Domino heck-aza-Michael reactions: A one-pot, sequential three-component approach to 1,1-dioxido-1,2-benzisothiazoline-3-acetic acid

Article abstract of DOI:10.1002/ejoc.200800651

The development of a new method for the synthesis of 1,1-dioxido-1,2- benzisothiazoline-3-acetic acid by a domino process is reported whereby a classical Heck reaction is coupled to an intramolecular aza-Michael reaction. Ultimately, this method has been expanded to a one-pot, sequential three-component protocol to generate diverse benzofused γ-sultams from a range of commercially available α-bromobenzenesulfonyl chlorides, amines and Michael acceptors. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800651

FULL PAPER
DOI: 10.1002/ejoc.200800651
Domino Heck–Aza-Michael Reactions: A One-Pot, Sequential Three-
Component Approach to 1,1-Dioxido-1,2-benzisothiazoline-3-acetic Acid
Alan Rolfe,[a,b] Kyle Young,[a,b] and Paul R. Hanson*[a,b]
Keywords: Domino reactions / Sultams / Heck reaction / Aza-Michael reaction / Multicomponent reactions
The development of a new method for the synthesis of 1,1-
dioxido-1,2-benzisothiazoline-3-acetic acid by a domino pro-
cess is reported whereby a classical Heck reaction is coupled
to an intramolecular aza-Michael reaction. Ultimately, this
method has been expanded to a one-pot, sequential three-
component protocol to generate diverse benzofused γ-sul-
tams from a range of commercially available α-bromoben-
zenesulfonyl chlorides, amines and Michael acceptors.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The development of facile methods to heterocyclic scaf-
folds is critical to the drug-discovery process.[1] Cascade or
domino reactions are highly efficient pathways that allow
for the synthesis of complex molecules from simple sub-
strates and encompass a variety of transformations such as
Mannich and Robinson annulation reactions to name a
few.[2] Ultimately, domino strategies require compatibility
of reagents with all products, along with efficient individual
steps to afford an overall high yielding process. Several ap-
proaches have emerged that couple transition-metal-cata-
lyzed reactions and classical protocols to achieve domino
processes in a single one-pot operation.[3] The Heck reac-
tion is well suited in this regard revealing the original func-
tionality of its olefinic partner for additional transforma-
tions. In particular, acrylates are ideal partners, because
they can undergo facile Heck coupling, and still retain
Michael accepting capabilities.[4] Despite successes in this
area, the existence of a domino process coupling Heck and
Scheme 1. Domino Heck–aza-Michael (HaM).
Compounds containing the sulfonamide moiety have
aza-Michael methodologies as a means to generate new gained wide popularity due to their extensive chemical and
heterocycles is restricted to two examples in the literature, biological profiles.[7] Sultams (cyclic sulfonamide analogs)
both limited by low yields and/or long reaction times.[5] To have emerged as privileged structures in drug discovery due
the best of our knowledge, no examples of a domino Heck– to their wide biological profile. A number of benzofused
aza-Michael approach towards the synthesis of sultams ex- sultams have recently surfaced that display potent activity
ist in the literature. Herein, we report the synthesis of 1,1- including anti-inflammatory,[8] anti-malarial,[9] anti-HIV[10]
dioxido-1,2-benzisothiazoline-3-acetic acid by a domino and lipoxygenase inhibition (Figure 1),[11] to name a few.
process whereby a classical Heck reaction is coupled to an Traditionally, syntheses of sultams have been accomplished
intramolecular aza-Michael reaction (HaM), ultimately re- by classical cyclization protocols such as Friedel–Craft,[12]
sulting in a one-pot, sequential three-component protocol dianion,[13] [3+2] cycloadditions,[14] and Diels–Alder reac-
from commercially available starting materials (Scheme 1).[6]
tions.[15] Recently, however, a number of transition-metal-
catalyzed approaches to sultams have emerged, including
use of ring-closing metathesis (RCM),[16] Heck,[17] as well
as Au-,[18] Cu-,[19] and Rh-catalyzed[20] cyclizations. Interest
in the development of new routes to structurally diverse het-
erocycles has led to the titled domino process, which is now
reported.[21]
[a] Department of Chemistry, University of Kansas,
1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
[b] The Center for Chemical Methodologies and Library Develop-
ment at The University of Kansas (KU-CMLD),
1501 Wakarusa Drive, Lawrence, KS 66047, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Domino Heck–Aza-Michael Reactions
Table 1. Domino Heck–aza-Michael.[a]
Entry Catalyst
Base
Additive
% Conv.[b]
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
PdCl2(PPh)3
Pd2(dba)3·CHCl3
Pd(OAc)2/PPh3
Pd2(dba)3·CHCl3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Et3N
Cs2CO3
Cs2CO3
Et3N
Et3N
Et3N
–
–
–
–
34
15
13
35
91
Bu4NCl
Bu4NCl
–
95
Et3N
Et3N
94[c]
95[d]
Bu4NCl
[a] Reaction conditions: 1 (0.12 mmol), Pd (2 mol-%), methyl acry-
late (0.36 mmol), base (0.36 mmol) in DMF at 110 °C for 14 h. [b]
Conversion by G.C. [c] Pd(OAc)2 (20 mol-%), PPh3 (40 mol-%) in
microwave 110 °C for 2 h. [d] Pd(OAc)2 (10 mol-%), PPh3 (20 mol-
%) in microwave 110 °C for 2 h.
Figure 1. Representative biologically active sultams.
Table 2. Domino Heck–aza-Michael.[a]
Results and Discussion
Initial reaction screening in this study was conducted on
preformed sulfonamide 1 where a variety of bases and Pd0-
sources were studied for the synthesis of sultam 2 (Table 1).
Sulfonamide 1 (0.1  in DMF) was heated at 110 °C in the
presence of methyl acrylate, Pd0-catalysts and base for 14 h.
Under these conditions, sulfonamide 1 underwent facile
Heck coupling, followed by intramolecular aza-Michael cy-
clization,[22] to afford 2 in an overall domino process. These
preliminary studies showed that the combination of Et3N
with either Pd(OAc)2/PPh3 or Pd2(dba)3·CHCl3 gave the
best results, with the presence of additive essential for high
yields (Table 1, Entry 1 vs. Entries 5/6). Moreover, it was
found that use of Pd2(dba)3·CHCl3 complex was preferred
over the use of Pd(OAc)2/PPh3 which produced reaction
mixtures containing Pd-mirror. Comparable results were
achieved using microwave irradiation, however, a higher
Entry
Additive
Water [mol-%]
% Conv.[b]
1
2
3
4
5
–
–
–
35
72
95
68
94
Bu4NCl
Bu4NCl
Bu4NI
Bu4NI
10 mol-%
–
10 mol-%
[a] Reaction conditions: 1 (0.12 mmol), Pd (2 mol-%), methyl acry-
late (0.36 mmol), Et3N (0.36 mmol) and Bu4NCl (0.12 mmol) in
DMF at 110 °C for 14 h. [b] Conversion by G.C.
catalyst load (10–20 mol-%) was required (Table 1, Entries In the presence of Pd2(dba)3·CHCl3, several Michael ac-
7/8). ceptors were subjected to the reaction conditions, affording
In the initial optimization phase, wet Bu4NCl was uti- the desired compounds in good to high yield (Table 3, En-
lized to promote the domino process. Further investigation tries 1–4). Attempts utilizing methyl methacrylate were un-
into this effect revealed that anhydrous Bu4NCl promoted successful, while the use of acrylonitrile and dimethyl vinyl
the reaction, however with diminished efficiency (Table 2). phosphonate gave low yields. Of notable importance is the
On further study of this empirical result, we found that the successful use of both acrylic acid and acrylamide to yield
addition of 10 mol-% of H2O to the reaction enhanced the the corresponding sultam bearing carboxylic or amide han-
yield when using either anhydrous Bu4NCl or Bu4NI. dles, which are primed for further diversification.
