High yield synthesis of 4H-1,4-benzothiazine-1,1-dioxide derivatives

Article abstract of DOI:10.1002/jhet.5570450530

(Chemical Equation Presented) 4H-1,4-Benzothiazine-1,1-dioxide derivatives were synthesized through a sequence of almost quantitative reactions. The commercial starting material 2-(methylsulfanyl)aniline was Boc-protected, N-acylated and oxidized at the sulfur atom to obtain a sulfonyl derivative. An anionic transposition of the acyl group followed by a simultaneous deprotection-cyclization gave the title products in excellent yields. All products and intermediates were fully characterized.

Full text of DOI:10.1002/jhet.5570450530

Sep-Oct 2008
1445
High Yield Synthesis of 4H-1,4-Benzothiazine-1,1-dioxide
Derivatives
Stefania De Montis, Claudia Fattuoni,* Enzo Cadoni, Maria G. Cabiddu,
Michele Usai, Salvatore Cabiddu
Dipartimento di Scienze Chimiche, University of Cagliari, Cittadella Universitaria di Monserrato,
SS. 554, Bivio per Sestu. I-09042 Monserrato (CA), Italy
Tel.: +39-070-6754387; fax: +39-070-6754388; E-mail: cfattuon@unica.it
Received March 28, 2008
4H-1,4-Benzothiazine-1,1-dioxide derivatives were synthesized through
a sequence of almost
quantitative reactions. The commercial starting material 2-(methylsulfanyl)aniline was Boc-protected, N-
acylated and oxidized at the sulfur atom to obtain a sulfonyl derivative. An anionic transposition of the
acyl group followed by a simultaneous deprotection-cyclization gave the title products in excellent yields.
All products and intermediates were fully characterized.
J. Heterocyclic Chem., 45, 1445 (2008).
INTRODUCTION
butoxycarbonyl), an easily removable protecting group,
to give 2 (Scheme I). This compound was then lithiated
with lithium diisopropylamide (LDA) at -50 °C and
treated with an acyl chloride RCOCl where R was an
aryl, heteroaryl or alkyl group to give the N-acylated
products 3a-e (yield 60-77%, Table 1). Compounds 3a-
1,4-Benzothiazine derivatives have drawn much
interest in the pharmacologic field due to their
structural similarity with the phenothiazine system [1].
In particular the synthesis of the S-oxidized system,
4H-1,4-benzothiazine-1,1-dioxide, has been the object
of several studies and patents for industrial and
pharmacological applications [2-5]. The synthesis of
such systems usually started from 2-aminobenzene-
thiols which were treated with ꢀ-diketones to give the
2,3-disubstituted heterocyclic ring through the
formation of an intermediate enaminoketone [4-8]. The
further step, i.e. the oxidation at the sulfur, was usually
performed with 30% hydrogen peroxide in glacial
acetic acid [6-8]. An alternative method reported by
Schou started from pyridinium sulfonate salts which
e
were oxidized at the sulfur atom with m-
chloroperbenzoic acid (MPCBA) to give the sulfones
4a-e (yield 80-100%, Table 1), which after treatment
with butyllithium (BuLi) at -50 °C underwent an acyl
migration from the nitrogen atom to the methylsulfonyl
group affording products 5a-e (yield 71-100%,
Table 1). The acyl group transfer is likely to occur by
an intramolecular mechanism: in fact, from the reaction
mixture no product of type A or B could be isolated,
even performing the reaction with a higher substrate
concentration (Figure 1).
were
converted
into
2-cyanomethylsulfonyl
acetanilides: base catalyzed ring closure gave the S-
oxidized benzothiazinic system [3]. Another recent
method involved the microwave assisted cyclization of
ꢁ-phenylsulfonyl enaminoacrylates [9].
In this paper we report a new high yield synthesis of
3-substituted 4H-1,4-benzothiazine-1,1-dioxides: this
procedure is characterized by few almost quantitative
steps allowing the preparation of the target compounds
bearing a free, unsubstituted NH suitable for further
functionalization. The starting compound 2-(methyl-
sulfanyl)aniline (1) is commercial and all reagents are
easily available and inexpensive.
The treatment of compounds of type
5
with
trifluoroacetic acid (TFA) allowed the simultaneous
Boc-deprotection and cyclization giving products 6a-e
(yield 70-100%, Table 1). It is noteworthy that products
of type 5 did not cyclize in the presence of BuLi, through
an attack of the anionic nitrogen to the carbonyl group:
this is due to the low reactivity as nucleophile of the Boc-
protected N, even as an anion (Figure 2).
