Solvent-dependent Baylis-Hillman reactions for the synthesis of 3-benzyl-3-hydroxyoxindoles and benzo-δ-sultams

Article abstract of DOI:10.1016/j.tet.2014.02.038

We have developed a solvent-dependent method for the preparation of novel benzo-δ-sultam and 3-benzyl-3-hydroxy-N-methyloxindole scaffolds. A variety of 3-(methoxy(phenyl)methyl)-1-methyl-1H-benzo-[c][1,2]thiazine 2,2-dioxides and 3-benzyl-3-hydroxy-1-methylindolin-2-ones were obtained in moderate to high yields via DBU-catalyzed Baylis-Hillman reaction of a number of (E)-N-(2-formylphenyl)-N-methyl-2-phenylethenesulfonamides in DMF and MeOH, respectively. The proof of the structures relies on analytical investigation and X-ray crystallography. Whereas reaction of (E)-N-(2-formylphenyl)-N-methyl-2- phenylethenesulfonamides in MeOH presumably proceeds through intramolecular Baylis-Hillman/dehydration, 3-hydroxy-N-methyloxindoles seem to have been generated via intramolecular Baylis-Hillman/1,3-H shift/oxidation/intramolecular cyclization tandem sequences in DMF.

Full text of DOI:10.1016/j.tet.2014.02.038

Tetrahedron 70 (2014) 2563e2569
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-dependent BayliseHillman reactions for the synthesis
of 3-benzyl-3-hydroxyoxindoles and benzo-d-sultams
,
a,
Mehdi Ghandi a , Shahzad Feizi b, Farhood Ziaie b, Behrouz Notash c
*
a School of Chemistry, College of Science, University of Tehran, Tehran, PO Box 14155 6455, Iran
b Agricultural, Medical and Industrial Research School (AMIRS), Karaj, PO Box 31485498, Iran
c Department of Chemistry, Shahid Beheshti University, G. C. Evin, Tehran, PO Box 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a solvent-dependent method for the preparation of novel benzo-d-sultam and 3-
Received 1 December 2013
Received in revised form 9 February 2014
Accepted 17 February 2014
Available online 27 February 2014
benzyl-3-hydroxy-N-methyloxindole scaffolds. A variety of 3-(methoxy(phenyl)methyl)-1-methyl-1H-
benzo-[c][1,2]thiazine 2,2-dioxides and 3-benzyl-3-hydroxy-1-methylindolin-2-ones were obtained in
moderate to high yields via DBU-catalyzed BayliseHillman reaction of
a number of (E)-N-(2-
formylphenyl)-N-methyl-2-phenylethenesulfonamides in DMF and MeOH, respectively. The proof of
the structures relies on analytical investigation and X-ray crystallography. Whereas reaction of (E)-N-(2-
formylphenyl)-N-methyl-2-phenylethenesulfonamides in MeOH presumably proceeds through intra-
molecular BayliseHillman/dehydration, 3-hydroxy-N-methyloxindoles seem to have been generated via
intramolecular BayliseHillman/1,3-H shift/oxidation/intramolecular cyclization tandem sequences in
DMF.
Keywords:
BayliseHillman reaction
Benzo-d-sultams
3-Benzyl-3-hydroxy-N-methyloxindoles
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
the subject of excellent reviews.18 In particular, the 3-substituted-3-
hydroxy-2-oxindole scaffold as a sub-class of oxindole natural
A base-catalyzed reaction of carbon electrophiles with the ac-
tivated alkenes (alkynes) or electron-deficient Michael-accepting
components, known as BayliseHillman (BH) reaction, is an efficient
process going cleanly under very mild conditions, affording a highly
functionalized adduct.1 Considerable progress has been achieved in
developing effective catalysts such as DBU,2 DABCO,3 DMAP,4 PR3,5
Et3N,6 quinuclidine,7 and imidazole.8 The BH reaction was discov-
ered in 1972.9 Recent attention has been focused on intramolecular
versions of the BH reaction.10 Such reactions in principle can pro-
vide carbocyclic or heterocyclic compounds in different ring sizes
with functionality.11
products is known to be at the core of several natural products with
different biological activities (Fig. 1b).19
To the best of our knowledge, there has been no report in the
literature on the intramolecular BH reaction of an electron-
deficient Michael-accepting electrophile tethered to a phenyl ring
by a sulfonamide link. Our own interest in the BH reaction20
prompted us to explore the synthesis of benzo-d-sultam template
as the structurally related analogue of COX-2 (see Fig. 1a). Herein,
we report the synthesis of novel 3-benzyl-3-hydroxy-1-
methylindolin-2-one and benzo-d-sultam scaffolds using a sol-
vent-dependent DBU-catalyzed BH reaction.
Sulfonamides have a rich chemical and biological history and are
an important class of compounds in drug discovery due to their
extensive chemical and biological activities.12 Significant interest
has been directed toward cyclic sulfonamides, also known as sul-
tams. Although not found in nature, sultams are known as privi-
leged structures in drug discovery due to their diverse biological
properties.13 Examples include the ampiroxicam (COX-2) anti-in-
flammatory agent,14 calpain inhibitor 1,15 benzodithiazine dioxides
displaying anti-HIV-1 activity,16 and antiepileptic agent sulthiame
(Fig. 1a).17 On the other hand, oxindole natural products have been
2. Results and discussion
Vinyl sulfonamides 1aeg were initially prepared using the
previously reported procedure.21 Vinyl sulfonamide 1a served for
our early exploration of intramolecular BH chemistry. Whereas
reaction of 1a in CH2Cl2, MeCN, H2O, and PhMe was almost in-
efficient toward BH reaction, upon addition of DBU (100 mol %,
0.10 M) (entries 1e4, Table 1), 3-benzyl-3-hydroxy-1-
methylindolin-2-one (2a)22 was identified as the sole product in
20 and 25% yield in DMF within 36 and 72 h, respectively (entries 5
and 6, Table 1). Changing the base concentration from 0.10 to 0.25,
0.50, and 0.75 M increased the product yield to 42, 52, and 83%,
respectively (entries 7e9, Table 1). Since no reaction progress
* Corresponding author. Tel.: þ98 21 61112250; fax: þ98 21 66495291; e-mail
addresses: meh.ghandi@gmail.com, ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.038

2564
M. Ghandi et al. / Tetrahedron 70 (2014) 2563e2569
(a)
(b)
Fig. 1. Biologically active (a) six-membered sultams, (b) simple 3-alkyl-3-hydroxyoxindoles.
Table 1
Table 2
Effect of solvent and base on the BH reaction of 1a
Products 2aeg obtained from DBU-catalyzed BH reaction of 1aeg in DMF
Entry
Solvent (base, M)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
CH2Cl2 (DBU, 0.10)
MeCN (DBU, 0.10)
H2O (DBU, 0.10)
36
36
36
36
36
72
72
72
72
72
36
72
72
72
72
(e)
(e)
(e)
(e)
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
H
H
H
Me
Me
OMe
OMe
H
2a (83)
2b (85)
2c (80)
2d (85)
2e (80)
2f (85)
2g (72)
Cl
Br
H
Cl
H
PhMe (DBU, 0.10)
DMF (DBU, 0.10)
DMF (DBU, 0.10)
DMF (DBU, 0.25)
DMF (DBU, 0.50)
DMF (DBU, 0.75)
DMF (DBU, 0.00)
DMF (DABCO, 0.10)
DMF (DABCO, 0.25)
DMF (DABCO, 0.50)
DMF (DABCO, 0.75)
DMF (NEt3, 0.25e0.75)
(20)
(25)
(42)
(52)
(83)
(e)
(15)
(25)
(35)
(42)
(e)
Cl
9
10
11
12
13
14
15
structures of 2aeg were deduced by elemental analysis, MS, IR, 1H
NMR, and 13C NMR spectroscopy. For example, part of the 1H NMR
spectrum of 2d exhibited two sharp and one broad singlets at
d
2.31,
3.13
a
Isolated yield.
2.96, and 3.58 due to Me, MeN, and OH together with a ABq at
d
and 3.28 (J¼12.9 Hz) for CH2Ph. The 1H-decoupled 13C NMR spec-
trum of 2d showed 15 distinct signals including a characteristic
occurs in the absence of DBU in DMF (entry 10, Table 1), the key role
of DBU in promoting BH reaction is concluded. Whereas utilization
of DABCO was partially effective in affording 2a (entries 11e14,
Table 1), triethylamine in 0.25e0.75 M was almost ineffective at
promoting cyclization of vinyl sulfonamide 1a (entry 15, Table 1).
Products 2beg were then obtained when this new method was
applied to a range of vinyl sulfonamides 1beg (Table 2). The
signal at d 178.1 due to C]O group, in agreement with the proposed
structure. Unambiguous evidence for the proposed structure of 2d
was finally obtained by single-crystal X-ray-diffraction analysis
(Fig. 2).23
It has been reported that the BH reaction is second order in
aldeyde.24 Therefore, effect of decreasing the amount of solvent on
rate enhancement is rationalized. That the reaction proceeds

M. Ghandi et al. / Tetrahedron 70 (2014) 2563e2569
2565
Fig. 2. X-ray crystal structure of compound 2d.
efficiently in DMF may be due to unique solvation of the polar
transition state in this solvent.
25
Whereas DBU has a high pKa but is also sterically hindered,
a feature that usually results in severely reduced rates. Observation
of the high rate increase with DBU indicates that, in this specific
case, the basicity of the amine is more important than its steric
hindrance. As indicated in Fig. 3a, the stabilization of the generated
b
-ammonium-a-carbanion sulfonamide intermediate from DBU
through conjugation seems to be a more likely explanation for the
origin of the increased reactivity of DBU.26 In contrast, DABCO not
only has lower pKa,27 but also lacks such conjugation stability
(Fig. 3b).
(a)
(b)
Fig. 3. (a) Stabilization of the
b-ammonium-
a-carbanion sulfonamide obtained from
DBU, (b) similar -ammonium-
b
a-carbanion sulfonamide obtained from DABCO.
The formation of 2aeg with extrusion of a SO2 group was
a surprising outcome. Our surprise was tempered when a literature
search disclosed that the sultone II obtained from cyclopentadiene
sulfonate
I has undergone similar oxidative ring fission to
hydroxyketone HKII with extrusion of a SO2 group in reaction with
molecular oxygen (Scheme 1a).28 As such, the in situ generated
sultam I0 from sulfonamide 1a20 has similarly undergone DBU-
catalyzed reaction with molecular oxygen, probably through the
initially generated anion II0 and implication of the sec-propyl
Scheme 1. (a) Oxidative ring fission of saltone II to hydroxylketone HKII, (b) suggested
mechanism for the formation of 3-benzyl-3-hydroxyoxinole 2a from 1a.

2566
M. Ghandi et al. / Tetrahedron 70 (2014) 2563e2569
hydroperoxide III0 in a series of steps, affording the aminoketone IV0
(Scheme 1b). In contrast to hydroxyketone II (see Scheme 1a), and
upon intramolecular cyclization, aminoketone IV0 is finally con-
verted to 2a (Scheme 1b).
To highlight the effect of molecular oxygen, reaction of vinyl
sulfonamide 1a with DBU was carried out under argon atmosphere.
A complex mixture of products obtained amongst, which 2a was
not identified. This experiment clearly indicates the key role of
molecular oxygen on the formation of 2a.
To our delight, reaction of 1g either with K2CO3 or NaOMe in
MeOH also afforded product 3g although in lower yields (entries 8
and 9, Table 3). These results clearly indicate the implication of
MeOꢀ in DBU-catalyzed BH reaction of 1ge3g in MeOH.
Notably, the BH reaction of a number of (E)-N-(2-formylphenyl)-
N-methyl-2-phenylethenesulfonamides in EtOH afforded the cor-
responding 3-(ethoxy(phenyl)methyl)-1-methyl-1H-benzo[c][1,2]
thiazine 2,2-dioxides (entries 1e4, Table 4). Almost no progress in
the BH reactions was observed either in isopropanol or cyclo-
hexanol (entries 5 and 6, Table 4).
When vinyl sulfonamides 1aeg were treated with an equimolar
amount of DBU in MeOH, benzo-d-sultams 3aeg were identified as
the sole products (Table 3). The structures of 3aeg were deduced by
elemental analysis, MS, IR, 1H NMR, and 13C NMR spectroscopy. For
example, part of the 1H NMR spectrum of 3f exhibited four singlets
Table 4
Effect of EtOH, isopropanol and cyclohexanol on DBU-catalyzed BH reaction of 1
at d 3.43, 3.48, 3.79, and 5.48 due to MeN, MeO, MeO, and CHPh. The
1H-decoupled 13C NMR spectrum of 3f revealed 16 distinct signals
in agreement with the proposed structure. Unambiguous evidence
for the proposed structure of 3f was finally obtained by single-
crystal X-ray-diffraction analysis (Fig. 4).29
Table 3
Products 3aeg obtained from base-catalyzed BH reaction of 1aeg in MeOH
Entry
R1
R2
ROH
Yield (%)
1
2
3
4
5
OMe
H
OMe
Me
H
Cl
Cl
H
H
EtOH
EtOH
EtOH
MeCH(OH)Me
C6H11OH
3h (90)
3i (88)
3j (84)
3k (e)
3l (e)
OMe
The suggested mechanism for the formation of 3a is shown in
Scheme 2. The in situ generated MeOꢀ via acidebase reaction of
MeOH with DBU promotes0 the intramolecular BH reaction,
affording intermediates M, M , and M00. The oxindole 3a is finally
obtained through elimination of the hemiacetal group rather than
the traditional reaction to BH adduct. The pseudoaromatic char-
acter, if any, of 3a may be the driving force for this process. This
mechanism was proposed on the basis of our previously reported
work as well as the one reported by Ciganek who showed that
NaOMe in THF could mediate the coupling of methyl acrylate with
aromatic aldehydes.30
Entry
Base
R1
R2
Product (yield, %)
1
2
3
4
5
6
7
8
9
DBU
DBU
DBU
DBU
DBU
DBU
DBU
K2CO3
NaOMe
H
H
H
Me
Me
OMe
OMe
OMe
OMe
H
3a (90)
3b (85)
3c (88)
3d (91)
3e (82)
3f (98)
3g (88)
3g (30)
3g (35)
Cl
Br
H
Cl
H
Cl
Cl
Cl
Fig. 4. X-ray crystal structure of compound 3f.

M. Ghandi et al. / Tetrahedron 70 (2014) 2563e2569
2567
3.2.1. 3-Benzyl-3-hydroxy-1-methyl-1,3-dihydro-indol-2-one
(2a). White solid (0.209 g, 83%); mp 156e158 ꢁC; IR (KBr) nmax
3378, 1694, 1614, 1086, 746 cmꢀ1 1H NMR (500 MHz, CDCl3) dH
;
6.94e7.27 (8H, m), 6.65 (1H, d, J¼7.8 Hz), 3.29 (1H, d, J¼13.0 Hz),
3.12 (1H, d, J¼13.0 Hz), 3.01 (3H, s), 2.87 (1H, br s) ppm; 13C NMR
(75 MHz, CDCl3) dC 178.1, 143.1, 134.0, 130.2, 129.5, 129.3, 127.7,
126.8, 124.5, 122.9, 108.2, 76.6, 44.8, 25.9 ppm; m/z (EI, 70 eV) 253
(22, Mþ), 162 (100), 161 (84), 91 (48), 77 (38), 65 (38%). Anal. Calcd
for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.87; H, 5.83; N,
5.47%; Rf (25% EtOAc/hexane) 0.14.
3.2.2. 3-(4-Chloro-benzyl)-3-hydroxy-1-methyl-1,3-dihydro-indol-
2-one (2b). White solid (0.243 g, 85%); mp 169e171 ꢁC; IR (KBr)
nmax 3324, 1693, 1615, 1084, 745 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
dH 7.13e7.15 (3H, m), 6.97e7.00 (2H, m), 6.76e6.79 (2H, m), 6.54
(1H, d, J¼9.3 Hz), 4.16 (1H, br s), 3.30 (1H, d, J¼12.9 Hz, part of
ABq), 3.15 (1H, d, J¼12.9 Hz, part of ABq), 3.00 (3H, s) ppm; 13C
NMR (75 MHz, CDCl3) dC 178.0, 156.0, 136.4, 134.1, 130.6, 130.3,
127.8, 126.8, 114.4, 111.3, 108.7, 76.6, 44.8, 26.0 ppm; m/z (EI, 70 eV)
289 (4, Mþþ2), 288 (24, Mþþ1), 287 (13, Mþ), 163 (38), 162 (100),
161 (36), 125 (85), 89 (35), 77 (37%). Anal. Calcd for C16H14ClNO2: C,
66.79; H, 4.90; N, 4.87. Found: C, 66.60; H, 4.47; N, 4.83%; Rf (25%
EtOAc/hexane) 0.13.
3.2.3. 3-(4-Bromo-benzyl)-3-hydroxy-1-methyl-1,3-dihydro-indol-
Scheme 2. Mechanistic rationalization for the formation of compound 3a.
2-one (2c). White solid (0.264 g, 80%); mp 152e153 ꢁC; IR (KBr)
nmax 3338, 1700, 1610, 1229, 1114, 752 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) dH 7.18e7.30 (2H, m), 7.23 (2H, d, J¼8.3 Hz), 7.07 (1H, t,
J¼7.5 Hz), 6.81 (2H, d, J¼8.3 Hz), 6.67 (1H, d, J¼7.5 Hz), 3.27 (1H, d,
J¼12.9 Hz, part of ABq), 3.11 (1H, d, J¼12.9 Hz, part of ABq), 3.02
(3H, s) ppm; 13C NMR (75 MHz, CDCl3) dC 177.7, 143.1, 133.0, 131.9,
130.8,129.8,128.9,124.3,122.9,120.9,108.4, 77.1, 44.1, 26.0 ppm; m/
z (EI, 70 eV) 284 (3, Mþþ1), 283 (15, Mþ), 192 (100), 149 (27), 121
(44), 91(77), 65 (22%). Anal. Calcd for C16H14BrNO2: C, 57.85; H,
4.25; N, 4.22. Found: C, 57.68; H, 3.83; N, 4.07%; Rf (25% EtOAc/
hexane) 0.14.
In conclusion, a number of solvent-dependent BH reactions were
carried out in this work for the synthesis of novel oxindole and
benzo-d-sultam scaffolds. Whereas the DBU-catalyzed BH reaction
of (E)-N-(2-formylphenyl)-N-methyl-2-phenylethenesulfonamides
exhibited 3-benzyl-3-hydroxy-1-methylindolin-2-one scaffolds in
moderate to good yields in DMF, reactions in MeOH afforded novel
benzo-d-sultams in high yields. These new structures broaden the
synthesis of interesting scaffolds and many of them may represent
interesting pharmacophores.
To the best of our knowledge, no method of using an intra-
molecular BH reaction in the synthesis of novel oxindole and
benzo-d-sultams scaffolds is found in literature.
3.2.4. 3-Benzyl-3-hydroxy-1,5-dimethyl-1,3-dihydro-indol-2-one
(2d). White solid (0.226 g, 85%); mp 143e145 ꢁC; IR (KBr) nmax
3272, 1690, 1614, 1100, 699 cmꢀ1 1H NMR (500 MHz, CDCl3) dH
;
7.09e7.14 (3H, m, Ar), 7.03 (1H, d, J¼7.85 Hz, Ar), 7.00 (1H, s, Ar),
6.93 (2H, m, Ar), 6.51 (1H, d, J¼7.8 Hz), 3.58 (1H, br s), 3.28 (1H, d,
J¼12.9 Hz, part of ABq), 3.13 (1H, d, J¼12.9 Hz, part of ABq), 2.96
(3H, s), 2.31 (3H, s) ppm; 13C NMR (125 MHz, CDCl3) dC 178.2, 141.2,
134.5, 132.8, 129.7, 130.7, 128.1, 130.7, 127.2, 125.7, 108.3, 77.9, 45.3,
26.4, 21.5 ppm; m/z (EI, 70 eV) 267 (1, Mþ), 176 (58), 91 (100), 65
(21%). Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.23; H, 6.56; N, 5.44%; Rf (25% EtOAc/hexane) 0.12.
3. Experimental section
3.1. General information
1H NMR, 13C NMR, MS, and elemental analysis were measured
with conventional spectrometers. All solvents were purified
and dried by following standard procedures unless otherwise
stated.
3.2.5. 3-(4-Chloro-benzyl)-3-hydroxy-1,5-dimethyl-1,3-dihydro-in-
dol-2-one (2e). White solid (0.240 g, 80%); mp 185e187 ꢁC; IR
3.2. Synthesis of 3-benzyl-3-hydroxy-1-methyl-1,3-dihydro-
(KBr) nmax 3292 (OH), 1691, 1492, 1103, 1082, 811 cmꢀ1 1H NMR
;
indol-2-one derivatives 2aeg
(500 MHz, CDCl3) dH 7.08 (2H, d, J¼8.4 Hz), 7.02e7.07 (2H, m, Ar),
6.86 (2H, d, J¼8.4 Hz), 6.54 (1H, d, J¼7.9 Hz, Ar), 3.24 (1H, d,
J¼12.9 Hz, part of ABq), 3.19 (1H, br s, OH), 3.11 (1H, d, J¼12.9 Hz,
part of ABq), 2.96 (3H, s), 2.32 (3H, s) ppm; 13C NMR (125 MHz,
CDCl3) dC 178.0, 141.1, 133.5, 132.8, 132.5, 132.0, 130.1, 129.9, 128.0,
125.4, 108.2, 77.5, 44.3, 26.2, 21.4 ppm; m/z (EI, 70 eV) 303 (25,
Mþþ2), 302 (56, Mþþ1), 301 (47, Mþ), 286 (37), 285 (23), 284
(100), 176 (40), 125 (16%). Anal. Calcd for C17H16ClNO2: C, 67.66; H,
5.34; N, 4.64. Found: C, 67.20; H, 5.20; N, 4.58%; Rf (25% EtOAc/
hexane) 0.13.
General procedure: To a stirring solution of DBU (0.453 g,
300 mol %) in DMF (3 mL) was added (E)-N-(2-formylphenyl)-N-
methyl-2-phenylethenesulfonamide (1aeg) (1.0 mmol) and the
mixture was heated at 150 ꢁC for 72 h. The progress of the reaction
was followed by TLC. After completion, CH2Cl2 (20 mL) and H2O
(20 mL) were added and the mixture was neutralized with 5% HCl.
The organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (3ꢂ10 mL). After drying the combined or-
ganic phases with anhydrous Na2SO4, the solvent was removed
under reduced pressure. The residue was purified by column
chromatography (SiO2, gradiantly hexane/ethyl acetate, 5:1, 3:1) to
afford products 2aeg.
3.2.6. 3-Benzyl-3-hydroxy-5-methoxy-1-methyl-1,3-dihydro-indol-
2-one (2f). White solid (0.240 g, 85%); mp 149e151 ꢁC; IR (KBr) nmax
3246, 1677, 1099, 697 cmꢀ1; 1H NMR (500 MHz, CDCl3) dH 6.76e7.14

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M. Ghandi et al. / Tetrahedron 70 (2014) 2563e2569
(7H, m), 6.53 (1H, d, J¼9.3 Hz), 4.39 (1H br s), 3.73 (3H, s), 3.34 (1H,
d, J¼12.9 Hz, part of ABq), 3.15(1H, d, J¼12.9 Hz, part of ABq), 2.97
(3H, s) ppm; 13C NMR (75 MHz, CDCl3) dC 178.0, 156.0, 136.4, 134.1,
130.5, 130.3, 127.7, 126.8, 114.4, 111.2, 108.7, 77.8, 55.8, 44.8,
26.0 ppm; m/z (EI, 70 eV) 284 (3, Mþþ1), 283 (15, Mþ), 192 (100),
149 (27), 121 (44), 91(77), 65 (22%). Anal. Calcd for C17H17NO3: C,
72.07; H, 6.05; N, 4.94. Found: C, 72.03; H, 6.02; N, 4.87%; Rf (25%
EtOAc/hexane) 0.08.
Calcd for C17H16BrNO3S: C, 51.79; H, 4.09; N, 3.55. Found: C, 51.67;
H, 3.94; N, 3.60%; Rf (25% EtOAc/hexane) 0.43.
3.3.4. 3-(Methoxy-phenyl-methyl)-1,6-dimethyl-1H-benzo[c][1,2]thi-
azine 2,2-dioxide (3d). Pale yellow solid (0.299 g, 91%); mp
127e129 ꢁC; IR (KBr) nmax 2941, 1321, 1252, 1145, 1059, 854 cmꢀ1
;
1H NMR (500 MHz, CDCl3) dH 7.48 (2H, d, J¼8.6 Hz), 7.39 (2H, t,
J¼7.0 Hz), 7.35e7.37 (1H, t, J¼6.2 Hz), 7.23 (1H, d, J¼8.4 Hz), 7.13
(1H, s), 7.02 (1H, d, J¼8.4 Hz), 6.86 (1H, s), 5.41 (1H, s), 3.47 (3H, s),
3.44 (3H, s), 2.31 (3H, s) ppm; 13C NMR (125 MHz, CDCl3) dC 138.5,
138.3, 137.2, 132.9, 132.2, 132.1, 130.8, 129.1, 128.9, 127.9, 121.4, 116.8,
79.8, 58.1, 31.3, 20.9 ppm; m/z (EI, 70 eV) 331 (1, Mþþ2), 330 (5,
Mþþ1), 329 (28, Mþ), 234 (100), 218 (32), 121 (35), 91 (20), 77
(35%). Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found
C, 65.51; H, 5.80; N, 4.28%; Rf (25% EtOAc/hexane) 0.40.
