Use of (Z)-β-(2-fluorobenzenesulfonyl)vinylamines as novel synthons in the synthesis of 1,4-benzothiazine derivatives

Article abstract of DOI:10.1055/s-0031-1289741

A novel synthetic route for arylated 1,4-benzothiazine derivatives has been developed. This method utilizes a key intramolecular nucleophilic aromatic substitution step of the corresponding (Z) - (2-fluorobenzenesulfonyl)vinylamine intermediate to construct the benzothiazine ring. A wide range of aryl and heteroaryl substituent groups can be installed from commercial boronic acids. Both mono- and diarylated products have been synthesized in good yields and with good functional group tolerance. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289741

PAPER
▌1359
paper
Use of (Z)-β-(2-Fluorobenzenesulfonyl)vinylamines as Novel Synthons in the
Synthesis of 1,4-Benzothiazine Derivatives
Synthesis of 1,4-Benzothiazine Derivatives
Gavin Chit Tsui, Yuttapong Singjunla, Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9468185 ; E-mail: mlautens@chem.utoronto.ca
Received: 22.02.2012; Accepted: 28.02.2012
key disconnections:
Abstract: A novel synthetic route for arylated 1,4-benzothiazine
derivatives has been developed. This method utilizes a key intramo-
H
NR1R2
N
R
O
O
lecular nucleophilic aromatic substitution step of the corresponding
(Z)-β-(2-fluorobenzenesulfonyl)vinylamine intermediate to con-
struct the benzothiazine ring. A wide range of aryl and heteroaryl
substituent groups can be installed from commercial boronic acids.
Both mono- and diarylated products have been synthesized in good
yields and with good functional group tolerance.
+
or
Br
R
Cl
R
conventional
approach
SR3
S
O
O
1
H
N
F
H2N
R
O
Key words: heterocycles, rhodium, sulfone, nucleophilic aromatic
substitution, cyclization
R
S
S
this work
O
O
O
1
(Z)-β-sulfonylvinylamine
1,4-Benzothiazine derivatives have drawn much attention
in the field of medicinal chemistry due to their wide range
of pharmacological properties and structural similarity to
phenothiazines.1 The S-oxidized system, 4H-1,4-benzo-
thiazine 1,1-dioxide 1, is of particular interest and several
reports have described their syntheses.2 Generally, these
methods involved the use of 2-aminobenzenethiol or its
derivative as a starting material for the construction of the
benzothiazine ring. However, they suffered from low
functional group tolerability due to the use of strong bases
such as lithium diisopropylamide and n-butyllithium, and
limited efficiency for divergent synthesis of multiple tar-
gets due to early installment of substituent group in the
linear synthetic sequence.
synthetic plan:
F
H2N
O
F
O
R
CN
Rh(I) cat
R-B(OH)2
+
S
S
addition reaction
of nitrile
O
O
base
H
–
HN
N4
R
F
3
O
R
2
nucleophilic
aromatic
substitution
S
1
S
O
O
O
1
1-aza-allyl anion
Scheme 1
We recently reported the discovery of a novel class of
arylated (Z)-β-sulfonylvinylamines via rhodium(I)-cata-
lyzed addition of arylboronic acids to (arylsulfonyl)aceto-
nitriles.3 Subsequently, their synthetic applications were
demonstrated in the preparations of arylated β-keto sul-
fones by simple hydrolysis3 and 2,4,6-triarylpyridines by
formation of 1-aza-allyl anion intermediates.4 We envi-
sioned that by subjecting the (Z)-β-sulfonylvinylamine,
bearing an ortho-fluoro substituent group on the sulfonyl
aromatic ring, to a base, the resulting anionic intermediate
could perform an intramolecular nucleophilic aromatic
substitution (SNAr) reaction via an addition-elimination
pathway and thus furnish the cyclic core of 4H-1,4-benzo-
thiazine 1,1-dioxide 1 in one step (Scheme 1).
substituent at the ortho-position of the sulfonyl aromatic
ring of the nitrile is tolerated in the rhodium(I)-catalyzed
addition reaction with arylboronic acids,3 but the reactiv-
ity of other substituents such as an ortho-halide was not
known. A variety of nitriles 2b–f were synthesized fol-
lowing the same procedure as 2a and subjected to the rho-
dium(I)-catalyzed addition conditions with phenylboronic
acid (Table 1).
F
F
1. Na2CO3, acetone,
50 °C, 12 h (quant.)
O
S
CN
Cl
CN
+
SH
2. MCPBA (4 equiv), CH2Cl2,
reflux, 12 h (97%)
O
2a
The starting (2-fluorobenzenesulfonyl)acetonitrile (2a)
was synthesized from commercially available 2-fluoro-
benzenethiol and chloroacetonitrile in two steps in 97%
yield (Scheme 2). It has been demonstrated that a methyl
Scheme 2
Phenylated vinylamines 3a,d–f were formed in good
yields under the standard catalytic protocol. The 2-fluoro
group was tolerated and product 3a was obtained in a
good yield (87%) (Table 1, entry 1). In sharp contrast, the
2-chloro- and 2-bromo-substituted substrates were com-
SYNTHESIS 2012, 44, 1359–1364
Advanced online publication: 10.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289741; Art ID: SS-2012-Z0189-OP
© Georg Thieme Verlag Stuttgart · New York

1360
G. C. Tsui et al.
PAPER
pletely unreactive (entries 2, 3). Poorer reactivity from 2- Table 2 Rhodium(I)-Catalyzed Addition of Arylboronic Acid to 2a:
Scope of Aryl Substituent Group
halo substituent groups has been observed in rhodium(I)-
catalyzed reactions and may be due to the reversible bi-
F
F
H2N
O
[Rh(cod)OH]2 (2 mol%)
BINAP (6 mol%)
O
S
CN
Ar
dentate binding of the metal to the halide and a neighbor-
ing coordinating group, which sequesters the catalyst
from the catalytic cycle.5 However, the 2-fluoro group did
not show such an inhibiting effect. Electron-rich ortho-
substituents gave a much higher yield than electron-poor
one (entries 4, 5). The sterically hindering isopropyl group
did not impede the reaction (entry 6).
+
ArB(OH)2
S
Cs2CO3 (1 equiv)
1,4-dioxane–H2O (10:1)
75 °C, 6 h
O
(2.5 equiv)
O
2a
3ab–al
Yield (%)a
Entry
Ar
Product
1
2
4-MeOC6H4
4-AcC6H4
4-CF3C6H4
4-ClC6H4
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
99
87
84
93
90
Table 1 Rhodium(I)-Catalyzed Addition of Phenylboronic Acid to
2-Substituted (Arylsulfonyl)acetonitriles 2a–f
3
R
R
H2N
O
[Rh(cod)OH]2 (2 mol%)
BINAP (6 mol%)
O
S
CN
4
Ph
+
PhB(OH)2
(2.5 equiv)
S
Cs2CO3 (1 equiv)
1,4-dioxane–H2O (10:1)
75 °C, 6 h
O
5
4-MeSC6H4
4-CNC6H4
3-thienyl
O
2a–f
3a–f
63b,c
94
6
Yield (%)a
Entry
R
Product
7
1
2
3
4
5
6
F
3a
3b
3c
3d
3e
3f
87
8
3-AcC6H4
3-MeOC6H4
2-MeC6H4
1-naphthyl
90
<5b
<5b
59
9
3aj
3ak
3al
68
Br
Cl
10
11
91
CF3
73
a Isolated yield.
b Reaction was run for 12 h.
c Recovered 29% of the starting material.
OMe
i-Pr
96
85
a Isolated yield.
b Recovered unreacted starting material.
ing previously found conditions to generate the 1-aza-
allyl anion.4 To our delight, sodium hydroxide facilitated
this process and after heating at 75 °C for only two hours,
the sulfonylvinylamines cyclized to give the arylated 4H-
1,4-benzothiazine 1,1-dioxides 1a–l in high yields (Table
3). The reaction was general despite the electronic and ste-
ric properties of the aryl substituent group, with the excep-
tion of the 4-acetyl group (entry 3) where incomplete
conversion was observed (29% starting material recov-
ery). Sodium hydroxide played the role of a base to depro-
tonate the amino hydrogen of the sulfonylvinylamine 3.
An anionic intermediate (1-aza-allyl anion) was formed
for the subsequent addition-elimination pathway leading
to the cyclized product 1 (cf. Scheme 1). During the
course of the reaction we observed the formation of a
white precipitate, which suggested the elimination of so-
dium fluoride. The strong electron-withdrawing ability of
the sulfone group presumably also enhanced the addition
process.6
The successful formation of 3a proved the feasibility of
our synthetic plan towards 4H-1,4-benzothiazine 1,1-di-
oxides 1. The scope of the aryl substituent of the vinyl-
amine was next broadened by reacting 2a with a wide
array of commercial arylboronic acids (Table 2). Both
electron-rich and electron-poor arylboronic acids provid-
ed the products in good yields (Table 2, entries 1–3), al-
though a higher yield was obtained with the more
electron-rich nucleophile (entry 1). Sensitive groups such
as Cl and SMe were tolerated (entries 4, 5). The reaction
was chemoselective with 4-cyanophenylboronic acid
since the aromatic cyano group in the product was intact
under the reaction conditions (entry 6), albeit an incom-
plete conversion was observed even after a prolonged re-
action time. A heteroaromatic group such as thienyl group
could be installed in good yield (entry 7). 3-Substituted ar-
ylboronic acids also showed good reactivity (entries 8, 9).
However, a strong electron-withdrawing nitro group at the
3-position gave the product in 18% yield. Neither a 2-
methyl nor 1-naphthyl group affected the reaction (entries
10, 11), but -CHO and -COOEt groups at the 2-position
were not tolerated. Vinyl boronic acid such as trans-2-
phenylvinylboronic acid gave no conversion.
To investigate the effect of the α-substituent and the po-
tential for synthesizing a diarylated product, an α-phenyl-
ated substrate 4 was prepared by a palladium-catalyzed α-
arylation reaction (Scheme 3).7 Rhodium(I)-catalyzed ad-
dition with phenylboronic acid took place smoothly to af-
ford the diphenyl sulfonylvinylamine 5 in 94% yield and
sodium hydroxide facilitated cyclization gave the 2,3-di-
phenylbenzothiazine product 6 in 88% yield. This reac-
tion sequence offers a novel modular approach for
With the (Z)-β-(2-fluorobenzenesulfonyl)vinylamines 3a,
3ab–al in hand, we proceeded to the intramolecular cycli-
zation step (via nucleophilic aromatic substitution) by us-
Synthesis 2012, 44, 1359–1364
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1,4-Benzothiazine Derivatives
1361
wide range of aryl substituent groups can be installed in
the product due to the availability of commercial arylbo-
ronic acids and the functional group tolerance of the
Rh(I)-catalyzed addition reaction. The potential for devel-
oping a one-pot procedure from the nitrile starting materi-
al to the final product is currently under investigation.
Table 3 Formation of Arylated 4H-1,4-Benzothiazine 1,1-Dioxides
1a–l by Intramolecular Nucleophilic Aromatic Substitution
H
F
H2N
O
N
Ar
NaOH (3 equiv)
Ar
1,4-dioxane, 75 °C, 2 h
S
S
O
O
O
3a, 3ab–al
1a–l
Yield (%)a
TLC was performed with Silicycle™ normal phase glass plates
(0.25 mm, 60-A pore size, 230–400 mesh). Purification of reaction
products was generally done by flash chromatography with Silicy-
cle™ Ultra-Pure 230–400 mesh silica gel. 1H NMR and 13C NMR
spectra were recorded at 23 °C with a Varian Mercury 400 (400
MHz/100 MHz) NMR spectrometer equipped with a Nalorac4N-
400 probe, or a Varian 400 (400 MHz/100 MHz) NMR spectrome-
ter equipped with ATB8123-400 probe. High-resolution mass spec-
Entry
Ar
Ph
Product
1
1a
1b
1c
1d
1e
1f
96
91
67
97
69
60
86
76
98
69
99
95
2
4-MeOC6H4
4-AcC6H4
4-CF3C6H4
4-ClC6H4
3
4
tra were obtained from
a SI2 Micromass 70S-250 mass
spectrometer (EI) or an ABI/Sciex Qstar mass spectrometer (ESI).
Melting points were taken on a Fisher-Johns melting point appara-
tus and are uncorrected.
5
6
4-MeSC6H4
4-CNC6H4
3-thienyl
(2-Fluorobenzenesulfonyl)acetonitrile (2a)
7
1g
1h
1i
Sulfide synthesis. To a 50-mL flask were added 2-fluorobenzene-
thiol (0.39 mL, 3.6 mmol), Na2CO3 (0.57 g, 5.6 mmol), acetone (20
mL) and chloroacetonitrile (0.23 mL, 3.6 mmol). The mixture was
heated at 50 °C for 12 h until all starting materials were consumed.
The mixture was then filtered through a fritted funnel to remove in-
solubles and the filtrate was concentrated in vacuo. The correspond-
ing crude sulfide product was obtained in quantitative yield and
used in the next step without further purification.
8
9
3-AcC6H4
3-MeOC6H4
2-MeC6H4
1-naphthyl
10
1j
11
1k
1l
Oxidation of sulfide to sulfone. To a 100-mL flask containing dis-
solved sulfide (384 mg, 2.3 mmol) in CH2Cl2 (30 mL), was added
MCPBA (77%) (2.1 g, 9.4 mmol) as a solid portion-wise at 0 °C.
The mixture was refluxed (with a condenser) for 12 h then cooled
to r.t. and quenched with sat. aq Na2S2O3 solution (20 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layer was washed with sat. aq NaHCO3 solution, H2O
then brine, dried over MgSO4, filtered and concentrated in vacuo.
The crude was purified by flash column chromatography on silica
gel (EtOAc–hexanes).
12
a Isolated yield.
synthesizing disubstituted products where each aryl sub-
stituent group can be chosen from the corresponding aryl
iodide and arylboronic acid via a palladium-catalyzed α-
arylation and a rhodium-catalyzed addition reaction.
Yield: 430 mg (97%); white solid; mp 62–63 °C.
1H NMR (300 MHz, CDCl3): δ = 8.07–8.03 (1 H, m), 7.82–7.76 (1
H, m), 7.47–7.43 (1 H, m), 7.37–7.32 (1 H, m), 4.29 (2 H, s).
13C NMR (100 MHz, CDCl3): δ = 159.4 (d, JC-F = 257.2 Hz), 137.9
(d, JC-F = 8.7 Hz), 131.4, 125.3 (d, JC-F = 3.7 Hz), 124.6 (d, JC-
F = 13.9 Hz), 117.5 (d, JC-F = 20.7 Hz), 109.6 (d, JC-F = 2.3 Hz), 45.1
(d, JC-F = 2.9 Hz).
Pd2(dba)3 (4 mol%)
Ph3P (22 mol%)
NaH (2 equiv)
F
F
O
S
O
S
CN
Ph
CN
iodobenzene
DME, reflux, 20 h
O
O
2a
4
65%
HRMS (EI): m/z calcd for C8H6FNO2S [M+]: 199.0103; found:
199.0106.
[Rh(cod)OH]2 (2 mol%)
BINAP (6 mol%)
PhB(OH)2 (2.5 equiv)
1,4-dioxane–H2O (10:1)
75 °C, 6 h
(Z)-β-(2-Fluorobenzenesulfonyl)vinylamines 3; General Proce-
dure
To a 2-dram vial equipped with a magnetic stir bar were added
[Rh(cod)OH]2 (2.9 mg, 0.0064 mmol, 2 mol%), BINAP (12.3 mg,
0.019 mmol, 6 mol%), and Cs2CO3 (104 mg, 0.32 mmol, 1.0 equiv).
The vial was capped with a septum and flushed with argon. 1,4-Di-
oxane (1.0 mL) was added and the solution was stirred for 10 min
in a 50 °C oil bath (slowly turned orange/reddish), then cooled to r.t.
(2-Fluorobenzenesulfonyl)acetonitrile (2a; 0.32 mmol) and arylbo-
ronic acid (0.80 mmol, 2.5 equiv) were added as a solution in 1,4-
dioxane–H2O (1.5 mL/0.25 mL). The vial was sealed and heated at
75 °C in an oil bath for 6 h. The solvent was removed in vacuo and
the crude was purified by flash column chromatography (EtOAc–
hexanes–1% Et3N) on silica gel (Tables 1 and 2).
F
H2N
O
H
N
Ph
Ph
NaOH (3 equiv)
1,4-dioxane, 75 °C, 2 h
S
S
Ph
Ph
O
O
O
5
6
88%
94%
Scheme 3
In summary, we have successfully developed an efficient
protocol for synthesizing arylated (mono- and di-) 4H-
1,4-benzothiazine 1,1-dioxide products utilizing (2-fluo-
robenzenesulfonyl)vinylamines as the key synthons. A
3a
Yield: 77 mg (87%); off-white solid; mp 88–89 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1359–1364

1362
G. C. Tsui et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 7.99 (1 H, td, J = 7.2, 1.6 Hz),
7.59–7.36 (6 H, m), 7.32–7.24 (1 H, m), 7.18 (1 H, td, J = 7.2, 1.2
Hz), 6.05 (2 H, br s), 5.18 (1 H, s).
13C NMR (100 MHz, CDCl3): δ = 159.6 (d, JC-F = 254.6 Hz), 157.0,
142.8, 134.3 (d, JC-F = 8.2 Hz), 132.9, 131.9 (d, JC-F = 14.4 Hz),
129.5, 128.5, 126.6, 125.9, 124.1 (d, JC-F = 3.7 Hz), 89.9, 15.2.
13C NMR (100 MHz, CDCl3): δ = 159.5 (d, JC-F = 253.0 Hz), 157.6,
136.9, 134.3 (d, JC-F = 8.0 Hz), 131.9 (d, JC-F = 14 Hz), 130.9,
128.9, 128.5, 126.3, 124.1 (d, JC-F = 4.0 Hz), 116.9 (d, JC-F = 21.0
Hz), 90.3.
HRMS (EI): m/z calcd for C14H12FNO2S [M+]: 277.0573; found:
277.0569.
HRMS (ESI): m/z calcd for C15H15FNO2S2 [MH+]: 324.0528;
found: 324.0531.
3ag
Yield: 61 mg (63%); white solid; mp 117–118 °C.
1H NMR (400 MHz, CDCl3): δ = 7.98 (1 H, td, J = 1.7, 7.6 Hz),
7.73–7.68 (2 H, m), 7.64–7.54 (3 H, m), 7.29 (1 H, dt, J = 0.9, 7.7
Hz), 7.19 (1 H, dt, J = 0.9, 8.3 Hz), 5.95 (2 H, br), 5.17 (1 H, s).
13C NMR (100 MHz, CDCl3): δ = 159.7 (d, JC-F = 255.2 Hz), 155.4,
141.3, 134.8 (d, JC-F = 8.3 Hz), 132.8, 131.3 (d, JC-F = 14.7 Hz),
128.8, 127.4, 124.4 (d, JC-F = 3.7 Hz), 117.8, 117.0 (d, JC-F = 21.1
Hz), 114.6, 92.6.
3ab
Yield: 109 mg (99%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.97 (1 H, td, J = 7.6, 1.7 Hz),
7.55–7.49 (1 H, m), 7.44 (2 H, d, J = 8.9 Hz), 7.26 (1 H, td, J = 1.0,
7.3 Hz), 7.16 (1 H, td, J = 8.2, 0.9 Hz), 6.89 (2 H, d, J = 8.9 Hz),
5.94 (2 H, br s), 5.14 (1 H, d, J = 1.2 Hz), 3.82 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 162.0, 159.5 (d, JC-F = 254.7 Hz),
157.3, 134.2 (d, JC-F = 8.3 Hz), 132.4 (d, JC-F = 14.6 Hz), 129.2,
128.8, 128.1, 124.1 (d, JC-F = 3.7 Hz), 116.8 (d, JC-F = 21.3 Hz),
114.2, 89.2, 55.4.
HRMS (ESI): m/z calcd for C15H12FN2O2S [MH+]: 303.0603;
found: 303.0612.
3ah
Yield: 85 mg (94%); yellow solid; mp 78–80 °C.
1H NMR (400 MHz, CDCl3): δ = 7.98 (1 H, td, J = 1.7, 7.6 Hz),
7.59–7.50 (2 H, m), 7.39–7.35 (1 H, m), 7.27 (1 H, td, J = 1.0, 7.7
Hz), 7.21–7.14 (2 H, m), 5.91 (2 H, br s), 5.26 (1 H, s).
HRMS (ESI): m/z calcd for C15H15FNO3S [MH+]: 308.0756; found:
308.0758.
13C NMR (100 MHz, CDCl3): δ = 159.9 (d, JC-F = 254.4 Hz), 158.2,
137.3, 135.3, 134.6 (d, JC-F = 8.0 Hz), 132.1 (d, JC-F = 14 Hz),
128.9, 127.7, 126.2, 124.4 (d, JC-F = 3.7 Hz), 117.0 (d, JC-F = 21.2
Hz), 91.6.
HRMS (EI): m/z calcd for C12H10FNO2S2 [M+]: 283.0137; found:
283.0130.
3ac
Yield: 89 mg (87%); white solid; mp 140–141 °C.
1H NMR (400 MHz, CDCl3): δ = 8.01–7.95 (3 H, m), 7.62–7.52 (3
H, m), 7.28 (1 H, td, J = 1.0, 7.7 Hz), 7.19 (1 H, td, J = 0.9, 8.4 Hz),
5.97 (2 H, br s), 5.20 (1 H, s), 2.61 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 197.1, 159.6 (d, JC-F = 254.8 Hz),
156.2, 141.1, 138.8, 134.6 (d, JC-F = 8.3 Hz), 131.5 (d, JC-F = 14.5
3ai
Hz), 128.9, 128.7, 126.8, 124.3 (d, JC-F = 3.7 Hz), 116.9 (d, JC-F
21.2 Hz), 91.7, 26.7.
=
Yield: 91 mg (90%); white solid; mp 122–124 °C.