RESULTS AND DISCUSSION
The first step of the synthetic pathway consisted in
the protection of the amino group in 1 with Boc (tert-

1446
S. De Montis, C. Fattuoni, E. Cadoni, M. G. Cabiddu, M. Usai, S. Cabiddu
Vol 45
EXPERIMENTAL
NMR spectra were recorded on
a
Varian VXR-300
spectrometer with tetramethylsilane as internal reference. IR
spectra were recorded on Perkin-Elmer 1310 grating
a
spectrophotometer. The GC-MS analyses were performed at 70
eV with a Hewlett-Packard 5989A GC-MS system with HP
5890 GC fitted with a capillary column (50 mꢀ0.2 mm) packed
with DH 50.2 Petrocol (0.50 μm film thickness) using a direct-
inlet system for solid products. Chromatography was performed
on silica gel 60, 0.04-0.063 mm (Fluka). Melting points were
determined with a Kofler hot stage microscope and are
uncorrected. Microanalyses were carried out on a Carlo Erba
1106 element analyzer. Reagent-grade commercially available
reagents and solvents were used. Solutions of BuLi in hexane
were purchased from Aldrich Chemical Company and were
analyzed before use [10]. 2-(Methylsulfanyl)aniline (1) (Fluka)
was protected by literature method to give 2 [11].
The cyclization took place only when the N was
deprotected in an acidic medium: the attack of the free
NH2 to the carbonyl carbon did not lead to the expected
imine, but to an enaminic product because of the strong
acidity of the SO2-CH2 hydrogens.
All products were fully characterized by elemental
1
analysis, IR, H-NMR, 13C-NMR and mass spectroscopy
(see Experimental).
The 13C NMR spectra of products 3e and 4e, bearing
two tert-butyl groups, showed a remarkable feature: the
signals due to the methyl groups of the tert-butyl moieties
are observed as an unresolved multiplet. This
phenomenon clearly depended upon the closeness of such
bulky groups, whose free rotation around the C-O or C-C
bond was forbidden. When the same spectra were
recorded at 55 °C, the signals relative to the CH3 appeared
as two clean singlets.
General procedure for the synthesis of compounds 3a-e.
To a stirred solution of LDA (24.0 mL, 31.6 mmol) in
anhydrous THF (60 mL) at -50 °C, a solution of 2 (3.00 g, 12.6
mmol) in anhydrous THF (60 mL) was added under argon, and
stirring was continued for 1h. Then the appropriate acyl chloride
was added at the same temperature, and after 30 minutes the
mixture was poured into a saturated solution of aqueous NH4Cl.
The organic layer was separated, the aqueous layer extracted
with CH2Cl2, the extracts combined, dried (Na2SO4) and
concentrated to give products 3a-e.
tert-Butyl benzoyl[2-(methylthio)phenyl]carbamate (3a).
The crude product was purified by chromatography using
diethyl ether/light petroleum (1:2) as eluent to give 3a as
colourless crystals, 3.33 g (77%), mp 122-123 °C (EtOH); ir
(Nujol): 1725, 1670 cm-1; 1H nmr (CDCl3): ꢀ 1.21 (s, 9H,
CH3C), 2.44 (s, 3H, SCH3), 7.23 (m, 2H, ArH), 7.35 (m, 2H,
ArH), 7.43 (m, 2H, ArH), 7.49 (m, 1H, ArH), 7.81 (m, 2H,
ArH); 13C nmr (CDCl3): ꢀ 15.7, 27.3, 83.4, 125.9, 127.3, 127.9,
128.1, 128.9, 129.3, 131.3, 136.9, 137.1, 137.7, 152.5, 172.0;
ms: m/z 343 (M+, 5), 243 (6), 196 (48), 165 (56), 105 (100), 77
(72), 57 (77), 41 (36). Anal. calcd. for C19H21NO3S: C, 66.45; H,
6.16; N, 4.08; S, 9.34. Found: C, 66.42; H, 6.18; N, 4.02; S,
9.30.
Table 1. Yields of pure isolated products 3a-e, 4a-e, 5a-e and 6a-e.
R
3
4
5
6
Ph
a
77
70
90
92
96
71
100
81
4-MeOC6H4
4-FC6H4
b
c
65
65
92
78
80
75
81
d
100
S
C(CH3)3
e
60
80
100
70
In conclusion, we have reported an easy method to
prepare monosubstituted 4H-1,4-benzothiazine-1,1-
dioxides, using inexpensive reagents and allowing to
introduce in the 3-position different groups (aryl,
heteroaryl or alkyl).
