Metal-free synthesis of 2-aminobenzothiazoles via aerobic oxidative cyclization/dehydrogenation of cyclohexanones and thioureas

Article abstract of DOI:10.1021/ol400773k

A metal-free process for the synthesis of 2-aminobenzothiazoles from cyclohexanones and thioureas has been developed using catalytic iodine and molecular oxygen as the oxidant under mild conditions. Various 2-aminobenzothiazoles, 2-aminonaphtho[2,1-d]thiazoles, and 2-aminonaphtho[1,2-d] thiazoles were prepared via this method in satisfactory yields.

Full text of DOI:10.1021/ol400773k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free Synthesis of
2‑Aminobenzothiazoles via Aerobic
Oxidative Cyclization/Dehydrogenation of
Cyclohexanones and Thioureas
Jinwu Zhao,†,‡ Huawen Huang,† Wanqing Wu,† Huoji Chen,† and Huanfeng Jiang*,†
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China, and School of Pharmacy, Guangdong Medical College,
Songshan Lake Science and Technology Industry Park, Dongguan 523808, P. R. China
jianghf@scut.edu.cn
Received March 21, 2013
ABSTRACT
A metal-free process for the synthesis of 2-aminobenzothiazoles from cyclohexanones and thioureas has been developed using catalytic iodine
and molecular oxygen as the oxidant under mild conditions. Various 2-aminobenzothiazoles, 2-aminonaphtho[2,1-d]thiazoles, and 2-aminonaphtho-
[1,2-d]thiazoles were prepared via this method in satisfactory yields.
2-Aminobenzothiazoles are an important class of
heterocycle whose diverse biological activities make them
privileged scaffolds in drug discovery.1 For example,
marketed Riluzole (A) is a 2-aminobenzothiazole com-
pound employed in the treatment of amyotrophic lateral
sclerosis;2 N-disubstituted 2-aminobenzothiazole (B) is
used as anti-HIV agent, and N-aryl substituted 2-amino-
benzothiazole (C, R116010) is serving as a potential in-
hibitor of retinoic acid metabolism for cancer treatment
(Figure 1).3,4 N-Alkyl substituted 2-aminobenzothiazoles
might also be biologically active and of pharmaceutical
value.5
† South China University of Technology.
‡ Guangdong Medical College.
(1) (a) Paget, C. J.; Kisner, K.; Stone, R. L.; DeLong, D. C. J. Med.
Chem. 1969, 12, 1016. (b) Young, R. C.; Mitchell, R. C.; Brown, T. H.;
Ganellin, C. R.; Griffiths, R.; Jones, M.; Rana, K. K.; Saunders, D.;
Smith, I. R.; Sore, N. E.; Wilks, T. J. J. Med. Chem. 1988, 31, 656. (c)
Raghavendra, N. M.; Jyothsna, A.; Rao, A. V.; Subrahmanyam, C. V. S.
Bioorg. Med. Chem. Lett. 2012, 22, 820. (d) Fajkusova, D.; Pesko, M.;
Keltosova, S.; Guo, J. H.; Oktabec, Z.; Vejsova, M.; Kollar, P.; Coffey,
A.; Csollei, J.; Kralova, K.; Jampilek, J. Bioorg. Med. Chem. 2012, 20,
7059. (e) Gardner, C. R.; Cheung, B. B.; Koach, J.; Black, D. S.;
Marshall, G. M.; Kumar, N. Bioorg. Med. Chem. 2012, 20, 6877.
(2) (a) McDonnell, M. E.; Vera, M. D.; Blass, B. E.; Pelletier, J. C.;
King, R. C.; Fernandez-Metzler, C.; Smith, G. R.; Wrobel, J.; Chen, S.;
Wall, B. A.; Reitz, A. B. Bioorg. Med. Chem. 2012, 20, 5642. (b) Cheah,
B. C.; Vucic, S.; Krishnan, A. V.; Kiernan, M. C. Curr. Med. Chem.
2010, 17, 1942.
