Regioselective construction of six-membered fused heterocyclic rings via Pd/C-mediated C-C coupling followed by iodocyclization strategy: a new entry to 2H-1,2-benzothiazine-1,1-dioxides

Article abstract of DOI:10.1016/j.tet.2006.12.040

We describe a practical and elegant method of constructing a thiazine ring fused with benzene under mild reaction conditions. A?variety of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides were prepared with high regioselectivity via a two-step process involvi

Full text of DOI:10.1016/j.tet.2006.12.040

Tetrahedron 63 (2007) 1775–1789
Regioselective construction of six-membered fused heterocyclic
rings via Pd/C-mediated C–C coupling followed by iodocyclization
strategy: a new entry to 2H-1,2-benzothiazine-1,1-dioxides*
Deepak Kumar Barange, Venkateswara Rao Batchu, Dhillirao Gorja,
Vijaya Raghavan Pattabiraman, Lakshmi Kumar Tatini, J. Moses Babu and Manojit Pal
*
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, Andhra Pradesh, India
Received 20 September 2006; revised 4 December 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—We describe a practical and elegant method of constructing a thiazine ring fused with benzene under mild reaction conditions.
A variety of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides were prepared with high regioselectivity via a two-step process involving Pd/
C-mediated C–C coupling of o-halobenzenesulfonamides with terminal alkynes, followed by iodocyclization of the resulting o-(1-alkynyl)-
arenesulfonamide using elemental iodine in acetonitrile. The coupling reaction was carried out using 10% Pd/C–PPh3–CuI as a catalyst sys-
tem in the presence of Et3N. The process worked well for bromides and iodides, and a wide array of terminal alkynes containing alkyl and aryl
substituents were employed. The iodocyclization step tolerated a variety of functional groups such as hydroxy, chloro, cyano, and methoxy,
producing the six-membered heterocyclic ring selectively. The resulting 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides participated in Sono-
gashira, Heck, and Suzuki reactions producing a wide range of functionally substituted benzothiazines in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
C–C triple bond with a wide variety of nucleophiles, includ-
ing N, O, and S nucleophiles, has been studied extensively3
and proved to be an efficient method for intramolecular cy-
clization. This approach is particularly attractive as it offers
the advantage of further transformation of the iodide func-
tional group of the resulting compound into other substitu-
ents that is not often feasible via organometallic tandem
coupling–cyclization method in a single pot. This has been
well exemplified by the recent synthesis of a wide array of
heterocycles.4–13 Notably, the nucleophilicity of the sulfon-
amide nitrogen of the o-(1-alkynyl)benzenesulfonamide
moiety towards the electrophilic species produced as a result
of activation of the triple bond under the conditions of iodo-
cyclization has not been studied well.13f
Transition metal mediated coupling–cyclization processes,
of which many rely on palladium catalysis and involve in
situ generation of acetylenic compounds bearing a nucleo-
philic substituent in close proximity to the triple bond,
have proven to be an efficient and versatile way of construct-
ing carbocyclic and heterocyclic structures.1 Generally, the
electrophilic cyclization of ortho-functionalized aryl (or het-
eroaryl) alkynes takes place in the same pot in a tandem fash-
ion. However, the efficiency of the cyclization step largely
depends on the reaction conditions employed and the nature
of the nucleophilic substituent present in the o-(1-alkynyl)-
aryl (or heteroaryl) derivatives produced. On several occa-
sions, the uncyclized acetylenic compounds have been
isolated, and then cyclized separately to afford the desired
products.2 For instance, coupling of N-ethyl-2-iodo-4-
methyl-benzenesulfonamide with trimethylsilyl acetylene
under Sonogashira conditions afforded the corresponding
ethynyl substituted product which, on treatment with NaH,
yielded benzoisothiazole.2c Recently, iodocyclization of
In conjunction with our new drug discovery research, we
have had a longstanding interest in the synthesis of acyclic
and cyclic derivatives of the benzenesulfonamide class,14
e.g., 1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl substituted
pyrazoles14b,c 2 (Fig. 1). In afurther continuationof the above
investigation, we became interested in the 2H-benzo[e][1,2]-
thiazine-1,1-dioxide ring system (3, Fig. 1), a common
structural subunit prevalent in numerous pharmaceutically
importantanti-inflammatoryagents,15,16 particularlyoxicams.
Earlier syntheses of 2H-benzo[e][1,2]thiazines, represented
by structure 3, involve heteroannulation of 2-iodobenzene-
sulfonamide with ketone enolates under photostimulated
*
DRL publication no. 604A.
Keywords: 2H-Benzo[e][1,2]thiazine-1,1-dioxides; o-Halobenzenesulfon-
amide; Palladium catalyst; Terminal alkynes.
* Corresponding author. Tel.: +91 40 23045439; fax: +91 40 23045438/
23045007; e-mail: manojitpal@drreddys.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.040

1776
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
R3
2.1. Optimization and scope of the Pd-mediated coupling
of o-halobenzenesulfonamide with terminal alkynes
Z
R2
NR1
Z
Z
NR
O
S
O
S
For assessing the generality of the overall approach, it was
necessary to examine the scope of the Pd-mediated coupling
of compound 9 with terminal alkynes. Moreover, a detailed
study was required to establish the optimum reaction condi-
tions for the preparation of iodocyclization precursor 7.
Thus, coupling of 9b with 3-butynol was examined under
various reaction conditions (Table 1). After assessing a
number of Pd-catalysts, e.g., Pd(PPh3)2Cl2, Pd(OAc)2,
Pd(PPh3)4, 10% Pd/C, etc., and solvents such as DMF, etha-
nol, 1,4-dioxane, and acetonitrile, it was observed that the
use of 10% Pd/C–PPh3–CuI as a catalyst system in the
presence of Et3N in acetonitrile afforded the best yield of
7b (Table 1, entry 8). We therefore used this methodology
for the preparation of alkynes 7 (Table 2). Importantly, the
use of Pd/C–CuI–PPh3 as catalyst system for efficient
Sonogashira coupling has attracted much attention recently,
since Pd/C-based methods have an economic advantage
especially in large or industrial scale preparations.22
SO2NHR
O
O
1
2
3
Z = substituted pyrazoles
Figure 1. Design of 2H-benzo[e][1,2]thiazine-1,1-dioxides derived from
the benzenesulfonamide class of compounds.
SRN1 conditions17 or multistep syntheses.18 Recently, in-
spired by the work of Lane and Snieckus,2c a new Pd-
mediated one-step synthesis of benzothiazines has been
developed by Harmata et al.19 (Scheme 1).
R
(PPh3)2PdCl2
HCCR, CuI
R
+
Br
NH
N
N
Et3N, DMF
60-70°C, 9h
S
S
S
O
CH3
CH3
O
CH3
O
4
5
6
Scheme 1. Pd-mediated one-step synthesis of benzothiazines.19
Generally, o-halobenzenesulfonamides showed high reactiv-
ity toward Pd/C-mediated Sonogashira coupling when all the
reactions were carried out using a 1:4:2 ratio of Pd/C–PPh3–
CuI at 80 ꢀC for 8–24 h. This allowed the preparation of a
variety of functionalized o-(1-alkynyl)benzenesulfonamides
(Table 2). Both bromo (9a) and iodo derivatives (9b–d) re-
acted well with terminal alkynes bearing various substituents
such as alkyl, hydroxyalkyl, chloroalkyl, cyanoalkyl, aryl,
and heterocyclic groups. Good to excellent yields (85–
97%) were obtained in all the cases, irrespective of the nature
of the substituents present in the halides as well as alkynes.
Except in case of arylalkynes no significant dimerization
(homocoupling)23 of the terminal alkynes was observed as
a side reaction under the conditions employed.23f All the
o-(1-alkynyl)benzenesulfonamides (7) synthesized were char-
acterized by the appearance of the sulfonamide (–SO2NH–)
moiety in the region of d 5–6 in the 1H NMR and an alkyne
absorption band at 2200–2300 cmꢁ1 in the IR spectra.
While this methodology, involving Sonogashira coupling of
bromosulfoximine 4 with terminal alkynes, afforded 1,2-
benzothiazines 5 in 16–70% yields, a substantial quantity
of 1,2-benzoisothiazoles 6 (13–81% yields) were isolated
as side products (or as major products in some cases) de-
pending on the nature of alkynes used. Moreover, this meth-
odology is applicable for the synthesis of 3-substituted
benzoisothiazines only, and an attempt towards the possible
synthesis of 3,4-disubstituted derivative by using an internal
alkyne remained inconclusive.19 Based on the observation of
Snieckus and Lane, and in search of an alternative and selec-
tive, but more general and versatile process for the synthesis
of 1,2-benzothiazines, we decided to explore20 the use of
a coupling–iodocyclization strategy. In this article, we
describe the first successful synthesis of 4-iodo-2H-benzo-
[e][1,2]thiazine-1,1-dioxide derivatives using the chemistry
represented in Scheme 2. To the best of our knowledge, syn-
thesis of 2H-benzo[e][1,2]thiazine-1,1-dioxide ring using
a similar strategy and a further structural elaboration of
this framework has not been disclosed earlier.
Table 1. Effect of catalyst, base, and solvent on the Pd-mediated coupling of
9b with 3-butynola
R2
MeO
MeO
I
R2
I
R2
NHCH3
S
Z
R2
NR1
Pd-Cu catalysis
Z
SO2NHCH3
O
I2
O
R2
NHR1 CH3CN
K2CO3
=
CH2CH2OH
9b
Entry Pd catalyst
7b
S
S
O
O
O
O
7
8
25°C
Solvent; base
Temp (ꢀC); Yieldb
time (h)
70; 18
DMF; 2-aminoethanol 70; 18
(%)
Scheme 2.
1
2
3
4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
DMF; Et3N
65
70
75
70
65
70
68
97
71
EtOH; Et3N
70; 18
70; 12
80; 24
80; 24
70; 18
70; 18
70; 18
2. Results and discussion
1,4-Dioxane; Et3N
DMF; Et3N
DMF; Et3N
5
6
Pd(PPh3)4
A two-step process to 4-iodo benzothiazines was examined.
This involved (i) Pd/C-mediated coupling21a–c of o-halo-
benzenesulfonamide 9 with terminal alkynes and (ii) iodo-
cyclization. The required sulfonamide 9 was prepared
from the corresponding sulfonyl chloride and alkylamines,
followed by treatment with BuLi and elemental iodine
according to the procedure reported in the literature.2c,21d
7c
8c
9c
10% Pd/C–PPh3 EtOH; Et3N
10% Pd/C–PPh3 Acetonitrile; Et3N
10% Pd/C–PPh3 DMF; Et3N
a
Reaction conditions: 9b (1.0 equiv), 4-butynol (3.0 equiv), Pd catalyst
(0.03 equiv), CuI (0.04 equiv), base (3 equiv) in a solvent under N2.
Isolated yields.
b
c
The reaction was carried out using a 1:4:2 ratio of Pd/C–PPh3–CuI.

