Aromatic ring transfer-a new synthesis of 2,4-diaryl-4H-3,1-benzothiazines

Article abstract of DOI:10.1016/j.tetlet.2006.04.010

A new synthetic approach to 2,4-diaryl-4H-3,1-benzothiazines is described based on the rearrangement of 2-isothiocyano triarylmethanes in the presence of AlCl₃. An aryl ring is found to migrate to the carbon atom of an isothiocyano group follow

Full text of DOI:10.1016/j.tetlet.2006.04.010

Tetrahedron Letters 47 (2006) 4029–4032
Aromatic ring transfer—a new synthesis of
2,4-diaryl-4H-3,1-benzothiazines
Vladimir T. Abaev,a Fatima A. Tsiunchik,b Andrey V. Gutnovc and Alexander V. Butinb,*
aNorth-Ossetian State University, Vatutina st. 46, Vladikavkaz 362025, Russia
bResearch Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology, Moskovskaya st. 2,
Krasnodar 350072, Russia
cLeibniz-Institut fu¨r Organische Katalyse, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany
Received 19 January 2006; revised 28 March 2006; accepted 5 April 2006
Abstract—A new synthetic approach to 2,4-diaryl-4H-3,1-benzothiazines is described based on the rearrangement of 2-isothiocyano
triarylmethanes in the presence of AlCl3. An aryl ring is found to migrate to the carbon atom of an isothiocyano group followed by
intramolecular cyclization as a result of electrophilic attack of the benzhydryl carbocation on the sulfur atom.
Ó 2006 Elsevier Ltd. All rights reserved.
4H-3,1-Benzothiazine derivatives with aromatic substit-
uents in positions 2 and (or) 4 exhibit many kinds of bio-
logical activity1 and are of interest for the production of
recording materials and photographic and laser tech-
niques.2 Moreover, they are valuable building blocks
and can be used, in particular, for the synthesis of indole
derivatives.3
method for the synthesis of 2-aryl(heteroaryl)-4H-
3,1-benzothiazine-4-ones is based on the acid-catalyzed
aroylation of aromatic (heteroaromatic) substrates with
2-isothiocyano benzoates followed by intramolecular
cyclization of the intermediate thioamides.8
We have discovered a new approach to the synthesis of
2,4-diaryl-4H-3,1-benzothiazines based on a rearrange-
ment of 2-isothiocyano triarylmethanes in the presence
of AlCl3. 2-Aminotriarylmethanes 4 were used as start-
ing materials for the synthesis of 2-isothiocyano tri-
arylmethanes. Compounds 4a and 4b were prepared
according to known methods.9,10 2-Nitrotriaryl-
methanes 3c–f were synthesized by condensation of
2-nitrobenzaldehydes 1 and substituted benzenes 2 in
the presence of AlCl3,11 and subsequent reduction with
hydrazine hydrate in the presence of Raney Ni led to
the corresponding amines 4c–f12 (Scheme 1).
Several synthetic approaches to 4H-3,1-benzothiazines
have been elaborated. For example, 4-aryl and 4,4-di-
aryl derivatives of 4H-3,1-benzothiazine were synthesized
through the cycloaddition reaction between ketenimines
and the corresponding thiones.4 2-Amino-4-aryl-4H-3,1-
benzothiazine derivatives are easy to obtain in high yield
by the reaction of 2-aminobenzhydrol derivatives with
thiourea in boiling ethanol in the presence of HBr.5
Interaction of 2-aminobenzyl chloride with benzothio-
amides leads to 2-aryl-4H-3,1-benzothiazines in high
yields.3b Sulfurization of aryl-substituted 4H-3,1-ben-
zoxazines with P2S5 furnishes the corresponding benzo-
thiazines in yields varying from good to high.6 Various
2-acetylaminobenzylic alcohol derivatives give 2-aryl,
4-aryl and 2,4-diaryl substituted 4H-3,1-benzothiazines
under treatment with Lawesson’s reagent,7 but this reac-
tion is not always selective and can be accompanied by
considerable formation of by-products. A rather original
Isothiocyanates 5 were obtained by treatment of amines
4 with thiophosgene in the presence of NaHCO3.13
Compound 5 underwent an easy rearrangement to 2,4-
diaryl-4H-3,1-benzothiazines 614 in the presence of AlCl3
in sym-tetrachloroethane at rt. Formation of minor
products was observed in all cases (TLC). Only in three
cases, compounds 7a,d,f were isolated in low yields and
characterized (Scheme 2).
Keywords: Triarylmethanes; Rearrangement; 4H-3,1-Benzothiazines.
*
The assumed mechanism of the transformation is
depicted in Scheme 3. The reaction probably begins with
Corresponding author. Tel.: +7 861 2559556; fax: +7 861 2596592;
e-mail: alexander_butin@mail.ru
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.010

