α-Haloarylsulfonamides: multiple cyclization pathways to skeletally diverse benzofused sultams

Article abstract of DOI:10.1016/j.tet.2008.11.053

The development of new methods to skeletally diverse sultams based on a central α-halo benzene sulfonamide building block is reported. Several salient features of this building block are utilized in multiple reaction pathways, including the Heck reaction, C- and O-arylation, Sonogashira-Pauson-Khand, Sonogashira-intramolecular hydroamination, and domino aza-Michael-Heck for the generation of five-, six-, and seven-membered benzofused bicyclic and tricyclic sultams.

Full text of DOI:10.1016/j.tet.2008.11.053

Tetrahedron 65 (2009) 3180–3188
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a-Haloarylsulfonamides: multiple cyclization pathways to skeletally diverse
benzofused sultams
,
,
,
,
,b
Dinesh Kumar Rayabarapu a b, Aihua Zhou a b, Kyu Ok Jeon a b, Thiwanka Samarakoon a b, Alan Rolfe a
,
Hina Siddiqui a b, Paul R. Hanson a
,
,b,
*
a Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
b The Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), 1501 Wakarusa Drive, Lawrence, KS 66047, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 October 2008
Received in revised form 15 November 2008
Accepted 19 November 2008
Available online 25 November 2008
The development of new methods to skeletally diverse sultams based on a central
a-halo benzene
sulfonamide building block is reported. Several salient features of this building block are utilized in
multiple reaction pathways, including the Heck reaction, C- and O-arylation, Sonogashira–Pauson–
Khand, Sonogashira-intramolecular hydroamination, and domino aza-Michael–Heck for the generation
of five-, six-, and seven-membered benzofused bicyclic and tricyclic sultams.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
additional sultams have shown promising bioactivity, such as an-
tiviral,10 anticancer,11 antimicrobial,12 antimalarial,13 antileuke-
In recent years, there has been a rapidly growing demand for
libraries of small molecules for high-throughput screening (HTS).
This demand has presented challenging opportunities in molecular
library development. In this regard, Diversity-Oriented Synthesis
(DOS)1,2 has emerged as an enabling platform for the production of
multiple scaffolds displaying skeletal diversity, where a lack there
of has been cited as a bottleneck in the drug discovery process.1
Among several features that define DOS, functional group pairing3
has surfaced as a significant component, which aims to selectively
pair functional groups resulting in the generation of multiple
scaffolds. Interest in the facile production of new sultams for bio-
logical screening has provided recent impetus for exploring new
mic,14 and AMPA receptor modulatory properties with potential for
treating disorders of the brain.15 This impressive biological profile is
augmented by a number of chemical properties inherent to sul-
fonamides including facile coupling/alkylation pathways for sul-
fonamide formation, stability to hydrolysis, polarity, and their
crystalline nature.16
R
O
S
R1
O
S
R1
R
O
S
O
O
O
O
R2
R2
O
N
S
N
N
N
F3C
O
F
FG-pairing cyclization pathways of
We herein report studies toward this goal revealing
a
-halo benzene sulfonamides.
-halo benzene
HO
R1
a
O
O
sulfonamides as versatile starting materials whose features can be
exploited in multiple reaction pathways to produce an array of
five-, six-, and seven-membered benzofused sultams. Ultimately,
we aim to utilize these methods in a broader DOS strategy for
library production of sultams (Fig. 1).
O
R1
N
S
R2
CH3
H2N
Cl
O
S
O
S
R1
O
O
N
X
MeO2C
MeO C
Br
Multiple
2
Cyclization
Sultams (cyclic sulfonamides) have emerged as privileged
structures in drug discovery due to their diverse biological prop-
erties.4 In particular, a number of benzofused sultams have recently
been reported that exhibit broad inhibitory properties against
a variety of enzymes including: COX-2,5 HIV integrase,6 lip-
oxygenase,7 Calpain I,8 and MMP-2.9 Moreover, a number of
OH
O
Pathways
F
H3C
R1
R
X
R1
O
S
O O
S
O O
S
O O
O
S
R2
N
R2
N
CO2Me
N
N
R1
CO2R2
O
CO2Et
* Corresponding author. Tel.: þ1 785 864 3094; fax: þ1 785 864 5396.
E-mail address: phanson@ku.edu (P.R. Hanson).
Figure 1. Multiple cyclization pathways toward skeletally diverse sultams.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.053

D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
3181
Table 1
a
-Haloarylsulfonamides represent an attractive building block
Pd(0)-catalyzed Heck cyclizations of substrate 3a
for the production of benzofused sultams,17 due to a number of key
features. The most prominent include: (i) click coupling between
R1
R1
R1
O
O
Pd(OAc)2
PPh3
O
S
O3
O
S
O
R2
O
R2
starting
conditions generating the corresponding sulfonamides in quanti-
tative yield, (ii) the -halo group enhances the acidity of the aryl
sulfonamide N–H enabling Mitsunobu and conventional alkylation
reactions to occur under mild conditions, (iii) the -halo group can
be utilized in metal-catalyzed cross coupling or Li-halogen ex-
change chemistry, and (iv) a number of substituted -halo benzene
a-halobenzenesulfonyl chlorides and amines under mild
S
CH2Cl2
N
R2
N
N
-78 °C
Me2S
Et3N
a
Br
3 R2 = CO2Me
CH3CN
MW, 1h
9
10
O
a
Entry
SM
Product
9 yieldb
%
10 yieldc
%
a
1
3
4
5
3a
3b
3c
3d
R1¼CH3
9a (72)
9b (91)
9c (70)
9d (62)
10a (84)
10b (82)
10c (78)
10d (78)
sulfonyl chlorides are commercially available. Taken collectively,
these attributes guided our efforts in this study.
R1¼CH2CHMe2
R1¼H
R1¼H, R2¼C6H5
2. Results and discussion
a
Isolated yields.
b
Heck conditions: substrate (1.00 mmol), Pd(OAc)2 (0.1 mmol, 10.0 mol %), PPh3
As outlined in Scheme 1, we began our initial investigation ex-
ploring Pd(0)-catalyzed Heck reactions with olefin containing sul-
fonamides 2, 3, and 4 (Scheme 1). Substrates 2 and 3 were designed
to alleviate any potential issues with regioselective Heck reactions.
Substrate 4 was a more promiscuous Heck substrate and deserves
mention first. Sulfonamide 4 was prepared via simple coupling of
(0.2 mmol) in CH3CN (0.25 M) at 100 ꢀC for 1 h under microwave.
c
O3, ꢁ78 ꢀC, CH2Cl2 then Me2S.
Heck reaction conditions. Thus, treatment of 1 with L-amino methyl
ester$HCl under the aforementioned conditions, followed by alky-
lation with ethyl 4-bromocrotonate, yielded the alkylated sulfon-
amide 2, which upon subjection to Heck conditions in refluxing
sulfonyl chloride 1 with L-amino methyl ester$HCl under standard
conditions (CH2Cl2, Et3N, DMAP) and allylation with allyl bromide.
Subsequent Heck conditions were explored [Pd(OAc)2, Et3N, 0.25 M
in CH3CN at 100 ꢀC in a microwave] and produced a mixture of
products via 6-exo-trig (5) and 7-endo-trig (6) pathways, along with
product 7 resulting from deallylation.18
CH3CN, afforded the desired d-sultam 8 as the sole product via
a selective 6-exo cyclization pathway.
The straightforward syntheses of the seven-membered sultams
9 were also realized as outlined in Scheme 1. Homo-allylation of the
sulfonamide with 4-bromo-1-butene produced the alkylated
product 3 in low yield. However, we found that performing the
Mitsunobu reaction with 3-buten-1-ol in the presence of DIAD and
PPh3 gave superior yields of 3.19 Subsequent intramolecular Heck
reaction of 3, cleanlyafforded the 7-exo-trig cyclizationproducts 9 in
excellent yields (Table 1). Ozonolysis of 9 produced the benzothia-
zepenones 10 in good to excellent yields. Similarly, the inseparable
mixture of Heck products 5 and 6 was subjected to ozonolysis fur-
nishing benzothiazenone 11 in pure form after isolation.
The regioselectivity concern of 6-exo versus 7-endo cyclization
was not an issue when sulfonamide 2 was subjected to standard
O O
S
O O
S
Pd(OAc)2
OMe
OMe
PPh3
1. (a)
N
N
Et3N
CH3CN
reflux
78%
2. (b)
61%
O
O
Br
2 78%
8
CO2Et
CO2Et
The chemistry of benzene sulfonamide was further extended to
an intramolecular arylation reaction whereby the
a-bromo aryl
R1
O
R1
sulfonamide group was paired with an aromatic group.20 The lit-
erature contains a single example of a six-membered sultam pro-
OMe
O
O O
O O
Pd(OAc)2
O
S
OMe
PPh3
S
S
1. (a)
2. (d)
N
N
Cl
duced from an a
-halobenzenesulfonamide using Pd(0)-catalysis.21
Et3N
CH3CN
MW, 1h
O
Br
Br
However, in this intramolecular direct C-arylation, the yield was
low. Treating 1 with aniline and subsequent alkylation with methyl
iodide or ethyl iodide produced the corresponding sulfonamide 12,
which was subjected to Pd(OAc)2, PPh3, Cs2CO3 in toluene at 110 ꢀC
affording cyclized product 13 via a C-arylation pathway. The pres-
ent method offers a practical method for synthesis of dibenzo-
thiazine dioxides in excellent yields (Table 2, Scheme 2).
