Synthesis of 2-N-alkyl(aryl)amino-7-nitrobenzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2004.10.117

A highly efficient synthesis of 2-N-alkyl(aryl)amino-7-nitrobenzothiazoles has been developed. The key step involves intramolecular cyclization of a thiourea facilitated by the nitro group. A highly efficient synthesis of 2-N-alkyl(aryl)amino-7-nitrobenzothiazoles has been developed. The key step involves intramolecular cyclization of a thiourea facilitated by the nitro group.

Full text of DOI:10.1016/j.tetlet.2004.10.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9373–9375
Synthesis of 2-N-alkyl(aryl)amino-7-nitrobenzothiazoles
Shenlin Huang* and Peter J. Connolly
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, Raritan, NJ 08869, USA
Received 22 August 2004; revised 20 October 2004; accepted 21 October 2004
Available online 5 November 2004
Abstract—A highly efficient synthesis of 2-N-alkyl(aryl)amino-7-nitrobenzothiazoles has been developed. The key step involves
intramolecular cyclization of a thiourea facilitated by the nitro group.
Ó 2004 Elsevier Ltd. All rights reserved.
In recent years, thousands of examples of the 2-N-
alkyl(aryl)aminobenzothiazole scaffold (1) have been
disclosed in the scientific and patent literature. Many
of these compounds have interesting biological proper-
ties. Accordingly, this bicyclic ring system has become
a popular building block in medicinal chemistry due to
its crucial role in agents having anti-inflammatory,
anti-microbial, anti-tumor, neuroprotective, and other
therapeutically useful activities. For instance, N-substi-
tuted 2-aminobenzothiazoles were reported to be potent
inhibitors of 5-lipoxygenase and thromboxane A2 syn-
thetase.1 In addition, 2-aminobenzothiazole analogues
having anti-bacterial and anti-fungal activities have
been described by several groups.2 Others have reported
the potential neuroprotectant activity of 2-(piper-
azinoalkyl)aminobenzothiazoles having high affinity
for dopaminergic D4 receptors.3 Recently, 2-amino-
benzothiazoles were found to suppress the formation
of insoluble polyglutamine-containing aggregates in
neurons and therefore may represent attractive agents
for the treatment of HuntingtonÕs disease and related
conditions.3 Moreover, 2-aminobenzothiazoles have
been reported to be inhibitors of serine/threonine and
tyrosine kinases such as those associated with fibroblast
growth factor (FGF), vascular endothelial growth factor
(VEGF), and platelet derived growth factor (PDGF)
receptors and hence are particularly important in hyper-
proliferative diseases such as cancer, psoriasis, and rheu-
matoid arthritis.4
Despite this attention, very few publications describing
7-nitro-2-aminobenzothiazoles have appeared and no
efficient methodology has been disclosed for the synthe-
sis of N-alkyl- or N-aryl-7-nitro derivatives (2). Concep-
tually, direct nitration of N-substituted 2-amino-
benzothiazoles (1) would provide 2 but is likely to
generate a mixture of regioisomers that would require
separation. One literature account describes the prepa-
ration of 7-nitro-2-aminobenzothiazole (2, R = H) via
bromine-mediated cyclization of N-(3-nitrophenyl)thio-
urea, but the methodology is not applicable to the
synthesis of analogues where the N-substituent is
susceptible to electrophilic bromination (i.e., methoxy-
phenyl).5 In this communication, a facile and general
method is described for the preparation of 2-N-alkyl-
(aryl)amino-7-nitrobenzothiazoles (2) that is applicable
to a broad variety of substituents on the amine
nitrogen.
Synthesis of the title compounds is shown in Scheme 1.
The starting material is 3-nitro-2-chloroaniline (4),
which can be generated in two steps from commercially
available 2,6-dinitroaniline (3) in 54% yield.6 Reaction
of amino compound 4 with thiophosgene provides isothio-
cyanate 5 (98%). Treatment of isothiocyanate 5 with
an alkyl- or aryl-substituted amine and potassium car-
bonate in isopropyl alcohol generates the corresponding
thiourea 6 that is then cyclized in situ at reflux to pro-
vide the desired product 7.7 Under typical experimental
Keyword: 2-N-alkyl(aryl)amino-7-nitrobenzothiazole.