1H NMR (400 MHz, CDCl3): δ = 8.06 (1 H, t, J = 1.5 Hz), 8.04–7.95
(2 H, m), 7.72–7.68 (1 H, m), 7.59–7.49 (2 H, m), 7.28 (1 H, td,
J = 1.0, 7.7 Hz), 7.18 (1 H, td, J = 0.9, 8.2 Hz), 6.02 (2 H, br s), 5.18
(1 H, s), 2.61 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 197.3, 159.8 (d, JC-F = 254.8 Hz),
157.7, 156.8, 137.8 (d, JC-F = 15.2 Hz), 134.8 (d, JC-F = 8.4 Hz),
131.8 (d, JC-F = 14.5 Hz), 131.1, 130.8, 129.6, 128.8, 126.3, 124.5
(d, JC-F = 3.7 Hz), 117.2 (d, JC-F = 21.2 Hz), 91.5, 26.9.
HRMS (ESI): m/z calcd for C16H15FNO3S [MH+]: 320.0756; found:
320.0767.
3ad
Yield: 92 mg (84%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.98 (1 H, td, J = 1.7, 7.7 Hz),
7.70–7.52 (5 H, m), 7.29 (1 H, td, J = 1.0, 7.7 Hz), 7.19 (1 H, td,
J = 1.0, 8.2 Hz), 5.94 (2 H, br s), 5.18 (1 H, d, J = 1.1 Hz).
13C NMR (100 MHz, CDCl3): δ = 159.9 (d, JC-F = 254.4 Hz), 158.2,
137.3, 135.3, 134.6 (d, JC-F = 8.0 Hz), 132.1 (d, JC-F = 14 Hz),
130.9, 129.8, 128.9, 127.7, 126.2, 124.4 (d, JC-F = 3.7 Hz), 117.0 (d,
HRMS (ESI): m/z calcd for C16H15FNO3S [MH+]: 320.0751; found:
320.0744.
3aj
JC-F = 21.2 Hz), 91.6.
Yield: 67 mg (68%); white solid; mp 109–110 °C.
HRMS (ESI): m/z calcd for C15H12F4NO2S [MH+]: 346.0524;
found: 346.0514.
1H NMR (400 MHz, CDCl3): δ = 7.98 (1 H, td, J = 1.7, 7.4 Hz),
7.59–7.49 (1 H, m), 7.33–7.23 (2 H, m), 7.18 (1 H, td, J = 1.0, 8.2
Hz), 7.09–7.08 (1 H, m), 7.02–6.97 (2 H, m), 5.99 (2 H, br s), 5.17
(1 H, s), 3.82 (3 H, s).
3ae
Yield: 93 mg (93%); white solid; mp 89–90 °C.
1H NMR (400 MHz, CDCl3): δ = 7.97 (1 H, td, J = 1.7, 7.5 Hz),
7.59–7.51 (1 H, m), 7.44 (2 H, d, J = 8.7 Hz), 7.37 (2 H, d, J = 8.7
Hz), 7.28 (1 H, td, J = 0.9, 7.7 Hz), 7.18 (1 H, td, J = 0.8, 8.2 Hz),
5.99 (2 H, br), 5.14 (1 H, s).
13C NMR (100 MHz, CDCl3): δ = 159.6 (d, JC-F = 254.7 Hz), 158.4,
157.5, 138.4, 134.4 (d, JC-F = 8.3 Hz), 131.9 (d, JC-F = 14.4 Hz),
130.2, 128.6, 124.2 (d, JC-F = 3.7 Hz), 118.6, 116.9 (d, JC-F = 21.3
Hz), 116.5, 112.0, 90.4, 55.5.
13C NMR (100 MHz, CDCl3): δ = 159.6 (d, JC-F = 254.6 Hz), 150.3,
137.0, 135.3, 134.5 (d, JC-F = 8.4 Hz), 131.7 (d, JC-F = 14.5 Hz),
129.2, 128.6, 127.8, 124.2 (d, JC-F = 3.8 Hz), 116.9 (d, JC-F = 21.2
Hz), 90.4.
HRMS (EI): m/z calcd for C14H11ClFNO2S [M+]: 311.0183; found:
311.0185.
HRMS (ESI): m/z calcd for C15H15FNO3S [MH+]: 308.0756; found:
308.0740.
3ak
Yield: 89 mg (91%); yellow solid; mp 125–126 °C.
1H NMR (400 MHz, CDCl3): δ = 7.98 (1 H, td, J = 1.7, 7.5 Hz),
7.49–7.56 (1 H, m), 7.15–7.31 (6 H, m), 4.84 (1 H, s), 4.50 (2 H, br
s), 2.34 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 159.9 (d, JC-F = 254.4 Hz), 158.2,
137.3, 135.3, 134.6 (d, JC-F = 8.0 Hz), 132.1 (d, JC-F = 14 Hz),
130.9, 129.8, 128.9, 127.7, 126.2, 124.4 (d, JC-F = 3.7 Hz), 117.0 (d,
3af
Yield: 93 mg (90%); white solid; mp 104–105 °C.
1H NMR (400 MHz, CDCl3): δ = 7.97 (1 H, td, J = 1.7, 7.4 Hz),
7.58–7.50 (1 H, m), 7.41 (2 H, d, J = 8.5 Hz), 7.30–7.14 (4 H, m),
5.95 (2 H, br s), 5.16 (1 H, s), 2.49 (3 H, s).
J
C-F = 21.2 Hz), 91.6, 19.3.
Synthesis 2012, 44, 1359–1364
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 1,4-Benzothiazine Derivatives
1363
HRMS (ESI): m/z calcd for C15H15FNO2S [MH+]: 292.0807; found:
292.0816.
