A new synthesis of 4H-1,4-benzothiazine derivatives based on ring closure of EWG-stabilized (2-isocyanophenylthio)methyl anions

Article abstract of DOI:10.1055/s-2006-926385

2-Cyano(phenylsulfinyl-, p-nitrophenyl-, or o-nitrophenyl-)methylthiophenyl isocyanides were synthesized from 2-aminobenzenethiols and were shown to undergo ring closure to 2,4-disubstituted 4H-1,4-benzothiazine derivatives by deprotonation of the hydroge

Full text of DOI:10.1055/s-2006-926385

PAPER
1077
A New Synthesis of 4H-1,4-Benzothiazine Derivatives Based on Ring Closure
of EWG-Stabilized (2-Isocyanophenylthio)methyl Anions
Synthesis of
4
H
-1,
a
4-Benzothi
z
azine
D
eriv
u
atives hiro Kobayashi,* Kazutaka Hayashi, Daisuke Iitsuka, Osamu Morikawa, Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 6 October 2005; revised 11 November 2005
SCH2Y
S
Y
1. NaH, DMF, 0 °C
Abstract: 2-Cyano(phenylsulfinyl-, p-nitrophenyl-, or o-nitrophen-
yl-)methylthiophenyl isocyanides were synthesized from 2-ami-
2. Electrophile, 0 °C
R
NC
R
N
E
nobenzenethiols and were shown to undergo ring closure to 2,4-
disubstituted 4H-1,4-benzothiazine derivatives by deprotonation of
the hydrogen adjacent to the sulfur atom with sodium hydride or po-
tassium tert-butoxide, followed by trapping with various electro-
philes.
1a R = H, Y = CN
2
1b R = CF3, Y = CN
1c R = H, Y = S(O)Ph
1d R = H, Y = p-O2NC6H4
Key words: benzothiazine, carbanion, heterocycle, isocyanide,
ring closure
Scheme 1
sulfinyl-4H-1,4-benzothiazine was too unstable to be
isolated in pure form (entry 16), though we cannot explain
the reason for its instability.
4H-1,4-Benzothiazine derivatives are potentially of bio-
logical usefulness,1 and some of their preparation2 have
been accomplished by starting from 2-aminobenzenethiol
derivatives. For example, Gupta et al. reported that benzyl
3-methyl-4H-1,4-benzothiazine-2-carboxylates could be
prepared by reactions of 2-aminobenzenethiols with ben-
zyl 3-oxobutanoate.2b In this paper, we wish to report on a
new method for constructing the 4H-1,4-benzothiazine
system. The method is based on a deprotonation–ring-clo-
sure process of 2-cyano(phenylsulfinyl-, p-nitrophenyl-,
or o-nitrophenyl-)methylthiophenyl isocyanides, which
are easily prepared from 2-aminobenzenethiols, with an
appropriate base.
The probable pathway to 4H-1,4-benzothiazine deriva-
tives 2 is illustrated in Scheme 2. Thus, the deprotonation
of the hydrogen adjacent to the sulfur atom with sodium
hydride generates the carbanion intermediate 3. This carb-
anion attacks intramolecularly on the isocyano carbon to
give the imidoyl anion intermediate 4, which undergoes
intra- or intermolecular proton migration to result in for-
mation of the stabilized carbanion 5. Its resonance form 6
is trapped with an electrophile to give 2.
Y
S
Y
S
N
NaH
We first attempted the transformation of (2-isocyanophen-
ylthio)acetonitrile (1a) into 4H-1,4-benzothiazine-2-car-
bonitrile (2a, E = H). Thus, the ring closure of 1a could be
accomplished simply by treating it with sodium hydride in
DMF at 0 °C, followed by quenching with aqueous acid,
to give 2a in good yield, as shown in Scheme 1 and
Table 1 (entry 1). This reaction proved to furnish a range
of 4-substituted derivatives 2b–m in acceptable yields by
treating various electrophiles before aqueous workup
(entries 2–13). It was shown that a similar sequence using
(2-isocyano-4-trifluoromethylphenyl)thioacetonitrile (1b)
H
1
N
C
R
R
R
3
5
4
S
Y
S
N
Y
H
E+
2
R
N
6
Scheme 2
was also uneventfully carried out to afford the corre- Similar treatment of 1-isocyano-2-(2-nitrophenylmeth-
sponding 4H-1,4-benzothiazine-2-carbonitriles 2n and 2o yl)thiobenzene (7) with sodium hydride proved to result in
in fair yields (entries 14 and 15). We also found that 1-iso- the formation of an intractable mixture of products, but
cyano-2-(phenylsulfinylmethylthio)benzene (1c) and 1- potassium tert-butoxide effected the deprotonation–ring-
isocyano-2-(4-nitrophenylmethylthio)benzene (1d) also closure sequence and furnished 2-(2-nitrophenyl)-4H-1,4-
underwent transformation into the corresponding 4H-1,4- benzothiazine (8) in moderate yield, as shown in
benzothiazine derivatives 2p–t in moderate to fair yields Scheme 3.