Though a true understanding of how the addition of water
The use of the Heck–aza-Michael reaction in a one-pot,
enhances yield is not entirely reached, it has been documen- sequential three-component process was next demon-
ted that higher yields can be achieved for Pd-catalyzed reac- strated. In this protocol, a variety of α-bromobenzenesulfo-
tions that use water as a co-solvent.[23]
nyl chlorides were coupled with a range of aromatic, cyclic
The scope of this chemistry was next examined with an and alkylamines to yield intermediate sulfonamides. After
array of commercially available Michael acceptors, yielding two hours, Et3N, Bu4NCl, Pd2(dba)3·CHCl3 and the corre-
products bearing a variety of functional handles (Table 3). sponding Michael acceptor were added to the reaction mix-
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A. Rolfe, K. Young, P. R. Hanson
FULL PAPER
Table 3. Scope of possible Michael acceptors.[a]
Table 5. Application of domino HAM protocol with 15.[a]
Entry
R1
R2
Product
% Yield[b]
Entry
R
Product
% Yield[b]
1
2
3
4
4-MeOPh
C8H17
4-MeOPh
2-MeOBn
Me
16
17
18
19
88
84
93
86
1
2
3
4
5
OMe
OEt
OH
Me
NH2
2
3
4
5
6
95
92
94
79
81
OMe
OMe
OEt
[a] Reaction conditions: 1 (0.12 mmol), Pd2(dba)3·CHCl3 (2 mol-
%), methyl acrylate (0.36 mmol), Bu4NCl (0.12 mmol) in DMF at
110 °C for 14 h. [b] Isolated yields. Compounds purified by mass-
directed fractionation.
[a] Reaction conditions: 1 (0.12 mmol), Pd2(dba)3·CHCl3 (2 mol-
%), methyl acrylate (0.36 mmol), Bu4NCl (0.12 mmol) in DMF at
110 °C for 14 h. [b] Isolated yields.
stantiates the aforementioned amide studies by Dyker and
coworkers.[5b,26] In addition to 20, sulfonamide derivatives
21 and 22 were subjected to this protocol and, to our sur-
prise, yielded only unreacted starting material. A plausible
explanation for the unreactive cases involving sulfonamides
21 and 22 is the possibility of the free NH coordinating to
palladium after the oxidative addition step and deactivating
it for further chemistry.
ture, which was subsequently heated to 110 °C and sub-
jected to workup after 14 h.[24] A small subset of 1,1-diox-
ido-1,2-benzisothiazoline-3-acetic acid was made using this
one-pot protocol (Table 4). Reactions were typically carried
out on the 0.27 mmol scale, affording products in good iso-
lated yields (79–90%).[25]
Table 4. Demonstration of a one-pot domino protocol.[a]
Entry R1
R2
R3
Product
% Yield[b]
1
2
3
4
5
6
7
H
H
4-F
4-F
H
4-F
H
c-C5H9
c-C6H11
Bn
Me
7
8
74
86
84
90
81
84
84
OH
OEt
OH
OEt
OH
OMe
9
C8H17
10
11
12
13
4-ClPh
c-C6H11
4-MeOPh
[a] Reaction conditions: 1 (0.12 mmol), Pd2(dba)3·CHCl3 (2 mol-
%), methyl acrylate (0.36 mmol), Bu4NCl (0.12 mmol) in DMF at
110 °C for 14 h. [b] Isolated yields.
Scheme 2.
Further application of this multicomponent protocol was
In order to further probe the results shown in Scheme 2,
demonstrated utilizing the commercially available 2,5-di- N-(o-bromobenzyl)-2-bromobenzenesulfonamide (23), pos-
bromosulfonyl chloride 15 (Table 5). In this method, 1,1- sessing both electron-poor and electron-rich bromoaryl
dioxido-1,2-benzisothiazoline-3-acetic acid 16–19 pos- moieties, was assembled and subjected to the domino
sessing both saturated and unsaturated side chains were Heck–aza-Michael conditions. In theory, this reaction can
generated in good to excellent yields (85-93%). In all cases produce two possible products, 24 and 25, depending on
the intramolecular aza-Michael reaction proceeded with which Heck–aza-Michael pathway is operative. According
high yield forming the desired γ-sultam.
to the data presented in Table 4, we would expect an initial
The versatility of this protocol was next examined with facile oxidative addition of Pd0 at the more electron-de-
a variety of other attractive substrates (20–22, Scheme 2). ficient aryl bromide. In the case of 23, this would be the
When submitted to the domino Heck–aza-Michael pro- bromide position ortho to the sulfonamide. Following the
cedure, amide 20 remained unreacted, which further sub- initial Heck addition, a facile aza-Michael reaction pro-
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Eur. J. Org. Chem. 2008, 5254–5262

Domino Heck–Aza-Michael Reactions
ceeds forming sultam 24. A second Heck reaction then pro- product was isolated from the reaction, only the product
ceeds on the remaining aryl bromide since no free NH is resulting from simple Heck reaction was observed in the
present to deactivate the Pd0 (as in the case of 21 and 22), crude mixture. Despite the utilization of a variety of both
resulting in the formation of only 24 (Scheme 3). When 23 1° and 2° amines, none of the desired sultam products were
was submitted to the standard HaM reaction conditions, isolated. A plausible explanation is that the corresponding
one sole product was isolated as predicted along with start- acrylamides are poorer Michael acceptors in comparison to
ing material. Despite inconclusive NMR spectroscopic data their acrylate counterparts, further demonstrating how sub-
due to the similar characteristics of 24 and 25, results dis- tle electronic effects are operative in these systems.
cussed have allowed for tentative assignment of sultam 24
as the isolated product.
Scheme 4.
To circumvent this problem, the sultam product derived
from use of acrylic acid was coupled with the corresponding
amine utilizing a high-load, soluble polymeric EDC variant
OACC, derived from ring-opening metathesis polymeriza-
tion (ROMP) (Scheme 5).[28] To this effect, some 1,1-diox-
ido-1,2-benzisothiazoline-3-acetamide derivatives 29–31
bearing both saturated and aromatic side chains were syn-
thesized. This was accomplished by a one-pot protocol
Scheme 3.
whereby the corresponding sultam acid was generated, fol-
lowed by OACC coupling with the corresponding amine.
tams outlined in Figure 1,[8–11] a number of related 1-
In addition to the aforementioned biologically active sul-
oxoisoindol-3-acetamide derivatives have been reported to
possess potent sedative-hypnotic activity, and are NHE1 in-
hibitors as well as allosteric modulators of glucokinase
(Figure 2).[27]
Figure 2. Biologically active 1-oxoisoindol-3-acetamides.