Figure 1. Examples of bioactive 2-aminobenzothiazoles.
In view of the importance of 2-aminobenzothiazoles, a
number of procedures have been developed to prepare this
(4) (a) Van Heusden, J.; Van Ginckel, R.; Bruwiere, H.; Moelans, P.;
Janssen, B.; Floren, W.; van der Leede, B. J.; van Dun, J.; Sanz, G.;
Venet, M.; Dillen, L.; Van Hove, C.; Willemsens, G.; Janicot, M.;
Wouters, W. Br. J. Cancer 2002, 86, 605. (b) Aelterman, W.; Lang, Y.;
Willemsens, B.; Vervest, I.; Leurs, S.; De Knaep, F. Org. Process Res.
Dev. 2001, 5, 467.
(3) Massari, S.; Daelemans, D.; Barreca, M. L.; Knezevich, A.;
Sabatini, S.; Cecchetti, V.; Marcello, A.; Pannecouque, C.; Tabarrini,
O. J. Med. Chem. 2010, 53, 641.
r
10.1021/ol400773k
XXXX American Chemical Society

class of heterocyclic compound.6 An overwhelming num-
ber of these involve transition-metal catalysts, such as
copper,7 palladium,8 iron,9 silver, etc.10,11 Some of these
metal-based catalysts are based on noble metals and are of
high cost. Moreover, transition metal catalysts may possi-
bly leave toxic traces of metals in the products. It was
reported that 2-aminobenzothiazoles could be produced
by reacting isothiocyanates with o-aminothiophenols or
o-iodoaniline under metal-free conditions.12,13 However,
these methods sufferfrom limited startingmaterials and/or
harsh reaction conditions. Therefore, the development of a
new practical process for the synthesis of 2-aminobenzothia-
zoles under mild conditions is desirable. Recently, our group
has developed a number of transition-metal-free processes
to synthesize nitrogen-containing heterocyclic compounds
through iodine mediated oxidative cyclization reactions.14
Herein, we disclose that cyclohexanones can react with
thioureas to provide 2-aminobenzothiazoles catalyzed by
iodine (Scheme 1). Moreover, the reaction utilizes molecular
oxygen as an oxidant, which avoids the environmentally
hazardous byproducts obtained with other oxidants.15
Our studies began by optimizing the reaction conditions
on cyclohexanone and thiourea. The results are tabulated
in Table 1. When this reaction was carried out in toluene at
95 °C for 24 h, using 20 mol % molecular iodine as the
catalyst, in the presence of 2.0 equiv ofaqueous HCl, under
Scheme 1. Metal-Free Synthesis of 2-Aminobenzothiazoles
from Cyclohexanones and Thioureas
1 atm of pressure of dioxygen, no desired 2-aminoben-
zothiazole was obtained (Table 1, entry 1). After screening
common polar solvents, DMSO was found to be superior
(Table 1, entries 2À4). When AcOH was used as the
solvent as well as acid proton donor, 3a was obtained in
7% yield (Table 1, entry 5). Our experimental results
suggested that organic strong acids were better than
inorganic acids, and p-toluenesulfonic acid (PTSA) fa-
vored the transformation to the greatest extent (Table 1,
entries 6À9). As shown in Table 1, the amount of acid used
had a significant effect on the yield of 2-aminobenzothia-
zole, and finally we found that 5 equiv of PTSA gave the
best results (Table 1, entries 10À12). Our investigations on
reaction temperature showed that 75 °C was optimal for
the process (Table 1, entries 13 and 14). When the loading
of the iodine catalyst was increased from 20 to 30 mol %,
the yield of 3a rose from 78% to 84% (Table 1, entry 15).
Increasing the amount of the catalyst further was not
beneficial (Table 1, entry 16).
