Direct access to 1,4-benzothiazine 4,4-dioxides and 4-oxides via a domino reaction

Article abstract of DOI:10.1016/j.tet.2017.03.056

The domino reactions of 2-fluoro benzensulfonyl acetonitrile and α-chloro oximes in the presence of Cs₂CO₃ in aprotic high boiling point solvents have been achieved to provide isoxazole?fused 4H-1,4-benzothiazine-4,4-dioxides via an

Full text of DOI:10.1016/j.tet.2017.03.056

Accepted Manuscript
Direct access to 1,4-benzothiazine 4,4-dioxides and 4-oxides via a domino reaction
Özge Kavas, Cevher Altug
PII:
S0040-4020(17)30299-5
10.1016/j.tet.2017.03.056
TET 28562
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 January 2017
Revised Date: 2 March 2017
Accepted Date: 20 March 2017
Please cite this article as: Kavas E, Altug C, Direct access to 1,4-benzothiazine 4,4-dioxides and 4-
oxides via a domino reaction, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.056.
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Özge Kavasa, Cevher Altuğa*
Department of Chemistry, Abant İzzet Baysal University, TR-14280 Bolu, Turkey

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Tetrahedron
journal homepage: www.elsevier.com
Direct access to 1,4-benzothiazine 4,4-dioxides and 4-oxides via a domino reaction
Özge Kavasa, Cevher Altuga,*
a Department of Chemistry, Abant İzzet Baysal University, TR-14280 Bolu, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
The domino reactions of 2-fluoro benzensulfonyl acetonitrile and α-chloro oximes
in the presence of Cs2CO3 in aprotic high boiling point solvents have been achieved to
provide isoxazole−fused 4H-1,4-benzothiazine-4,4-dioxides via an unprecented
transition metal-free one-pot addition/cyclization process. The tunable synthesis of
either isoxozolo-1,4-benzothiazin-4-oxides or their precursor 5-aminoisoxazoles can
be controlled depending on the solvent selection. The observed products were
characterized by means of (IR, 1H, 13C NMR and HRMS) and physical methods.
Available online
Keywords:
1,4-benzothiazine
α-chloro oxime
isoxazole
one-pot
cyclization
domino reaction
aminothiols with unsaturated C-C bonds,19,20 ring expansions
or ring cleavages of various heterocyclic systems21–24 and
metal catalyzed C-S bond formations25–27 but, to the best of
our knowledge, there is no literature concerning the synthesis
of heterocycles, which contain isoxazolo-1,4-benzothiazines
from simple starting materials via domino reactions. In
1. Introduction
A domino reaction includes a consecutive series of
organic reactions, which often proceed with highly reactive
intermediates in a reaction vessel or in nature.1,2 Single
acyclic organic starting materials can be converted into
multifunctional cyclic or heterocyclic organic molecules in
this way.3 It is well known that phenothiazine analogues of
1,4-benzothiazines have stimulated considerable interest in
recent years due to their broad spectrum of pharmacological
properties.4 Their biological features have been well
documented over the years.5,6 Structure−activity analyses
have revealed that the biological properties of 1,4-
benzothiazines are strongly dependent on substitution, which
makes them pharmacologically relevant and highly
attractive.7 In particular, antimalarial activity,8 histamine H-
receptor antagonist,9 central nervous system depressants,10
antifungal agents,11 calcium ion channel antagonists,12
potassium ion channel openers13 and anticancer properties14
make this class of compounds good candidates for biological
studies.
addition, reports of isoxazole−fused heterocyclic systems are
very limited in the literature.28,29
In continuation of our isoxazole chemistry,30–34 herein, we
have developed a robust, convenient and atom-economical
method to obtain potentially bioactive isoxazolo-
benzothiazines by reacting ortho-fluoro substituted
phenylsulfonyl acetonitrile and α-chloro oximes. The
reaction conditions produce an enamino moiety which is
used as a reactive intermediate for obtaining the title
compounds.
There are examples of the enamino
intramolecular nucleophilic substitution reaction with ortho-
substituted halides to obtain 1,4-benzothiazine 4,4-dioxides.
Lautens’ group prepared enamines by the Rh-catalyzed
addition
of
arylboronic
acids
The
to
(o-
fluorophenylsulfonyl)acetonitrile.
subsequent
intramolecular nucleophilic substitution of those enamines
gave
N-unsubstituted
2-aryl-1,4-benzothiazine
S,S-
dioxides.35 Another method, employing 2-aminopyrroles
bearing a 2-chlorophenylsulfone group at the 3-position to
obtain 1,4-benzothiazines via Pd-catalyzed intramolecular
cyclization with carboxylic acid auxiliary, has also been
reported.36 However, the aforementioned studies required
expensive metal catalysts to obtain either the starting
materials or cyclization products. Recently, Gu et al.
developed a method to obtain benzothiazines via the K2S
initiated sulfur insertion into enaminones without using a
In addition, isoxazole-fused heterocyclic systems have
broad application in both synthetic organic chemistry and
biological studies.15–18 The synthesis of new heterocyclic
systems, the development of facile procedures for the
synthesis of these compounds and the improvement of
available methods have been, and still remain, important
areas of research in synthetic organic chemistry.
Several synthetic methods have been developed for the
synthesis of 1,4-benzothiazines.4 Reported procedures for the
preparation of 1,4-benzothiazines include the reaction of 2-
transition-metal catalyst.37 In our work, a one-pot metal
−free
synthesis of isoxazolo-1,4-benzothiazine-4 oxides and 4,4-
dioxides is reported for the first time. This method enables
1

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several advantages such as simple work-up procedure, high
Table 2 Synthesis of 1,4-benzothiazine-4-oxides
yields, broad applicability and practicability.