This promising bioactivity prompted use of the titled
Scheme 5.
protocol to generate the analogous sultam derivatives in a
one-pot procedure. The corresponding sulfonamide 26 and
As previously discussed, the formation of the sultam car-
acrylamide 27 were thus generated in situ, followed by com- boxylic acids requires the use of excess acrylic acid. This
bination and submission to the domino HaM reaction con- excess reagent itself can undergo coupling with the free
ditions (Scheme 4). In the case of 28, none of the desired amine to form the corresponding amide. To circumvent this
Eur. J. Org. Chem. 2008, 5254–5262
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5257

A. Rolfe, K. Young, P. R. Hanson
FULL PAPER
provided 5.02 g (98% yield) of the title compound as a white solid,
problem, the crude mixture was concentrated in situ to re-
move the excess acrylic acid. This is followed by resolvation
and formation of the corresponding amide by coupling uti-
lizing 2GOACC50.[29] Attempts to develop a “true” one-pot
process starting from the corresponding sulfonamide were
investigated. However, it was discovered that lowering the
equivalents of acrylic acid from 3 to 1–1.5 significantly re-
duced the amount of cyclic acid formed and hence the
amount of corresponding amide isolated.
m.p. 93–96 °C. FTIR (neat): ν = 3319, 1409, 1332, 1253, 1163 cm–1.
˜
1H NMR (500 MHz, CDCl3: δ = 8.12 (dd, J = 7.8, 1.8 Hz, 1 H),
7.69 (dd, J = 7.8, 1.2 Hz, 1 H), 7.44 (dt, J = 7.6, 1.26 Hz, 1 H),
7.39 (dt, J = 5.6, 1.8 Hz, 1 H), 7.27–7.25 (m, 3 H), 7.18–7.23 (m,
2 H), 5.41–5.43 (m, 1 H), 4.10 (d, J = 6.2 Hz, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 138.7, 135.6, 135.0, 133.7, 131.4, 128.7,
128.2, 128.0, 127.6, 119.7, 47.5 ppm. HRMS calculated for
C13H12BrNO2SNa [M + Na] 347.9670; found 347.9700 (TOF MS
ES+).
Methyl (2-Benzyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)-
acetate (2): Into
a microwave vial was added 1 (39.1 mg,
Conclusions
0.12 mmol), Et3N (50 µL, 0.36 mmol), Pd(OAc)2 (20 mol-%,
5.4 mg, 0.024 mmol), PPh3 (40 mol-%, 12.6 mg, 0.048 mmol) and
CH3CN (0.6 mL). After stirring for 5 min, methyl acrylate (32 µL,
0.36 mmol) was added and the reaction placed in the microwave
oven at 120 °C for 2 h. Then the reaction was concentrated under
reduced pressure and purified using flash chromatography (hexane/
EtOAc, 6:4) to provide 37.7 mg (95%) of the title compound as a
In conclusion, a new method has been developed for the
rapid synthesis of 1,1-dioxido-1,2-benzisothiazoline-3-ace-
tic acid via a domino Heck–aza-Michael reaction. Expan-
sion of the method to a one-pot, sequential three-compo-
nent protocol to generate diverse benzofused sultams from
commercially available α-bromobenzenesulfonyl chlorides,
amines and Michael acceptors has been accomplished. This
method has been utilized to synthesize a small demonstra-
tion library of 1,1-dioxido-1,2-benzisothiazoline-3-acetic
acids bearing both saturated and unsaturated side chains.
With this method in hand, a number of sultam derivatives
of bioactive related isoindol-1-one amides were synthesized
in a one-pot manner utilizing a ROMP-derived coupling
reagent OACC. All of the compounds reported are cur-
rently undergoing broad biological screening through the
NIH Molecular Library Screening Network (NIH-
MLSCN) and the results will be reported in due course.
yellow oil. FTIR (neat): ν = 1735, 1294, 1172 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 7.85 (d, J = 7.2 Hz, 1 H), 7.52–7.63 (m, 2
H), 7.42 (d, J = 7.2 Hz, 1 H), 7.28–7.36 (m, 5 H), 4.83 (t, J =
6.0 Hz, 1 H), 4.61 (d, J = 15.6 Hz, 1 H), 4.49 (d, J = 15.6 Hz, 1
H), 3.59 (s, 3 H), 2.86 (dd, J = 16.3, 5.4 Hz, 1 H), 2.70 (dd, J =
16.3, 6.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.5,
137.3, 135.3, 132.9, 131.0, 130.3, 129.5, 128.8, 128.4, 128.0, 124.1,
121.4, 119.5, 57.0, 52.0, 46.6, 38.9 ppm. HRMS calculated for
C17H18NO4S [M + H]+ 332.0956; found 332.0958 (TOF MS EI+).
General Procedure (A) for the Synthesis of 1,1-Dioxido-1,2-benziso-
thiazoline-3-acetic Acid Derivatives Using a Range of Michael Ac-
ceptors from 1: Into a 1-dram vial was added 1 (40 mg, 0.12 mmol),
Et3N (51 µL, 0.36 mmol), Bu4NCl (30 mg, 0.12 mmol), Pd2(dba)
3·CHCl3 (2 mol-%, 2.5 mg, 0.0024 mmol) and dry DMF (1.22 mL).
After stirring for 5 min at room temp., Michael acceptor
(0.36 mmol) was added and the reaction vial was placed immedi-
ately into a preheated reaction block. The reaction mixture 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 (hexane/EtOAc, 6:4).
Experimental Section
General Procedures: All air- and moisture-sensitive reactions were
carried out in flame- or oven-dried glassware under argon using
standard gastight syringes, cannulas, and septa. Stirring was
achieved with oven-dried, magnetic stir bars. CH3CN was purified
by passage through the Solv-Tek purification system employing ac-
tivated Al2O3.[30] Et3N was purified by passage over basic alumina
and stored over KOH. Flash column chromatography was per-
formed with SiO2 from Sorbent Technology (30930M-25, Silica Gel
60A, 40-63 um). Thin-layer chromatography was performed on sil-
ica gel 60F254 plates (EM-5717, Merck). Deuterated solvents were
purchased from Cambridge Isotope laboratories. 1H and 13C NMR
spectra were recorded with a Bruker DRX-400 NMR spectrometer
operating at 400 MHz, 100 MHz, or 162 MHz, respectively; or a
Bruker Avance operating at 500 MHz or 125 MHz, respectively.
High-resolution mass spectrometry (HRMS) and FAB spectra were
obtained in one of two manners: (i) on a VG Instrument ZAB
double-focusing mass spectrometer and (ii) on a LCT Premier
Spectrometer (Micromass UK Limited) operating on ESI (MeOH).
Ethyl (2-Benzyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)ace-
tate (3): Prepared using general method (A) with ethyl acrylate
(39.9 µL, 0.366 mmol) to yield 38 mg of 3 (92%) as a yellow oil.
FTIR (neat): ν = 2361, 1733, 1290, 1172 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 7.84 (dd, J = 6.9, 1.2 Hz, 1 H), 7.53–7.60 (m, 2 H),
7.43 (d, J = 7.2 Hz, 2 H), 7.30–7.38 (m, 4 H), 4.82 5(t, J = 6.1 Hz,
1 H), 4.62 (d, J = 15.6 Hz, 1 H), 4.52 (d, J = 15.6 Hz, 1 H), 4.03–
4.06 (m, 2 H), 2.86 (dd, J = 16.3, 5.2 Hz, 1 H), 2.70 (dd, J = 16.3,
3.6 Hz 1 H), 1.14 (t, J = 5.6 Hz 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.0, 137.3, 135.3, 134.6, 132.8, 129.5, 128.7, 128.4,
128.0, 124.18, 121.40, 61.1, 57.0, 46.4, 39.0, 13.9 ppm. HRMS cal-
culated for C18H19NO4SNa [M + Na]+ 368.0932; found 368.0930
(TOF MS EI+).