1
3 (63-67%)
X
O3, CH2Cl2
then Me2S
9: X = CH2
10: X = O
O
O
R1
O O
S
S
OMe
1. (a)
2. (e)
(f)
N
OMe
N
(g)
O
Br
4 85%
O
11
Table 2
Pd(0)-catalyzed C-arylation of substrates 12 and 14a
O
R1= CH(CH3)2
R1
O
S
(39% over 2 steps)
R1
R1
N
O
O
O
( )n
( )n
S
Pd(OAc)2, PPh3
R1
O O
S
N
O O
Pd(OAc)2
PPh3
O
N
O
R1
Cs2CO3
S
R2
toluene, 110 °C
R2
N
R2
N
R2
S
Br
Et3N
CH3CN, MW
+
R2
Br
5
6
Entry
SM
Product
Yieldb (%)
4 R1 = CHMe2, R2 = CO2Me
R1
O O
S
1
2
3
4
5
12a
12b
14a
14b
14c
n¼0, R1¼Me, R2¼H
n¼0, R1¼Et, R2¼H
n¼1, R1¼Me, R2¼H
n¼1, R1¼Me, R2¼OMe
n¼1, R1¼Bn, R2¼H
13a (83)
13b (77)
15a (85)
15b (56)
15c (95)
N
R2
Combined yeild = 89 %;
Ratio (5:6:7 = 7: 1: 5)
7
H
Br
Scheme 1. Intramolecular Heck reaction. (a) Amino ester, Et3N, DMAP, CH2Cl2; (b)
ethyl 4-bromocrotonate, K2CO3, CH3CN, 60 ꢀC; (c) amino ester, Et3N, DMAP, CH2Cl2; (d)
4-buten-1-ol, DIAD, PPh3, CH2Cl2, rt; (e) allyl bromide, K2CO3, CH3CN, rt; (f) Pd(OAc)2,
PPh3, Et3N, CH3CN; (g) O3, CH2Cl2, ꢁ78 ꢀC then Me2S.
a
Isolated yields.
b
Conditions: substrate (1.0 mmol), Pd(OAc)2 (0.1 mmol, 10.0 mol %), PPh3
(0.2 mmol), Cs2CO3 (2.0 mmol) intoluene (4.0 mL)at 110 ꢀC insealedtubefor12–24 h.

3182
D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
O
O O
O
O
O
1. Et3N, DMAP
R1
O
O
Pd(OAc)2
PPh3
S
S
S
I
CH3NH2, CH2Cl2, 0 °C
CH3
N
Cl
N
S
1. (a)
H
N
2. n-BuLi, I2
THF, 25 °C
Cs2CO3
toluene, 110 °C
(77-83%)
R1
H3C
H3C
2. (b)
(75-78%)
18
19 (80%)
Br
over 2 steps
12
13
PdCl2(Ph3)2, CuI
TMS
O
S
O
CH3
O
O
O
O
O
O
Pd(OAc)2
PPh3
N
CH3
O
O
S
S
S
CH3
CH3
N
N
H
N
K2CO3
CH3CN
50 °C
1. (c)
S
Cl
Cs2CO3
toluene, 110 °C
2. (b)
(82-85%)
Br
H3C
Br
H3C
22 (78%)
TMS
20 (58%)
R2
1
(56-95%)
14
15
R2
K2CO3, CH3CN
CH3
O
50 °C
Br
Ph
N
S
O
O
O
S
O
S
CuI
(20 mol%)
O
O
1. (d)
2. (e)
O
OH
CH3
S
N
N
N
Co2(CO)8
Ethylene
glycol
Cs2CO3, DMF,
120 °C
3. (f)
21 (53%)
Br
16(41% over 3 steps)
Ph
Toluene,
90 °C
H3C
O
O
+
H3C
23 (67%)
22 (9%)
17 (49%)
Scheme 3. Sonogashira-PK and Sonogashira-IHA strategies.
Scheme 2. C- and O-arylation reactions. (a) Aniline, pyridine, CH2Cl2; (b) methyl io-
dide or ethyl iodide, K2CO3, CH3CN, 50 ꢀC; (c) benzyl amine, Et3N, DMAP, CH2Cl2; (d)
phenylalanine methyl ester, Et3N, DMAP, CH2Cl2; (e) DIAD, PPh3, 4-buten-1-ol; (f)
LiAlH4, THF, 0 ꢀC to rt.
for the synthesis of 1,2-benzisothiazoline-3-acetic acid 1,1-dioxides
24 (Scheme 4).26 Such domino protocols are attractive strategies for
the incorporation of multiple points of diversity in a one-pot multi-
component transformation. Thus, we investigated the application
With this result in hand, we attempted the direct C-arylation
to furnish a seven-membered sultam 15. Treatment of 1 with
benzyl amine and subsequent alkylation with methyl iodide fur-
nished 14, which was again subjected to Pd(OAc)2 conditions at
110 ꢀC for 24 h to afford the seven-membered benzofused sultam
15 in 85% yield (Scheme 2).
of
a-haloaryl sulfonamides toward a domino aza-Michael–Heck
protocol, whereby initial Michael addition of the sulfonamide into
methyl propiolate, followed by an intramolecular Heck reaction
yields the corresponding benzofused sultam. Thus, N-benzyl-2-
iodobenzenesulfonamide was reacted with methyl propiolate un-
der standard reaction conditions at 110 ꢀC to cleanly afford the
desired sultam 25 in 74% yield. We are currently investigating ad-
ditional variants of this protocol.
As a final example, we explored additional chemistry of the
seven-membered benzothiazepenones using a classical aldol re-
action to produce enone 26. The underlying principle behind this
was a reagent-based DOS approach toward skeletal diversity. Thus,
treatment of 10e with benzaldehyde in the presence of KOH fur-
nished 26 bearing an unsaturated ketone as a single isomer in 80%
yield. This aldol condensation set the stage for further modifica-
tions as outlined in Scheme 5.2a Subsequent hetero-Diels–Alder
(HDA) reaction of ethyl vinyl ether and 26 under neat conditions at
70 ꢀC generated the tricyclic benzosultam 27 as a single regio- and
diastereoisomer in 62% yield. Condensation reaction of 26 with
phenyl hydrazine produced the pyrozoline-containing sultam 28 in
82% yield as a 1:1 mixture of diastereomers.27 Finally, reaction of
malononitrile with 26 produced the tricyclic sultams 29 in 68%
yield.
The method was next applied to an intramolecular O-aryla-
tion reaction22 whereby the
a-bromo aryl sulfonamide group
was paired with an alcohol. Thus, 1 was coupled with phenyl-
alanine methyl ester, followed by Mitsunobu reaction with 3-
buten-1-ol and reduction with LiAlH4 to furnish sulfonamide 16
in 41% over 3 steps. Sulfonamide 16 was treated with CuI
(20 mol %) in the presence of HOCH2CH2OH as a ligand in DMF at
120 ꢀC to afford the O-arylation, cyclized product 17 in 49% yield
(Scheme 2).
The chemistry of
tended to both Pauson–Khand (PK) and intramolecular hydro-
amination (IHA) reactions.23 In this method, the
-bromo aryl
a-halobenzenesulfonamide was further ex-
a
sulfonamide group was attached to an alkyne under Sonogashira
conditions and subsequently paired with both an alkene (PK) as
well as an N–H (IHA). The reaction sequence began with the
sulfonylation of methylamine with tosyl chloride 18 followed by
iodination to afford 2-iodosulfonamide 19 in 80% over 2 steps
(Scheme 3).24 Compound 19 was subjected to Sonogashira re-
action with trimethylsilyl acetylene in presence of PdCl2(PPh3)2
and CuI to furnish sulfonamide 20.25 Alkylation of 20 with allyl
bromide in presence of K2CO3 in CH3CN at 50 ꢀC afforded ally-
lated enyne product 21 along with a small amount of the cor-
responding IHA product 22. However, when the reaction of 20
was carried out in the same conditions in the absence of allyl
bromide, sultam 22 was produced as the sole product in 78%
yield, representing a formal intramolecular hydroamination of an
acetylene via a 5-exo cyclization pathway. Finally, treatment of
sulfonamide enyne 21 with [Co2(CO)8] under thermal conditions
(90 ꢀC) furnished the tricyclic Pauson–Khand product 23 in 67%
yield.
i. R2NH2, Et3N (2 equiv.)
O
O
O
S
DMF, RT 2 h
O
S
ii. Pd2(dba)3 CHCl3 (2 mol%)
Et3N (2 equiv.), Bu4NCl
Cl
N
R2
R1
Br
R1
R3
110 °C
COR3
24
(3 equiv.)
O
O
O
O
S
O
Pd2(dba)3 CHCl3 (2 mol%)
Et3N (2 equiv.), Bu4NCl
S
Bn
N
The production of sultam 22 via an intramolecular hydro-
amination pathway prompted us to explore the development of
a one-pot protocol that would take advantage of the inherent
nucleophilicity of the sulfonamide N–H. In this regard, we have
previously reported a one-pot domino Heck-aza-Michael protocol
H
N
Bn
CO2Me 110 °C, 74%
(3 equiv.)
I
25
CO2Me
Scheme 4. Domino aza-Michael–Heck strategy.

D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
3183
O
S
at rt, Et3N (2.32 mL, 16.4 mmol) was added and the reaction flask
stirred at rt for 2 h. The crude reaction mixture was filtered and
concentrated under reduced pressure. A portion of the crude material
(208 mg, 0.56 mmol) was added to a flame-dried flask, to which
Cs2CO3 (294 mg, 1.165 mmol) and dry CH3CN (6 mL, 0.1 M) were
added. After stirring for 5 min, (E)-ethyl 4-bromobut-2-enoate
(0.66 mmol) was added and the reaction mixture was stirred at 60 ꢀC
untilcompletionofreaction(asmonitoredbyTLC). Thecrudereaction
mixture was filtered through a pad of Celite, washed with CH2Cl2,
concentrated under reduced pressure, and subjected to flash chro-
matography (1:1 EtOAc/hexane) to provide 2 (201 mg, 0.44 mmol,
78%) as a clear oil. FTIR (neat): 2972, 1739, 1720, 1342,1163 cmꢁ1; 1H
O
Bn
N
Neat, 70 °C
OEt
Ph
O
62%
27
EtO
O
S
O
Bn
O
S
O
O
S
O
N
KOH
Bn
Bn
PhNHNH2
N
EtOH
N
cat. H+
EtOH
74%
PhCHO
80%
Ph
N
Ph
28
N
26
O
X
NMR (500 MHz, CDCl3)
d
(ppm) 8.11 (dd, J¼1.7, 7.9 Hz, 1H), 7.71 (dd,
Ph
O
S
O
O3, CH2Cl2
-78 °C, then
Me2S
J¼7.8,1.3 Hz,1H), 7.43 (td, J¼7.7,1.3 Hz,1H), 7.37 (dt, J¼7.5,1.8 Hz,1H),
6.84 (ddd, J¼15.8, 7.8, 5.1 Hz, 1H), 5.87 (dt, J¼15.8, 1.5 Hz, 1H), 4.41
(dddd, J¼18.4, 9.0, 6.4, 1.5 Hz, 2H), 4.14 (q, J¼7.1 Hz, 2H), 4.09 (d,
J¼10.3 Hz,1H), 3.54 (s, 3H), 2.15–2.06 (m,1H),1.29–1.23 (m, 3H),1.02
(d, J¼6.6 Hz, 3H), 0.91 (dd, J¼9.0, 3.8 Hz, 3H); 13C NMR (125 MHz,
9e: X = CH2
Bn
N
10e: X = O
(78%)
NC
CN
Ph
CN
O
EtOH
68%
29
CDCl3)
d (ppm) 171.0, 165.7, 144.4, 139.2, 135.4, 133.8, 133.1, 127.6,
H2N
123.1,120.3, 65.5, 60.4, 51.7, 46.5, 28.9,19.8,19.3,14.2; HRMS calcd for
C18H24BrNNaO6S (MþNa)þ 484.0405, found 484.0379.
