Syntheses of five- and seven-membered ring sultam derivatives by Michael addition and Baylis-Hillman reactions

Article abstract of DOI:10.1016/j.tet.2012.12.083

Five- and seven-membered sultam derivatives were conveniently synthesized via intra- or intermolecular Michael additions and an improved vinyl sulfonamide Baylis-Hillman reaction. Two different cyclization pathways were explored for the oxa-Michael reaction. A good solvent was discovered for an otherwise sluggish ketone-type Baylis-Hillman reaction in which vinyl sulfonamide ketones were used as the precursors. Furthermore, a strong base caused vinyl sulfonamide ketones to undergo 5-endo-trig intramolecular cyclizations, which are disfavored according to Baldwin's rule. Finally Baylis-Hillman reaction products were used as scaffolds for diversity-oriented sultam syntheses.

Full text of DOI:10.1016/j.tet.2012.12.083

Tetrahedron 69 (2013) 2369e2375
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses of five- and seven-membered ring sultam derivatives
by Michael addition and BayliseHillman reactions
Kun Tong a, Jinchang Tu a, Xueyong Qi a, Min Wang a, Yanjie Wang a, Haizhen Fu a,
,
Charles U. Pittman, Jr. b, Aihua Zhou a
*
a Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu 212013, China
b Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 October 2012
Received in revised form 5 December 2012
Accepted 14 December 2012
Available online 9 January 2013
Five- and seven-membered sultam derivatives were conveniently synthesized via intra- or intermolecular
Michael additions and an improved vinyl sulfonamide BayliseHillman reaction. Two different cyclization
pathways were explored for the oxa-Michael reaction. A good solvent was discovered for an otherwise
sluggish ketone-type BayliseHillman reaction in which vinyl sulfonamide ketones were used as the
precursors. Furthermore, a strong base caused vinyl sulfonamide ketones to undergo 5-endo-trig intra-
molecular cyclizations, which are disfavored according to Baldwin’s rule. Finally BayliseHillman reaction
products were used as scaffolds for diversity-oriented sultam syntheses.
Keywords:
Sultam
Cyclic sulfonamide
Oxa-Michael addition
BayliseHillman
Vinyl sulfonamide
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
BayliseHillman reaction is an important carbonecarbon bond-
forming method,15 but it is very sluggish when a ketone function
Cyclic sulfonamides (sultams) and their analogs are known to
possess broad-spectrum bioactivity.1 This potency, when coupled
with their unique chemical properties, elevates sultams to
a promising class of compounds for drug discovery. Our efforts here
are focused on the syntheses of different cyclic sulfonamides. In
Fig. 1, several tertiary sulfonamide and sultam derivatives are
shown, which display biological activity. These effects include
serving as an HIV integrase inhibitor,2 a carbonic anhydrase
inhibitor,3 a COX-2 inhibitor,1a an MMP inhibitor,4 an HIV-1 pro-
tease inhibitor,5 and an inhibitor of both falcipain-2 and plasmo-
dium falciparum W-2.6
is used verses employing an aldehyde. This greatly limits the
CH3
N
O
O
N
N
S
O
S
S
N
R1
O
N
R2
N
H2N
OMe
HN
S
R3
NH2
O
O
H4 Receptor Inver se Agonist
Carbonic anhydrase inhibitor
O
O
H
N
S O
Me3C
S
HO
N
Synthetic methods employed for the generation of sultam
derivatives include the PicteteSpengler reaction,7 FriedeleCraft
reaction,8 ring-closing metathesis,9 cyclizations of aminosulfonyl
chlorides,10 [3þ2] cycloadditions,11a the DielseAlder reaction12 and
Heck reactions.13a In a previous communication,14 sultam syntheses
via intramolecular oxa-Michael and BayliseHillman reactions were
reported, in which primary alcohol and aldehyde functional groups
were used to react with the electron-deficient double bond of
vinyl sulfonamides. In this paper, we extend this research to the
use of secondary alcohol and ketone functional groups. The
O
N
Et
O
HO
CMe3
N
S-2474
MMP-2 inhibitor
COX -2 Inhibitor
R1
Ph
O
O
O
O
O
H
S
R2
N
S
Bz
N
N
H
N
N
N
N
O
H
HO
O
O
O
Ph
O
Inhibitors of F alcipain-2 and
Plasmodium F alcipar um W -2
HIV -1 Protease Inhibitor
* Corresponding author. E-mail address: ahz@ujs.edu.cn (A. Zhou).
Fig. 1. Representative biologically active sulfonamides.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.083

2370
K. Tong et al. / Tetrahedron 69 (2013) 2369e2375
Table 1
reaction application scope. This phenomenon was already men-
tioned in our previous paper, where the intramolecular Bay-
liseHillman reaction using a ketone function took three days to
only achieve a moderate 53% yield. In this paper, ketone-type
BayliseHillman reactions were reinvestigated. After a trial of
different solvents, an improved solvent was discovered where all
these ketone-type BayliseHillman reactions were completed
within several hours.
Synthesis of seven-membered ring sultams via the intramolecular oxa-Michael
addition reaction
O
O
O
O
O
O
Method A:
R
S
S
S
R
R
N
1) RNH2, CH3OH
Cl
Cl
TBAF, THF
N
O
1
HN
TBSO
2) TBSCl, Et3N,
DCM
TBSO
Et3N, DCM
O
41~50% over
3 steps
4a-h
2a-h
3a-h
HCl aq.
O
O
2. Results and discussion
O
O
Method B:
R
S
S
R
N
NaH, THF
N
Opening monosubstituted epoxide rings with amines conve-
niently generates secondary amino alcohols. Reacting these pro-
tected amino alcohols with 2-chloroethylsulfonyl chloride affords
vinyl sulfonamides. Vinyl sulfonamides are good Michael acceptors.
Therefore, intramolecular oxa-Michael reactions were designed to
generate seven-membered ring sultams (Table 1). The synthesis
started with the ring-opening of propylene oxide 1 with different
amines. The resultant secondary amino alcohols were then reacted
with TBSCl to form the TBS-protected amino alcohols 2aeh, TBS-
protection of resultant amino alcohols is an important step. It
prevented side reactions from occurring, greatly increasing product
yields. Then these cheap and versatile TBS-protected building
blocks were reacted with 2-chloroethanesulfonyl chloride to afford
vinyl sulfonamides 3aeh in good yields (Table 1). Intramolecular
oxa-Michael reactions were initiated by TBS-deprotection using
TBAF in THF to form alkoxide intermediates (Method A). These
alkoxides subsequently underwent oxa-Michael addition reactions
to produce the unique seven-membered ring sultams 4aeh in good
yields in short reaction times (2 h). This route provides remarkably
easy access to seven-member ring sultams under mild reaction
conditions in the absence of toxic metal compounds or catalysts.
An alternative method to perform this intramolecular oxa-
Michael reaction involves removal of the TBS protecting group
first by HCl to afford vinyl sulfonamide alcohols 5aeh (Table 1,
method B) in good yields, then NaH was used as a base to initiate
the oxa-Michael additions, which also led to seven-membered ring
sultams 4aeh in good yields (Table 1). From these experimental
results, it can be found that one-step method A gave similar yields
of final products as two-step method B did (Table 1). A key reason to
pursue method B was that it provides vinyl sulfonamide alcohols
5aeh, which are necessary precursors for the BayliseHillman
reaction shown in Tables 2 and 3.