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
Table 2. Pd/C-mediated synthesis of 2-alkynyl-N-methyl-benzenesulfonamidea (7)
1777
R2
R2
Z
Z
X
10%Pd/C, PPh3, CuI
NHR1
Et3N, CH3CN, 80°C
S
O
SO2NHR1
O
9
7
Entry
1
Aryl halide
Arylalkyne
Reaction time (h)
18
Yieldb (%)
Br
OH
O
S
7a
85
97
94
O
NHEt
S
O
O
NHEt
9a
OH
MeO
I
O
S
MeO
2
3
7b
7c
18
18
NHMe
O
O
S
9b
NHMe
O
OH
MeO
9b
O
S
NHMe
O
4
5
9a
9a
7d
7e
8
89
87
O
S
O
NHEt
10
O
S
NHEt
O
Et
I
Et
O
6
7
7f
8
90
87
O
S
NHMe
S
O
NHMe
O
9c
Me
I
Me
O
7g
12
O
S
NHMe
S
O
NHMe
O
Me
8
9
9d
7h
7i
8
87
87
O
S
O
NHMe
Me
Cl
9d
9d
12
O
S
NHMe
O
CN
Me
10
7j
24
94
O
S
NHMe
O
(continued)

1778
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
Table 2. (continued)
Entry
Aryl halide
Arylalkyne
Reaction time (h)
Yieldb (%)
O
N
Et
11
12
9c
7k
24
98
O
O
S
NHMe
O
Et
9c
7l
12
94
90
O
S
NHMe
O
Me
Me
Me
13
9d
7m
8
O
S
NHMe
O
Et
14
9c
7n
10
89
90
O
S
O
NHMe
MeO
15
9b
7o
8
O
S
NHMe
O
a
All the reactions were carried out using 1:4:2 ratio of Pd/C–PPh3–CuI.
Isolated yields.
b
2.2. Optimization and scope of the iodocyclization
of o-(1-alkynyl)benzenesulfonamides
these reagents were found to be less efficient under the con-
ditions studied. Thus, iodine was found to be the best electro-
phile in this intramolecular cyclization reaction and was
chosen for further study. The structure of 8a was confirmed
by its 13C and 1H NMR, IR, and MS spectra, and was further
supported by the molecular structure of 8m determined
We have observed that o-(1-alkynyl)benzenesulfonamide (7)
undergoes smooth iodocyclization to afford 4-iodo-2H-
benzo[e][1,2]thiazine-1,1-dioxides (8). Initially, we examined
the reaction of N-ethyl-2-(5-hydroxy-pent-1-ynyl)-benzene-
sulfonamide (7a) with 2.5 equiv of iodine at room tempera-
ture, by changing a number of factors such as solvent, base,
and time (Table 3, entries 1–6). After assessing a number
of solvents (e.g., ethanol, 1,4-dioxane, dichloromethane,
and acetonitrile) and bases (e.g., triethylamine, NaHCO3,
Na2CO3, and K2CO3), a combination of acetonitrile–
K2CO3 was found to be optimum with respect to the yield
of product isolated (Table 3, entry 3). Under these condi-
tions, the reaction proceeded smoothly, and the best yield
of 8a (76%) was achieved when the reaction was carried
out for 16 h. However, the reaction time varied from 6 to
24 h depending on the type of alkynyl derivatives 7 used
(vide infra). Notably, iodocyclization of 7a was observed
even in the absence of a base (Table 3, entry 7) affording
8a, albeit in low yield. Presumably, deprotonation of the in-
termediate generated after cyclization leading to 8a was fa-
cilitated in the presence of a base (see later for a discussion
on mechanism). While the use of other electrophiles such as
ICl, NBS, etc. was investigated (Table 3, entries 8 and 9),
Table 3. Effect of electrophile, base, and solvent on the cyclization of 7aa
catalyst
solvent
base
I
R
R
NEt
NHEt
25°C
S
S
O
O
O
O
7a
R = (CH2)2CH2OH
8a
Entry Catalyst Solvent; base
Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
I2
I2
I2
I2
I2
I2
I2
ICl
NBS
1,4-Dioxane; Et3N
Ethanol; Et3N
Acetonitrile; K2CO3
CH2Cl2; K2CO3
Acetonitrile; Na2CO3
24
24
16
24
24
40
35
76
50
60
55
25
55
27
Acetonitrile; NaHCO3 18
Acetonitrile; No base
Acetonitrile; K2CO3
Acetonitrile; K2CO3
48
24
24
a
All the reactions were carried out at room temperature using a catalyst
(2.5 equiv) and a base (3 equiv).
Isolated yield.
b

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
1779
unambiguously by X-ray crystallographic analysis
(Fig. 2).24 Unlike the earlier synthesis of benzothiazines19
(Scheme 1), no five-membered-ring product was detected
in the present study.
was isolated in 25% yield after stirring for 24 h at 25 ꢀC.
We then repeated the same reaction sequence by passing
the reaction mixture through Celite after completion of the
coupling reaction, then carried out iodocyclization in the
same pot. Encouragingly, 8b was isolated in 75% yield
demonstrating the potential of this process to be utilized
for the preparation of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-
dioxides without isolating the intermediates.
Using the optimized reaction conditions for iodocyclization
as described above (Table 3, entry 3), a variety of other
alkynes 7 were tested in acetonitrile at room temperature,
and the results are summarized in Table 4. As indicated,
iodocyclization of 7 was efficient in most cases affording
a number of corresponding 4-iodo-2H-benzo[e][1,2]thi-
azine-1,1-dioxides 8 in good to excellent yields (62–87%).
Substituents such as methyl (Table 4, entries 7–10 and 13),
ethyl (Table 4, entries 6, 11, 12, and 14), and methoxy groups
(Table 4, entries 2, 3, and 15) on the benzene ring, and alkyl
(Table 4, entries 4–8), chloroalkyl (Table 4, entry 9), cyano-
alkyl (Table 4, entry 10), heterocyclyl alkyl (Table 4, entry
11), and aryl groups (Table 4, entries 12–15) at the acetyl-
enic end were well tolerated. In general, simple alkyl and
aryl substituents on the triple bond of compound 7 cyclized
more rapidly (e.g., 6–12 h) than others (12–24 h), where var-
ious groups such as hydroxy, chloro or cyano were present at
the distal end of the alkyl side chain. In a separate study,
we coupled 9a and trimethylsilyl acetylene under Pd/C–
PPh3–CuI catalysis, and the resulting alkyne was examined
for iodocyclization. In our hands, the cyclization did not pro-
ceed, perhaps due to the unfavorable steric crowding caused
by the bulky trimethylsilyl group.
2.3. Proposed reaction mechanism
Mechanistically, the Pd/C-mediated coupling of 9 with ter-
minal alkynes follows a typical Sonogashira pathway.21b
The high reactivity shown by 9 could be due to the coordina-
tion of the sulfonamide moiety to palladium in the presumed
intermediate, thereby stabilizing the arylpalladium interme-
diate as shown in Figure 3. A plausible mechanism for the
formation of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides
8 via iodocyclization is shown in Scheme 3. The reaction
proceeds via (i) activation of the triple bond of 7 by co-
ordination to I+ followed by (ii) intramolecular nucleophilic
attack by the nitrogen of the sulfonamide group in an ‘endo-
dig’ fashion. A ‘5-exo-dig’ cyclization, although feasible in
the presence of a strong base,2c was not observed in the
present case. In an alternative pathway, the reaction may
proceed via deprotonation of the NH of the sulfonamide
moiety, followed by intramolecular nucleophilic attack of
the resulting anion on the vinylic cation. This anionic sulfon-
amide moiety now can react either via nitrogen or oxygen
producing two regioisomeric products. Since the isomeric
(4-iodo-1-oxo-1H-1l6-benzo[c][1,2]oxathiin-1-ylidene)-
methylamine derivative was never isolated from the reaction
mixture even in trace quantity we believe that this cycliza-
tion follows the former pathway.26 This is further supported
by the fact that iodocyclization can proceed in the absence of
a base (Table 1, entry 7). In a separate experiment, iodocyc-
lization of 2-(5-hydroxy-pent-1-ynyl)benzenesulfonamide
(N-de ethyl analogue of 7a) was attempted under the condi-
tion described above (Table 3, entry 3) where no formation
of cyclized product was observed. Thus, the iodocyclization
seems to be facilitated by several factors. (1) The alkyl group
enhances the nucleophilicity of the nitrogen of sulfonamide
The present iodocyclization of 7 showed very high selectiv-
ity for six-membered ring formed as a result of ‘6-endo-dig’
ring closure. No isomeric five-membered ring products were
detected under the conditions employed,25 nor the product
involving the simple addition of iodine to the triple bond
of 7. More importantly, these reactions produced only
water-soluble (KI) by-products, thus rendering work-up pro-
cedures very simple. However, the use of 2.5 equiv of iodine
could be a disadvantage in a relatively large-scale prepara-
tion, therefore we attempted to conduct coupling and cycli-
zation step in a single pot. Accordingly, iodine and K2CO3
were added to the reaction mixture of 9b and 4-pentynol at
the end of the coupling reaction (Table 1, entry 8), and 8b
Figure 2. X-ray crystal structure of 8m (ORTEP diagram).

1780
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
Table 4. Synthesis of 2H-1,2-benzothiazine-1,1-dioxides via iodocyclizationa
Entry
1
Alkyne
OH
Time (h)
16
Product
Yieldb (%)
I
OH
7a
7b
8a
8b
76
O
NEt
S
S
NHEt
O
O
O
OH
I
MeO
OH
MeO
2
12
80
NMe
O
S
S
O
I
O
NHMe
O
OH
MeO
MeO
OH
3
7c
7d
7e
7f
18
8c
8d
8e
8f
74
70
62
67
74
70
69
80
O
NMe
S
S
NHMe
O
O
O
I
4
8
O
NEt
S
S
NHEt
O
O
O
I
5
10
O
S
NEt
S
NHEt
O
O
O
I
Et
Et
6
8
O
NMe
S
S
NHMe
O
O
I
O
Me
Me
7
7g
7h
7i
12
8g
8h
8i
O
NMe
S
S
NHMe
O
O
O
I
Me
Me
8
6
O
S
NMe
S
NHMe
O
O
O
I
Me
Me
Cl
Cl
9
16
12
24
O
S
NMe
S
I
NHMe
O
O
O
CN
Me
Me
Et
CN
10
11
7j
8j
O
NMe
S
O
S
NHMe
O
I
O
O
O
N
Et
N
7k
8k
85
NMe
O
S
O
S
O
O
O
NHMe
O
(continued)

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
1781
Table 4. (continued)
Entry
Alkyne
Time (h)
Product
Yieldb (%)
I
Et
Et
12
13
7l
8
8
8l
87
80
NMe
O
S
S
O
O
NHMe
O
Me
Me
Me
I
Me
Et
Me
7m
8m
NMe
O
S
S
O
O
O
NHMe
O
Me
I
Et
14
7n
8
8
8n
87
82
NMe
O
S
S
O
NHMe
O
I
MeO
MeO
15
7o
8o
NMe
O
S
S
O
O
NHMe
O
a
All the reactions were carried out at room temperature using 2.5 equiv of I2 and 3 equiv of K2CO3 in acetonitrile.
Isolated yields.
b
moiety. (2) The electron withdrawing effect of the sulfon-
of a terminal alkyne, olefin or aryl boronic acid individually,
the corresponding products formed via C–C bond forming
reactions were isolated in 82–92% yields (Scheme 4). Nota-
bly, 3,4-diaryl substituted 2H-benzo[e][1,2]thiazine-1,1-di-
oxides are of pharmacological interest,27 and can now be
easily accessed via Suzuki coupling, as described above.
Compound 8n was de-iodinated in the presence of a Pd(0)-
catalyst and sodium formate in DMF to afford the
amide moiety makes the vinylic cation susceptible for nucleo-
philic attack leading to the formation of six-membered ring.
(3) The presence of a base facilitates the efficient N–H bond
cleavage as cyclization proceeds.
X
Z
NHR1
S
O
O
OH
Figure 3. Sulfonamide stabilized arylpalladium intermediate.
I+
Me
R2
I-
NHR1
R2
NHR1
Z
Me
Z
Z
I2
HCCCH2CH2CH2OH
N
Pd(PPh3)2Cl2
CuI, Et3N
S
O
S
I
S
Me
Me
O
O
O
O
O
7
9a
9b
I
O
OEt
84 %
R2
NR1
Z
R2
NHR1
base
Me
Me
+
CH2CHCO2Et
Pd(OAc)2, n-Bu4NCl
Na2CO3, 1h,
DMF/ 85 °C
92 %
S
O
S
O
Me
O
O
8m
8
N
S
Scheme 3. Plausible mechanism of iodocyclization of 7.
O
O
COCH3
2.4. Structural elaboration of the benzothiazine ring
(m-CH3COC6H4)B(OH)2
Pd(PPh3)4,
2M Na2CO3
DMF, 80°C, 2h
82 %
Me
The presence of the iodo group at the C-4 position of the ben-
zothiazine ring allows further structural elaboration through
conversion of the iodide functionality into other substituents.
For example, when compound 8m was exposed to Sonoga-
shira, Heck, and Suzuki coupling conditions in the presence
N
9c
Me
S
O
O
Scheme 4.

