Electrooxidative cyclization of benzylideneaminothiophenols to the corresponding 2-arylbenzothiazoles

Article abstract of DOI:10.3987/COM-07-11195

Several benzylideneaminothiophenols were electrochemically oxidized in methanol containing sodium acetate as the supporting electrolyte, to afford the corresponding 2-arylbenzothiazols. The reaction proceeded via intramolecular cyclization involving the formation of a new bond between the benzylic carbon of the substrate and the sulfur of the thiol group. Based on the yields, room temperature and the use of two equivalents of sodium acetate relative to the substrate as the supporting electrolyte were found to be the optimal reaction conditions. The electrooxidation presumably involves a two-electron oxidation process.

Full text of DOI:10.3987/COM-07-11195

HETEROCYCLES, Vol. 75, No. 1, 2008
35
HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 35 - 42. © The Japan Institute of Heterocyclic Chemistry
Received, 8th August, 2007, Accepted, 28th September, 2007, Published online, 2nd October, 2007. COM-07-11195
ELECTROOXIDATIVE
BENZYLIDENEAMINOTHIOPHENOLS
CORRESPONDING 2-ARYLBENZOTHIAZOLES
CYCLIZATION
OF
TO
THE
Mitsuhiro Okimoto,* Takashi Yoshida, Masayuki Hoshi, Kazuyuki Hattori,
Masashi Komata, Kenta Tomozawa, and Tomohito Chiba
Department of Applied and Environmental Chemistry, Kitami Institute of
Technology, Koen-cho 165, Kitami, Hokkaido 090-8507, Japan
E-mail: oki@chem.kitami-it.ac.jp
Abstract – Several benzylideneaminothiophenols were electrochemically
oxidized in methanol containing sodium acetate as the supporting electrolyte, to
afford the corresponding 2-arylbenzothiazols. The reaction proceeded via
intramolecular cyclization involving the formation of a new bond between the
benzylic carbon of the substrate and the sulfur of the thiol group. Based on the
yields, room temperature and the use of two equivalents of sodium acetate
relative to the substrate as the supporting electrolyte were found to be the optimal
reaction conditions. The electrooxidation presumably involves a two-electron
oxidation process.
2-Arylbenzothiazoles (2) have been proven as remarkably important and useful compounds for, not only
industrial, but also pharmaceutical organic synthesis, especially as antitumor agents.1 Among the
various methods for preparing the 2-arylbenzothiazole nucleus,2 a popular route involves the oxidative
cyclization of a benzylideneaminothiophenol (1), which can be readily formed in-situ as an intermediate
by the condensation of equimolar amounts of aminothiophenol and an aromatic aldehyde (Scheme 1).3
S
N
SH
SH
oxidation
condensation
C Ar
+
ArCHO
CH
NH2
N
Ar
1
2
Scheme 1
Formation of 2-Arylbenzothiazols