TBS removal by HCl, which afforded vinyl sulfonamide alcohols
5aeh, was also the entry point for the route to five-membered ring
sultams via BayliseHillman reactions. Alcohols 5aeh served as
precursors for ketone formation. Jones oxidation of these alcohols
afforded vinyl sulfonamide ketones 6aeh (Tables 2 and 3). Vinyl
sulfonamide ketones 6aeh were then demonstrated to be good
precursors for the BayliseHillman reaction. Aldehydes are typically
used for BayliseHillman reactions instead of ketones, because al-
dehydes are significantly more active than ketones for this reaction.
Ketones usually react very slowly in BayliseHillman reactions. In
our previous paper,14 one example ketone-type BayliseHillman
reaction using a vinyl sulfonamide ketone was investigated, but it
proved to be very sluggish. Three days were needed to achieve
a moderate yield. Herein, we reinvestigated the reaction conditions
to find ways to accelerate this sluggish transformation. Different
solvents for the BayliseHillman reaction were tried. Example
results are summarized in Table 2 for the model conversion of
6a to 7a.
HO
O
4a-h
5a-h
Entry
1
Reactants 3aeh
Reactants 5aeh
Product
Yielda
O
O
O O
O
O
S
S
S
A: 81%
B: 78%
N
N
N
TBSO
HO
O
4a
5a
O
3a
O
O
N
O
O
O
S
S
S
N
2
3
4
A: 83%
B: 82%
N
TBSO
HO
O
4b
5b
3b
O
O
O
O
O
O
S
S
S
N
N
A: 80%
B: 75%
N
TBSO
HO
O
4c
3c
5c
O
O
O
O
O
O
S
S
S
N
N
A: 86%
B: 79%
N
TBSO
HO
O
4d
5d
3d
O
O
N
O
O
O
O
S
S
S
N
5
6
7
A: 81%
B: 82%
N
TBSO
HO
O
4e
5e
3e
O
O
O
O
O
O
S
S
S
N
N
N
A: 83%
B: 78%
TBSO
HO
O
5f
4f
3f
O
O
O
O
O
O
S
S
S
N
N
N
A: 88%
B: 82%
HO
TBSO
O
4g
3g
5g
O
O
O
O
O
O
S
S
S
N
N
N
A: 76%
B: 78%
8
TBSO
HO
O
4h
3h
5h
a
A refers to yields of converting 3 into 4 by method A; B refers to yields of
converting 5 into 4 by method B.
solvents. Different solvents were used at room temperature and
dioxane/H2O was found to give the fastest rate (see Table 2) at room
temperature. The reaction rate in dioxane/H2O is much higher than
using CH2Cl2, THF or CH3CN; it just took 6 h to complete this
reaction. At least three days were required when CH2Cl2 was used
as a solvent. According to these experimental results, polar/protic
solvents are favorable for BayliseHillman (BeH) reaction, while
polar/non-protic solvents are not good solvents for BeH reactions.
To obtain the keto BayliseHillman reactant, a 10% HCl aqueous
solution was used to remove the TBS protecting group from vinyl
sulfonamides 3a instead of using TBAF. Subsequent Jones oxidation
of compound 5a gave the vinyl sulfonamide ketone 6a, which was
used for intramolecular BayliseHillman reactions in several

K. Tong et al. / Tetrahedron 69 (2013) 2369e2375
2371
Table 2
Table 3
Synthesis of five-membered ring sultams via the intramolecular BayliseHillman
Synthesis of five-membered ring sultams via intramolecular BayliseHillman and
reaction in different solvents
Michael addition reactions on ketone substrates in dioxane/H2O
O
O
O
O
O
O
O
O
1) aq. HCl
S
DBACO
solvent
S
R
S
:
S
N
A
N
N
N
h
t
2) Jones
oxidation
a
O
P
C
TBSO
B
O
O
H 2
A
D
D
/
HO
e
OH
n
61-73% over
2 steps
7a-h
a
x
o
i
O
O
t
r
O
O
7a
3a
1) aq. HCl
6a
S
R
S
R
N
N
P
a
2) Jones'
Oxidation
61~73% over
2 steps
O
t
h
TBSO
Entry
Solvent
Reaction timea
Yielda
%
N
T
B
:
a
O
S
O
O
F
t
-
B
u
R
H
1
2
3
4
5
6
7
8
9
CH2Cl2
CH3OH
Dioxane
DMF
4 d
6 h
6 h
4 d
4 d
4 d
6 h
4 d
4 d
4 d
30
82
80
10
20
15
82
35
10
20
N
3a-h
6a-h
O
8a-h
CHCl3
CH3CN
Dioxane/H2Ob
THF
DMA
DMSO
Entry
1
Reactant 6
Product 7
Product 8
O
Yielda
%
O
O
O
O
O
S
S
S
N
N
10
N
A: 82%
B: 70
O
a
O
Reaction times and yields in these columns refer to the conversions of 6a into 7a.
Volume ratio of dioxane/H2O is 1:1.
HO
b
7a
O
8a
6a
O
O
O O
O
S
S
S
Proton donation by solvent may increase stability and assist quick
formation of BeH reaction intermediates, leading to easy formation
of BeH reaction products. Since dioxane/H2O gave the fastest rate,
eight examples of the BayliseHillman reaction were then carried
out in this solvent. All reactions were completed in 6 h at room
temperature; experimental results are shown in Table 3, path A.
As compounds 6aeh each has a ketone function with a relatively
N
N
N
2
3
4
A: 74%
B: 68%
O
O
HO
6b
7b
8b
O
O
O O
O
O
S
S
S
N
N
N
A: 79%
B: 71%
O
O
HO
active a-proton, sodium tert-butoxide was used to promote cycli-
6c
7c
O
8c
zation. Unexpectedly, all reactions gave five-membered ring sul-
tams instead of seven-membered ring sultams (Table 3, path B).
Besides NaOt-Bu, other bases, such as NaH, NaOMe, NaOEt, and
NaOH were also used successfully for the above reaction. They also
gave five-membered ring sultams as major products instead of
seven-membered ring sultams. Interestingly, compound 8e was not
formed via path B due to the unfavorable steric influence of the tert-
butyl group on nitrogen. All products were formed via 5-endo-trig
cyclizations, According to Baldwin’s rule, this cyclization is dis-
favored. Our experimental results provide another exception to this
rule (Table 3) along with others that have been reported.16 Al-
though 7-endo-trig cyclization is favored according to Baldwin’s
rule, in our case 7-endo-trig cyclization products were not major
products. Apparently, they are not easily formed due to confor-
mational constraints of the intermediate sulfonamide ketone
enolate, leading to higher energy barriers to form 7-endo-trig cy-
clization products.
Sultams 7aeh have three different reactive functions, which
make them a good scaffold for diversity-oriented synthesis (DOS).
Five-membered ring sultams 7aeh each has an electron-deficient
double bond, which can be used to react with different nucleo-
philes to achieve different sultam derivative structures. Herein,
sultams 7f and 7h were selected for DOS synthesis. In Scheme 1,
an amine (n-BuNH2), an alcohol (EtOH), a malonate ester, a thiol
(4-fluorothiophenol), and cyclohexylamine were used as repre-
sentative reagents to react with sultam 7f, respectively, and six
different sultam derivatives 9e13 were obtained in good yields.
After the BayliseHillman reaction forming 7f was over, n-BuNH2
was directly added to the reaction mixture. The aza-Michael
reaction proceeded smoothly in EtOH/H2O solvent to afford sul-
tam 9 in 86% yield within 8 h. When the BayliseHillman reaction
was carried at reflux temperature instead of room temperature, the
BayliseHillman product 7f further reacted with EtOH solvent to
give compound 10 in 63% yield catalyzed by DABCO. Sultam 7h
reacted easily with malonate under the action of NaH in THF to give
product 11 in 51% yield. 4-Fluorothiophenol was also used as a thiol
O
O O
O
O
S
S
S
N
N
N
A: 80%
B: 64%
O
O
HO
6d
O
7d
O
8d
O
O
O O
S
S
S
N
N
N
5
6
7
A: 77%
B: N/A
O
O
HO
6e
8e
7e
O
O
O
O
O
O
S
S
S
n-Bu
n-Bu
n-Bu
N
N
N
A: 76%
B: 65%
O
O
HO
6f
O
7f
8f
O
O
O
O O
S
S
Bn
S
Bn
Bn
N
N
N
A: 81%
B: 64%
O
O
HO
8g
7g
6g
O
O
O
O
O
O
S
S
S
Bn
N
N
N
Bn
Bn
A: 80%
B: 65
8
O
O
HO
6h
7h
8h
a
A refers to yields of converting 6aeh into 7aeh; B refers to yields of converting
6aeh into 8aeh. Volume ratio of dioxane/H2O is 1:1.
nucleophile. It was directly added into the reactor after the Bay-
liseHillman reaction forming 7f was over. A thiol-Michael addition
reaction proceeded smoothly to give sultam 12 in 92% yield. Sultam
7f also reacted with cyclohexylamine to give amino alcohol 13 in
good yield (Scheme 1).

2372
K. Tong et al. / Tetrahedron 69 (2013) 2369e2375
was dried over Na2SO4, after the removal of solvent, and the crude
product was purified by flash column chromatography (Hexane/
EtOAc¼3:1) to give TBS-protected amino alcohol 2.
O
O
S
n-Bu
N
N
H
F
82%
OH 13
2-Chloroethanesulfonyl chloride (1.1 equiv) was added drop-
wise into the solution of compound 2 in CH2Cl2 at 0 ꢀC. After the
addition was over, stirring was continued at 0 ꢀC for 2 h, and then
the mixture was diluted with CH2Cl2, washed with brine solution,
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(Hexane/EtOAc¼10:1) to give vinyl sulfonamide 3 as a colorless oil.
For different amines, the yields range from 41e50% over three
steps. Compounds 3beh were made by the same procedure.
NH2
EtOH/H2O
O
O
S
S
O O
n-Bu
SH
N
n-Bu
S
n
N
H
-
B
n-Bu
N
u
N
F
H
2
O
O
O
2
E
H
/
H
O
t
O
OH
9
H
/
H
S
t
E
O
R
2
N
OH
86%
92%
12
7f/h
OEt
OH
OEt
O
O
O
N
a
H
,
C
O
B
A
2
H
/
D
x
T
H
H
u
l
O
f
t
e
F
O
O
E
R
O
O
4.3. Procedure for the syntheses of seven-membered ring
sultams via oxa-Michael addition reaction
O
S
n-Bu
S
N
Et
N
O
EtO
EtO
Bn
(R= -CH2Bn)
51%
Scheme 1. Diversity-oriented synthesis of five-membered ring sultam.
OH
O
OH
Method A: To a stirred solution of vinyl sulfonamide 3a (50 mg,
0.14 mmol) in THF was added small amount of TBAF (1.0 M in THF).
Stirring was continued for an additional 2 h at rt. Aqueous NH4Cl
(satd) solution (3 mL) was added and the organic layer was
extracted with CH2Cl2 (2ꢁ3 mL), dried over MgSO4 and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography (Hexane/EtOAc¼9:1) to afford the
seven-membered ring sultam 4a (27 mg, 0.14 mmol) in 81% yield as
a sticky liquid. Compounds 4beh were made in the same way.
Method B: To a stirred solution of vinyl sulfonamide 3a (125 mg,
0.35 mmol) in THF was added small amount of 10 N HCl solution.
Stirring was continued for an additional 2 h at rt (monitored by TLC
analysis). The organic layer was extracted with CH2Cl2 (2ꢁ2 mL),
and then solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography (Hexane/
EtOAc¼3:1) to afford vinyl sulfonamide alcohol 5a (67 mg,
0.28 mmol) in a 78% yield as a sticky liquid. Vinyl sulfonamide al-
cohols 5beh were produced in the same way.
To a stirred solution of the vinyl sulfonamide alcohol 5a (30 mg,
0.12 mmol) in THF was added NaH (7.2 mg, 60% dispersion in mineral
oil, 1.5 equiv). Stirring was continued until TLC showed that the
starting material has disappeared. 1 N HCl was added dropwise to
neutralize the remaining base, and then CH2Cl2 (2ꢁ2 mL) was added
to extract the organic layer. The organic layers were combined, dried
over MgSO4, concentrated under reduced pressure, and purified by
flash chromatography (Hexane/EtOAc¼9:1) to afford the seven-
membered ring sultam 4a (23 mg, 0.09 mmol) in a 78% yield as
a sticky liquid. Compounds 4beh were made by the same route.
63%
10
11
3. Conclusion
In conclusion, we have investigated two different intramolecular
oxa-Michael cyclization pathways and the intramolecular Bay-
liseHillman reaction of vinyl sulfonamide ketones. Five-membered
and seven-membered ring sultam derivatives were produced in
good yields. By trying different solvents, we also found that polar/
protic solvents were more suitableforaccelerating thereaction rate of
the sluggish keto-type BayliseHillman reaction. Under basic condi-
tions, the vinyl sulfonamide ketones underwent 5-endo-trig Michael
addition cyclizations, which are disfavored according to Baldwin’s
rule, while the normally favored 7-endo-trig cyclization products
werenotformed.Finally, BayliseHillmanreactionproductswereused
as scaffolds for the diversity-oriented syntheses of sultam derivatives.
Four intermolecular Michael additions to vinyl sulfonamides with
carbon, nitrogen, oxygen, and sulfur nucleophiles were explored.
4. Experimental section
4.1. General information and materials
All reactions were carried out under nitrogen atmosphere unless
otherwise noted. Commercially available reagents were used
throughout without further purification other than as detailed be-
low. THF was dried by distillation from sodium; other solvents for
reactions were purchased from Aladdin Company and used without
further purification. Flash column chromatography was performed
on silica gel (200e300 mesh). All reactions were monitored by TLC
analysis. Deuterated solvents were purchased from Cambridge Iso-
tope laboratories. 1H and 13C NMR spectra were recorded on a Bruker
DRX-400 spectrometer operating at 400 MHz,100 MHz, respectively.
Mass spectrometry (LC-MS) was recorded on a LXQ Spectrometer
(Thermo Scientific) operating on ESI (MeOH as a solvent).
4.3.1. 5-Cyclohexyl-7-methyl-[1,4,5]-oxathiazepane-4,4-dioxide
(4a). IR (neat): 2934, 1449, 1324, 1138, 1030, 723 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz): d (ppm) 4.05 (m, 2H), 3.74 (m, 2H), 3.24 (m, 2H),
3.10 (d, J¼12.0 Hz, 1H), 2.96 (t, J¼12.0 Hz, 1H), 1.83 (m, 1H), 1.76 (d,
J¼4.0 Hz, 3H), 1.60 (m, 2H), 1.35 (m, 4H), 1.14 (d, J¼4.0 Hz, 3H), 1.02
(m, 1H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 19.5, 25.2, 25.7, 26.0,
31.2, 32.8, 47.6, 57.7, 57.7, 64.1, 77.5; MS (ESI) m/z calculated for
C11H21NO3SNa 270.11 (MþNa)þ, found 270.28.
4.3.2. 5-iso-Propyl-7-methyl-[1,4,5]-oxathiazepane-4,4-dioxide
4.2. General procedure for syntheses of vinyl sulfonamides
(3aeh)
(4b). IR (neat): 2975, 2875, 1465, 1333, 1105, 1026, 748 cmꢂ1 1H
;
NMR (CDCl3, 400 MHz):
d
(ppm) 4.25 (m, 1H), 4.11 (t, J¼12.0 Hz,
2H), 3.77 (m, 1H), 3.26 (s, 2H), 3.11 (d, J¼16.0 Hz, 1H), 2.90 (t,
Propylene oxide (1.0 equiv) was dissolved in CH3OH solvent, and
then the primary amine (3 equiv) was added. The mixture was
stirred at room temperature for 2 days, and then CH3OH was re-
moved under reduced pressure. The residue was re-dissolved in
CH2Cl2, and Et3N (6.0 equiv) and TBSCl (1.2 equiv) were added to
the above solution (a catalytic amount of DMAP was also added).
The solution was stirred at room temperature for 36 h, and then
reaction mixture was washed with brine solution. The organic layer
J¼12.0 Hz, 1H), 1.23 (s, 3H), 1.18 (s, 6H); 13C NMR (CDCl3, 100 MHz):
d
(ppm) 19.7, 20.4, 22.3, 46.6, 49.6, 57.3, 64.4, 77.5; MS (ESI) m/z
calculated for C8H17NO3SNa 230.08 (MþNa)þ, found 230.33.
4.3.3. 7-Methyl-5-propyl-[1,4,5]-oxathiazepane-4,4-dioxide (4c). IR
(neat): 2957, 2934, 1461, 1337, 1142, 1018, 740 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz):
d
(ppm) 4.15 (m,1H), 4.02 (d, J¼16.0 Hz,1H), 3.71

K. Tong et al. / Tetrahedron 69 (2013) 2369e2375
2373
(m, 1H), 3.29 (m, 6H), 1.55 (m, 2H), 1.12 (s, 3H), 0.87 (d, J¼8.0 Hz,
3H); 13C NMR (CDCl3, 100 MHz):
(ppm) 10.9, 19.0, 21.7, 50.4, 50.9,
55.7, 61.9, 75.4; MS (ESI) m/z calculated for C8H17NO3SNa 230.08
(MþNa)þ, found 230.28.
ketone 6a (42 mg, 0.17 mmol) in a 72% yield as a sticky liquid. 6beh
were produced in the same way, their yields range from 61e73%
over two steps.
d
To a stirred solution of sulfonamide 6a (35.0 mg, 0.14 mmol) in
dioxane/H2O (0.8 mL) was added 10 mol % DABCO (0.10 equiv).
Stirring was continued until TLC analysis indicated that the starting
material 6a was consumed (normally 2e4 h). The solvent was
removed under reduced pressure and the crude product was
purified by flash column chromatography to yield a five-membered
ring sultam 7a (28 mg, 0.11 mmol) in an 82% yield as a sticky liquid.
Compounds 7beh were produced in the same way.
4.3.4. 5-iso-Butyl-7-methyl-[1,4,5]-oxathiazepane-4,4-dioxide
(4d). IR (neat): 2967, 2857, 1465, 1333, 1138, 1018, 773 cmꢂ1 1H
;
NMR (CDCl3, 400 MHz):
d (ppm) 4.16 (m, 1H), 4.02 (m, 1H), 3.70
(t, J¼8.0 Hz, 1H), 3.29 (m, 2H), 3.21 (d, J¼4.0 Hz 2H), 3.05 (m, 2H),
1.81 (m, 1H), 1.11 (d, J¼4 Hz, 3H), 0.86 (d, J¼8.0 Hz, 6H); 13C NMR
(CDCl3, 100 MHz):
d (ppm) 19.0, 19.8, 19.81, 27.0, 51.4, 55.4, 56.1,
61.9, 75.2; MS (ESI) m/z calculated for C9H19NO3SNa 244.10
(MþNa)þ, found 244.22.
4.4.1. 2-Cyclohexyl-4-methyl-5-methylene-1,1-dioxo-isothiazolidin-
4-ol (7a). IR (neat): 3444, 2929, 2851, 1449, 1287, 1125, 1080,
574 cmꢂ1 1H NMR (CDCl3, 400 MHz):
; d (ppm) 6.00 (s, 1H), 5.82
4.3.5. 7-Methyl-5-phenyl-[1,4,5]-oxathiazepane-4,4-dioxide (4e). IR
(neat): 2925, 2880, 1333, 1192, 723 cmꢂ1
;
1H NMR (CDCl3,
(s, 1H), 3.78 (s, 1H), 3.45 (m, 1H), 3.16 (s, 2H), 1.88 (m, 2H), 1.77
(m, 2H), 1.61 (m, 1H), 1.49 (s, 3H), 1.36 (m, 4H), 1.05 (m, 1H); 13C
400 MHz):
d
(ppm) 4.03 (m, 2H), 3.81 (m, 1H), 3.46 (m, 2H), 3.31 (m,
(ppm)
2H), 1.48 (s, 9H), 1.12 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
NMR (CDCl3,100 MHz): d (ppm) 25.2, 25.4, 27.1, 31.0, 31.1, 52.6, 54.0,
18.4, 30.6, 49.8, 59.5, 59.8, 60.9, 77.4; MS (ESI) m/z calculated for
C9H19NO3SNa 244.10 (MþNa)þ, found 244.14.
70.4, 116.2, 153.0; MS (ESI) m/z calculated for C11H19NO3SH 268.10
(MþNa)þ, found 268.20.
4.3.6. 5-Butyl-7-methyl-[1,4,5]-oxathiazepane-4,4-dioxide (4f). IR
4.4.2. 2-iso-Propyl-4-methyl-5-methylene-1,1-dioxo-isothiazolidin-
(neat): 2958, 2871, 1333, 1138, 1022, 765 cm-1 1H NMR (CDCl3,
;
4-ol (7b). IR (neat): 3473, 2927, 2880, 1457, 1284, 1122, 566 cmꢂ1
;
1H NMR (CDCl3, 400 MHz):
(s, 1H), 3.89 (m, 1H), 3.15 (s, 2H), 1.52 (s, 3H), 1.21 (d, J¼8.0 Hz, 6H);
13C NMR (CDCl3, 100 MHz):
(ppm) 20.6, 20.6, 27.0, 29.6, 44.7, 53.0,
d
(ppm) 6.03 (s, 1H), 5.85 (s, 1H), 5.85
400 MHz):
d
(ppm) 4.16 (m, 1H), 4.02 (m, 1H), 3.71 (t, J¼8.0 Hz, 1H),
3.21 (m (overlap), 6H), 1.51 (s, 2H), 1.31 (m, 2H), 1.13 (s, 3H), 0.87
(d, J¼8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 13.6, 19.0,
d
19.6, 30.4, 48.5, 50.8, 55.7, 61.9, 75.3; MS (ESI) m/z calculated for
70.3, 116.3, 152.9; MS (ESI) m/z calculated for C8H15NO3SNa 228.07
C9H19NO3SNa 244.10 (MþNa)þ, found 244.22.
(MþNa)þ, found 228.16.
4.3.7. 7-Methyl-5-benzyl-[1,4,5]-oxathiazepane-4,4-dioxide (4g). IR
4.4.3. 4-Methyl-5-methylene-1,1-dioxo-2-propyl-isothiazolidin-4-ol
(neat): 2934, 2875, 1453, 1329, 1142, 1095, 748 cmꢂ1 1H NMR
;
(7c). IR (neat): 3467, 2932, 2876, 1458, 1292, 1122, 1085, 575 cmꢂ1
;
(CDCl3, 400 MHz):
d (ppm) 7.37e7.32 (aromatic H, 5H), 4.59
1H NMR (CDCl3, 400 MHz):
d (ppm) 6.08 (s, 1H), 5.90 (s, 1H), 3.76
(d, J¼16.0 Hz, 1H), 4.43 (d, J¼16.0 Hz, 1H), 4.14 (m, 1H), 3.84 (m, 1H),
(s, 1H), 3.17 (q, J¼8 Hz, 2H), 3.00 (s, 2H), 1.62 (m, 2H), 1.54 (s, 3H),
3.45 (m, 2H), 3.16 (t, J¼16.0 Hz, 1H), 3.04 (d, J¼16.0 Hz, 1H), 1.13
0.93 (t, J¼8 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 11.3, 20.7,
27.1, 45.3, 58.8, 70.3, 117.1, 152.4; MS (ESI) m/z calculated for
(s, 3H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 19.0, 50.0, 52.3, 55.9,
61.6, 75.1, 128.0, 128.2, 128.8, 135.90; MS (ESI) m/z calculated for
C8H15NO3SNa 228.07 (MþNa)þ, found 228.26.
C12H17NO3SNa 278.08 (MþNa)þ, found 278.23.
4.4.4. 2-iso-Butyl-4-methyl-5-methylene-1,1-dioxo-isothiazolidin-4-
4.3.8. 7-Methyl-5-phenethyl-[1,4,5]-oxathiazepane-4,4-dioxide
ol (7d). IR (neat): 3457, 2961, 2872, 1467, 1296, 1086, 572 cmꢂ1; 1H
(4h). IR (neat): 2975, 2875, 1453, 1329, 1142, 1030, 752 cmꢂ1 1H
;
NMR (CDCl3, 400 MHz):
(s, 1H), 3.16 (t, J¼12 Hz, 2H), 2.80 (s, 2H), 1.85 (m, 1H), 1.54 (s, 3H),
0.93 (s, 6H); 13C NMR (CDCl3, 100 MHz):
(ppm) 20.1, 20.2, 26.7,
d (ppm) 6.08 (s, 1H), 5.90 (s, 1H), 3.68
NMR (CDCl3, 400 MHz):
d (ppm) 7.32e7.24 (aromatic H, 5H), 4.18
(d, J¼8.0 Hz, 1H), 4.08 (d, J¼4.0 Hz, 1H), 3.75 (m, 1H), 3.63 (m, 1H),
d
3.57 (m, 1H), 3.45 (s, 2H), 3.24 (s, 2H), 2.93 (t, J¼8.0 Hz, 3H),
27.2, 51.1, 59.5, 70.5, 117.1, 152.5; MS (ESI) m/z calculated for
C9H17NO3SNa 242.08 (MþNa)þ, found 242.31.
1.18(d, J¼4.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 19.1, 36.0,
50.8, 52.0, 55.9, 62.1, 75.5, 126.6, 128.6, 128.9, 138.3; MS (ESI) m/z
calculated for C13H19NO3SNa 292.10 (MþNa)þ, found 292.22.
4.4.5. 2-tert-Butyl-4-methyl-5-methylene-1,1-dioxo-isothiazolidin-
4-ol (7e). IR (neat): 3456, 2983, 2857,1283,1042, 561 cmꢂ1; 1H NMR
4.4. Procedure for vinyl sulfonamides (6aeh)
(CDCl3, 400 MHz):
d
(ppm) 6.09 (s, 1H), 5.85 (s, 1H), 3.30 (s, 2H), 2.63
(ppm)
(s, 1H), 1.58 (s, 3H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz):
d
Here the production of vinyl keto sulfonamide 6a was used as an
example. To a stirred solution of vinyl sulfonamide 3a (125 mg,
0.35 mmol) in THF was added small amount of 10 N HCl solution.
Stirring was continued for an additional 2 h at rt (monitored by TLC
analysis). The organic layer was extracted with CH2Cl2 (2ꢁ2 mL),
and then solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography (Hexane/
EtOAc¼3:1) to afford vinyl sulfonamide alcohol 5a (67 mg,
0.28 mmol) in a 78% yield as a sticky liquid.
A solution of vinyl sulfonamide 5a (60 mg, 0.24 mmol) in ace-
tone (1.5 mL) was cooled to 0 ꢀC, and then Jones reagent was added
slowly. Stirring was continued for an additional about 5 h at rt. The
reaction was monitored by TLC analysis. After completion, K2CO3
was added, and after stirring 5 min at rt the insoluble salts were
filtered through Celite. The solvent was removed under reduced
pressure and the crude product was purified by flash column
chromatography (Hexane/EtOAc¼10:1) to afford vinyl sulfonamide
25.6, 28.1, 55.6, 56.8, 69.4, 76.7, 115.9, 153.9; MS (ESI) m/z calculated
for C9H17NO3SNa 242.08 (MþNa)þ, found 242.22.
4.4.6. 2-Butyl-4-methyl-5-methylene-1,1-dioxo-isothiazolidin-4-ol
(7f). IR (neat): 3473, 2959, 2871,1461,1291,1080, 570 cmꢂ1; 1H NMR
(CDCl3, 400 MHz): d (ppm) 6.09 (s, 1H), 5.90 (s, 1H), 3.68 (s, 1H), 3.38
(s, 1H), 3.17 (m, 2H), 3.05 (s, 2H), 1.58 (m, 2H), 1.54 (s, 3H), 1.37
(m, 2H), 0.93 (t, J¼8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d (ppm)
13.6, 20.0, 27.0, 29.4, 43.3, 58.9, 70.3, 117.0, 152.5; MS (ESI) m/z
calculated for C9H17NO3SNa 242.08 (MþNa)þ, found 242.19.
4.4.7. 2-Benzyl-4-methyl-5-methylene-1,1-dioxo-isothiazolidin-4-ol
(7g). IR (neat): 3471, 2925, 1455, 1295, 1085, 790 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz):
(s, 1H), 4.23 (m, 2H), 3.47 (s, 1H), 3.06 (m, 2H), 1.51 (s, 3H); 13C NMR
(CDCl3, 100 MHz): (ppm) 27.0, 47.2, 58.1, 70.4, 117.5, 128.2, 128.7,
d (ppm) 7.36 (aromatic H, 5H), 6.16 (s, 1H), 5.95
d

2374
K. Tong et al. / Tetrahedron 69 (2013) 2369e2375
128.9, 134.5, 152.3; MS (ESI) m/z calculated for C12H15NO3SNa
276.07 (MþNa)þ, found 276.20.
400 MHz):
d
(ppm) 7.31 (aromatic H, 5H), 4.34 (d, J¼16.0 Hz, 1H),
4.27 (d, J¼16.0 Hz, 1H), 3.74 (m, 1H), 3.25 (m, 1H), 3.02 (m, 1H), 2.54
(m, 1H), 2.24 (m, 1H), 1.95 (s, 3H); 13C NMR (CDCl3, 100 MHz):
4.4.8. 4-Methyl-5-methylene-1,1-dioxo-2-phenethyl-isothiazolidin-
d (ppm) 22.0, 25.2, 45.9, 49.4, 64.5, 76.9, 77.2, 77.5, 128.4, 128.9,
4-ol (7h). IR (neat): 3469, 2926, 2864, 1454, 1293, 1124, 1085,
129.4, 134.7, 206.1; MS (ESI) m/z calculated for C12H15NO3SNa
750 cmꢂ1; 1H NMR (CDCl3, 400 MHz):
d
(ppm) 7.33e7.25 (aromatic
H, 5H), 6.12 (s, 1H), 5.91 (s, 1H), 3.36 (m, 2H), 3.17 (q, J¼8.0 Hz, 2H),
2.97 (m, 2H), 1.51 (s, 3H); 13C NMR(CDCl3, 100 MHz):
(ppm) 26.7,
276.07 (MþNa)þ, found 276.28.
d
4.4.16. 1-(2-Phenethyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone
34.3, 45.1, 59.4, 70.5, 117.2, 126.8, 128.7, 128.8, 138.2, 152.3; MS (ESI)
(8h). IR (neat): 2975, 2875, 1453, 1329, 1142, 1030, 752 cmꢂ1 1H
;
m/z calculated for C13H17NO3SNa 290.08 (MþNa)þ, found 290.20.
NMR (CDCl3, 400 MHz): d (ppm) 7.32e7.25 (aromatic H, 5H), 3.77
(t, J¼8.0 Hz, 1H), 3.50 (m, 1H), 3.27 (m, 2H), 3.03e2.95 (m, 3H), 2.58
4.4.9. General procedure for syntheses of vinyl sulfonamides (8a). To
a stirred solution of sulfonamide 6a (35.0 mg, 0.14 mmol) in THF
(0.8 mL) was added t-BuONa (18 mg, 0.17 mmol). Stirring was
continued until TLC analysis indicated that the starting material
was consumed (normally 6e8 h). The solvent was removed under
reduced pressure and the crude product was purified by flash
column chromatography to give a five-membered ring sultam 8a
(24.5 mg. 0.1 mmol) in a 70% yield as a sticky liquid. Compounds
8beg were made by the same procedure.
(m, 1H), 2.26 (m, 1H), 2.07 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
(ppm) 22.3, 24.9, 34.9, 46.0, 48.1, 66.4, 126.8, 128.7, 128.9, 138.2,
206.5; MS (ESI) m/z calculated for C13H17NO3SNa 290.08 (MþNa)þ,
found 290.21.
4.4.17. 2-Butyl-5-((butylamino)methyl)-4-hydroxy-4-methyl-1,1-
dioxo-isothiazolidine (9). n-Butylamine (2.5 equiv) was added to
a stirred 7f sultam solution (100 mg, 0.45 mmol) in 2 mL of
CH3CH2OH/H2O (1:1 v/v). The reaction was stirred and monitored
until TLC analysis indicated that the starting material was con-
sumed (normally 2e4 h). The resulting mixture was concentrated
under reduced pressure and purified by flash chromatography
(Hexane/EtOAc¼2:1) to afford 9 (113 mg) in a yield of 85.7%.
Compound 14 was also made in the same way.
4.4.10. 1-(2-Cyclohexyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone
(8a). IR (neat): 2934, 1719, 1313, 1138, 1051, 765 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz):
d
(ppm) 3.99 (t, J¼4.0 Hz, 1H), 3.50 (t, J¼4.0 Hz,
1H), 3.24 (m,1H), 2.86 (dd, J¼12.0, 8.0 Hz,1H), 2.57 (m,1H), 2.29 (m,
1H), 2.26 (s, 3H), 1.93e1.64 (m, 4H), 1.63 (d, J¼12.0 Hz, 1H),
1.45e1.22 (m, 4H), 1.07 (q, J¼12.0 Hz, 1H); 13C NMR (CDCl3,
IR (neat): 3319, 2958, 1466, 1304, 1134, 744 cmꢂ1
(CDCl3, 400 MHz):
(overlap, 5H), 2.86 (m, 1H), 2.55 (m, 1H), 2.47 (m, 1H), 1.52 (m, 2H),
;
1H NMR
d
(ppm) 3.38 (dd, J¼9.6, 2.4 Hz, 1H), 2.98
100 MHz):
d
(ppm) 22.6, 24.7, 25.1, 25.5, 25.9, 29.4, 32.4, 46.8, 56.5,
61.9, 208.7; MS (ESI) m/z calculated for C11H19NO3SNa 268.10
1.48 (s, 3H), 1.31 (m, 7H), 0.85 (t, J¼7.2 Hz, 3H), 0.85 (t, J¼7.2 Hz,
(MþNa)þ, found 268.26.
3H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 13.5, 13.8, 19.9, 20.1, 28.2,
29.5, 31.4, 43.5, 49.1, 60.6, 64.1, 73.1; MS (ESI) m/z calculated for
4.4.11. 1-(2-iso-Propyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone
C13H29N2O3S 293.19 (MþH)þ, found 293.27.
(8b). IR (neat): 2922, 1719, 1308, 1184, 1043, 753 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz):
d
(ppm) 3.95 (m, 2H), 3.26 (m, 1H), 2.88
4.4.18. 2-Butyl-5-ethoxymethyl-4-hydroxy-4-methyl-1,1-dioxo-iso-
thiazolidine (10). DABCO (20% mol) was added to a stirred solution
of 7f sulfonamide (100 mg, 0.45 mmol) in 2 mL of CH3CH2OH/H2O
(1:1 v/v) was added. The vial was heated at 70 ꢀC, and the reaction
was monitored until TLC analysis indicated that the starting
material was consumed (normally 2e4 h). The resulting mixture
was concentrated under reduced pressure and purified by flash
chromatography (Hexane/EtOAc¼4:1) to afford 76 mg (0.29 mmol)
in a yield of 63%.
(dd, J¼16.0, 12.0 Hz, 1H), 2.61 (m, 1H), 2.31 (s, 3H), 2.28 (m, 1H), 1.25
(t, J¼8.0 Hz, 3H), 1.22 (t, J¼8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d
(ppm) 19.0, 21.7, 22.5, 24.5, 46.7, 48.7, 61.5, 208.6; MS (ESI) m/z
calculated for C6H15NO3SNa 228.07 (MþNa)þ, found 228.19.
4.4.12. 1-(2-Propyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone (8c). IR
(neat): 2967, 1461, 1717, 1305, 1136, 668 cmꢂ1 1H NMR (CDCl3,
;
400 MHz):
d
(ppm) 3.80 (t, J¼8.0 Hz, 1H), 3.20e3.02 (m, 2H),
2.99e2.86 (m, 2H), 2.59 (m, 1H), 2.28 (m, 1H), 2.23 (s, 3H), 1.55
IR (neat): 2959, 1472, 1303, 1136, 913, 744 cmꢂ1; 1H NMR (CDCl3,
(q, J¼4.0 Hz, 2H), 0.88 (t, J¼4.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
400 MHz):
d
(ppm) 3.53 (dd, J¼14.4, 4.8 Hz, 1H), 3.08 (m, 5H), 2.99
d
(ppm) 11.3, 21.5, 22.2, 25.1, 45.8, 48.5, 66.3, 206.7; MS (ESI) m/z
(m, 1H), 2.67 (m, 1H), 2.57 (m, 1H), 1.61 (m, 2H), 1.49 (s, 3H), 1.47 (m,
calculated for C6H15NO3SNa 228.07 (MþNa)þ, found 228.19.
1H), 1.37 (m, 5H), 0.97 (m, J¼7.2 Hz, 3H), 0.92 (m, J¼7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz):
d (ppm) 13.6, 13.8, 20.0, 20.2, 28.2, 29.6,
4.4.13. 1-(2-iso-Butyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone
31.3, 43.6, 44.8, 49.2, 60.7, 64.1, 73.2, 77.2; MS (ESI) m/z calculated
(8d). IR (neat): 2960, 1716, 1305, 1137, 1057, 759 cmꢂ1 1H NMR
;
for C11H23NO4SNa 288.12 (MþNa)þ, found 288.20.
(CDCl3, 400 MHz):
d
(ppm) 3.80 (t, J¼4.0 Hz, 1H), 3.26 (m, 1H), 3.11
(m, 1H), 3.02 (m, 1H), 2.72 (m, 1H), 2.68 (m, 1H), 2.32 (m, 1H), 2.29
4.4.19. Diethyl-2-((4-hydroxy-4-methyl-2-phenethyl-1,1-dioxo-iso-
thiazolidin-5-yl)methyl)malonate (11). To the solution of diethyl
malonate (192 mg, 1.2 mmol) in THF (3 mL) was added NaH (60 mg,
60% dispersion in mineral oil, 1.5 equiv) portion wise. The mixture
was stirred for 30 min, and then sulfonamide 7f (220 mg, 1 mmol)
was added to the reaction. The reaction was stirred and monitored
until TLC analysis indicated that the starting material was consumed
(normally 4 h). The reaction mixture was concentrated under
reduced pressure and purified by flash chromatography (Hexane/
EtOAc¼6:1) to afford 11 (219 mg, 0.51 mmol) in a yield of 51.3%.
IR (neat): 2934, 1731, 1296, 1142, 1030, 744 cmꢂ1; 1H NMR (CDCl3,
(s, 3H), 1.83(m, 1H), 0.97 (t, J¼8.0 Hz, 3H), 0.96 (t, J¼8.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz):
d (ppm) 20.1, 20.2, 22.3, 27.4, 45.7, 55.3,
67.6, 206.6; MS (ESI) m/z calculated for C9H17NO3SNa 242.08
(MþNa)þ, found 242.27.
4.4.14. 1-(2-Butyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone
(neat): 2960, 1721, 1306, 1157, 1056, 741 cmꢂ1 1H NMR (CDCl3,
400 MHz):
(ppm) 3.80 (t, J¼8.0 Hz, 1H), 3.26 (m, 2H), 2.91 (m, 2H),
(8f). IR
;
d
2.59 (m, 1H), 2.28 (m, 1H), 2.30 (s, 3H), 1.57 (m, 2H), 1.36 (m, 2H),
0.94 (t, J¼8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d (ppm) 11.3, 21.5,
22.2, 25.1, 45.8, 48.5, 66.3, 206.7; MS (ESI) m/z calculated for
400 MHz): d (ppm) 7.33e7.22 (aromatic H, 5H), 4.23 (m, 4H), 3.85
C9H17NO3SNa 242.08 (MþNa)þ, found 242.27.
(m, 1H), 3.39 (m, 1H), 3.25 (m, 2H), 3.16 (d, J¼8.0 Hz, 1H), 3.07
(d, J¼8.0 Hz, 1H), 2.92 (m, 2H), 2.35 (m. 1H), 2.27 (m. 1H), 1.41
(m, 3H), 1.31 (t, J¼6.0 Hz, 3H), 1.28 (t, J¼6.0 Hz, 3H); 13C NMR (CDCl3,
4.4.15. 1-(2-Benzyl-isothiazolidin-3-yl)-1,1-dioxo-ethanone (8g). IR
(neat): 2926, 1719, 1304, 1138, 757 cmꢂ1
;
1H NMR (CDCl3,
100 MHz): d (ppm) 14.0, 22.9, 23.7, 34.7, 45.8, 48.8, 60.3, 62.0 (62,1),

K. Tong et al. / Tetrahedron 69 (2013) 2369e2375
2375
Kato, M.; Matsumoto, S. J. Med. Chem. 2000, 43, 2040e2048; (b) Brzozowski, F.;
Sa˛czewski, F.; Neamati, N. Bioorg. Med. Chem. Lett. 2006, 16, 5298e5302; (c)
Gold, H.; Ax, A.; Vrang, L.; Samuelsson, B.; Karlen, A.; Hallberg, A.; Larhed, M.
64.8, 72.7, 126.7, 128.6, 128.8, 138.3, 168.6, 168.8; MS (ESI) m/z cal-
culated for C20H29NO7SNa 450.16 (MþNa)þ, found 450.31.
ꢀ
Tetrahedron 2006, 62, 4671e4675; (d) Di Santo, R.; Costi, R.; Artico, M.; Ragno,
R.; Lavecchia, A.; Novellino, E.; Gavuzzo, E.; La Torre, F.; Cirilli, R.; Cancio, R.;
Maga, G. ChemMedChem 2006, 1, 82e95; (e) Valente, C.; Guedes, R. C.; Moreira,
R.; Iley, J.; Gut, J.; Rosenthal, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 4115e4119; (f)
4.4.20. 2-Butyl-5-(4-fluorophenylthio-methyl)-4-hydroxy-4-methyl-
1,1-dioxo-isothiazolidine (12). 4-Fluorothiophenol (144 mg,
1.12 mmol) was added to a stirred solution of sulfonamide 7f
(100 mg, 0.45 mmol) in 2 mL CH3CH2OH/H2O (1:1 v/v) was added.