(2-Benzyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)acetic Acid
(4): Prepared using general method (A) with acrylic acid (25.0 µL,
0.366 mmol) to give 36 mg of 4 (94%) as a white solid, m.p. 120–
N-Benzyl-2-bromobenzenesulfonamide (1): Into a flame-dried flask
under argon was added benzylamine (1.87 mL, 17.2 mmol) and dry
CH2Cl2 (36 mL). Et3N (4.35 mL, 31.2 mmol) was added and the
reaction flask stirred at r.t for 15 min at which time N-benzyl-2-
bromobenzene (4.0 g, 15.6 mmol) was added and the reaction mix-
ture stirred for 2 h. The crude reaction mixture was concentrated
and the resulting slurry was suspended in EtOAc (20 mL). The or-
ganic salts were removed by filtration and the solvent removed un-
der reduced pressure. Flash chromatography (EtOAc/hexane, 1:1)
122 °C. FTIR (neat): ν = 2923 (br), 1712, 1290, 1170, 1130 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J = 7.2 Hz, 1 H), 7.55–
7.62 (m, 2 H), 7.38–7.42 (m, 3 H), 7.27–7.34 (m, 3 H), 4.82 (t, J =
5.4 Hz, 1 H), 4.62 (d, J = 15.6 Hz, 1 H), 4.51 (d, J = 15.6 Hz, 1
H), 2.91 (dd, J = 16.6, 5.0 Hz, 1 H), 2.70 (dd, J = 16.6, 6.9 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.8, 137.0, 135.0,
134.6, 133.0, 129.6, 128.8, 128.5, 128.1, 124.16, 121.49, 56.6, 46.7,
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Domino Heck–Aza-Michael Reactions
38.6 ppm. HRMS calculated for C16H16NO4S [M + H]+ 318.0800;
found 318.0817 (TOF MS EI+).
3.08 (dd, J = 16.5, 4.2 Hz, 1 H), 2.84 (dd, J = 16.5, 8.1 Hz, 1 H),
1.94–2.04 (m, 4 H), 1.79–1.85 (m, 2 H), 1.59–1.68 (m, 2 H), 1.28–
1.36 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.4, 136.4,
130.9, 127.5, 122.2, 119.0, 54.6, 52.8, 38.8, 30.3, 28.2, 24.1, 23.9,
23.4 ppm. HRMS calculated for C15H23N2O4S [M + NH4]+
327.1379; found 327.1399 (TOF MS EI+).
1-(2-Benzyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)propane-
2-one (5): Prepared using general method (A) with methyl vinyl
ketone (25.0 µL, 0.366 mmol) to give 30 mg of 5 (79%) as a clear
oil. FTIR (neat): ν = 1716, 1454, 1292, 1172, 1132 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 7.83 (m, 1 H), 7.51–7.58 (m, 2 H), 7.40 (d,
J = 7.2 Hz, 2 H), 7.25–7.36 (m, 4 H), 4.98 (t, J = 5.9 Hz, 1 H),
4.56 (d, J = 14.7 Hz, 1 H), 4.42 (d, J = 15.6 Hz, 1 H), 2.97 (dd, J
= 18.0, 5.6 Hz, 1 H), 2.77 (dd, J = 18.0, 6.3 Hz, 1 H), 1.90 (s, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 205.4, 138.1, 135.8, 134.6,
132.95, 129.3, 128.7, 128.5, 127.9, 124.2, 121.3, 56.3, 48.2,
30.27 ppm. HRMS calculated for C17H17NO3SNa [M + Na]+
338.0827 found 338.0800 (TOF MS EI+).
Ethyl (2-Benzyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)ace-
tate (9): Prepared using general method (B) using, 4-fluoro-2-bro-
mobenzenesulfonyl chloride, benzylamine and ethyl acrylate to af-
ford 92 mg of 9 (84%) as a yellow oil. FTIR (neat): ν = 1731, 1593,
˜
1475, 1298, 1174 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.82 (dd,
J = 8.6, 4.8 Hz, 1 H), 7.40–7.42 (m, 2 H), 7.30–7.36 (m, 3 H), 7.22–
7.26 (m, 1 H), 7.09 (dd, J = 8.4, 2.1 Hz, 1 H), 4.78 (dd, J = 6.8,
6.7 Hz, 1 H), 4.60 (d, J = 15.6 Hz, 1 H), 4.48 (d, J = 15.6 Hz, 1
H), 4.02–4.10 (m, 2 H), 2.86 (dd, J = 16.4, 4.9 Hz, 1 H), 2.68 (dd,
J = 16.4, 7.1 Hz, 1 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 167.9, 164.5 (d, JC-F = 250.5 Hz), 138.6,
133.1, 127.2, 126.7, 126.4, 126.1, 121.7, 115.6, 109.9, 59.3, 54.7,
44.7, 36.7, 12.0 ppm. HRMS calculated for C18H22FN2O4S [M +
NH4]+ 381.1284; found 381.1295 (TOF MS EI+).
(2-Benzyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)acetamide
(6): Prepared using general method (A) with acrylamide (26 mg,
0.366 mmol) to yield 31 mg of 6 (81%) as a white solid. FTIR
(neat): ν = 1685, 1450, 1295, 1172, 1128 cm–1. 1H NMR (500 MHz,
˜
[D4]MeOD): δ = 7.81 (d, J = 7.7 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1
H), 7.59 (t, J = 7.2 Hz, 1 H), 7.51 (d, J = 7.7 Hz, 1 H), 7.47 (d, J
= 7.3 Hz, 2 H), 7.28–7.38 (m, 3 H), 4.92 (t, J = 6.6 Hz, 1 H), 4.87
(br. s, 2 H), 4.64 (d, J = 15.6 Hz, 1 H), 4.50 (d, J = 15.6 Hz, 1 H),
2.84 (dd, J = 15.1, 6.1 Hz, 1 H), 2.61 (dd, J = 15.1, 7.0 Hz, 1 H)
ppm. 13C NMR (125 MHz, [D4]MeOD): δ = 174.8, 139.7, 137.5,
136.3, 134.6, 131.2, 130.3, 130.2, 130.1, 129.1, 59.5, 48.1, 41.6 ppm.
HRMS calculated for C16H17N2O3S [M + H]+ 317.0960 found
317.0932 (TOF MS EI+).
(2-Octyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)acetic Acid
(10): Prepared using general method (B) using 4-fluoro-2-bromo-
benzenesulfonyl chloride, octylamine and acrylic acid to yield
87 mg of 10 (90%) as a pale yellow solid, m.p. 123–127 °C. FTIR
(neat): ν = 2927, 2856, 1714, 1593, 1475 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 9.02–9.16 (br. s, 1 H), 7.79 (dd, J = 8.6, 4.7 Hz, 1 H),
7.24–7.26 (m, 1 H), 7.16 (dd, J = 8.3, 2.0 Hz, 1 H), 4.86 (m, 1 H),
3.30 (t, J = 15.3 Hz, 2 H), 3.06 (dd, J = 21.6, 4.7 Hz, 1 H), 2.83
(dd, J = 16.9, 7.4 Hz, 1 H), 1.66–1.75 (m, 2 H), 1.23–1.39 (m, 10
H), 0.85 (t, J = 6.8 Hz, 2 H). 13C NMR (125 MHz, CDCl3)δ =
173.5, 163.3 (d, JC-F = 254.9 Hz), 138.4, 129.1, 121.8, 115.7, 109.7,
54.8, 41.8, 36.7, 29.8, 27.2, 26.1, 25.0, 20.7, 12.16 ppm. HRMS cal-
culated for C17H28FN2O4S (M + NH4)+ 375.1754; found 375.1769
(TOF MS EI+).