Scheme 5. Reagent-based DOS approach.
3. Conclusion
4.2.2. (S)-Methyl-2-(2-bromo-N-(but-3enyl)phenylsulfonamido)-
propanoate (3a)
In conclusion, we have developed a variety of new reaction
pathways toward the synthesis of skeletally diverse benzofused
sultams. These methods employ commercially available a-haloaryl
Into a flame-dried flask under argon were added 1 (7.82 mmol),
amino ester/amine (7.82 mmol), and CH2Cl2 (20 mL). Et3N
(16.4 mmol) was added and the reaction flask stirredat rt for 2 h. The
crude reaction mixturewas filtered and concentratedunder reduced
pressure. A portion of the crude (2.56 g, 7.64 mmol) was added to
a flame-dried flask under argon (2.56 g, 7.64 mmol), to which were
added PPh3 (2.21 g, 8.45 mmol) and dry CH2Cl2 (40 mL). After
stirring for 5 min, 3-buten-1-ol (0.72 mL, 8.45 mmol) was added
followed by dropwise addition of diisopropyl azodicarboxylate
(DIAD) (1.71 mL, 8.45 mmol) at rt. The reaction mixture was stirred
for 3 h, after which time the crude mixture was concentrated under
reduced pressure and purified by flash chromatography (1:1 EtOAc/
hexane) to provide 3a (2.34 g, 79% yield) as awhite solid. FTIR (neat):
3064, 2950, 1795, 1448, 1434, 1342, 1163 cmꢁ1; 1H NMR (500 MHz,
sulfonyl chlorides in achieving multiple reaction pathways such
as Heck, Sonogashira-NH addition, Sonogashira–Pauson–Khand,
C- and O-arylations to produce five-, six-, and seven-membered
sultams in good to excellent yields. We also demonstrated that Heck
reaction products undergo facile ozonoly sis/aldol to produce an
intermediate unsaturated ketone, which was utilized in a reagent-
based DOS approach to furnish additional diverse sultams. All the
sultam reported herein have been submitted to NIH biological out-
reach partners for biological screening through the NIH Molecular
Library Screening Network (NIH-MLSCN). The utilization of the
reported method is currently being employed in library production
and the results will be reported in due course.
CDCl3)
d
(ppm) 8.15 (dd, J¼7.9,1.7 Hz,1H), 7.71 (dd, J¼7.8,1.3 Hz,1H),
7.44 (td, J¼7.7, 1.3 Hz, 1H), 7.37 (td, J¼7.6, 1.7 Hz, 1H), 5.62 (ddt,
J¼17.2, 10.5, 7.7 Hz, 1H), 4.96 (dd, J¼3.4, 1.8 Hz, 1H), 4.94 (dq, J¼11.8,
1.7 Hz,1H), 4.82 (q, J¼7.4 Hz,1H), 3.63 (s, 3H), 3.57–3.47 (m,1H), 3.17
(ddd, J¼15.3, 9.3, 7.2 Hz, 1H), 2.28–2.21 (m, 2H), 1.50 (d, J¼7.4 Hz,
4. Experimental section
4.1. General
3H); 13C NMR (125 MHz, CDCl3)
d 172.06, 135.44, 134.40, 133.47,
All reactions were carried out in flame-dried glassware under
argon. Toluene, THF, Et2O, and CH2Cl2 were purified by passage
through a purification system (Solv-Tek) employing activated
Al2O3.28 Et3N was distilled from CaH2. Flash column chromatogra-
phy was performed with Merck silica gel (230–400 mesh). Thin
layer chromatography was performed on silica gel 60F254 plates. 1H
and 13C spectra were recorded in CDCl3 on either a Bruker DRX-400
or a Bruker AM-500 spectrometer operating at 400/100 MHz and
500/125 MHz, respectively. High-resolution mass spectrometry
(HRMS) and FAB spectra were obtained on a VG Instrument ZAB
double-focusing mass spectrometer. Infrared data was obtained on
a Nicolet 320 Fourier Transform Infrared Spectrophotometer.
Melting points were obtained on a Thomas Hoover capillary
melting point apparatus. Optical rotations were carried out on
a Rudolph Automatic Polarimeter (AUTOPOL IV).
132.16, 127.50, 116.92, 55.43, 52.29, 45.14, 34.69, 16.48; HRMS
calcd for C14H18BrNNaO4S (MþNa)þ 398.0038, found 398.0045.
4.2.3. (S)-Methyl 2-(2-bromo-N-(but-3-enyl)phenylsulfonamido)-
4-methylpentanoate (3b)
Using a similar procedure as that used to produce sultam 3a,
sultam 3b was produced in 69% yield. FTIR (neat): 3064, 2955, 1795,
1448, 1434, 1336, 1163 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d (ppm)
8.14 (dd, J¼7.9, 1.7 Hz, 1H), 7.45 (td, J¼7.7, 1.3 Hz, 1H), 7.38 (td, J¼7.6,
1.7 Hz, 2H), 5.72 (ddt, J¼17.1, 10.2, 6.8 Hz, 1H), 5.04 (dddd, J¼16.0,
1.5, 1.5, 1.5 Hz, 1H), 5.03 (m, 1H), 4.56 (dd, J¼8.8, 5.6 Hz, 1H), 3.59–
3.51 (m, 1H), 3.54 (s, 3H), 3.32 (ddd, J¼16.0, 11.0, 5.2 Hz, 1H), 2.57–
2.48 (m, 1H), 2.34–2.25 (m, 1H), 1.78–1.69 (m, 2H), 1.65–1.56 (m,
1H), 0.93 (dd, J¼17.1, 6.2 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d 171.7,
139.2, 135.5, 134.7, 133.4, 132.4, 127.5, 120.4, 117.0, 58.3, 52.1, 45.8,
39.4, 35.5, 24.5, 22.6, 21.7; HRMS calcd for C17H24BrNNaO4S
(MþNa)þ 440.0507, found 440.0500.
4.2. Synthetic studies
4.2.1. (S,E)-Ethyl-4-(2-bromo-N-(1-methoxy-3-methyl-1-
oxobutan-2-yl)phenylsulfonamido)but-2-enoate (2)
4.2.4. Methyl-2-(2-bromo-N-(but-3-enyl)phenylsulfonamido)-
acetate (3c)
Into a flame-dried flask were added 1 (2.0 g, 7.82 mmol), H-Leu-
OMe (1.42 g, 7.82 mmol), and CH2Cl2 (20 mL). After stirring for 5 min
Using a similar procedure as that used to produce sultam 3a,
sultam 3c was produced in 87% yield. FTIR (neat): 2951, 1753, 1340,

3184
D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
1161, 760 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
(ppm) 8.19 (dd, J¼7.8,
(ddd, J¼8.0, 6.4, 2.5 Hz, 2H), 6.96 (s,1H), 4.56 (d, J¼10.4 Hz,1H), 4.16
1.8 Hz, 1H), 7.74 (dd, J¼7.8, 1.3 Hz, 1H), 7.45 (td, J¼7.5, 1.3 Hz, 1H),
7.40 (td, J¼7.5, 1.7 Hz, 1H), 5.59 (ddt, J¼17.0, 10.2, 6.8 Hz, 1H), 5.01
(ddd, J¼11.0, 6.6, 5.5 Hz, 2H), 4.28 (s, 2H), 3.71 (s, 3H), 3.57–3.38 (m,
(q, J¼7.1 Hz, 2H), 3.78 (s, 3H), 3.59 (s, 2H), 2.24 (ddt, J¼13.3, 10.4,
6.7 Hz, 1H), 1.22 (t, J¼7.1 Hz, 3H), 0.97 (d, J¼6.6 Hz, 3H), 0.79 (d,
J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm) 170.7, 170.6,
2H), 2.34–2.11 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 169.5,
132.5, 132.1, 131.4, 128.1, 127.8, 124.0, 122.1, 113.5, 62.5, 61.2, 52.5,
36.6, 29.9, 19.1, 18.6, 14.1; HRMS calcd for C18H23NO6SNa (MþNa)þ
404.1144, found 404.1146.
139.3, 135.5, 134.1, 133.6, 132.2, 127.5, 120.5, 117.5, 52.3, 48.5, 47.6,
32.0; HRMS calcd for C13H16BrNNaO4S (MþNa)þ 383.9881, found
383.9882.
4.2.9. (S)-1,2-Benzothiazepine-2(3H)-acetic acid, 4,5-dihydro-5-
4.2.5. N-Benzyl-2-bromo-N-(but-3-enyl)benzenesulfonamide (3d)
Using a similar procedure as that used to produce sultam 3a,
sultam 3d was produced in 67% yield. FTIR (neat): 3064, 2927, 1641,
methylene-a-(2-methylpropyl)-, methyl ester, 1,1-dioxide (9b)
Into a microwave vial were added sulfonamide 3b (1.8 g,
4.30 mmol), Pd(OAc)2 (0.43 mmol, 96 mg), PPh3 (0.86 mmol,
225 mg), CH3CN (17 mL), and Et3N (1.8 mL, 12.9 mmol). After stir-
ring for 5 min, the reaction was run in the microwave at 100 ꢀC for
1 h. After 1 h, the reaction mixture was cooled to rt and filtered
through a small Celite pad and thoroughly washed with CH2Cl2. The
reaction mixture was concentrated under reduced pressure and
1448, 1434, 1332, 1124 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d (ppm)
8.16 (dd, J¼7.8,1.8 Hz,1H), 7.76 (dd, J¼7.8,1.4 Hz,1H), 7.44 (td, J¼7.6,
1.4 Hz, 1H), 7.40 (td, J¼7.6, 1.9 Hz, 1H), 7.34–7.26 (m, 5H), 5.56–5.47
(m, 1H), 4.94–4.92 (m, 1H), 4.90 (t, J¼1.3 Hz, 1H), 4.57 (s, 2H), 3.26
(dd, J¼8.4, 6.8 Hz, 2H), 2.16–2.10 (m, 2H); 13C NMR (126 MHz,
CDCl3)
d
139.47, 135.90, 135.53, 134.30, 133.49, 132.34, 128.63,
purified using flash chromatography (4:1 hexane/EtOAc) to provide
25
128.26, 127.80, 127.51, 120.52, 117.13, 77.25, 77.00, 76.75, 51.26,
46.01, 31.90; HRMS calcd for C17H18BrNNaO2S (MþNa)þ 402.0140,
found 402.0139.