(5) (a) Liu, C. J.; Lin, J.; Pitt, S.; Zhang, R. F.; Sack, J. S.; Kiefer,
S. E.; Kish, K.; Doweyko, A. M.; Zhang, H. J.; Marathe, P. H.;
Trzaskos, J.; Mckinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven,
G. L.; Leftheris, K. Bioorg. Med. Chem. Lett. 2008, 18, 1874. (b) Ouyang,
L.; Huang, Y. H.; Zhao, Y. W.; He, G.; Xie, Y. M.; Liu, J.; He, J.; Liu,
B.; Wei, Y. Q. Bioorg. Med. Chem. Lett. 2012, 22, 3044.
(6) (a) Stewart, G. W.; Baxter, C. A.; Cleator, E.; Sheen, F. J. J. Org.
Chem. 2009, 74, 3229. (b) Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org.
Chem. 2003, 68, 8693. (c) Neo, A. G.; Carrillo, R. M.; Marcos, C. F. Org.
Biomol. Chem. 2011, 9, 4850. (d) Wang, R.; Yang, W. J.; Yue, L.; Pan,
W.; Zeng, H. Y. Synlett 2012, 23, 1643.
Table 1. Optimization of Reaction Conditions for the Synthesis
of 2-Aminobenzothiazole from Cyclohexanone and Thioureaa
(7) (a) Ma, D. W.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y. W.; Liu, X. Q.
Angew. Chem., Int. Ed. 2011, 50, 1118. (b) Rout, S. K.; Guin, S.; Nath, J.;
Patel, B. K. Green Chem. 2012, 14, 2491. (c) Sun, Y. L.; Zhang, Y.; Cui,
X. H.; Wang, W. Adv. Synth. Catal. 2011, 353, 1174. (d) Li, F.; Shan,
H. X.; Kang, Q. K.; Chen, L. Chem. Commun. 2011, 47, 5058. (e) Saha,
P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T.
J. Org. Chem. 2009, 74, 8719.
(8) (a) McGowan, M. A.; Henderson, J. L.; Buchwald, S. L. Org. Lett.
2012, 14, 1432. (b) Inamoto, K.; Hasegawa, C.; Kawasaki, J.; Hiroya, K.;
Doi, T. Adv. Synth. Catal. 2010, 352, 2643. (c) Stewart, G. W.; Baxter,
C. A.; Cleator, E.; Sheen, F. J. J. Org. Chem. 2009, 74, 3229. (d) Joyce,
L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792. (e) Inamoto, K.; Hasegawa,
C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. (f) Joyce, L. L.; Evindar,
G.; Batey, R. A. Chem. Commun. 2004, 446.
(9) (a) Qiu, J. W.; Zhang, X. G.; Tang, R. Y.; Zhong, P.; Li, J. H. Adv.
Synth. Catal. 2009, 351, 2319. (b) Ding, Q. P.; Cao, B. P.; Liu, X. J.;
Zong, Z.; Peng, Y. Y. Green Chem. 2010, 12, 1607.
(10) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int.
Ed 2009, 48, 9127.
(11) For other metal catalysts, see: (a) Li, F.; Shan, H. X.; Chen, L.;
Kang, Q. K.; Zou, P. Chem. Commun. 2012, 48, 603. (b) Murthy, S. N.;
Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Adv. Synth. Catal. 2010,
352, 3241.
(12) Zhang, X. Y.; Jia, X. F.; Wang, J. J.; Fan, X. S. Green Chem.
2011, 13, 413.
acid
temp
yieldb
(%)
entry
solvent
(equiv)
(°C)
1
toluene
DMF
HCl (2.0)
HCl (2.0)
HCl (2.0)
HCl (2.0)
À
95
95
95
95
95
95
95
95
95
95
95
95
75
55
75
75
N. P.
15
45
N. P.
7
2
3
DMSO
H2O
4
5
AcOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
H2SO4 (1.0)
MsOH(2.0)
PTSA (2.0)
TfOH (2.0)
PTSA (3.0)
PTSA (5.0)
PTSA (6.0)
PTSA (5.0)
PTSA (5.0)
PTSA (5.0)
PTSA (5.0)
36
53
60
58
66
77
76
78
42
84
84
7
8
9
10
11
12
13
14
15c
16d
(13) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 654.