on treatment with sodium hydride and suitable electro-
philes (entries 17–21). It should be noted that 2-phenyl-
It is concluded from the results described that a facile syn-
thetic method of 4H-1,4-benzothiazine derivatives in four
steps from commercially available 2-aminobenzenethiols,
via intermediate isocyano compounds, has been devel-
oped. This method has advantages over previously report-
SYNTHESIS 2006, No. 07, pp 1077–1082
Advanced online publication: 08.03.2006
DOI: 10.1055/s-2006-926385; Art ID: F17505SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

1078
K. Kobayashi et al.
PAPER
Table 1 Synthesis of 4H-1,4-Benzothiazine Derivatives 2
Entry
Isocyanide 1
Electrophile
H2O
E in 2
Product
2a
Yield (%)a
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
1d
1d
H
85
61
65
68
50
58
70
77
58
72
64
31
47
70
68
2
MeI
Me
2b
2c
3
CH2=CHCH2Br
BnBr
Allyl
4
Bn
2d
2e
5
2-CNC6H4CH2Br
4-CNC6H4CH2Br
4-CO2MeC6H4CH2Br
BrCH2CO2Me
EtCOCl
2-CNC6H4CH2
6
4-CNC6H4CH2
2f
7
4-CO2MeC6H4CH2
2g
8
CH2CO2Me
COEt
CO2Me
CO2t-Bu
CONHPh
Ts
2h
2i
9
10
MeOCOCl
(Boc)2O
PhNCO
2j
11
2k
2l
12
13
TsCl
2m
2n
2o
14
H2O
H
15
MeI
Me
b
b
16
H2O
H
–
–
17
MeI
Me
2p
2q
2r
2s
2t
68
58
60
42
46
18
BrCH2CN
PhCOCl
H2O
CH2CN
COPh
H
19
20
21
MeI
Me
a Isolated yields.
b The corresponding product was too unstable to be isolated.
NMR spectra were determined using SiMe4 as an internal reference
in CDCl3 with a JEOL ECP500 FT NMR spectrometer operating at
500 MHz or a JEOL LA400 FT NMR spectrometer operating at 400
MHz. Low-resolution mass spectra were recorded on a JEOL AU-
TOMASS 20 spectrometer (Center for Joint Research and Develop-
ment, this University). Thin-layer chromatography (TLC) was
carried out on Merck Kieselgel 60 PF254. All of the solvents used
were dried over appropriate drying agents and distilled under argon
prior to use. All of the reactions were carried out under argon.
S
S
t-BuOK
NO2
NO2
THF, 0 °C
N
H
NC
7
8 38%
Scheme 3
(2-Aminophenylthio)acetonitrile3 and chloromethyl phenyl
sufoxide4 were prepared by appropriate reported procedures. All
other chemicals used in this study were commercially available.
ed methods,2 because it makes possible the synthesis of
4H-1,4-benzothiazine derivatives bearing a variety of
functional groups from readily available starting materials
by simple operations. We are presently attempting to ex-
tend the present ring-closure process to the synthesis of
related heterocycles.
2-[(Formylamino)phenylthio]acetonitrile
A solution of (2-aminophenylthio)acetonitrile3 (2.2 g, 13 mmol) in
toluene (13 mL) containing formic acid (3.1 g, 67 mmol) was re-
fluxed under azeotropic conditions for 15 min. After cooling the
solvent and excess formic acid were removed under reduced pres-
sure to give a residue, which was purified by column chromatogra-
phy on silica gel (1:1 hexane–THF) to afford the title compound
(2.1 g, 83%); pale-yellow solid; mp 77–78 °C (hexane–Et2O).
Melting points were determined on a Laboratory Devices MEL-
TEMP II melting-point apparatus and are uncorrected. The IR spec-
tra were recorded on a Shimadzu FTIR-8300 spectrometer. The 1H
Synthesis 2006, No. 07, 1077–1082 © Thieme Stuttgart · New York

PAPER
Synthesis of 4H-1,4-Benzothiazine Derivatives
1079
IR (KBr): 3317, 2245, 1693 cm–1.
IR (KBr): 3441, 3327, 1614, 1043 cm–1.
1H NMR (500 MHz): d = 3.46 (2 H, s), 7.16–7.76 (4 H, m), 8.21–
1H NMR (500 MHz): d = 3.97 (1 H, d, J = 13.3 Hz), 3.99 (1 H, d,
J = 13.3 Hz), 4.57 (2 H, br s), 6.66 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz),
6.73 (1 H, dd, J = 7.8, 1.4 Hz), 7.16 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz),
7.39 (1 H, dd, J = 7.8, 1.4 Hz), 7.49–7.54 (3 H, m), 7.65–7.69 (2 H,
m).
8.83 (2 H, m).
Anal. Calcd for C9H8N2OS: C, 56.23; H, 4.19; N, 14.57; S, 16.68.
Found: C, 56.09; H, 4.20; N, 14.50; S, 16.80.
2-(Isocyanophenylthio)acetonitrile (1a)
Anal. Calcd for C13H13NOS2: C, 59.28; H, 4.98; N, 5.32; S, 24.35.
Found: C, 59.18; H, 5.01; N, 5.37; S, 24.19.
To a stirred solution of [2-(formylamino)phenylthio]acetonitrile
(0.49 g, 2.6 mmol) in THF (4 mL) containing Et3N (1.8 g, 18 mmol)
at 0 °C was added POCl3 (0.39 g, 2.6 mmol) dropwise. After 5 min,
sat. aq NaHCO3 (20 mL) was added and the mixture was extracted
with Et2O (3 × 15 mL). The combined extracts were washed with
sat. aq NaHCO3 and brine, dried (K2CO3), and evaporated. The res-
idue was subjected to purification by column chromatography on
silica gel (2:1 hexane–THF) to give 1a (0.32 g, 71%); yellow solid;
mp 62–63 °C (hexane–Et2O).
IR (KBr): 2247, 2122 cm–1.
1H NMR (500 MHz): d = 3.72 (2 H, s), 7.43–7.51 (3 H, m), 7.69 (1
H, dd, J = 8.2, 1.4 Hz).
