Novel copper-catalyzed rearrangement of 2-aminobenzothiazoles to phenothiazines

Full text of DOI:10.1007/s10593-012-1154-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
NOVEL COPPER-CATALYZED REARRANGEMENT OF
2-AMINOBENZOTHIAZOLES TO PHENOTHIAZINES
1
1
T. Beresneva and E. Abele *
Keywords: 2-aminobenzothiazoles, 2,3-dibromopyridine, 1,2-dihalobenzenes, phenothiazines, copper
catalysis.
Phenothiazines and related compounds are of great interest as biologically active compounds [1-4].
Historically, the first phenothiazines were prepared by interaction of diphenylamine hydrochloride with sodium
thiosulfate [5]. These compounds were also prepared from 2-phenylaminobenzoic acids and iodine in the
presence of sulfur [6], diarylamines and iodine / sulfur [7, 8], 2-azidodiaryl sulfides / decahydronaphthalene / I2 /
pyridine (then Cu / quinoline) [9], and 2-nitrodiaryl sulfides and triethyl phosphite [10]. Recently, two
Cu-catalyzed methods for the synthesis of phenothiazines using the systems 2-amino-2'-bromodiaryl sulfides /
CuI / K CO / L-proline / methoxymethyl ester [11] and 2-aminomercaptanes / 1,2-dibromobenzene / CuI /
2
3
K CO / DMSO [12] have been developed. However, synthesis of phenothiazines by Cu-catalyzed
2
3
rearrangement of 2-aminobenzothiazoles in the presence of 1,2-dibromobenzene is described for the first time.
Br
X
2
R
2
1
R
Y
R
N
S
Y
7
a–c
Cs CO3
2
NH2
1
CuI, Cs CO , Phen
DMSO, 170°C
2
3
R
N
S
Br
NH
R
1
–6
R
A
2
R
H
1
2
Y
R
N
Y
R
S
N
CuI
+
1
R
NH
Br
R
S
N
H
11
8
–10,12–16
Cs+
R
S
(
from 1+7c)
B
_
*
______
To whom correspondence should be addressed, e-mail: abele@osi.lv.
1
Latvian Institute of Organic Synthesis, 21 Аizkraukles St., Riga LV-1006, Latvia.
_
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1521-1524, September, 2012.
Original article submitted May 23, 2012.
420
0009-3122/12/4809-1420©2012 Springer Science+Business Media New York
1

TABLE 1. Synthesis of Phenothiazines 8-16 from 2-Aminobenzothiazoles
1
–6 and o-Dihaloarenes 7a–c
Starting
aminothiazole
Reaction
time, h
1
2
R
R
Dihalide
R
X
Y
Products
Yield, %
1
1
1
H
H
7a
7b
7c
H
Br CH
8
24
24
24
57
H
H
H
H
Me
H
I
CH
N
9
50
Br
10 + 11
39 (10),
traces (11)
2
3
4
5
6
Cl
H
7a
7a
7a
7a
7a
H
H
H
H
H
Br CH
Br CH
Br CH
Br CH
Br CH
12
13
14
15
16
24
24
24
34
24
42
15
73
45
38
H
Br
Me
H
Me
OMe
OEt
H
Synthesis of phenothiazine derivatives 8-16 was carried out starting from the corresponding 2-amino-
benzothiazoles 1-6 by one-pot cascade type reaction in the system 1,2-dihalobenzenes 7a,b or 2,3-dibromo-
pyridine (7c) / Cs CO / CuI / 1,10-phenanthroline (Phen, ligand) / DMSO at 170°C (Table 1).
2 3
The proposed mechanism for the formation of phenothiazines includes N-3 arylation of 2-amino-
benzothiazoles 1–6 leading to intermediates A. The ring opening of benzothiazoline imine A in the presence of
Cs CO afforded the cesium salt of thiol B. Similar transformation of 2-imino-3-phenylbenzothiazoline to
2
3
N-phenyl-o-aminothiophenol in the presence of KOH / EtOH was described in [13]. Intermediate B readily
undergoes Cu-catalyzed cyclization to phenothiazines 8-16.
Reaction of amine 1 with 2,3-dibromopyridine (7c) in the above-mentioned system leads to product 10
in 39% yield. It means that in the first reaction step almost selective substitution of bromine at position 2 of the
pyridine ring leads to the intermediate A which undergo further transformations to product 10. The minor
product of this reaction was identified as pyrido[2,3-b][1,4]benzothiazine (11). Formation of this product was
the result of the reaction of bromide in position 3 of the pyridine ring in the first step of the reaction.
However, sometimes yields of products 8-16 (especially for halogen-containing phenothiazines 12 and
1
3) are not high because of dimerization and polymerization processes at the high temperature (170°C) in the
presence of copper catalyst and Cs CO .
2
3
In summary, a new and simple one-pot method for the preparation of phenothiazines by Cu-catalyzed
rearrangement of 2-aminobenzothiazoles has been developed.
1
13
H and С NMR spectra were registered on a Varian Mercury BB 400 (400 and 100 MHz, respectively)
in CDCl , internal standard hexamethyldisiloxane. Mass spectra were recorded on an Alliance Waters 2695
3
instrument with Full scan POS NEG 16 detector.
Synthesis of Phenothiazines 8-16 (General Method). Solid Cs CO (0.980 g, 3.0 mmol) was added to
2
3
a solution of 2-aminobenzothiazoles 1-6 (1.0 mmol) and 1,2-dihalobenzenes 7a,b or 2,3-dibromopyridine (7c)
1.0 mmol), CuI (0.038 g, 0.2 mmol), and 1,10-phenanthroline (0.040 g, 0.2 mmol) in dry DMSO (8 ml) in a
(
glass reactor (50 ml) under argon. The reaction mixture was stirred at 170°C for 24–34 h (TLC control, see
Table 1) under argon. The solvent was removed under reduced pressure and the crude residue was
chromatographed on silica gel using hexane–EtOAc (5:1, 4:1 or 2:1) mixture as eluents. Spectroscopic and
physical properties of 10H-phenothiazine (8) [14], 2-methyl-10H-phenothiazine (9) [11], 10H-pyrido[3,2-b]-
[
[
1,4]benzothiazine (10) [15], 5H-pyrido[2,3-b][1,4]benzothiazine (11) [16], 3-chloro-10H-phenothiazine (12)
10], 2-bromo-10H-phenothiazine (13) [17], 2,3-dimethyl-10H-phenothiazine (14) [11], 3-methoxy-10H-
phenothiazine (15) [15], and 3-ethoxy-10H-phenothiazine (16) [18] are identical with those described in the
literature.
The authors thank the European Social Fund for financial support (Project No.
2
009/0197/1DP/1.1.1.2.0/09/APIA/VIAA/014).
1
421

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