General Procedure (B) for the Synthesis of 1,1-Dioxido-1,2-benziso-
thiazoline-3-acetic Acid Derivatives: Into a 1-dram vial was added
amine (0.273 mmol), Et3N (0.547 mmol) and dry DMF (0.59 mL)
and reaction mixture was stirred at r.t. for 15 min. Then, α-bromo-
benzenesulfonyl chlorides (0.273 mmol) were added and the reac-
tion mixture was stirred for 2 h. To the reaction vial was added
Et3N (76 µL, 0.548 mmol), Bu4N (74.5 mg, 0.273 mmol), Pd2(dba)3·
CHCl3 (2 mol-%, 25.6 mg, 0.0056 mmol) and dry DMF (1.4 mL).
After stirring for 5 min at room temp., Michael acceptor
(0.819 mmol) was added and the reaction vial was placed immedi-
ately into a preheated reaction block. The reaction mixture was
stirred at 110 °C for 14 h after which time the reaction was cooled
and concentrated under reduced pressure. The crude was purified
using flash chromatography (hexane/EtOAc, 6:4).
Ethyl (4-Chlorophenyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-
yl)acetate (11): Prepared using general method (B) using 2-bromo-
benzenesulfonyl chloride, 4-chlorobenzylamine and ethyl acrylate
to afford 73 mg of 11 (81%) as a yellow oil. FTIR (neat): ν = 1730,
˜
1294, 1172 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.77 (d, J =
7.1 Hz, 1 H), 7.47–7.56 (m, 2 H), 7.30–7.34 (m, 3 H), 7.25 (d, J =
8.5 Hz, 2 H), 4.77 (t, J = 5.9 Hz, 1 H), 4.48 (q, J = 15.9 Hz, 2 H),
3.98–4.06 (m, 2 H), 2.78 (dd, J = 16.4, 5.8 Hz, 1 H), 2.66 (dd, J =
16.4, 6.2 Hz, 1 H), 1.09 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.0, 137.1, 134.6, 134.1, 133.1, 133.0,
129.8, 129.2, 128.7, 124.1, 121.4, 61.2, 57.3, 46.2, 39.4, 14.2 ppm.
HRMS calculated for C18H19ClNO4S [M + H]+ 380.0723; found
380.0739 (TOF MS EI+).
1-(2-Cyclopentyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)pro-
pane-2-one (7): Prepared using general method (B) using ben-
zenesulfonyl chloride, cyclopentylamine and methyl vinyl ketone to
afford 52 mg of 7 (76%) as a yellow oil. FTIR (neat): ν = 1714,
˜
1294, 1168 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J =
7.1 Hz, 1 H), 7.40–7.51 (m, 2 H), 7.32 (d, J = 7.6 Hz, 1 H), 5.02
(dd, J = 8.7, 3.7 Hz, 1 H), 3.15 (dd, J = 17.9, 5.7 Hz, 1 H), 2.86
(dd, J = 17.9, 7.6 Hz, 1 H), 2.11 (s, 3 H), 1.92–1.98 (m, 2 H),
1.64–1.75 (m, 4 H), 1.51–1.54 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 206.3, 139.3, 135.9, 132.8, 130.2, 129.7, 124.5, 121.1,
57.6, 55.3, 48.7, 31.0, 30.85, 28.9, 24.1, 22.7 ppm. HRMS calcu-
lated for C15H23N2O3S [M + NH4]+ 311.1429; found 311.1446
(TOF MS EI+).
(2-Cyclohexyl-6-fluoro-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-
yl)acetic Acid (12): Prepared using general method (B) using 4-
fluoro-2-bromobenzenesulfonyl chloride, cyclohexylamine and
acrylic acid to yield 65 mg of 12 (84%) as a yellow oil. FTIR (neat):
ν = 2935, 1718, 1288, 1172, 1122 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 7.73–7.76 (m, 1 H), 7.17–7.30 (m, 3 H), 5.01–5.08 (m,
1 H), 3.62 (t, J = 11.9 Hz, 1 H), 3.10 (d, J = 16.8 Hz, 1 H), 2.86
(dd, J = 16.8, 8.5 Hz, 2 H), 2.04 (d, J = 11.9 Hz, 1 H), 1.95 (d, J
= 11.6 Hz, 1 H), 1.84 (t, J = 15.0 Hz, 1 H), 1.58–1.68 (m, 3 H),
1.30–1.38 (dd, J = 12.8, 13.1 Hz, 2 H), 1.08–1.17 (m, 1 H) ppm.
(2-Cyclohexyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-3-yl)acetic
Acid (8): Prepared using general method (B) using α-bromoben-
zenesulfonyl chloride, cyclohexylamine and acrylic acid to yield
76 mg of 8 (86%) as a white solid, m.p. 121–124 °C. FTIR (neat):
ν = 2933, 2856, 1712, 1288, 1170 cm–1
CDCl3): δ = 9.08–9.48 (br. s, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.57
.
1H NMR (500 MHz, 13C NMR (125 MHz, CDCl3): δ = 174.7, 165.1 (d, JC-F
254.6 Hz), 141.4, 132.4, 123.3, 117.4, 111.6, 56.7, 54.0, 40.6, 32.1,
=
˜
(td, J = 7.5, 1.0 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.46 (d, J = 26.0, 25.8, 25.3 ppm. HRMS calculated for C15H18FNO4S [M +
7.6 Hz, 1 H), 5.06 (dd, J = 8.1, 4.2 Hz, 1 H), 3.58–3.64 (m, 1 H), H]+ 328.1019; found 328.1036 (TOF MS EI+).
Eur. J. Org. Chem. 2008, 5254–5262
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5259

A. Rolfe, K. Young, P. R. Hanson
FULL PAPER
Methyl [2-(4-Methoxyphenyl)-1,1-dioxido-2,3-dihydro-1,2-benziso-
thiazol-3-yl]acetate (13): Prepared using general method (B) using
benzenesulfonyl chloride, p-methoxybenzylamine and methyl acry-
H), 4.79 (dd, J = 6.9, 5.1 Hz, 1 H), 4.59 (d, J = 15.3 Hz, 1 H), 4.40
(d, J = 15.3 Hz, 1 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.63 (s, 3 H),
2.88 (dd, J = 16.3, 5.0 Hz, 1 H), 2.70 (dd, J = 16.3, 7.0 Hz, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 170.3, 166.6, 159.4, 141.1,
late to produce 71 mg of 13 (84%) as a yellow oil. FTIR (neat): ν
˜
= 1735, 1514, 1292 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.85 138.7, 136.2, 135.9, 132.3, 129.9, 126.7, 124.8, 120.7, 120.2, 114.1,
(d, J = 7.1 Hz, 1 H), 7.51–7.59 (m, 2 H), 7.42 (d, J = 8.5 Hz, 3 H),
6.86 (d, J = 8.6 Hz, 2 H), 4.80 (t, J = 6.4 Hz, 1 H), 4.57 (d, J =
12.4 Hz, 1 H), 4.41 (d, J = 15.4 Hz, 1 H), 3.80 (s, 3 H), 3.63 (s, 3
H), 2.87 (dd, J = 16.3, 5.3 Hz, 1 H), 2.69 (dd, J = 16.3, 6.9 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.6, 159.4, 137.3,
134.8, 132.0, 130.2, 129.3, 127.0, 124.0, 121.4, 114.0, 56.6, 55.3,
46.0 ppm. HRMS calculated for C18H23N2O5S [M + NH4]+
379.1328; found 379.1337 (TOF MS EI+).
56.4, 55.2, 52.1, 46.0, 38.5 ppm. HRMS calculated for C22H24NO7S
[M + H]+ 446.1273; found 446.1269 (TOF MS EI+).