N-[2-(Phenylsulfinylmethylthio)phenyl]formamide
This compound was prepared from 2-(phenylsulfinylmethyl-
thio)benzeneamine as described for the preparation of [2-(formyl-
amino)phenylthio]acetonitrile; yield: 99%; pale-yellow viscous
oil; Rf = 0.18 (1:1 EtOAc–hexane).
IR (neat): 3244, 1693, 1084 cm–1.
1H NMR (500 MHz): d = 4.02 (1 H, d, J = 13.7 Hz), 4.12 (1 H, d,
J = 13.7 Hz), 7.03–7.66 (9 H, m), 8.36–9.83 (2 H, m).
Anal. Calcd for C14H13NO2S2: C, 57.71; H, 4.50; N, 4.81; S, 22.01.
Found: C, 57.65; H, 4.51; N, 4.64; S, 22.22.
MS: m/z (%) = 174 (100, [M+]).
1-Isocyano-2-(phenylsufinylmethylthio)benzene (1c)
Anal. Calcd for C9H6N2S: C, 62.04; H, 3.47; N, 16.08; S, 18.41.
Found: C, 62.14; H, 3.51; N, 15.98; S, 18.28.
This compound was prepared from N-[2-(phenylsulfinylmethyl-
thio)phenyl]formamide as described for the preparation of 1a;
yield: 71%; pale-yellow solid; mp 51–53 °C (hexane–Et2O).
IR (KBr): 2120, 1047 cm–1.
1H NMR (500 MHz): d = 4.20 (1 H, d, J = 13.7 Hz), 4.22 (1 H, d,
J = 13.7 Hz), 7.31 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.37 (1 H, ddd,
J = 7.8, 7.3, 1.4 Hz), 7.39 (1 H, dd, J = 7.8, 1.4 Hz), 7.51–7.54 (3 H,
m), 7.64 (1 H, dd, J = 7.8, 1.4 Hz), 7.70–7.73 (2 H, m).
(2-Amino-4-trifluoromethylphenylthio)acetonitrile
This compound was prepared from 2-amino-4-trifluoromethylben-
zenethiol and bromoacetonitrile according to the procedure
previously reported for the preparation of 2-(amino-
phenylthio)acetonitrile;3 yield: 88%; pale-yellow oil; Rf = 0.21 (1:2
THF–hexane).
IR (neat): 3470, 3368, 2247, 1622 cm–1.
1H NMR (400 MHz): d = 3.48 (2 H, s), 4.59 (2 H, br s), 6.97–6.70
(2 H, m), 7.62 (1 H, d, J = 7.7 Hz).
Anal. Calcd for C14H11NOS2: C, 61.51; H, 4.06; N, 5.12; S, 23.46.
Found: C, 61.46; H, 4.09; N, 5.11; S, 23.46.
2-(4-Nitrophenylmethylthio)benzenamine
Anal. Calcd for C9H7F3N2S: C, 46.55; H, 3.04; N, 12.06; S, 13.81.
Found: C, 46.43; H, 3.12; N, 12.05; S, 13.77.
This compound was prepared from 2-aminobenzenethiol and 1-bro-
momethyl-4-nitrobenzene according to the procedure previously re-
ported for the preparation of 2-(aminophenylthio)acetonitrile;3
yield: 70%; yellow solid; mp 58–60 °C (hexane–Et2O).
(2-Formylamino-4-trifluoromethylphenylthio)acetonitrile
This compound was prepared from (2-amino-4-trifluoromethyl-
phenylthio)acetonitrile as described for the preparation of [2-
(formylamino)phenylthio]acetonitrile; yield 80%; pale-yellow sol-
id; mp 95–96 °C (hexane–Et2O).
IR (KBr): 3283, 2253, 1695 cm–1.
1H NMR (500 MHz): d = 3.52 and 3.54 (combined 2 H, 2 s), 7.37–
7.58 (1 H, m), 7.81–7.87 (1 H, m), 8.19–8.84 (3 H, m).
IR (KBr): 1618, 1512, 1342 cm–1.
1H NMR (500 MHz): d = 3.93 (2 H, s), 4.27 (2 H, br s), 6.58 (1 H,
ddd, J = 7.8, 7.3, 1.4 Hz), 6.71 (1 H, dd, J = 7.8, 1.4 Hz), 7.07 (1 H,
dd, J = 7.8, 1.4 Hz), 7.12 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.21 (2 H,
d, J = 8.7 Hz), 8.07 (2 H, d, J = 8.7 Hz).
Anal. Calcd for C13H12N2O2S: C, 59.98; H, 4.65; N, 10.76; S, 12.32.
Found: C, 59.77; H, 4.62; N, 10.76; S, 12.32.
Anal. Calcd for C10H7F3N2OS: C, 46.15; H, 2.71; N, 10.76; S,
12.32. Found: C, 46.04; H, 2.82; N, 10.54; S, 12.29.
N-[2-(4-Nitrophenylmethylthio)phenyl]formamide
This compound was prepared from 2-(4-nitrophenylmethyl-
thio)benzenamine as described for the preparation of [2-(formyl-
amino)phenylthio]acetonitrile; yield: 81%; white solid; mp 119–
121 °C (hexane–Et2O–CH2Cl2).
IR (KBr): 3234, 1666, 1515, 1342 cm–1.
1H NMR (500 MHz): d = 3.94 and 3.95 (combined 3 H, 2 s), 6.99–
7.39 (5 H, m), 8.09 (2 H, d, J = 8.7 Hz), 8.24–8.68 (2 H, m).
(2-Isocyano-4-trifluoromethylphenylthio)acetonitrile (1b)
This compound was prepared from (2-formylamino-4-trifluoro-
methylphenylthio)acetonitrile as described for the preparation of
1a; yield: 64%; pale-yellow solid; mp 59–62 °C (hexane–Et2O).