1.29 g (89%) of the title compound 9b as a yellow oil. [
a]
ꢁ35.4 (c
7.30, CHCl3); colorless liquid; FTIR (neat): 2954, 2869, 1741, 1467,
1153 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
(ppm) 8.46 (dd, J¼7.8,
1.1 Hz, 1H), 8.03 (td, J¼7.5, 1.3 Hz, 1H), 7.97–7.89 (m, 2H), 5.86 (d,
J¼0.7 Hz, 1H), 5.82 (d, J¼1.2 Hz, 1H), 5.23 (dd, J¼9.4, 6.0 Hz, 1H),
4.32 (ddd, J¼13.0, 8.2, 4.6 Hz, 1H), 4.19 (dt, J¼10.7, 5.1 Hz, 1H), 3.92
(s, 3H), 3.22–2.96 (m, 2H), 2.19 (dq, J¼17.1, 8.7 Hz, 2H), 2.04 (ddd,
J¼13.6, 6.7, 6.5 Hz, 1H), 1.44 (d, J¼6.6 Hz, 6H); 13C NMR (125 MHz,
4.2.6. (S)-Methyl 3-(N-allyl-2-bromophenylsulfonamido)-5-
methyl-2-oxohexanoate (4)
Using a similar procedure as that used to produce sultam 2,
20
sultam 4 was produced as a clear oil in 85% yield. [
a
]
ꢁ42.8 (c
D
3.38, CH2Cl2), colorless oil; FTIR (neat): 2966, 1740, 1340, 1163,
CDCl3) d (ppm) 171.4, 147.0, 139.7, 139.7, 132.2, 129.9, 127.2, 126.1,
748 cmꢁ1 1H NMR (CDCl3, 400 MHz)
;
d
(ppm) 8.01–7.28 (aromatic
119.0, 57.5, 51.7, 45.0, 38.1, 35.0, 24.3, 22.8, 21.3; HRMS calcd for
H, 4H), 5.80 (m, 1H), 5.06 (d, J¼17.2 Hz, 1H), 4.91 (d, J¼10.2 Hz, 1H),
4.49 (dd, J¼6.4, 3.9 Hz, 1H), 4.10 (dd, J¼16.4, 8.0 Hz, 1H), 3.93 (d,
J¼10.4 Hz, 1H), 3.40 (s, 3H), 2.10 (m, 1H), 0.94 (d, J¼6.6 Hz, 3H), 0.80
C17H23NNaO4S (MþNa)þ 360.1245, found 360.1224.
4.2.10. (S)-1,2-Benzothiazepine-2(3H)-acetic acid, 4,5-dihydro-
(d, J¼6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
(ppm) 170.7, 139.4,
a-methyl-5-methylene-, methyl ester, 1,1-dioxide (9a)
135.5, 135.3, 133.6, 132.8, 127.5, 120.1, 117.3, 65.5, 51.3, 48.6, 28.5,
19.5, 18.8; HRMS (ESI) m/z calcd for C15H20BrNO4SNa 412.0194
(MþNa)þ, found 412.0181.
Using a similar procedure as that used to produce sultam 9b,
25
sultam 9a was produced in 72% yield. [
a]
ꢁ34.0 (c 3.45, CHCl3);
colorless liquid; FTIR (neat): 2951, 1750, 1365, 1170, 1158 cmꢁ1
NMR (500 MHz, CDCl3)
;
1H
d
(ppm) 7.88 (dd, J¼7.9, 1.1 Hz, 1H), 7.46 (td,
4.2.7. Sultam (5)
J¼7.6,1.3 Hz,1H), 7.36 (td, J¼7.7,1.5 Hz, 2H), 5.29 (s,1H), 5.26 (s,1H),
4.69 (q, J¼7.3 Hz, 1H), 3.70 (t, J¼4.3 Hz, 2H), 3.46 (s, 3H), 2.52 (ddd,
J¼14.4, 6.2, 5.9 Hz, 2H), 1.33 (d, J¼7.3 Hz, 3H); 13C NMR (125 MHz,
Into a microwave vial were added sulfonamide 4 (1.77 g,
4.30 mmol), Pd(OAc)2 (0.43 mmol, 96 mg), PPh3 (0.86 mmol,
225 mg), CH3CN (17 mL), and Et3N (1.8 mL, 12.9 mmol). After stir-
ring for 5 min, the reaction was run in the microwave at 100 ꢀC for
1 h. After 1 h, the reaction mixture was cooled to rt, filtered through
a small Celite pad, and thoroughly washed with CH2Cl2. The re-
action mixture was concentrated under reduced pressure and pu-
rified using flash chromatography (4:1 hexane/EtOAc) to provide
a 1.24 g (89%) of a mixture of compounds 5/6/7 [1:0.14:0.74 based
on 1H NMR] as a yellow oil. FTIR (neat): 2964, 1740, 1340, 1170,
CDCl3)
d (ppm) 171.7, 147.0, 139.8, 139.7, 132.2, 130.1, 127.3, 126.2,
119.3, 55.1, 52.0, 45.5, 35.5, 16.1; HRMS calcd for C14H17NNaO4S
(MþNa)þ 318.0776, found 318.0780 (FAB).
4.2.11. (S)-1,2-Benzothiazepine-2(3H)-acetic acid, 4,5-dihydro-5-
methylene-, methyl ester, 1,1-dioxide (9c)
Using a similar procedure as that used to produce sultam 9b,
sultam 9c was produced in 70% yield. FTIR (neat): 2952, 1755, 1417,
748 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.06–7.41 (aromatic
1128, 860 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
(ppm) 7.92 (dd, J¼7.8,
H, 4H), 5.78 (s, 1H), 5.25 (s, 1H), 4.67 (d, J¼6.7 Hz, 1H), 4.49 (d,
J¼6.8 Hz, 1H), 4.11 (d, J¼10.6 Hz, 1H), 3.25 (s, 3H), 1.68 (m, 1H), 0.92
(d, J¼6.8 Hz, 3H), 0.06 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
1.2 Hz, 1H), 7.52 (td, J¼7.5, 1.4 Hz, 1H), 7.44–7.35 (m, 2H), 5.36 (d,
J¼0.9 Hz,1H), 5.28 (d, J¼1.2 Hz,1H), 3.83 (s, 4H), 3.70 (s, 3H), 2.58 (t,
J¼4.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d (ppm) 168.9, 146.8,
d
(ppm) 170.2, 136.0, 134.3, 133.5, 131.1, 127.6, 125.3, 120.4, 113.8,
140.2, 137.7, 132.8, 130.5, 127.5, 127.5, 119.7, 52.2, 50.5, 48.8,
32.6; HRMS calcd for C13H15NNaO4S (MþNa)þ 304.0619, found
304.0613.
64.3, 51.4, 47.9, 27.9, 19.2, 18.8; HRMS (ESI) m/z calcd for
C15H19NO4SNa 332.0932 (MþNa)þ, found 332.0936.
4.2.8. Intramolecular Heck reaction to sultam 8
4.2.12. 1,2-Benzothiazepine, 2,3,4,5-tetrahydro-5-methylene-2-
(phenylmethyl)-, 1,1-dioxide (9d)
Using a similar procedure as that used to produce sultam 9b,
sultam 9d was produced in 62% yield. FTIR (neat): 2943, 1352, 1336,
To the alkylated sulfonamide 2 were added Pd(OAc)2 (12.5 mg,
0.056 mmol), PPh3 (29 mg, 0.11 mmol), and Et3N (0.23 mL,
1.68 mmol) and the reaction mixture was heated at 70 ꢀC for
overnight. After 12 h the reaction mixture was cooled to rt, filtered
through a small Celite pad, and thoroughly washed with CH2Cl2.
The reaction mixture was concentrated under reduced pressure
1163, 727 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
(ppm) 8.05 (dd, J¼7.7,
1.3 Hz, 1H), 7.56 (td, J¼7.5, 1.4 Hz, 1H), 7.45 (ddd, J¼16.2, 7.6, 1.3 Hz,
2H), 7.38–7.29 (m, 5H), 5.38 (d, J¼0.7 Hz, 1H), 5.31 (t, J¼2.0 Hz, 1H),
4.18 (s, 2H), 3.60 (s, 2H), 2.55 (t, J¼5.6 Hz, 2H); 13C NMR (100 MHz,
and purified using flash chromatography (4:1 hexane/EtOAc) to
25
provide 8 (67% yield) as a yellow oil. [
a
]
ꢁ12.1 (c 0.05, CHCl3); FTIR
CDCl3) d (ppm) 147.1, 140.6, 137.4, 135.7, 132.8, 130.6, 128.6, 128.3,
(neat): 2968, 1739, 1332, 1199, 1117, 1026 cmꢁ1; 1H NMR (500 MHz,
CDCl3)
(ppm) 7.94 (dd, J¼7.9, 0.9 Hz, 1H), 7.68–7.58 (m, 1H), 7.51
128.2, 128.2, 127.9, 127.6, 119.7, 50.0, 47.6, 31.5; HRMS calcd for
d
C17H17NNaO2S (MþNa)þ 322.0878, found 322.0865.

D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
3185
4.2.13. (S)-1,2-Benzothiazepine-2(3H)-acetic acid, 4,5-dihydro-
(101 MHz, CDCl3)
d
(ppm) 188.4, 170.3, 140.1, 134.2, 132.9, 129.9,
a
-(2-methylpropyl)-5-oxo-, methyl ester, 1,1-dioxide (10b)
To a round bottom flask were added 9b (1.88 g, 5.57 mmol),
128.1, 123.4, 65.3, 54.0, 51.6, 28.4, 19.1, 19.1; HRMS calcd for
C14H17NNaO5S (MþNa)þ 334.0725, found 334.0737.
Sudan III (1 mg), and CH2Cl2 (50 mL). The reaction mixture was
cooled down to ꢁ78 ꢀC and O3 was bubbled into the solution for
15 min. After such time, Me2S (5 mL) was added dropwise upon
disappearance of the pink color of the crude reaction mixture. The
reaction mixture was concentrated under reduced pressure and
4.2.18. N-Benzyl-2-bromo-N-methylbenzenesulfonamide (12a)
Into a flame-dried flask under argon were added sulfonyl chlo-
ride 1 (1.0 g, 3.9 mmol), aniline (0.36 mL, 3.9 mmol), dry CH2Cl2
(39 mL, 0.1 M), and pyridine (1.58 mL, 1.95 mmol). After stirring at
rt for 2 h the crude reaction mixture was filtered, washed with
water (2ꢂ20 mL), dried with MgSO4, and concentrated under re-
duced pressure. A portion of the crude material (1.0 g, 0.32 mmol)
was added to a flame-dried flask followed by the addition of
CH3I (1.0 mL, 1.61 mmol), K2CO3 (2.22 g, 1.61 mmol), and dry
CH3CN (12 mL, 0.1 M) and the reaction mixture was stirred at rt,
until the starting material disappeared as monitored by TLC.
The crude reaction mixture was filtered through a pad of Celite
and washed with CH2Cl2. The mixture was concentrated under
reduced pressure and purified by flash chromatography (1:1
hexane/EtOAc) to provide 12a (88% yield) as a clear oil; FTIR
(neat): 1493, 1339, 1157, 741, 565 cmꢁ1; 1H NMR (500 MHz, CDCl3)
purified bycolumn chromatography (4:1 hexanes/EtOAc) to provide
82% yield of the desired product (10c) as a colorless oil. [
25
a
]
8.7
(c 1.39, CHCl3); FTIR (neat): 2956, 1741, 1693, 1342, 1203, 1172,
754 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
(ppm) 8.00 (ddd, J¼7.0, 4.4,
2.5 Hz, 1H), 7.90 (ddd, J¼8.8, 4.8, 2.2 Hz, 1H), 7.65–7.62 (ddd, J¼5.0,
2.4, 2.1 Hz, 2H), 4.78 (dd, J¼8.3, 7.3 Hz,1H), 3.75–3.50 (m, 2H), 3.49–
3.36 (m, 3H), 3.18 (dt, J¼13.9, 5.0 Hz, 1H), 1.81–1.57 (m, 4H), 1.02 (s,
3H), 1.00 (s, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm) 198.9, 171.1,
140.8, 135.6, 132.4, 132.0, 129.4, 126.3, 58.9, 52.0, 42.3, 39.9, 38.0,
24.5, 23.1, 21.0; HRMS calcd for C16H21NNaO5S (MþNa)þ 362.1038,
found 362.1047.
4.2.14. (S)-1,2-Benzothiazepine-2(3H)-acetic acid, 4,5-dihydro-
methyl-5-oxo-, methyl ester, 1,1-dioxide (10a)
a-
d
(ppm) 7.83 (dd, J¼7.1, 2.0 Hz, 1H), 7.66 (dd, J¼7.0, 2.0 Hz, 1H),
7.36–7.07 (m, 7H), 3.37 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
(ppm)
Using a similar procedure as that used to produce sultam 10b,
sultam 10a was produced in 84% yield as a colorless oil. [
25 30.5 (c
0.67, CHCl3); FTIR (neat): 2935, 1693, 1589, 1315, 1280, 1153 cmꢁ1
1H NMR (400 MHz, CDCl3)
141.0, 138.2, 135.8, 133.9, 133.1, 129.4, 127.6, 127.6, 127.2, 120.7,
39.7; HRMS calcd for C13H12BrNNaO2S (MþNa)þ 347.9670, found
347.9636.
a
]
;
d
(ppm) 7.99 (ddd, J¼8.8, 4.8, 2.4 Hz, 1H),
7.87 (ddd, J¼9.2, 4.8, 2.4 Hz, 1H), 7.66 (ddd, J¼8.8, 4.4, 2.0 Hz, 2H),
4.81 (q, J¼7.2 Hz, 1H), 3.50 (s, 3H), 3.45–3.64 (m, 3H), 3.24 (ddd,
J¼10.8, 6.4, 4.4 Hz, 1H), 1.45 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
4.2.19. N-Benzyl-2-bromo-N-ethylbenzenesulfonamide (12b)
Using a similar procedure as that used to produce sultam 12a,
sultam 12b was produced as a yellow oil in 85% yield. FTIR (neat):
CDCl3)
d
(ppm) 199.1, 171.1, 140.7, 135.7, 132.4, 132.0, 129.4, 126.2,
2974, 1490, 1336, 1174, 741, 696 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
56.2, 52.2, 42.3, 40.0, 16.0; HRMS calcd for C13H15NNaO5S (MþNa)þ
d
(ppm) 7.77 (dd, J¼7.8, 1.8 Hz, 1H), 7.65 (dd, J¼7.8, 1.3 Hz, 1H), 7.33–
320.0569, found 320.0570.
7.08 (m, 7H), 3.86 (q, J¼7.1 Hz, 2H), 1.09 (t, J¼7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3)
d (ppm) 138.8, 138.3, 135.6, 133.7, 133.1, 129.7,
4.2.15. 1,2-Benzothiazepine-2(3H)-acetic acid, 4,5-dihydro-5-oxo-,
methyl ester, 1,1-dioxide (10c)
129.4,128.2,127.5,120.6, 47.7,14.9; HRMS calcd for C14H14BrNNaO2S
(MþNa)þ 361.9827, found 361.9830.
Using a similar procedure as that used to produce sultam 10b,
sultam 10c was produced in 78% yield as a colorless oil. FTIR (neat):
4.2.20. Intramolecular C-arylation to 6H-dibenzo[c,e][1,2]thiazine,
6-methyl-, 5,5-dioxide (13a)
2954, 1751, 1693, 1342, 1163, 769 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
(ppm) 7.95 (ddd, J¼9.0, 5.6, 3.2 Hz, 1H), 7.83 (ddd, J¼9.0, 6.4,
To 12a were added Pd(OAc)2 (3.02 mg, 0.0135 mmol), PPh3
(7.08 mg, 0.027 mmol), Cs2CO3 (131 mg, 0.405 mmol), and toluene
(4 mL). The crude reaction mixture was heated at 110 ꢀC for
12–24 h, until the SM was consumed, as indicated by TLC. After 24 h
the reaction mixture was cooled to rt, filtered through a small
Celite pad, and thoroughly washed with CH2Cl2. The reaction
mixture was concentrated under reduced pressure and purified
using flash chromatography (4:1 hexane/EtOAc) to afford the de-
sired product 13a in 83% yield as a yellow oil. FTIR (neat): 1477,
3.0 Hz, 1H), 7.68 (ddd, J¼10.0, 5.7, 3.3 Hz, 2H), 4.11 (s, 2H), 3.66 (s,
3H), 3.62 (t, J¼6.0 Hz, 2H), 3.34 (t, J¼6.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d (ppm) 199.8, 168.8, 138.8, 136.0, 132.7, 132.0,
129.5, 126.3, 52.3, 51.2, 45.3, 41.7; HRMS calcd for C12H13NNaO5S
(MþNa)þ 306.0412, found 306.0425.
4.2.16. 1,2-Benzothiazepin-5(2H)-one, 3,4-dihydro-2-
(phenylmethyl)-, 1,1-dioxide (10d)
Using a similar procedure as that used to produce sultam 10b,
sultam 10d was produced in 78% yield as a colorless oil. FTIR
1327, 1174, 754 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d (ppm) 8.03 (td,
J¼6.5, 1.4 Hz, 2H), 7.98 (d, J¼8.0 Hz, 1H), 7.72 (td, J¼7.5, 1.4 Hz, 1H),
(neat): 2956, 1693, 1512, 1340, 1160 cmꢁ1 1H NMR (500 MHz,
;
7.58 (td, J¼7.7, 1.1 Hz, 1H), 7.52 (ddd, J¼8.1, 7.5, 1.5 Hz, 1H), 7.38–7.29
CDCl3)
d
(ppm) 8.06 (ddd, J¼8.8, 5.6, 3.6 Hz, 1H), 7.83–7.60 (m, 3H),
(m, 2H), 3.46 (s, 3H); 13C NMR (126 MHz, CDCl3)
d (ppm) 139.4,
7.49–7.24 (m, 5H), 4.30 (s, 2H), 3.49 (t, J¼6.0 Hz, 2H), 3.14 (t,
134.1, 132.4, 132.3, 130.4, 128.2, 125.5, 125.4, 124.6, 123.9, 122.4,
119.3, 32.7; HRMS calcd for C13H11NNaO2S (MþNa)þ 268.0408,
found 268.0430.
J¼6.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d (ppm) 200.6, 137.5,
137.2, 135.0, 132.9, 131.7, 129.3, 128.8, 128.3, 128.2, 127.2, 52.5, 43.5,
41.2; HRMS calcd for C16H15NNaO3S (MþNa)þ 324.0670, found
324.0667 (FAB).
4.2.21. 6H-Dibenzo[c,e][1,2]thiazine, 6-ethyl-, 5,5-dioxide (13b)
Using a similar procedure as that used to produce sultam 13a,
sultam 13a was produced in 77% yield as a yellow oil. FTIR (neat):
4.2.17. Sultam (11)
Using a similar procedure as that used to produce sultam 8,
sultam 4 was produced and carried through crude using a similar
procedure as that used to produce sultam 10, to yield 11 (39% over 2
1635, 1336, 1166, 1095, 977 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
(ppm) 8.03–7.95 (m, 3H), 7.71 (td, J¼7.6, 1.3 Hz, 1H), 7.62 (dd,
J¼7.7, 1.0 Hz, 1H), 7.57 (td, J¼7.7, 1.1 Hz, 1H), 7.50 (ddd, J¼8.3, 7.3,
1.5 Hz, 1H), 7.40 (dd, J¼8.0, 1.1 Hz, 1H), 7.37 (td, J¼7.6, 1.1 Hz, 1H),
3.99 (q, J¼7.1 Hz, 2H), 1.18 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz,
steps) as a clear oil. FTIR (neat): 2964, 1739, 1469, 1340, 1170 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
(ppm) 8.05 (d, J¼7.3 Hz, 1H), 7.82 (d,
J¼7.5 Hz, 1H), 7.78–7.66 (m, 2H), 4.70 (d, J¼18.8 Hz, 1H), 4.39 (d,
J¼18.9 Hz, 1H), 4.22 (d, J¼10.0 Hz, 1H), 3.20 (s, 3H), 2.28–2.03 (m,
1H), 1.05 (d, J¼6.7 Hz, 4H), 0.96 (d, J¼6.6 Hz, 3H); 13C NMR
CDCl3) d (ppm) 140.9, 139.4, 134.8, 133.5, 133.3, 130.2, 129.9, 129.5,
129.0, 128.5, 128.3, 127.5, 56.1, 39.0; HRMS calcd for C14H13NNaO2S
(MþNa)þ 282.0565, found 282.0553.

