One-pot Sonogashira coupling-cyclization toward regioselective synthesis of benzosultams

Article abstract of DOI:10.1021/acs.joc.5b00274

A one-pot method for the Sonogashira coupling and cyclization of 2-bromobenzenesulfonamides and terminal alkynes is presented. This method allows access to a variety of substituted benzosultams regioselectively in excellent yields. The reasons for regioselectivity are interpreted through density functional theory (DFT) studies.

Full text of DOI:10.1021/acs.joc.5b00274

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Article
One-pot Sonogashira coupling-cyclization
toward regioselective synthesis of benzosultams
Sudarshan Debnath, and Shovan Mondal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00274 • Publication Date (Web): 24 Mar 2015
Downloaded from http://pubs.acs.org on March 27, 2015
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One-pot Sonogashira coupling-cyclization toward regioselective synthesis of
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benzosultams
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Sudarshan Debnath and Shovan Mondal*
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Department of Chemistry, Visva-Bharati University, Santiniketan 731235, India.
*E-mail: shovan.mondal@visva-bharati.ac.in; shovanku@gmail.com (S.M.)
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Cyclization
O
O
O
O
Pd(PPh3)2Cl2,CuI, Et3N,
S
R
S
R
DMF, 70 οC, sealed tube, 7 h
N
N
H
R'
One-pot Sonogashira
coupling-cyclization
Br
R'
35 examples
Sonogashira
coupling
90-98%
A one-pot method for the Sonogashira coupling and cyclization of 2-bromobenzenesulfonamides
and terminal alkynes is presented. This method allows access to a variety of substituted
benzosultams regioselectively in excellent yields. The reasons for regioselectivity are interpreted
through density functional theory (DFT) studies.
INTRODUCTION:
Benzosultams are pivotal structures which are found to be generously utilized in many drugs.1
Compounds privileged with benzosultam core manifest a wide spectrum of bioactivities, such as
antiviral, antimicrobial, antileukemic, anticancer, enzyme inhibition, etc.2 Among the
benzosultams, benzothiazine dioxide derivatives have been found to show resourceful inhibitory
properties against a variety of enzymes. For example, Oxicams (e.g., Ampiroxicam 1, Fig. 1)3
are a large family of nonsteroidal anti-inflammatory agents. 11β-Hydroxysteroid dehydrogenase
type 1 (11β-HSD1) is an endoplasmic reticulum-associated enzyme that acts as a NADPH
dependent reductase and is able to convert inactive cortisone to the active glucocorticoid
cortisol.4 Benzothiazine dioxide derivative 2 i.e. benzosultam 2 (Fig. 1) has been found to show
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active inhibitory property against 11β-HSD1.5 Moreover, benzothiazine dioxide derivatives have
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strong inhibitory properties against HIV integrand,6 Calpain I7 etc.
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O2
S
O
N
Ph
Ph
Me
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O2
S
N
H
N
N
Me
O
O
OH
O
OCO2Et
β
11 -HSD2 inhibitor
Ampiroxicam (COX-2)
1
2
O2
O2
S
Me
S
Me
N
N
H
H
N
N
N
S
OH
O
OH
O
N
Picrotoxic
Melodica
4
3
Figure 1. Biologically active benzosultams
In contrast to the importance, only limited synthetic approaches towards the benzosultams have
been reported.8-10 For instance, Che et al. reported a series of benzothiazine dioxides formed by
Au(PPh3)OTf-catalyzed cycloisomerization of terminal alkenes (Equ.1, Scheme 1).11 Murakami
and coworkers reported the synthesis of benzothiazine dioxide derivatives by exploiting a
rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols. Mechanistically,
this reaction involves the C−C bond cleavage by β-carbon elimination and C−H bond cleavage
by a 1,5-rhodium shift (Equ.2, Scheme 1).12 Pal and co-workers gave a preliminary approach to
the synthesis of benzothiazine dioxide derivatives by a Sonogashira coupling and a subsequent
internal cyclization by the presence of an Ag(I) salt (Equ.3, Scheme 1).13 In our continuous effort
on the synthesis of sultams and sultones,14 our present aim is to develop a new, efficient and
divergent route for the synthesis of benzothiazine dioxide derivatives. The results are reported
here.
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Previous work
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O
O
NHR1
O
O
NR1
1-5 mol% of (PR3)AuOTf
S
S
toluene, 100 οC, 12-48 h
(1)
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Intramolecular Hydro-
amination of Alkenes
Me
95-99%
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Previous work
HO Ph
[Rh(OH)(cod)]2 (2 mol%)
rac-DM-BINAP (5 mol%)
K2CO3 (2.0 equiv.), toluene,
60 οC, 12 h
O
S
O
N
N
Me
O
S
(2)
O
Me
1,5-Rhodium Shift
HO Ph
Me
96%
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Previous work
O
O
O
O
10% Pd/C, PPh3,
O
O
N
R'
S
CH3
S
I
CH3
+
CuI,Et3N, CH3CN,
N
H
N
H
S
CH3
R'
80 οC, 10 h
AgSbF6
(3)
R
R
Sonogashira
coupling
Metal-mediated
R'
cyclization
R
85-97%
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10
85-93%
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Present work
Cyclization
O
O
O
O
Pd(PPh3)2Cl2,CuI, Et3N,
S
R
S
R
DMF, 70 οC, sealed tube, 7 h
N
N
(4)
H
R'
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One-pot Sonogashira
coupling-cyclization
Br
R'
13
90-98%
Sonogashira
coupling
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Scheme 1. Some synthetic approaches to benzosultams (benzothiazine dioxide derivatives).
RESULTS AND DISCUSSION:
The required precursors for our present study 13a-g were synthesized in excellent yields by the
condensation reaction between 2-bromobenzenesulfonyl chloride 15 and different substituted
o
anilines 16 in pyridine at 80 C for 1 h (Scheme 2). Versatile aromatic and aliphatic acetylenes
(10a-i) with electron donating, withdrawing and neutral groups were taken for the synthesis of
various substituted benzothiazine dioxide derivatives (Figure 2).
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NH2
O2
S
R
SO2Cl
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7
8
ο
Py, 80 C, 1 h
N
H
R
+
Br
Br
13
15
16
NO2
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O2
S
O2
S
O2
S
N
N
H
NO2
N
H
OMe
H
Br
Br
Br
13c (95%)
13b (96%)
13a (98%)
Me
OMe
O2
O2
S
O2
O2
S
S
S
N
N
H
N
H
N
H
H
Cl
Br
Br
Br
Br
13d (95%)
13e (97%)
13f (94%)
13g (98%)
Scheme 2. Synthesis of starting materials 13a-g.
OMe
Me
OEt
F
10a
10d
10b
10c
10e
C6H13
10h
10i
OCH2Ph
10f
10g
Figure 2. Various acetylenes taken for the synthesis of benzosultams.
The optimization of the reaction of 13a to 14aa was conducted and is presented in Table 1.
Among the palladium catalysts, Pd(PPh3)2Cl2 gave the best result rather than Pd2dba3 or Pd-C.
The solvent screening revealed that DMF was the most appropriate solvent. The smooth
Sonogashira coupling and cyclization occurred when the reaction was carried out under pressure
i.e. in sealed tube (Entry 4, Table 1). It is very interesting to note that this reaction works well in
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gram-scale synthesis also. Upon treatment of compound 13a (1 gm, 2.80 mmol) with
Phenylacetylene (345 mg, 3.36 mmol) under the optimized condition afforded compound 14aa
(1 gm, 98%) as the only product.
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Table 1. Optimization of conditions.