IR (KBr): 2251, 2124, 1612 cm–1.
1H NMR (500 MHz): d = 3.80 (2 H, s), 7.70–7.74 (3 H, m).
Anal. Calcd for C10H5F3N2S: C, 49.59; H, 2.08; N, 11.57; S, 13.24.
Found: C, 49.46; H, 2.11; N, 11.36; S, 13.22.
Anal. Calcd for C14H12N2O3S: C, 58.32; H, 4.20; N, 9.72; S, 11.12.
Found: C, 58.30; H, 4.44; N, 9.69; S, 11.09.
2-(Phenylsulfinylmethylthio)benzenamine
1-Isocyano-2-(4-nitrophenylmethylthio)benzene (1d)
This compound was prepared from N-[2-(4-nitrophenylmethyl-
thio)phenyl]formamide as described for the preparation of 1a; yield
74%; pale-yellow solid; mp 110–113 °C (hexane).
This compound was prepared from 2-aminobenzenethiol and chlo-
romethyl phenyl sufoxide4 according to the procedure previously
reported for the preparation of 2-(aminophenylthio)acetonitrile;3
yield: 97%; pale-yellow solid; mp 96–100 °C (hexane–Et2O–
CH2Cl2).
IR (KBr): 2120, 1607, 1520, 1346 cm–1.
Synthesis 2006, No. 07, 1077–1082 © Thieme Stuttgart · New York

1080
K. Kobayashi et al.
PAPER
1H NMR (500 MHz): d = 4.23 (2 H, s), 7.26–7.41 (4 H, m), 7.44 (2
H, d, J = 8.7 Hz), 8.14 (2 H, d, J = 8.7 Hz).
4-(2-Cyanophenylmethyl)-4H-1,4-benzothiazine-2-carbonitrile
(2e)
Yield: 50%; yellow solid; mp 135–136 °C (hexane–Et2O).
IR (KBr): 2222, 2197, 1636 cm–1.
Anal. Calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36; S, 11.86.
Found: C, 62.24; H, 3.76; N, 10.46; S, 11.78.
1H NMR (400 MHz): d = 4.92 (2 H, s), 6.51 (1 H, dd, J = 8.1, 1.5
Hz), 6.80 (1 H, s), 6.91–7.03 (3 H, m), 7.46 (1 H, t, J = 7.7 Hz), 7.57
(1 H, d, J = 7.3 Hz), 7.64 (1 H, ddd, J = 8.1, 7.7, 1.1 Hz), 7.74 (1 H,
dd, J = 7.7, 1.1 Hz).
4H-1,4-Benzothiazine-2-carbonitrile (2a)
To a stirred suspension of NaH (29 mg, 60% in oil, 0.72 mmol) in
DMF (2 mL) at 0 °C was added a solution of 1a (0.13 g, 0.72 mmol)
in DMF (1.5 mL) dropwise. After 5 min, sat. aq NH4Cl (10 mL) was
added and the mixture was extracted with Et2O (3 × 10 mL). The
combined extracts were washed with H2O (2 ×) and brine (1 ×),
dried (Na2SO4), and evaporated. The residue was purified by pre-
parative TLC on silica gel (2:1 hexane–THF) to give 2a (0.11 g,
85%); brownish-yellow solid; mp 119–120 °C (hexane–Et2O).
MS: m/z (%) = 289 (32, [M+]), 173 (100).
Anal. Calcd for C17H11N3S: C, 70.56; H, 3.83; N, 14.52; S, 11.08.
Found: C, 70.48; H, 3.69; N, 14.35; S, 11.14.
4-(4-Cyanophenylmethyl)-4H-1,4-benzothiazine-2-carbonitrile
(2f)
Yield: 58%; yellow solid; mp 143–144 °C (hexane–Et2O).
IR (KBr): 2222, 2199, 1630 cm–1.
1H NMR (400 MHz): d = 4.77 (2 H, s), 6.45 (1 H, dd, J = 7.3, 2.4
Hz), 6.78 (1 H, s), 6.90–7.00 (3 H, m), 7.48 (2 H, d, J = 7.9 Hz),
7.69 (2 H, d, J = 7.9 Hz).
IR (KBr): 3282, 2193, 1628 cm–1.
1H NMR (500 MHz): d = 5.96 (1 H, br s), 6.41 (1 H, dd, J = 7.8, 1.4
Hz), 6.80 (1 H, d, J = 6.9 Hz), 6.82 (1 H, dd, J = 7.8, 1.4 Hz), 6.91
(1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 6.99 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz).
MS: m/z (%) = 174 (100, [M+]).
Anal. Calcd for C9H6N2S: C, 62.04; H, 3.47; N, 16.08; S, 18.41.
Found: C, 62.03; H, 3.40; N, 15.98; S, 18.33.
MS: m/z (%) = 289 (2.4, [M+]), 173 (100).
Anal. Calcd for C17H11N3S: C, 70.56; H, 3.83; N, 14.52; S, 11.08.
Found: C, 70.53; H, 3.78; N, 14.26; S, 11.46.
4-Substituted 4H-1,4-Benzothiazine Derivatives; 4-Methyl-4H-
1,4-benzothiazine-2-carbonitrile (2b); Typical Procedure
After treatment of 1a (0.22 g, 1.3 mmol) with NaH (61 mg, 60% in
oil, 1.5 mmol) in a manner similar to that described above for the
preparation of 2a, MeI (0.22 g, 1.5 mmol) was added and stirring
was continued for 30 min. Similar workup of the resulting mixture
was followed by purification by preparative TLC on silica gel (3:1
hexane–THF) to give 2b (0.15 g, 61%); yellow solid; mp 72–73 °C
(hexane–Et2O).