(14) (a) Huang, H. W.; Ji, X. C.; Wu, W. Q.; Jiang, H. F. Adv. Synth.
Catal. 2013, 355, 170. (b) Jiang, H. F.; Huang, H. W.; Cao, H.; Qi, C. Q.
Org. Lett. 2010, 12, 5561.
(15) For general reviews, see: (a) Punniyamurthy, T.; Velusamy, S.;
Iqbal, J. Chem. Rev. 2005, 105, 2329. (b) Shi, Z. Z.; Zhang, C.; Tang,
C. H.; N. Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (c) Wu, W. Q.; Jiang,
H. F. Acc. Chem. Res. 2012, 45, 1736.
a Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), 2a (0.5 mmol), I2 (20 mol %), and acid
(indicated amount), in a tested solvent (2 mL) at a selected temperature
under O2 (1atm) for24h. b Isolated yield. N. P. = no product. c 30 mol % I2
was used. d 50 mol % I2 was used.
B
Org. Lett., Vol. XX, No. XX, XXXX

The scope of the protocol was further tested after the
optimal reaction conditions were established. Thiourea
was reacted with various cyclohexanones under the best
reaction conditions, and the results are listed in Scheme 2.
4-Substituted cyclohexanones such as 4-methylcyclohexa-
none, 4-phenylcyclohexanone, 4-(tert-pentyl)cyclohexanone,
and 4-(ethoxycarbonyl) cyclohexanone reacted smoothly
to produce the desired 2-aminobenzothiazoles (3bÀe). The
product 3e was obtained in relatively low yield for the
probable reason that the ethoxycarbonyl is an electron-
withdrawing group. The 2-substituted cyclohexanones,
2-methylcyclohexanone and 2-phenylcyclohexanone, also
provided the target products in yields of 71% and 66%
respectively (3fÀg). Unexpectedly, when 3-methylcyclo-
hexanone was subjected to the reaction, the ratio of regio-
isomeric 5-methylbenzo[d]thiazol-2-amine and 7-methylbenzo-
[d]thiazol-2-amine was 93:7 as determined by GC, and the
formerwas obtainedin 43% islated yield(3h). Presumably,
the regioselectivity was high because the 3-substituent of
the cyclohexanone exerted steric hindrance on its neighbor-
ing R-position. The 2-tetralones, β-tetralone, 7-methoxy-2-
tetralone, and 6-bromo-2-tetralone also all reacted with
thiourea efficiently and provided the target 2-aminonaphtho-
[2,1-d]thiazoles in excellent yields (3iÀk). To the best of
our knowledge, a practical synthetic process for these
2-aminonaphtho[2,1-d]thiazoles has not been reported
yet. 1-Tetralones such as β-tetralone, 6-methoxy-1-tetra-
lone, and 4-methyl-1-tetralone were also able to undergo
the transformation under the optimum reaction condi-
tions, and 2-aminonaphtho[1,2-d]thiazoles were obtained
in yields of 88%, 92%, and 89% respectively (3lÀn). Another
cycylohexanone of notable structure, 6,7-dihydrobenzo-
[b]thiophen-4(5H)-one, was a good substrate for the reac-
tion, and the desired 2-aminobenzothiazole compound
was isolated in 94% yield (3o). On the whole, cyclohex-
anones fused with an aromatic ring gave the corresponding
2-aminobenzothiazoles in higher yield since they could
enolize and participate in dehydrogenation more readily.