1e
Yield: 40 mg (69%); white solid; mp >300 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.91 (1 H, s), 7.92 (1 H, d,
J = 7.5 Hz), 7.82 (2 H, d, J = 8.5 Hz), 7.65–7.73 (3 H, m), 7.59 (1
H, d, J = 8.3 Hz), 7.39 (1 H, t, J = 7.4 Hz), 6.42 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 143.7, 136.8, 135.4, 132.3,
132.2, 129.4, 128.8, 123.5, 123.3, 121.8, 118.2, 96.8.
HRMS (ESI): m/z calcd for C14H11ClNO2S [MH+]: 292.0199;
found: 292.0192.
3al
Yield: 76 mg (73%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.12–8.17 (1 H, m), 8.03 (1 H, td,
J = 1.7, 7.4 Hz), 7.84–7.91 (2 H, m), 7.43–7.61 (5 H, m), 7.22–7.33
(2 H, m), 5.08 (1 H, s), 4.67 (2 H, br s).
13C NMR (100 MHz, CDCl3): δ = 159.9 (d, JC-F = 254.4 Hz), 157.4,
135.3, 134.6 (d, JC-F = 8.0 Hz), 133.8, 132.1 (d, JC-F = 14 Hz),
130.4, 130.2, 129.0, 128.7, 127.3, 126.7, 126.0, 125.3, 124.9, 124.4
(d, JC-F = 3.7 Hz), 117.0 (d, JC-F = 21.2 Hz), 91.6.
1f
Yield: 36 mg (60%); white solid; mp 244–246 °C.
HRMS (ESI): m/z calcd for C18H15FNO2S [MH+]: 328.0807; found:
328.0815.
1H NMR (400 MHz, DMSO-d6): δ = 10.77 (1 H, s), 7.84 (1 H, dd,
J = 1.2, 8.1 Hz), 7.59–7.70 (3 H, m), 7.54 (1 H, d, J = 7.7 Hz), 7.42
(2 H, d, J = 8.5 Hz), 7.32 (1 H, d, J = 7.1 Hz), 6.29 (1 H, s), 2.54 (3
H, s).
13C NMR (100 MHz, DMSO-d6): δ = 144.4, 141.9, 136.9, 132.1,
129.6, 127.8, 125.4, 123.3, 121.7, 118.2, 99.4, 95.6, 14.2.
4H-1,4-Benzothiazine 1,1-Dioxides 1; General Procedure
To a 2-dram vial equipped with a magnetic stir bar were added
freshly ground NaOH (24 mg, 0.6 mmol, 3 equiv), (Z)-β-(2-fluoro-
benzenesulfonyl)vinylamines 3 (0.2 mmol), and 1,4-dioxane (2.0
mL). The vial was heated at 75 °C in an oil bath for 2 h. The solvent
was removed in vacuo and the crude was purified by flash column
chromatography (EtOAc–hexanes) on silica gel (Table 3).
HRMS (ESI): m/z calcd for C15H14NO2S2 [MH+]: 304.0465; found:
304.0480.
1g
1a
Yield: 24 mg (86%); white solid; mp >300 °C.
Yield: 25 mg (96%); white solid; mp 258–262 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.94 (1 H, s), 8.05 (2 H, d,
J = 8.4 Hz), 7.93 (2 H, d, J = 8.5 Hz), 7.87 (1 H, dd, J = 1.2, 8.1 Hz),
7.64 (1 H, td, J = 1.3, 7.1 Hz), 7.52 (1 H, d, J = 8.0 Hz), 7.35 (1 H,
t, J = 7.3 Hz), 6.48 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 143.2, 137.8, 136.8, 132.6,
132.3, 128.5, 123.6, 123.3, 121.9, 118.2, 118.1, 113.1, 97.6.
1H NMR (400 MHz, DMSO-d6): δ = 10.80 (1 H, s), 7.84 (1 H, dd,
J = 1.2, 8.1 Hz), 7.68–7.74 (2 H, m), 7.50–7.65 (5 H, m), 7.29–7.34
(1 H, m), 6.27 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 144.9, 136.9, 133.7, 132.1,
130.6, 128.8, 127.5, 123.4, 123.3, 121.8, 118.2, 96.3.
HRMS (ESI): m/z calcd for C14H12NO2S [MH+]: 258.0588; found:
258.0585.
HRMS (ESI): m/z calcd for C15H11N2O2S [MH+]: 283.0541; found:
283.0552.
1b
1h
Yield: 52 mg (91%); white solid; mp 248–250 °C.
Yield: 42 mg (76%); white solid; mp >300 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.74 (1 H, s), 7.85 (1 H, dd,
J = 1.2, 8.1 Hz), 7.70 (2 H, d, J = 8.8 Hz), 7.63 (1 H, td, J = 1.3, 7.0
Hz), 7.56 (1 H, d, J = 7.6 Hz), 7.33 (1 H, td, J = 1.0, 7.1 Hz), 7.12
(2 H, d, J = 8.8 Hz), 6.22 (1 H, s), 3.36 (3 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 144.7, 136.9, 131.9,
129.0, 125.7, 123.3, 123.2, 121.7, 118.2, 114.1, 95.1, 55.4.
1H NMR (400 MHz, DMSO-d6): δ = 10.67 (1 H, s), 8.29 (1 H, s),
7.89 (1 H, d, J = 7.9 Hz), 7.81 (1 H, dd, J = 2.9, 4.8 Hz), 7.58–7.72
(3 H, m), 7.37 (1 H, t, J = 7.4 Hz), 6.53 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 139.6, 136.8, 134.6, 132.2,
127.8, 126.6, 126.4, 123.5, 123.4, 121.8, 118.2, 95.6.
HRMS (ESI): m/z calcd for C12H10NO2S2 [MH+]: 264.0153; found:
264.0158.
