A novel and facile one-pot synthesis of 3-aryl-4H-benzo[1,4]thiazin-2-amine

Article abstract of DOI:10.1055/s-0028-1088114

A high-yielding and fast method for the synthesis of 3-aryl-4H-benzo[1,4] thiazin-2-amine via one-pot, three-component reaction of an aromatic aldehyde, isocyanide, and o-amino thiophenol using PTSA as a catalyst is described. Georg Thieme Verlag Stuttgar

Full text of DOI:10.1055/s-0028-1088114

LETTER
1123
A Novel and Facile One-Pot Synthesis of 3-Aryl-4H-benzo[1,4]thiazin-2-amine
S
ynthesis of 3-Aryl-4
H
a
-benzo[1,4
j
]
thiazin
i
-2-am
d
ine M. Heravi,* Bita Baghernejad, Hossein A. Oskooie
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran 1993891176, Iran
Fax +98(21)88047861; E-mail: mmh1331@yahoo.com
Received 1 December 2008
H
N
NH2
Ar
Abstract: A high-yielding and fast method for the synthesis of 3-
R1
PTSA
R1
R2NC
aryl-4H-benzo[1,4]thiazin-2-amine via one-pot, three-component
reaction of an aromatic aldehyde, isocyanide, and o-amino thiophe-
nol using PTSA as a catalyst is described.
ArCHO
+
+
EtOH
reflux
SH
NHR2
S
1
2
3
4
Key words: one-pot synthesis, 3-aryl-4H-benzo[1,4]thiazin-2-
amine, catalyst
Scheme 1
In a typical procedure, benzaldehyde (1 mmol), malo-
nitrile (1 mmol), and o-aminothiophenol (1 mmol) in the
presence of a catalytic amount of PTSA in ethanol at re-
flux afforded the desired 3-phenyl-4H-benzo[1,4]thiazin-
2-amine (4a) in 88% yield (entry 1, Table 1). The reaction
then was applied to a variety of aromatic aldehydes with
good yields (as shown in Table 1). To the best of our
knowledge there are no reports in the literature for the
synthesis of these compounds.
Benzofused heterocycles containing a sulfur moiety pos-
sess many biological activities across wide therapeutic
fields, including vasodilator,1 antidiabetic,2 anticataract,3
and antiarrhythmic activities.4 Benzothiazines have been
reported as calcium channel blockers,5 phosphodiesterase
inhibitors,6 5-HT3 antagonists,7 anticataract agents,8
dopamine D4,9 Na+/H+ exchange inhibitors,10 coagulation
factor Xa inhibitors,11 and matrix metalloproteinase inhib-
itors.12 Therefore, a wide range of studies for the synthetic
development of benzothiazine derivatives has been car-
ried out.13–15 In recent years, multicomponent reactions
(MCR) have become important tools in modern prepara-
tive synthetic chemistry because these reactions increase
the efficiency by combining several operational steps
without any isolation of intermediates or change of the
conditions16,17 and MCR have recently emerged as valu-
able tools in the preparation of structurally diverse chem-
ical libraries of druglike heterocyclic compounds.18–20 In
1921, Passerini21 pioneered the use of isocyanides and
successfully developed a three-component synthesis of a-
acyloxycarboxamides by reaction of a carboxylic acid, an
aldehyde, and an isonitrile.22 However, the most impor-
tant breakthrough came in 1959 when Ugi described a
four-component synthesis of a-acylamino amides from an
aldehyde, an amine, an acid, and an isocyanide.23,24 This
reaction, named after Ugi (Ugi 4CR or U-4CR) has be-
come a widely investigated transformation during the past
decade, in conjunction with technologies such as high-
throughput screening and combinatorial chemistry.25–27
All aromatic aldehydes containing electron-withdrawing
or electron-donating groups reacted well to give the corre-
sponding products 4 in good to excellent yields under
these reaction conditions. We also found that the reaction
did not proceed in the cases when aliphatic aldehydes
were used. In order to show the generality and scope of
this new protocol, we used various o-aminothiophenols
and isocyanides in the presence of PTSA, and the results
obtained are summarized in Table 1.
A plausible mechanism for this reaction is suggested in
Scheme 2. The first step, similar to the Ugi reaction,
involves reaction of the aromatic aldehyde with the o-
aminothiophenol followed by isocyanide attack on the re-
sulting intermediate followed by intramolecular trapping
by the sulfur nucleophile29 to give the desired product.
+
NH2
NH
SH
CH Ar
PTSA
R1
R1
+
Ar CHO
SH
+
C–
H
Ar
R1
N
N
+
H
As part of our program aimed at developing new methods
for the preparation of new compounds,28 we would like to
report one-pot synthesis of 3-aryl-4H-benzo[1,4]thiazin-
2-amines via a three-component reaction of an aromatic
aldehyde, an isocyanide, and an ortho-amino thiophenol
using PTSA as a catalyst (Scheme 1).
H
R2
N
Ar
R1
SH
N
+
S
N
H
N
Ar
R1
S
N
H
SYNLETT 2009, No. 7, pp 1123–1125
Advanced online publication: 26.03.2009
x
x.
x
x.
2
0
0
9
Scheme 2
DOI: 10.1055/s-0028-1088114; Art ID: D40108ST
© Georg Thieme Verlag Stuttgart · New York