*
Corresponding author. Tel.: +1 908 707 3422; fax: +1 908 526
6469; e-mail: shuang6@prdus.jnj.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.117

9374
S. Huang, P. J. Connolly / Tetrahedron Letters 45 (2004) 9373–9375
Scheme 1. Synthesis of 2-N-alkyl(aryl)amino-7-nitrobenzothiazoles via cyclization of N-(2-chloro-3-nitrophenyl)thioureas.
conditions, 1.0equiv of 2-chloro-1-isothiocyanato-3-nitro-
benzene (5) was dissolved in isopropanol, followed by
the addition of 2.0equiv of potassium carbonate and
1.0equiv of the desired amine. The mixture was refluxed
until the cyclization was complete, then filtered. The fil-
trate was concentrated and the residue was purified by
flash chromatography. Using this methodology, numer-
ous 2-amino-7-nitrobenzothiazoles (7) were synthesized
as shown in Table 1. Yields for the two-step, one-pot
sequence ranged from 61 to 98%. When aliphatic amines
were used, the conversion of intermediate 5 to products
7 was fast and proceeded in high yields. When aromatic
amines such as aniline or electron-rich 3,4,5-trimethoxy-
aniline were used, similar results were achieved. How-
ever, electron deficient aromatic amines required
longer reaction times and resulted in comparatively
lower yields.8
Acknowledgements
The authors thank Dr. Ignatius Turchi of J & JPRD for
suggesting the benzothiazole scaffold and for many help-
ful discussions during the course of this work.
References andnotes
1. (a) Lazer, E. S.; Adams, J.; Miao, C. K.; Farina, P. Eur.
Pat. Appl. EP 535 521, 1993; (b) Okamoto, Y.; Tagami, K.;
Hibi, S.; Numata, H.; Kobayashi, N.; Shinoda, M.;
Kawahara, T.; Murakami, M.; Oketani, K. Eur. Pat. Appl.
EP 507 318, 1992; (c) Tsubuki, T.; Nomura, M.; Sawada,
T.; Kono, Y.; Sakoe, Y. Jpn. Kokai Tokkyo Koho, JP
20000086641, 2000; (d) Nishimura, H.; Sakurai, S.; Tsu-
ruki, T.; Yamagishi, Y.; Ichino, T.; Komatsu, T.; Minami,
N.; Okamato, Y.; Numata, H.; Abe, S. Jpn. Kokai Tokkyo
Koho, JP 07089948, 1995; (e) Hibi, S.; Okamoto, Y.;
Tagami, K.; Numata, H.; Kobayashi, N.; Shinoda, M.;
Kawahara, T.; Murakami, M.; Oketani, K. J. Med. Chem.
1994, 37, 3062–3070; (f) Sakai, H.; Suzuki, T.; Murota, M.;
Oketani, K.; Uchiumi, T.; Murakami, M.; Takeguchi, N.
Br. J. Pharmacol. 2002, 136, 383–390.
2. (a) Pandeya, S.; Naik, P. J. Indian Chem. Soc. 1996, 73,
363–365; (b) Naik, P. R.; Pandeya, S. N.; Pandey, A. Acta
Pharm. 1996, 38, 37–42; (c) Paget, C. J.; Kishner, K.; Stone,
R. L.; Delong, D. C. J. Med. Chem. 1969, 12, 1016–1018;
(d) Delmas, F.; Di Giorgio, C.; Robin, M.; Azas, N.;
Gasquet, M.; Detang, C.; Costa, M.; Timon-David, P.;
Galy, J. P. Antimicrob. Agents Chemother. 2002, 46, 2588–
2594; (e) Ra, C. S.; Jung, B. Y.; Park, G. Heterocycles 2004,
62, 793–802.