36
HETEROCYCLES, Vol. 75, No. 1, 2008
Alternatively, as our continuous study, we have reported on the oxidative cyclization via electrochemical
oxidation of various nitrogen-containing substrates.4 In recent years, much attention have been given to
the unique and efficient strategy of organic synthesis involving electrochemical methods due to: 1)
environment friendly reaction conditions, 2) ease of control of the reaction, 3) ability to access
uncommon reactions that are challenging via chemical reagent, and 4) very mild reaction conditions.5
Herein, we report on successful application of the electrochemical technique for the effective
electrooxidative cyclization of benzylideneaminothiophenols into the corresponding 2-arylbenzothiazoles,
which, to the best of our knowledge, has yet to be reported.
To determine the optimal reaction conditions, electrooxidations were carried out using a model substrate,
2-(benzylideneamino)benzenethiol (1a), into the corresponding fused-ring heterocyclic compound,
2-phenylbenzothiazole (2a).
Using various supporting electrolytes, as listed in Table 1, the
electrooxidation reactions revealed significant differences in the yields of the product. In the cases of
basic supporting electrolytes such as NaCN (Run 8), NaOH (Run 9), and NaOMe (Run 10), the yields
were 40%, 48%, and 36%, respectively. Higher yields were obtained by using neutral salts such as
NaClO4 (Run 1) 62%, LiClO4 (Run 2) 74%, and p-TsON(Et)4 (Run 3) 69%. Halide ion sources such as
KI (Run 4) 30% and KBr (Run 5) 72%, which can often act as mediator (indirect electrooxidation), did
not exhibit any significant effects on the yields.6 In the cases of low yields, the starting material was
recovered and/or considerable amounts of an unidentified tar-like material was formed. A maximum yield
of 82% was obtained when 20 mmol of NaOAc was used (Run 7). In a separate study, reactions (using
10 mmol substrate) showed that the amount of NaOAc (5, 10, 20, and 30 mmol) affected the yield of the
product (72%, 76%, 82%, and 77%, respectively). Moreover, preliminary electrooxidations studies
revealed that amount of the charge passed (0.5, 1.0, and 1.5 F mol-1) increased the formation of 2a
proportionally (25%, 47%, and 62%, respectively). The maximum yield of 82% was obtained after
passage of 2.1 F mol-1 (ca. 110 min); whereas, excessive passage (3.0 F mol-1) caused a decrease in the
yield (70%).

HETEROCYCLES, Vol. 75, No. 1, 2008
37
Table 1
Electrochemical cyclization of 2-(benzylideneamino)benzenethiola
SH
N
S
N
oxidation
CH
C Ph
Ph
1a
2a
Recovery of 1a
Yield of 2a
Runs
1
Supporting electrolytes
NaClO4
mmol
10
(%)b
2
(%)b
62
74
69
30
72
76
82
40
48
36
28
2
LiClO4
10
13
6
3
p-TsON(Et)4
KI
5
4
10
44
0
5
KBr
10
6
NaOAc
10
5
7
NaOAc
20
0
8
NaCN
10
10
32
12
36
9
NaOH
10
10
11
NaOMe
10
NaOMe + KI
5 + 5
aSubstrate 1: 10 mmol, MeOH: 40 mL, Current passed: 2.1 F mol-1, Constant current:
0.3 A, rt: ca 15 ˚C, Anode: Pt, Cathode: Ni. b Determinedby GC analysis.
Based on the above observations, electrooxidations were subsequently carried out using various
benzylideneaminothiophenols (1a-1k) to form the corresponding 2-arylbenzothiazols (2a-2k). For each
electrooxidation, the composition of the anolyte was monitored using GC or TLC – when the
substrate was deemed as almost completely consumed, the DC power supply was switched off.

38
HETEROCYCLES, Vol. 75, No. 1, 2008
Table 2 Electrochemical cyclization of benzylideneaminothiophenolsa
SH
N
S
N
oxidation
CH
C
Ar
Ar
1
2
Current passed
Mp (˚C)
Yield of 2a-2k
Substrate
Ar
Ph
(F mol-1)
2.10
Obs.
Lit.
113 2(a)
(%)c
69
1a
109-111
1b
1c
1d
1e
1f
p-Me-C6H4
o-Me-C6H4
p-MeO-C6H4
2.24
2.24
2.15
2.06
2.23
2.15
2.15
2.24
2.15
2.15
82-83
85 3(b)
70
80
71
68
72
81
63
74
82
83
55-57
53-54 3(b)
119-121 2(a)
117-118 3(b)
81-82 3(b)
229-230 2(a)
127-128 3(b)
107-108 2(d)
129-130 3(h)
-
b
119-120
115-117
80-82
b
p-Cl-C6H4
o-Cl-C6H4
p-NO2-C6H4
o-NO2-C6H4
b
1g
1h
1i
224-226
123-125
105-107
130-132
125-127
b
p-tert-Bu-C6H4
2-pyridyl
1j
1k
3-pyridyl
aSubstrate 1: 10 mmol, NaOAc: 20 mmol, MeOH: 40 mL, rt: ca 15 ˚C, Anode: Pt, Cathode: Ni.
b
c
Mixture of MeOH (25 mL) and acetone (15 mL) was used as the solvent. Isolated yield.
As listed in Table 2, 2-arylbenzothiazols 2a-2k were obtained in moderate to good yields by passing 2.06
to 2.24 F mol-1 of electricity. The nature of the substituents on the phenyl group did not show significant
effects on the yield of the products. Unexpectedly, in the cases of 1d, 1e, 1g, and 1h, the reactions under
the same reaction conditions as 1a did not give satisfactory yields – moreover, during the course of the
electrooxidations, the surface of the anode was gradually covered with a dark-brown tar-like material that
was difficult to dissolve in methanol. Upon further investigations, the yield of the product was
improved by the addition of acetone (methanol, 25 mL and acetone, 15 mL) – for example, in the case of

