Straightforward Route to γ-Sultams via Novel Tandem S N/Michael Addition

Article abstract of DOI:10.1055/a-1343-9451

A novel tandem approach to trisubstituted γ-sultams has been developed involving N -alkylation of methanesulfonanilides with EWG-substituted allyl bromides followed by intramolecular Michael addition. A series of various isothiazolidine 1,1-dioxides have been prepared under mild transition-metal-free conditions in high yields and trans -diastereoselectivity (confirmed by X-ray crystallography). The dependence of reactivity on electronic properties of substrates has been investigated.

Full text of DOI:10.1055/a-1343-9451

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1795–1804
paper
1795
en
A. Klochkova et al.
Paper
Synthesis
Straightforward Route to -Sultams via Novel Tandem SN/Michael
Addition
Anastasiia Klochkova
Andrey Bubyrev
Dmitry Dar’in
- 31 examples
EWG'
EWG
- up to 98% yield
- diastereoselective
- one-pot
- transition-metal-free
- SN/Michael addition
EWG'
Br
H
N
N
Ar
S
Ar
S
EWG
K2CO3, DMF
0–55 °C
O
O
O
O
Olga Bakulina*
Mikhail Krasavin
Viktor Sokolov
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Saint Petersburg State University, 7/9 Universitetskaya nab,
199034 Saint Petersburg, Russian Federation
o.bakulina@spbu.ru
OSeaMlginatiClBPooaer.kbtrueearlskispnuboaluinnrdgai@nSgtsapAtbeuutU.hrnuoirversity, 7/9 Universitetskaya nab, 199034 Saint Petersburg, Russian Federation
Received: 04.11.2020
Accepted after revision: 29.12.2020
Published online: 29.12.2020
R2
O
O
R
N
O
O
R1
S
R2
O
O
S
S
N
N
CO2Me
N
R1
O
R1
(a)
reported
previously
DOI: 10.1055/a-1343-9451; Art ID: ss-2020-z0566-op
N
CO2R3
CO2R4
O
S
R2
O
O
Abstract A novel tandem approach to trisubstituted -sultams has
been developed involving N-alkylation of methanesulfonanilides with
EWG-substituted allyl bromides followed by intramolecular Michael ad-
dition. A series of various isothiazolidine 1,1-dioxides have been pre-
pared under mild transition-metal-free conditions in high yields and
trans-diastereoselectivity (confirmed by X-ray crystallography). The de-
pendence of reactivity on electronic properties of substrates has been
investigated.
R3
aza-Michael
oxa-Michael
classic Michael addition
EWG'
Br
EWG'
EWG'
EWG
1. SN
(b)
in this
work
N
+
H
N
2. Michael
addition
Ar
S
EWG
N
Ar
S
Ar
S
EWG
O
O
O
O
O
O
γ-sultams
Scheme 1 (a) Key intermediates from previously reported Michael ad-
dition-based strategies towards sultams. (b) Novel N-alkylation/Michael
tandem addition developed in this work.
Keywords sultam, isothiazolidine, tandem, nucleophilic substitution,
Michael addition, cyclic sulfonamide, allyl bromide, stereoselective
The history of fruitful application of sulfonamides in
biomedical chemistry goes back almost 100 years and
counts more than 100 approved drugs,1 making them one
of the most important pharmacophores. Cyclic sulfon-
amides – sultams – have gained special attention due to di-
verse range of bioactivities, such as antiviral,2 anticancer,3
antimalarial,4 antiglaucoma,5 anticonvulsant,6 and anti-
coagulant,7 combined with increased metabolic stability.8
Additionally, sultams have found applications in organic
synthesis and synthesis of natural products as chiral auxil-
iaries.9
To date, a wide variety of general strategies towards
construction of sultams with different ring size and substi-
tution pattern have been reported in the literature, employ-
ing following key transformations: cycloaddition,10 nucleo-
philic substitution,11 ring-closing metathesis,12 CH-activa-
tion,13 Heck reaction,14 radical cyclizations,15 Smiles
rearrangement,16 amination,17 Friedel–Crafts reaction,18
and Michael addition. The latter approach involved inter-
mediates bearing activated double bond at the sulfonamide
sulfur atom19 or in the aromatic side group14,20 (Scheme 1a).