3186
D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
4.2.22. 2-Bromo-N-(4-methoxybenzyl)-N-methylbenzene-
sulfonamide (14b)
134.7, 133.3, 131.4, 128.4, 127.5, 125.6, 114.6, 113.7, 55.5, 55.3, 38.9;
HRMS calcd for C15H15NNaO3S (MþNa)þ 312.0670, found 312.0652.
Into a flame-dried flask under argon were added 2-bromo-
benzenesulfonyl chloride (150 mg, 0.58 mmol), methylamine
(1.76 mmol), and dry CH2Cl2 (6 mL). Et3N (0.11 mL, 0.76 mmol) and
DMAP (5 mg, 0.1 mmol) were added and the reaction flask stirred
at rt for 2 h. The crude reaction mixture was filtered and washed
with water. The mixture was dried (MgSO4), concentrated under
reduced pressure, and purified by flash chromatography (1:1 hex-
ane/EtOAc) to provide the corresponding N-methyl sulfonamide in
98% yield as a yellow solid. To the 2-bromo-N-methylbenzene
sulfonamide (0.56 mmol) in dry CH3CN (6 mL, 0.1 M) was added
Cs2CO3 (294 mg, 1.165 mmol). p-Methoxy benzyl bromide
(0.66 mmol) was added and the reaction mixture was stirred at
60 ꢀC, until the SM disappeared as monitored by TLC. The crude
reaction mixture was filtered through a pad of Celite, washed with
CH2Cl2, concentrated under reduced pressure, and purified by flash
chromatography (1:1 hexane/EtOAc) to provide 2-bromo-N-(4-
methoxybenzyl)-N-methylbenzene sulfonamide 14b in 88% yield.
4.2.27. Sultam (15c)
Using a similar procedure as that used to produce sultam 13a,
sultam 15c was produced in 95% yield as a yellow oil. FTIR (neat):
3058, 3028, 1446, 1334, 1168, 912, 746 cmꢁ1 1H NMR (500 MHz,
;
CDCl3)
d
(ppm) 8.07 (dd, J¼7.8, 1.1 Hz, 1H), 7.71 (td, J¼7.6, 1.2 Hz,
1H), 7.58 (ddd, J¼10.5, 8.7, 4.4 Hz, 2H), 7.60 (d, J¼7.6 Hz, 1H), 7.57
(td, J¼7.6, 1.1 Hz, 1H), 7.42 (d, J¼7.1 Hz, 2H), 7.40–7.34 (m, 3H), 7.33
(d, J¼7.1 Hz, 1H), 7.24 (d, J¼7.5 Hz, 1H), 4.45 (s, 2H), 3.70 (s, 2H);
13C NMR (125 MHz, CDCl3)
d (ppm) 135.8, 133.6, 133.2, 130.1, 129.9,
129.4, 129.0, 128.7, 128.6, 128.5, 128.3, 127.9, 127.0, 55.0, 52.7;
HRMS calcd for C20H17NNaO2S (MþNa)þ 358.0878, found
358.0868.
4.2.28. (S)-2-Bromo-N-(but-3-enyl)-N-(1-hydroxy-3-phenyl-
propan-2-yl)benzenesulfonamide (16)
A flame-dried flask was charged with the homo allylated sul-
fonamide (0.917 g, 2.027 mmol) and Et2O (4 mL) and cooled to
0 ꢀC. LiAlH4 (81 mg, 2.128 mmol) was added portionwise to the
reaction mixture over 10 min after which the reaction was allowed
to warm to rt and stirred for 1 h. The reaction was quenched using
the Fieser workup procedure. The organic layer was extracted with
Et2O (5 mLꢂ2), dried (Na2SO4), concentrated under reduced
pressure, and purified by flash chromatography (1:1 hexane/
EtOAc) to afford the alcohol in 95% yield. FTIR (neat): 3527, 3028,
1H NMR (500 MHz, CDCl3)
d
(ppm) 8.15 (dd, J¼7.8, 1.8 Hz, 1H), 7.78
(dd, J¼7.8, 1.3 Hz, 1H), 7.47 (td, J¼7.6, 1.3 Hz, 1H), 7.41 (td, J¼7.6,
1.8 Hz, 1H), 7.24 (d, J¼7.8 Hz, 1H), 6.89 (d, J¼7.5 Hz, 1H), 6.86 (d,
J¼2.2 Hz, 1H), 6.83 (dd, J¼8.1, 2.2 Hz, 1H), 4.40 (s, 2H), 3.79 (s, 3H),
2.76 (s, 3H); 13C NMR (500 MHz, CDCl3)
d 159.8, 135.6, 133.6, 132.4,
129.6, 127.5, 120.5, 113.6, 113.2, 55.20, 54.04, 33.94; HRMS calcd for
C15H16BrNNaO3S (MþNa)þ 391.9932, found 398.9906.
4.2.23. N-Benzyl-2-bromo-N-methylbenzenesulfonamide (14a)
Using a similar procedure as that used to produce sultam 14b,
sultam14a wasproducedasayellowoilin71%yield.FTIR (neat):3062,
1446, 1326, 1124, 919, 750 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
(ppm) 7.83–7.79 (m, 2H), 7.58–7.54 (m, 1H), 7.50–7.45 (m, 1H),
7.24–7.16 (m, 2H), 7.02–6.98 (m, 1H), 5.78 (ddt, J¼17.1, 10.2, 6.9 Hz,
1H), 5.12 (dd, J¼3.1, 1.5 Hz, 1H), 5.09 (td, J¼3.3, 1.9 Hz, 1H), 5.07 (s,
1H), 4.03–3.97 (m, 1H), 3.60 (t, J¼6.1 Hz, 1H), 3.41 (dt, J¼8.3,
7.3 Hz, 1H), 3.31–3.23 (m, 1H), 2.70 (dd, J¼13.5, 9.5 Hz, 1H), 2.61
(dd, J¼13.5, 5.3 Hz, 1H), 2.47 (dt, J¼14.5, 7.2 Hz, 1H), 1.97 (t, J¼5.9,
2912, 1795, 1446, 1434, 1332, 1163 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
(ppm) 8.15 (dd, J¼7.8,1.8 Hz,1H), 7.78 (dd, J¼7.8,1.3 Hz,1H), 7.47 (td,
J¼7.6, 1.4 Hz, 1H), 7.41 (td, J¼7.6, 1.8 Hz, 1H), 7.36–7.34 (m, 1H), 7.33–
7.32 (m, 2H), 7.31 (d, J¼1.0 Hz,1H), 7.30–7.27 (m,1H), 4.44 (s, 2H), 2.75
(s, 3H); 13C NMR (126 MHz, CDCl3)
d
(ppm) 138.4, 135.8, 135.7, 133.6,
1H); 13C NMR (126 MHz, CDCl3)
d 140.5, 137.4, 134.9, 132.6, 129.1,
132.4,128.7,128.2,127.8,127.6,120.3, 77.2, 77.0, 76.7, 54.1, 33.9; HRMS
128.9, 128.6, 127.2, 126.7, 117.4, 77.3, 77.2, 77.0, 76.8, 62.2, 62.1,
44.3, 36.3, 35.4; HRMS calcd for C19H22NBrNaO3S (MþNa)þ
446.0401, found 446.0402.
calcd for C14H14BrNNaO2S (MþNa)þ 361.9827, found 361.9843.
4.2.24. N,N-Dibenzyl-2-bromobenzenesulfonamide (14c)
Using a similar procedure as that used to produce sultam 14b,
sultam 14a was produced as a white solid in 96% yield. Mp: 110 ꢀC;
4.2.29. Procedure for intramolecular O-arylation reaction 17
To sulfonamide 16 (0.301 g, 0.70 mmol) were added CuI
(0.117 mmol, 22 mg), ethylene glycol (0.26 mL, 4.702 mmol),
Cs2CO3 (1.53 g, 4.70 mmol), and DMF (3 mL) under Ar. The crude
mixture was heated at 120 ꢀC for 12–24 h, till the SM is consumed,
as indicated on TLC. After 24 h the reaction mixture was cooled to
rt, filtered through a small Celite pad, thoroughly washed with
CH2Cl2, concentrated under reduced pressure, and purified using
FTIR (neat): 1332, 1159, 698 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
(ppm)8.48–8.09(m,1H), 8.09–7.65(m,1H), 7.58–7.16(m, 8H), 7.16–
6.91 (m, 4H), 4.42 (s, 4H); 13C NMR (126 MHz, CDCl3)
d
(ppm) 139.7,
135.6,135.4,133.6,132.5,128.6,128.6,127.8,127.6,120.8, 50.2; HRMS
calcd for C20H18BrNNaO2S (MþNa)þ 452.0170, found 452.0238.