In summary, a highly efficient synthesis of 2-N-alkyl-
(aryl)amino-7-nitrobenzothiazoles (7) was developed
that generates the desired compounds in four steps
and in moderate to high yields from commercially avail-
able starting materials. These nitro compounds repre-
sent versatile intermediates that may be useful in the
synthesis of potent inhibitors of many drug targets.
They can be further elaborated by reducing the nitro
groupto an amino groupthat may serve as an attach-
ment point for various pharmacologically interesting
substituents.
Table 1.
3. (a) Flohr, A.; Jakob-Roetne, R.; Norcross, R. D.; Riemer,
C. WO 03053946, 2003; (b) Dargazanli, G.; George, P.;
Lardenois, P.; Frost, J.; Schoemaker, J.; Renones, M. C.;
Magat, P. WO 9814444, 1998; (c) Kennis, L.; Edmond, J.;
Mertense, J. C.; Pieters, S. M. A. WO 9743271, 1997; (d)
Heiser, V.; Engemann, S.; Brocker, W.; Dunkel, I.; Boedd-
rich, A.; Waelter, S.; Nordhoff, E.; Lurz, R.; Schugardt, N.;
Rautenberg, S.; Herhaus, C.; Barnickel, G.; Bottcher,
Henning; Lehrach, H.; Wanker, E. E. Proc. Natl. Acad.
Sci. U. S. A. 2002, 99(Suppl. 4), 16400–16406; (e) Boettcher,
H.; Herhaus, C.; Barnickel, G.; Wanker, E. E.; Heiser, V.;
Lehrch, H.; Broeker, W.; Dunkel, I. WO 03015772, 2003;
(f) Alanine, A.; Flohr, A.; Miller, A. K.; Norcross, R. D.;
Riemer, C. WO 01097786, 2001.
Entry
R
Product Yield Reaction
(%)a
time (h)
1
2
3
4
5
6
7
8
9
10
Methyl
n-Butyl
7a
7b
7c
7d
7e
7f
98
94
61
96
94
96
98
92
81
62
3
3
Pyridin-2-yl
Phenyl
5
3
2,6-Dimethylphenyl
Cyclopentyl
Cyclohexyl
3
3
7g
7h
7i
3
3,4,5-Trimethoxyphenyl
4-Chlorophenyl
3
12
12
4-Chloro-2-fluorophenyl 7j
a Isolated yields from compound 5, after purification by flash
chromatography.
4. (a) Cusack, K. P.; Scott, B.; Arnold, L. D.; Ericsson, A.
WO 2001057008, 2001; (b) Renhowe, P. A.; Ramurthy, S.;

S. Huang, P. J. Connolly / Tetrahedron Letters 45 (2004) 9373–9375
9375
Amiri, P.; Levine, B. H.; Poon, D. J.; Subramanian, S.;
Sung, L.; Fantl, W. WO 2003082272, 2003; (c) Bonjouklian,
R.; James, H. WO 2004014900, 2004.
122.60, 119.35, 117.28; FTIR (neat, cmÀ1): 2300, 1550,
1310; MS (ES) m/z: 272.2 (M+H+).
2-(N-2,6-Dimethylphenyl)amino-7-nitrobenzothiazole (7e):
1H NMR (400MHz, DMSO): d 10.0 (s, 1H), 8.03 (d,
J = 8.3Hz, 1H), 7.84 (d,J = 7.9Hz, 1H), 7.55 (t, J = 8.1Hz,
1H), 7.23 (s, 3H), 2.27 (s, 6H); 13C NMR (100MHz,
DMSO): d 155.06, 141.61, 136.72, 135.86, 128.50, 127.59,
126.41, 124.35, 116.90, 17.86; FTIR (neat, cmÀ1): 3490,
1600, 1250; MS (ES) m/z: 300.0 (M+H+).