In this work, we present the first example of sultam ring
formation via intramolecular Michael addition involving
Michael acceptor attached to the nitrogen atom of sulfon-
amide (Scheme 1b). The latter moiety was introduced by
reacting allyl bromides with -EWG-substituted methane-
sulfonanilides via nucleophilic substitution. These two
base-promoted transformations occurred sequentially in a
one-pot fashion without changing conditions, thus repre-
senting a tandem reaction.
The starting methanesulfonanilides 1 were readily ac-
cessed from anilines and -acyl-/aryl-substituted methane-
sulfonyl chlorides via standard procedure under mild condi-
tions (Scheme 2).
H
Ar NH2
N
EWG:
CO2Me/Et
COMe
Ar
S
EWG
EWG
SO2Cl
O
O
PhNEt2, CH2Cl2
r.t., 20 h
1a–x,d'
25–97%
Aryl
Scheme 2 Synthesis of methanesulfonanilides 1
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1796
A. Klochkova et al.
Paper
Synthesis
The first dielectrophile studied in tandem reaction with
prepared sulfonanilides was commercially available methyl
-bromocrotonate (2a) (Table 1). Employing classical reac-
tion conditions for alkylation of sulfonamides, namely heat-
ing with potassium carbonate in DMF, afforded a series of
eleven 5-acyl-substituted sultams 3a–k (Table 1) mostly in
high yields and diastereoselectivities after chromatographic
purification or crystallization. -Acetyl-substituted sul-
fonanilides (1, R = Me) were smoothly converted into com-
pounds 3a–c at slight heating to 35 °C. Switching to carbo-
methoxy group at -position (1, R = OMe) resulted in de-
creased reactivity of sulfonanilides; full conversion was
achieved only at 55 °C (compounds 3d–k). Preparation of
compound 3k was performed in a gram-scale (7.3 mmol
loading). The substitution pattern in the N-aryl moiety was
also varied, demonstrating that strong electron-withdraw-
ing groups as well as steric hindrance dropped yields of sul-
tams, most likely due to decreased nucleophilicity of nitro-
gen atom. Notably, even at room temperature the product
of the first step, N-alkylation, was not detected (by 1H NMR
analysis of crude reaction mixtures).
To explore the reaction scope further, we have intro-
duced a series of aryl -substituents to sulfonanilides 1.
When compound 1l, bearing p-tolyl moiety instead of -
acyl, was reacted with the same dielectrophile 2a, only in-
termediate N-alkylated sulfonanilide 4l was isolated
(Scheme 3). Most likely this outcome arises from significant
decrease in CH-acidity of sulfonanilide, thus making it a
poor Michael donor incapable of entering the cyclization
step. Treatment of compound 4l with a stronger base, t-BuOK,
afforded isolation of the desired sultam 3l only in 38% yield.
Analysis of crude 1H NMR spectrum revealed a side reaction
of double bond migration (compound 4′l, Scheme 3). Nota-
bly the isolation of intermediate 4l supports the reaction
pathway proposed on Scheme 1b.
The introduction of strong electron-withdrawing
groups such as CN or CO2Me to -aryl moiety of sulfonani-
lide facilitated Michael addition step drastically, which al-
lowed to our delight obtaining a series of fifteen 5-aryl-
substituted sultams 3m–aa under typical conditions in a
one-pot fashion (Table 2). The obtained yields and dr values
were similar to those observed for acyl substituted sul-
fonanilides.