4.2.25. Dibenzo[d,f][1,2]thiazepine, 6,7-dihydro-6-methyl-, 5,5-
dioxide (15a)
flash chromatography (4:1 hexane/EtOAc) to provide 17 in 49%
25
yield as a yellow oil. [
a]
ꢁ56.7 (c 2.39, CHCl3); FTIR (neat): 3064,
Using a similar procedure as that used to produce sultam 13a,
sultam 15a was produced in 85% yield as a yellow oil. FTIR (neat):
1593, 1440, 1218, 1153, 1008, 918 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
(ppm) 7.83 (dd, J¼7.9, 1.6 Hz, 1H), 7.36 (dddd, J¼19.4, 17.4, 12.1,
1635,1336,1166,1095, 977 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
(ppm)
4.5 Hz, 6H), 7.17–7.11 (m, 1H), 7.03–6.97 (m, 1H), 5.56 (dddd,
J¼16.3, 13.6, 9.5, 6.8 Hz, 1H), 4.94 (s, 1H), 4.91 (dd, J¼3.7, 2.1 Hz,
1H), 4.78 (t, J¼12.0 Hz, 1H), 4.34 (dd, J¼13.2, 4.6 Hz, 1H), 3.86 (s,
1H), 3.21 (dd, J¼13.7, 7.9 Hz, 1H), 3.06 (t, J¼7.7 Hz, 2H), 2.91 (dd,
J¼13.6, 7.3 Hz, 1H), 2.14–2.03 (m, 1H), 1.96 (dt, J¼14.1, 7.2 Hz, 1H);
8.01 (dd, J¼7.8,1.0 Hz,1H), 7.73 (td, J¼7.6,1.3 Hz,1H), 7.62 (dd, J¼7.7,
1.0 Hz,1H), 7.57 (td, J¼7.7,1.3 Hz,1H), 7.54–7.42 (m, 4H), 3.78 (s, 2H),
2.89 (s, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm) 140.9, 139.4, 134.8,
133.5, 133.3, 130.2, 129.9, 129.5, 129.0, 128.5, 128.3, 127.5, 56.1, 39.0;
HRMS calcd for C14H13NNaO2S (MþNa)þ 282.0565, found 282.0553.
13C NMR (100 MHz, CDCl3)
d (ppm) 155.5, 137.6, 134.4, 133.4, 132.1,
129.5, 129.4, 128.8, 128.7, 126.8, 123.2, 121.3, 117.0, 73.8, 64.6, 51.4,
37.3, 32.9; FTIR (neat): 3064, 1593, 1440, 1218, 1153, 1008,
918 cmꢁ1; HRMS calcd for C19H21NNaO3S (MþNa)þ 366.1140,
found 366.1136.
4.2.26. Sultam (15b)
Using a similar procedure as that used to produce sultam 13a,
sultam 15b was produced in 56% yield as a yellow oil. FTIR (neat):
3335,1636,1340,1120, 967 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d (ppm)
8.00 (dd, J¼1.1, 7.8 Hz,1H), 7.71 (td, J¼7.6,1.3 Hz,1H), 7.60 (dd, J¼7.7,
1.0 Hz, 1H), 7.56 (td, J¼7.7, 1.3 Hz, 1H), 7.34 (d, J¼8.3 Hz, 1H), 6.99 (d,
J¼2.6 Hz, 1H), 6.93 (dd, J¼2.7, 8.3 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 2H),
4.2.30. N,4-Dimethyl-2-((trimethylsilyl)ethynyl)-
benzenesulfonamide (20)
To a stirring solution of tosyl chloride (1.0 g, 5.24 mmol) in
CH2Cl2 (10 mL) at 0 ꢀC were added Et3N (2.2 mL) and methylamine
2.85 (s, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm) 160.2, 142.1, 139.3,

D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
3187
(0.23 mL, 5.24 mmol). After stirring for 2 h, the reaction was
quenched with H2O (10 mL), the organic layer removed, and the
aqueous layer extracted with CH2Cl2 (2ꢂ10 mL). The combined
organic layers were washed with satd brine (10 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure to
give the desired sulfonamide as a pale yellow solid. A portion of
this crude (0.8 g, 4.31 mmol) in Et2O (43 mL) was cooled to ꢁ78 ꢀC
and stirred for 15 min. After such time n-BuLi (1.0 M, 4.31 mmol)
was added dropwise to the crude mixture and the reaction was
stirred for an additional 15 min. Elemental I2 (0.65 g, 5.17 mmol)
was added to the reaction mixture and after 15 min was warmed
to rt and stirred for 2 h. The reaction was quenched with aqueous
satd NH4Cl (10 mL), extracted with EtOAc (2ꢂ20 mL), and the
combined organic layers were washed with aqueous satd Na2SO3
(10 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure to afford sulfonamide 19 as pale yellow solid. To a portion
of crude material (500 mg, 1.6 mmol) in DMF (8.2 mL) were added
PdCl2(PPh3)2 (33.8 mg, 0.048 mmol), PPh3 (51 mg, 0.192 mmol),
CuI (8.8 mg, 0.08 mmol), and Et3N (0.67 mL, 4.818 mmol). After
the addition of TMS acetylene (0.68 mL, 4.818 mmol), the reaction
was heated to 80 ꢀC and stirred for 14 h after which time the crude
mixture was cooled to rt and concentrated under reduced pres-
sure. The crude material was purified using flash chromatography
(1:1 hexane/EtOAc) to provide 20 in 46% yield over 3 steps as
a yellow oil. FTIR (neat): 2359, 1731, 1330, 1315, 1174, 1141,
0.13 mmol), Pd2(dba)3$CHCl3 (2 mol %, 2.8 mg, 0.0027 mmol), and
dry DMF (0.98 mL). After stirring for 5 min at rt, methyl propiolate
(33 mL, 0.40 mmol) was added and the reaction vial was placed
immediately into a preheated reaction block. The reaction was
stirred at 110 ꢀC for 14 h after which time the reaction was cooled
and concentrated under reduced pressure. The crude product was
purified using flash chromatography (8:1 hexane/EtOAc) to yield 25
as a yellow oil (31.6 mg, 76%, 0.096 mmol). FTIR (neat): 2362, 1730,
1291, 1172 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d (ppm) 9.26 (dd,
J¼17.2, 1.3 Hz, 1H), 7.92–7.83 (m, 1H), 7.73–7.63 (m, 2H), 7.38–7.21
(m, 3H), 5.25 (s, 1H), 4.79 (s, 2H), 3.62 (s, 3H); 13C NMR (126 MHz,
CDCl3)
d (ppm) 166.1, 143.1, 133.9, 133.7, 132.8, 132.1, 129.6, 129.0,
128.1, 127.3, 126.9, 121.1, 96.1, 53.6, 44.4; HRMS calcd for
C17H15NO4SNa (MþNa)þ 352.0619, found 352.0593 (TOF MS EIþ).
4.2.34. Sultam (26)
Into a flame-dried round bottom flask were added benzothia-
zepenone 10e (0.1 g, 0.33 mmol), benzaldehyde (0.5 mL,
0.49 mmol), and EtOH (2 mL). To this mixture was added KOH
(0.48 mmol) and the reaction mixture was heated at 50 ꢀC for 4 h.
After such time, the crude mixture was filtered and recrystallized
from EtOH to produce 26 (80% yield) as a white solid. Mp: 171 ꢀC;
FTIR (neat): 3060, 1676, 1607, 1172, 958 cmꢁ1
CDCl3) (ppm) 7.94 (s, 1H), 7.91 (m, 2H), 7.73–7.65 (m, 2H), 7.36–
7.24 (m, 7H), 7.19 (m, 2H), 7.09 (t, J¼7.5 Hz, 1H), 4.24 (s, 2H), 3.52 (s,
2H); 13C NMR (125 MHz, CDCl3)
(ppm) 192.1, 143.3, 136.9, 134.8,
;
1H NMR (500 MHz,
d
846 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
(ppm) 7.72 (d, J¼8.1 Hz,
d
1H), 7.27 (dd, J¼1.1, 0.5 Hz, 1H), 7.09–7.05 (m, 1H), 2.40 (d,
134.6, 134.0, 133.4, 132.7, 130.8, 130.7, 129.9, 129.7, 129.5, 128.8,
128.6, 128.4, 126.3, 55.9, 47.8; HRMS calcd for C23H19NNaO3S
(MþNa)þ 412.0984, found 412.0983.
J¼5.5 Hz, 3H), 2.21 (s, 3H), 0.11 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
(ppm) 142.9, 137.2, 135.0, 129.6, 129.6, 120.0, 103.1, 101.5, 29.4,
21.1; HRMS calcd for C13H19NNaO2SSi (MþNa)þ 304.0803, found
304.0806.
4.2.35. Sultam (27)
To a flame dried round bottom flask were added benzothiaze-
penone (0.1 g, 0.33 mmol) and benzaldehyde (0.5 mL, 0.49 mmol)
dissolved in EtOH (2 mL). The reaction mixture was treated with
KOH (0.48 mmol) and heated at 50 ꢀC for 4 h. The crude product
was filtered and recrystallized from EtOH producing the desired
aldol product in 80% yield. To a flame-dried screw cap vial, aldol
product (0.1 mmol) and ethyl vinyl ether (0.30 mmol) were heated
at 70 ꢀC in neat condition for overnight. The TLC analysis indicated
that the reaction was complete and the crude product was purified
by column chromatography (2:1 hexanes/EtOAc) to afford desired
hetero-Diels–Alder product in 62% yield as a yellow oil. FTIR (neat):
4.2.31. Sultam (22)
To a flame-dried round bottom flask charged with 20 (0.5 g,
0.177 mmol) were added CH3CN (2.0 mL) and K2CO3 (0.7 g,
0.523 mmol) and the reaction mixture was stirred at 60 ꢀC for 2 h.
After such time, the crude reaction mixture was filtered through
a silica pad, concentrated under pressure, and purified by flash
chromatography (4:1 hexane/EtOAc) to provide 22 in 67% yield as
a yellow oil. FTIR: (neat) 2358, 2341, 1298, 1140, 790 cmꢁ1
NMR (500 MHz, CDCl3)
;
1H
d
(ppm) 7.62 (d, J¼8.0 Hz, 1H), 7.55–7.39
(m, 1H), 7.31 (dd, J¼8.0, 0.7 Hz, 1H), 4.89 (d, J¼2.8 Hz, 1H), 4.35 (d,
J¼2.8 Hz, 1H), 3.05 (s, 3H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3)
2974, 1336, 1296, 1168, 1081 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
(ppm) 144.0, 138.9, 131.3, 130.6, 129.4, 121.5, 120.7, 84.2, 25.8,
d
(ppm) 7.95 (dd, J¼7.8. 1.1 Hz, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.56 (td,
21.8; HRMS calcd for C10H11NNaO2S (MþNa)þ 232.0408, found
J¼7.7,1.3 Hz,1H), 7.44 (td, J¼7.7,1.2 Hz,1H), 7.35–7.29 (m, 2H), 7.29–
7.17 (m, 3H), 7.06–7.01 (m, 3H), 6.77 (d, J¼7.1 Hz, 2H), 5.20 (t,
J¼3.0 Hz, 1H), 4.13 (d, J¼14.6 Hz, 1H), 3.95 (dq, J¼9.5, 7.1 Hz, 1H),
3.82 (d, J¼14.6 Hz, 1H), 3.66 (dq, J¼9.5, 7.1 Hz, 1H), 3.51 (t, J¼8.2 Hz,
1H), 3.08 (d, J¼13.8 Hz, 1H), 2.93 (d, J¼13.7 Hz, 1H), 2.20–2.04 (m,
232.0392.