F
O
S
Ar
O
2-((2-Fluorophenyl)sulfonyl)acetonitrile (1) and 2-((2-
fluorophenyl)sulfinyl)acetonitrile (4) were obtained from the
oxidation of 2-((2-fluorophenyl)thio)acetonitrile with H2O2
(30%) and m-CPBA respectively. Then, 2-((2-
fluorophenyl)sulfonyl)acetonitrile (1) reacted with α-
chlorooximes to furnish isoxazolo[5,4-e][1,4]benzothiazine
4,4-dioxides 3a-k and reaction conditions were optimized
with conventional and microwave heating methods, see
Table 1. Reactions with microwave heating had slightly
higher yields and shorter reaction times than conventional
heating. The reaction yields were similar for both electron−
withdrawing and electron−releasing substituents of α-
chlorooximes.
N
NaOH
Ar
Cl
OH
N
S
N
MeOH
O
+
F
H2N
5
2
4
Cs2CO3
DMSO
O
S
Ar
Cs2CO3
DMSO
N
O
N
H
6
Entry
Compound
Ar
Yield for Yield for
Table 1 Reactions of 2-((2-fluorophenyl)sulfonyl)
acetonitrile (1) with α-chloro oximes (2)
6 (%)
17a
5 (%)
1
2
3
4
5
6
7
8
a
b
c
2,6-di-ClC6H3
2,4-di-ClC6H3
4-F-C6H4
H
O
S
19a
18a
19a
N
O
O
Ar
Cl
OH
N
Cs2CO3
DMSO
N
+
N
S
F
Ar
O
O
3
d
e
4-Br-C6H4
4-Cl-C6H4
16a, 81b
73b
81b
37
38
50
46
1
2
f
C6H5
g
h
2-Cl-4,5-diMeOC6H3
2-O2NC6H4
Yields*
(%)
Yields**
(%)
Compound
Ar
Entry
83b
aYields obtained through one-pot single step reaction.
1
2
3a
3b
3c
3d
3e
3f
2,6-di-ClC6H3
2,4-di-ClC6H3
4-F-C6H4
30
53
40
54
59
46
58
50
54
65
52
37
67
58
58
67
51
67
69
68
72
64
bYields obtained through isolation of compounds 5 e–h and then,
reaction in the presence of Cs2CO3 in DMSO.
3
4
4-Br-C6H4
4-Cl-C6H4
C6H5
The structures of all compounds were elucidated
1
according to IR, H and 13C NMR spectroscopy and HRMS
5
methods. The IR spectra of compounds 3a–k showed NH
stretching between 3244 cm-1 and 3214 cm-1, SO2
asymmetric stretching of compounds 3a–k was seen at 1342-
1261 cm-1 and symmetric stretching at 1173–1142 cm-1.
While NH2 asymmetric and symmetric stretching frequencies
for compounds 5e–h appeared between 3383–3310 cm-1 and
3317–3171 cm-1, NH stretching frequencies of compounds
6a–h were observed between 3445 and 3433 cm-1. The
compounds 5e–h and 6a–h exhibited a SO stretching
frequency at 1007–1069 cm-1 and 999–957 cm-1,
6
7
3g
3h
3i
2-Cl-4,5-diMeO-C6H3
2-O2N-C6H4
8
9
4-O2N-C6H4
10
11
3j
5-Cl-2-thienyl
5-Cl-2-furyl
3k
* Yields obtained by conventional heating method.
** Yields obtained by microwave heating method.
1
respectively. The H NMR spectra of compounds 3a–k and
Having examined the scope of the sulfone functionality
in the reaction, we next examined the synthesis of isoxazolo-
1,4-benzothiazin-4-oxides. The reaction in a one-pot manner
gave lower yields (for 6a-d), but firstly isolation of 5-
aminoisoxazole 5e-h intermediate and then, its heating in
high boiling point aprotic solvents (DMSO or DMF) in the
presence of Cs2CO3 afforded the corresponding isoxazolo-
1,4-benzothiazine 4-oxides 6a–h with better yields, see
Table 2.
6a–h displayed a broad singlet for NH protons between
13.28–13.14 ppm and 13.21–12.97 ppm in DMSO
respectively. When the 1H NMR was run in DMSO, the
amino protons resonated at 8.08–8.29 ppm due to interaction
with water in DMSO, when same pattern of compound 5f
was run in CDCl3, the amino group protons resonated at 5.57
ppm. The 13C NMR spectra of compounds 3a–k contained a
signal in the range of 163.0–161.5, 158.7–147.9 and 95.1–
91.3 ppm, which are in accordance with isoxazole carbons.
There is no dramatic effect of the sulfoxide or sulfone groups
on the carbon signals in isoxazole ring for the two series of
compounds. In addition, the isoxazole ring showed similar
signals for compounds 5e–h for the C5 carbon at 171.0–
169.1 ppm, for the C4 carbon at 161.2–159.3 ppm, for the C3
carbon at 91.9–90.6 ppm and for compounds 6a–h for the C5
carbon at 161.8–160.7, for the C4 carbon at 160.2–157.6, for
the C3 carbon at 95.0–93.0 ppm. Moreover, the proposed
intermolecular nucleophilic substitution reaction can be
easily understood by the disappearance of C-F couplings
2

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from starting materials (5e–h). When the 13C NMR of
The solvent was evaporated under reduced pressure and the
resulting solid was recrystallized from benzene.
compound 6a was analyzed the restricted rotation for the 2,6-
dichloro substituents results in each carbon atom on the ring
having different resonances. HRMS results were in
agreement with the expected molecular weights of all novel
compounds.