Table 1 Tandem Sultam Synthesis from Acyl-Substituted Sulfon-
amides and Bromocrotonate
Br
CO2Me
CO2Me
O
H
2a
N
O
N
S
K2CO3, DMF
35 or 55 °C, 20 h
S
X
O
O
R
X
O
O
R
1a–k
Another Michael acceptor, namely -tosylallyl bromide
2b, was also introduced into the developed sultam synthe-
sis (Table 3). It was found to be a more potent dielectrophile
than 2a, providing full conversion of -acetyl-substituted
sulfonanilides 1a–c to sultams within 0.5 hour at 0 °C.
To perform the reaction with the less reactive sulfon-
amide 1d′ the reaction temperature was elevated to 25 °C.
According to the NMR spectra of the reaction mixtures,
these reactions proceeded with very high NMR yields
(>90%). However, the isolated yields were only moderate
since chromatographic isolation of pure compounds failed
(due to the presence of a small impurity with similar reten-
tion) and crystallization led to significant weight loss. In the
case of compound 3ab (Table 3), we also performed an al-
ternative isolation – HPLC, which afforded 92% yield.
The structure and relative trans-configuration of sul-
tams obtained from bromocrotonate were confirmed by X-
ray crystallography (Figure 1 and Table S1). Moreover, in all
three series of the obtained products (Tables 1–3), the addi-
tional criteria for establishing stereochemistry were found:
the value of chemical shifts of the proton at C-5 and the val-
ue of the coupling constants between the C-4 and C-5
protons (Table S2). These values were well reproduced and
3a–k
1/3
R
X
Yield (%) (dr)
aa
ba
ca
dc
ec
fc
Me
Me
Me
H
96 (16:1)b
94 (>20:1)b
98 (17:1)b
4-F
4-MeO
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
77 (8:1)b/52 (>20:1)d
84 (>20:1)d,e
46 (>20:1)d
4-MeO
4-Me
2,6-Me2
4-Cl
gc
hc
ic
61 (>20:1)d
50 (>20:1)d
4-CN
4-CF3
4-F
36 (>20:1)d
jc
45 (>20:1)d
kc
83 (>20:1)f,g
a Reaction temperature: 35 °C.
b Isolated yield and diastereomeric ratio after chromatography.
c Reaction temperature: 55 °C.
d Yield and dr after chromatography + crystallization.
e Structure confirmed by X-ray crystallography.
f Yield after crystallization.
g Prepared in gram-scale.
CO2Me
CO2Me
CO2Me
2a
H
+
N
N
N
t-BuOK
THF, rt
N
Ph
S
Tol-p K2CO3, DMF
Ph
S
Tol-p
Ph
S
Tol-p
Ph
S
Tol-p
O
O
55 °C 20 h
O
O
O
O
O
O
1l
4l, 72%
3l, 38% (>20:1)
4'l (not isolated)
Scheme 3 Reaction of bromocrotonate 2a with a weak -CH-acidic sulfonanilide 1l
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804

1797
A. Klochkova et al.
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Synthesis
Table 2 Tandem Sultam Synthesis from -Aryl-Substituted Sulfon-
Table 3 Tandem Sultam Synthesis from Acyl-Substituted Sulfon-
amides and Bromocrotonate
amides and Allyl Bromide 2b
CO2Me
O
S
Ts
H
Br
N
2a
N
O
S
S
H
X
2b
EWG
O
O
X
EWG
N
O
O
O
K2CO3
DMF
55 °C
O
S
N
S
O
O
O
O
R
1m–aa
3m–aa
K2CO3, DMF
0 or 25 °C, 0.5–1 h
X
R
X
1a–c,d'
3ab–cb,d'b
1/3
EWG
4-CO2Me
X
Yield (%)a (dr)
1
3
R
X
Yield (%) (dr)
m
n
o
p
q
r
H
82 (>20:1)
65 (>20:1)
56 (9:1)
a
aba
Me
Me
Me
OEt
H
92b/60c (19:1)
66c (13:1)
4-CO2Me
4-CO2Me
4-CO2Me
4-CO2Me
4-CN
4-CF3
2,6-Me2
4-MeO
4-CN
H
b
c
bba
cba
F
MeO
H
62c (13:1)
62 (>20:1)
58 (>20:1)
57 (>20:1)b
67 (>20:1)
63 (>20:1)
88 (>20:1)
61 (>20:1)
79 (>20:1)
57 (>20:1)
53 (>20:1)
79 (>20:1)
51 (>20:1)
d′
d′bd
80 (6.4:1)
a Reaction temperature: 0 °C.