4-(4-Methoxycarbonylphenylmethyl)-4H-1,4-benzothiazine-2-
carbonitrile (2g)
Yield: 70%; yellow solid; mp 147–148 °C (hexane–Et2O).
IR (KBr): 2195, 1707, 1628 cm–1.
1H NMR (400 MHz): d = 3.92 (3 H, s), 4.75 (2 H, s), 6.50 (1 H, dd,
J = 7.3, 1.8 Hz), 6.79 (1 H, s), 6.88–6.98 (3 H, m), 7.41 (2 H, d,
J = 8.0 Hz), 8.06 (2 H, d, J = 8.0 Hz).
IR (KBr): 2201, 1626 cm–1.
MS: m/z (%) = 322 (21, [M+]), 173 (100).
1H NMR (500 MHz): d = 3.16 (3 H, s), 6.65 (1 H, dd, J = 7.8, 0.9
Hz), 6.74 (1 H, s), 6.88 (1 H, dd, J = 7.8, 1.4 Hz), 6.96 (1 H, dd,
J = 7.8, 7.3, 0.9 Hz), 7.09 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz).
Anal. Calcd for C18H14N2O2S: C, 67.06; H, 4.38; N, 8.69; S, 9.95.
Found: C, 66.77; H, 4.38; N, 8.62; S, 9.92.
MS: m/z (%) = 188 (100, [M+]).
4-Methoxycarbonylmethyl-4H-1,4-benzothiazine-2-carboni-
trile (2h)
Yield: 77%; yellow solid; mp 118–119 °C (hexane–Et2O).
Anal. Calcd for C10H8N2S: C, 63.80; H, 4.28; N, 14.88; S, 17.03.
Found: C, 63.72; H, 4.24; N, 14.76; S, 17.16.
IR (KBr): 2195, 1738, 1634 cm–1.
4-Allyl-4H-1,4-benzothiazine-2-carbonitrile (2c)
Yield: 65%; brownish-yellow oil; Rf = 0.35 (1:5 EtOAc–hexane).
IR (neat): 2197, 1622 cm–1.
1H NMR (500 MHz): d = 4.10–4.12 (2 H, m), 5.33–5.38 (2 H, m),
5.84–5.92 (1 H, m), 6.65 (1 H, dd, J = 8.2, 0.9 Hz), 6.79 (1 H, s),
6.89 (1 H, dd, J = 7.8, 1.4 Hz), 6.95 (1 H, ddd, J = 7.8, 7.3, 0.9 Hz),
7.62 (1 H, ddd, J = 8.2, 7.3, 1.4 Hz).
1H NMR (400MHz): d = 3.82 (3 H, s), 4.18 (2 H, s), 6.43 (1 H, d,
J = 8.4 Hz), 6.78 (1 H, s), 6.92 (1 H, dd, J = 7.8, 1.5 Hz), 6.97 (1 H,
ddd, J = 7.8, 7.3, 1.1 Hz), 7.06 (1 H, ddd, J = 8.4, 7.3, 1.5 Hz).
MS: m/z (%) = 246 (44, [M+]), 187 (100).
Anal. Calcd for C12H10N2O2S: C, 58.52; H, 4.09; N, 11.37; S, 13.02.
Found: C, 58.44; H, 4.01; N, 11.25; S, 12.89.
MS; m/z (%) = 214 (13, [M+]), 173 (100).
4-Propanoyl-4H-1,4-benzothiazine-2-carbonitrile (2i)
Yield: 58%; pale-yellow solid; mp 89–90 °C (hexane–Et2O).
IR (KBr): 2230, 1703, 1607 cm–1.
Anal. Calcd for C12H10N2S: C, 67.26; H, 4.70; N, 13.07; S, 14.96.
Found: C, 67.18; H, 4.73; N, 12.99; S, 14.96.
1H NMR (500 MHz): d = 1.26 (3 H, t, J = 7.3 Hz), 2.63 (2 H, q,
J = 7.3 Hz), 7.25–7.28 (2 H, m), 7.34 (1 H, ddd, 7.8, 7.3, 1.8 Hz),
7.42 (1 H, d, J = 8.2 Hz), 7.65 (1 H, s).
4-Benzyl-4H-1,4-benzothiazine-2-carbonitrile (2d)
Yield: 68%; brownish-yellow viscous oil; Rf = 0.31 (1:5 EtOAc–
hexane).
MS: m/z (%) = 230 (8.5, [M+]), 174 (100).
IR (neat): 2195, 1626 cm–1.
1H NMR (500 MHz): d = 4.70 (2 H, s), 6.60 (1 H, dd, J = 7.8, 1.4
Hz), 6.80 (1 H, s), 6.90 (1 H, dd, J = 7.8, 1.8 Hz), 6.93 (1 H, ddd,
J = 7.8, 7.3, 1.4 Hz), 6.98 (1 H, ddd, J = 7.8, 7.3, 1.8 Hz), 7.30–7.34
(3 H, m), 7.40 (2 H, t, J = 7.3 Hz).
Anal. Calcd for C12H10N2OS: C, 62.59; H, 4.38; N, 12.16; S, 13.92.
Found: C, 62.55; H, 4.30; N, 12.10; S, 14.03.
4-Methoxycarbonyl-4H-1,4-benzothiazine-2-carbonitrile (2j)
Yield: 72%; yellow solid; mp 94–95 °C (hexane–Et2O).
IR (KBr): 2230, 1744, 1624 cm–1.
MS: m/z (%) = 264 (15, [M+]), 92 (100).