4030
V. T. Abaev et al. / Tetrahedron Letters 47 (2006) 4029–4032
R3
R3
R4
R4
R1
R2
R3
O
AlCl3
Ni-Ra
NH2-NH2
+
R4
R4
R3
R4
R3
R1
R2
R1
R2
NO2
2
1
NO2
NH2
4c-f
3c-f
Yield, %
3, 4
R1
R2
R3
OCH2CH2O
OMe OMe
R4
3
4
H
H
76
76
c
d
e
f
H
H
28
27
50
84
91
78
OMe
OMe
OMe
OMe
OMe
OEt
OMe
OEt
Scheme 1.
R3
R3
R4
R4
R4
R1
R2
CSCl2
NaHCO3
R4
R3
R1
R2
R3
NCS
NH2
5a-f
4a-f
R3
R3
R4
R4
R4
R1
R2
AlCl3
(CHCl2)2
R3
R1
R2
S
+
R4
R3
N
N
H
S
7a, d, f
6a-f
Yield, %
4 - 7
R1
R2
R3
R4
5
6
7
H
H
H
H
H
H
OH
Me
H
H
57
87
59
77
78
65
49
60
61
37
30
26
3
a
b
c
d
e
f
–
–
H
OCH2CH2O
H
OMe
OMe
OMe
OEt
7
–
5
OMe
OMe
OMe
OMe
OMe
OEt
Scheme 2.

V. T. Abaev et al. / Tetrahedron Letters 47 (2006) 4029–4032
4031
R3
R3
R3
R4
R4
R4
R4
R4
R3
R4
R3
R1
R1
R2
R1
R2
+
R2
R3
+
N
N
H
-
N
S
AlCl3
C
S
AlCl3
-
S
AlCl3
5
R3
R3
R4
R4
R4
R3
R1
-
R1
R2
+
AlCl3
S
R2
7
6
R4
R3
- AlCl3
- AlCl3
N
N
-
AlCl3
S
+
H
A
Scheme 3.
59,197,051, 1984; Chem. Abstr. 1985, 102, 176471; (c)
Ishige, S.; Usui, H.; Saeki, K. Ger. Patent 2,704,724, 1977;
Chem. Abstr. 1977, 87, 144134; (d) Usui, H.; Ishige, S.;
Saeki, K. Ger. Patent 2,658,246, 1977; Chem. Abstr. 1977,
87, 137318.
activation of the isothiocyano group of 5 with AlCl3 fol-
lowed by intramolecular electrophilic attack on one of
the aromatic rings. ipso-Substitution at the Csp3–CAr
bond is the main reaction pathway, which leads to for-
mation of benzhydryl cation A. Next, the cation is
attacked by the sulfur atom of a newly formed
thioamide group to accomplish the formation of the
benzothiazine ring. Intramolecular electrophilic attack
on the ortho-position of an aromatic ring is responsible
for the concurrent formation of minor dibenzoazepine-
thiones 7.
3. (a) Lednicer, D.; Emmert, D. E. J. Heterocycl. Chem.
1971, 8, 903–910; (b) El-Desoky, S. I.; Kandeel, E. M.;
Abd-el-Rahman, A. H.; Schmidt, R. R. J. Heterocycl.
Chem. 1999, 36, 153–160.
4. (a) Dondoni, A.; Battaglia, A.; Giorgianni, P.; Gilli, G.;
Sacerdoti, M. J. Chem. Soc., Chem. Commun. 1977, 43–44;
(b) Dondoni, A.; Battaglia, A.; Giorgianni, P. J. Org.
Chem. 1980, 45, 3766–3773; (c) Dondoni, A.; Battaglia,
A.; Giorgianni, P. J. Org. Chem. 1982, 47, 3998–4000; (d)
Carisi, P.; Mazzanti, G.; Zani, P.; Barbaro, G.; Battaglia,
A.; Giorgianni, P. J. Chem. Soc., Perkin Trans. 1 1987,
2647–2651.
In conclusion, we have reported a general rearrange-
ment reaction of 2-isothiocyano triarylmethanes, which
can be used for the synthesis of 2,4-diaryl-4H-3,1-benzo-
thiazines. The mechanistic aspects involving ipso-attack
of the isothiocyano group activated with AlCl3 is worthy
of further investigation.
5. Gauthier, J.; Duceppe, Jean S. J. Heterocycl. Chem. 1984,
21, 1081–1086.
6. Gromachevskaya, E. V.; Kosulina, T. P.; Kulnevich, V. G.
Khim. Geterotsikl. Soedin. 1993, 537–541.
7. (a) Nishio, T. J. Org. Chem. 1997, 62, 1106–1111; (b)
Nishio, T.; Sekiguchi, H. Heterocycles 2002, 58, 203–212.
8. (a) Dean, W. D.; Papadopoulos, E. P. J. Heterocycl.
Chem. 1982, 19, 1117–1124; (b) Looney-Dean, V.; Linda-
mood, B. S.; Papadopoulos, E. P. Synthesis 1984, 68–71;
(c) Deck, L. M.; Turner, S. D.; Deck, J. A.; Papadopoulos,
E. P. J. Heterocycl. Chem. 2001, 38, 343–347.
Acknowledgement
Financial support provided by Bayer HealthCare AG is
gratefully acknowledged.
9. Schultz, O.-E.; Geller, L. Pharmazie 1955, 60, 234–246.
10. Tolstaya, T. P.; Vanchikov, A. N.; Vinnik, E. V.; Asulyan,
L. D. Khim. Geterotsikl. Soedin. 1999, 1112–1118.
References and notes
1. (a) Gauthier, J. A.; Asselin, A. A. Can. Patent 1,210,396,
1986; Chem. Abstr. 1987, 106, 176409; (b) Dreikorn, B. A.
U.S. Patent 4,001,227, 1977; Chem. Abstr. 1977, 86,
155674; (c) Fr. Patent 7,359, 1969; Chem. Abstr. 1971,
75, 151817; (d) Umio, S.; Kariyone, K.; Kishimoto, T.
Jpn. Patent 45,037,020, 1970; Chem. Abstr. 1971, 74,
76433; (e) Umio, S.; Kariyone, K.; Kishimoto, T. Jpn.
Patent 44,027,032, 1969; Chem. Abstr. 1970, 72, 79068.
2. (a) Obayashi, T.; Okawa, A. Jpn. Patent 2,001,253,172,
2001; Chem. Abstr. 2001, 135, 233952; (b) Jpn. Patent
11. A typical procedure is as follows: To a cooled (5 °C)
solution of 2-nitroveratraldehyde (2 g, 9.5 mmol) and 1,2-
diethoxybenzene (3.3 g, 19.9 mmol) in CH2Cl2 (80 mL),
AlCl3 (1.9 g, 14.2 mmol) was added in small portions with
stirring. The reaction mixture was stirred for 2.5 h, the
cooling bath was removed, and stirring was continued at rt
until full conversion was achieved (TLC). The mixture was
poured into water (300 mL) and extracted with CH2Cl2.
The organic layer was separated, dried with Na2SO4 and
the solvent was removed in vacuo. Recrystallization of the