b After HPLC.
c After crystallization.
s
4-CN
4-CF3
2,6-Me2
4-MeO
4-CN
H
d Reaction temperature: 25 °C.
t
4-CN
u
v
4-CN
4-CN
trans-configuration according to X-ray crystallography and
NMR data. The developed approach offers the advantages of
cost-effective one-pot protocol, easily accessible substrates,
general scope, high yields and stereoselectivity, mild reac-
tion conditions, and lack of metal catalysis. To the best of
our knowledge, this is the first example of sultam construc-
tion via cyclization of Michael acceptor attached to the ni-
trogen atom of sulfonamide.
w
x
2-CN
2-CN
4-CF3
2,6-Me2
4-MeO
4-CN
y
2-CN
z
2-CN
aa
2-CN
a Yield after crystallization.
b Structure confirmed by X-ray crystallography.
coincided with the data for compounds with crystal struc-
tures, therefore, all sultams 3 were assigned the trans-con-
figuration.
In conclusion, we have described a new synthesis of tri-
substituted -sultams involving tandem SN/Michael addi-
tion sequence. A series of -EWG substituted methanesul-
fonanilides was N-alkylated with allyl bromides followed by
cyclization via Michael addition. The CH-acidity of -posi-
tion in sulfonamide was found to be crucial for proceeding
of the cyclization step. All isolated sultams were assigned
NMR spectra were acquired with a 400 MHz Bruker Avance III spec-
1
trometer (400.13 MHz for H and 100.61 MHz for 13C) in CDCl3, ace-
tone-d6 or DMSO-d6 and were referenced to residual solvent proton
signals (H = 7.26, 2.05, or 2.50) and solvent carbon signals (C = 77.2,
29.8, or 39.5, respectively). Melting points were determined with a
melting point apparatus Stuart SMP 50 in open capillary tubes. Mass
spectra were acquired with a Bruker maXis HRMS-ESI-qTOF spec-
trometer (electrospray ionization mode, positive ions detection). Col-
umn chromatography was carried out on silica gel grade 60 (0.040–
0.063 mm) 230–400 mesh. TLC was performed on aluminum-backed
precoated plates (0.25 mm) with silica gel 60 F254 and was visualized
using UV fluorescence. Preparative HPLC was carried out on Shimadzu
Figure 1 Crystal structure of compounds 3e and 3r. Thermal ellipsoid plots shown at 50% probability level.21
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804

1798
A. Klochkova et al.
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Synthesis
LC-20AP instrument, equipped with a spectrophotometric detector.
Column: Agilent Zorbax prepHT XDB-C18, 5 m, 21.2 × 150 mm. Mo-
bile phase: MeCN/H2O + 0.1% TFA, 40 °C, 12 mL/min. Sulfonamides
1d–i,l,m,r,d′[11,22] were prepared according to published procedures.
Methyl -bromocrotonate (2a) was obtained from commercial sourc-
es (85:15 E/Z-mixture).
1H NMR (400 MHz, CDCl3):  = 7.28–7.23 (m, 2 H), 6.91 (s, 1 H), 6.90–
6.86 (m, 2 H), 4.03 (s, 2 H), 3.81 (s, 3 H), 2.37 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 198.4, 158.5, 128.4, 125.6, 114.8, 59.4,
55.5, 31.6.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H13NO4SNa: 266.0457;
found: 264.0463.
