Novel copper-catalyzed rearrangement of 2-aminobenzothiazoles to phenothiazines
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NOVEL COPPER-CATALYZED REARRANGEMENT OF 2-AMINOBENZOTHIAZOLES TO PHENOTHIAZINES T. Beresneva1 and E. Abele1* 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 / K2CO3 / L-proline / methoxymethyl ester [11] and 2-aminomercaptanes / 1,2-dibromobenzene / CuI / K2CO3 / DMSO [12] have been developed. However, synthesis of phenothiazines by Cu-catalyzed rearrangement of 2-aminobenzothiazoles in the presence of 1,2-dibromobenzene is described for the first time.
Br
R
1
R
N NH2
S
R
1–6
2
Y
R
X
Y
7a–c CuI, Cs2CO3, Phen DMSO, 170°C
R
1
1
R
CuI Br
NH
B
Br NH
A
S
2
Y R
Cs2CO3
N
R R
2
S
Cs+
R
1
H N
Y
R
2
S
N
+ R
S 8–10,12–16
N H 11 (from 1+7c)
_______ *To whom correspondence should be addressed, e-mail: [email protected]. 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. 1420
0009-3122/12/4809-1420©2012 Springer Science+Business Media New York
TABLE 1. Synthesis of Phenothiazines 8-16 from 2-Aminobenzothiazoles 1–6 and o-Dihaloarenes 7a–c Starting aminothiazole
R
R1
Dihalide
R2
X
Y
Products
Reaction time, h
1 1 1
H H H
H H H
7a 7b 7c
H Me H
Br I Br
CH CH N
8 9 10 + 11
24 24 24
2 3 4 5 6
Cl H Me OMe OEt
H Br Me H H
7a 7a 7a 7a 7a
H H H H H
Br Br Br Br Br
CH CH CH CH CH
12 13 14 15 16
24 24 24 34 24
Yield, % 57 50 39 (10), traces (11) 42 15 73 45 38
Synthesis of phenothiazine derivatives 8-16 was carried out starting from the corresponding 2-aminobenzothiazoles 1-6 by one-pot cascade type reaction in the system 1,2-dihalobenzenes 7a,b or 2,3-dibromopyridine (7c) / Cs2CO3 / CuI / 1,10-phenanthroline (Phen, ligand) / DMSO at 170°C (Table 1). The proposed mechanism for the formation of phenothiazines includes N-3 arylation of 2-aminobenzothiazoles 1–6 leading to intermediates A. The ring opening of benzothiazoline imine A in the presence of Cs2CO3 afforded the cesium salt of thiol B. Similar transformation of 2-imino-3-phenylbenzothiazoline to 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
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