1782
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
corresponding 3-aryl-2H-benzo[e][1,2]thiazine-1,1-dioxide
in 78% yield. It is therefore possible to generate a variety
of either 3,4-disubstituted or only 3-substituted 2H-benzo-
[e][1,2]thiazine-1,1-dioxides using the iodo compounds 8
and known palladium catalyzed reactions.
determined by using melting point apparatus and are uncor-
rected. Thermal analysis data [differential scanning calori-
metry (DSC)] were generated with the help of DSC-50
detector. MS spectra were obtained on a mass spectrometer.
Chromatographic purity by HPLC was determined by using
area normalization method and the condition specified in
each case: column, mobile phase (range used), flow rate, de-
tection wavelength, and retention times. All the terminal al-
kynes used are commercially available except 2-prop-2-ynyl
isoindole-1,3-dione that was prepared according to a known
procedure.28 All the o-halobenzenesulfonamides were either
prepared according to the literature procedure or according
to the method described below.
3. Conclusions
A novel two-step strategy has been devised for the synthesis
of 2H-benzo[e][1,2]thiazine-1,1-dioxides that proceeds with
high regioselectivity. The process involves (i) Pd/C-medi-
ated facile synthesis of o-(1-alkynyl)arenesulfonamide via
C–C coupling followed by (ii) the construction of the six-
membered ring via efficient iodocyclization with elemental
iodine under mild conditions. The coupling reaction worked
well for bromides and iodides, which can be readily prepared
according to the known methods. This is the first time Pd/C
has been employed as a catalyst in a coupling–iodocycliza-
tion sequence. The second step of the present synthesis is
also the first example of iodocyclization involving intramo-
lecular attack of a –SO2NH– moiety to a C–C triple bond
leading to the formation of benzothiazine ring. Overall,
this two-step process tolerates a variety of functional groups
such as hydroxy, chloro, cyano, and methoxy, and is gener-
ally free from producing any significant side products, e.g.,
homocoupled products from the terminal alkynes (except
in the case of arylalkynes) in the first step or regioisomeric
products of benzothiazines in the second step. The process
is simple, easy to handle and does not involve the use of
expensive reagents or catalysts. The presence of the iodo
group on the resulting 4-iodo-2H-benzo[e][1,2]thiazine-
1,1-dioxides makes them useful substrates for derivatization
by conversion to a wide range of functionally substituted
benzothiazines via various Pd-catalyzed transformations.
Thus we believe that the present Pd/C-mediated coupling–
iodocyclization followed by Pd-catalyzed substitution not
only opens up a new path, but also provides a powerful
tool for the preparation of diversely substituted benzothi-
azines. The provision of a wide array of these substances
may represent the bottleneck for further studies and develop-
ment in medicinal chemistry. Further work is in progress to
extend the scope of this methodology for the synthesis of
more complex structures.
4.2. Preparation of N-ethyl-2-bromobenzenesulfon-
amide (9a)
To a stirred solution of 2-bromobenzenesulfonyl chloride
(2 g, 7.82 mmol) in chloroform at 0 ꢀC was added 40% aq
solution of ethylamine (1.05 g, 1.45 mL) dropwise. The re-
sulting mixture was refluxed for about 4 h. After completion
of the reaction, the solvent was removed under vacuum. The
residue was dissolved in chloroform and washed with dil
HCl followed by brine. The organic layer was dried over an-
hydrous Na2SO4 and concentrated under vacuum to afford
a white solid (1.18 g, 57% yield) as a desired product; mp
100–102 ꢀC; 1H NMR (200 MHz, CDCl3) d 8.16 (d,
J¼8.2 Hz, 1H), 7.75 (d, J¼8.2 Hz, 1H), 7.52–7.26 (m,
2H), 5.07 (br s, NH, 1H), 3.05 (q, J¼5.7 Hz, 2H), 1.10 (t,
J¼5.6 Hz, 3H); Mass (m/z) 265 (M+1, 100%); IR (cmꢁ1
,
KBr) 3292, 1430, 1323; Elemental analysis found C,
36.50; H, 3.80; N, 5.23; C8H10BrNO2S requires C, 36.38;
H, 3.82; N, 5.30.
4.3. Preparation of N-methyl-2-iodo-4-ethylbenzene-
sulfonamide (9c)
A solution of N-methyl-4-ethylbenzenesulfonamide (2 g,
10.05 mmol) in THF (20 mL) was cooled to 0 ꢀC under
nitrogen atmosphere and treated with a solution of n-BuLi
in hexane (12 mL, 21.05 mmol) dropwise. The mixture
was stirred at 0 ꢀC for 15 min and then warmed to room
temperature with stirring. After stirring for 1 h at room tem-
perature, the resulting bright yellow solution was cooled
to ꢁ78 ꢀC and stirred for 15 min. A solution of iodine
(2.79 g, 11.05 mmol) in THF (15 mL) was added and the re-
sulting mixture was then stirred at ꢁ78 ꢀC for 1 h, quenched
with a saturated aq solution of NH4Cl (15 mL), treated with
a saturated aq solution of Na2S2O3 (50 mL), and was ex-
tracted with ethyl acetate. The organic layers were collected,
combined, dried over anhydrous Na2SO4, and concentrated
under vacuum. The residue was then purified by column
chromatography using EtOAc–petroleum ether to give the
desired product as a white solid (2.8 g, 86% yield); mp
90–92 ꢀC; 1H NMR (200 MHz, CDCl3) d 8.07 (d,
J¼8.2 Hz, 1H), 7.90 (s, 1H), 7.32 (d, J¼8.2 Hz, 1H), 5.12
(br s, NH, 1H), 2.69 (q, J¼8.0 Hz, 2H), 2.59 (d, J¼8.1 Hz,
3H), 1.29 (t, J¼8.0 Hz, 3H); Mass (m/z) 326 (M+1,
100%); IR (cmꢁ1, KBr) 3317, 1321, 1163; HPLC 97.62%,
Symmetry shield RP18 (150ꢂ4.6) mm, mobile phase A:
0.01 M KH2PO4, mobile phase B: CH3CN, gradient
(T/% B): 0/30, 2/30, 14/80, 20/80, 21/30, 22/30, flow rate
1.5 mL/min, UV 210 nm, retention time 7.84 min;
4. Experimental
4.1. General methods
Unless stated otherwise, reactions were performed under
a nitrogen atmosphere. Reactions were monitored by thin
layer chromatography (TLC) on silica gel plates (60 F254),
visualizing with ultraviolet light or iodine spray. Flash chro-
matography was performed on silica gel (60–120 mesh) us-
ing distilled petroleum ether and ethyl acetate. 1H NMR and
13C NMR spectra were determined in CDCl3 solution on 200
and 400 and 50 MHz spectrometers, respectively. Proton
chemical shifts (d) are relative to tetramethylsilane (TMS,
d¼0.00) as internal standard and expressed in parts per mil-
lion. Spin multiplicities are given as s (singlet), d (doublet),
t (triplet), and m (multiplet) as well as b (broad). Coupling
constants (J) are given in hertz. Infrared spectra were
recorded on a FTIR spectrometer. Melting points were

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
1783
Elemental analysis found C, 33.06; H, 3.75; N, 4.37;
C9H12INO2S requires C, 33.24; H, 3.72; N, 4.31.
4.6.3. 2-(4-Hydroxy-but-1-ynyl)-4-methoxy-N-methyl-
benzenesulfonamide (7b). Low melting brown solid; H
1
NMR (CDCl3, 200 MHz) d 7.89 (d, J¼8.3 Hz, 1H), 7.39
(s, 1H), 7.20 (d, J¼8.3 Hz, 1H), 5.50 (br s, NH, 1H), 3.88
(s, 3H), 3.86 (t, J¼7.0 Hz, 2H), 3.78 (t, J¼7.0 Hz, 2H),
4.4. Preparation of N-methyl-2-iodo-4-methyl-benzene-
sulfonamide (9d)
2.54 (d, J¼6.8 Hz, 3H), 1.50 (br s, 1H, –OH); IR (cmꢁ1
,
This compound was prepared in 75% yield via iodination of
N-methyl-4-methyl-benzenesulfonamide using n-BuLi in
THF followed by treatment with iodine according to the
procedure as described above; mp 65–67 ꢀC; 1H NMR
(200 MHz, CDCl3) d 8.05 (d, J¼8.1 Hz, 1H), 7.89 (s, 1H),
7.28 (d, J¼8.1 Hz, 1H), 5.12 (br s, NH, 1H), 2.58 (d,
J¼8.5 Hz, 3H), 2.37 (s, 3H); Mass (m/z) 311 (M++1,
100%); IR (cmꢁ1, KBr) 3296, 1312, 1156; HPLC 98.62%,
Symmetry shield RP18 (150ꢂ4.6) mm, mobile phase A:
0.01 M KH2PO4, mobile phase B: CH3CN, gradient
(T/% B): 0/30, 2/30, 14/80, 20/80, 21/30, 22/30, flow rate
1.5 mL/min, UV 210 nm, retention time 7.84 min; Elemen-
tal analysis found C, 30.97; H, 3.22; N, 4.42; C8H10INO2S
requires C, 30.88; H, 3.24; N, 4.50.
KBr) 3348, 2211, 1412, 1132; m/z (ES Mass) 270 (M+1,
100%); Elemental analysis found C, 53.39; H, 5.54; N,
5.29; C12H15NO4S requires C, 53.52; H, 5.61; N, 5.20.
4.6.4. 2-(5-Hydroxy-pent-1-ynyl)-4-methoxy-N-methyl-
benzenesulfonamide (7c). Low melting yellow solid; H
1
NMR (CDCl3, 200 MHz) d 7.89 (d, J¼7.8 Hz, 1H), 7.39
(s, 1H), 7.20 (d, J¼7.8 Hz, 1H), 5.50 (br s, NH, 1H), 3.88
(s, 3H), 3.86 (t, J¼6.0 Hz, 2H), 3.76 (t, J¼6.0 Hz, 2H),
2.54 (d, J¼6.5 Hz, 3H), 1.89–1.87 (m, 2H), 1.52 (br s, 1H,
–OH); IR (cmꢁ1, neat) 3357, 2228, 1362, 1160; m/z (ES
Mass) 284 (M+1, 100%); Elemental analysis found C,
55.23; H, 6.07; N, 4.64; C13H17NO4S requires C, 55.11; H,
6.05; N, 4.94.
4.5. Preparation of N-methyl-2-iodo-4-methoxy-
benzenesulfonamide (9b)
4.6.5. N-Ethyl-2-hept-1-ynyl-benzenesulfonamide (7d).
Low melting yellow solid; H NMR (CDCl3, 200 MHz)
1
d 8.16 (d, J¼7.0 Hz, 1H), 8.01 (d, J¼7.2 Hz, 1H), 7.55 (t,
J¼7.2 Hz, 1H), 7.46 (t, J¼7.0 Hz, 1H), 5.06 (br s, NH,
1H), 3.70 (t, J¼7.5 Hz, 2H), 2.98–2.90 (m, 4H), 2.51 (t,
J¼7.0 Hz, 3H), 1.66 (q, J¼5.0 Hz, 2H), 1.46–1.40 (m,
2H), 0.94 (t, J¼5.0 Hz, 3H); IR (cmꢁ1, neat) 3331, 2227,
1469, 1125; m/z (ES Mass) 280 (M+1, 100%); Elemental
analysis found C, 64.62; H, 7.50; N, 4.68; C15H21NO2S
requires C, 64.48; H, 7.58; N, 5.01.
This compound was prepared in 66% yield via iodination of
N-methyl-4-methoxybenzenesulfonamide using n-BuLi in
THF followed by treatment with iodine according to the
procedure as described above; mp 86–88 ꢀC; 1H NMR
(200 MHz, CDCl3) d 8.48 (d, J¼8.5 Hz, 1H), 7.55 (s, 1H),
6.95 (d, J¼8.5 Hz, 1H), 5.12 (br s, NH, 1H), 3.86 (s, 3H),
2.58 (d, J¼5.2 Hz, 3H); Mass (m/z) 326 (M+1, 100%); IR
(cmꢁ1, KBr) 3317, 1400, 1321, 1163; Elemental analysis
found C, 30.48; H, 3.06; N, 4.19; C8H10INO3S requires C,
29.37; H, 3.08; N, 4.28.
4.6.6. N-Ethyl-2-oct-1-ynyl-benzenesulfonamide (7e).
Low melting yellow solid; H NMR (CDCl3, 200 MHz)
1
d 8.03 (t, J¼7.3 Hz, 1H), 7.55 (d, J¼7.3 Hz, 1H), 7.47 (t,
J¼8.0 Hz, 1H), 7.39 (d, J¼8.0 Hz, 1H), 5.14 (br s, NH,
1H), 2.93 (q, J¼6.9 Hz, 2H), 2.54 (t, J¼7.0 Hz, 3H), 1.70–
1.56 (m, 4H), 1.35–1.28 (m, 4H), 1.25 (t, 7.0 Hz, 2H),
1.28 (t, J¼7.1 Hz, 3H); IR (cmꢁ1, neat) 3332, 2220, 1462,
1125; m/z (ES Mass) 294 (M+1, 100%); Elemental analysis
found C, 65.58; H, 7.88; N, 4.75; C16H23NO2S requires C,
65.49; H, 7.90; N, 4.77.
4.6. Preparation of o-(1-alkynyl)benzenesulfonamides
(7)
4.6.1. Typical procedure for the preparation of 7n. A
mixture of 4-ethyl-2-iodo-N-methyl-benzenesulfonamide
9c (0.3 g, 0.925 mmol), 10% Pd/C (0.027 g, 0.029 mmol),
PPh3 (0.029 g, 0.11 mmol), CuI (0.010 g, 0.05 mmol), and
triethylamine (0.279 g, 0.385 mL, 2.77 mmol) in aceto-
nitrile (15 mL) was stirred at 25 ꢀC for 30 min under nitro-
gen. To this mixture was added 1-ethynyl-4-methylbenzene
(0.321 g, 2.77 mmol) slowly with stirring. The reaction
mixture was then stirred at 80 ꢀC for 10 h, cooled to room
temperature, diluted with EtOAc (50 mL), and filtered
through Celite. The filtrate was collected and concentrated
under vacuum. The residue was purified by column chroma-
tography to afford the desired product as brown gum (0.26 g,
89% yield).
4.6.7. 4-Ethyl-2-hex-1-ynyl-N-methyl-benzenesulfon-
amide (7f). Low melting brown solid; H NMR (CDCl3,
1
200 MHz) d 7.91 (d, J¼8.2 Hz, 1H), 7.40 (s, 1H), 7.22 (d,
J¼8.2 Hz, 1H), 5.12 (br s, NH, 1H), 2.69 (q, J¼7.0 Hz,
2H), 2.58 (d, J¼7.9 Hz, 3H), 2.52 (t, J¼7.0 Hz, 2H), 1.66–
1.64 (m, 2H), 1.40–1.47 (m, 2H), 1.28 (t, J¼7.0 Hz, 3H),
0.98 (t, J¼7.1 Hz, 3H); IR (cmꢁ1, neat) 3346, 2227, 1332,
1160; m/z (ES Mass) 280 (M+1, 100%); Elemental analysis
found C, 64.39; H, 7.59; N, 5.21; C15H21NO2S requires C,
64.48; H, 7.58; N, 5.01.
4.6.2. N-Ethyl-2-(5-hydroxy-pent-1-ynyl)-benzenesulfon-
amide (7a). Low melting brown solid; H NMR (CDCl3,
1
4.6.8. 2-Hept-1-ynyl-4,N-dimethyl-benzenesulfonamide
(7g). Low melting yellow solid; 1H NMR (CDCl3,
200 MHz) d 7.89 (d, J¼8.1 Hz, 1H), 7.38 (s, 1H), 7.21 (d,
J¼8.1 Hz, 1H), 5.12 (br s, NH, 1H), 2.49 (d, J¼7.0 Hz,
3H), 2.47 (t, J¼6.5 Hz, 2H), 2.38 (s, 3H), 1.69–1.60 (m,
2H), 1.44 (m, 4H), 0.94 (t, J¼6.5 Hz, 3H); IR (cmꢁ1, neat)
3344, 2227, 1325, 1164; m/z (ES Mass) 280 (M+1, 100%);
Elemental analysis found C, 64.51; H, 7.55; N, 4.95;
C15H21NO2S requires C, 64.48; H, 7.58; N, 5.01.
200 MHz) d 8.02 (d, J¼7.0 Hz, 1H), 7.56 (d, J¼6.5 Hz,
1H), 7.42 (t, J¼7.0 Hz, 1H), 7.38 (t, J¼6.5 Hz, 1H), 5.65
(br s, NH, 1H), 3.67 (t, J¼7.1 Hz, 2H), 2.96–2.91 (m, 2H),
2.68 (t, J¼7.0 Hz, 2H), 2.42 (q, J¼7.0 Hz, 2H), 1.54 (br s,
1H, D2O exchangeable, –OH), 1.08 (t, J¼7.5 Hz, 3H); IR
(cmꢁ1, KBr) 3354, 2231, 1433, 1162; m/z (ES Mass) 268
(M+1, 100); Elemental analysis found C, 58.49; H, 6.43;
N, 5.03; C13H17NO3S requires C, 58.40; H, 6.41; N, 5.24.