3.2.7. 3-(4-Chloro-benzyl)-3-hydroxy-5-methoxy-1-methyl-1,3-
dihydro-indol-2-one (2g). White solid (0.228 g, 72%); mp
99e101 ꢁC; IR (KBr) nmax 3315 (OH), 1701, 1213, 1088 cmꢀ1; 1H NMR
(500 MHz, CDCl3) dH 6.98 (2H, d, J¼8.4 Hz), 6.80 (2H, d, J¼8.4 Hz),
6.65e6.67 (2H, m), 6.46 (1H, d, J¼9.1 Hz). 4.94 (1H, br s), 3.64 (3H,
s), 3.14 (1H, d, J¼12.9 Hz, part of ABq), 2.98 (1H, d, J¼12.9 Hz, part of
ABq), 2.88 (3H, s) ppm; 13C NMR (125 MHz, CDCl3) dC 177.9, 156.3,
136.9, 133.5, 132.9, 132.1, 131.3, 128.1, 114.4, 111.7, 108.9, 77.7, 56.2,
44.4, 26.3 ppm; m/z (EI, 70 eV) 319 (11, Mþþ2), 318 (6, Mþþ1), 317
(29, Mþ),193 (47),192 (100),149 (29),125 (28), 89 (15%). Anal. Calcd
for C17H16ClNO3: C, 64.26; H, 5.08; N, 4.41. Found: C, 64.18; H, 5.07;
N, 4.28%; Rf (25% EtOAc/hexane) 0.08.
3.3.5. 3-[(4-Chloro-phenyl)-methoxy-methyl]-1,6-dimethyl-1H-
benzo[c][1,2]thiazine 2,2-dioxide (3e). Yellow oil (0.297 g, 82%); IR
(KBr) nmax 2930, 1316, 1145, 1087, 808 cmꢀ1 1H NMR (500 MHz,
;
CDCl3) dH 7.42 (2H, d, J¼8.4 Hz), 7.37 (2H, d, J¼8.4 Hz), 7.24 (1H, d,
J¼8.9 Hz), 7.16 (1H, s), 7.03 (1H, d, J¼8.4 Hz), 6.91 (1H, s), 5.36 (1H,
s), 3.46 (3H, s), 3.43 (3H, s), 2.32 (3H, s) ppm; 13C NMR (75 MHz,
CDCl3) dC 138.4, 137.1, 136.7, 134.8, 133.1, 132.3, 132.1, 130.8, 129.3,
129.2, 121.3, 116.8, 79.2, 58.1, 31.3, 20.9 ppm; m/z (EI, 70 eV) 365 (21,
Mþþ2), 364 (17, Mþþ1), 363 (56, Mþ), 332 (37), 268 (94), 155 (100),
103 (70), 91 (83), 77 (51), 51 (43%). Anal. Calcd for C18H18ClNO3S: C,
59.42; H, 4.99; N, 3.85. Found C, 59.41; H, 4.85; N, 3.39%; Rf (25%
EtOAc/hexane) 0.55.
3.3. Synthesis of 3-(methoxy-phenyl-methyl)-1-methyl-1H-
benzo[c][1,2]thiazine 2,2-dioxide derivatives 3aej
General procedure: To a stirring solution of DBU (0.304 g,
200 mol %) in alcohol (3 mL) was added (E)-N-(2-formylphenyl)-N-
methyl-2-phenylethenesulfonamide derivatives 3aeg (1.0 mmol)
and the mixture was heated at reflux for 18 h. The progress of the
reaction was followed by TLC. After completion, the solvent was
removed under reduced pressure and the crude residue purified by
column chromatography (SiO2, 6:1, n-hexane/ethyl acetate) to af-
ford product 3aej.
3.3.6. 6-Methoxy-3-(methoxy-phenyl-methyl)-1-methyl-1H-benzo
[c][1,2]thiazine 2,2-dioxide (3f). Pale yellow solid (0.338 g, 98%); mp
110e112 ꢁC; IR (KBr) nmax 2929,1309,1247,1139,1058, 853 cmꢀ1; 1H
NMR (300 MHz, CDCl3) dH 7.50 (2H, d, J¼7.3 Hz), 7.35e7.46 (3H, m),
7.10 (1H, d, J¼9.0 Hz), 7.02 (1H, dd, J¼9.0, 2.7 Hz), 6.87 (1H, s), 6.84
(1H, d, J¼2.7 Hz), 5.40 (1H, s), 3.79 (3H, s), 3.48 (3H, s), 3.43 (3H,
s) ppm; 13C NMR (75 MHz, CDCl3) dC 155.3, 137.7, 137.6, 134.0, 131.2,
128.7, 128.5, 127.4, 122.2, 118.4, 117.9, 113.2, 79.4, 57.6, 55.6,
31.8 ppm; m/z (EI, 70 eV) 347 (9, Mþþ2), 346 (25, Mþþ1), 345 (100,
Mþ), 250 (87), 121 (66), 77 (34%). Anal. Calcd for C18H19NO4S: C,
62.59; H, 5.54; N, 4.06. Found C, 62.76; H, 5.51; N, 4.03%; Rf (25%
EtOAc/hexane) 0.30.