General Synthesis of 3-Aryl-9H-benzo[b]isoxazolo[5,4-
e][1,4] thiazine 4,4-dioxide (Microwave Heating Method)
(2-Fluorobenzensulfonyl)acetonitrile (199 mg, 1.0 mmol)
and α-chloro oxime (1.0 mmol) were dissolved in DMSO (5
mL). To this mixture Cs2CO3 (652 mg, 2.0 mmol) was
added. The mixture was heated in microwave reactor at 200
W, 150 °C for 10 min. Progress of the reaction was
monitored by TLC. After completion of the reaction, the
mixture was washed with ice-cold water (10 mL) and
extracted with EtOAc (3x15 mL). Then, the combined
organic layers were washed with brine and dried (Na2SO4).
The solvent was removed under reduced pressure and the
remaining solid was recrystallized from benzene.
Regarding the reaction mechanism, it would be
reasonable to assume that two reaction mechanisms may
occur until the formation of 5-aminoisoxazoles. First
proposed mechanism may work through deprotonation of the
carbon atom next to the nitrile occurs. This would then be
followed by nucleophilic addition to the iminic carbon atom
of α-hydroxymoyl chlorides. Finally, the cyclisation occurs
with firstly the attack of the OH onto the nitrile carbon atom
to give 5-aminoisoxazoles. Another mechanism may involve,
under basic conditions α-chloro oximes will form nitrile
oxides. These will then engage in 1,3-dipolar cycloaddition
with the deprotonated starting material to give 5-
aminoisoxazoles. Then an SNAr displacement reaction of
fluoride with NH2 group results in cyclization 1,4-
benzothiazines.38,39
3-(2,6-Dichlorophenyl)-9H-benzo[b]isoxazolo[5,4-
e][1,4]thiazine 4,4-dioxide (3a)
White solid; 112 mg, 30% (conventional), 136 mg, 37%
(microwave); mp 228–230 °C; Rf = 0.45 (EtOAc 1:1 Hex).
IR (KBr): 3244 (NH), 3090 (CH), 1636 (C=N) and 1261–
1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 13.28
(br s, 1H, NH), 7.92 (dd, J = 8.2, 1.3 Hz, 1H), 7.76 – 7.72
(m, 1H), 7.72 – 7.63 (m, 3H), 7.45 – 7.41 (m, 1H), 7.40 –
7.37 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 161.9,
154.0, 134.6, 133.6, 133.5, 133.1, 128.5, 125.7, 124.5, 124.2,
122.9, 118.2, 94.4. MS (TOF ES+): m/z (%) = 367 (M+H+,
100%). HRMS: m/z [M+H]+ calc. for C15H937Cl2N2O3S:
366.9711; found: 366.9706.
2. Conclusion
In conclusion, we have developed a very efficient
synthesis of the new tricyclic isoxazole−fused 1,4-
benzothiazine 4,4-dioxides and 4-oxides via a domino
reaction under transition-metal free conditions.
3. Experimental Section
3-(2,4-Dichlorophenyl)-9H-benzo[b]isoxazolo[5,4-
e][1,4]thiazine 4,4-dioxide (3b)
Anhydrous solvents and all reagents were purchased from
Sigma–Aldrich and Carlo Erba. NMR spectra were recorded
in DMSO-d6 or CDCl3 at 400 or 300 MHz (for 1H NMR) and
at 125 or 100 MHz (for 13C NMR) with Jeol 400 or Bruker
Avance 300 instruments at 25 °C. Chemical shifts are
reported in parts per million (ppm) and the coupling
constants (J) are expressed in Hertz (Hz). Splitting patterns
are designated as follows: s (singlet); d (doublet); m
(multiplet); broad s (broad singlet); dd (doublet of doublets);
app s (apparent singlet); app d (apparent doublet); app t
(apparent triplet). Fourier Transform Infrared (FT-IR)
spectra were recorded on a SHIMADZU FT-IR-8400S. The
mass analyses were performed on a Waters 2695 Alliance
Micromass ZQ (LC-MS) and Waters SYNAPT (HRMS).
Analytical thin-layer chromatography (TLC) was carried out
on Merck silica gel F-254 plates. Flash chromatography
purifications were performed on Merck Silica gel 60 (230–
400 mesh ASTM) as the stationary phase and ethyl acetate/n-
hexane were used as eluents. Melting points (mp) were
measured in open capillary tubes with a MELTEMP
apparatus and are uncorrected.
White solid; 229 mg, 62% (conventional), 246 mg, 67%
(microwave); mp 229–231 °C; Rf = 0.46 (EtOAc 1:1 Hex).
IR (KBr): 3214 (NH), 3090 (CH), 1632 (C=N) and 1265–
1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 13.20
(br s, 1H, NH), 7.93 (dd, J = 8.2, 1.1 Hz, 1H), 7.91 (d, J =
2.0 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.75 – 7.70 (m, 1H),
7.68 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 – 7.36 (m, 2H). 13C NMR
(100 MHz, DMSO-d6): δ = 162.4, 155.6, 137.0, 134.2, 134.0,
133.8, 133.4, 130.4, 128.4, 126.2, 124.9, 124.6, 123.5, 118.7,
95.1. MS (TOF ES+): m/z (%) = 367 (M+H+, 100%), 369
(65%), 329 (28%), 307 (18%), 143 (12%). HRMS: m/z
[M+H]+ calc. for C15H937Cl2N2O3S: 366.9711; found:
366.9703.