NO2
Ph
NO2
O
O
O
O
S
S
H
N
N
H
+
Br
Ph
13a
10a
14aa
Entry
Catalytic system
Solvent: Base Time (h)
(2:1)
Conditions
Yield (%)
1
5 mol% Pd(PPh3)2Cl2,
5 mol% CuI
THF:Et3N
THF:Et3N
DMF:Et3N
DMF:Et3N
DMF:Et3N
THF:Et3N
THF:Et3N
DMF:Et3N
36
12
12
7
Room
temperature
reflux
trace
70
2
3
4
5
6
7
8
5 mol% Pd(PPh3)2Cl2,
12 mol% CuI
5 mol% Pd(PPh3)2Cl2,
12 mol% CuI
5 mol% Pd(PPh3)2Cl2,
12 mol% CuI
100 oC
75
70 oC in sealed
tube
70 oC in sealed
tube
98
3 mol% Pd(PPh3)2Cl2,
12 mol% CuI
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93
2.5 mol% Pd2dba3, 15
mol% PPh3, 5 mol% CuI
2 mol% Pd–C (10%), 2.5
mol% PPh3, 5 mol% CuI
5 mol% Pd(PPh3)2Cl2,
12 mol% CuI
12
8
reflux
20
reflux
70 oC
No
reaction
50
7
The sole product got after treatment of compound 13a with the optimized conditions showed one
singlet aromatic proton at δ 7.15 along with other 13 aromatic protons in proton NMR and in
carbon NMR there was no peak found for acetylinic carbons. From this result it is confirmed that
the product got from 13a is a cyclized one and the HRMS value of the synthesized compound
came as 401.0574 which also well matched with the theoretical value of cyclized product
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401.0572 for [M+Na]+. Now the question is whether the regioselective product formed is - 14aa
or 14aa'. If the cyclization passed through 6-endo-dig mode, then 14aa would be formed and if
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the cyclization went through 5-exo-dig mode then 14aa' would be formed (Scheme 3).
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NO2
O
O
S
6-
-
endo dig
N
NO2
O
NO2
O
Work-up
Ph
Ph, Pd(PPh3)2Cl2,
O
O
S
CuI, Et3N, THF, 70 οC,
sealed tube,7 h
H
14aa
N
S
H
N
Br
O O
S
N
13a
Ph
5-
-
exo dig
Cu+
NO2
Work-up
13a'
H
Ph
14aa'
Scheme 3. Different mode of cyclizations.
Finally, the structure was confirmed by X-ray data and it showed that the structure of the product
got from 13a was 14aa not 14aa' (Figure 3).15
Figure 3. Ortep diagrams of benzosultam 14aa (The thermal ellipsoid are drawn at the 50%
probability level).
Now to find out the reasons of the selectivity observed in this cyclization, the energies of both
the transition states (6-endo-dig and 5-exo-dig) were calculated by DFT. Coordinates of
optimized geometry are given in supporting information.
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For 6-endo-dig mode of cyclization the reaction passed through lower activation energy barrier
(3 kcal/mol) compared to that of 5-exo-dig mode (Figure 4). This is the probable reason for the
formation of benzosultum 14aa as the only product in the reaction between 13a and 10a. Now
for confirmation of formation of intermediate 13a', we performed the reaction with N-Me
substituent 13h under our optimized condition and we were able to separate 1513 which on
treatment with CuI at refluxing DMF afforded the sultam 1613 in 90% yield (Scheme 4). From
this observation it is quite sure that reaction of 13a to 14aa must be gone through the
intermediate 13a'.
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Ph, Pd(PPh3)2Cl2,
Me CuI, Et3N, THF, 70 οC,
sealed tube,7 h
O
O
O
O
O
O
S
Me
S
Me
Ph
S
N
N
H
N
CuI, DMF, reflux, 1 h
90%
H
Br
91%
Ph
15
16
13h
Scheme 4. Isolation of Sonogashira product.
NO2
O2
S
NH3
N H
2.25Å
2.54Å
Cu
24.23 kcal/mol
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NO2
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O2
S
NH3
N H
2.23Å
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2.56Å
Cu
27.23 kcal/mol
Figure 4. Optimized geometries of transition states for different modes of cyclizations (ethyl
group of triethylamine is replaced by hydrogen to reduce computational time).
After standardization of the synthesis of benzothiazine dioxide 14aa, we made a number of
benzothiazine dioxide derivatives 14aa-14ga (35 examples) (Figure 5) to make the method very
wide and general.
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NO2
NO2
NO2
NO2
O2
S
O2
S
O2
S
O2
S
N
N
N
N
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Ph
14aa
14ab
14ac
14ad
, 98%
O2
, 95%
O2
, 94%
O2
, 91%
O2
OEt
OMe
NO2
Me
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NO2
NO2
NO2
S
S
S
S
N
N
N
N
Ph
14ae
14af
14ag
14ah
, 93%
O2
, 95%
O2
, 92%
, 95%
O2
F
O
Ph
NO2
O2
S
S
S
S
N
N
NO2
N
NO2
N
NO2
Me
C6H13
Ph
14ai
14bc
, 96%
14bd
, 90%
O2
14ba
, 91%
, 96%
OMe
O2
S
O2
S
O2
S
S
N
NO2
N
NO2
N
NO2
N
NO2
Ph
14be
14bf
14bg
14bh
, 95%
, 92%
O2
, 94%
, 93%
F
O
Ph
O2
S
N
O2
S
O2
S
S
NO2
N
OMe
N
OMe
N
OMe
C6H13
Ph
14bi
14cf
14ca
14cc
14ce
, 90%
O2
, 90%
, 93%
O2
, 91%
O2
OMe
OMe
F
O2
S
N
S
S
S
N
OMe
OMe
N
N
OMe
Ph
Me
C6H13
14ci
, 91%
14ch
, 94%
, 90%
O2
14cg
, 92%
O
Me
Ph
Me
Me
O2
S
O2
S
O2
S
S
N
N
N
N
Ph
Ph
14db, 93%
14da, 95%
14dd, 90%
O2
14dg, 92%
OEt
Me
Me
O2
O2
O2
S
O2
S
S
S
S
N
N
N
N
N
C6H13
Ph
C6H13
14di, 90%
14ea, 95%
14ed, 92%
14eh, 94%
14ei, 91%
Me
OMe
O2
O2
S
S
N
N
Cl
Ph
Ph
14ga, 97%
14fa, 90%
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Figure 5. Summarized results of benzosultams.
The single crystal XRD analysis for benzosultams 14bi,16 14ch,17 14db18 had also been done for
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further confirmation of structures (Figure 6).
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14bi
14ch
14db
Figure 6. Ortep diagrams of benzosultams (The thermal ellipsoid are drawn at the 50%
probability level).
In conclusion, we have successfully realized the synthesis of benzothiazine dioxide derivatives
i.e. benzosultams via the Pd-catalyzed Sonogashira coupling and cyclization. This synthetic
method is an efficient and convergent route to prepare benzo-delta-sultams. This method benefits
from the advantages of mild and clean conditions, high efficiency, and regioselectivity.
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EXPERIMENTAL SECTION
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General information
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The reactions sensitive to air or moisture were carried out under nitrogen atmosphere using dry
solvents, unless otherwise noted. Column chromatography was performed on silica gel (60-120
mesh). Reaction progress was monitored by thin-layer chromatography (TLC). TLC plates were
visualized with ultraviolet light (256 nm) and in an iodine chamber. IR spectra were recorded
using KBr discs. Wavelengths (ν) are reported in cm-1. Melting points were recorded in open
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capillaries and are uncorrected. HRMS were recorded on a QTOF instrument. All H and C
NMR spectra were recorded in 400 MHz and 100 MHz spectrometer respectively. Chemical
shifts were given in parts per million (ppm, δ) and are relative to internal CHCl3 (1H, δ= 7.26)
and CDCl3 (13C, δ= 77.16). Multiplicity is indicated by one or more of the following
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), pentet (p), septet (se), octet (o).
Splitting patterns that could not be interpreted or easily visualized were designated as multiplet
(m) or broad (br). The lists of coupling constants (J) correspond to the order of multiplicity
assignment and are reported in Hertz (Hz).
DFT calculations were performed with Gaussian09 program package.19 Geometry were
optimized with hybrid density functional (B3LYP) theory20 using 6-31G(d) basis set.21 For Cu
atom LanL2DZ basis set22 was used with LanL2 effective core potential. Frequency calculations
were used to characterize the transition state and stationary points (reactants/products) as
minima. Transition states were connected with corresponding reactants and products by intrinsic
reaction coordinate (IRC) calculation.23 Conductor-like polarizable continuum solvation model
(CPCM) was used for solvation of stationary points and transition states.24
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General procedure for preparation of 2-bromo-N-arylbenzenesulfonamide
derivatives
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Preparation of 2-bromo-N-(4-nitrophenyl)benzenesulfonamide (13a): Commercially
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available 2-bromobenzenesulfonyl chloride (400 mg, 1.56 mmol) was heated with 4-nitroaniline
o
(216 mg, 1.56 mmol) in presence of pyridine (0.5 mL) at 80 C for 1 hr. The resulting reaction
mixture was poured then into ice-water. A white precipitated of compound 13a (548 mg, 98%)
o
was appeared which was filtered, dried and collected for next step; mp 124-126 C; IR (KBr):
3323, 1336, 1167 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 8.19 (dd, J= 7.8, 1.9 Hz, 1H), 8.10 (dt,
J= 9.0, 1.9 Hz, 2H), 7.86 (bs, 1H), 7.70 (dd, J= 7.8, 1.3 Hz, 1H), 7.50-7.40 (m, 2H), 7.25 (dt, J=
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9.0, 1.8 Hz, 2H); C NMR (CDCl3, 100 MHz): δ= 144.4, 141.9, 137.3, 135.6, 135.0, 132.6,
128.2, 125.5, 119.9, 119.1; Anal. Calcd for C12H9BrN2O4S: C, 40.35; H, 2.54; N, 7.84. Found:
C, 40.63; H, 2.39; N, 7.69.
Preparation of 2-bromo-N-(3-nitrophenyl)benzenesulfonamide (13b): 96% yield (537 mg),
white solid; mp 134-136 oC; IR (KBr): 3267, 1336, 1169 cm-1; 1H NMR (CDCl3, 400 MHz): δ=
8.13 (dd, J= 7.4, 2.1 Hz, 1H), 7.99 (t, J= 2.1 Hz, 1H), 7.94-7.91 (m, 1H), 7.73-7.69 (m, 2H),
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7.51-7.39 (m,4H); C NMR (CDCl3, 100 MHz): δ= 148.8, 137.3, 137.2, 135.5, 134.8, 132.5,
130.5, 128.2, 126.4, 120.1, 119.8, 115.3; Anal. Calcd for C12H9BrN2O4S: C, 40.35; H, 2.54; N,
7.84. Found: C, 40.04; H, 2.72; N, 8.01.
Preparation of 2-bromo-N-(3-methoxyphenyl)benzenesulfonamide (13c): 95% yield (509
mg), white solid; mp 80-82 oC; IR (KBr): 3388, 1326, 1164 cm-1; 1H NMR (CDCl3, 400 MHz):
δ= 8.07-8.05 (m, 1H), 7.69-7.67 (m, 1H), 7.38-7.34 (m, 2H), 7.27 (bs, 1H), 7.09 (t, J= 8.1 Hz,
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1H), 6.73 (t, J= 1.7 Hz, 1H), 6.69-6.67 (m, 1H), 6.62-6.59 (m, 1H), 3.71 (s, 3H); C NMR
(CDCl3, 100 MHz): δ= 160.3, 137.8, 137.0, 135.2, 134.2, 132.5, 130.2, 127.9, 119.8, 113.6,
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111.3, 107.3, 55.4; Anal. Calcd for C13H12BrNO3S: C, 45.63; H, 3.53; N, 4.09. Found: C, 45.84;
H, 3.70; N, 3.85.
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Preparation of 2-bromo-N-p-tolylbenzenesulfonamide (13d): 95% yield (485 mg), white
solid; mp 144-146 oC; IR (KBr): 3263, 1336, 1163 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 8.00-
7.97 (m, 1H), 7.70-7.67 (m, 1H), 7.36-7.31 (m, 2H), 7.21 (bs, 1H), 7.03-6.97 (m, 4H), 2.22 (s,
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3H); C NMR (CDCl3, 100 MHz): δ= 137.9, 135.9, 135.1, 134.1, 133.1, 132.4, 129.9, 127.9,
122.4, 119.8, 20.9; Anal. Calcd for C13H12BrNO2S: C, 47.86; H, 3.71; N, 4.29. Found: C, 47.98;
H, 3.59; N, 4.44.
Preparation of 2-bromo-N-phenylbenzenesulfonamide (13e): 97% yield (474 mg), white
solid; mp 129-131 oC; IR (KBr): 3286, 1331, 1165 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 8.04-
8.01 (m, 1H), 7.71-7.68 (m, 1H), 7.38-7.34 (m, 2H), 7.23-7.19 (m, 3H), 7.14-7.11 (m, 2H), 7.09-
7.06 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ= 137.9, 135.8, 135.1, 134.2, 132.4, 129.5, 127.9,
125.9, 121.8, 119.8; Anal. Calcd for C12H10BrNO2S: C, 46.17; H, 3.23; N, 4.49. Found: C,
46.40; H, 3.38; N, 4.34.
Preparation of 2-bromo-N-(2-chlorophenyl)benzenesulfonamide (13f): 94% yield (510 mg),
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white solid; mp 95-97 C; IR (KBr): 3338, 1417,1116 cm-1; H NMR (CDCl3, 400 MHz): δ=
8.13 (dd, J= 7.4, 2.1 Hz, 1H), 7.70 (dd, J= 7.3, 1.7 Hz, 1H), 7.64 (brs, 1H), 7.53 (dd, J= 8.2, 1.3
Hz, 1H), 7.44-7.37 (m, 2H), 7.28 (dd, J= 8.0, 1.4 Hz, 1H), 7.15 (td, J= 7.9, 1.3 Hz, 1H), 6.98 (td,
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J= 7.7, 1.4 Hz, 1H); C NMR (CDCl3, 100 MHz): δ= 138.0, 135.6, 134.5, 133.2, 132.3, 129.8,
127.9, 127.8, 125.4, 123.9, 120.4, 120.2; Anal. Calcd for C12H9BrClNO2S: C, 41.58; H, 2.62; N,
4.04. Found: C, 41.77; H, 2.46; N, 4.18.
Preparation of 2-bromo-N-(4-methoxyphenyl)benzenesulfonamide (13g): 98% yield (525
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mg), white solid; mp 111-113 C; IR (KBr): 3280, 1265, 1157 cm-1; H NMR (CDCl3, 400
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MHz): δ= 7.91 (d, J= 5.2 Hz, 1H), 7.71 (d, J= 6.0 Hz, 1H), 7.42-7.28 (m, 2H), 7.12-6.90 (m,
3H), 6.71 (d, J= 8.0 Hz, 2H), 3.70 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ= 158.1, 137.8, 134.9,
133.9, 132.3, 128.0, 127.8, 125.4, 119.6, 114.4, 55.3; Anal. Calcd for C13H12BrNO3S: C, 45.63;
H, 3.53; N, 4.09. Found: C, 45.49; H, 3.42; N, 4.27.
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General procedure for preparation of benzothiazine dioxide derivatives
Preparation of 2-(4-nitrophenyl)-3-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14aa): The
solution of compound 13a (70 mg, 0.20 mmol) in anhydrous DMF (2 mL) and Et3N (1 mL) was
bubbled through nitrogen gas for 10 mins. Pd(PPh3)2Cl2 (7 mg, 5 mol%) and CuI (4.5 mg, 12
mol%) was then added to this solution and stirred for further 5 mins. Phenylacetylene (24 mg,
0.23 mmol) was then added to this reaction mixture and heated at 70 oC for 7 h in a sealed tube.
The reaction mixture was cooled, H2O (10 mL) was added, and it was extracted with EtOAc (3 ×
10 mL). The combined EtOAc extracts were washed with H2O (4 × 10 mL) and brine (10 mL),
and dried (Na2SO4). The solvent was distilled off to furnish a viscous mass that was purified by
column chromatography on silica gel, to yield compound 14aa (73 mg, 98%) as a white solid;
mp 169-171 oC; IR (KBr): 1598, 1350, 1176 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 8.06 (d, J=
8.9 Hz, 2H), 7.84 (d, J= 7.8 Hz, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.64-7.62 (m, 3H), 7.55 (t, J=7.7
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Hz, 1H), 7.34-7.29 (m, 5H), 7.15 (s, 1H); C NMR (CDCl3, 100 MHz): δ= 146.3, 143.0, 142.2,
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134.3, 133.1, 132.6, 132.4, 130.1, 129.1, 128.4, 127.8, 127.6, 127.5, 124.4, 123.3, 115.6; C
DEPT-135 (CDCl3, 100 MHz): 133.1, 130.2, 129.2, 128.4, 127.8, 127.6, 127.5, 124.4, 123.3,
115.6; HRMS (ES+): MNa+, found 401.0574. C20H14N2NaO4S requires 401.0572.