3.3.1. 3-(Methoxy-phenyl-methyl)-1-methyl-1H-benzo[c][1,2]thia-
zine 2,2-dioxide (3a). Yellow solid (0.283 g, 90%); mp 85e87 ꢁC; IR
(KBr) nmax 2949, 1317, 1143, 753 cmꢀ1; 1H NMR (500 MHz, CDCl3) dH
7.11e7.51 (9H, m), 6.91 (1H, s), 5.42 (1H, s), 3.49 (3H, s), 3.48 (3H,
s) ppm; 13C NMR (75 MHz, CDCl3) dC 140.1, 137.7, 136.7, 131.8, 130.9,
130.2, 128.7, 128.6, 127.5, 122.9, 120.9, 116.2, 79.4, 57.7, 30.6 ppm; m/
z (EI, 70 eV) 317 (3, Mþþ2), 316 (12, Mþþ1), 315 (58, Mþ), 221 (44),
220 (100), 121 (72), 105 (37), 77 (47%). Anal. Calcd for C17H17NO3S C,
64.74; H, 5.43; N, 4.44. Found: C, 64.82; H, 5.21; N, 4.63%; Rf (25%
EtOAc/hexane) 0.43.
3.3.7. 3-[(4-Chloro-phenyl)-methoxy-methyl]-6-methoxy-1-methyl-
1H-benzo[c][1,2]thiazine 2,2-dioxide (3g). Yellow solid (0.333 g,
88%); mp 116e118 ꢁC; IR (KBr) nmax 2942, 1311, 1252, 1143, 1082,
811 cmꢀ1; 1H NMR (500 MHz, CDCl3) dH 7.43 (2H, d, J¼8.5 Hz), 7.37
(2H, d, J¼8.5 Hz), 7.08 (1H, d, J¼9.0 Hz), 7.00 (1H, dd, J¼9.0, 2.9 Hz),
6.91(1H, s), 6.85 (1H, d, J¼2.9 Hz), 5.34 (1H, s), 3.78 (3H, s), 3.45 (3H,
s), 3.93 (3H, s) ppm; 13C NMR (125 MHz, CDCl3) dC 155.9,
137.7, 137.0, 134.8, 134.5, 131.6, 129.3, 129.2, 122.6, 119.0, 118.5, 113.8,
112.0, 79.2, 58.1, 56.1, 32.4 ppm; m/z (EI, 70 eV) 381 (17, Mþþ2), 380
(9, Mþþ1), 379 (44, Mþ), 312 (37), 284 (63), 162 (57), 155 (100),
139 (70), 91 (75%). Anal. Calcd for C18H18ClNO4S: C, 56.91; H, 4.78;
N, 3.69. Found C, 56.93; H, 4.82; N, 3.71%; Rf (25% EtOAc/hexane)
0.33.
3.3.2. 3-[(4-Chloro-phenyl)-methoxy-methyl]-1-methyl-1H-benzo[c]
[1,2]thiazine 2,2-dioxide (3b). White solid (0.296 g, 85%); mp
122e124 ꢁC; IR (KBr) nmax 2939, 1297, 1144, 1088, 828, 758 cmꢀ1; 1H
NMR (300 MHz, CDCl3) dH 7.14e7.49 (8H, m), 6.97 (1H, s), 5.39 (1H,
s), 3.48 (3H, s), 3.47 (3H, s) ppm; 13C NMR (75 MHz, CDCl3) dC 140.1,
136.5, 136.2, 134.4, 131.7, 131.0, 130.2, 128.9, 128.8, 122.9, 120.8,
116.2, 78.7, 57.6, 30.6 ppm; m/z (EI, 70 eV) 351 (7, Mþþ2), 350 (3,
Mþþ1), 349 (18, Mþ), 256 (44), 255 (26), 254 (100), 218 (33), 155
(41), 89 (24%). Anal. Calcd for C17H16ClNO3S: C, 58.37; H, 4.61; N,
4.00. Found C, 58.53; H, 4.57; N, 4.03%; Rf (25% EtOAc/hexane) 0.42.
3.3.8. 3-(Ethoxy-phenyl-methyl)-6-methoxy-1-methyl-1H-benzo[c]
[1,2]thiazine 2,2-dioxide (3h). White solid (0.323 g, 90%); mp
140e142 ꢁC; IR (KBr) nmax 2934, 1310, 1247, 1141, 1057, 819 cmꢀ1; 1H
NMR (300 MHz, CDCl3) dH 7.33e7.53 (5H, m), 7.10 (1H, d, J¼8.9 Hz),
7.01 (1H, dd, J¼8.9, 2.8 Hz), 6.91 (1H, s), 6.84 (1H, d, J¼2.8 Hz), 5.52
(1H, s), 3.80 (3H, s), 3.65 (2H, m), 3.42 (3H, s), 1.30 (3H, t,
J¼7.0 Hz) ppm; 13C NMR (75 MHz, CDCl3) dC 155.4, 138.4, 138.2,
134.1, 131.0, 128.6, 128.4, 127.4, 122.3, 118.4, 117.8, 113.2, 77.4, 65.5,
55.7, 31.8, 15.2 ppm; m/z (EI, 70 eV) 361 (8, Mþþ2), 360 (29, Mþþ1),
359 (100, Mþ), 314 (77), 250 (76), 207 (17), 135 (27), 79 (14%). Anal.