Anal. Calcd for C16H12N2S: C, 72.70; H, 4.58; N, 10.60; S, 12.13.
Found: C, 72.58; H, 4.72; N, 10.71; S, 11.99.
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Synthesis of 4H-1,4-Benzothiazine Derivatives
1081
1H NMR (500 MHz): d = 3.95 (3 H, s), 7.18 (1 H, dd, J = 7.8, 1.8
Hz), 7.21 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.31 (1 H, ddd, J = 7.8,
7.3, 1.8 Hz), 7.57 (1 H, s), 7.60 (1 H, dd, J = 7.8, 1.4 Hz).
Anal. Calcd for C11H7F3N2S: C, 51.56; H, 2.75; N, 10.93; S, 12.51.
Found: C, 51.48; H, 2.95; N, 10.71; S, 12.49.
4-Methyl-2-phenylsulfinyl-4H-1,4-benzothiazine (2p)
Yield: 68%; yellow solid; mp 139–141 °C (Et2O–CH2Cl2).
IR (KBr): 1622, 1040 cm–1.
1H NMR (500 MHz): d = 3.18 (3 H, s), 6.59 (1 H, dd, J = 8.2, 0.9
Hz), 6.75 (1 H, dd, J = 7.8, 1.4 Hz), 6.82 (1 H, ddd, J = 7.8, 7.3, 0.9
Hz), 6.96 (1 H, s), 7.00 (1 H, ddd, J = 8.2, 7.3, 1.4 Hz), 7.46–7.54
(3 H, m), 7.67 (2 H, dd, J = 8.2, 1.4 Hz).
MS: m/z (%) = 232 (70, [M+]), 173 (100).
Anal. Calcd for C11H8N2O2S: C, 56.88; H, 3.47; N, 12.06; S, 13.81.
Found: C, 56.91; H, 3.50; N, 12.02; S, 14.05.
4-tert-Butoxycarbonyl-4H-1,4-benzothiazine-2-carbonitrile
(2k)
Yield: 64%; white solid; mp 122 °C (hexane–Et2O).
IR (KBr): 2232, 2218, 1738, 1614 cm–1.
MS: m/z (%) = 287 (0.44, [M+]), 162 (100).
1H NMR (500 MHz): d = 1.59 (9 H, s), 7.16 (1 H, dd, J = 7.8, 1.8
Hz), 7.18 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.28 (1 H, ddd, J = 7.8,
7.3, 1.8 Hz), 7.54 (1 H, s), 7.59 (1 H, d, J = 7.8 Hz).
Anal. Calcd for C15H13NOS2: C, 62.69; H, 4.56; N, 4.87; S, 22.31.
Found: C, 62.59; H, 4.56; N, 4.79; S, 22.30.
(2-Phenylsulfinyl-4H-1,4-benzothiazin-4-yl)acetonitrile (2q)
Yield: 58%; yellow solid; mp 122–124 °C (hexane–Et2O–CH2Cl2).
IR (KBr): 2210, 1626, 1040 cm–1.
1H NMR (500 MHz): d = 4.39 (2 H, s), 6.72 (1 H, d, J = 8.2 Hz),
6.86 (1 H, d, J = 7.8, 1.4 Hz), 6.93 (1 H, ddd, J = 7.8, 7.3, 0.9 Hz),
7.02 (1 H, s), 7.12 (1 H, J = 8.2, 7.3, 1.4 Hz), 7.50–7.56 (3 H, m),
7.69 (2 H, dd, 7.8, 1.4 Hz).
MS: m/z (%) = 274 (0.44, [M+]), 174 (100).
Anal. Calcd for C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21; S, 11.69.
Found: C, 61.24; H, 5.14; N, 10.18; S, 11.75.
4-Phenylaminocarbonyl-4H-1,4-benzothiazine-2-carbonitrile
(2l)
Yield: 31%; yellow solid; mp 124–125 °C (hexane–Et2O).
IR (KBr): 3304, 2220, 1697, 1601 cm–1.
MS: m/z (%) = 312 (100, [M+]).
1H NMR (500 MHz): d = 7.11 (1 H, br s), 7.17 (1 H, t, J = 7.3 Hz),
7.27–7.32 (2 H, m), 7.33–7.39 (4 H, m), 7.43 (2 H, d, J = 8.2 Hz),
7.97 (1 H, s).
Anal. Calcd for C16H12N2OS2: C, 61.51; H, 3.87; N, 8.97; S, 20.53.
Found: C, 61.42; H, 3.86; N, 9.22; S, 20.53.
4-Benzoyl-2-phenylsulfinyl-4H-1,4-benzothiazine (2r)
Yield: 60%; pale-yellow solid; mp 148–150 °C (CH2Cl2).
IR (KBr): 1668, 1612, 1051 cm–1.
MS: m/z (%) = 293 (2.2, [M+]), 216 (31), 173 (100).
Anal. Calcd for C16H11N3OS: C, 65.51; H, 3.78; N, 14.32; S, 10.93.
Found: C, 65.58; H, 3.78; N, 14.19; S, 11.08.
1H NMR (500 MHz): d = 6.78 (1 H, d, J = 7.8 Hz), 6.96 (1 H, ddd,
J = 7.8, 7.3, 1.4 Hz), 7.06 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.19 (1 H,
dd, J = 7.8, 1.4 Hz), 7.35 (2 H, dd, J = 8.2, 7.8 Hz), 7.47 (1 H, tt,
J = 7.8, 1.4 Hz), 7.54–7.58 (5 H, m), 7.72 (2 H, dd, J = 8.2, 1.4 Hz),
8.12 (1 H, s).