HETEROCYCLES, Vol. 75, No. 1, 2008
39
1d, the yield of 2d increased from 46% to 71% by modifying the solvent.
Although experiments that illustrate the reaction mechanism have not been carried out, a possible
mechanism (as shown in Scheme 2) can be described as follow: first, substrate 1 would exist in
equilibrium with A,3(e) which can lose one electron from the lone electron pair on the nitrogen atom to the
anode to form cation radical B. The radical would immediately undergo deprotonation and a
one-electron oxidation to give iminum ion C, which would then undergo deprotonation of the nitrogen
atom to produce the desired cyclization product 2. In this scheme, NaOAc would serve as the
appropriate base to facilitate the deprotonation of both cation radical B and iminum ion C. Overall,
substrate 1 would lose two protons and two electrons during the course of the reaction to form 2. It is
interesting to note that the reaction is analogous to the dehydrogenations of benzyl-type amines that were
reported in our previous work. 7
S
SH
CH Ar
CH
N
H
Ar
N
A
1
S
S
- e
- e, - H+
S
N
- H+
CH Ar
C Ar
C Ar
N
H
N
H
B
C
2
Scheme 2
Proposed scheme of the oxidative cyclization
In conclusion, we have been shown a novel method toward the synthesis of various 2-arylbenzothiazoles
via electrooxidation of benzylideneaminothiophenols. Although the yields are moderate to good, our
methodology possess the following benefits: 1) the reaction does not require any oxidants and/or special
reagents, 2) the reaction can be carried out at room temperature, and 3) the substrates are readily available,
4) the reaction involves a simple, one-pot procedure. Further investigations on the preparation of
products having a similar nucleus, such as 2-arylbenzoxazoles and 2-arylbenzimidazoles from the
corresponding Schiff base are currently underway in our laboratories.8
REFERENCES
1. (a) I. H. Hall, N. J. Peaty, J. R. Henry, J. Easmon, G. Heinisch, and G, Pürstinger, Arch. Pharm.
Pharm. Med. Chem., 1999, 332, 115. (b) L. W. Wattenberg, M. A. Page, and J. L. Leong, Cancer

