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009, 50, 1411–1415; (c)
Rao, R. K.; Naidu, A. B.; Jaseer, E. A.; Sekar, G. Tetrahedron 2009, 65, 4619–4624;
(d) Thakur, K. G.; Jaseer, E. A.; Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009, 50,
2865–2869; (e) Jaseer, E. A.; Prasad, D. J. C.; Sekar, G. Tetrahedron 2010, 66,
2077–2082; (f) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11, 1923–1926;
(g) Prasad, D. J. C.; Sekar, G. Org. Biomol. Chem. 2009, 7, 5091–5097; (h) Prasad,
D. J. C.; Sekar, G. Synthesis 2010, 79–84.
3064, 1476, 1439, 1312, 1224, 962, 764, 690, 622 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d 7.39 (t, J = 7.6 Hz, 1H), 7.47–7.54 (m, 4H), 7.91 (d, J = 7.6 Hz, 1H),
8.07–8.14 (m, 3H); 13C NMR (100 MHz, CDCl3): d 121.8, 123.3, 125.3, 126.5,
127.7, 129.2, 131.1, 133.7, 135.1, 154.2, 168.2; HRMS (m/z): [MH]+ calcd for
C
13H10NS: 212.0534; found: 212.0534.
16. All the products gave satisfactory spectral data.
17. Entries 3, 6, 7, and of Table gave good yield of the corresponding
14. Diol ligand L1 (trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dimethanol)
with CuI was used as an efficient catalyst for the arylation of phenols and
thiophenols under mild reaction conditions (82 °C).13a,13h
8
4
benzothiazoles at 110 °C (in pressure tube). At 82 °C, these reactions gave
approximately 20% less yield.