4-(4-Methylphenylsulfonyl)-4H-1,4-benzothiazine-2-carboni-
trile (2m)
Yield: 47%; yellow solid; mp 122–122.5 °C (hexane–Et2O).
IR (KBr): 2214, 1602, 1373, 1175 cm–1.
1H NMR (500 MHz): d = 2.43 (3 H, s), 6.99 (1 H, dd, J = 7.8, 1.4
Hz), 7.23 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.25 (2 H, d, J = 8.7 Hz),
7.33 (1 H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.36 (1 H, s), 7.57 (2 H, dd,
J = 8.7 Hz), 7.70 (1 H, dd, J = 7.8, 1.4 Hz).
MS: m/z (%) = 377 (5.6, [M+]), 256 (100).
Anal. Calcd for C21H15NO2S2: C, 66.82; H, 4.01; N, 3.71; S, 16.99.
Found: C, 66.71; H, 3.97; N, 3.46; S, 16.96.
2-(4-Nitrophenyl)-4H-1,4-benzothiazine (2s)
Prepared from 1d as described for the preparation of 2a; yield: 42%;
dark-red solid; mp 145–147 °C (hexane–Et2O).
IR (KBr): 3387, 1634, 1568, 1329 cm–1.
MS: m/z (%) = 328 (8.6, [M+]), 278 (23), 173 (100).
Anal. Calcd for C16H12N2O2S2: C, 58.52; H, 3.68; N, 8.53; S, 19.53.
Found: C, 58.49; H, 3.66; N, 8.50; S, 19.79.
6-Trifluoromethyl-4H-1,4-benzothiazine-2-carbonitrile (2n)
Prepared from 1b as described for the preparation of 2a; yield 70%;
yellow solid; mp 97–99 °C (hexane–Et2O).
IR (KBr): 3279, 2199, 1634 cm–1.
1H NMR (500 MHz): d = 6.23 (1 H, br s), 6.61 (1 H, d, J = 1.4 Hz),
6.76 (1 H, d, J = 6.4 Hz), 6.89 (1 H, d, J = 7.8 Hz), 7.12 (1 H, dd,
J = 7.8, 1.4 Hz).
1H NMR (500 MHz): d = 5.66 (1 H, br d, J = 5.5 Hz), 6.45 (1 H, d,
J = 6.9 Hz), 6.81 (1 H, d, J = 6.4 Hz), 6.87 (1 H, dd, J = 7.3, 6.9 Hz),
6.95 (1 H, d, J = 7.3 Hz), 6.98 (1 H, t, J = 7.3 Hz), 7.51 (2 H, d,
J = 8.7 Hz), 8.15 (2 H, d, J = 8.7 Hz).
MS: m/z (%) = 270 (100, [M+]).
Anal. Calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36; S, 11.86.
Found: C, 62.21; H, 3.92; N, 10.24; S, 11.63.
MS: m/z (%) = 242 (100, [M+]).
4-Methyl-2-(4-nitrophenyl)-4H-1,4-benzothiazine (2t)
Yield: 46%; dark-red solid; mp 130–133 °C (hexane–Et2O).
IR (KBr): 1628, 1560, 1315 cm–1.
Anal. Calcd for C10H5F3N2S: C, 49.59; H, 2.08; N, 11.57; S, 13.24.
Found: C, 49.29; H, 2.08; N, 11.66; S, 13.17.
4-Methyl-6-trifluoromethyl-4H-1,4-benzothiazine-2-carboni-
trile (2o)
Yield: 68%; yellow solid; mp 134–135 °C (hexane–Et2O).
IR (KBr): 2197, 1634 cm–1.
1H NMR (400 MHz): d = 3.17 (3 H, s), 6.71 (1 H, s), 6.76 (1 H, s),
6.94 (1 H, d, J = 8.1 Hz), 7.19 (1 H, d, J = 8.1 Hz).
1H NMR (500 MHz): d = 3.22 (3 H, s), 6.66 (1 H, dd, J = 8.2, 0.9
Hz), 6.77 (1 H, s), 6.92 (1 H, ddd, J = 7.8, 7.3, 0.9 Hz), 7.02 (1 H,
dd, 7.8, 1.4 Hz), 7.10 (1 H, ddd, J = 8.2, 7.3, 1.4 Hz), 7.52 (2 H, d,
J = 9.2 Hz), 8.15 (2 H, d, J = 9.2 Hz).
MS: m/z (%) = 284 (100, [M+]).
Anal. Calcd for C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85; S, 11.28.
Found: C, 63.30; H, 4.51; N, 9.69; S, 11.19.
MS: m/z (%) = 256 (100, [M+]).
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K. Kobayashi et al.
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2-[(2-Nitrophenyl)methylthio]benzenamine
IR (KBr): 3383, 1651, 1526, 1360 cm–1.
This compound was prepared from 2-aminobenzenethiol and 1-bro-
momethyl-2-nitrobenzene according to the procedure previously re-
ported for the preparation of 2-(aminophenylthio)acetonitrile;3
yield: 80%; mp 74–75 °C (hexane–Et2O).
1H NMR (500 MHz): d = 5.50 (1 H, br d, J = 5.5 Hz), 6.30 (1 H, d,
J = 6.4 Hz), 6.46 (1 H, dd, J = 7.8, 1.4 Hz), 6.86 (1 H, ddd, J = 7.8,
7.3, 1.4 Hz), 6.92 (1 H, dd, J = 7.8, 1.4 Hz), 6.98 (1 H, ddd, J = 7.8,
7.3, 1.4 Hz), 7.34–7.40 (1 H, m), 7.48–7.52 (2 H, m), 7.76 (1 H, d,
J = 8.2 Hz).
IR (KBr): 3466, 3368, 1607, 1519, 1344 cm–1.