3.3.3. 3-[(4-Bromo-phenyl)-methoxy-methyl]-1-methyl-1H-benzo[c]
[1,2]thiazine 2,2-dioxide (3c). White solid (0.347 g, 88%); mp
139e142 ꢁC; IR (KBr) nmax 2936, 1297, 1143, 1092, 825, 758 cmꢀ1; 1H
NMR (500 MHz, CDCl3) dH 7.53 (2H, d, J¼8.4 Hz), 7.35e7.46 (2H, m),
7.37 (2H, d, J¼8.4 Hz), 7.14 (2H, dd, J¼8.9, 7.7 Hz), 6.97 (1H, s), 5.36
(1H, s), 3.47 (3H, s), 3.46 (3H, s) ppm; 13C NMR (125 MHz, CDCl3) dC
140.6,137.6,136.6,132.3,132.1,131.5,130.7,129.5,123.4,123.0,121.3,
116.7, 79.2, 58.1, 31.1 ppm; m/z (EI, 70 eV) 396 (17, Mþþ1), 395 (88,
Mþ), 393 (79, Mþꢀ2), 300 (100), 219 (51), 199 (36), 89 (44%). Anal.

M. Ghandi et al. / Tetrahedron 70 (2014) 2563e2569
2569
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Calcd for C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found: C, 63.18; H,
5.88; N, 3.80%; Rf (25% EtOAc/hexane) 0.38.
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3.3.9. 3-[(4-Chloro-phenyl)-ethoxy-methyl]-1-methyl-1H-benzo[c]
[1,2]thiazine 2,2-dioxide (3i). Yellow solid (0.319 g, 88%); mp
135e136 ꢁC; IR (KBr) nmax 2973, 1309, 1219, 1143, 1087, 751 cmꢀ1
;
1H NMR (300 MHz, CDCl3) dH 7.36e7.48 (6H, m), 7.15 (1H, dd,
J¼7.8, 7.1 Hz, Ar), 7.03 (1H, s), 5.51 (1H, s, CHeOe), 3.65 (2H, m),
3.47 (3H, s), 1.30 (3H, t, J¼7.0 Hz) ppm; 13C NMR (75 MHz, CDCl3)
dC 140.1, 137.2, 136.6, 134.2, 131.5, 130.9, 130.2, 128.8, 128.7, 122.9,
120.9, 116.2, 76.7, 65.6, 30.5, 15.2 ppm; m/z (EI, 70 eV) 365 (16,
Mþþ2), 364 (5, Mþþ1), 363 (41, Mþ), 256 (89), 254 (100), 141 (85),
139 (73), 77 (67%). Anal. Calcd for C18H18ClNO3S: C, 59.42; H, 4.99;
N, 3.85. Found: C, 59.24; H, 4.98; N, 3.81%; Rf (25% EtOAc/hexane)
0.38.
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3.3.10. 3-[(4-Chloro-phenyl)-ethoxy-methyl]-6-methoxy-1-methyl-
1H-benzo[c][1,2]thiazine 2,2-dioxide (3j). Yellow solid (0.330 g,
84%); mp 139e140 ꢁC; IR (KBr) nmax 2971, 1304, 1247, 1142, 1089,
813 cmꢀ1; 1H NMR (300 MHz, CDCl3) dH 7.45 (1H, d, J¼8.5 Hz), 7.37
(1H, d, J¼8.5 Hz), 6.68e7.11 (4H, m), 5.47 (1H, s), 3.80 (3H, s),
3.57e3.73 (2H, m), 3.41 (3H, s), 1.29 (3H, t, J¼7.0 Hz) ppm; 13C NMR
(75 MHz, CDCl3) dC 155.5, 137.7, 137.2, 134.2, 134.0, 130.9, 128.8,
128.7, 122.2, 118.5, 117.9, 113.2, 76.7, 65.6, 55.7, 31.9, 15.2 ppm; m/z
(EI, 70 eV) 395 (33, Mþþ2), 394 (18, Mþþ1), 393 (73, Mþ), 312 (62),
284 (100),162 (35),141 (47), 77 (31%). Anal. Calcd for C19H20ClNO4S:
C, 57.94; H, 5.12; N, 3.56. Found: C, 58.03; H, 5.31; N, 3.75%; Rf (25%
EtOAc/hexane) 0.38.
Acknowledgements
The authors acknowledge the University of Tehran for financial
support of this research.
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Supplementary data
́
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.02.038.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
23. The CCDC deposition number for compound 2d is 950191. Formula: C16H15NO2.
Unit cell parameters: a¼9.0171(18), b¼9.0680(18), c¼9.822(2), Pꢀ1.
24. (a) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7,
147e150; (b) Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org.
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References and notes
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wal, V. K.; Mereu, A. Chem. Commun. 1999, 2311e2312; (d) Hwu, J. R.;
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28. Doye, S.; Hotopp, T.; Winterfeldt, E. Chem. Commun. 1997, 1491e1492.
29. The CCDC deposition number for compound 3f is 950190. Formula:
C
Pꢀ1.
17H17NO3S. Unit cell parameters: a¼9.1990(18), b¼10.209(2), c¼10.616(2),
30. Ciganek, E. J. Org. Chem. 1995, 60, 4635e4637.