Preparation of 3-(4-ethoxyphenyl)-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14ab): 95% yield (79 mg), white solid; mp 177-179 C; IR (KBr): 1598, 1348, 1174 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.07-8.04 (m, 2H), 7.81 (d, J= 7.8 Hz, 1H), 7.68 (td, J= 7.6, 0.9
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Hz, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.55-7.49 (m, 3H), 7.30-7.26 (m, 2H), 7.06 (s, 1H), 6.82 (d, J=
8.7 Hz, 2H), 3.98 (q, J= 7.0 Hz, 2H), 1.38 (t, J= 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ=
160.5, 146.2, 143.2, 142.1, 133.1, 132.9, 132.0, 129.2, 128.7, 128.2, 127.5, 126.5, 124.3, 123.2,
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115.0, 113.9, 63.7, 14.8; C DEPT-135 (CDCl3, 100 MHz): 133.1, 129.2, 128.7, 128.2, 127.5,
124.3, 123.2, 115.0, 113.9, 63.7, 14.8; Anal. Calcd for C22H18N2O5S: C, 62.55; H, 4.29; N, 6.63.
Found: C, 62.74; H, 4.16; N, 6.75.
Preparation of 3-(4-methoxyphenyl)-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14ac): 94% yield (75 mg), white solid; mp 187-189 C; IR (KBr): 1596, 1350, 1176 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.06 (dd, J= 7.0, 2.0 Hz, 2H), 7.82 (d, J= 7.9 Hz, 1H), 7.68 (td, J=
7.5, 0.8 Hz, 1H), 7.60 (d, J= 7.4 Hz, 1H), 7.56-7.49 (m, 3H), 7.30-7.26 (m, 2H), 7.06 (s, 1H),
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7.84 (dd, J= 6.9, 1.8 Hz, 2H), 3.77 (s, 3H); C NMR (CDCl3, 100 MHz): δ= 161.1, 146.2,
143.2, 142.0, 133.1, 132.9, 132.1, 129.2, 128.7, 128.2, 127.5, 126.8, 124.3, 123.3, 114.6, 114.0,
55.5; 13C DEPT-135 (CDCl3, 100 MHz): 133.1, 129.2, 128.7, 128.2, 127.5, 124.3, 123.3, 114.6,
114.0, 55.5; Anal. Calcd for C21H16N2O5S: C, 61.76; H, 3.95; N, 6.86. Found: C, 61.58; H, 4.12;
N, 6.95.
Preparation of 3-(4-methylphenyl)-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14ad): 91% yield (70 mg), white solid; mp 202-204 C; IR (KBr): 1598, 1346, 1174 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.05 (d, J= 9.0 Hz, 2H), 7.82 (d, J= 7.8 Hz, 1H), 7.68 (t, J= 7.4 Hz,
1H), 7.61 (d, J= 7.6 Hz, 1H), 7.55-7.49 (m, 3H), 7.29 (d, J= 9.0 Hz, 2H), 7.13 (superimposed d,
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J= 8.2 Hz, 2H), 7.11 (superimposed s, 1H), 2.30 (s, 3H); C NMR (CDCl3, 100 MHz): δ=
146.2, 143.1, 142.2, 140.5, 133.1, 132.8, 132.2, 131.5, 129.9, 128.9, 128.3, 127.7, 127.5, 124.3,
123.2, 114.8, 21.4; 13C DEPT-135 (CDCl3, 100 MHz): 133.1, 129.9, 128.9, 128.3, 127.7, 127.5,
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124.3, 123.2, 114.8, 21.4; Anal. Calcd for C21H16N2O4S: C, 64.27; H, 4.11; N, 7.14. Found: C,
64.48; H, 4.26; N, 6.95.
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Preparation of 3-(4-fluorophenyl)-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14ae): 93% yield (72 mg), white solid; mp 181-183 C; IR (KBr): 1598, 1348, 1174 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.09-8.05 (m, 2H), 7.83 (d, J= 7.7 Hz, 1H), 7.70 (td, J= 7.6, 1.0
Hz, 1H), 7.63-7.60 (m, 3H), 7.55 (td, J= 7.6, 1.0 Hz, 1H), 7.30-7.27 (m, 2H), 7.10 (s, 1H), 7.03
(t, J= 8.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ= 163.7 (d, J= 249.5 Hz), 146.4, 142.8, 141.2,
133.2, 132.5, 132.3, 130.6, 129.7 (d, J= 8.6 Hz), 129.3, 128.4, 127.5, 124.4, 123.3, 116.4 (d, J=
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21.9 Hz), 115.6; C DEPT-135 (CDCl3, 100 MHz): 133.2, 129.7, 129.3, 128.4, 127.5, 124.4,
123.3, 116.4, 115.6; Anal. Calcd for C20H13FN2O4S: C, 60.60; H, 3.31; N, 7.07. Found: C,
60.39; H, 3.19; N, 7.24.
Preparation of 3-(4-benzyloxyphenyl)-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14af): 95% yield (90 mg), white solid; mp 155-157 C; IR (KBr): 1599, 1348, 1172 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.06 (d, J= 8.9 Hz, 2H), 7.82 (d, J= 7.7 Hz, 1H), 7.68 (t, J= 7.6 Hz,
1H), 7.61-7.50 (m, 4H), 7.38-7.27 (m, 7H), 7.06 (s, 1H), 7.91 (d, J=8.6 Hz, 2H), 5.02 (s, 2H);
13C NMR (CDCl3, 100 MHz): δ= 160.3, 146.3, 143.2, 142.0, 136.4, 133.1, 132.9, 132.1, 129.3,
128.8, 128.3, 128.2, 127.6, 127.5, 127.0, 124.4, 123.3, 115.4, 114.1, 70.3; 13C DEPT-135
(CDCl3, 100 MHz): 133.1, 129.3, 128.8, 128.3, 128.2, 127.6, 127.5, 124.4, 123.3, 115.4, 114.1,
70.3; Anal. Calcd for C27H20N2O5S: C, 66.93; H, 4.16; N, 5.78. Found: C, 67.21; H, 3.99; N,
5.62.
Preparation of 2-(4-nitrophenyl)-3-(2-phenylethyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14ag): 92% yield (73 mg), white solid; mp 110-112 C; IR (KBr): 1596, 1348, 1174 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.21 (d, J= 8.8 Hz, 2H), 7.79 (d, J= 7.8 Hz, 1H), 7.63 (t, J= 7.4 Hz,
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127.8, 126.5, 124.6, 122.8, 115.1, 36.2, 33.9; C DEPT-135 (CDCl3, 100 MHz): 132.9, 128.7,
128.6, 128.2, 127.8, 126.5, 124.6, 122.8, 115.1, 36.2, 33.9; Anal. Calcd for C22H18N2O4S: C,
65.01; H, 4.46; N, 6.89. Found: C, 65.16; H, 4.35; N, 6.72.
Preparation of 3-cyclopropyl-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide (14ah):
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95% yield (64 mg), white solid; mp 97-99 C; IR (KBr): 1606, 1344, 1172 cm-1; H NMR
(CDCl3, 400 MHz): δ= 8.22 (d, J= 8.9 Hz, 2H), 7.76 (d, J= 7.8 Hz, 1H), 7.60 (t, J= 7.6 Hz, 1H),
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MHz): δ= 146.9, 144.9, 142.2, 132.8, 132.6, 131.7, 128.6, 128.1, 127.4, 124.5, 122.7, 110.8,
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15.3, 8.6; C DEPT-135 (CDCl3, 100 MHz): 132.8, 128.6, 128.1, 127.5, 124.4, 122.7, 110.8,
15.4, 8.6; Anal. Calcd for C17H14N2O4S: C, 59.64; H, 4.12; N, 8.18. Found: C, 59.42; H, 4.34; N,
7.95.
Preparation of 3-hexyl-2-(4-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide (14ai): 90% yield
(68 mg), red gummy liquid; IR (KBr): 1610, 1350, 1174 cm-1; 1H NMR (CDCl3, 400 MHz): δ=
8.21 (d, J= 8.8 Hz, 2H), 7.76 (d, J= 7.7 Hz, 1H), 7.61 (t, J= 7.5 Hz, 1H), 7.56 (t, J= 9.1 Hz, 2H),
7.33 (d, J= 8.9 Hz, 2H), 6.63 (s, 1H), 2.27 (t, J= 7.4 Hz, 2H), 1.55 (p, J= 7.3 Hz, 2H), 1.33-1.20
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(m, 6H), 0.84 (t, J= 6.6 Hz, 3H); C NMR (CDCl3, 100 MHz): δ= 146.8, 143.1, 141.7, 132.8,
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132.4, 131.7, 128.4, 128.2, 127.6, 124.5, 122.6, 114.6, 34.0, 31.5, 28.3, 27.4, 22.5, 14.1; C
DEPT-135 (CDCl3, 100 MHz): 132.8, 128.4, 128.2, 127.6, 124.5, 122.6, 114.6, 34.0, 31.5, 28.3,
27.4, 22.5, 14.1; Anal. Calcd for C20H22N2O4S: C, 62.16; H, 5.74; N, 7.25. Found: C, 62.00; H,
5.61; N, 7.44.