A variety of thioureas were then probed, and the results
are summarized in Scheme 3. Alkyl thioureas such as
1-methylthiourea, 1-benzylthiourea, 1-butylthiourea, and
1-phenethylthiourea all furnished the target 2-aminoben-
zothiazole products in good yield when they were treated
with β-tetralone under the favored conditions (3pÀs). Aryl
thioureas, 1-phenylthiourea and 1-(4-methoxyphenyl)-
thiourea, gave the corresponding 2-aminonaphtho[2,1-d]-
thiazoles in relatively lower yield compared with alkyl thioureas
(3tÀu). 1,1-Disubstituted thioureas 1-methyl-1-phenylthiourea
and piperidine-1-carbothioamide afforded the desired
2-aminonaphtho[2,1-d]thiazole in 72% and 75% yields
(3vÀw). Substituted thioureas, such as 1-methylthiourea
and 1-benzylthiourea, also reacted with R-tetralone to give
N-substituted 2-aminonaphtho[1,2-d]thiazole products in
satisfactory yields (3xÀy).
Scheme 2. Scope of Cyclohexanones for Metal-Free Synthesis of
2-Aminobenzothiazolesa,b
a Reactions were performed with 1 (0.5 mmol), 2a (0.5 mmol), I2
(30 mol %), and PTSA (5 equiv), in DMSO (2 mL) under O2 (1 atm) at 75 °C
for 24 h. b Isolated yield.
Promoted by protonation, cyclohexanone first enolizes
into I which can then undergo R-iodination to generate
II. Then, the thiourea tautomer III engages in a nucleo-
philic substitution reaction with II to afford the R-sulfur
substituted cyclohexanone IV, in which the nitrogen atom
of the imine group launches anintramolecular nucleophilic
attack on the carbonyl to provide V. Dehydration of V
would then yield intermediate VI, which can be dehydro-
genated by iodine to give the final 2-aminobenzothiazole
product.16 The resultant iodide anion throughout the trans-
formation is oxidized by oxygen under the acidic conditions
to regenerate the molecular iodine.
Based on the experimental results mentioned above and
our previous work on iodine-catalyzed oxidative cycliza-
tion reactions,14 a reasonable reaction pathway for the
metal-free synthesis of 2-aminobenzothiazoles from cyclo-
hexanones and thioureas is illustrated in Scheme 4.
(16) Adams, C. T.; Brandenberger, S. G.; DuBois, J. B.; Mill, G. S.;
Nager, M.; Richardson, D. B. J. Org. Chem. 1977, 42, 1.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of Thioureas for Metal-Free Synthesis of
2-Aminobenzothiazolesa,b
Scheme 4. Possible Reaction Pathway for Metal-Free Synthesis
of 2-Aminobenzothiazoles
readily available cyclohexanones and thioureas. This
metal-free method offers a convenient alternative in the
construction of 2-aminobenzothiazoles. Particularly,
2-aminonaphtho[2,1-d]thiazoles and 2-aminonaphtho-
[1,2-d]thiazoles can be produced via this protocol. This
strategy also employs oxygen as a green oxidant and
avoids transition metals.
Acknowledgment. The authors thank the National
Natural Science Foundation of China (21172076 and
20932002), the National Basic Research Program of
China (973 Program) (2011CB808600), the Changjiang
Scholars and Innovation Team Project of Ministry of
Education, Guangdong Natural Science Foundation
(10351064101000000 and S2012040007088), China Post-
doctoral Science Foundation (2012T50673), and the Fun-
damental Research Funds for the Central Universities
(2012ZP0003 and 2012ZB0011) for financial support.
Supporting Information Available. Typical experimen-
tal procedure and characterization for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reactions were performed with 1h or 1k (0.5 mmol), 2a (0.5 mmol),
I2 (30 mol %), PTSA (5 equiv), in DMSO (2 mL) under O2 (1 atm) at
75 °C for 24 h. b Isolated yield.
In conclusion, we have developed a practical proce-
dure for the synthesis of 2-aminobenzothiazoles from
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX