Mild and convenient synthesis of benzodithiazoles by oxidative cyclization of bis(thiobenzanilides)

Article abstract of DOI:10.1055/s-0032-1317510

Benzodithiazoles were prepared by oxidative cyclization of bis(thiobenzanilides). The reactions were performed at room temperature under mild conditions and rely on the use of N-benzyl-DABCO tribromide. Copyright

Full text of DOI:10.1055/s-0032-1317510

LETTER
▌2811
lMetteirld and Convenient Synthesis of Benzodithiazoles by Oxidative Cyclization
of Bis(thiobenzanilides)
Synthesis of Benzodithiazoles
Zahid Hassan,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received: 23.08.2012; Accepted: 28.09.2012
Benzothiazoles have been prepared by condensation of 2-
Abstract: Benzodithiazoles were prepared by oxidative cyclization
aminothiophenols with substituted nitriles, aldehydes,
of bis(thiobenzanilides). The reactions were performed at room
carboxylic acids, acid chlorides, or esters.8 Intramolecular
temperature under mild conditions and rely on the use of N-benzyl-
cyclizations of N-(2-halophenyl)benzothioamides have
also been reported for the synthesis of benzothiazoles.
Hugerschoff found that aminobenzothiazoles can be syn-
thesized from arylthioureas by reaction with liquid bro-
mine in chloroform.9 Despite good yields and low
reaction times, several drawbacks are associated with the
use of liquid bromine, which is a highly toxic, corrosive
reagent.
DABCO tribromide.
Key words: benzodithiazoles, thioamides, organic ammonium tri-
bromides, cyclization, C–S bond formation
Benzothiazoles are of considerable importance as phar-
maceuticals and functionalized materials.1,2 Benzothia-
zoles have been reported to act as adrenergic receptor
agonists, neuroprotective agents, antineoplastic agents,
and electron-transporting materials. Benzothiazole moi-
eties are also found in a variety of biologically important
natural products.3 They are used as active drugs for sever-
al diseases such as tumors, diabetes, Parkinson’s disease,
tuberculosis, inflammatory diseases, epilepsy, viral infec-
tions, insomnia, and atherosclerosis.4 They have also been
reported as inhibitors of several enzymes and as antioxi-
dants.5 Benzothiazoles 1 and 2 act as metabotropic gluta-
mate receptor-5 (mGluR5) antagonists (Figure 1).6
Benzothiazoles and benzodithiazoles are also important in
the field of material sciences. For example, diarylbenzo-
dithiazole 3 represents a dye used in photon fluorescence
microscopy and exhibits an excellent lysosomal selectivity.7
Benzothiazole derivatives can be synthesized by oxida-
tive cyclization using organic ammonium tribromides
(OATB).10 These reagents, which include benzyltrimethyl
ammonium tribromide, tetrabutylammonium tribromide,
and N-benzyl-DABCO tribromide, are more easy and safe
to use than bromine. For example, benzyltrimethyl ammo-
nium tribromide has been successfully used for the con-
version of substituted aryl thioureas into the
corresponding 2-aminobenzothiazoles.11 Herein, we re-
port what is, to the best of our knowledge, a new synthesis
of benzodithiazoles based on the OATB-mediated two-
fold cyclization of bis(thiobenzanilides).
O
O
i
H3C
R
N
H
N
H
R
S
N
H2N
NH2
S
N
6a–f
ii
4
N
N+
H3C
R
R
–
Br3
Ph
2
1
OATB
iii
fluorene-based fluorophores
for bioimaging
highest affinity for mGluR5
S
S
S
N
S
N
R
R
R
N
H
N
H
R
7a–f
O
8a–f
P
OEt
OEt
N
S
S
N
Scheme 1 Synthesis of 8a–f. Reagents and conditions: (i) 4 (1.0
equiv), ArCOCl 5a–f (2.0 equiv), Et3N (4.0 equiv), CH2Cl2, 0–20 °C,
10–12 h; (ii) 6a–f (1.0 equiv), Lawesson’s reagent (0.5 equiv), tolu-
ene, reflux at 140 °C, 1–2 h; (iii) 7a–f (1.0 equiv), OATB (1.0 equiv
per cyclization), CH2Cl2–CCl4 (1:1, 10 ml), 1–2 h.
EtO
EtO
P
O
3
benzobisthiazolylfluorene precursor
Figure 1 Important thiazoles and benzodithiazoles
Benzanilides 6a–f were synthesized from diaminoben-
zene (4) and aroyl chlorides 5a–f according to a known
procedure.12 The products were subsequently transformed
to thioamides 7a–f by reaction with Lawesson’s reagent
(LR, Scheme 1).13,14–17 The reaction of thiobenzanilides
7a–f with N-benzyl-DABCO-tribromide, prepared by a
SYNLETT 2012, 23, 2811–2813
Advanced online publication: 07.11.2012
DOI: 10.1055/s-0032-1317510; Art ID: ST-2012-D0708-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2812
Z. Hassan, P. Langer
LETTER
known procedure,12 afforded benzodithiazoles 8a–f in
good yields (Table 1).18,19 The best yields were obtained
when the reactions were carried out in a mixture of dichlo-
romethane and carbon tetrachloride (1:1). It is important
to note that the cyclizations proceeded with very good re-
gioselectivity via the carbon located para to the second
amino group.
Copeland, L. F.; Vartanian, M. G.; Boxer, P. A. J. Pharm.
Sci. 1994, 83, 1425. (e) Paget, C. J.; Kisner, K.; Stone, R. L.;
Delong, D. C. J. Med. Chem. 1969, 12, 1016. (f) Bergman,
J. M.; Coleman, P. J.; Cox, C.; Hartman, G. D.; Lindsley, C.;
Mercer, S. P.; Roecker, A. J.; Whitman, D. B. WO
2006127550, 2006. (g) Yoshino, K.; Kohno, T.; Uno, T.;
Morita, T.; Tsukamoto, G. J. Med. Chem. 1986, 29, 820.
(5) (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. (b) Sato, G.; Chimoto,
T.; Aoki, T.; Hosokawa, S.; Sumigama, S.; Tsukidate, K.;
Sagami, F. J. Toxicol. Sci. 1999, 24, 165.
Table 1 Synthesis of 8a–f
Entry
7, 8
R
Yield of 7 (%)a Yield of 8 (%)a
(6) Kulkarni, S. S.; Newman, A. H. Bioorg. Med. Chem. Lett.
2007, 17, 2987.
(7) Sheng, Y.; Hyo, Y. A.; Xuhua, W.; Jie, F.; Van Stryland, E.
W.; Hagan, D. J.; Belfield, K. D. J. Org. Chem. 2010, 75,
3965.
(8) (a) Alloum, A. B.; Bakkas, S.; Soufiaoui, M. Tetrahedron
Lett. 1997, 38, 6395. (b) Seijas, J. A.; Vazquez, M. P. T.;
Reboredo, M. R.; Campo, J. C.; Lopez, L. R. Synlett 2007,
313.
(9) (a) Hungerschoff, H. Ber. Dtsch. Chem. Ges. 1901, 34,
3130. (b) Hungerschoff, H. Ber. Dtsch. Chem. Ges. 1903,
36, 3121.
(10) Moghaddam, F. M.; Boeini, H. Z. Synlett 2005, 1612.
(11) Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org. Chem. 2003, 68,
8693.
(12) (a) Pierron, P. Ann. Chim. Phys. 1908, 15, 269.
(b) Hutchison, K. A.; Sraganov, G.; Hicks, R.; Yudl, H.;
Strassner, T.; Nendel, M.; Houk, K. N. J. Am. Chem. Soc.
1998, 120, 2989.
1
2
3
4
5
6
a
b
c
d
e
f
Ph
90
85
87
82
80
84
70
75
67
72
60
67
4-MeC6H4
4-ClC6H4
4-FC6H4
4-Et
4-t-Bu
a Yields of isolated compounds.
In conclusion, we have reported a convenient and mild
method for the synthesis of benzodithiazoles. Both aryl-
and alkyl-substituted derivatives were successfully pre-
pared. Regarding the arylated derivatives, both electron-
rich and electron-poor derivatives could be successfully
employed. The reactions proceeded with excellent regio-
selectivity.
(13) Dongho, C.; Jiyoung, A.; Kathlia, A. C.; Hyunseok, A.;
Hakjune, R. Tetrahedron 2010, 66, 5583.
(14) General Procedure A for the Synthesis of 6a–f
To a cold suspension of 1,3-benzenediamine 4 (1.0 equiv,
18.5 mmol) and Et3N (5.1 mL, 37 mmol, 2.0 equiv) in dry
CH2Cl2 (50 mL), a CH2Cl2 solution (10 mL) of benzoyl
chloride 5a–g (2.0 equiv) was added dropwise. The reaction
mixture was stirred at 20 °C for 12 h and subsequently
poured into 100 mL of H2O. The organic layer was
separated, washed with an aq solution of NaHCO3 and with
H2O (30 mL), and dried by Mg2SO4. The solution was
filtered and concentrated under reduced pressure.
(15) N,N′-(1,3-Phenylene)bis(4-methylbenzamide) (6a)
Starting with 4 (2.00 g, 18.5 mmol, 1.0 equiv), Et3N (5.1 mL,
37 mmol, 2.0 equiv), 4-methylbenzoyl chloride (4.8 mg, 37
mmol, 2.0 equiv), CH2Cl2 (25 mL), following General
Procedure A, 6a was isolated (3.5 g, 55%); mp 257–259 °C.
1H NMR (300 MHz, DMSO-d6): δ = 3.37 (s, 6 H, CH3),
7.29–7.37 (m, 5 H), 7.51 (dd, J = 7.9, 1.8 Hz, 2 H), 7.92 (d,
J = 8.2 Hz, 4 H), 8.34 (t, J = 3.2 Hz, 1 H), 10.2 (s, 2 H, NH).
13C NMR (75.5 MHz, DMSO-d6): δ = 20.7 (2-CH3), 112.9,
115.9, 127.7, 128.4, 128.8 (CH), 132.0, 139.3, 141.5 (C),
165.3 (CO). GC–MS (EI, 70 eV): m/z (%) = 344 (67) [M+],
119 (99), 91 (44), 65 (13). HRMS (EI, 70 eV): m/z calcd for
C22H20N2O2 [M]+: 344.1519; found: 344.1522.
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern is gra-
tefully acknowledged.
References and Notes
(1) (a) Pena, P.; Perez, D.; Guitián, E.; Castedo, L. J. Org.
Chem. 2000, 65, 6944. (b) Damani, A. Sulfur-containing
Drugs and Related Organic Compounds – Chemistry,
Biochemistry, and Toxicology; Ellis Harwood: Chichester,
1989. (c) Cremlyn, R. J. An Introduction to Organosulfur
Chemistry; John Wiley: New York, 1996. (d) Polshettiwar,
V.; Kaushik, M. P. J. Sulfur Chem. 2006, 27, 353.
(2) For selected reviews on the synthesis of benzothiazole ring
systems, see: (a) Yadav, P. S.; Devprakash Senthilkumar, G.
P. Int. J. Pharm. Sci. Drug Res. 2011, 3, 1. (b) Weekes, A.
A.; Westwell, A. D. Curr. Med. Chem. 2009, 16, 2430.
(c) Gupta, A.; Rawat, S. J. Curr. Pharm. Res. 2010, 3, 13.
(3) (a) Bradshaw, T. D.; Westwell, A. D. Curr. Med. Chem.
2004, 11, 1241. (b) Su, X.; Vicker, N.; Ganeshapillai, D.;
Smith, A.; Purohit, A.; Reed, M. J.; Potter, B. V. L. Mol.
Cell. Endocrinol. 2006, 248, 214.
(4) (a) Chakraborti, A. K.; Rudrawar, S.; Kaur, G.; Sharma, L.
Synlett 2004, 1533. (b) Shirke, V. G.; Bobade, A. S.;
Bhamaria, R. P.; Khadse, B. G.; Sengupta, S. R. Indian
Drugs 1990, 27, 350. (c) 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. J. Bioorg. Med.
Chem. Lett. 2003, 13, 2587. (d) Hays, S. J.; Rice, M. J.;
Ortwine, D. F.; Johnson, G.; Schwarz, R. D.; Boyd, D. K.;
(16) General Procedure B for the Synthesis of 7a–f
The amide starting material (0.5 mmol) and Lawesson’s
reagent (0.5 mmol) were refluxed in toluene (30 mL) for 1 h.
Upon cooling, the solvent was evaporated using a rotary
evaporator. The crude mixture was purified by column
chromatography (silica gel, CH2Cl2–hexane = 1:1) to obtain
the deep yellow colored compounds 7a–f in high yields (76–
82%).
(17) N,N′-(1,3-Phenylene)bis(4-methylbenzothioamide) (7a)
Starting with 6a (1.00 g, 1.0 equiv), Lawesson’s reagent
(0.80 g, 1.0 equiv), toluene (25 mL), following General
Synlett 2012, 23, 2811–2813
© Georg Thieme Verlag Stuttgart · New York

LETTER
Procedure B, 7a was isolated (1.34 g, 92%). 1H NMR (300
Synthesis of Benzodithiazoles
2813
column chromatography (CH2Cl2–hexane, 1:1) to obtain
products 8a–f.
(19) 1,4-Bis[4-methylphenyl]benzo[1,2-d:4,5-d]bisdithiazole
(8a)
MHz, DMSO-d6): δ = 2.39 (s, 6 H, CH3), 7.29 (d, J = 8.1 Hz,
4 H), 7.49 (t, 3 H), 7.69 (d, J = 7.6 Hz, 4 H), 8.35 (s, 1 H),
11.74 (s, 2 H, NH). 13C NMR (75.5 MHz, DMSO-d6): δ =
20.8 (2-CH3), 120.1, 122.2, 127.5, 128.3, 128.5 (CH), 139.4,
140.1, 140.9 (C), 197.4 (CS). GC–MS (EI, 70 eV): m/z (%)
= 377 (76) [M+], 343 (67), 240 (43), 226 (93), 135 (70);
HRMS (EI, 70 eV): m/z calcd for C22H20N2S2 [M]+:
377.1140; found: 377.1138.
Starting with 7a (200 mg, 1.0 equiv), N-benzyl-DABCO
tribromide (450 mg, 2.0 equiv), CH2Cl2–CCl4 (1:1, 10 mL),
following General Procedure C, 8a was isolated as a yellow
solid (138 mg, 70%); mp 221–223 °C. 1H NMR (300 MHz,
DMSO-d6): δ = 2.38 (s, 6 H, CH3), 7.31 (d, J = 8.1 Hz, 4 H),
7.98 (d, J = 8.4 Hz, 5 H), 8.03 (s, 1 H). 13C NMR (75.5 MHz,
DMSO-d6): δ = 26.3 (CH3), 124.8, 125.1, 132.2, 134.8 (CH),
135.3, 141.4, 146.6, 158.6, 172.2 (C). GC–MS (EI, 70 eV):
m/z (%) = 372 (100) [M+], 186 (16), 138 (43). HRMS (EI, 70
eV): m/z calcd for C22H16N2S2 [M]+: 372.0749; found:
372.0751.
(18) General Procedure C for the Oxidative Cyclization of
Thiobenzanilides
To a stirred solution of thiobenzanilide 7a–f (1.0 equiv) in
CH2Cl2–CCl4 (1:1, 10 mL), N-benzyl-DABCO tribromide
(2.0 equiv) was added. The reaction mixture was stirred for
30–90 min at 20 °C (TLC control). The solvent was removed
under reduced pressure, and the residue was subjected to
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2811–2813

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