HRMS (ESI): m/z calcd for C15H14NO3S [MH+]: 288.0694; found:
288.0688.
1i
1c
Yield: 59 mg (98%); white solid; mp 235–237 °C.
Yield: 40 mg (67%); white solid; mp 267–269 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.97 (1 H, s), 8.31 (1 H, s),
8.27 (1 H, d, J = 7.6 Hz), 8.15 (1 H, d, J = 7.5 Hz), 7.88 (1 H, d,
J = 7.9 Hz), 7.73 (1 H, t, J = 7.7 Hz), 7.66 (1 H, t, J = 7.6 Hz), 7.47
(1 H, d, J = 8.2 Hz), 7.36 (1 H, t, J = 7.4 Hz), 6.47 (1 H, s), 2.70 (3
H, s).
1H NMR (400 MHz, DMSO-d6): δ = 10.91 (1 H, s), 8.11 (2 H, d,
J = 8.5 Hz), 7.85–7.91 (3 H, m), 7.62–7.67 (1 H, m), 7.55 (1 H, d,
J = 7.8 Hz), 7.31 (1 H, t, J = 7.1 Hz), 6.43 (1 H, s), 2.65 (3 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 197.4, 143.8, 138.1, 137.6,
136.8, 132.2, 128.4, 127.8, 123.5, 123.3, 121.8, 118.2, 97.2, 26.8.
HRMS (EI): m/z calcd for C16H13NO3S [M+]: 299.0616; found:
299.0623.
13C NMR (100 MHz, DMSO-d6): δ = 197.4, 144.2, 137.1, 136.9,
134.1, 132.2, 132.1, 130.0, 129.3, 127.4, 123.5, 123.3, 121.9, 118.3,
96.8, 26.9.
HRMS (ESI): m/z calcd for C16H14NO3S [MH+]: 300.0688; found:
300.0694.
1d
Yield: 63 mg (97%); white solid; mp 265–269 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.97 (1 H, s), 7.87–8.00 (5 H,
m), 7.66 (1 H, td, J = 1.2, 7.1 Hz), 7.55 (1 H, d, J = 8.2 Hz), 7.37 (1
H, t, J = 7.4 Hz), 6.44 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 143.5, 137.6, 136.8, 132.3,
130.6 (q, JC-F = 32.0 Hz), 128.6, 125.6 (q, JC-F = 3.8 Hz), 123.9 (q,
1j
Yield: 30 mg (69%); white solid; mp 229–231 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.79 (1 H, s), 7.85 (1 H, d,
J = 7.9 Hz), 7.63 (1 H, t, J = 7.1 Hz), 7.54 (1 H, d, J = 8.2 Hz), 7.47
(1 H, t, J = 7.9 Hz), 7.23–7.37 (3 H, m), 7.14 (1 H, dd, J = 2.1, 8.1
Hz), 6.34 (1 H, s), 3.85 (3 H, s).
JC-F = 270.0 Hz), 123.6, 123.3, 122.5, 118.2, 97.5.
HRMS (ESI): m/z calcd for C15H11F3NO2S [MH+]: 326.0469;
found: 326.0462.
13C NMR (100 MHz, DMSO-d6): δ = 159.3, 144.7, 136.8, 135.0,
132.1, 130.0, 123.4, 123.3, 121.8, 119.6, 118.2, 116.4, 112.4, 96.3,
55.3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1359–1364

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G. C. Tsui et al.
PAPER
HRMS (ESI): m/z calcd for C15H14NO3S [MH+]: 288.0694; found:
288.0691.
13C NMR (100 MHz, CDCl3): δ = 159.8 (d, JC-F = 255.1 Hz), 155.7,
137.9, 134.4 (d, JC-F = 8.3 Hz), 133.6, 133.2, 130.2, 129.8 (d, JC-F =
13.9 Hz), 129.0, 128.3, 128.0, 127.5, 127.0, 123.8 (d, JC-F = 3.7 Hz),
116.4 (d, JC-F = 21.2 Hz), 103.2.
HRMS (ESI): m/z calcd for C20H17FNO2S [MH+]: 354.0958; found:
1k
Yield: 50 mg (99%); white solid; mp 187–189 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.86 (1 H, s), 7.87 (1 H, d,
J = 7.6 Hz), 7.60 (1 H, td, J = 1.3, 7.1 Hz), 7.28–7.48 (6 H, m), 6.02
(1 H, d, J = 0.9 Hz), 2.31 (3 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 144.8, 136.8, 135.9, 134.9,
132.2, 132.5, 129.9, 128.9, 126.0, 123.4, 123.2, 121.9, 117.7, 97.9,
18.9.
354.0950.
6
Prepared from 5 following the general procedure given for 1; yield:
59 mg (88%); white solid; mp >300 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.88 (1 H, s), 7.88 (1 H, dd,
J = 1.0, 8.1 Hz), 7.64 (1 H, td, J = 1.2, 8.4 Hz), 7.50 (1 H, d, J = 8.2
Hz), 7.30–7.38 (6 H, m), 7.18–7.24 (5 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 142.7, 136.8, 134.0, 132.4,
132.2, 129.7, 129.5, 129.3, 128.1, 127.8, 127.6, 123.1, 122.9, 122.1,
117.9, 110.3.
HRMS (ESI): m/z calcd for C15H14NO2S [MH+]: 272.0745; found:
272.0752.
1l
Yield: 44 mg (95%); white solid; mp 252–255 °C.
1H NMR (400 MHz, DMSO-d6): δ = 11.13 (1 H, s), 8.13 (1 H, dd,
J = 1.9, 7.3 Hz), 8.04–8.10 (1 H, m), 7.93 (1 H, dd, J = 1.2, 8.1 Hz),
7.79–7.88 (1 H, m), 7.58–7.75 (5 H, m), 7.34–7.42 (2 H, m), 6.23 (1
H, s).