1124
M. M. Heravi et al.
LETTER
N-Cyclohexyl-3-(4-chlorophenyl)-4H-benzo[1,4]thiazin-2-
Table 1 Synthesis of N-Cyclohexyl-3-aryl-4H-benzo[1,4]thiazin-
2-amines Using Various Aldehydes
amine (4b)
Mp 202 °C. IR (KBr): nmax = 3185, 3165 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.22–2.23 (m, 10 H), 3.42 (m, 1 H), 4.35 (s, 1 H, NH),
4.66 (s, 1 H, NH), 7.44–8.26 (m, 8 H, arom.) ppm. 13C NMR (125
MHz, CDCl3): d = 22.35, 26.45 (2 CH2), 33.61 (2 CH2), 49.18,
121.84 (2 CH), 123.55, 124.13 (2 CH), 127.19, 129.67, 130.39,
131.51, 138.47, 140.26, 142.37, 147.87, 149.99 (CCl) ppm. GC-
MS: m/z = 356 [M+]. Anal. Calcd (%) for C20H21N2SCl: C, 67.30;
H, 5.93; N, 7.85. Found: C, 67.11; H, 5.63; N, 7.91.
Entry R1
R2
Ar
Product Yield (%)a
1
2
H
H
H
H
H
H
H
H
H
H
Me
Cl
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
t-Bu
Ph
4a
4b
4c
4d
4e
4f
88
90
89
90
88
88
87
89
88
91
89
86
4-ClC6H4
3-O2NC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
4-HOC6H4
Ph
3
4
N-Cyclohexyl-3-(4-nitrophenyl)-4H-benzo[1,4]thiazin-2-amine
(4d)
5
Mp 207 °C. IR (KBr): nmax = 3178, 3150 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.16–2.38 (m, 10 H), 3.55 (m, 1 H), 4.39 (s, 1 H, NH),
4.71 (s, 1 H, NH), 7.42–8.39 (m, 8 H, arom.) ppm. 13C NMR (125
MHz, CDCl3): d = 23.42, 24.33 (2 CH2), 26.21 (2 CH2), 48.68,
121.99 (2 CH), 123.72, 125.34 (2 CH), 126.27, 128.08, 131.33,
137.42, 139.57, 141.64, 142.18, 146.97, 150.22 (CNO2) ppm. GC-
MS: m/z = 367 [M+]. Anal. Calcd (%) for C20H21N3SO2: C, 65.37;
H, 5.76; N, 11.43. Found: C, 65.22; H, 5.77; N, 11.33.
6
7
4g
4h
4i
8
9
t-Bu
4-MeOC6H4
4-O2NC6H4
Ph
10
11
12
t-Bu
4j
N-Cyclohexyl-3-(4-methylphenyl)-4H-benzo[1,4]thiazin-2-
amine (4e)
c-Hex
c-Hex
4k
4l
Mp 205 °C. IR (KBr): nmax = 3169, 3157 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.16–2.28 (m, 10 H), 2.44 (s, 3 H), 3.63 (m, 1 H), 4.43
Ph
a Yields refer to isolated products.
(s, 1 H, NH), 4.72 (s, 1 H, NH), 7.29–8.06 (m, 8 H, arom.) ppm. 13
C
NMR (125 MHz, CDCl3): d = 23.13, 24.18 (2 CH2), 27.17 (2 CH2),
40.84, 53.51, 124.67 (2 CH), 122.56, 125.40 (2 CH), 127.17,
128.74, 129.25, 137.17, 138.56, 140.69, 141.09, 143.91, 149.93
ppm. GC-MS: m/z = 336 [M+]. Anal. Calcd (%) for C21H24N2S: C,
74.96; H, 7.19; N, 8.32. Found: C, 79.84; H, 7.20; N, 8.21.
In conclusion, we have described a highly efficient proce-
dure for the preparation of 3-aryl-4H-benzo[1,4]thiazin-
2-amines by a three-component condensation using PTSA
as a catalyst, furnishing the products in good yield without
further purification in moderate to good yields.
N-Cyclohexyl-3-(4-hydroxyphenyl)-4H-benzo[1,4]thiazin-2-
amine (4g)
Mp 188 °C. IR (KBr): nmax = 3163, 3147 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.18–2.23 (m, 10 H), 3.36 (m, 1 H), 4.22 (s, 1 H, NH),
4.62 (s, 1 H, NH), 4.93 (s, 1 H, OH), 7.34–8.09 (m, 8 H, arom.) ppm.
13C NMR (125 MHz, CDCl3): d = 23.43, 24.88 (2 CH2), 26.72 (2
CH2), 52.19, 121.13 (2 CH), 123.31, 124.32 (2 CH), 125.29, 130.96,
131.46, 133.51, 137.16, 139.17, 143.01, 148.82, 149.23 ppm. GC-