1784
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
4.6.9. 4,N-Dimethyl-2-oct-1-ynyl-benzenesulfonamide
(7h). Low melting brown solid; 1H NMR (CDCl3,
200 MHz) d 7.90 (d, J¼8.2 Hz, 1H), 7.23 (s, 1H), 7.19 (d,
J¼8.2 Hz, 1H), 5.08 (br s, NH, 1H), 2.55 (d, J¼6.0 Hz,
3H), 2.46 (t, J¼7.0 Hz, 2H), 2.38 (s, 3H), 2.72–1.61 (m,
2H), 1.58–1.41 (m, 2H), 1.39–1.21 (m, 4H), 0.93 (t,
J¼7.0 Hz, 3H); IR (cmꢁ1, KBr) 3348, 2226, 1332, 1163;
m/z (ES Mass) 294 (M+1, 100%); Elemental analysis found
C, 65.75; H, 7.88; N, 4.72; C16H23NO2S requires C, 65.49;
H, 7.90; N, 4.77.
1H), 7.21 (s, 1H), 7.15–7.10 (m, 4H), 5.02 (br s, NH, 1H),
2.60 (d, J¼6.0 Hz, 3H), 2.42 (s, 3H), 2.39 (q, J¼7.9 Hz,
2H), 0.98 (t, J¼8.0 Hz, 3H); IR (cmꢁ1, KBr) 3346, 2210,
1330, 1113; m/z (ES Mass) 314 (M+1, 100%); Elemental
analysis found C, 68.76; H, 6.15; N, 4.58; C18H19NO2S
requires C, 68.98; H, 6.11; N, 4.47.
4.6.16. 2-(5-Chloro-pent-1-ynyl)-4,N-dimethyl-benzene-
sulfonamide (7o). Low melting yellow solid; 1H NMR
(CDCl3, 200 MHz) d 8.01 (d, J¼8.3 Hz, 1H), 7.96 (s, 1H),
7.40 (d, J¼8.3 Hz, 2H), 7.18 (d, J¼8.3 Hz, 1H), 6.99–6.94
(m, 3H), 5.08 (br s, NH, 1H), 3.85 (s, 3H), 2.60 (d,
J¼6.5 Hz, 3H); IR (cmꢁ1, neat) 3344, 2224, 1426, 1162;
m/z (ES Mass) 302 (M+1, 100%); Elemental analysis found
C, 64.85; H, 4.97; N, 4.49; C16H15NO3S requires C, 63.77;
H, 5.02; N, 4.65.
4.6.10. 2-(5-Chloro-pent-1-ynyl)-4,N-dimethyl-benzene-
sulfonamide (7i). Low melting yellow solid; 1H NMR
(CDCl3, 200 MHz) d 8.05 (d, J¼8.0 Hz, 1H), 7.39 (s, 1H),
7.23 (d, J¼8.0 Hz, 1H), 5.03 (br s, NH, 1H), 3.80 (t,
J¼7.0 Hz, 2H), 2.72 (t, J¼7.0 Hz, 2H), 2.56 (d, J¼7.8 Hz,
3H), 2.38 (s, 3H), 2.12–1.06 (m 2H); IR (cmꢁ1, neat)
3345, 2228, 1326, 1162; m/z (ES Mass) 287 (M+1, 100%);
Elemental analysis found C, 54.71; H, 5.60; N, 4.98;
C13H16ClNO2S requires C, 54.63; H, 5.64; N, 4.90.
4.7. Preparation of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-
dioxides (8)
4.7.1. Typical procedure for the preparation of 8n. To
a stirred mixture of 7n (0.20 g, 0.638 mmol) and K2CO3
(0.264 g, 1.194 mmol) in acetonitrile (5 mL) was added
2.5 equiv of I2 (0.405 g, 1.59 mmol) dissolved in acetonitrile
(2 mL). The reaction mixture was stirred at room tempera-
ture (25 ꢀC) for 8 h. After completion of the reaction (indi-
cated by TLC), the mixture was diluted with cold water
(10 mL), washed with a saturated solution of Na2S2O3
(15 mL), and extracted with ethyl acetate (50 mL). The or-
ganic layers were collected, combined, dried over anhydrous
Na2SO4, and concentrated under vacuum. The residue was
purified by column chromatography on silica gel using ethyl
acetate–petroleum ether to afford the desired product as
a white solid (0.245 g, 87%).
4.6.11. 2-(5-Cyano-pent-1-ynyl)-4,N-dimethyl-benzene-
sulfonamide (7j). Low melting yellow solid; 1H NMR
(CDCl3, 200 MHz) d 7.90 (d, J¼8.5 Hz, 1H), 7.38 (s, 1H),
7.19 (d, J¼8.5 Hz, 1H), 5.23 (br s, NH, 1H), 2.57 (d,
J¼6.5 Hz, 3H), 2.38 (s, 3H), 2.38–2.27 (m, 4H), 1.29 (t,
J¼7.0 Hz, 2H); IR (cmꢁ1, neat) 3345, 2226, 1326, 1160;
m/z (ES Mass) 277 (M+1, 100%); Elemental analysis found
C, 60.74; H, 5.85; N, 10.27; C14H16N2O2S requires C, 60.85;
H, 5.84; N, 10.14.
4.6.12. 2-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-prop-
1-ynyl]-4-ethyl-N-methyl-benzenesulfonamide (7k). Low
melting yellow solid; H NMR (CDCl3, 200 MHz) d 8.07–
1
7.90 (m, 4H), 7.94–7.84 (m, 2H), 7.40 (s, 1H), 5.88 (br s,
NH, 1H), 4.73 (s, 2H), 2.69 (q, J¼8.0 Hz, 2H), 2.60 (d,
J¼6.5 Hz, 3H), 1.25 (t, J¼8.0 Hz, 3H); IR (cmꢁ1, neat)
3322, 2228, 1719, 1391, 1160; m/z (ES Mass) 383 (M+1,
100%); Elemental analysis found C, 62.60; H, 4.79; N,
7.21; C20H18N2O4S requires C, 62.81; H, 4.74; N, 7.33.
4.7.2. 3-(2-Ethyl-4-iodo-1,1-dioxo-1,2-dihydro-1l6-
benzo[e][1,2]thiazin-3-yl)propan-1-ol (8a). Low melting
yellow solid; 1H NMR (CDCl3, 400 MHz) d 8.11 (d,
J¼7.6 Hz, 1H), 7.86 (d, J¼7.0 Hz, 1H), 7.77 (t, J¼7.6 Hz,
1H), 7.70 (t, J¼7.0 Hz, 1H), 3.50 (q, J¼7.5 Hz, 2H), 3.52–
3.37 (m, 2H), 2.94–2.87 (m, 1H), 2.57–2.39 (m, 1H),
4.6.13. 4-Ethyl-N-methyl-2-phenylethynyl-benzenesulfon-
amide (7l). Low melting brown solid; H NMR (CDCl3,
2.22–2.13 (m, 2H), 1.14 (t, J¼7.5 Hz, 3H); IR (cmꢁ1
,
1
neat) 3428, 1337, 1146; m/z (ES Mass) 394 (M+1, 100%);
13C NMR (CDCl3, 50 MHz) d 155.0, 137.0, 131.9, 131.6,
128.0, 126.5, 125.4, 63.1 (CH2), 58.9 (C–I), 34.8 (NCH2),
27.5 (CH2), 26.1 (CH2), 12.7 (CH3); HPLC 99.73%, column
Inertsil ODS 3V (150ꢂ4.6) mm, mobile phase A: 0.01 M
KH2PO4, mobile phase B: acetonitrile, gradient (T/% B):
0/40, 2/40, 12/80, 20/80, 21/40, 22/40, flow rate: 1.0 mL/
min, UV 210 nm, retention time 9.98 min; Elemental analy-
sis found C, 39.59; H, 4.12; N, 3.67; C13H16INO3S requires
C, 39.71; H, 4.10; N, 3.56.
200 MHz) d 7.99 (s, 1H), 7.58–7.41 (m, 2H), 7.39–7.32
(m, 3H), 7.27 (d, J¼7.8 Hz, 2H), 5.04 (br s, NH, 1H), 2.74
(q, J¼8.0 Hz, 2H), 2.61 (d, J¼6.5 Hz, 3H), 1.25 (t,
J¼8.0 Hz, 3H); IR (cmꢁ1, KBr) 3348, 2208, 1331, 1166;
m/z (ES Mass) 300 (M+1, 100%); Elemental analysis found
C, 68.09; H, 5.73; N, 4.70; C17H17NO2S requires C, 68.20;
H, 5.72; N, 4.68.
4.6.14. 4,N-Dimethyl-2-p-tolylethynyl-benzenesulfon-
amide (7m). Low melting brown solid; H NMR (CDCl3,
1
200 MHz) d 7.95 (d, J¼8.1 Hz, 1H), 7.45 (d, J¼8.1 Hz,
1H), 7.21 (s, 1H), 7.15–7.10 (m, 4H), 5.05 (br s, NH, 1H,)
2.60 (d, J¼6.5 Hz, 3H), 2.42 (s, 3H), 2.39 (s, 3H); IR
(cmꢁ1, KBr) 3323, 2205, 1323, 1144; m/z (ES Mass) 300
(M+1, 100%); Elemental analysis found C, 68.54; H, 5.70;
N, 4.38; C17H17NO2S requires C, 68.20; H, 5.72; N, 4.68.
4.7.3. 2-(4-Iodo-6-methoxy-2-methyl-1,1-dioxo-1,2-di-
hydro-1l6-benzo[e][1,2]thiazin-3-yl)-ethanol (8b). Low
melting brown solid; H NMR (CDCl3, 400 MHz) d 7.68
(d, J¼8.4 Hz, 1H), 7.37 (s, 1H), 7.01 (d, J¼8.4 Hz, 1H),
4.04–3.92 (m, 2H), 3.91 (s, 3H), 3.11 (s, 3H), 3.10–3.03
(m, 2H), 2.16 (br s, –OH, 1H); IR (cmꢁ1, KBr) 3545,
1331, 1140; m/z (ES Mass) 396 (M+1, 100%); 13C NMR
(CDCl3, 50 MHz) d 162.7, 144.5, 135.9, 124.5, 122.9,
117.7, 116.4, 61.6 (CH2), 60.8 (OCH3), 55.9 (C–I), 40.6
(NCH3), 34.2 (CH2); HPLC 98.94%, Hichrom RPB
1
4.6.15. 4-Ethyl-N-methyl-2-p-tolylethynyl-benzenesulfon-
amide (7n). Low melting brown solid; H NMR (CDCl3,
1
200 MHz) d 7.95 (d, J¼8.2 Hz, 1H), 7.45 (d, J¼8.2 Hz,

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
1785
(250ꢂ4.6) mm, mobile phase A: 0.01 M KH2PO4 (pH 6.5
with KOH), mobile phase B: acetonitrile, gradient (T/% B):
0/60, 5/60, 15/80, 30/80, 34/60, 35/60, flow rate: 1.0 mL/
min, UV 210 nm, retention time 17.16 min; Elemental ana-
lysis found C, 36.38; H, 3.55; N, 3.63; C12H14INO4S
requires C, 36.47; H, 3.57; N, 3.54.
1H NMR (CDCl3, 400 MHz) d 7.67 (s, 1H), 7.65 (d,
J¼8.1 Hz, 1H), 7.30 (d, J¼8.1 Hz, 1H), 3.17 (s, 3H),
2.98–2.71 (m, 4H), 2.81 (q, J¼8.5 Hz, 2H), 1.72–1.63 (m,
2H), 1.30 (t, J¼8.5 Hz, 3H), 0.95 (t, J¼8.0 Hz, 3H); IR
(cmꢁ1, KBr) 3545, 1331, 1140; m/z (ES Mass) 406 (M+1,
100%); 13C NMR (CDCl3, 50 MHz) d 149.2, 146.0, 134.0,
131.6 (2C), 130.8, 129.4, 56.0 (C–I), 33.3 (NCH3), 29.7
(CH2), 29.1 (CH2), 23.7 (CH2), 21.9 (CH2), 15.4 (CH3),
15.0 (CH3); HPLC 98.31%, Hichrom RPB (250ꢂ4.6) mm,
mobile phase: A: 0.01 M KH2PO4 (pH 6.5 with KOH),
mobile phase B: acetonitrile, gradient (T/% B): 0/50, 5/50,
20/80, 30/80, 34/50, 35/50, flow rate: 1.0 mL/min, UV:
210 nm, retention time 12.34 min; Elemental analysis found
C, 44.45; H, 5.29; N, 3.46; C15H20INO2S requires C, 44.43;
H, 5.28; N, 3.47.
4.7.4. 3-(4-Iodo-6-methoxy-2-methyl-1,1-dioxo-1,2-di-
hydro-1-l6-benzo[e][1,2]thiazin-3-yl)-propan-1-ol (8c).
White solid; H NMR (CDCl3, 400 MHz) d 7.64 (s, 1H),
1
7.63 (d, J¼7.1 Hz, 1H), 7.30 (d, J¼7.1 Hz, 1H), 3.80 (t,
J¼7.0 Hz, 2H), 3.16 (s, 3H), 2.96 (t, J¼7.1 Hz, 2H), 2.48
(s, 3H), 1.99–1.97 (m, 2H), 1.56 (br s, 1H, –OH); IR
(cmꢁ1, KBr) 3545, 1331, 1140; m/z (ES Mass) 410 (M+1,
100%); 13C NMR (CDCl3, 50 MHz) d 149.8, 143.2, 133.9,
132.7, 130.6, 129.6, 122.1, 61.5 (CH2), 55.8 (OCH3), 53.6
(C–I), 32.6 (NCH3), 27.2 (CH2), 19.2 (CH2); HPLC
99.42%, Inertsil ODS 3V (150ꢂ4.6) mm, mobile phase A:
0.01 M KH2PO4, mobile phase B: CH3CN, gradient (T/% B):
0/40, 2/40, 14/80, 25/80, 29/40, 30/40, flow rate: 1.5 mL/min,
UV 210 nm, retention time 13.63 min; Elemental analysis
found C, 38.41; H, 3.85; N, 3.23; C13H16INO4S requires C,
38.15; H, 3.94; N, 3.42.
4.7.8. 4-Iodo-2,6-dimethyl-3-pentyl-2H-benzo[e][1,2]-
thiazine-1,1-dioxide (8g). Low melting yellow solid, H
1
NMR (CDCl3, 400 MHz) d 7.64 (s, 1H), 7.63 (d, J¼7.0 Hz,
1H), 7.28 (d, J¼7.0 Hz, 1H), 3.16 (s, 3H), 2.81–2.79 (m,
2H), 2.47 (s, 3H), 1.73–1.65 (m, 2H), 1.54–1.42 (m, 2H),
1.39–1.25 (m, 2H), 0.94–0.90 (t, J¼4.5 Hz, 3H); IR (cmꢁ1
,
neat) 3524, 1432, 1121; m/z (ES Mass) 406 (M+1, 100%);
13C NMR (CDCl3, 50 MHz) d 146.1, 142.9, 133.9, 132.5,
130.7, 128.6, 121.8, 58.0 (C–I), 37.9 (NCH3), 31.5 (CH2),
29.9 (CH2), 29.3 (CH2), 28.8 (CH2), 26.9 (CH3), 14.0
(CH3); HPLC 99.20%, Symmetry shield RP8 (150ꢂ
4.6) mm, mobile phase A: 0.01 M KH2PO4, mobile phase
B: acetonitrile, gradient (T/% B): 0/50, 2/50, 12/80, 20/80,
21/50, 22/50, flow rate: 1.5 mL/min, UV 210 nm, retention
time 9.44 min; Elemental analysis found C, 44.75; H, 4.90;
N, 3.37; C15H20INO2S requires C, 44.45; H, 4.97; N, 3.46.
4.7.5. 2-Ethyl-4-iodo-3-pentyl-2H-benzo[e][1,2]thiazine-
1,1-dioxide (8d). Low melting yellow solid; 1H NMR
(CDCl3, 400 MHz) d 7.80–7.74 (m, 2H), 7.62 (t, J¼8.2 Hz,
1H), 7.45 (t, J¼8.2 Hz, 1H), 3.44–3.33 (m, 2H), 3.52 (q,
J¼7.0 Hz, 2H), 2.89–2.73 (m, 2H), 1.74–1.67 (m, 2H),
1.56–1.30 (m, 2H), 1.28 (t, J¼7.0 Hz, 3H), 0.95 (t,
J¼4.0 Hz, 3H); IR (cmꢁ1, neat) 3524, 1432, 1121; m/z (ES
Mass) 406 (M+1, 100%); 13C NMR (CDCl3, 50 MHz)
d 156.6, 144.9, 134.3, 133.2, 132.1, 130.1, 128.6, 86.3,
39.1, 37.8 (CH2), 32.2 (CH2), 30.6 (CH2), 29.2 (CH2), 29.2
(CH3), 19.6 (CH3); HPLC 99.20, Symmetry shield RP8
(150ꢂ4.6) mm, mobile phase A: 0.01 M KH2PO4, mobile
phase B: CH3CN, gradient (T/% B): 0/50, 2/50, 12/80, 20/
80, 21/50, 22/50, flow rate: 1.5 mL/min, UV 210 nm, reten-
tion time 9.44 min; Elemental analysis found C, 44.64;
H, 4.91; N, 3.26; C15H20INO2S requires C, 44.45; H, 4.97;
N, 3.46.
4.7.9. 3-Hexyl-4-iodo-2,6-dimethyl-2H-benzo[e][1,2]thi-
azine-1,1-dioxide (8h). Low melting yellow solid; 1H NMR
(CDCl3, 400 MHz) d 7.64 (s, 1H), 7.63 (d, J¼8.1 Hz, 1H),
7.28 (d, J¼8.1 Hz, 1H), 3.16 (s, 3H), 2.81–2.79 (m, 2H),
2.47 (s, 3H), 1.73–1.65 (m, 2H), 1.54–1.42 (m, 3H), 1.39–
1.25 (m, 3H), 0.94–0.90 (m, 3H); IR (cmꢁ1, neat) 3526,
1335, 1144; m/z (ES Mass) 420 (M+1, 100%); 13C NMR
(CDCl3, 50 MHz) d 146.10, 142.9, 133.9, 132.5, 130.7,
128.6, 121.8, 58.2 (C–I), 37.9 (NCH3), 31.5 (CH2), 29.9
(CH2), 29.3 (CH2), 28.8 (CH2), 26.9 (CH2), 22.9 (CH3),
14.0 (CH3); HPLC 98.72%, ACE 5 C18 (250ꢂ4.0) mm,
mobile phase A: 0.01 M KH2PO4, mobile phase B: aceto-
nitrile, gradient (T/% B): 0/30, 2/30, 13/80, 26/80, 28/30,
30/30, flow rate: 1.0 mL/min, UV 210 nm, retention time
12.38 min; Elemental analysis found C, 45.99; H, 5.26; N,
3.30; C16H22INO2S requires C, 45.83; H, 5.29; N, 3.34.
4.7.6. 2-Ethyl-3-hexyl-4-iodo-2H-benzo[e][1,2]thiazine-
1,1-dioxide (8e). Low melting yellow solid; 1H NMR
(CDCl3, 400 MHz) d 8.83 (d, J¼7.8 Hz, 1H), 7.75 (d,
J¼7.5 Hz, 1H), 7.61 (t, J¼7.8 Hz, 1H), 7.51 (t, J¼7.5 Hz,
1H), 3.51 (q, J¼7.0 Hz, 2H), 2.93 (t, J¼7.1 Hz, 2H), 1.71–
1.64 (m, 2H), 1.54–1.41 (m, 2H), 1.37–1.17 (m, 4H), 1.14
(t, J¼7.0 Hz, 3H), 0.92 (t, J¼7.2 Hz, 3H); IR (cmꢁ1, neat)
3525, 1335, 1182; m/z (ES Mass) 420 (M+1, 100%); 13C
NMR (CDCl3, 50 MHz) d 156.6, 144.9, 134.3, 133.2,
132.1, 130.1, 128.6, 77.8, 39.1 (CH2), 37.8 (CH2), 32.2
(CH2), 30.6 (CH2), 29.2 (CH2), 19.6 (CH2), 17.7 (CH3),
14.8 (CH3); HPLC 98.39%, Inertsil ODS 3V (150ꢂ
4.6) mm, mobile phase A: 0.01 M KH2PO4, mobile phase
B: acetonitrile, gradient (T/% B): 0/40, 2/40, 12/80, 20/80,
21/40, 22/40, flow rate: 1.0 mL/min, UV 210 nm, retention
time 7.60 min; Elemental analysis found C, 45.67; H,
5.38; N, 3.65; C16H22INO2S requires C, 45.83; H, 5.29;
N, 3.34.
4.7.10. 3-(3-Chloro-propyl)-4-iodo-2,6-dimethyl-2H-
benzo[e][1,2]thiazine-1,1-dioxide (8i). Low melting yellow
solid; H NMR (CDCl3, 400 MHz) d 7.70 (s, 1H), 7.65 (d,
1
J¼7.0 Hz, 1H), 7.35 (d, J¼7.0 Hz, 1H), 3.71 (t, J¼7.0 Hz,
2H), 3.28 (t, J¼6.5 Hz, 2H), 3.07 (s, 3H), 2.48 (s, 3H),
2.25–2.19 (m, 2H); IR (cmꢁ1, neat) 3534, 1433, 1112; m/z
(ES Mass) 412 (M+1, 100%); 13C NMR (CDCl3, 50 MHz)
d 144.1, 141.0, 134.2, 132.9, 130.9, 125.4 (2C), 58.2 (C–I),
44.1 (CH2), 33.2 (NCH3), 29.9 (CH2), 23.5 (CH2), 21.8
(CH3); HPLC 99.23%, Inertsil ODS 3V (150ꢂ4.6) mm,
mobile phase A: 0.01 M KH2PO4, mobile phase B: aceto-
nitrile, gradient (T/% B): 0/40, 2/40, 12/80, 20/80, 21/40,
22/40, flow rate: 1.0 mL/min, UV 210 nm, retention time
4.7.7. 3-Butyl-6-ethyl-4-iodo-2-methyl-2H-benzo[e][1,2]-
thiazine-1,1-dioxide (8f). Low melting white solid;