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V. T. Abaev et al. / Tetrahedron Letters 47 (2006) 4029–4032
solid residue from methanol furnished 2.49 g (50%) of 3f
14. A typical procedure is as follows: To a solution of
compound 5f (0.89 g, 1.66 mmol) in sym-tetrachloro-
ethane (5 mL), AlCl3 (0.3 g, 2.25 mmol) was added. The
reaction mixture was stirred for 24 h at rt (TLC), then
poured into water (100 mL) and extracted with CH2Cl2.
The organic layer was separated, dried over Na2SO4 and
the solvent was removed in vacuo. The oily residue was
purified by chromatography on silica gel (benzene–ethyl
acetate–hexane, 2:3:6) to yield compound 6f (0.23 g, 26%
yield) as colorless crystals. Mp 124–125 °C (ethyl acetate–
hexane). Anal. Found: C, 67.21; H, 6.72%. C30H35NO6S
requires: C, 67.02; H, 6.56%; 1H NMR (250 MHz, DMSO-
d6): d 1.23–1.28 (6H, m, OCH2CH3), 1.33–1.38 (6H, m,
OCH2CH3), 3.75 (3H, s, OCH3), 3.86 (3H, s, OCH3),
3.88–3.96 (4H, m, OCH2CH3), 4.06–4.13 (4H, m,
OCH2CH3), 5.53 (1H, s, CH), 6.49 (1H, dd, J = 2.0,
8.3 Hz, HAr), 6.77 (1H, d, J = 8.3 Hz, HAr), 6.82 (1H, s,
as yellow crystals. Mp 103–104 °C. Anal. Found: C, 66.16;
H, 6.80%. C29H35NO8; requires: C, 66.27; H, 6.71%; 1H
NMR (250 MHz, DMSO-d6): d 1.25 (6H, t, J = 7.0 Hz,
OCH2CH3), 1.31 (6H, t, J = 7.0 Hz, OCH2CH3), 3.61
(3H, s, OCH3), 3.85 (3H, s, OCH3), 3.91 (4H, q,
J = 7.0 Hz, OCH2CH3), 3.99 (4H, q, J = 7.0 Hz,
OCH2CH3), 6.09 (1H, s, CH), 6.49 (2H, dd, J = 1.7,
8.2 Hz, HAr), 6.53 (1H, s, HAr), 6.67 (2H, d, J = 1.7 Hz,
H
Ar), 6.87 (2H, d, J = 8.2 Hz, HAr), 7.60 (1H, s, HAr).
12. A typical procedure is as follows: A mixture of the
compound 3f (2.4 g, 4.6 mmol), hydrazine hydrate (2 mL)
and Raney Ni (1.5 g) in ethanol (40 mL) was stirred under
reflux (TLC). The catalyst was filtered off, and the solution
was treated with active charcoal followed by filtration and
evaporation. Compound 4f was obtained as a yellow oil
(1.78 g, 78% yield), which was used for the next step
without further purification.
H
Ar), 6.86 (1H, d, J = 2.0 Hz, HAr), 7.02 (1H, d,
13. A typical procedure is as follows: To a stirred solution of
the compound 4f (1.6 g, 3.2 mmol) in CH2Cl2 (10 mL)
solutions of CSCl2 (0.3 mL, 3.9 mmol) in CH2Cl2 (4 mL)
and NaHCO3 (0.84 g, 10 mmol) in water (30 mL) were
added simultaneously at rt. At the end of the reaction
(TLC) the mixture was poured into water (150 mL) and
stirred for 6 h. The organic layer was extracted with
CH2Cl2, separated and dried over Na2SO4. The solvent
was evaporated and the oily residue was dissolved in hot
hexane and filtered through a pad of silica gel. The
solution was concentrated and crystallization from hexane
furnished compound 5f (1.12 g, 65% yield) as a colourless
solid. Mp 117 °C. Anal. Found: C, 66.89; H, 6.68%.
C30H35NO6S requires: C, 67.02; H, 6.56%; 1H NMR
(250 MHz, CDCl3): d 1.39 (6H, t, J = 7.0 Hz, OCH2CH3),
1.44 (6H, t, J = 7.0 Hz, OCH2CH3), 3.65 (3H, s, OCH3),
3.85 (3H, s, OCH3), 3.99 (4H, q, J = 7.0 Hz, OCH2CH3),
4.07 (4H, q, J = 7.0 Hz, OCH2CH3), 5.57 (1H, s, CH),
6.40 (1H, s, HAr), 6.53 (2H, dd, J = 1.8, 8.2 Hz, HAr), 6.66
(2H, d, J = 1.8 Hz, HAr), 6.73 (1H, s, HAr), 6.79 (2H, d,
J = 8.2 Hz, HAr).
J = 8.6 Hz, HAr), 7.08 (1H, s, HAr), 7.52 (1H, dd,
J = 1.9, 8.6 Hz, HAr), 7.64 (1H, d, J = 1.9 Hz, HAr). 13C
NMR (50 MHz, DMSO-d6): d 14.65 (4C); 43.31; 55.58;
55.72; 63.71; 63.81 (2C); 63.99; 110.34; 110.71; 111.15;
112.26; 112.64; 113.09; 114.62; 119.28; 121.36; 130.25;
135.06; 137.36; 147.61; 147.85; 148.06; 148.12; 148.50;
151.26; 154.35. MS (m/z, % relative intensity): 537 (M+,
100), 507 (45), 506 (98), 328 (14), 327 (21), 43 (20). Yield of
7f 0.04 g (5% yield), yellow crystals. Mp 186–187 °C (ethyl
acetate–hexane). Anal. Found: C, 67.17; H, 6.41%.
C30H35NO6S requires: C, 67.02; H, 6.56%; 1H NMR
(250 MHz, DMSO-d6):
d 1.21 (3H, t, J = 7.0 Hz,
OCH2CH3), 1.24 (3H, t, J = 7.0 Hz, OCH2CH3), 1.31
(3H, t, J = 7.0 Hz, OCH2CH3), 1.37 (3H, t, J = 7.0 Hz,
OCH2CH3), 3.71 (3H, s, OCH3), 3.78 (2H, q, J = 7.0 Hz,
OCH2CH3), 3.83 (3H, s, OCH3), 3.92 (2H, q, J = 7.0 Hz,
OCH2CH3), 4.03 (2H, q, J = 7.0 Hz, OCH2CH3), 4.15
(2H, q, J = 7.0 Hz, OCH2CH3), 5.18 (1H, s, CH), 6.30
(1H, d, J = 8.1 Hz, HAr), 6.32 (1H, s, HAr), 6.75 (1H, d,
J = 8.1 Hz, HAr), 6.86 (1H, s, HAr), 7.01 (1H, s, HAr), 7.11
(1H, s, HAr), 7.71 (1H, s, HAr), 11.81 (1H, s, NH).