MS: m/z = 338 [M+]. Anal. Calcd (%) for C20H22N2SO: C, 70.97; H,
6.56; N, 8.28. Found: C, 70.81; H, 6.35; N, 8.11.
All products were characterized by mp, IR, 1H NMR, and GC-MS.
Melting points were measured by using the capillary tube method
1
with an electrothermal 9200 apparatus. H NMR and 13C NMR
spectra were recorded on a Bruker DRX Avance spectrometer at
500 MHz and 125 MHz, respectively, with CDCl3 as solvent. IR
spectra were recorded from KBr disk on the FT-IR Bruker Tensor
27. GC-MS spectra were recorded on an Agilent Technologies 6890
network GC system and an Agilent 5973 network mass selective de-
tector. Thin-layer chromatography on commercial aluminum-
backed plates of silica gel 60 F254 was used to monitor the progress
of reactions.
N-tert-Butyl-3-phenyl-4H-benzo[1,4]thiazin-2-amine (4h)
Mp 232 °C. IR (KBr): nmax = 3158, 3143 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.32 (s, 9 H), 4.14 (s, 1 H, NH), 4.68 (s, 1 H, NH), 7.28–
7.99 (m, 9 H, arom.) ppm. 13C NMR (125 MHz, CDCl3): d = 26.36
(3 CH3), 40.49, 122.55 (2 CH), 124.64, 124.87, 125.46, 126.86 (2
CH), 128.77, 131.74, 132.89, 136.88, 137.62, 138.93, 141.54 ppm.
GC-MS: m/z = 296 [M+]. Anal. Calcd (%) for C18H20N2S: C, 72.93;
H, 6.80; N, 9.45. Found: C, 72.88; H, 6.62; N, 9.34.
N-Cyclohexyl-3-aryl-4H-benzo[1,4]thiazin-2-amines; Typical
Procedure
A mixture of the aromatic aldehyde 1 (1 mmol), o-aminothiophenol
(1 mmol), cyclohexyl isocyanide (1 mmol), and PTSA (0.05 g) in
EtOH (5 mL) was refluxed for 5 h and then cooled to r.t. The prod-
uct was precipitated by addition of 10 mL of H2O. The precipitate
was filtered off and washed with H2O. The residue was crystallized
from EtOH to give the pure product.
N-Cyclohexyl-6-methyl-3-phenyl-4H-benzo[1,4]thiazin-2-
amine (4k)
Mp 241 °C. IR (KBr): nmax = 3166, 3158 cm–1. 1H NMR (300 MHz,
CDCl3) d = 1.14–2.26 (m, 10 H), 3.09 (s, 3 H), 3.64 (m, 1 H), 4.66
(s, 1 H, NH), 4.98 (s, 1 H, NH), 7.29–7.93 (m, 8 H, arom.) ppm.
13C NMR (125 MHz, CDCl3): d = 24.11, 24.43 (2 CH2), 28.88 (2
CH2), 30.98, 47.98, 121.99 (2 CH), 124.44, 124.76, 125.33, 126.88
(2 CH), 127.19, 130.87, 131.49, 136.55, 137.90, 138.49, 140.98
ppm. GC-MS: m/z = 336 [M+]. Anal. Calcd (%) for C21H24N2S: C,
74.96; H, 7.19; N, 8.32. Found: C, 74.85; H, 7.09; N, 8.21.
N-Cyclohexyl-3-phenyl-4H-benzo[1,4]thiazin-2-amine (4a)
Mp 192 °C. IR (KBr): nmax = 3167, 3153 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.10–2.10 (m, 10H), 3.56 (m, 1H), 4.32 (s, 1H, NH),
4.65 (s, 1H, NH), 7.42-7.94 (m, 9H, arom.) ppm. 13C NMR (125
MHz, CDCl3): d = 23.21, 24.67 (2 CH2), 28.82 (2 CH2), 47.76,
121.11 (2 CH), 123.33, 123.98, 124.78, 126.95 (2 CH), 127.76,
130.07, 131.12, 136.11, 137.97, 138.81, 140.32 ppm. GC-MS:
m/z = 322 [M+]. Anal. Calcd (%) for C20H22N2S: C, 74.49; H, 6.88;
N, 8.69. Found: C, 73.98; H, 6.35; N, 8.55.
Synlett 2009, No. 7, 1123–1125 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Aryl-4H-benzo[1,4]thiazin-2-amine
1125
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