tert-Butyl 4-methoxybenzoyl[2-(methylthio)phenyl]-car-
bamate (3b). The crude product was purified by
chromatography using first light petroleum and then diethyl
ether/light petroleum (1:2) as eluents to give 3b as white
crystals, 3.29 g (70%), mp 114-115 °C (EtOH/ H2O); ir (nujol):

Sep-Oct 2008
High Yield Synthesis of 4H-1,4-Benzothiazine-1,1-dioxide Derivatives
1447
1720, 1665 cm-1; 1H nmr (CDCl3): ꢀ 1.27 (s, 9H, CH3C), 2.43 (s,
3H, SCH3), 3.84 (s, 3H, OCH3), 6.92 (d, 2H, J=9.0 Hz, ArH),
7.20 (m, 2H, ArH), 7.31 (m, 2H, ArH), 7.81 (d, 2H, J=9.0 Hz,
ArH); 13C nmr (CDCl3): ꢀ 15.6, 27.5, 55.3, 83.0, 113.2, 125.8,
127.1, 128.7, 128.7, 129.3, 130.7, 137.5, 137.7, 152.8, 162.4,
171.3; ms: m/z 373 (M+, 0.1), 273 (2), 226 (14), 165 (18), 135
(100), 107 (8), 77 (18), 57 (35), 41 (32). Anal. calcd. for
C20H23NO4S: C, 64.32; H, 6.21; N, 3.75; S, 8.59. Found: C,
64.28; H, 6.25; N, 3.78; S,8.61.
tert-Butyl 4-fluorobenzoyl[2-(methylthio)phenyl]-carbam-
ate (3c). The crude product was washed with light petroleum
first and then with diethyl ether to give 3c as white crystals, 2.96
g (65%), mp 109-111 °C (EtOH); ir (nujol): 1725, 1670 cm-1; 1H
nmr (CDCl3): 1.35 (s, 9H, CH3C), 2.51 (s, 3H, SCH3), 7.20 (m,
2H, ArH), 7.30 (br s, 2H, ArH), 7.42 (br s, 2H, ArH), 7.93 (m,
2H, ArH); 13C nmr (CDCl3): ꢀ 15.4, 27.3, 83.3, 114.9 (JCF = 22.0
Hz), 125.7, 127.0, 128.9, 129.1, 130.6 (JCF = 8.6 Hz), 132.7 (JCF
= 3.6 Hz), 136.9, 137.5, 152.3, 164.4 (JCF = 252.8 Hz), 170.6;
ms: m/z 361 (M+, 3), 261 (17), 214 (100), 165 (80), 123 (93), 95
(32), 57 (43), 41 (26). Anal. calcd. for C19H20FNO3S: C, 63.14;
H, 5.58; N, 3.88; S, 8.87. Found: C, 63.11; H, 5.61; N, 3.92; S,
8.92.
129.5, 130.8, 131.4, 131.8, 134.7, 136.5, 137.6, 137.6, 152.1,
172.6; ms: m/z 276 (3), 197 (23), 196 (29), 105 (100), 77 (45),
57 ( 47), 41 (28). Anal. calcd. for C19H21NO5S: C, 60.78; H,
5.64; N, 3.73; S, 8.54. Found: C, 60.72; H, 5.66; N, 3.76; S,
8.57.