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Preparation of 2-(3-nitrophenyl)-3-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14ba): 96%
yield (71 mg), white solid; mp 207-209 oC; IR (KBr): 1614, 1348, 1172 cm-1; 1H NMR (CDCl3,
400 MHz): δ= 7.99 (d, J= 7.4 Hz, 1H), 7.84-7.82 (m, 2H), 7.73-7.62 (m, 5H), 7.55 (t, J= 7.5 Hz,
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148.4, 142.2, 138.6, 134.2, 133.5, 133.1, 132.6, 132.1, 130.1, 129.7, 129.2, 129.1, 128.5, 127.8,
123.2, 122.5, 121.6, 115.6; 13C DEPT-135 (CDCl3, 100 MHz): 133.5, 133.1, 130.1, 129.7,
129.2, 129.1, 128.5, 127.8, 123.2, 122.5, 121.6, 115.6; Anal. Calcd for C20H14N2O4S: C, 63.48;
H, 3.73; N, 7.40. Found: C, 63.73; H, 3.87; N, 7.17.
Preparation of 3-(4-methoxyphenyl)-2-(3-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14bc): 96% yield (77 mg), white solid; mp 180-182 C; IR (KBr): 1602, 1348, 1172 cm-1; H
NMR (CDCl3, 400 MHz): δ= 7.99 (dd, J= 8.1, 1.5 Hz, 1H), 7.83-7.80 (m, 2H), 7.69 (td, J= 8.0,
1.1 Hz, 1H), 7.62 (d, J= 7.7 Hz, 2H), 7.57 (d, J= 8.8 Hz, 2H), 7.51 (td, J= 7.7, 0.8 Hz, 1H), 7.43
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(t, J= 8.1 Hz, 1H), 7.06 (s, 1H), 6.83 (d, J= 8.7 Hz, 2H), 3.77 (s, 3H); C NMR (CDCl3, 100
MHz): δ= 161.0, 148.4, 142.1, 138.8, 133.5, 133.1, 132.9, 131.8, 129.7, 129.3, 128.8, 128.3,
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126.7, 123.2, 122.4, 121.7, 114.6, 114.0, 55.5; C DEPT-135 (CDCl3, 100 MHz): 133.5, 133.1,
129.7, 129.3, 128.8, 128.3, 123.2, 122.4, 121.7, 114.6, 114.0, 55.5; Anal. Calcd for
C21H16N2O5S: C, 61.76; H, 3.95; N, 6.86. Found: C, 61.59; H, 3.74; N, 7.11.
Preparation of 3-(4-methylphenyl)-2-(3-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14bd): 91% yield (70 mg), white solid; mp 217-219 C; IR (KBr): 1610, 1348, 1174 cm-1; H
NMR (CDCl3, 400 MHz): δ= 7.99 (dd, J= 8.1, 1.1 Hz, 1H), 7.83-7.81 (m, 2H), 7.69 (td, J= 7.8,
0.8 Hz, 1H), 7.63 (d, J= 7.9 Hz, 2H), 7.54-7.51 (m, 3H), 7.43 (t, J= 8.1 Hz, 1H), 7.13
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(superimposed d, J= 8.4 Hz, 2H), 7.11 (superimposed s, 1H), 2.29 (s, 3H); C NMR (CDCl3,
100 MHz): δ= 148.4, 142.3, 140.4, 138.8, 133.5, 133.1, 132.8, 132.0, 131.4, 129.9, 129.7, 128.9,
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129.9, 129.7, 128.9, 128.4, 127.8, 123.2, 122.4, 121.7, 114.8, 21.4; Anal. Calcd for
C21H16N2O4S: C, 64.27; H, 4.11; N, 7.14. Found: C, 64.11; H, 4.30; N, 7.24.
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Preparation of 3-(4-fluorophenyl)-2-(3-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14be): 95% yield (73 mg) as a white solid; mp 200-202 C; IR (KBr): 1606, 1350, 1172 cm-1;
1H NMR (CDCl3, 400 MHz): δ= 8.01 (dd, J= 8.0, 1.0 Hz, 1H), 7.84-7.80 (m, 2H), 7.71 (t, J=7.4
Hz, 1H), 7.65-7.61 (m, 4H), 7.55 (t, J= 7.6 Hz, 1H), 7.44 (t, J= 8.1 Hz, 1H), 7.10 (s, 1H), 7.02 (t,
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J= 8.5 Hz, 2H); C NMR (CDCl3, 100 MHz): δ= 163.7 (d, J= 250.5 Hz), 148.4, 141.2, 138.5,
133.4, 133.2, 132.4, 132.0, 130.4 (d, J= 2.8 Hz), 129.8, 129.7 (d, J= 8.8 Hz), 129.3, 128.5, 123.3,
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122.6, 121.6, 116.4 (d, J= 21.9 Hz), 115.5; C DEPT-135 (CDCl3, 100 MHz): 133.4, 133.2,
129.8, 129.7, 129.3, 128.5, 123.3, 122.6, 121.6, 116.4, 115.5; Anal. Calcd for C20H13FN2O4S: C,
60.60; H, 3.31; N, 7.07. Found: C, 60.83; H, 3.47; N, 6.81.
Preparation of 3-(4-benzyloxyphenyl)-2-(3-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14bf): 92% yield (87 mg), white solid; mp 142-144 C; IR (KBr): 1606, 1350, 1172 cm-1; H
NMR (CDCl3, 400 MHz): δ= 8.00 (dd, J= 8.0, 0.9 Hz, 1H), 7.82-7.80 (m, 2H), 7.69 (t, J= 7.4
Hz, 1H), 7.63-7.61 (m, 2H), 7.57 (d, J= 8.7 Hz, 2H), 7.51 (t, J= 7.6 Hz, 1H), 7.46-7.32 (m, 6H),
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7.06 (s, 1H), 6.91 (d, J= 8.7 Hz, 2H), 5.01 (s, 2H); C NMR (CDCl3, 100 MHz): δ= 160.3,
148.4, 142.0, 138.8, 136.4, 133.5, 133.1, 132.9, 131.9, 129.7, 129.4, 128.8, 128.3, 127.6, 126.9,
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123.2, 122.4, 121.6, 115.4, 114.1, 70.2; C DEPT-135 (CDCl3, 100 MHz): 133.5, 133.1, 129.7,
129.3, 128.8, 128.3, 127.6, 123.2, 122.4, 121.6, 115.4, 114.1, 70.2; Anal. Calcd for
C27H20N2O5S: C, 66.93; H, 4.16; N, 5.78. Found: C, 67.11; H, 4.29; N, 5.52.
Preparation of 2-(3-nitrophenyl)-3-(2-phenylethyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14bg): 94% yield (89 mg), white solid; mp 127-129 C; IR (KBr): 1625, 1350, 1172 cm-1; H
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NMR (CDCl3, 400 MHz): δ= 8.23-8.20 (m, 1H), 7.92-7.90 (m, 1H), 7.81 (d, J= 7.8 Hz, 1H),
7.66 (td, J= 7.6, 0.9 Hz, 1H), 7.62-7.56 (m, 2H), 7.51 (t, J= 7.7 Hz, 1H), 7.47 (d, J= 7.7 Hz, 1H),
7.30-7.26 (m, 2H), 7.23-7.19 (m, 1H), 7.14 (d, J= 7.0 Hz, 2H), 6.61 (s, 1H), 2.95 (t, J= 7.5 Hz,
2H), 2.60 (t, J= 7.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ= 148.6, 142.1, 140.1, 137.3, 134.2,
132.9, 132.3, 131.6, 130.0, 128.6, 128.6, 127.8, 126.5, 123.1, 122.7, 122.4, 114.7, 36.0, 33.9; 13C
DEPT-135 (CDCl3, 100 MHz): 134.2, 132.9, 130.0, 128.6, 128.6, 127.8, 126.5, 123.1, 122.7,
122.4, 114.7, 36.0, 33.9; Anal. Calcd for C22H18N2O4S: C, 65.01; H, 4.46; N, 6.89. Found: C,
64.75; H, 4.62; N, 6.81.