40
HETEROCYCLES, Vol. 75, No. 1, 2008
Res., 1968, 28, 2539. (c) I. Hutchinson, S. A. Jennings, B. R. Vishnuvajjala, A. D. Westwell, and M.
F. G. Stevens, J. Med. Chem., 2002, 45, 744. (d) A. Benazzouz, T. Boraud, P. Dubédat, A. Boireau,
J.-M. Stutzmann, and C. Gross, Eur. J. Pharmacol., 1995, 284, 299. (e) I. Hutchinson, M.-S. Chua,
H. L. Browne, V. Trapani, T. D. Bradshaw, A. D. Westwell, and M. F. G. Stevens, J. Med. Chem.,
2001, 44, 1446. (f) C. A. Mathis, Y. Wang, D. P. Holt, G.-F. Huang, M. L. Debnath, and W. E.
Klunk, J. Med. Chem., 2003, 46, 2740. (g) T. D. Bradshaw, S. Wrigley, D.-F. Shi, R. J. Schultz, K. D.
Paull, and M. F. G. Stevens, Br. J. Cancer, 1998, 77, 745. (h) S. R. Nagarajan, G. A. D. Crescenzo,
D. P. Getman, H.-F. Lu, J. A. Sikorski, J. L. Walker, J. J. McDonald, K. A. Houseman, G. P. Kocan,
N. Kishore, P. P. Mehta, C. L. Funkes-Shippy, and L. Blystone, Bioorg. Med. Chem., 2003, 11, 4769.
(i) T. D. Bradshaw and A. D. Westwell, Curr. Med. Chem., 2004, 11, 1009. (j) P. J. Palmer, R. B.
Trigg, and J. V. Warrington, J. Med. Chem., 1971, 14, 248.
2. (a) S. Paul, M. Gupta, and R. Gupta, Synth. Commun., 2002, 32, 3541. (b) M. Takahashi and M.
Ohba, Heterocycles, 1995, 41, 455. (c) J. J. Ares, Synth. Commun., 1991, 21, 625. (d) A. Brembilla,
D. Roizard, and P. Lochon, Synth. Commun., 1990, 20, 3379. (e) S. Mourtas, D. Gatos, and K.
Barlos, Tetrahedron Lett., 2001, 42, 2201. (f) R. H. Tale, Org. Lett., 2002, 4, 1641. (g) S. Kamila, H.
Zhang, and E. R. Biehl, Heterocycles, 2005, 65, 2119. (h) A. K. Chakraborti, C. Selvam, G. Kaur,
and S. Bhagat, Synlett, 2004, 851. (i) A. Osuka, Y. Uno, H. Horiuchi, and H. Suzuki, Synthesis, 1984,
145. (j) A. K. Chakraborti, S. Rudrawar, G. Kaur, and L. Sharma, Synlett, 2004, 1533. (k) X.-J. Mu,
J.-P. Zou, R.-S. Zeng, and J.-C. Wu, Tetrahedron Lett., 2005, 46, 4345. (l) C. Benedí, F. Bravo, P.
Uriz, E. Fernández, C. Claver, and S. Castillón, Tetrahedron Lett., 2003, 44, 6073. (m) V. J. Majo, J.
Prabhakaran, J. J. Mann, and J. S. D. Kumar, Tetrahedron Lett., 2003, 44, 8535. (n) W. H. Zhong, Y.
M. Zhang, and X. Y. Chen, J. Indian Chem. Soc., 2001, 78, 316. (o) G. Posini and A. Medici,
Synthesis, 1977, 892. (p) B. George and E. P. Papadopoulos, J. Org. Chem., 1977, 42, 441. (q) Y.-H.
So and R. DeCaire, Synth. Commun., 1998, 28, 4123.
3. (a) F. M. Moghaddam, G. R. Bardajee, H. Ismaili, and S. M. D. Taimoory, Synth. Commun., 2006,
36, 2543. (b) M. Kodomari, Y. Tamaru, and T. Aoyama, Synth. Commun., 2004, 34, 3029. (c) T.
Itoh, K. Nagata, H. Ishikawa, and A. Ohsawa, Heterocycles, 2004, 63, 2769; (d) T. Itoh, K. Nagata,
H. Ishikawa, and A. Ohsawa, Heterocycles, 2004, 62, 197. (e) F. M. Moghaddam, H. Ismaili, and G.
R. Bardajee, Heteroatom Chem., 2006, 17, 136. (f) R. S. Kenny and U. C. Mashelkar, J. Heterocycl.
Chem., 2006, 43, 1367. (g) M. A. Chari, D. Shobha, and K. Syamasundar, J. Indian Chem. Soc.,
2006, 83, 291. (h) S. V. Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, and A. A. Tolmachev,
Synthesis, 2006, 3715. (i) A. Ben-Alloum, S. Bakkas, and M. Soufiaoui, Tetrahedron Lett., 1997, 38,