tert-Butyl 4-methoxybenzoyl[2-(methylsulfonyl)phenyl]-
carbamate (4b). The crude product was washed with diethyl
ether to give 4b as colourless crystals, 2.09 g (92%), mp 166-
168 °C (EtOH); ir (nujol): 1715, 1670, 1310, 1150 cm-1; 1H nmr
(CDCl3): ꢀ 1.26 (s, 9H, CH3C), 3.12 (s, 3H, SO2CH3), 3.87 (s,
3H, OCH3), 6.96 (d, 2H, J = 8.8 Hz, ArH), 7.38 (d, 1H, J = 7.8
Hz, ArH), 7.60 (t, 1H, J = 7.8 Hz, ArH), 7.72 (t, 1H, J = 7.8 Hz,
ArH), 7.79 (d, 2H, J = 8.8 Hz, ArH), 8.14 (d, 1H, J = 7.8 Hz,
ArH); 13C nmr (CDCl3): ꢀ 27.4, 44.3, 55.4, 83.9, 113.2, 128.1,
129.3, 130.7, 130.8, 131.8, 134.6, 137.5, 137.9, 152.4, 162.6,
171.8; ms: m/z 305 (2), 226 (13), 135 (100), 77 (7), 57 (14), 41
(10). Anal. calcd. for C20H23NO6S: C, 59.24; H, 5.72; N, 3.45; S,
7.91. Found: C, 59.22; H, 5.74; N, 3.43; S, 7.90.
tert-Butyl 4-fluorobenzoyl[2-(methylsulfonyl)phenyl]-car-
bamate (4c). The crude product was washed with diethyl ether
to give 4c as white crystals, 2.02 g (92%), mp 178-179 °C
(EtOH); ir (nujol): 1710, 1670, 1310, 1150 cm-1; 1H nmr
(CDCl3): ꢀ 1.25 (s, 9H, CH3C), 3.12 (s, 3H, SO2CH3), 7.14 (t,
2H, J =8.2 Hz, ArH), 7.38 (d, 1H, J = 7.8 Hz, ArH), 7.62 (t, 1H,
J = 7.8 Hz, ArH), 7.74 (t, 1H, J = 7.8 Hz, ArH), 7.81 (m, 2H,
ArH), 8.14 (d, 1H, J = 7.8 Hz, ArH); 13C nmr (CDCl3): ꢀ 27.4,
44.4, 83.5, 115.2 (JCF = 22.0 Hz), 129.6, 130.7 (JCF = 8.6 Hz),
130.8, 131.8, 132.4 (JC F= 3.6 Hz), 134.7, 137.4, 137.5, 152.1,
164.7 (JCF = 252.8 Hz), 171.4; ms: m/z 293 (8), 214 (70), 197
(22), 123 (100), 77 (25), 57 (9), 41 (7). Anal. calcd. for
C19H20FNO5S: C, 58.00; H, 5.12; N, 3.56; S, 8.15. Found: C,
57.99; H, 5.14; N, 3.57; S, 8.18.
tert-Butyl 2-(methylthio)phenyl(2-thienylcarbonyl)-carba-
mate (3d). The crude product was purified by flash-
chromatography using diethyl ether/light petroleum (1:2) as
eluent to give 3d as yellow crystals, 2.86 g (65%), mp 123-125
1
°C (EtOH); ir (nujol): 1720, 1665 cm-1; H nmr (CDCl3): ꢀ 1.28
(s, 9H, CH3C), 2.29 (s, 3H, SCH3), 6.88 (br s, 1H, ArH), 7.08 (br
s, 2H, ArH), 7.19 (br s, 2H, ArH), 7.39 (br s, 1H, ArH), 7.45 (br
s, 1H, ArH); 13C nmr (CDCl3): ꢀ 15.3, 27.4, 83.1, 125.6, 126.8,
126.8, 128.9, 129.2, 131.9, 132.6, 137.0, 138.1, 138.4, 152.3,
164.2; ms: m/z 349 (M+, 15), 294 (52), 250 (44), 249 (38), 232
(29), 202 (100), 165 (66), 111 (68), 57 (79), 41 (42). Anal. calcd.
for C17H19NO3S2: C, 58.43; H, 5.48; N, 4.01; S, 18.35. Found: C,
58.39; H, 5.50; N, 4.03; S, 18.37.
tert-Butyl 2-(methylsulfonyl)phenyl(2-thienylcarbonyl)-
carbamate (4d). The crude product was washed with diethyl
ether to give 4d as colourless crystals, 2.13 g (100%), mp 138-
139 °C (EtOH); ir (nujol): 1720, 1680, 1320, 1165 cm-1; 1H nmr
(CDCl3): ꢀ 1.24 (s, 9H, CH3C), 3.04 (s, 3H, SO2CH3), 7.00 (t,
1H, J = 4.3 Hz, ArH), 7.27 (d, 1H, J = 7.7 Hz, ArH) 7.48 (m,
tert-Butyl 2,2-dimethylpropanoyl[2-(methylthio)phenyl]-
carbamate (3e). The crude product was purified by
chromatography using diethyl ether/light petroleum (1:8) as
eluent to give 3e as colourless crystals, 2.44 g (60%), mp 69-71
2H, ArH), 7.60 (m, 2H, ArH), 8.01 (d, 1H, J = 7.7 Hz, ArH); 13
C
1
°C (H2O); ir (nujol): 1720 and 1665 cm-1; H nmr (CDCl3): ꢀ
nmr (CDCl3): ꢀ 27.3, 44.1, 84.1, 127.0, 129.4, 130.5, 131.6,
132.0, 132.9, 134.5, 137.3, 137.4, 137.9, 152.1, 165.1; ms: m/z
282 (19), 281 (12), 264 (20), 202 (46), 197 (16), 111 (100), 57
(47), 41 (31). Anal. calcd. for C17H19NO5S2: C, 53.53; H, 5.02;
N, 3.67; S, 16.81. Found: C, 53.50; H, 5.05; N, 3.65; S, 16.84.