3-(4-Florophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]thiazine
4,4-dioxide (3c)
Light yellow solid; 126 mg, 40% (conventional), 184 mg,
58% (microwave); mp 239–240 °C; Rf = 0.45 (EtOAc 1:1
Hex). IR (KBr): 3244 (NH), 3090 (CH), 1632 (C=N) and
1
1269–1142 (SO2) cm−1. H NMR (400 MHz, DMSO-d6) δ =
4
General Synthesis of 3-Aryl-9H-benzo[b]isoxazolo[5,4-
e][1,4] thiazine 4,4-dioxide (Conventional Heating Method)
13.16 (br s, 1H, NH), 8.11 (dd, J = 8.9, JH-F 5.4 Hz, 2H),
8.01 (dd, J = 8.1, 1.0 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.47 (t, J
= 8.9 Hz, 2H), 7.43 – 7.38 (m, 2H). 13C NMR (100 MHz,
2-((2-Fluorophenyl)sulfonyl)acetonitrile (199 mg, 1.0 mmol)
and α-chloro oxime (1.0 mmol) were dissolved in DMSO (5
mL). Subsequently, Cs2CO3 (652 mg, 2.0 mmol) was added
to this solution and the mixture was stirred at reflux for 2 h.
The progress of the reaction was monitored by TLC. The
1
DMSO-d6): δ = 164.3 (d, JC-F = 249.6 Hz), 162.5, 157.7,
3
134.2, 133.5, 130.9 (d, JC-F = 9.0 Hz), 125.8, 124.5, 123.8,
4
2
123.3 (d, JC-F = 3.2 Hz), 118.4, 116.9 (d, JC-F = 22.2 Hz),
93.6. MS (TOF ES+): m/z (%) = 317 (M+H+, 100%), 281
(15%), 271 (17%). HRMS: m/z [M+H]+ calc. for
C15H10FN2O3S: 317.0396; found: 317.0407.
mixture was extracted with EtOAc (3
x 15 mL),
subsequently washed with brine (15 mL) and dried (Na2SO4).
3

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3-(4-Bromophenyl)-9H-benzo[b]isoxazolo[5,4-
e][1,4]thiazine 4,4-dioxide (3d)
Light brown solid, 170 mg, 50% (conventional), 236 mg,
69% (microwave); mp 253–256 °C; Rf = 0.33 (EtOAc 1:1
Hex). IR (KBr): 3221 (NH), 3082 (CH), 1640 (C=N) and
1273–1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ =
13.26 (br s, 1H, NH), 8.28 (dd, J = 8.4, 1.2 Hz, 1H), 8.01 –
7.96 (m, 1H), 7.95 – 7.88 (m, 3H), 7.73 (ddd, J = 8.5, 7.2,
1.4 Hz, 1H), 7.44 – 7.41 (m, 1H), 7.39 (dd, J = 8.1, 1.0 Hz,
1H). 13C NMR (100 MHz, DMSO-d6): δ = 161.7, 155.6,
147.8, 134.2, 133.7, 133.2, 132.6, 131.8, 125.5, 125.2, 124.1,
122.9, 120.4, 118.2, 94.0. MS (TOF ES+): m/z (%) = 344
(M+H+, 100%), 274 (25%). HRMS: m/z [M+H]+ calc. for
C15H10N3O5S: 344.0341; found: 344.0344.
White solid; 204 mg, 54% (conventional), 216 mg, 58%
(microwave); mp 253–255 °C; Rf = 0.45 (EtOAc 1:1 Hex).
IR (KBr): 3229 (NH), 3090 (CH), 1643 (C=N) and 1269–
1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 13.19
(br s, 1H, NH), 8.02 – 8.00 (m, 1H), 7.98 (d, J = 8.5 Hz, 2H),
7.83 (d, J = 8.5 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.41 (t, J =
7.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 162.2,
157.3, 133.8, 133.0, 132.4, 129.9, 125.6, 125.3, 125.2, 124.0,
123.3, 118.0, 93.1. MS (TOF ES+): m/z (%) = 377 (M+H+,
88%), 379 (100%), 329 (20%), 307 (20%), 291 (17%).
HRMS: m/z [M+H]+ calc. for C15H1079BrN2O3S: 376.9596;
found: 376.9585.
3-(4-Nitrophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]thiazine
4,4-dioxide (3i)
3-(4-Chlorophenyl)-9H-benzo[b]isoxazolo[5,4-
e][1,4]thiazine 4,4-dioxide (3e)
Light brown solid; 184 mg, 54% (conventional), 134 mg,
68% (microwave); mp 285–287 °C; Rf = 0.34 (EtOAc 1:1
Hex). IR (KBr): 3221 (NH), 3093 (CH), 1628 (C=N) and
1342–1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ =
13.18 (br s, 1H, NH), 8.44 (d, J = 8.9 Hz, 2H), 8.29 (d, J =
8.9 Hz, 2H), 8.02 (dd, J = 8.4, 1.2 Hz, 1H), 7.83 – 7.65 (m,
1H), 7.42 (t, J = 7.4 Hz, 2H). 13C NMR (100 MHz, DMSO-
d6): δ = 160.0, 157.1, 149.6, 134.3, 133.5, 132.8, 129.8,
125.8, 124.9, 124.6, 123.7, 118.6, 93.9. MS (TOF ES+): m/z
(%) = 344 (M+H+, 100%). HRMS: m/z [M+H]+ calc. for
C15H10N3O5S: 344.0341; found: 344.0324.
White solid; 196 mg, 59% (conventional), 222 mg, 67%
(microwave); mp 241–242 °C; Rf = 0.46 (EtOAc 1:1 Hex).