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Preparation of 3-cyclopropyl-2-(3-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide (14bh):
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93% yield (62 mg), white solid; mp 134-136 C; IR (KBr): 1631, 1346, 1170 cm-1; H NMR
(CDCl3, 400 MHz): δ= 8.19 (dd, J= 8.1, 1.0 Hz, 1H), 8.01 (t, J= 2.0 Hz, 1H), 7.77 (d, J= 7.7 Hz,
1H), 7.69 (dt, J= 8.0, 0.8 Hz, 1H), 7.63-7.56 (m, 2H), 7.47-7.42 (m, 2H), 6.46 (s, 1H), 1.45 (p,
J= 7.0 Hz, 1H), 0.78-0.76 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ= 148.5, 144.9, 137.7, 134.7,
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132.8, 132.7, 131.5, 129.9, 128.0, 127.5, 123.2, 122.6, 110.1, 15.3, 8.4; C DEPT-135 (CDCl3,
100 MHz): 134.7, 132.8, 129.9, 128.0, 127.5, 123.2, 122.6, 110.1, 15.3, 8.4; Anal. Calcd for
C17H14N2O4S: C, 59.64; H, 4.12; N, 8.18. Found: C, 59.86; H, 3.93; N, 8.35.
Preparation of 3-hexyl-2-(3-nitrophenyl)-2H-1,2-benzothiazine 1,1-dioxide (14bi): 90%
o
yield (68 mg), white solid; mp 99-101 C; IR (KBr): 1633, 1350, 1176 cm-1; 1H NMR (CDCl3,
400 MHz): δ= 8.20-8.17 (m, 1H), 7.91 (t, J= 2.0 Hz, 1H), 7.76 (d, J= 7.5 Hz, 1H), 7.65-7.61 (m,
2H), 7.58 (t, J= 8.0 Hz, 1H), 7.47 (t, J= 7.6 Hz, 2H), 6.62 (s, 1H), 2.26 (t, J= 7.4 Hz, 2H), 1.56
(p, J= 7.4 Hz, 2H), 1.34-1.20 (m, 6H), 0.84 (t, J= 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ=
148.6, 143.2, 137.4, 134.2, 132.8, 132.5, 131.6, 130.0, 128.4, 127.7, 123.1, 122.6, 122.5, 114.2,
34.0, 31.5, 28.3, 27.4, 22.5, 14.1; 13C DEPT-135 (CDCl3, 100 MHz): 134.2, 132.8, 130.0, 128.4,
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127.7, 123.1, 122.6, 122.5, 114.2, 34.0, 31.5, 28.3, 27.4, 22.5, 14.1; Anal. Calcd for
C20H22N2O4S: C, 62.16; H, 5.74; N, 7.25. Found: C, 61.87; H, 6.00; N, 7.37.
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Preparation of 2-(3-methoxyphenyl)-3-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14ca):
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(CDCl3, 400 MHz): δ= 7.83 (d, J= 7.7 Hz, 1H), 7.69-7.64 (m, 3H), 7.59 (d, J= 7.5 Hz, 1H), 7.51
(t, J= 7.6 Hz, 1H), 7.34-7.28 (m, 3H), 7.08 (t, J= 8.3 Hz, 1H), 7.05 (s, 1H), 6.74-6.67 (m, 3H),
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3.69 (s, 3H); C NMR (CDCl3, 100 MHz): δ= 159.8, 143.2, 138.4, 135.0, 133.0, 132.6, 132.1,
129.6, 129.4, 128.8, 128.7, 128.1, 127.9, 123.3, 119.8, 114.3, 113.6, 113.3, 55.5; 13C DEPT-135
(CDCl3, 100 MHz): 132.6, 129.6, 129.4, 128.8, 128.7, 128.1, 127.9, 123.3, 119.8, 114.3, 113.6,
113.3, 55.5; Anal. Calcd for C21H17NO3S: C, 69.40; H, 4.71; N, 3.85. Found: C, 69.56; H, 4.83;
N, 3.74.
Preparation of 2-(3-methoxyphenyl)-3-(4-methoxyphenyl)-2H-1,2-benzothiazine 1,1-dioxide
(14cc): 93% yield (75 mg), white solid; mp 145-147 C; IR (KBr): 1598, 1348, 1170 cm-1; H
NMR (CDCl3, 400 MHz): δ= 7.81 (d, J= 7.8 Hz, 1H), 7.65-7.55 (m, 4H), 7.47 (t, J= 8.8 Hz, 1H),
7.08 (t, J= 7.9 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J= 8.8 Hz, 2H), 6.72-6.66 (m, 3H), 3.77 (s, 3H),
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129.4, 129.3, 128.3, 127.8, 127.6, 123.3, 119.8, 114.2, 113.6, 113.2, 112.9, 55.5, 55.4; 13C
DEPT-135 (CDCl3, 100 MHz): 132.6, 129.4, 129.3, 128.3, 127.8, 123.3, 119.8, 114.2, 113.6,
113.2, 112.9, 55.5, 55.4; Anal. Calcd for C22H19NO4S: C, 67.16; H, 4.87; N, 3.56. Found: C,
67.31; H, 5.00; N, 3.34.
Preparation of 3-(4-fluorophenyl)-2-(3-methoxyphenyl)-2H-1,2-benzothiazine 1,1-dioxide
(14ce): 91% yield (71 mg), white solid; mp 148-150 C; IR (KBr): 1596, 1346, 1174 cm-1; H
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1H), 7.51 (t, J= 7.8 Hz, 1H), 7.09 (t, J= 8.1 Hz, 1H), 7.02-6.98 (m, 3H), 6.71-6.68 (m, 2H),
6.65-6.64 (m, 1H), 3.69 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ= 163.5 (d, J= 248.0 Hz), 159.9,
142.2, 138.2, 132.9, 132.7, 132.0, 131.2 (d, J= 3.1 Hz), 129.7 (d, J= 8.7 Hz), 129.6, 128.8, 128.0,
123.3, 119.8, 115.9 (d, J= 21.8 Hz), 114.2, 113.7, 113.3, 55.5; 13C DEPT-135 (CDCl3, 100
MHz): 132.7, 129.7, 129.5, 128.8, 128.0, 123.3, 119.8, 115.9, 114.2, 113.7, 113.3, 55.5; Anal.
Calcd for C21H16FNO3S: C, 66.13; H, 4.23; N, 3.67. Found: C, 65.94; H, 4.06; N, 3.89.
Preparation of 3-(4-benzyloxyphenyl)-2-(3-methoxyphenyl)-2H-1,2-benzothiazine 1,1-
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7.6 Hz, 1H), 7.47 (t, J= 7.4 Hz, 1H), 7.44-7.29 (m, 5H), 7.09 (t, J= 8.0 Hz, 1H), 6.97 (s, 1H),
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(CDCl3, 100 MHz): 132.6, 129.4, 129.3, 128.7, 128.3, 128.3, 127.9, 127.7, 123.2, 119.8, 115.1,
113.6, 113.2, 113.0, 70.2, 55.5; Anal. Calcd for C28H23NO4S: C, 71.62; H, 4.94; N, 2.98. Found:
C, 71.36; H, 5.07; N, 3.15.
Preparation of 2-(3-methoxyphenyl)-3-(2-phenylethyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14cg): 92% yield (74 mg), red gummy liquid; IR (KBr): 1596, 1346, 1170 cm-1; H NMR
(CDCl3, 400 MHz): δ= 7.81 (d, J= 7.8 Hz, 1H), 7.59 (td, J= 7.6, 0.9 Hz, 1H), 7.45 (t, J= 7.5 Hz,
1H), 7.39 (d, J= 7.8 Hz, 1H), 7.30-7.23 (m, 3H), 7.18 (d, J= 7.2 Hz, 1H), 7.10 (d, J= 7.1 Hz, 2H),
6.90 (dd, J= 8.1, 1.9 Hz, 1H), 6.79 (dd, J= 7.7, 0.8 Hz, 1H), 6.74 (t, J= 2.1 Hz, 1H), 6.43 (s, 1H),
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160.2, 143.3, 140.7, 137.0, 132.8, 132.3, 131.5, 129.9, 128.6, 128.5, 127.9, 127.3, 126.3, 122.6,
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Calcd for C23H21NO3S: C, 70.56; H, 5.41; N, 3.58. Found: 70.79; H, 5.52; N, 3.39.