tert-Butyl 2,2-dimethylpropanoyl[2-(methylsulfonyl)-phen-
yl]carbamate (4e). The crude product was purified by flash-
chromatography using diethyl ether/light petroleum (1:1) as
eluent to give 4e as colourless crystals, 1.59 g (80%), mp 119-
120 °C (EtOH); ir (nujol): 1725, 1700, 1310, 1150 cm-1; 1H nmr
(CDCl3): ꢀ 1.37 (s, 9H, CH3C), 1.45 (s, 9H, CH3C), 3.10 (s, 3H,
SO2CH3), 7.17 (d, 1H, J = 7.6 Hz, ArH), 7.53 (t, 1H, J = 7.6 Hz,
ArH), 7.66 (t, 1H, J = 7.6 Hz, ArH), 8.07 (d, 1H, J = 7.6 Hz,
ArH); 13C nmr (CDCl3): ꢀ 27.6, 43.2, 69.0, 83.5, 128.7, 130.3,
130.9, 134.4, 136.9, 139.4, 152.1, 183.6; ms: m/z 197 (15), 176
(14), 171 (29), 149 (18), 85 (18), 57 (100), 41 (47). Anal. calcd.
for C17H25NO5S: C, 57.44; H, 7.09; N, 3.94; S, 9.02. Found: C,
57.41; H, 7.11; N, 3.92; S, 9.03.
1.38 (s, 9H, CH3C), 1.40 (s, 9H, CH3C), 2.42 (s, 3H, SCH3),
7.04 (d, 1H, J = 7.6 Hz, ArH), 7.16 (m, 1H, ArH), 7.27 (m, 2H,
ArH); 13C nmr (CDCl3): ꢀ 15.5, 27.9, 43.5, 82.4, 125.5, 126.9,
128.3, 128.5, 137.7, 138.3, 153.1, 183.7; ms: m/z 323 (M+, 6),
224 (13), 223 (17), 232 (29), 176 (47), 165 (98), 57 (100), 41
(60). Anal. calcd. for C17H25NO3S: C, 63.13; H, 7.79; N, 4.33; S,
9.91. Found: C, 63.11; H, 7.82; N, 4.30; S, 9.94.
General procedure for the synthesis of compounds 4a-e. A
solution of one compound of type 3 (5.6 mmol) in CH2Cl2 (150
mL) was treated with MCPBA (3.03 g, 12.3 mmol) at 0 °C.
After the addition was complete the temperature was allowed to
warm to room temperature and the reaction was monitored by tlc
till completion. The mixture was treated with 10% aqueous
NaOH, the organic layer was dried (Na2SO4) and concentrated to
give products 4a-e.
tert-Butyl benzoyl[2-(methylsulfonyl)phenyl]carbamate (4a).
The crude product was washed with diethyl ether to give 4a as
colourless crystals, 1.89 g (90%), mp 178-179 °C (EtOH); ir
(nujol): 1715, 1680, 1310, 1155 cm-1; 1H nmr (CDCl3): ꢀ 1.20 (s,
9H, CH3C), 3.14 (s, 3H, SO2CH3), 7.40 (m, 4H, ArH), 7.62 (t,
1H, J = 7.5 Hz, ArH), 7.76 (m, 3H, ArH), 8.15 (d, 1H, J = 7.5
Hz, ArH); 13C nmr (CDCl3): ꢀ 27.3, 44.4, 84.3, 128.0, 128.0,
General procedure for the synthesis of compounds 5a-e. A
solution of one compound of type 4 (1.3 mmol) in anhydrous
THF (50 mL) was treated dropwise with a 1.6 M solution of
BuLi in hexane (2.0 mL, 3.2 mmol) at -50 °C under argon, and
stirring was continued for 10 minutes. The mixture was poured

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Vol 45
into a saturated solution of aqueous NH4Cl, the organic layer
was separated, the aqueous layer extracted with CH2Cl2, the
extracts combined, dried (Na2SO4) and concentrated to give
products 5a-e.
tert-Butyl 2-[(3,3-dimethyl-2-oxobutyl)sulfonyl]phenyl-car-
bamate (5e). The crude product was washed with diethyl ether
to give 5e as colourless crystals, 0.46 g (100%), mp 56-58 °C
1
(EtOH/H2O); ir (nujol): 3350, 1730, 1710, 1320, 1150 cm-1; H
nmr (CDCl3): ꢀ 1.04 (s, 9H, CH3C), 1.46 (s, 9H, CH3C), 4.24 (s,
2H, SO2CH2), 7.10 (t, 1H, J = 7.9 Hz, ArH), 7.52 (t, 1H, J = 7.9
Hz, ArH), 7.78 (d, 1H, J = 7.9 Hz, ArH), 8.23 (d, 1H, J = 7.9 Hz,
ArH), 8.64 (s, 1H, NH); 13C nmr (CDCl3): ꢀ 25.4, 28.2, 45.3,
59.9, 81.4, 121.9, 122.6, 125.3, 130.4, 135.4, 138.3, 152.2,
202.3; ms: m/z 355 (M+, 14), 299 (17), 256 (18), 198 (67), 171
(15), 156 (19), 57 (100), 41 (66). Anal. calcd. for C17H25NO5S:
C, 57.44; H, 7.09; N, 3.94; S, 9.02. Found: C, 57.42; H, 7.10; N,
3.97; S, 9.05.