Ethyl (2E)-3-[3-(2-Ethoxy-2-oxoethyl)-2-(2-methoxybenzyl)-1,1-di-
oxido-2,3-dihydro-1,2-benzisothiazol-6-yl]acrylate (19): Prepared
using general method (B) using 2,5-dibromobenzenesulfonyl chlo-
ride, 2-methoxyphenylamine and ethyl acrylate to produce 107 mg
of 19 (86%) as a yellow oil. FTIR (neat): ν = 1720, 1602, 1492,
˜
1
1307, 1207, 1172 cm–1. H NMR (500 MHz, CDCl3): δ = 7.99 (s,
Ethyl 3-[2-(N-tert-Butylsulfamoyl)-5-fluorophenyl]propanoate (14): 1 H), 7.76 (dd, J = 8.1, 1.5 Hz, 1 H), 7.71 (d, J = 16.0 Hz, 1 H),
Prepared using general method (A) using 4-fluoro-2-bromoben-
zenesulfonyl chloride, tert-butylamine and ethyl acrylate to afford
7.56 (d, J = 8.1 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.05–7.08 (m,
1 H), 7.36 (t, J = 2.2 Hz, 1 H), 6.88 (dd, J = 8.4, 2.5 Hz, 1 H), 6.53
(d, J = 16.0 Hz, 1 H), 5.56 (dd, J = 7.9, 4.1 Hz, 1 H), 4.28 (q, J =
41 mg of 14 (48%) as a clear oil. FTIR (neat): ν = 1718, 1573,
˜
1291, 1212, 1150 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.38 (dd, 7.9 Hz, 1 H), 4.08 (q, J = 11.4 Hz, 1 H), 3.83 (s, 3 H), 2.97 (dd, J
J = 15.9, 0.65 Hz, 1 H), 8.15 (dd, J = 11.2, 5.6 Hz, 1 H), 7.30 (dd,
J = 9.2, 2.6 Hz, 1 H), 7.14 (ddd, J = 10.3, 7.7, 2.6 Hz, 1 H), 6.35
(d, J = 21.5 Hz, 1 H), 4.68 (s, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 1.33
= 16.3, 4.2 Hz, 1 H), 2.76 (dd, J = 16.4, 8.0 Hz, 1 H), 1.34 (t, J =
9.8 Hz, 1 H), 1.16 (t, J = 11.4 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.0, 169.18, 160.6, 141.6, 137.5, 136.6, 135.5, 135.0,
(t, J = 7.1 Hz, 3 H), 1.16 (s, 9 H) ppm. 13C NMR (125 MHz, 134.8, 132.6, 130.8, 124.9, 121.4, 120.4, 117.4, 113.2, 111.0, 61.3,
CDCl3): δ = 165.8, 163.63, 140.1, 137.5, 136.4, 132.6, 123.7, 116.4,
114.9, 61.3, 55.1, 30.1, 14.1 ppm. HRMS calculated for
C15H21FNO4S [MH]+ 330.1175; found 330.1193 (TOF MS EI+).
60.9, 58.1, 55.2, 38.5, 14.2, 13.8 ppm. HRMS calculated for
C23H26NO7S [M + H]+ 460.1430; found 460.1442 (TOF MS EI+).
N-Benzyl-2-bromobenzamide (20): To a round-bottomed flask un-
der Ar was added benzylamine (0.51 cm3, 4.66 mmol), dry DCM
(0.46 , 10 cm3) and Et3N (1.29 cm3, 9.33 mmol). The reaction was
cooled to 0 °C and after stirring for 5 min, 2-bromobenzyl bromide
(0.547 cm3, 4.19 mmol) was added. The reaction was warmed to r.t
Compound 16: Prepared using general method (B) using 2,5-dibro-
mobenzenesulfonyl chloride, p-methoxybenzylamine and methyl vi-
nyl ketone to yield 86 mg of 16 (88%) as a yellow oil. FTIR (neat):
ν = 1716, 1612, 1292, 1249, 1157 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 7.95 (s, 1 H), 7.67 (dd, J = 8.1, 1.4 Hz, 1 H), 7.51 (d, and stirred for 2 h. Then the crude reaction was concentrated in
J = 16.2 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.30 (d, J = 6.7 Hz, situ and suspended in EtOAc (10 cm3). The resulting suspension
2 H), 6.62 (d, J = 11.3 Hz, 2 H), 6.77 (d, J = 10.9 Hz, 1 H), 4.94
(m, 1 H), 4.43 (d, J = 3.84 Hz, 2 H), 3.78 (s, 3 H), 2.98 (dd, J =
18.1, 5.3 Hz, 1 H), 2.78 (dd, J = 18.1, 6.7 Hz, 1 H), 2.39 (s, 3 H),
was filtered through a silica plug and the solvent removed to yield
1.1 g of 20 (95%) as a white solid. FTIR (neat): ν = 3269, 2923,
˜
1643, 1537, 1427, 1313 cm–1. 1H NMR (500 MHz, CDCl3): δ =
1.98 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 205.5, 197.8, 7.58 (dd, J = 8.0, 1.0 Hz, 1 H), 7.56 (dd, J = 7.6, 1.7 Hz, 1 H),
159.4, 140.9, 139.8, 136.1, 136.0, 132.44, 129.9, 129.0, 126.9, 125.0,
120.4, 114.1, 55.8, 55.2, 47.8, 46.7, 30.3, 28.0 ppm. HRMS calcu-
lated for C22H24NO5S [M + H]+ 414.1375; found 414.1364 (TOF
MS EI+).
7.33–7.40 (m, 4 H), 7.31 (dt, J = 7.0, 1.5 Hz, 1 H), 7.27 (td, J =
8.1, 1.8 Hz, 2 H), 6.24 (br. s, 1 H), 4.66 (d, J = 5.7 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3)δ = 167.5, 137.6, 137.5, 133.4, 131.7,
129.6, 128.8, 128.0, 127.7, 127.6, 119.3, 44.2 ppm. HRMS calcu-
lated for C14H13BrNO [M + H]+ 290.0181; found 290.0179 (TOF
MS EI+).1H and 13C NMR spectroscopic data corresponded to
that reported by Catellani and coworkers.[31]
Methyl (2E)-3-[2-Octyl-3-(2-methoxy-2-oxoethyl)-1,1-dioxido-2,3-
dihydro-1,2-benzisothiazol-6-yl]acrylate (17): Prepared using gene-
ral method (B) using 2,5-dibromobenzenesulfonyl chloride, p-meth-
oxybenzylamine and methyl acrylate to produce 86 mg of 17 (84%)
N-(2-Bromobenzyl)-4-methylbenzenesulfonamide (21): To a round-
as a yellow oil. FTIR (neat): ν = 2925, 1724, 1641, 1436, 1298,
bottomed flask under Ar was added 2-bromobenzylamine (0.5 g,
˜
1
1205, 1159 cm–1. H NMR (500 MHz, CDCl3): δ = 7.91 (s, 1 H), 2.68 mmol), dry DCM (0.46 , 5.8 cm3) and Et3N (0.75 cm3,
7.67–7.74 (m, 2 H), 7.46 (d, J = 8.1 Hz, 1 H), 6.51 (d, J = 16.0 Hz, 5.36 mmol). The reaction was cooled to 0 °C and after stirring for
2 H), 4.92 (t, J = 5.5 Hz, 1 H), 3.81 (s, 3 H), 3.73 (s, 3 H), 3.30 (t,
J = 7.5 Hz, 2 H), 2.99 (dd, J = 16.4, 5.3 Hz, 1 H), 2.77 (dd, J =
16.4, 7.1 Hz, 1 H) 1.66–1.74 (m, 2 H), 1.25–1.37 (s, 12 H), 0.86 (t,
J = 5.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.7,
166.6, 142.0, 138.9, 136.2, 136.0, 132.4, 124.8, 120.7, 120.4, 119.9,
57.4, 53.7, 51.5, 43.7, 38.8, 31.7, 29.5, 28.9, 26.4, 26.6, 14.1 ppm.