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Preparation of 3-cyclopropyl-2-(3-methoxyphenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14ch): 94% yield (63 mg), white solid; mp 173-175 C; IR (KBr): 1602, 1332, 1170 cm-1; H
NMR (CDCl3, 400 MHz): δ= 7.77 (d, J= 7.8 Hz, 1H), 7.53 (td, J= 7.6, 0.8 Hz, 1H), 7.38 (t, J=
7.5 Hz, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.22 (t, J= 4.7 Hz, 1H), 6.88-6.78 (m, 3H), 6.27 (s, 1H),
3.76 (s, 3H), 1.44 (p, J= 6.7 Hz, 1H), 0.71 (d, J= 6.8 Hz, 4H); 13C NMR (CDCl3, 100 MHz): δ=
160.1, 146.1, 137.3, 133.2, 132.3, 131.4, 129.7, 127.4, 127.0, 122.5, 121.2, 114.7, 114.6, 107.7,
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55.6, 15.3, 8.3; C DEPT-135 (CDCl3, 100 MHz): 132.3, 129.7, 127.4, 127.0, 122.5, 121.2,
114.7, 114.6, 107.7, 55.6, 15.3, 8.3; Anal. Calcd for C18H17NO3S: C, 66.03; H, 5.23; N, 4.28.
Found: C, 66.28; H, 5.31; N, 4.15.
Preparation of 3-hexyl-2-(3-methoxyphenyl)-2H-1,2-benzothiazine 1,1-dioxide (14ci): 91%
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yield (69 mg), red gummy liquid; IR (KBr): 1596, 1348, 1170 cm-1; H NMR (CDCl3, 400
MHz): δ= 7.79 (d, J= 7.8 Hz, 1H), 7.58 (td, J= 7.5, 1.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.25 (t, J=
8.0 Hz, 1H), 6.88 (dd, J= 7.9, 2.4 Hz, 1H), 6.76 (dd, J= 7.6, 1.0 Hz, 1H), 6.72 (t, J= 2.2 Hz, 1H),
6.47 (s, 1H), 3.78 (s, 3H), 2.25 (t, J= 7.4 Hz, 2H), 1.62-1.53 (m, 4H), 1.32-1.20 (m, 4H), 0.85 (t,
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129.8, 127.7, 127.1, 122.6, 120.7, 114.4, 114.3, 111.8, 55.6, 34.1, 31.6, 28.5, 27.6, 22.6, 14.2;
13C DEPT-135 (CDCl3, 100 MHz): 132.3, 129.8, 127.7, 127.1, 122.6, 120.7, 114.4, 114.3,
111.8, 55.6, 34.1, 31.6, 28.5, 27.6, 22.6, 14.2; Anal. Calcd for C21H25NO3S: C, 67.89; H, 6.78;
N, 3.77. Found: 67.73; H, 6.68; N, 3.94.
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Preparation of 2-(4-methylphenyl)-3-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14da): 95%
yield (71 mg), white solid; mp 192-194 oC; IR (KBr): 1616, 1346, 1176 cm-1; 1H NMR (CDCl3,
400 MHz): δ= 7.83 (d, J= 7.8 Hz, 1H), 7.69-7.63 (m, 3H), 7.59 (d, J= 7.4 Hz, 1H), 7.50 (td, J=
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129.5, 128.7, 128.6, 128.0, 127.9, 127.3, 123.3, 114.1, 21.1; HRMS (ES+): MH+, found
348.1055. C21H18NO2S requires 348.1058.
Preparation of 3-(4-ethoxyphenyl)-2-(4-methylphenyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14db): 93% yield (78 mg), white solid; mp 179-181 C; IR (KBr): 1604, 1348, 1174 cm-1; H
NMR (CDCl3, 400 MHz): δ= 7.80 (d, J= 7.8 Hz, 1H), 7.63 (td, J= 7.9, 1.1 Hz, 1H), 7.60-7.54
(m, 3H), 7.46(td, J= 7.7, 1.0 Hz, 1H), 7.00-6.96 (m, 4H), 6.95 (s, 1H), 6.80 (d, J= 8.8 Hz, 2H),
3.97 (q, J= 7.0 Hz, 2H), 2.20 (s, 3H), 1.37 (t, J= 7.0 Hz, 3H) ; 13C NMR (CDCl3, 100 MHz): δ=
160.1, 143.3, 137.8, 134.9, 133.4, 132.5, 131.7, 129.6, 129.4, 128.1, 127.8, 127.4, 127.2, 123.3,
114.6, 112.5, 63.6, 21.1, 14.8; 13C DEPT-135 (CDCl3, 100 MHz): 132.5, 129.6, 129.4, 128.1,
127.8, 127.2, 123.3, 114.6, 112.5, 63.6, 21.1, 14.8; Anal. Calcd for C23H21NO3S: C, 70.56; H,
5.41; N, 3.58. Found: C, 70.75; H, 5.23; N, 3.50.
Preparation of 2,3-bis(4-methylphenyl)-2H-1,2-benzothiazine 1,1-dioxide (14dd): 90% yield
o
(70 mg), white solid; mp 187-189 C; IR (KBr): 1608, 1346, 1174 cm-1; 1H NMR (CDCl3, 400
MHz): δ= 7.81 (d, J= 7.6 Hz, 1H), 7.64 (t, J= 7.5 Hz, 1H), 7.56 (t, J= 7.7 Hz, 3H), 7.48 (t, J= 7.5
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Hz, 1H), 7.12 (d, J= 7.8 Hz, 2H), 7.05-6.88 (m, 5H), 2.29 (s, 3H), 2.20 (s, 3H); C NMR
(CDCl3, 100 MHz): δ= 143.5, 139.8, 137.9, 134.9, 133.3, 132.5, 132.3, 131.9, 129.6, 129.5,
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128.4, 127.9, 127.9, 127.2, 123.3, 113.4, 21.4, 21.2; C DEPT-135 (CDCl3, 100 MHz): 132.5,
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129.6, 129.5, 128.4, 127.9, 127.9, 127.2, 123.3, 113.4, 21.4, 21.2; Anal. Calcd for C22H19NO2S:
C, 73.10; H, 5.30; N, 3.88. Found: 73.31; H, 5.49; N, 3.70.
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Preparation of 2-(4-methylphenyl)-3-(2-phenylethyl)-2H-1,2-benzothiazine 1,1-dioxide
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(14dg): 92% yield (74 mg), red gummy liquid; IR (KBr): 1616, 1346, 1172 cm-1; H NMR
(CDCl3, 400 MHz): δ= 7.80 (d, J= 7.7 Hz, 1H), 7.57 (td, J= 7.6, 0.8 Hz, 1H), 7.43 (td, J= 7.6, 0.6
Hz, 1H), 7.37 (d, J= 7.8 Hz, 1H), 7.23 (d, J= 6.8 Hz, 2H), 7.18-7.16 (m, 3H), 7.10-7.07 (m, 4H),
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6.41 (s, 1H), 2.90 (t, J= 7.5 Hz, 2H), 2.53 (t, J= 7.5 Hz, 2H), 2.35 (s, 3H); C NMR (CDCl3,
100 MHz): δ= 143.4, 140.7, 138.9, 133.3, 132.9, 132.2, 131.4, 130.0, 128.6, 128.5, 128.3, 127.8,
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127.2, 126.3, 122.5, 111.8, 36.2, 34.0, 21.3; C DEPT-135 (CDCl3, 100 MHz): 132.3, 130.0,
128.6, 128.5, 128.3, 127.8, 127.2, 126.3, 122.5, 111.8, 36.2, 34.0, 21.3; Anal. Calcd for
C23H21NO2S: C, 73.57; H, 5.64; N, 3.73. Found: C, 73.79; H, 5.48; N, 3.92.