4.2.32. Sultam (23)
To a flame-dried round bottom flask charged with 21 (45 mg,
0.14 mmol) and toluene (5 mL) was added Co2(CO)8 (52 mg,
0.15 mmol). The reaction mixture was heated at 90 ꢀC for 2 h,
concentrated, and the crude product was purified by column
chromatography (1:1 hexanes/EtOAc) furnishing the tricyclic
product in 67% yield as a yellow oil. FTIR (neat): 2948, 1780, 1323,
2H), 1.21 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm) 147.3,
142.3, 136.9, 135.7, 134.4, 132.4, 129.3, 128.8, 128.6, 128.6, 128.4,
127.8, 127.3, 127.0, 126.9, 111.3, 97.0, 64.3, 54.0, 48.9, 39.4, 36.0, 15.3;
HRMS calcd for C27H27NNaO4S (MþNa)þ 484.1558, found 484.1534.
1147, 1122, 946, 906 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
(ppm) 8.03
4.2.36. Sultam (28)
(s, 1H), 7.81 (d, J¼8.2 Hz, 1H), 7.30–7.23 (m, 1H), 7.20 (s, 1H), 4.57
(d, J¼14.4 Hz, 1H), 3.46–3.33 (m, 1H), 3.29 (dd, J¼14.4, 1.3 Hz, 1H),
2.83 (s, 3H), 2.77–2.62 (m, 1H), 2.44 (s, 3H), 2.33 (dd, J¼17.6, 1.9 Hz,
To a solution of aldol 26 (0.1 g, 0.25 mmol) in EtOH (3 mL) were
added phenyl hydrazine (0.1 mL, 1.0 mmol) and a drop of sulfuric
acid. The reaction mixture was stirred at rt overnight. The product
was obtained after concentration of the solution, filtration, and
recrystallization from hexanes to afford 28 in 74% yield as a yellow
1H); 13C NMR (125 MHz, CDCl3)
d (ppm) 206.0, 164.4, 143.7, 143.1,
142.0, 130.4, 130.0, 129.9, 129.2, 60.4, 43.6, 40.3, 39.0, 21.4; HRMS
calcd for C14H15NNaO3S (MþNa)þ 300.0670, found 300.0677.
oil. FTIR (neat): 1593, 1493, 1336, 1163, 1139, 746 cmꢁ1
(500 MHz, CDCl3)
;
1H NMR
d
(ppm) 8.08–7.91 (m, 2H), 7.54 (td, J¼7.6, 1.3 Hz,
4.2.33. (Z)-Methyl 2-(2-benzyl-3-benzisothiazoline-1-ylidene)-
acetate (25)
1H), 7.43 (td, J¼7.6, 1.3 Hz, 1H), 7.32–7.17 (m, 6H), 7.16–7.00 (m, 6H),
6.95 (d, J¼7.8 Hz, 2H), 6.77 (t, J¼7.3 Hz, 1H), 4.69 (d, J¼7.0 Hz, 1H),
4.37 (d, J¼13.6 Hz, 1H), 3.97–3.74 (m, 2H), 3.61 (s, 1H), 3.36 (d,
Into a 1 dram vial were added N-benzyl-2-idobenzenesulfona-
mide (50 mg, 0.13 mmol), Et3N (37
mL, 0.26 mmol), Bu4NCl (50 mg,
J¼8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d (ppm) 145.8, 143.7,

3188
D.K. Rayabarapu et al. / Tetrahedron 65 (2009) 3180–3188
4. Levy, L. Drugs Future 1992, 17, 451–454.
140.6, 138.3, 135.0, 132.6, 130.8, 130.5, 129.5, 129.0, 128.8, 128.8,
128.5, 128.3, 128.2, 125.3, 120.4, 113.7, 76.8, 69.6, 54.4, 48.7; HRMS
calcd for C29H25N3NaO2S (MþNa)þ 502.1565, found 502.1560.
5. (a) Rabasseda, X.; Hopkins, S. J. Drugs Today 1994, 30, 557–563; (b) Inagaki, M.;
Tsuri, T.; Jyoyama, H.; Ono, T.; Yamada, K.; Kobayashi, M.; Hori, Y.; Arimura, A.;
Yasui, K.; Ohno, K.; Kakudo, S.; Koizumi, K.; Suzuki, R.; Kawai, S.; Kato, M.;
Matsumoto, S. J. Med. Chem. 2000, 43, 2040–2048.
6. Brzozowski, F.; Saczewski, F.; Neamati, N. Bioorg. Med. Chem. Lett. 2006, 16,
5298–5302.
7. Misu, Y.; Togo, H. Org. Biomol. Chem. 2003, 1, 1342–1346.
8. Wells, G. J.; Tao, M.; Josef, K. A.; Bihovsky, R. J. Med. Chem. 2001, 44, 3488–
3503.
9. Cherney, R. J.; Mo, R.; Meyer, D. T.; Hardman, K. D.; Liu, R.-Q.; Covington, M. B.;
Qian, M.; Wasserman, Z. R.; Christ, D. D.; Trzaskos, J. M.; Newton, R. C.; Decicco,
C. P. J. Med. Chem. 2004, 47, 2981–2983.
10. Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Marongiu, M. E.; Loi, A. G.; De
Montis, A.; La Colla, P. Antiviral Chem. Chemother. 1998, 9, 127–137.
11. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003,
10, 925–953.
12. Zia-ur-Rehman, M.; Choudary, J. A.; Ahmad, S.; Siddiqui, H. L. Chem. Pharm. Bull.
2006, 54, 1175–1178.
13. Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gut, J.; Rosenthal, P. J. Bioorg. Med.
Chem. Lett. 2006, 16, 4115–4119.
14. Silvestri, R.; Marfe, G.; Artico, M.; La Regina, G.; Lavecchia, A.; Novellino, E.;
Morgante, M.; Di Stefano, C.; Catalano, G.; Filomeni, G.; Abruzzese, E.; Ciriolo,
M. R.; Russo, M. A.; Amadori, S.; Cirilli, R.; La Torre, F.; Sinibaldi Salimei, P.
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4.2.37. Sultam (29)
To a solution of aldol product 26 (50 mg, 0.128 mmol) in EtOH
(3 mL) were added malononitrile (9.3 mg, 0.14 mmol) and a drop of
piperidine. The reaction mixture was stirred at rt for overnight,
after which time the crude reaction mixture was concentrated and
the crude product was purified by column chromatography (4:1
hexanes/EtOAc) furnishing the desired product 29 in 68% yield as
a clear oil. FTIR (neat): 2974, 1650, 1512, 1336, 1168, 1081, 767 cmꢁ1
1H NMR (500 MHz, CDCl3)
;
d
(ppm) 8.10 (dd, J¼7.8, 1.3 Hz, 1H), 8.02
(dd, J¼8.1, 1.0 Hz, 1H), 7.68 (td, J¼1.4, 7.8 Hz, 1H), 7.54 (td, J¼7.7,
1.1 Hz, 1H), 7.36–7.27 (m, 3H), 7.22–7.12 (m, 5H), 6.92–6.84 (m, 2H),
4.65 (s, 2H), 4.02 (d, J¼14.1 Hz, 1H), 3.86 (s, 1H), 3.80 (d, J¼17.8 Hz,
1H), 3.53 (d, J¼14.1 Hz, 1H), 3.45 (d, J¼17.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d (ppm) 158.7, 141.9, 140.3, 137.4, 134.5, 132.9,
129.2, 129.1, 128.8, 128.7, 128.6, 128.4, 128.4, 128.1, 128.0, 127.9,
127.7, 118.9, 116.40, 76.8, 60.4, 52.4, 48.2, 42.8; HRMS calcd for
C26H21N3NaO3S (MþNa)þ 478.1201, found 478.1211.
Acknowledgements
´
16. (a) Zhou, A.; Hanson, P. Org. Lett. 2008, 10, 2951–2954; (b) Jiminez-Hopkins, M.;
Hanson, P. R. Org. Lett. 2008, 10, 2223–2226.
This work was generously supported by funds provided by the
NIH Center for Chemical Methodologies and Library Development
at the University of Kansas (KU-CMLD) (P50 GM069663), Pilot Scale
Libraries Program (P41 GM076302), NIH COBRE award P20
RR015563, and the Umaer Basha Research fellowship for student
support (H.S.). The authors thank Dr. David Vander Velde and Sarah
Neuenswander for assistance with NMR measurements, Dr. Todd
Williams for HRMS analysis.
17. For the use of
a-halo arylsulfonamides in synthesis of sultams, for Heck re-
actions, see: (a) Grigg, R.; York, M. Tetrahedron Lett. 2000, 41, 7255–7258; (b)
Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 44–46; (c) Va-
sudevan, A.; Tseng, P.-S.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8591–8593; (d)
Paquette, L. A.; Dura, R.; Fosnaugh, N.; Stephanian, M. J. Org. Chem. 2006, 71,
8438–8445; For radical cyclization: (e) Bressy, C.; Menant, C.; Piva, O. Synlett
2005, 577–582; For alkyne 6-endo cyclizations: (f) Barange, D. K.; Nishad, T. C.;
Swamy, K.; Bandameedi, V.; Kumar, D.; Bukkapattanam, R. S.; Vyas, K.; Pal, M.
J. Org. Chem. 2007, 72, 8547–8550.
18. Sultam 5 could not be separated from by-products and isolated for character-
ization. The crude reaction mixture was taken through crude and subjected to
ozonolysis to afford sultam 11.
Supplementary data
19. The Mitsunobu reaction of unsubstituted benzene sulfonamides did not occur
under standard conditions. Plausibly, the presence of the electron-withdrawing
a
-bromide group reduces the pKa of the sulfonamide sufficiently to enable
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.053.
Mitsunobu alkylation.
20. (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731–1769; (b) Ka-
kiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077–1101.
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T. E.; Beller, M. Chem. Rev. 1998, 98, 675–703.
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