IR (KBr): 3244 (NH), 3090 (CH), 1632 (C=N) and 1273–
1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 13.16
(br s, 1H, NH), 8.06 (d, J = 8.7 Hz, 2H), 8.02 (dd, J = 8.1,
1.2 Hz, 1H), 7.74 (app. dd, J = 7.2, 1.4 Hz, 1H), 7.70 (d, J =
8.7 Hz, 2H), 7.44 – 7.38 (m, 2H). 13C NMR (101 MHz,
DMSO-d6): δ = 162.1, 157.2, 136.3, 133.8, 133.0, 129.7,
129.4, 125.3, 125.2, 124.04, 123.3, 118.0, 93.2. MS (TOF
ES+): m/z (%) = 333 (M+H+, 100%), 291 (35%). HRMS: m/z
[M+H]+ calc. for C15H1037ClN2O3S: 333.0101; found:
333.0108.
3-(5-Chlorothiophen-2-yl)-9H-benzo[b]isoxazolo[5,4-e]
[1,4]thiazine 4,4-dioxide (3j)
White solid; 197 mg, 65% (conventional), 243 mg, 72%
(microwave); mp 215–217 °C; Rf = 0.47 (EtOAc 1:1 Hex).
IR (KBr): 3221 (NH), 3082 (CH), 1640 (C=N) and 1265–
1138 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 13.24
(br s, 1H, NH), 8.04 (d, J = 8.2 Hz, 1H), 7.92 – 7.84 (m, 1H),
7.73 (t, J = 8.4 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.41 – 7.38
(m, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 162.5, 152.5,
134.3, 133.4, 133.3, 132.2, 128.9, 126.0, 125.7, 124.6, 123.8,
118.6, 92.6. MS (TOF ES+): m/z (%) = 339 (M+H+, 100%),
329 (53%). HRMS: m/z [M+H]+ calc. for C13H8N2O3S237Cl:
338.9665; found: 338.9674.
3-Phenyl-9H-benzo[b]isoxazolo[5,4-e][1,4]thiazine
dioxide (3f)
4,4-
White solid; 136 mg, 46% (conventional), 152 mg, 51%
(microwave); mp 238–239 °C; Rf = 0.45 (EtOAc 1:1 Hex).
IR (KBr): 3217 (NH), 3075 (CH), 1640 (C=N) and 1261–
1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 13.14
(br s, 1H, NH), 8.08 – 8.04 (m, 2H), 8.01 (d, J = 8.1 Hz, 1H),
7.73 (td, J = 7.7, 1.3 Hz, 1H), 7.67 – 7.56 (m, 3H), 7.41 (t, J
= 7.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 162.5,
158.7, 134.2, 133.5, 131.9, 129.7, 128.5, 126.8, 125.9, 124.5,
123.8, 118.4, 93.7. MS (TOF ES+): m/z (%) = 299 (M+H+,
100%). HRMS: m/z [M+H]+ calc. for C15H11N2O3S:
299.0490; found: 299.0489.
3-(5-Chlorofuran-2-yl)-9H-benzo[b]isoxazolo[5,4-e][1,4]
thiazine 4,4-dioxide (3k)
Brown solid; 150 mg, 52% (conventional), 206 mg, 64%
(microwave); mp 233 °C decomp; Rf = 0.42 (EtOAc 1:1
Hex). IR (KBr): 3225 (NH), 3078 (CH), 1636 (C=N) and
1282–1173 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ =
13.20 (br s, 1H, NH), 8.03 (dd, J = 8.1, 1.3 Hz, 1H), 7.73
(ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.41 –
7.38 (m, 1H), 6.86 (d, J = 3.7 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6): δ = 161.7, 147.9, 140.0, 138.9, 133.7, 132.9,
125.3, 124.1, 123.2, 118.1, 118.0, 109.8, 91.3. MS (TOF
ES+): m/z (%) = 323 (M+H+, 100%). HRMS: m/z [M+H]+
calc. for C13H837ClN2O3S2: 322.9893; found: 322.9899.
3-(2-Chloro-4,5-dimethoxyphenyl)-9H-benzo[b]isoxazolo
[5,4-e][1,4]thiazine 4,4-dioxide (3g)
Light brown solid; 209 mg, 58% (conventional), 238 mg,
67% (microwave); mp 197–199 °C; Rf = 0.33 (EtOAc 1:1
Hex). IR (KBr): 3221 (NH), 3090 (CH), 1636 (C=N) and
1261–1142 (SO2) cm−1. 1H NMR (400 MHz, DMSO-d6): δ =
13.14 (br s, 1H, NH), 7.96 (dd, J = 8.1, 1.2 Hz, 1H), 7.72
(ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.41 (s, 1H), 7.41 – 7.36 (m,
2H), 7.24 (s, 1H), 3.87 (s, 3H), 3.79 (s, 3H). 13C NMR (100
MHz, DMSO-d6): δ = 161.5, 155.9, 150.9, 147.5, 133.6,
133.1, 125.6, 123.9, 123.7, 123.1, 118.0, 116.4, 114.1, 113.5,
94.5, 56.1 55.8. MS (TOF ES+): m/z (%) = 393 (M+H+,
100%). HRMS: m/z [M+H]+ calc. for C17H1437ClN2O5S:
393.0312; found: 393.0315.
General Synthesis of 3-Aryl-4-((2-fluorophenyl)sulfinyl)
isoxasazol-5-amine
2-((2-Fluorophenyl)sulfinyl)acetonitrile (1.0 eq, 183.2 mg,
2.0 mmol) and any α-chloro oxime (1.0 eq, 2.0 mmol) were
dissolved in MeOH. NaOH (3.0 eq, 120.0 mg, 6 mmol) was
added and the reaction mixture was refluxed 2 h. Progress of
the reaction was monitored by TLC. The solvent was
3-(2-Nitrophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]thiazine
4,4-dioxide (3h)
4

ACCEPTED MANUSCRIPT
General Synthesis of 3-Aryl-9H-benzo[b]isoxazolo[5,4-
evaporated in vacuo. Column chromatography was applied
e][1,4]thiazine 4-oxide (Method A)
for purification. (EtOAc 1:2 Hexane)
2-((2-fluorophenyl)sulfinyl)acetonitrile (1.0 eq., 183 mg, 1.0
3-(4-Chlorophenyl)-4-((2-fluorophenyl)sulfinyl)isoxazol-5-
amine (5e)
mmol,) and α-chloro oxime (1.0 eq., 1.0 mmol)
were
dissolved in DMSO (5 mL) and Cs2CO3 (2.0 eq., 652 mg, 2.0
mmol) was added, and the mixture stirred at reflux for 2 h.
The progress of the reaction was monitored by TLC. The
White solid; 247 mg, 37%; mp 157–158 °C; Rf = 0.40
(EtOAc 1:1 Hex). IR (KBr): 3383–3178 (NH2), 1643 (C=N)
1
and 1069 (SO) cm−1. H NMR (300 MHz, DMSO-d6): δ =
mixture was extracted with EtOAc (3
x 15 mL),
8.15 (s, 2H, NH2), 7.66 – 7.55 (m, 3H), 7.46 – 7.34 (m, 3H),
subsequently washed with brine (15 mL) and dried (Na2SO4).
The solvent was removed under reduced pressure and the
resulting solid was recrystallized from benzene.
7.19 – 7.10 (m, 2H). 13C NMR (75 MHz, DMSO-d6): δ =
1
171.0, 161.0, 156.6 (d, JC-F = 246.0 Hz), 134.9, 132.6 (d,
2’
3JC-F = 7.9 Hz), 130.2, 129.4, 128.95 (d,
J
C-F
= 14.8 Hz),
General Synthesis of 3-Aryl-9H-benzo[b]isoxazolo[5,4-
e][1,4]thiazine 4-oxide (Method B)
127.0, 126.4, 124.2 (d, 3’JC-F = 3.2 Hz), 115.8 (d, 2JC-F = 19.9
Hz), 90.7. MS (TOF ES+): m/z (%) = 337 (M+H+, 100%).
HRMS: m/z [M+H]+ calc. for C15H1137ClFN2O2S: 337.0214;
found: 337.0215.
3-Aryl-4-((2-fluorophenyl)sulfinyl)isoxazol-5-amine
(1.0
mmol) was dissolved in DMSO (5 mL) and Cs2CO3 (326
mg, 1.0 mmol) was added, and the mixture stirred at reflux
for 1 h. The progress of the reaction was monitored by TLC.
Then, the mixture was extracted with EtOAc (3 x 15 mL),
subsequently washed with brine and dried on Na2SO4. The
solvent was evaporated under reduced pressure and the
resultant solid was recrystallized from benzene.
4-((2-Fluorophenyl)sulfinyl)-3-phenylisoxazol-5-amine (5f)
White solid; 232 mg, 38%; mp 164–166 °C; Rf = 0.37
(EtOAc 1:1 Hex). IR (KBr): 3383–3317 (NH2), 1643 (C=N)
1
and 1069 (SO) cm−1. H NMR (300 MHz, CDCl3): δ = 7.77
(ddd, J = 8.9, 7.4, 1.5 Hz, 1H), 7.67 – 7.61 (m, 2H), 7.41 –
7.32 (m, 4H), 7.23 (ddd, J = 8.7, 7.6, 1.1 Hz, 1H), 6.98 (ddd,
J = 9.5, 8.2, 1.0 Hz, 1H), 5.57 (s, 2H, NH2). 13C NMR (75
3-(2,6-Dichlorophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]
thiazine 4-oxide (6a)
1
MHz, CDCl3): δ = 169.1, 161.2, 158.2 (d, JC-F = 250.4 Hz),
3
2’
133.3 (d, JC-F = 7.8 Hz), 130.4, 130.1 (d,
J
C-F
= 15.5 Hz),
Brown solid; 60 mg, 17% (method A); mp 209 °C decomp;
Rf = 0.31 (EtOAc 2:1 Hex). IR (KBr): 3433 (NH), 1636
128.7, 128.3, 127.6, 126.5 (d, 4JC-F = 1.4 Hz), 124.7 (d, 3’JC-F
= 3.5 Hz), 116.5 (d, JC-F = 20.2 Hz), 90.6. MS (TOF ES+):
2
1
(C=N) and 995 (SO) cm−1. H NMR (400 MHz, DMSO-d6):
m/z (%) = 303 (M+H+, 100%). HRMS: m/z [M+H]+ calc. for
δ = 13.10 (br s, 1H, NH), 7.96 (dd, J = 7.9, 1.3 Hz, 1H), 7.74
– 7.73 (m, 1H), 7.72 – 7.65 (m, 3H), 7.47 (dd, J = 8.3, 0.9
Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6): δ = 160.9, 157.6, 134.8, 134.4, 133.4, 133.3,
132.9, 132.3, 128.9, 128.6, 124.9, 124.3, 124.1, 118.2, 94.7.
MS (TOF ES+): m/z (%) = 351 (M+H+, 100%). HRMS: m/z
[M+H]+ calc. for C15H937Cl2N2O2S: 350.9762; found:
350.9762.
C15H12FN2O2S: 303.0604; found: 303.0618.
3-(2-Chloro-4,5-dimethoxyphenyl)-4-((2-fluorophenyl)
sulfinyl)isoxazol-5-amine (5g)
Yellow solid; 401 mg, 50%; mp 118–120 °C; Rf = 0.17
(EtOAc 1:1 Hex). IR (KBr): 3314–3171 (NH2), 1640 (C=N)
1
and 1011 (SO) cm−1. H NMR (300 MHz, DMSO-d6): δ =
8.08 (s, 2H, NH2), 7.45 – 7.35 (m, 1H), 7.31 (td, J = 7.6, 1.7
Hz, 1H), 7.23 – 7.15 (m, 1H), 7.07 (td, J = 7.7, 1.0 Hz, 1H),
6.88 (s, 1H), 6.75 (s, 1H), 3.78 (s, 3H), 3.71 (s, 3H). 13C
NMR (75 MHz, DMSO-d6): δ = 170.1, 159.5, 156.7 (d, J =
246.0 Hz), 150.2, 148.1, 147.0, 132.3 (d, J = 7.8 Hz), 129.1
(d, J = 15.1 Hz), 125.6, 124.1 (d, J = 3.2 Hz), 123.7, 118.0,
115.8 (d, J = 19.9 Hz), 113.4 (d, J = 124.8 Hz), 91.9, 56.0,
55.6. MS (TOF ES+): m/z (%) = 397 (M+H+, 100%). HRMS:
m/z [M+H]+ calc. for C17H1537ClFN2O4S: 397.0425; found:
397.0437.
3-(2,4-Dichlorophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]
thiazine 4-oxide (6b)
Brown solid; 67 mg, 19% (method A), 312 mg, 89%
(method B); mp 139–141 °C; Rf = 0.31 (EtOAc 2:1 Hex). IR
(KBr): 3433 (NH), 1632 (C=N) and 957 (SO) cm−1. 1H NMR
(300 MHz, DMSO-d6): δ = 13.14 (br s, 1H, NH), 8.01 (dd, J
= 7.9, 1.3 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.79 (d, J = 8.3
Hz, 1H), 7.76 – 7.68 (m, 2H), 7.49 (d, J = 7.5 Hz, 1H), 7.39
(t, J = 7.5 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ =
160.9, 158.6, 136.5, 133.4, 133.2, 132.9, 132.8, 132.3, 130.2,
128.2, 124.8, 124.1, 124.0, 118.1, 95.0. MS (TOF ES+): m/z
(%) = 351 (M+H+, 100%), 203 (22%), 143 (17%). HRMS:
m/z [M+H]+ calc. for C15H937Cl2N2O2S: 350.9762; found:
350.9760.
4-((2-Fluorophenyl)sulfinyl)-3-(2-nitrophenyl)isoxazol-5-
amine (5h)
Yellow solid; 319 mg, 46%; mp 156–157 °C; Rf = 0.17
(EtOAc 1:1 Hex). IR (KBr): 3310–3178 (NH2), 1647 (C=N)
1
and 1007 (SO) cm−1. H NMR (300 MHz, DMSO-d6): δ =
3-(4-Fluorophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]
thiazine 4-oxide (6c)
8.29 (s, 2H, NH2), 8.00 – 7.94 (m, 1H), 7.68 – 7.63 (m, 2H),
7.38 – 7.27 (m, 2H), 7.18 – 7.10 (m, 1H), 7.02 (td, J = 7.6,
1.8 Hz, 1H), 6.88 (td, J = 7.7, 1.0 Hz, 1H). 13C NMR (75
Brown solid; 55 mg, 18% (method A), mp 165–166 °C; Rf =
0.32 (EtOAc 2:1 Hex). IR (KBr): 3433 (NH), 1636 (C=N)
1
MHz, DMSO-d6): δ = 170.2, 159.3, 156.8 (d, JC-F = 246.5
3
1
and 995 (SO) cm−1. H NMR (300 MHz, DMSO-d6): δ =
Hz), 147.4, 133.3, 132.3 (d, JC-F = 7.8 Hz), 132.1, 131.3,
2’
3’
128.8 (d,
J
C-F
= 15.1 Hz), 123.9 (d,
J
C-F
= 3.2 Hz), 125.1,
13.02 (br s, 1H, NH), 8.07 – 8.03 (m, 2H), 8.02 (d, J = 1.7
Hz, 1H), 7.71 (ddd, J =8.5, 7.2, 1.4 Hz, 1H), 7.51 (t, J = 8.9
2
124.3, 122.1, 115.8 (d, JC-F = 19.8 Hz), 91.6. MS (TOF
ES+): m/z (%) = 348 (M+H+, 100%). HRMS: m/z [M+H]+
calc. for C15H11FN3O4S: 348.0454; found: 348.0454.
Hz, 2H), 7.46 (dd, J = 8.3, 0.9 Hz, 1H), 7.39 (t, J = 8.1 Hz,
1
1H). 13C NMR (75 MHz, DMSO-d6): δ = 163.7 (d, JC-F
=
249.0 Hz), 162.0, 161.2, 159.4, 133.2, 132.9, 132.2, 130.1 (d,
5

ACCEPTED MANUSCRIPT
3JC-F = 8.9 Hz), 123.9, 123.7 (d, 4JC-F = 2.2 Hz), 117.9, 116.7
3-(2-Nitrophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]thiazine
4-oxide (6h)
2
(d, JC-F = 22.1 Hz), 93.0. MS (TOF ES+): m/z (%) = 301
(M+H+, 100%). HRMS: m/z [M+H]+ calc. for C15H10FN2O2S:
301.0447; found: 301.0144.