5 min, p-toluenesulfonyl chloride (0.51 g, 2.68 mmol) was added.
The reaction was warmed to r.t and stirred for 2 h. Then the crude
reaction was concentrated in situ and suspended in EtOAc
(10 cm3). The resulting suspension was filtered through a silica plug
and the solvent removed to yield 0.87 g of 21 (96%) as a white
solid. FTIR (neat): ν = 3282, 1467, 1326, 1159, 1093 cm–1. 1H
˜
HRMS calculated for C22H32NO6S [M + H]+ 438.1950; found NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 8.2 Hz, 2 H), 7.45 (d,
438.1964 (TOF MS EI+).
J = 7.9 Hz, 1 H), 7.19–7.30 (m, 4 H), 7.10 (dt, J = 9.3, 1.5 Hz, 1
H), 4.92 (m, 1 H), 4.22 (d, J = 6.5 Hz, 2 H), 2.40 (s, 3 H) ppm. 13
C
Methyl (2E)-3-[2-(4-Methoxyphenyl)-3-(2-methoxy-2-oxoethyl)-1,1-
dioxido-2,3-dihydro-1,2-benzisothiazol-6-yl]acrylate (18): Prepared
using general method (B) using 2,5-Dibromobenzenesulfonyl chlo-
ride, p-methoxybenzylamine and methyl acrylate to yield 98 mg of
NMR (125 MHz, CDCl3)δ = 162.1, 143.5, 136.8, 135.4, 132.8,
1
130.6, 129.7, 129.6, 127.7, 127.6, 127.1, 123.5, 47.5, 21.5 ppm. H
and 13C NMR spectroscopic data corresponded to that reported
by Malacria and coworkers.[32]
18 (93%) as a yellow oil. FTIR (neat): ν = 1720, 1641, 1492, 1307,
˜
1
1207, 1172, 1155 cm–1. H NMR (500 MHz, CDCl3): δ = 7.95 (s,
N-(2-Bromobenzyl)methanesulfonamide (22): To a round-bottomed
1 H), 7.65–7.69 (m, 2 H), 7.38 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = flask under Ar was added 2-bromobenzylamine (0.5 g, 2.68 mmol),
11.5 Hz, 2 H), 6.86 (d, J = 9.6 Hz, 2 H), 6.52 (d, J = 16.0 Hz, 1
dry DCM (0.46 , 5.8 cm3) and Et3N (0.75 cm3, 5.36 mmol). The
5260
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5254–5262

Domino Heck–Aza-Michael Reactions
reaction was cooled to 0 °C and after stirring for 5 min, meth-
anesulfonyl chloride (0.22 cm3, 2.95 mmol) was added. The reac-
tion was warmed to r.t and stirred for 2 h. Then the crude reaction
was concentrated in situ and suspended in EtOAc (10 cm3). The
resulting suspension was filtered through a silica plug and the sol-
vent removed to yield 0.65 g of 22 (92%) as a white solid. FTIR
tion vial. After stirring for 5 min at room temp., acrylic acid
(8.19ϫ10–5 mol mmol) was added and the reaction vial was placed
immediately into a preheated reaction block. The reaction mixture
was stirred at 110 °C for 14 h after which time the reaction was
cooled and concentrated. The crude was then solvated in dry DCM
(0.1 mL), to which N-methylmorpholine (35 µL, 4.09ϫ10–5 mol)
was added. After stirring for 5 min a solution of OACC50 (17 mg,
5.46ϫ10–5 mol) in dry DCM (0.1 mL) was added and the reaction
mixture stirred for 10 h at room temp. Then, the crude was ab-
sorbed onto silica and purified by flash chromatography (hexane/
EtOAc).
(neat): ν = 3284, 1440, 1319, 1149 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 7.59 (d, J = 7.9 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H),
7.33 (t, J = 7.5 Hz, 1 H), 7.21 (dt, J = 7.5, 1.5 Hz, 1 H), 4.90 (m,
1 H), 4.41 (d, J = 6.4 Hz, 2 H), 2.81 (s, 3 H). 13C NMR (125 MHz,
CDCl3)δ = 162.1, 135.8, 133.2, 130.7, 130.0, 128.0, 123.7, 47.63,
41.3; 1H and 13C NMR spectroscopic data corresponded to that
reported by Malacria and coworkers.[32]
Compound 29: Prepared using general method (C) using ben-
zenesulfonyl chloride, cyclopentylamine, acrylic acid and morph-
oline. The crude material was purified by flash chromatography
(hexane/EtOAc, 1:1 ) to yield 5.92 mg of 30 (56%) as a white solid.
2-Bromo-N-(2-bromobenzyl)benzenesulfonamide (23): To a round-
bottomed flask under Ar was added 2-bromobenzylamine (0.5 g,
2.68 mmol), dry DCM (0.46 , 5.8 cm3) and Et3N (0.75 cm3,
5.36 mmol). The reaction was cooled to 0 °C and after stirring for
5 min, 2-bromobenzenesulfonyl chloride (0.61 g, 2.41 mmol) was
added. The reaction was warmed to r.t and stirred for 2 h. Then the
crude reaction was concentrated in situ and suspended in EtOAc
(10 cm3). The resulting suspension was filtered through a silica plug
and the solvent removed to yield 0.90 g of 23 (93%) as a white
FTIR (neat): ν = 2956, 1637, 1458, 1298, 1170, 1114, 1041 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 8.1 Hz, 1 H), 7.54–
7.57 (m, 1 H), 7.49–7.54 (m, 2 H), 5.13–5.17 (m, 1 H), 3.96 (h, J
= 7.6 Hz, 1 H), 3.71–3.74 (m, 1 H), 3.67 (t, J = 4.7 Hz, 2 H), 3.54–
3.58 (m, 2 H), 3.40–3.56 (m, 2 H), 3.29–3.33 (m, 1 H), 3.04 (dd, J
= 15.3, 5.4, Hz, 1 H), 2.71 (dd, J = 15.3, 7.9, Hz, 1 H), 2.02–2.08
(m, 1 H), 1.91–1.96 (m, 1 H), 1.71–1.78 (m, 2 H), 1.56–1.68 (m, 4
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.4, 139.6, 136.3,
132.8, 129.3, 124.8, 121.0, 66.7, 58.4, 57.1, 46.2, 42.1, 38.8, 30.8,
28.3, 23.4, 22.8 ppm. HRMS calculated for C18H24N2O4SNa [M +
Na]+ 387.1354; found 387.1354 (TOF MS EI+).
solid. FTIR (neat): ν = 3326, 1440, 1336, 1164, 1026 cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 8.80 (dd, J = 7.8, 1.7 Hz, 1 H), 7.58
(dd, J = 7.8, 1.1 Hz, 1 H), 7.45 (dd, J = 6.9, 2.2 Hz, 1 H), 7.40 (dt,
J = 7.7, 1.1 Hz, 1 H), 7.33 (dt, J = 7.6, 1.7 Hz, 1 H), 7.12 (dd, J =
7.7, 1.5 Hz, 1 H), 7.05–7.08 (m, 2 H), 5.79 (m, 1 H), 4.26 (d, J =
6.6 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 162.1, 139.1,
134.9, 133.5, 132.7, 131.4, 130.6, 129.8, 129.6, 127.6, 127.4, 123.8,
119.9, 47.7 ppm. HRMS calculated for C13H11Br2NO2SNa [M +
Na]+ 425.8775; found 425.8781 (TOF MS EI+).