1786
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
9.81 min; Elemental analysis found C, 37.64; H, 3.77; N,
3.48; C13H15ClINO2S requires C, 37.93; H, 3.67; N, 3.40.
13C NMR (CDCl3, 50 MHz) d 145.2, 143.1, 140.1, 134.7,
134.6, 133.4, 133.4, 129.9, 129.7 (2C), 129.2, 123.2,
121.8, 58.3 (C–I), 35.3 (NCH3), 21.8 (CH3), 21.5 (CH3);
HPLC 98.95%, Inertsil ODS 3V (150ꢂ4.6) mm, mobile
phase A: 0.01 M KH2PO4 (pH 6.5 with KOH), mobile phase
B: acetonitrile, gradient (T/% B): 0/60, 2/60, 8/60, 20/80, 24/
60, 25/60; flow rate: 1.5 mL/min, UV 210 nm, retention time
9.47 min; Elemental analysis found C, 48.12; H, 3.75; N,
3.20; C17H16INO2S requires C, 48.01; H, 3.79; N, 3.29.
4.7.11. 4-(4-Iodo-2,6-dimethyl-1,1-dioxo-1,2-dihydro-1-
benzo[e][1,2]thiazin-3-yl)-butyronitrile (8j). Low melting
brown solid; 1H NMR (CDCl3, 400 MHz) d 7.68 (d,
J¼8.2 Hz, 1H), 7.55 (s, 1H), 7.28 (d, J¼8.2 Hz, 1H),
3.11–3.00 (m, 1H), 2.99 (s, 3H), 2.98–2.87 (m, 1H), 2.53–
2.50 (m, 2H), 2.49 (s, 3H), 2.11 (t, J¼6.5 Hz, 2H); IR
(cmꢁ1, neat) 3534, 1432, 1133; m/z (ES Mass) 403 (M+1,
100%); 13C NMR (CDCl3, 50 MHz) d 153.7, 144.4, 143.2,
133.6, 132.7, 132.5, 129.8, 122.0, 79.4, 30.1 (NCH3), 24.0
(CH2), 23.1 (CH2), 21.5 (CH3), 15.9 (CH2); HPLC
99.20%, Symmetry shield RP8 (150ꢂ4.6) mm, mobile
phase A: 0.01 M KH2PO4, mobile phase B: acetonitrile, gra-
dient (T/% B): 0/50, 2/50, 12/80, 20/80, 21/50, 22/50, flow
rate: 1.5 mL/min, UV 210 nm, retention time 10.09 min;
Elemental analysis found C, 41.58; H, 3.74; N, 6.99;
C14H15IN2O2S requires C, 41.80; H, 3.76; N, 6.96.
4.7.15. 6-Ethyl-4-iodo-2-methyl-3-p-tolyl-2H-benzo-
[e][1,2]thiazine-1,1-dioxide (8n). White solid; mp 102–
1
104 ꢀC; H NMR (CDCl3, 400 MHz) d 7.74 (d, J¼8.1 Hz,
1H), 7.73 (d, J¼8.2 Hz, 1H), 7.43 (d, J¼8.1 Hz, 1H), 7.42
(d, J¼8.2 Hz, 1H), 7.38 (d, J¼8.0 Hz, 2H), 7.36 (s, 1H),
2.91 (s, 3H), 2.81 (q, J¼8.0 Hz, 2H), 2.43 (s, 3H), 1.33 (t,
J¼8.0 Hz, 3H); IR (cmꢁ1, KBr) 3545, 1342, 1183; m/z
(ES Mass) 440 (M+1, 100%); 13C NMR (CDCl3, 50 MHz)
d 149.4, 145.2, 140.1, 134.8, 134.6, 132.5 (2C), 129.9
(2C), 129.2, 128.7, 121.9, 121.2, 58.3, 35.3 (NCH3), 29.1
(CH2), 21.5 (CH3), 15.4 (CH3); HPLC 98.16%, Symmetry
shield RP8 (150ꢂ4.6) mm, mobile phase A: 0.01 M
KH2PO4, mobile phase B: acetonitrile, gradient (T/% B):
0/50, 2/50, 12/80, 20/80, 24/50, 25/50, flow rate: 1.5 mL/
min, UV 210 nm, retention time 11.03 min; Elemental anal-
ysis found C, 49.01; H, 4.18; N, 3.29; C18H18INO2S requires
C, 49.21; H, 4.13; N, 3.19.
4.7.12. 2-(6-Ethyl-4-iodo-2-methyl-1,1-dioxo-1,2-dihy-
dro-1l6-benzo[e][1,2]thiazin-3-ylmethyl)-isoindole-1,3-
dione (8k). Off-white solid; mp 198–200 ꢀC; 1H NMR
(CDCl3, 400 MHz) d 7.97 (t, J¼8.0 Hz, 1H), 7.94 (d,
J¼8.2 Hz, 1H), 7.92 (t, J¼8.0 Hz, 1H), 7.76 (d, J¼8.0 Hz,
1H), 7.40 (d, J¼7.0 Hz, 1H), 7.26 (d, J¼7.2 Hz, 1H), 7.95
(s, 1H), 2.68 (q, J¼7.5 Hz, 2H), 2.50 (s, 3H), 2.49 (s, 2H),
1.18 (t, J¼8.0 Hz, 3H); IR (cmꢁ1, KBr) 3331, 1716
(C]O), 1390, 1160; m/z (ES Mass) 509 (M+1, 100%);
13C NMR (CDCl3, 50 MHz) d 166.9 (2C), 149.2, 145.9,
141.7, 139.0, 134.8 (2C), 133.1, 131.5, 129.2 (2C), 128.3,
123.5, 123.4, 56.7 (C–I), 40.8 (CH2), 33.6 (NCH3), 28.9
(CH2), 15.0 (CH3); HPLC 98.17%, Inertsil ODS 3V
(150ꢂ4.6) mm, mobile phase A: 0.01 M KH2PO4, mobile
phase B: acetonitrile, gradient (T/% B): 0/30, 2/30, 12/80,
18/80, 19/30, 20/30; flow rate: 1.5 mL/min, UV 225 nm, re-
tention time 8.92 min; Elemental analysis found C, 47.57;
H, 3.30; N, 5.48; C20H17IN2O4S requires C, 47.26; H,
3.37; N, 5.51.
4.7.16. 4-Iodo-6-methoxy-2-methyl-3-phenyl-2H-benzo-
[e][1,2]thiazine-1,1-dioxide (8o). Low melting brown solid;
1H NMR (CDCl3, 400 MHz) d 7.77 (d, J¼7.0 Hz, 1H), 7.52
(d, J¼7.0 Hz, 1H), 7.51–7.50 (m, 2H), 7.49–7.43 (m, 3H),
7.05 (s, 1H), 3.93 (s, 3H), 2.92 (s, 3H); IR (cmꢁ1, KBr)
3543, 1452, 1324, 1170; m/z (ES Mass) 428 (M+1, 100%);
13C NMR (CDCl3, 50 MHz) d 145.1, 142.8, 139.0, 134.0,
132.9, 129.3, 128.4 (2C), 127.7, 126.4, 126.2 (2C), 113.6,
56.7, 55.3, 34.7 (CH3); HPLC 98.90%, Inertsil ODS 3V
(150ꢂ4.6) mm, mobile phase A: 0.01 M KH2PO4, mobile
phase B: acetonitrile, gradient (T/% B): 0/30, 2/30, 12/80,
18/80, 19/30, 20/30, flow rate: 1.0 mL/min, UV 240 nm,
retention time 6.79 min; Elemental analysis found C, 44.58;
H, 3.32; N, 3.20; C16H14INO3S requires C, 44.98; H, 3.30;
N, 3.28.
4.7.13. 6-Ethyl-4-iodo-2-methyl-3-phenyl-2H-benzo-
[e][1,2]thiazine-1,1-dioxide (8l). White solid; mp 98–
1
99 ꢀC; H NMR (CDCl3, 400 MHz) d 7.76 (d, J¼8.0 Hz,
1H), 7.55–7.51 (m, 2H), 7.49–7.40 (m, 4H), 7.36 (d,
J¼8.2 Hz, 1H), 2.92 (s, 3H), 2.82 (q, J¼7.9 Hz, 2H), 1.32
(t, J¼8.0 Hz, 3H); IR (cmꢁ1, KBr) 3549, 1455, 1325; m/z
(ES Mass) 426 (M+1, 100%); 13C NMR (CDCl3, 50 MHz)
d 149.4, 145.1, 140.1, 137.7, 134.5, 132.5, 130.9, 130.0,
129.9 (2C), 128.8, 128.5, 121.9, 59.2 (C–I), 35.3 (NCH3),
29.1 (CH2), 15.4 (CH3); HPLC 97.08%, Inertsil ODS 3V
(150ꢂ4.6) mm, mobile phase A: 0.01 M KH2PO4, mobile
phase B: acetonitrile, gradient (T/% B): 0/50, 2/50, 8/80,
24/80, 25/50, 26/50, flow rate: 1.0 mL/min, UV 210 nm, re-
tention time 13.37 min; Elemental analysis found C, 47.64;
H, 3.82; N, 3.38; C17H16INO2S requires C, 48.01; H, 3.79;
N, 3.29.
4.8. Preparation of 5-(2,6-dimethyl-1,1-dioxo-3-p-tolyl-
1,2-dihydro-1-benzo[e][1,2]thiazin-4-yl)-pent-4-yn-1-ol
(9a)
Amixtureofcompound8m(0.2 g,0.470 mmol), Pd(PPh3)Cl2
(16 mg, 0.023 mmol), CuI (5 mg, 0.028 mmol), and triethyl-
amine (0.190 g, 0.262 mL, 1.88 mmol) in acetonitrile (8 mL)
was stirred at 25 ꢀC for 30 min undernitrogen. 4-Pentyne-1-ol
(0.118 g, 0.130 mL, 1.41 mmol) was added slowly to the mix-
ture with stirring. The resulting mixture was then stirred at
25 ꢀC for 12 h, diluted with water (50 mL), and extracted
with ethyl acetate (3ꢂ20 mL). The organic layers were col-
lected, combined, dried over anhydrous Na2SO4, and concen-
trated under low vacuum. The residue was then purified by
column chromatography using petroleum ether–ethyl acetate
to give the desired product as a low melting colorless solid
4.7.14. 4-Iodo-2,6-dimethyl-3-p-tolyl-2H-benzo[e][1,2]-
thiazine-1,1-dioxide (8m). White solid; mp 158–160 ꢀC;
1H NMR (CDCl3, 400 MHz) d 7.72 (d, J¼8.1 Hz, 2H),
7.42 (d, J¼8.0 Hz, 2H), 7.34 (d, J¼8.2 Hz, 2H), 7.29 (s,
1
(0.150 g, 84% yield); H NMR (CDCl3, 400 MHz) d 7.77
(d, J¼7.0 Hz, 2H), 7.64 (d, J¼8.0 Hz, 2H), 7.34 (d,
1H), 2.91 (s, 3H), 2.51 (s, 3H), 2.43 (s, 3H); IR (cmꢁ1
,
KBr) 3545, 1336, 1169; m/z (ES Mass) 426 (M+1, 100%);
J¼7.0 Hz, 2H), 7.25 (s, 1H), 3.60 (t, J¼6.0 Hz, 2H), 2.93