General procedure for the synthesis of compounds 6a-e. A
solution of one compound of type 5 (1.3 mmol), CH2Cl2 (4.5
mL) and trifluoroacetic acid (1.9 mL, 24.3 mmol) was stirred at
room temperature for 10 minutes, then cooled at 0 °C and
treated with 20% aqueous NaOH. The solid thus separated was
filtered and ir lamp dried.
tert-Butyl 2-[(2-oxo-2-phenylethyl)sulfonyl]phenyl-carba-
mate (5a). The crude product was washed with diethyl ether to
give 5a as colourless crystals, 0.47 g (96%),; mp 118-120°C
1
(EtOH); ir (nujol): 3350, 1730, 1675, 1315, 1155 cm-1; H nmr
(CDCl3): ꢀ 1.51 (s, 9H, CH3C), 4.76 (s, 2H, SO2CH2), 7.07 (t,
1H, J = 8.2 Hz, ArH), 7.41 (t, 2H, J = 7.5 Hz, ArH), 7.56 (m,
2H, ArH), 7.78 (d, 1H, J = 8.2 Hz, ArH), 7.85 (d, 2H, J = 8.2
Hz, ArH), 8.30 (d, 1H, J = 8.2 Hz, ArH), 8.75 (s, 1H, NH); 13C
nmr (CDCl3): ꢀ 27.9, 62.4, 81.1, 120.5, 122.2, 124.2, 128.6,
128.8, 130.1, 134.0, 135.4, 135.4, 138.4, 151.8, 187.1; ms: m/z
375 (M+, 7), 319 (12), 275 (40), 152 (15), 106 (45), 105 (100),
77 (19), 57 (90), 41 (37). Anal. calcd. for C19H21NO5S: C, 60.78;
H, 5.64; N, 3.73; S, 8.54. Found: C, 60.75; H, 5.66; N, 3.75; S,
8.57.
tert-Butyl 2-{[2-(4-methoxyphenyl)-2-oxoethyl]sulfonyl}-
phenylcarbamate (5b). The crude product was washed with
light petroleum to give 5b as colourless crystals, 0.37 g (71%),
mp 114-117°C (EtOH/H2O); ir (nujol): 3340, 1720, 1665, 1310,
3-Phenyl-4H-1,4-benzothiazine 1,1-dioxide (6a). White
crystals, 0.33 g (100%), mp 250-252 °C (EtOH) (lit. [12] 271-
1
274 °C); ir (nujol): 3300, 1310, 1110 cm-1; H nmr (CDCl3): ꢀ
1
1155 cm-1; H nmr (CDCl3): ꢀ 1.49 (s, 9H, CH3C), 3.83 (s, 3H,
6.39 (s, 1H), 7.45 (t, 1H, J = 7.5 Hz), 7.66-7.77 (m, 5H), 7.83-
7.86 (m, 2H), 8.00 (d, 1H, J = 7.5 Hz), 11.02 (s, 1H, D2O
exchangeable, NH); 13C nmr (CDCl3): ꢀ 96.4, 118.5, 122.1,
123.6, 123.7, 127.7, 129.1, 130.9, 132.4, 133.9, 137.2, 145.3;
ms: m/z 257 (M+, 30), 193 (100), 165 (17). Anal. calcd. for
C14H11NO2S: C, 65.35; H, 4.31; N, 5.44; S, 12.46. Found: C,
65.32; H, 4.34; N, 5.47; S, 12.49.
3-(4-Methoxyphenyl)-4H-1,4-benzothiazine 1,1-dioxide (6b).
White crystals, 0.30 g (81%), mp 278-280 °C (EtOH) (lit. [12]
256-260 °C); ir (nujol): 3280, 1260, 1115 cm-1; 1H nmr
(DMSO): ꢀ 3.95 (s, 3H, OCH3), 6.22 (s, 1H), 7.20 (d, 2H, J = 8.6
Hz), 7.39 (t, 1H, J = 7.4 Hz), 7.63 (d, 1H, J = 7.4 Hz), 7.70 (t,
1H, J = 7.4 Hz), 7.82 (d, 2H, J = 8.6 Hz), 7.93 (d, 1H, J = 7.4
Hz); 13C nmr (DMSO): ꢀ 55.53, 95.17, 114.30, 118.46, 121.90,
123.35, 123.58, 125.96, 129.15, 132.11, 137.24, 144.96, 161.29;
ms: m/z 287 (M+, 40), 223 (86), 208 (100), 180 (38), 152 (14).