1H NMR (500 MHz): d = 4.24 (2 H, s), 4.32 (2 H, br s), 6.55 (1 H,
dd, J = 7.8, 7.3, 1.4 Hz), 6.98 (1 H, dd, J = 7.8, 1.4), 6.98–7.01 (1
H, m), 7.05 (1 H, dd, J = 7.8, 1.4 Hz), 7.11 (1 H, ddd, J = 7.8, 7.3,
1.4 Hz), 7.33–7.40 (2 H, m), 7.96–7.99 (1 H, m).
MS: m/z (%) = 270 (100, [M+]).
Anal. Calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36; S, 11.86.
Found: C, 62.09; H, 3.85; N, 10.45; S, 11.79.
Anal. Calcd for C13H12N2O2S: C, 59.98; H, 4.65; N, 10.76; S, 12.32.
Found: C, 59.96; H, 4.68; N, 10.74; S, 12.24.
Acknowledgment
We are grateful to Mrs. Miyuki Tanmatsu of this Department for de-
termining mass spectra and performing combustion analyses. This
research was partially supported by a Grant-in-Aid for Scientific
Research (C) 15550092 from Japan Society for the Promotion of
Science.
N-{2-[(2-Nitrophenyl)methylthio]phenyl}formamide
This compound was prepared from 2-[(2-nitrophenyl)methyl-
thio]benzenamine as described for the preparation of [2-(formyl-
amino)phenylthio]acetonitrile; yield: 76%; white solid; mp 102–
105 °C (hexane–Et2O–CH2Cl2).
IR (KBr): 3337, 1701, 1607, 1510, 1342 cm–1.
1H NMR (500 MHz): d = 4.24 and 4.27 (combined 2 H, 2 s), 6.88–
7.21 (2 H, m), 7.31–7.46 (4 H, m), 7.99–8.67 (4 H, m).
References
(1) For biological activities of 4H-1,4-benzothiazine
derivatives, see: (a) Armenise, D.; Trapani, G.; Arrivo, V.;
Laraspata, E.; Morlacchi, F. J. Heterocycl. Chem. 2000, 37,
1611. (b) Cecchetti, V.; Calderone, V.; Tabarrini, O.;
Sabatini, S.; Filipponi, E.; Testai, L.; Spogli, R.; Martinotti,
E.; Fravolini, A. J. Med. Chem. 2003, 46, 3670. For
previous reports on the synthesis and biological activity of
4H-1,4-benzothiazine-2-carbonitrile derivatives, see:
(c) Kano, S.; Yuasa, Y.; Ono, T.; Shibuya, S. Heterocycles
1979, 12, 681. (d) Liso, G.; Trapani, G.; Berardi, V.;
Latrofa, A.; Marchini, P. J. Heterocycl. Chem. 1980, 17,
793. (e) Schou, S. C.; Hansen, H. C.; Tagmose, T. M.;
Boonen, H. C. M.; Worsaae, A.; Drabowski, M.; Wahl, P.;
Arkhammar, P. O. G.; Bodvarsdottir, T.; Antonine, M.-H.;
Lebrun, P.; Hansen, J. B. Bioorg. Med. Chem. 2005, 13, 141.
(2) (a) Pippich, S.; Bartsch, H. Heterocycles 1996, 43, 1967.
(b) Gupta, R.; Verma, P. S.; Gupta, R. R. Heterocycl.
Commun. 1998, 5, 479. (c) Sharma, P. R.; Gupta, V.;
Gautam, D. C.; Gupta, R. R. Phosphorus, Sulfur Silicon
Relat. Elem. 2003, 178, 1483; and references cited therein.
(3) Kay, D. P.; Kennewell, P. D.; Westwood, R. J. Chem. Soc.,
Perkin Trans. 1 1982, 1879.
Anal. Calcd for C14H12N2O3S: C, 58.32; H, 4.20; N, 9.72; S, 11.12.
Found: C, 58.45; H, 4.45; N, 9.68; S, 10.95.
1-Isocyano-2-[(2-nitrophenyl)methylthio]benzene (7)
This compound was prepared from N-{2-[(2-nitrophenyl)methyl-
thio]phenyl}formamide as described for the preparation of 1a,
yield: 74%; yellow solid; mp 88–90 °C (hexane–Et2O).
IR (KBr): 2120, 1609, 1522, 1350 cm–1.
1H NMR (500 MHz): d = 4.53 (2 H, m), 7.24–7.31 (2 H, m), 7.30–
7.43 (3 H, m), 7.42 (1 H, J = 7.8, 1.4 Hz), 7.48 (1 H, ddd, J = 7.8,
7.3, 1.4 Hz), 8.01 (1 H, dd, J = 7.8, 1.4 Hz).
Anal. Calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36; S, 11.86.
Found: C, 62.19; H, 3.96; N, 10.34; S, 11.79.
2-(2-Nitrophenyl)-4H-1,4-benzothiazine (8)
To a stirred solution of t-BuOK (83 mg, 0.74 mmol) in THF (2 mL)
at 0 °C was added a solution of 7 (0.20 g, 0.74 mmol) in THF (2 mL)
dropwise. After 30 min stirring, the mixture was worked up in a
manner similar to that described for the preparation of 2a. Purifica-
tion of the crude product by preparative TLC on silica gel gave 8 (76
mg, 38%); red solid; mp 92–94 °C (hexane–Et2O).
(4) Cadman, M. L. F.; Crombie, L.; Freeman, S.; Mistry, J. J.
Chem. Soc., Perkin Trans. 1 1995, 1397.
Synthesis 2006, No. 07, 1077–1082 © Thieme Stuttgart · New York