5. VelÕtman, R. P. Uk. Khim. Zh. 1956, 22, 363–367; VelÕtman,
R. P. Chem. Abstr. 1957, 51, 4358.
6. (a) Sienkowska, M.; Benin, V.; Kaszynski, P. Tetrahedron
2000, 56, 165–173; (b) Rodygin, M. Y.; Mikhailov, V. A.;
Savelova, V. A.; Chernovol, P. A. J. Org. Chem. U.S.S.R.
(Engl. Transl.) 1992, 28, 1543–1544, In this reference the
corresponding 2-bromo-3-nitroaniline was prepared via
direct bromination of 3-nitroaniline using bis(dimethyl-
acetamide) hydrogen dibromobromate. However, signifi-
cant dibromination was reported under the reaction
conditions.
1
2-(N-Cyclopentyl)amino-7-nitrobenzothiazole (7f): H NMR
(400MHz, CDCl3): d 7.97 (d, J = 8.2Hz, 1H), 7.72 (d,
J = 7.9Hz, 1H), 7.39 (t, J = 8.1Hz, 1H), 7.18 (s, 1H), 4.14
(m, 1H), 2.14 (m, 2H), 1.66 (m, 6H); 13C NMR (100MHz,
CDCl3): d 170.25, 154.81, 141.98, 126.66, 125.95, 123.73,
116.81, 57.32, 33.13, 23.07; FTIR (neat, cmÀ1): 3480, 1620,
1240; MS (ES) m/z: 264.1 (M+H+).
7. (a) Sipido, V. EP 21806, 1981; (b) Sipido, V. EP 21807,
1981.
1
8. Spectroscopic data for compounds in Table 1: 2-(N-Methyl)-
amino-7-nitrobenzothiazole (7a): 1H NMR (300MHz,
CDCl3): d 8.07 (d, J = 8.2Hz, 1H), 7.82 (d, J = 7.8Hz,
1H), 7.44 (t, J = 8.1Hz, 1H), 5.4 (br s, 1H), 3.19 (d,
J = 3.6Hz, 3H); 13C NMR (100MHz, THF): d 168.28,
154.59, 140.71, 125,58, 124.07, 122.29, 114.65, 28.59; FTIR
(neat, cmÀ1): 2890, 1650, 1500; MS (ES) m/z: 210.2
(M+H+).
2-(N-Cyclohexyl)amino-7-nitrobenzothiazole (7g): H NMR
(400MHz, DMSO): d 8.41 (d, J = 7.4Hz, 1H), 7.95 (d,
J = 8.2Hz, 1H), 7.76 (d, J = 7.8Hz, 1H), 7.46 (t, J = 8.1Hz,
1H), 3.77 (br s, 1H), 2.04 (m, 2H), 1.74 (m, 2H), 1.62 (m,
1H), 1.43-1.18 (m, 5H); 13C NMR (100MHz, CDCl3): d
167.46, 155.28, 141.40, 126.49, 126.03, 123.51, 116.16,
54.83, 32.11, 25.15, 24.30; FTIR (neat, cmÀ1): 3320, 2980,
1520, 1375; MS (ES) m/z: 278.1 (M+H+).
2-(N-n-Butyl)amino-7-nitrobenzothiazole (7b): 1H NMR
(300MHz, CDCl3): d 8.05 (dd, J = 8.2Hz, 0.9Hz, 1H),
7.78 (dd, J = 8.0, 0.9Hz, 1H), 7.78 (t, J = 8.1Hz, 1H), 5.60
(br s, 1H), 3.50 (t, J = 7.1Hz, 2H), 1.72 (p, J = 7.2Hz, 2H),
1.50 (sextet, J = 7.6Hz, 2H), 0.99 (t, J = 7.3Hz, 3H); 13C
NMR (100MHz, THF): d 169.80, 156.78, 142.86, 127.67,
126.14, 124.38, 116.76, 44.85, 32.06, 20.65, 13.82; FTIR
(neat, cmÀ1): 2950, 2850, 2350, 1630, 1480; MS (ES) m/z:
252.1 (M+H+).