HETEROCYCLES, Vol. 75, No. 1, 2008
41
6395. (j) Y. Kawashita, C. Ueda, and M. Hayashi, Tetrahedron Lett., 2006, 47, 4231. (k) B. C. Ranu,
R. Jana, and S. S. Dey, Chem. Lett., 2004, 33, 274.
4. (a) T. Chiba, M. Okimoto, H. Nagai, and Y. Takata, J. Org. Chem., 1979, 44, 3519. (b) M. Okimoto
and T. Chiba, J. Org. Chem., 1990, 55, 1070. (c) T. Chiba and M. Okimoto, J. Org. Chem., 1992, 57,
1375. (d) M. Okimoto and T. Chiba, J. Org. Chem., 1993, 58, 6194. (e) M. Okimoto and Y.
Takahashi, Synthesis, 2002, 2215. (f) M. Okimoto and Y. Takahashi, Bull. Chem. Soc. Jpn., 2003,
76, 427. (g) M. Okimoto, T. Yoshida, M. Hoshi, K. Hattori, M. Komata, K. Numata, and K.
Tomozawa, Heterocycles, 2006, 68, 2563. (h) M. Okimoto, T. Yoshida, M. Hoshi, K. Hattori, M.
Komata, K. Numata, and K. Tomozawa, Synlett, 2005, 2507.
5. (a) J. B. Sperry and D. L. Wright, J. Am. Chem. Soc., 2005, 127, 8034. (b) D. Nematollahi and E.
Tammari, J. Org. Chem., 2005, 70, 7769. (c) K. M. Dawood and T. Fuchigami, J. Org. Chem., 2005,
70, 7537. (d) D. Xu, A. Chiaroni, M.-B. Fleury, and M. Largeron, J. Org. Chem., 2006, 71, 6374.
6. (a) M. Okimoto and Y. Takahashi, Curr. Org. Synth., 2004, 1, 233. (b) S. Torii, ‘Electroogranic
Synthesis,’ Kodansha, Inc., Tokyo, 1985.
7. M. Okimoto, Y. Takahashi, K. Numata, and G. Sasaki, Heterocycles, 2005, 65, 371.
8. (a) M. Yoshifuji, R. Nagase, T. Kawashima, and N. Inamoto, Heterocycles, 1978, 10, 57. (b) J.-Z.
Zhang, Q. Zhu, and X. Huang, Synth. Commun., 2002, 32, 2175. (c) M. Kidwai, V. Bansal, A.
Saxena, S. Aerry, and S. Mozumdar, Tetrahedron Lett., 2006, 47, 8049.
General procedures: Benzylideneaminothiophenols were prepared via typical condensation of
aminothiophenol and the corresponding aromatic aldehydes in ethanol at room temperature.
Melting points of the products were in good agreement with those of the authentic samples. New
compound (product 2k) was characterized by IR, mass, and NMR spectroscopy. Preparative-scale
electrooxidations were carried out in a tall 50-mL beaker equipped with a fine frit cup (porosity, ca.
100 µm) as the cathode compartment with a nickel coil (diameter, 0.8 mm; length, 250 mm) as the
cathode, and an insert cylindrical platinum net (diameter, 32 mm; height, 35 mm; 55 mesh) as the
anode. Electrooxidations of the substrates were carried out as follow: a solution of the substrate
(1a-1k, 10 mmol) and NaOAc (1.64 g, 20 mmol) in MeOH (40 mL) or MeOH/acetone (25 mL / 15
mL) was electrooxidized under a constant current (0.3 A).
During the course of the
electrooxidation, the anolyte was magnetically stirred while the temperature of the cell was
maintained between 15 and 20 °C. Upon passage of electricity, if the anode was covered with
product, it was washed with CHCl3. The reaction mixture was concentrated in vacuo at
approximately 50 °C to remove most of the solvent. Subsequently, the residue was treated with

42
HETEROCYCLES, Vol. 75, No. 1, 2008
water (ca. 40 mL), and the resulting solid material was extracted using Et2O or CHCl3 (3 x 60 mL),
which were combined, and dried over magnesium sulfate. After the removal of the solvent, the
residue was purified by silica gel column chromatography (diameter, 30 mm; length, 600 mm) using
CHCl3 or a mixture of EtOAc and hexane (1 : 9) as the elution solvent.