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
1787
(s, 3H), 2.50 (s, 3H), 2.46 (t, J¼7.0 Hz, 2H), 2.42 (s, 3H),
1.75–1.68 (m, 2H), 1.54 (br s, 1H, –OH); IR (cmꢁ1, neat)
3396, 1339, 1170; m/z (ES Mass) 382 (M+1, 100%); 13C
NMR (CDCl3, 50 MHz) d 146.5, 142.7, 139.9 (2C), 129.9,
129.9, 128.9, 128.9, 128.9, 128.8, 128.8, 127.7, 121.7,
108.5, 94.8, 77.6, 61.3 (CH2), 35.3 (NCH3), 30.9 (CH2),
21.8 (CH2), 21.4 (CH3), 16.0 (CH3); HPLC 98.42%, Inertsil
ODS 3V (150ꢂ4.6) mm, mobile phase A: 0.01 M KH2PO4,
mobile phase B: acetonitrile, gradient (T/% B): 0/40, 2/40,
12/80, 20/80, 21/40, 22/40, flow rate: 1.5 mL/min, UV
210 nm, retention time 8.73 min; Elemental analysis found
C, 69.32; H, 6.06; N, 3.61; C22H23NO3S requires C, 69.26;
H, 6.08; N, 3.67.
acetate–hexane to afford the desired product (160 mg, 82%
yield) as white powder; mp 164–165 ꢀC; 1H NMR (CDCl3,
400 MHz) d 7.87 (d, J¼8.1 Hz, 1H), 7.81 (s, 1H), 7.80 (d,
J¼8.1 Hz, 1H), 7.41–7.25 (m, 4H), 7.13 (d, J¼7.5 Hz,
1H), 7.00–6.95 (m, 3H), 2.98 (s, 3H), 2.52 (s, 3H), 2.33 (s,
3H), 2.24 (s, 3H); IR (cmꢁ1, KBr) 3423, 1684 (C]O),
1335, 1171; m/z (ES Mass) 418 (M+1, 100%); 13C NMR
(CDCl3, 50 MHz) d 182.3 (C]O), 141.5, 138.6, 136.8,
136.0, 133.6, 131.2, 130.9, 129.9, 128.9 (2C), 128.7 (2C),
128.6 (2C), 128.3 (2C), 127.1, 126.9, 122.4, 121.8, 34.1
(NCH3), 26.6 (CH3), 21.8 (CH3), 15.7 (CH3); HPLC
99.32%, Inertsil ODS 3V (150ꢂ4.6) mm, mobile phase A:
0.01 M KH2PO4, mobile phase B: acetonitrile, gradient
(T/% B): 0/40, 2/40, 12/80, 20/80, 21/40, 22/40, flow rate:
1.0 mL/min, UV 210 nm, retention time 10.30 min; Elemen-
tal analysis found C, 71.81; H, 5.57; N, 3.39; C25H23NO3S
requires C, 71.92; H, 5.55; N, 3.35.
4.9. Preparation of 3-(2,6-dimethyl-1,1-dioxo-3-p-tolyl-
1,2-dihydro-1-benzo[e][1,2]thiazine-4-yl)-acrylic acid
ethyl ester (9b)
To a solution of 8m (0.175 g, 0.41 mmol) and ethyl acrylate
(0.164 g, 1.64 mmol, 4.0 equiv) in DMF (10 mL) were added
Pd(OAc)2 (0.005 g, 0.022 mmol), n-Bu4NCl (0.114 g,
0.41 mmol), and Na2CO3 (0.11 g, 1.03 mmol). The mixture
was then stirred at 85 ꢀC for 1 h under nitrogen. After com-
pletion of the reaction (indicated by TLC), the mixture was
cooled to room temperature, diluted with water (80 mL),
and extracted with ethyl acetate (3ꢂ15 mL). Organic layers
were collected, combined, washed with saturated aq NaCl
solution, dried over anhydrous Na2SO4, and concentrated un-
der reduced pressure. The residue was purified by column
chromatography using ethyl acetate–petroleum ether to af-
ford the desired product (150 mg, 92% yield) as yellow pow-
der; mp 142–144 ꢀC; 1H NMR (CDCl3, 400 MHz) d 7.83 (d,
J¼8.0 Hz, 1H), 7.72 (s, 1H), 7.60 (d, J¼16.1 Hz, 1H), 7.39–
7.38 (m, 3H), 7.37 (d, J¼7.0 Hz, 2H), 6.17 (d, J¼16.8 Hz,
1H), 4.14 (q, J¼7.0 Hz, 2H), 2.91 (s, 3H), 2.50 (s, 3H),
1.53 (s, 3H), 1.22 (t, J¼7.0 Hz, 3H); IR (cmꢁ1, KBr) 3405,
1718, 1336, 1179; m/z (ES Mass) 398 (M+1, 100%); 13C
NMR (CDCl3, 50 MHz) d 167.1 (C]O), 146.2, 142.3,
140.6, 140.4, 132.3, 130.9, 129.9 (2C), 129.8 (2C), 129.5,
129.0, 127.6, 122.2, 120.5, 117.4, 60.3 (OCH2), 34.2
(NCH3), 21.9 (CH2), 21.4 (CH3), 14.2 (CH3); HPLC
97.50%, Inertsil ODS 3V (150ꢂ4.6) mm, mobile phase A:
0.01 M KH2PO4, mobile phase B: acetonitrile, gradient
(T/% B): 0/40, 2/40, 12/80, 20/80, 21/40, 22/40, flow rate:
1.5 mL/min, UV 210 nm, retention time 11.20 min; Elemen-
tal analysis found C, 66.35; H, 5.81; N, 3.60; C22H23NO4S
requires C, 66.48; H, 5.83; N, 3.52.
4.11. Preparation of 6-ethyl-2-methyl-3-p-tolyl-2H-
benzo[e][1,2]thiazine-1,1-dioxide (9d)
To a mixture of compound 8m (0.160 g, 0.364 mmol) and
sodium formate (0.042 g, 0.620 mmol) in DMF (2 mL)
was added Pd(PPh3)4 (0.016 g, 0.0145 mmol) and the mix-
ture was stirred at 80 ꢀC for about 3 h under nitrogen. The
mixture was then cooled to room temperature, diluted with
water (70 mL), washed with saturated NaCl solution
(25 mL), and extracted with ethyl acetate (3ꢂ10 mL). Or-
ganic layers were collected, combined, dried over anhydrous
Na2SO4, and concentrated under vacuum. The residue was
purified by column chromatography using ethyl acetate–hex-
ane to afford the desired product (90 mg, 78% yield) as white
powder; mp 101–102 ꢀC; 1H NMR (CDCl3, 400 MHz) d 7.80
(s, 1H), 7.56 (dd, J¼7.4 and 2.0 Hz, 2H), 7.33 (dd, J¼7.4 and
1.8 Hz, 2H), 7.25 (dd, J¼8.0 and 2.0 Hz, 2H), 6.65 (s, 1H),
2.99 (s, 3H), 2.74 (q, J¼8.0 Hz, 2H), 2.41 (s, 3H), 1.30 (t,
J¼7.8 Hz, 3H); IR (cmꢁ1, KBr) 3545, 1332, 1145; m/z (ES
Mass) 314 (M+1, 100%); 13C NMR (CDCl3, 50 MHz)
d 148.9, 144.7, 139.9, 133.0, 131.9, 129.6, 129.5, 128.9,
127.8, 127.5 (2C), 126.6, 122.5, 96.8 (CH]), 35.7
(NCH3), 28.9 (CH2), 21.3 (CH3), 15.3 (CH3); HPLC
97.32%, Inertsil ODS 3V (150ꢂ4.6) mm, mobile phase A:
0.01 M KH2PO4, mobile phase B: acetonitrile, gradient
(T/% B): 0/40, 2/40, 12/80, 20/80, 21/40, 22/40, flow rate:
1.0 mL/min, UV 210 nm, retention time 7.92 min; Elemen-
tal analysis found C, 66.77; H, 6.13; N, 4.51; C18H19NO2S
requires C, 66.98; H, 6.11; N, 4.47.
4.10. Preparation of 1-[3-(2,6-dimethyl-1,1-dioxo-3-p-
tolyl-1,2-dihydro-1-benzo[e][1,2]thiazine-4-yl)-phenyl]-
ethanone (9c)
Acknowledgements
The authors thank Dr. A. Venkateswarlu, Dr. R. Rajagopalan
and Prof. J. Iqbal for their encouragement and the analytical
group for spectral data. Mr. D.G. thanks DRL and Jawaharlal
Nehru Technological University, Kukatpally, Hyderabad,
India for allowing him to pursue this work as a part of his
summer training program.
To a mixture of 8m (0.2 g, 0.47 mmol) and 3-acetyl bezene-
boronic acid (0.083 g, 0.51 mmol) in DMF (10 mL) were
added Pd(PPh3)4 (0.016 g, 0.014 mmol) and 2 M Na2CO3
solution (0.4 g, 3.77 mmol in 3.5 mL of water). The mixture
was then stirred at 80 ꢀC under for 2 h under nitrogen. After
completion of the reaction (indicated by TLC), the mixture
was cooled to room temperature, diluted with water
(80 mL), and extracted with ethyl acetate (3ꢂ20 mL). Or-
ganic layers were collected, combined, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by column chromatography using ethyl
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.12.040.

1788
D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
Veeramaneni, V. R.; Kumar, S.; Vangoori, A.; Mullangi, R.;
References and notes
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Wacharasindhu, S.; Hong, X. Org. Lett. 2005, 7, 143.
20. Our interest stems from the fact that in 1992 one of us (MP) ob-
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erated in situ under Sonogashira conditions, in the presence
of ICl afforded the corresponding 3-iodo substituted ylidene-
phthalide, see: (a) Kundu, N. G.; Pal, M.; Nandi, B.
J. Chem. Soc., Perkin Trans. 1 1998, 561; (b) Kundu, N. G.;
Pal, M. J. Chem. Soc., Chem. Commun. 1993, 86.
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Willis, A. C.; Hamel, E. Aust. J. Chem. 1999, 52, 767; (b)
Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
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O. Eur. J. Org. Chem. 2005, 3334; (d) Yue, D.; Yao, T.;
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S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409; (b) For
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Roman, D. J. Org. Chem. 2003, 68, 6788.
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1037; (b) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez,
J. M. Angew. Chem., Int. Ed. 2003, 42, 2406; (c) Yao, D.;
Yue, D.; Larock, R. C. J. Comb. Chem. 2005, 7, 809.
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J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437.
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I
C(CH3)2OH
ICl
C(CH3)2OH
O
CO2H
O
21. (a) Batchu, V. R.; Subramanian, V.; Parasuraman, K.; Swamy,
N. K.; Kumar, S.; Pal, M. Tetrahedron 2005, 61, 9869; (b)
Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org.
Chem. 2005, 70, 4778; (c) Pal, M.; Batchu, V. R.; Swamy,
N. K.; Padakanti, S. Tetrahedron Lett. 2006, 47, 3923; (d)
MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem.
2001, 66, 3662.
12. For coumestans, see: Yao, T.; Yue, D.; Larock, R. C. J. Org.
Chem. 2005, 70, 9985.
22. For a review, see: Seki, M. Synthesis 2006, 2975.
13. For other recent examples of iodonium-promoted heterocycli-
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K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769; (b) Liu, Y.;
Song, F.; Cong, L. J. Org. Chem. 2005, 70, 6999; (c) Yao, T.;
Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679; (d)
Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609; (e) Waldo, J. P.;
Larock, R. C. Org. Lett. 2005, 7, 5203; (f) For iodocyclization
of sulfonamide derivatives of o-(1-alkynyl)anilines leading to
3-iodoindoles, see: Amjad, M.; Knight, D. W. Tetrahedron
Lett. 2004, 45, 539.
23. Dimerization of terminal alkynes (Glaser coupling), a side re-
action often observed under the Sonogashira coupling condi-
tions, predominates in the presence of oxygen or other
reagents, see for example: (a) Kundu, N. G.; Pal, M.;
Chowdhury, C. J. Chem. Res. Synop. 1993, 432; (b) Lei, A.;
Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 1969; (c)
Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 5752;
(d) Batsanov, A. S.; Collings, J. C.; Fairlamb, I. J. S.;
Holland, J. P.; Howard, J. A. K.; Lin, Z.; Marder, T. B.;
Parsons, A. C.; Ward, R. M.; Zhu, J. J. Org. Chem. 2005, 70,
703; (e) Fairlamb, I. J. S.; Bauerlein, P. S.; Marrison, L. R.;
Dickinson, J. M. Chem. Commun. 2003, 632; (f) Formation
of 5–10% of dimeric product was observed when arylalkynes
were used. CuI in the presence of an amine base is known to
14. (a) Pal, M.; Madan, M.; Srinivas, P.; Pattabiraman, V. R.;
Kalleda, S. R.; Akhila, V.; Ramesh, M.; Rao Mamidi,
N. V. S.; Casturi, S. R.; Malde, A.; Gopalakrishnan, B.;
Yeleswarapu, K. R. J. Med. Chem. 2003, 46, 3975; (b) Pal, M.;

D. K. Barange et al. / Tetrahedron 63 (2007) 1775–1789
1789
have a significant role in the oxidative homocoupling of termi-
nal acetylenes and arylalkynes perhaps due to their higher reac-
tivity than other alkynes are prone to undergo faster oxidative
homocoupling.
of the sulfoximine, which invariably led to the mixture of
regioisomeric five and six-membered ring products, see
Ref. 19; (b) Recently, the intramolecular cyclization of
alkynylamides has been studied by Larock et al., which mainly
produced isoindolin-1-ones in the presence of iodine, see
Ref. 9.
24. Single crystals suitable for X-ray diffraction of 8m were grown
from a mixture of methanol, ethyl acetate, and petroleum ether.
The compound crystallizes in monoclinic space group P21
26. The possibility that the formation of 8 may proceed through (i)
deprotonation, (ii) cyclization, and (iii) iodination of the resul-
tant 3-substituted benzothiazines is ruled out by the following
experiment: 6-ethyl-2-methyl-3-p-tolyl-2H-benzo[e][1,2]thi-
azine-1,1-dioxide (9d) prepared from 8n was recovered
unchanged after treatment with iodine and K2CO3 in aceto-
nitrile at 25 ꢀC for 16 h.
˚
˚
with cell dimensions a¼9.183(1) A, b¼9.118(1) A, c¼
3
ꢀ
˚
˚
10.428(1) A, b¼101.829(5) , and V¼854.6(2) A with Z¼2.
The intensity data have been collected on Rigaku AFC-7S
diffractometer with Mercury CCD area detector using graphite
monochromatic Mo Ka radiation. The structure has been
solved with direct methods and refined using least squares
procedure using the Crystal Structure software. The present
R factors are R1¼0.034 and Rw¼0.42. The number of observed
reflections is 3420. Crystallographic data (excluding structure
factors) for 8m have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 620161.
Me
I2
CH3CN
K2CO3
Et
No reaction
25°C
N
S
Me
O
O
27. Pandey, V. K.; Pathak, S. R. Indian J. Chem., Sect. B 2002, 41,
1749.
28. Lee, K. Y.; Lee, M. J.; Kim, J. N. Tetrahedron 2005, 61,
8705.
25. (a) This behavior, which is not clear at this stage, perhaps could
be ascribed to the structural features of the starting sulfon-
amide, was different from the previously reported cyclizations