Anal. calcd. for C15H13NO3S: C, 62.70; H, 4.56; N, 4.87; S,
11.16. Found: C, 62.67; H, 4.58; N, 4.85; S, 11.19.
3-(4-Fluorophenyl)-4H-1,4-benzothiazine 1,1-dioxide (6c).
Colourless crystals, 0.27 g (75%), mp 315-317 °C (EtOH); ir
(nujol): 3300, 1310, 1115 cm-1; 1H nmr (CDCl3): ꢀ 6.37 (s, 1H),
7.43-7.98 (m, 9H); 13C nmr (CDCl3): ꢀ 96.3, 116.1 (JCF = 22.0
Hz), 118.8, 122.1, 123.7, 123.7, 130.3 (JCF = 8.6 Hz), 130.7,
132.4, 137.5, 144.6, 163.7 (JCF = 247.8 Hz); ms: m/z 275 (M+,
40), 211 (100), 165 (19). Anal. calcd. for C14H10FNO2S: C,
61.08; H, 3.66; N, 5.09; S, 11.65. Found: C, 61.05; H, 3.68; N,
5.11; S, 11.67.
OCH3), 4.67 (s, 2H, SO2CH2), 6.87 (d, 2H, J = 8.1 Hz, ArH),
7.07 (t, 1H, J = 7.9 Hz, ArH), 7.54 (t, 1H, J = 7.9 Hz, ArH), 7.76
(d, 1H, J = 7.9 Hz, ArH), 7.83 (d, 2H, J = 8.1 Hz, ArH), 8.30 (d,
1H, J = 7.9 Hz, ArH), 8.72 (s, 1H, NH); 13C nmr (CDCl3): ꢀ
28.1, 55.5, 62.5, 81.2, 114.0, 120.7, 122.4, 124.4, 128.6, 130.2,
131.5, 135.5, 138.5, 152.0, 164.4, 185.3;. ms: m/z 405 [M+] (4),
305 (32), 135 (100), 77 (13), 57 (47), 41 (78). Anal. calcd. for
C20H23NO6S: C, 59.24; H, 5.72; N, 3.45; S, 7.91. Found: C,
59.22; H, 5.75; N, 3.48; S, 7.90.
tert-Butyl 2-{[2-(4-fluorophenyl)-2-oxoethyl]sulfonyl}-
phenylcarbamate (5c). The crude product was purified by
chromatography using diethyl ether/light petroleum (1:1) as
eluent to give 5c as colourless crystals, 0.40 g (78%), mp 137-
139 °C (EtOH); ir (nujol): 3350, 1730, 1670, 1320, 1155 cm-1;
1H nmr (CDCl3): ꢀ 1.44 (s, 9H, CH3C), 4.63 (s, 2H, SO2CH2),
7.06 (m, 3H, ArH), 7.51 (t, 1H, J = 8.0 Hz, ArH), 7.70 (d, 1H, J
= 8.0 Hz, ArH), 7.85 (m, 2H, ArH), 8.25 (d, 1H, J = 8.0 Hz,
ArH), 8.60 (s, 1H, NH);. 13C nmr (CDCl3): 28.2, 62.8, 81.5,
116.1 (JCF = 22.0 Hz), 120.9, 122.6, 124.3, 130.3, 132.0 (JCF
=
9.7 Hz), 135.8, 138.6, 138.6, 152.0, 166.4 (JCF = 257.6 Hz),
185.6; ms: m/z 393 (M+, 2), 293 (32), 211 (10), 171 (17), 152
(15), 123 (65), 106 (20), 95 (12), 57 (100), 41 (48). Anal. calcd.
for C19H20FNO5S: C, 58.00; H, 5.12; N, 3.56; S, 8.15. Found: C,
57.99; H, 5.14; N, 3.58; S, 8.18.