The reaction was stirred and monitored until TLC analysis indicated
that the starting material was consumed (normally 2e4 h). The
resulting mixture was concentrated under reduced pressure and
purified by flash chromatography (Hexane/EtOAc¼6:1) to afford 12
(145 mg) in a yield of 91.8%.
ꢁ
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.; Salimei, P. S. J. Med. Chem.
2006, 49, 5840e5844; (g) Lebegue, N.; Gallet, S.; Flouquet, N.; Carato, P.;
Pfeiffer, B.; Renard, P.; Leonce, S.; Pierre, A.; Chavatte, P.; Berthelot, P. J. Med.
Chem. 2005, 48, 7363e7373.
2. Smits, R. A.; Adami, M.; Istyastono, E. P.; Zuiderveld, O. P.; Van Dam, C. M.; de
Kanter, F. J. J.; Jongejan, A.; Coruzzi, G.; Leurs, R.; de Esch, I. J. P. J. Med. Chem.
2010, 53, 2390e2400.
3. Kim, C.-Y.; Whittington, D. A.; Chang, J. S.; Liao, J.; May, J. A.; Christianson, D. W.
J. Med. Chem. 2002, 45, 888e893.
4. 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, 2981e2983.
IR (neat): 3477, 2959, 2871, 1491, 1258, 1130, 831, 741 cmꢂ1; 1H
NMR (CDCl3, 400 MHz):
d (ppm) 7.50e7.45 (aromatic H, 2H),
7.06e7.02 (aromatic H, 2H), 3.33 (m, 2H), 3.15 (m, 1H), 3.06 (m, 4H),
1.55 (m, 3H), 1.41 (s, 3H), 1.37 (m, 1H), 0.93 (t, J¼7.2 Hz, 1H); 13C
5. Ali, A.; Kiran, G. S.; Reddy, K.; Cao, H.; Anjum, S. G.; Nalam, M. N. L.; Schiffer, C.
A.; Rana, T. M. J. Med. Chem. 2006, 49, 7342e7356.
NMR (CDCl3, 100 MHz):
d (ppm) 13.6, 20.0, 25.7, 29.4, 29.7, 44.3,
59.6, 65.5, 72.3, 116.4, 116.5, 116.6, 116.7, 129.0, 129.0, 133.9, 134.0,
134.2, 134.3, 161.2, 163.7; MS (ESI) m/z calculated for
C15H22FNO3S2Na 370.09 (MþNa)þ, found 370.18.
6. McKeown, S. C.; Hall, A.; Blunt, R.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.;
Giblin, G. M. P.; Healy, M. P.; Johnson, M. R.; Lorthioir, O.; Michel, A. D.; Naylor,
A.; Xiao, L.; Roman, S.; Watson, S. P.; Winchester, W. J.; Wilson, R. J. Bioorg. Med.
Chem. Lett. 2007, 17, 1750e1754.
ꢀ
7. (a) Bravo, R. D.; Canepa, A. S. Synth. Commun. 2002, 32, 3675e3680; (b) Orazi, O.
4.4.21. 2-Butyl-5-((cyclohexylamino)methyl)-4-hydroxy-4-methyl-
O.; Corral, R. A.; Bravo, R. J. Heterocycl. Chem. 1986, 23, 1701e1708; (c) Katritzky, A.
R.; Wu, J.; Rachwal, S.; Rachwal, B.; Macomber, D. W.; Smith, T. P. Org. Prep. Proced.
Int. 1992, 24, 463e467.
8. Lee, J.; Zhong, Y.-L.; Reamer, R. A.; Askin, D. Org. Lett. 2003, 5, 4175e4177.
9. (a) Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40,
4761e4764; (b) Wanner, J.; Harned, A. M.; Probst, D. A.; Poon, K. W. C.; Klein, T. A.;
Snelgrove, K. A.; Hanson, P. H. Tetrahedron Lett 2002, 43, 917e921; (c) Hanessian,
S.; Sailes, H.; Therrien, E. Tetrahedron 2003, 59, 7047e7056; (d) Jimenez-Hopkins,
M.; Hanson, P. R. Org. Lett. 2008, 10, 2223e2226.
1,1-dioxo-isothiazolidine (13). IR (neat): 3311, 2930, 1445, 1300,
1134, 914, 749 cmꢂ1 1H NMR (CDCl3, 400 MHz):
; d (ppm) 3.52
(dd, J¼13.2, 2.8 Hz, 1H), 3.14 (m, 3H), 2.97 (m, 3H), 2.40 (m, 1H), 1.87
(d, J¼12.0 Hz, 2H), 1.72 (m, 2H), 1.53 (m, 3H), 1.47 (s, 3H), 1.36 (m,
2H), 1.26 (m, 3H), 1.13 (m, 2H), 0.93 (m, 3H); 13C NMR (CDCl3,
100 MHz):
d (ppm) 13.6, 19.9, 24.6, 24.7, 25.8, 28.2, 29.6, 32.8, 41.9,
43.6, 56.5, 60.8, 64.2, 73.1; MS (ESI) m/z calculated for C15H30N2O3S
10. Chiacchio, U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.; Grassi, G.; Piperno, A.
Tetrahedron 2001, 57, 3425e3433.
319.21 (MþH)þ, found 319.30.
ꢁ
11. (a) Chiacchio, U.; Corsaro, A.; Gumina, G.; Pistara, V.; Rescifina, A.; Alessi, M.;
Piperno, A.; Roeo, G.; Romeo, R. Tetrahedron 1997, 53, 13855e13866.
12. (a) Brosius, A. D.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 700e709; (b) Greig,
I. R.; Tozer, M. J.; Wright, P. T. Org. Lett. 2001, 3, 369e371; (c) Rogatchov, V. O.;
Acknowledgements
€
Bernsmann, H.; Schwab, P.; Frohlich, R.; Wibbeling, B.; Metz, P. Tetrahedron Lett.
We gratefully acknowledge Jiangsu University for financial
support.
ꢀ
2002, 43, 4753e4756; (d) Bernabeu, M. C.; Chinchilla, R.; Falvello, L. R.; Najera,
C. Tetrahedron: Asymmetry 2001, 12, 1811e1815.
€
13. (a) Merten, S.; Frohlich, R.; Kataeva, O.; Metz, P. Adv. Synth. Catal. 2005, 347,
Supplementary data
754e758.
14. (a) Zhou, A.; Hanson, R. P. Org. Lett. 2008, 10, 2951e2954; (b) Zhou, A.; Rayabarapu,
D.; Hanson, R. P. Org. Lett. 2009, 11, 531e534.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.12.083.
15. (a) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447e5674;
(b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811e892; (c)
Majumdar, K. C.; Mondal, S. Chem. Rev. 2011, 111, 7749e7773.
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Kadoh, Y.; Fujii, N.; Tanaka, T. Org. Lett. 2006, 8, 947e950; (c) Poonoth, M.;
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References and notes
1. (a) 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.;