HRMS (ESI): m/z calcd for C20H16NO2S [MH+]: 334.0896; found:
334.0904.
13C NMR (100 MHz, DMSO-d6): δ = 143.9, 136.8, 133.0, 132.2,
131.9, 130.3, 130.1, 128.4, 127.3, 127.0, 126.5, 125.3, 124.2, 123.5,
123.4, 122.1, 117.8, 99.1.
Acknowledgment
This research was supported by NSERC, Merck Frosst Canada, and
the University of Toronto.
HRMS (ESI): m/z calcd for C18H14NO2S [MH+]: 308.0739; found:
308.0740.
References
2-(2-Fluorophenylsulfonyl)-2-phenylacetonitrile (4)
(1) (a) Armenise, D.; Trapani, G.; Arrivo, V.; Laraspata, E.;
Morlacchi, F. J. Heterocycl. Chem. 2000, 37, 1611.
(b) Gupta, R. R.; Ojha, K. G. In Phenothiazines and 1,4-
Benzothiazines: Chemical and Biomedical Aspects; Gupta,
R. R., Ed.; Elsevier: Amsterdam, 1988, 163. (c) Brown, C.;
Davidson, R. M. In Advances in Heterocyclic Chemistry,
Vol. 38; Katritzky, A. R., Ed.; Academic Press: New York,
1985, 135. (d) Krapcho, J.; Turk, C. F. J. Med. Chem. 1973,
16, 776.
(2) (a) De Montis, S.; Fattuoni, C.; Cadoni, E.; Cabiddu, M. G.;
Usai, M.; Cabiddu, S. J. Heterocycl. Chem. 2008, 45, 1445.
(b) Sabatini, S.; Kaatz, G. W.; Rossolini, G. M.; Brandini,
D.; Fravolini, A. J. Med. Chem. 2008, 51, 4321. (c) Thomas,
L.; Gupta, A.; Gupta, V. J. Fluorine Chem. 2003, 122, 207.
(d) Armenise, D.; Trapani, G.; Arrivo, V.; Laraspata, E.;
Morlacchi, F. J. Heterocycl. Chem. 2000, 37, 1611.
(e) Babudri, F.; Florio, S.; Vitrani, A. M. J. Chem. Soc.,
Perkin Trans. 1 1984, 1899.
To a 10-mL flask were added Pd2(dba)3 (36.6 mg, 0.04 mmol) and
Ph3P (58 mg, 0.22 mmol), the flask was capped with a septum and
flushed with argon. DME (2 mL) was added and the mixture was
stirred at r.t. for 10 min. (2-Fluorobenzenesulfonyl)acetonitrile 2a
(220 mg, 1.1 mmol) was added as a solution in DME (2 mL) fol-
lowed by the addition of NaH (50.4 mg, 2.1 mmol), the mixture was
stirred at r.t. for 15 min. Iodobenzene (0.11 mL, 1.0 mmol) was add-
ed and the reaction was refluxed (with a condenser) for 20 h under
argon then cooled to r.t. The crude mixture was filtered through sil-
ica gel, the filtrate was concentrated in vacuo and purified by flash
column chromatography on silica gel (EtOAc–hexanes).
Yield: 178 mg (65%); orange solid; mp 128–129 °C.
1H NMR (400 MHz, CDCl3): δ = 7.89 (1 H, td, J = 1.7, 6.9 Hz),
7.71–7.78 (1 H, m), 7.41–7.52 (5 H, m), 7.36 (1 H, td, J = 0.9, 7.8
Hz), 7.29 (1 H, td, J = 0.8, 8.5 Hz), 5.37 (1 H, m).
13C NMR (100 MHz, CDCl3): δ = 159.8 (d, JC-F = 258.4 Hz), 137.8
(d, JC-F = 8.7 Hz), 132.4, 130.8, 130.1, 129.2, 125.1 (d, JC-F = 3.8
Hz), 123.9, 123.4 (d, JC-F = 13.9 Hz), 117.4 (d, JC-F = 21.6 Hz),
112.7, 62.3 (d, JC-F = 2.3 Hz).
(3) Tsui, G. C.; Glenadel, Q.; Lau, C.; Lautens, M. Org. Lett.
2011, 13, 208.
(4) Lau, C.; Tsui, G. C.; Lautens, M. Synthesis 2011, 3908.
(5) Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2,
1677; and references cited therein.
+
HRMS (ESI): m/z calcd for C14H14FN2O2S [M + NH4 ]: 293.0760;
found: 293.0766.
5
(6) For descriptions of sulfone chemistry, see: (a) El-Awa, A.;
Noshi, M. N.; Mollat du Jourdin, X.; Fuchs, P. L. Chem. Rev.
2009, 109, 2315. (b) Simpkins, N. S. Sulphones in Organic
Synthesis; Baldwin, J. E., Ed.; Pergamon Press: Oxford,
1993.
Prepared from 4 following the general procedure given for 3; yield:
106 mg (94%); white solid; mp 130–131 °C.
1H NMR (400 MHz, CDCl3): δ = 7.56 (1 H, td, J = 1.7, 7.6 Hz),
7.42–7.49 (1 H, m), 7.10–7.24 (6 H, m), 7.06 (1 H, td, J = 0.9, 7.7
Hz), 6.87–6.98 (5 H, m), 2.61 (2 H, s).
(7) Sakamoto, T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1990, 38, 1513.
Synthesis 2012, 44, 1359–1364
© Georg Thieme Verlag Stuttgart · New York