Compound 30: Prepared using general method (C) using ben-
zenesulfonyl chloride, cyclohexylamine, acrylic acid and pyridin-3-
amine. The crude material was purified by flash chromatography
(EtOAc) to yield 4.3 mg of 31 (43%) as a off white solid. FTIR
(neat): ν = 2933, 2360, 1683, 1683, 1292, 1170 cm–1. 1H NMR
˜
(500 MHz, MeOD): δ = 8.74 (s, 1 H), 8.28 (d, J = 3.2 Hz, 1 H),
8.12 (dt, J = 8.4, 1.5 Hz, 1 H), 7.73 (d, J = 7.7 Hz, 1 H), 7.64 (dt,
J = 7.6, 1.0 Hz, 1 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.54 (t, J = 7.5 Hz,
1 H), 7.41 (dd, J = 8.3, 4.8 Hz, 1 H), 5.26 (t, J = 6.6 Hz, 1 H), 3.57
(tt, J = 11.8, 3.6 Hz, 1 H), 3.07 (dd, J = 14.9, 6.1 Hz, 1 H), 3.07
(dd, J = 14.9, 6.1 Hz, 1 H), 2.85 (dd, J = 14.9, 7.1 Hz, 1 H), 1.97
(d, J = 12.6 Hz, 1 H), 1.90 (d, J = 12.3 Hz, 1 H), 1.69–1.83 (m, 4
H), 1.63 (d, J = 12.7 Hz, 1 H), 1.23–1.37 (m, 2 H), 1.18 (tt, J =
12.7, 2.9 Hz, 1 H) ppm. 13C NMR (125 MHz, MeOD): δ = 171.0,
165.2 (d, JC-F = 254.1 Hz), 145.6, 142.0, 140.4, 137.8, 134.3, 130.8,
129.2, 125.8, 121.7,58.7, 57.4, 44.9, 32.8, 31.4, 27.3, 27.2, 26.6 ppm.
HRMS calculated for C20H24N3O3S [M + H]+ 386.1538; found
386.1547 (TOF MS EI+).
Methyl (E)-3-(2-{[3-(2-methoxy-2-oxoethyl)-1,1-dioxido-1,2-benziso-
thiazol-2(3H)-yl]methyl}phenyl)acrylate (24): To a 1-dram vial was
added 23 (76 mg, 0.19 mmol), Et3N (79 µL, 0.56 mmol), Bu4NCl
(70 mg, 0.19 mmol), Pd2(dba)3·CHCl3 (2 mol-%, 3.9 mg,
0.0038 mmol) and dry DMF (1.89 mL). After stirring for 5 min at
room temp., methyl acrylate (51 µL, 0.56 mmol) was added and the
reaction vial was placed immediately into a preheated reaction
block. The reaction mixture was stirred at 110 °C for 14 h after
which time the reaction was cooled and concentrated under re-
duced pressure. The crude was purified by column chromatography
(1:1 hexane/EtOAc) to yield 59 mg of 24 (76%) as a yellow oil.
FTIR (neat): ν = 2950, 2358, 1716, 1299, 1172, 763 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 8.10 (d, J = 15.7 Hz, 1 H), 7.83 (d, J =
7.3 Hz, 1 H), 7.61 (ddd, J = 7.5, 1.2 Hz, 2 H), 7.55 (ddd, J = 5.3,
0.7 Hz, 2 H), 7.32–7.40 (m, 3 H), 6.35 (d, J = 15.7 Hz, 1 H), 4.87
(t, J = 6.3 Hz, 1 H), 4.76 (d, J = 15.9 Hz, 1 H), 4.60 (d, J = 15.9 Hz,
1 H), 3.80 (s, 3 H), 3.54 (s, 3 H), 2.87 (dd, J = 16.6, 5.5 Hz, 1 H),
2.70 (dd, J = 16.6, 6.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3)
δ = 170.5, 166.9, 140.8, 137.2, 134.5, 134.3, 133.7, 133.3, 130.3,
129.6, 128.9, 127.1, 126.2, 124.2, 121.5, 120.9, 58.3, 52.0, 51.8, 45.0,
39.1 ppm. HRMS calculated for C21H21NO6SNa [M + Na]+
438.0987; found 438.0981 (TOF MS EI+).
Compound 31: Prepared using general method (C) using 4-fluoro-
benzenesulfonyl chloride, 4-methoxybenzylamine, acrylic acid and
piperidine. The crude material was purified by flash chromatog-
raphy (hexane/EtOAc, 1:1) to yield 6.46 mg of 32 (52%) as a white
solid. FTIR (neat): ν = 2937, 1635, 1514, 1296, 1247, 1174 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 7.79 (dd, J = 8.4, 4.7 Hz, 1 H),
7.33 (d, J = 8.6 Hz, 2 H), 7.21 (d, J = 8.6 Hz, 2 H), 6.85 (d, J =
8.7 Hz, 2 H), 5.06 (dd, J = 7.8, 5.0 Hz, 1 H), 4.47 (d, J = 3.7 Hz,
2 H), 3.65 (s, 3 H), 3.47–3.58 (m, 2 H), 3.11–3.21 (m, 2 H), 2.81
(dd, J = 16.2, 5.0 Hz, 1 H), 2.57 (dd, J = 16.2, 7.9 Hz, 1 H), 1.57–
1.62 (m, 2 H), 1.48–1.54 (m, 2 H), 1.34–1.42 (m, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 167.1, 165.2 (d, JC,F = 2.1 Hz),
159.39, 131.0, 130.0, 127.3, 123.4, 123.3, 117.2, 117.0, 114.2, 112.7,
112.5, 55.3, 47.0, 46.5, 42.9, 38.2, 26.2, 25.5, 24.3 ppm. HRMS cal-
culated for C22H25FN2O4SNa [M + Na]+ 455.1417; found 455.1422
(TOF MS EI+).
General Procedure (C) for the Synthesis of 1,1-Dioxido-1,2-benziso-
thiazol-3-acetamide Derivatives 29–31: Into a 1-dram vial was
added amine (2.73ϫ10–5 mol), Et3N (5.47ϫ10–5 mol) and dry
DMF (0.1 mL) were the reaction mixture was stirred at room temp.
for
15 min.
Then,
α-bromobenzenesulfonyl
chlorides
(2.73ϫ10–5 mol) were added and the reaction mixture was stirred
for 2 h. Then, Et3N (5.482.73ϫ10–5 mol), Bu4N (7.45 mg,
2.73ϫ10–5 mol),
Pd2(dba)3·CHCl3
(2 mol-%,
2.56 mg,
Supporting Information (see also the footnote on the first page of
this article): Copies of NMR spectra.
0.056ϫ10–5 mol) and dry DMF (0.14 mL) were added to the reac-
Eur. J. Org. Chem. 2008, 5254–5262
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5261

A. Rolfe, K. Young, P. R. Hanson
FULL PAPER
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Acknowledgments
This work was generously supported by funds provided by the
National Institutes of Health (NIH), Center for Chemical Method-
ologies and Library Development at the University of Kansas
(KU-CMLD) (P50 GM069663), Pilot Scale Libraries Program
(P41 GM076302) and NIH COBRE award (P20 RR015563).
Undergraduate funding was provided via an NIH K-INBRE award
(P20 R016475) (to K. Y.) and the KU Center of Research (to
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Published Online: September 22, 2008
5262
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5254–5262