2-(N-3,4,5-Trimethoxyphenyl)amino-7-nitrobenzothiazole (7h):
1H NMR (400MHz, DMSO): d 10.73 (s, 1H), 8.08 (d,
J = 8.1Hz, 1H), 7.94 (d, J = 7.8Hz, 1H), 7.57 (t, J = 8.1Hz,
1H), 7.16 (s, 2H), 3.84 (s, 6H), 3.68 (s, 3H); 13C NMR
(100MHz, DMSO): d 164.25, 154.47, 152.97, 141.54,
136.01, 133.17, 126.43, 126.01, 125.17, 117.82, 96.37,
60.10, 55.75; FTIR (neat, cmÀ1): 3450, 1510cmÀ1. MS
(ES) m/z: 362.0 (M+H+).
2-(N-4-Chlorophenyl)amino-7-nitrobenzothiazole (7i): 1H
NMR (400MHz, DMSO): d 10.93 (s, 1H), 8.13 (d,
J = 8.0Hz, 1H), 8.02 (d, J = 7.9Hz, 1H), 7.83 (d,
J = 8.1Hz, 2H), 7.60 (t, J = 7.8Hz, 2H), 7.42 (d, 2H); 13C
NMR (100MHz, DMSO): d 164.04, 154.29, 141.65, 138.84,
128.92, 126.68, 126.22, 126.13, 125.41, 119.67, 118.22;
FTIR (neat, cmÀ1): 3470, 1600; MS (ES) m/z: 306.0
(M+H+).
2-(N-4-Chloro-2-fluorophenyl)amino-7-nitrobenzothiazole (7j):
1H NMR (400MHz, DMSO): d 10.75 (s, 1H), 8.59 (t,
J = 8.8Hz, 1H), 8.14 (d,J = 8.2Hz, 1H), 8.02 (d, J = 7.8Hz,
1H), 7.60 (t, J = 7.8Hz, 2H), 7.54 (d, J = 11.1Hz, 2H), 7.36
(d, J = 8.8Hz, 1H); 13C NMR (100MHz, DMSO): 164.56,
153.74, 150.78, 141.62, 127.00, 126.90, 126.57, 125.63,
124.75, 122.17, 118.41, 116.06, 115.83; FTIR (neat, cmÀ1):
3450, 1610; MS (ES) m/z: 324.0 (M+H+).
2-(N-Pyridin-2-yl)amino-7-nitrobenzothiazole (7c): 1H NMR
(300MHz, DMSO): d 11.9 (s, 1H), 8.47 (d, J = 5.1Hz, 1H),
8.18 (d, J = 8.1Hz, 1H), 8.05 (d, J = 7.9Hz, 1H), 7.83 (t,
J = 7.1Hz, 1H), 7.65 (t, J = 7.0Hz, 1H), 7.21 (d, J = 8.3Hz,
1H), 7.09 (t, J = 5.8Hz, 1H); 13C NMR (100MHz, DMSO):
163.20, 152.20, 151.10, 146.90, 142.37, 138.89, 128.44,
126.62, 125.98, 118.38, 117.75, 118.38, 117.75, 111.78.
FTIR (neat, cmÀ1): 1600, 1520, 1400, 1290; MS (ES) m/z:
273.1 (M+H+).
2-(N-Phenyl)amino-7-nitrobenzothiazole (7d): 1H NMR
(300MHz, DMSO): d 10.8 (s, 1H), 8.04 (d, J = 8.2Hz,
1H), 7.90 (d, J = 7.8Hz, 1H), 7.75 (d, J = 7.8Hz, 2H), 7.53
(t, J = 8.1Hz, 1H), 7.37 (t, J = 7.6Hz, 2H), 7.03 (t,
J = 7.3Hz, 1H); 13C NMR (100MHz, DMSO): d 165.57,
155.66, 142.21, 141.93, 129.29, 126.94, 126.59, 124.42,