Preparation of 3-hexyl-2-(4-methylphenyl)-2H-1,2-benzothiazine 1,1-dioxide (14di): 90%
yield (69 mg), red gummy liquid; IR (KBr): 1622, 1348, 1174 cm-1; H NMR (CDCl3, 400
1
MHz): δ= 7.78 (d, J= 7.9 Hz, 1H), 7.57 (td, J= 7.6, 1.0 Hz, 1H), 7.44-7.39 (m, 2H), 7.16 (d, J=
8.1 Hz, 2H), 7.06 (dt, J= 8.3, 1.7 Hz, 2H), 6.46 (s, 1H), 2.34 (s, 3H), 2.24 (t, J= 7.4 Hz, 2H), 1.56
(p, J= 7.3 Hz, 2H), 1.32-1.20 (m, 6H), 0.86 (t, J= 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ=
144.6, 138.7, 133.4, 133.1, 132.2, 131.3, 129.9, 128.3, 127.6, 127.0, 122.5, 111.4, 34.0, 31.6,
28.5, 27.5, 22.6, 21.3, 14.1; 13C DEPT-135 (CDCl3, 100 MHz): 132.2, 129.9, 128.3, 127.6,
127.0, 122.5, 111.4, 34.0, 31.6, 28.5, 27.5, 22.6, 21.3, 14.1; HRMS (ES+): MNa+, found
378.1503. C21H25NNaO2S requires 378.1504.
Preparation of 2,3-diphenyl-2H-1,2-benzothiazine 1,1-dioxide (14ea): 95% yield (71 mg) as a
white solid; mp 226-228 oC; IR (KBr): 1606, 1348, 1170 cm-1; 1H NMR (CDCl3, 400 MHz): δ=
7.83 (d, J= 7.8 Hz, 1H), 7.68-7.64 (m, 3H), 7.60 (d, J= 7.4 Hz, 1H), 7.51 (t, J= 7.4 Hz, 1H),
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7.33-7.27 (m, 3H), 7.21-7.10 (m, 5H), 7.06 (s, 1H); C NMR (CDCl3, 100 MHz): δ= 143.3,
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137.4, 135.0, 133.1, 132.6, 132.1, 129.6, 128.9, 128.8, 128.7, 128.1, 128.0, 127.8, 127.5, 123.2,
114.3; 13C DEPT-135 (CDCl3, 100 MHz): 132.6, 129.6, 128.9, 128.8, 128.7, 128.1, 128.0,
127.8, 127.5, 123.2, 114.3; HRMS (ES+): MH+, found 334.0902. C20H16NO2S requires
334.0902.
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Preparation of 3-(4-methylphenyl)-2-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14ed): 92%
yield (72 mg), white solid; mp 179-181 oC; IR (KBr): 1610, 1346, 1172 cm-1; 1H NMR (CDCl3,
400 MHz): δ= 7.82 (d, J= 7.7 Hz, 1H), 7.65 (t, J= 7.8 Hz, 1H), 7.59-7.53 (m, 3H), 7.49 (t, J= 7.6
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Hz, 1H), 7.22-7.17 (m, 2H), 7.15-7.09 (m, 5H), 7.02 (s, 1H), 2.29 (s, 3H); C NMR (CDCl3,
100 MHz): δ= 143.4, 139.8, 137.5, 133.2, 132.5, 132.2, 132.0, 129.5, 128.9, 128.5, 127.9, 127.9,
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127.8, 127.5, 123.2, 113.6, 21.4; C DEPT-135 (CDCl3, 100 MHz): 132.5, 129.5, 128.9, 128.5,
127.9, 127.9, 127.8, 127.5, 123.3, 113.6, 21.4; Anal. Calcd for C21H17NO2S: C, 72.60; H, 4.93;
N, 4.03. Found: C, 72.76; H, 4.76; N, 4.15.
Preparation of 3-cyclopropyl-2-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14eh): 94% yield
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(63 mg), white solid; mp 90-101 C; IR (KBr): 1612, 1338, 1170 cm-1; H NMR (CDCl3, 400
MHz): δ= 7.80 (d, J= 7.8 Hz, 1H), 7.57 (t, J= 7.2 Hz, 1H), 7.44-7.35 (m, 5H), 7.28-7.25 (m, 2H),
6.31 (s, 1H), 1.44 (p, J= 7.0 Hz, 1H), 0.73 (t, J= 5.0 Hz, 4H); 13C NMR (CDCl3, 100 MHz): δ=
13
146.1, 136.3, 133.2, 132.3, 131.4, 129.2, 129.0, 128.7, 127.4, 127.0, 122.5, 107.7, 15.3, 8.3; C
DEPT-135 (CDCl3, 100 MHz): 132.3, 129.2, 129.0, 128.7, 127.4, 127.0, 122.5, 107.7, 15.3, 8.3;
Anal. Calcd for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71. Found: C, 68.86; H, 4.93; N, 4.81.
Preparation of 3-hexyl-2-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14ei): 91% yield (70
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mg), red gummy liquid; IR (KBr): 1608, 1350, 1172 cm-1; H NMR (CDCl3, 400 MHz): δ=
7.79 (d, J= 7.9 Hz, 1H), 7.58 (td, J= 7.8, 1.2 Hz, 1H), 7.45-7.35 (m, 5H), 7.20-7.17 (m, 2H), 6.49
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(s, 1H), 2.24 (t, J= 7.4 Hz, 2H), 1.56 (p, J= 7.6 Hz, 2H), 1.29-1.23 (m, 6H), 0.86 (t, J= 7.1 Hz,
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3H); C NMR (CDCl3, 100 MHz): δ= 144.5, 136.0, 133.0, 132.3, 131.5, 129.2, 128.6, 128.4,
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127.7, 127.1, 122.5, 111.9, 34.1, 31.5, 28.5, 27.5, 22.6, 14.1; 13C DEPT-135 (CDCl3, 100 MHz):
132.3, 129.2, 128.6, 128.4, 127.7, 127.1, 122.5, 111.9, 34.1, 31.5, 28.5, 27.5, 22.6, 14.1; Anal.
Calcd for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10. Found: C, 70.09; H, 6.92; N, 4.27.
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Preparation of 2-(2-chlorophenyl)-3-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14fa): 90%
yield (67 mg), white solid; mp 199-201 oC; IR (KBr): 1608, 1342, 1174 cm-1; 1H NMR (CDCl3,
400 MHz): δ= 7.86 (d, J= 7.7 Hz, 1H), 7.70-7.65 (m, 3H), 7.58 (d, J= 7.5 Hz, 1H), 7.52 (td, J=
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7.6, 0.9 Hz, 1H), 7.33-7.29 (m, 4H), 7.12-7.02 (m, 3H), 6.91 (s, 1H); C NMR (CDCl3, 100
MHz): δ= 143.7, 135.0, 134.9, 134.5, 133.0, 132.6, 132.1, 130.8, 130.4, 129.8, 128.6, 128.5,
128.1, 127.8, 127.3, 122.7, 113.3; 13C DEPT-135 (CDCl3, 100 MHz): 132.6, 130.8, 130.4,
129.8, 128.6, 128.5, 128.1, 127.8, 127.3, 122.7, 113.3; Anal. Calcd for C20H14ClNO2S: C, 65.30;
H, 3.84; N, 3.81. Found: C, 65.50; H, 3.97; N, 3.63.
Preparation of 2-(4-methoxyphenyl)-3-phenyl-2H-1,2-benzothiazine 1,1-dioxide (14ga):
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97% yield (72 mg), white solid; mp 165-167 C; IR (KBr): 1598, 1332, 1186 cm-1; H NMR
(CDCl3, 400 MHz): δ= 7.82 (d, J= 6.8 Hz, 1H), 7.73-7.54 (m, 4H), 7.54-7.42 (m, 1H), 7.37-7.24
(m, 3H), 7.10-6.90 (m, 3H), 6.67 (d, J= 7.2 Hz, 2H), 3.67 (s, 3H); 13C NMR (CDCl3, 100 MHz):
δ= 158.9, 143.4, 134.9, 133.0, 132.4, 131.7, 130.6, 129.9, 129.4, 128.6, 128.4, 127.8, 123.1,
114.1, 113.6, 55.3; Anal. Calcd for C21H17NO3S: C, 69.40; H, 4.71; N, 3.85. Found: C, 69.56; H,
4.62; N, 3.77.
ASSOCIATED CONTENT
Supporting Information
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Scanned copies of H and C NMR spectra of all new compounds are available. CIF files for
crystal structures of 14aa, 14bi, 14ch and 14db are available. The coordinates of optimized
structures are also available. This material is available free of charge via the Internet at
http://pubs.acs.org.
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ACKNOWLEDGMENTS
DST, Government of India, is greatly acknowledged for giving a research grant to S. M. through
INSPIRE Faculty Award (No. IFA12/CH/56) and S.D. is thankful to DST, for a junior research
fellowship under the same project. We again thank the DST (New Delhi) for providing Single
Crystal XRD under the DST-FIST program in our department. We are highly grateful to
Professor S. K. Chandra, department of chemistry, Visva-Bharati for help in the studies of X-ray
data. We also thank Md. Asif Amin (Junior Research Fellow, Indian Association for the
Cultivation of Science) for HRMS Spectroscopy.
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