tert-Butyl 2-{[2-oxo-2-(2-thienyl)ethyl]sulfonyl}phenyl-car-
bamate (5d). The crude product was purified by
chromatography using diethyl ether/light petroleum (1:1) as
eluent to give 5d as colourless crystals, 0.40 g (80%), mp 104-
106 °C (EtOH/H2O); ir (nujol): 3360, 1740, 1670, 1330, 1170
cm-1; 1H nmr (CDCl3): ꢀ 1.53 (s, 9H, CH3C), 4.64 (s, 2H,
SO2CH2), 7.09-7.14 (m, 2H, ArH), 7.58 (t, 1H, J = 8.0 Hz, ArH),
7.68 (d, 1H, J = 4.5 Hz, ArH), 7.74 (d, 1H, J = 4.5 Hz, ArH),
7.81 (d, 1H, J = 8.0 Hz, ArH), 8.32 (d, 1H, J = 8.0 Hz, ArH),
8.71 (s, 1H, NH); 13C nmr (CDCl3): ꢀ 28.2, 63.7, 81.4, 120.8,
122.5, 124.1, 128.6, 130.3, 134.8, 135.8, 136.5, 138.6, 143.0,
152.0, 179.1; ms: m/z 381 (M+, 5), 282 (21), 281 (37), 152 (14),
111 (35), 106 (20), 57 (100), 41 (48). Anal. calcd. for
C17H19NO5S2: C, 53.53; H, 5.02; N, 3.67; S, 16.81. Found: C,
53.50; H, 5.05; N, 3.65; S, 16.82.
3-(2-Thienyl)-4H-1,4-benzothiazine 1,1-dioxide (6d). White
crystals, 0.30 g (81%), mp 276-278 °C (EtOH); ir (nujol): 3300,
1290, 1100 cm-1; 1H nmr (CDCl3): ꢀ 6.44 (s, 1H), 7.38 (t, 1H, J = 4.2
Hz), 7.46 (t, 1H, J = 7.2 Hz), 7.69-7.78 (m, 2H), 7.89 (d, 1H, J = 4.2
Hz), 7.88-7.99 (m, 2H), 10.94 (s, 1H, D2O exchangeable, NH); 13C
nmr (CDCl3): ꢀ 95.5, 118.4, 121.9, 123.8, 123.8, 128.4, 129.0,
129.8, 132.4, 135.4, 136.8, 139.0; ms: m/z 263 (M+, 62), 199 (100),
171 (17), 167 (15). Anal. calcd. for C12H9NO2S2: C, 54.73; H, 3.44;
N, 5.32; S, 24.35. Found: C, 54.70; H, 3.48; N, 5.30; S, 24.30.
3-tert-Butyl-4H-1,4-benzothiazine 1,1-dioxide (6e). Colourless
crystals, 0.22 g (70%), mp 260-262 °C (EtOH); ir (nujol): 3310,
1
1240, 1100 cm-1; H nmr (DMSO): ꢀ 1.39 (s, 9H, CH3C), 5.91
(s, 1H), 7.37 (t, 1H, J = 7.2 Hz), 7.70 (m, 2H), 7.90 (d, 1H, J =

Sep-Oct 2008
High Yield Synthesis of 4H-1,4-Benzothiazine-1,1-dioxide Derivatives
1449
7.2 Hz); 13C nmr (DMSO): ꢀ 28.1, 35.9, 94.3, 118.0, 121.9,
122.8, 123.0, 132.1, 137.4, 154.3; ms: m/z 237 (M+, 37), 222
(30), 173 (14), 158 (100). Anal. calcd. for C12H15NO2S: C,
60.73; H, 6.37; N, 5.90; S, 13.51. Found: C, 60.70; H, 6.39; N,
5.92; S, 13.54.
[3] 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.; Antoine, M. H.; Lebrun, P.; Hansen, J. B. Bioorg.
Med. Chem. 2005, 13, 141-155.
[4] Armenise, D.; Trapani, G.; Stasi, F.; Morlacchi, F. Arch.
Pharm. Pharm. Med. Chem. 1998, 331, 54-58.
Acknowledgement. Financial support from the Ministero
dell’Università e della Ricerca Scientifica e Tecnologica,
(Rome) and from the University of Cagliari is gratefully
acknowledged. One of us (Michele Usai) acknowledges
financial support from Consorzio Interuniversitario
[5] Rathore, B. S.; Kumar, M. Bioorg. Med. Chem. 2006, 14,
5678-5682.
[6] Hamadi, M. Y.; Gupta, R.; Gupta, R. R. J. Fluor. Chem.
1999, 94, 169-174.
[7] Sharma, P. R.; Gupta, V.; Gautam, D. C.; Gupta, R. R.
Phosphorus, Sulfur, Silicon Relat. Elem. 2003, 178, 1483-1488.
[8] Kumar, G.; Gupta, V.; Gautam, D. C.; Gupta, R. R.
Phosphorus, Sulfur, Silicon Relat. Elem. 2004, 179, 1941-1948.
[9] Lopez, S.E.; Salazar, J.; Rebollo, O.; Restrepo, J. J.
Heterocyclic Chem. 2005, 42, 1007-1010.
Nazionale Metodologie
(C.I.N.M.P.I.S.) Bari.
e Processi Innovativi di Sintesi
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