Yellow solid; 272 mg, 83% (method B); mp 191–193 °C; Rf
= 0.14 (EtOAc 2:1 Hex). IR (KBr): 3445 (NH), 1632 (C=N)
1
and 999 (SO) cm−1. H NMR (300 MHz, DMSO-d6): δ =
3-(4-Bromophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]
thiazine 4-oxide (6d)
13.21 (br s, 1H, NH), 8.32 (dd, J = 8.2, 1.1 Hz, 1H), 8.10 –
8.03 (m, 2H), 8.02 – 7.95 (m, 2H), 7.78 (ddd, J = 8.5, 7.3,
1.4 Hz, 1H), 7.54 (dd, J = 8.3, 0.8 Hz, 1H), 7.45 (t, J = 8.1
Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ = 160.9, 158.5,
148.5, 134.1, 133.2, 133.1, 132.5, 132.4, 131.8, 125.3, 124.2,
123.9, 120.6, 118.2, 94.4. MS (TOF ES+): m/z (%) = 328
(M+H+, 100%). HRMS: m/z [M+H]+ calc. for C15H10N3O4S:
328.0392; found: 328.0399.
Light brown solid; 70 mg, 19% (method A); mp 175–176 °C;
Rf = 0.34 (EtOAc 2:1 Hex). IR (KBr): 3445 (NH), 1628
1
(C=N) and 991 (SO) cm−1. H NMR (300 MHz, DMSO-d6):
δ = 13.05 (br s, 1H, NH), 8.04 (dd, J = 7.9, 1.3 Hz, 1H), 7.93
(d, J = 8.7 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.71 (ddd, J =
8.4, 7.4, 1.4 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.39 (t, J =
7.5 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ = 161.3,
159.4, 133.2, 133.0, 132.6, 132.2, 129.5, 126.3, 124.8, 124.0,
123.6, 118.0, 93.0. MS (TOF ES+): m/z (%) = 361 (M+H+,
98%), 363 (100%). HRMS: m/z [M+H]+ calc. for
C15H1079BrN2O2S: 360.9646; found: 360.9646.
Acknowledgment
We are grateful to TUBITAK (Project No:114Z181) for
financial support.
3-(4-Chlorophenyl)-9H-benzo[b]isoxazolo[5,4-e][1,4]
thiazine 4-oxide (6e)
References
(1)
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Brown solid; 50 mg, 16% (method A), 257 mg 81% (method
B), mp 165–167 °C; Rf = 0.31 (EtOAc 2:1 Hex). IR (KBr):
1
3433 (NH), 1632 (C=N) and 991 (SO) cm−1. H NMR (400
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MHz, DMSO-d6): δ = 12.97 (br s, 1H, NH), 8.01 (dd, J =
7.9, 1.1 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5
Hz, 2H), 7.68 (dd, J = 8.4, 1.2 Hz, 1H), 7.44 (d, J = 7.9 Hz,
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d6): δ = 161.8, 159.8, 136.5, 133.7, 133.4, 132.7, 130.1,
129.8, 126.5, 124.4, 124.1, 118.5, 93.5.MS (TOF ES+): m/z
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m/z [M+H]+ calc. for C15H1037ClN2O2S: 317.0152; found:
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White solid; 220 mg, 78% (method B); mp 144–145 °C; Rf =
0.33 (EtOAc 2:1 Hex). IR (KBr): 3445 (NH), 1632 (C=N)
1
and 991 (SO) cm−1. H NMR (300 MHz, DMSO-d6): δ =
13.05 (br s, 1H, NH), 8.08 (dd, J = 7.9, 1.3 Hz, 1H), 8.06 –
8.03 (m, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.75 (ddd, J = 8.5,
7.2, 1.5 Hz, 1H), 7.72 – 7.65 (m, 3H), 7.50 (dd, J = 8.3, 0.9
Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H). 13C NMR (75 MHz,
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129.5, 127.6, 127.2, 123.9, 123.7, 118.0, 93.1. MS (TOF
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(8)
(9)
(10)
3-(2-Chloro-4,5-dimethoxyphenyl)-9H-benzo[b]isoxazolo
[5,4-e][1,4]thiazine 4-oxide (6g)
Light yellow solid; 323 mg, 81% (method B); mp 164–
166 °C; Rf = 0.16 (EtOAc 2:1 Hex). IR (KBr): 3445 (NH),
1624 (C=N) and 984 (SO) cm−1. 1H NMR (300 MHz,
DMSO-d6): δ = 13.07 (br s, 1H, NH), 8.06 (dd, J = 7.9, 1.3
Hz, 1H), 7.76 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.52 (dd, J =
8.2, 0.8 Hz, 1H), 7.46 – 7.39 (m, 1H), 7.36 (s, 1H), 7.34 (s,
1H), 3.94 (s, 3H), 3.87 (s, 3H). 13C NMR (75 MHz, DMSO-
d6): δ = 160.7, 159.3, 151.0, 147.9, 133.3, 132.9, 132.3,
124.0, 123.9, 123.7, 118.0, 117.1, 113.9, 113.6, 95.0, 56.2,
56.0. MS (TOF ES+): m/z (%) = 377 (M+H+, 100%), 290
(10%), 143 (13%). HRMS: m/z [M+H]+ calc. for
C17H1437ClN2O4S: 377.0363; found: 377.0367.
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6

ACCEPTED MANUSCRIPT
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Supplementary Material
Copies of 1H and 13C NMR spectra of all new compounds.
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