Sulfonamides 1a–c; General Procedure
Methansulfonanilides 1i–k,n–q,s–aa; General Procedure
To a suspension of finely ground crude sodium 2-oxopropane-1-sul-
fonate (1.64 g, 7.5 mmol, 1 equiv, containing 27% NaCl by weight) in
anhyd MeCN (7 mL) was added DMF (100 L). The mixture was cooled
in an ice-bath and oxalyl chloride (536 L, 6.25 mmol, 1 equiv) was
quickly added under vigorous stirring. The reaction mixture was
stirred for 10 min at 0 °C, and then at r.t. until gas evolution (CO2, CO)
had finished. The precipitate was filtered off, washed with anhyd
MeCN (3 × 5 mL) and discarded. The resulting solution of sulfonyl
chloride in MeCN was directly introduced into the next step (the yield
of sulfonyl chloride was estimated as 90% according to NMR of evapo-
rated sample).
To a stirred solution of the corresponding aniline (2–27 mmol) and
PhNEt2 (1.2 equiv) in anhyd DCM (30–60 mL) was slowly added drop-
wise a solution of methyl 2-(chlorosulfonyl)acetate (1.2 equiv) at r.t.
After 24 h, the reaction mixture was washed with 5% aq HCl (2 × 30
mL), sat. aq NaHCO3 (30 mL), and H2O (2 × 30 mL). The organic layer
was separated, dried (Na2SO4), filtered, and concentrated to give
crude sulfonamides 1, which were purified using crystallization.
Methyl 2-[N-(4-Cyanophenyl)sulfamoyl]acetate (1i)
Yield: 1.19 g (34%); white solid; mp 134–136 °C (CHCl3).
A solution of the corresponding aniline (6.75 mmol, 1 equiv), pyridine
(616 L, 7.76 mmol, 1.15 equiv), and DMAP (24 mg, 0.2 mmol, 3
mol%) in anhyd THF (15 mL) was cooled in an ice/salt bath to –10 °C
and the solution of sulfonyl chloride from the previous step (6.75
mmol, 1 equiv) was slowly added dropwise with vigorous stirring.
The solution was stirred at the same temperature until the amine was
completely consumed (about 5 min, TLC: SiO2, eluent n-hexane/ace-
tone, 80:20). The precipitate of Et3N·HCl was filtered off and washed
with THF (3 × 7 mL). THF was evaporated in vacuo and the residue
was dissolved in EtOAc (70 mL), the organic phase was washed suc-
cessively with aq 1 M HCl (2 × 30 mL), H2O (2 × 30 mL) and brine (50
mL), dried (Na2SO4), filtered, and concentrated to obtain the desired
pure sulfonamide 1a–c.
1H NMR (400 MHz, DMSO-d6):  = 10.87 (s, 1 H), 7.79 (d, J = 8.7 Hz, 2
H), 7.34 (d, J = 8.7 Hz, 2 H), 4.41 (s, 2 H), 3.61 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 163.3, 142.4, 133.9, 119.0, 118.9,
105.7, 56.1, 52.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H10N2O4SNa: 277.0253;
found: 277.0252.
Methyl 2-{N-[4-(Trifluoromethyl)phenyl]sulfamoyl}acetate (1j)
Yield: 1.33 g (48%); light blue solid; mp 136–138 °C (Et2O/hexane).
1H NMR (400 MHz, CDCl3):  = 7.63 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.3
Hz, 2 H), 7.33 (s, 1 H), 4.01 (s, 2 H), 3.81 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.3, 139.5, 128.2 (q, 2JC,F = 33.1 Hz),
127.1 (q, 3JC,F = 3.7 Hz), 123.9 (q, 1JC,F = 271.9 Hz), 121.5, 53.6, 53.5.
2-Oxo-N-phenylpropane-1-sulfonamide (1a)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H10F3NO4SNa: 320.0175;
found: 320.0175.
Yield: 1.39 g (97%); brown crystals; mp 96.2–98.1 °C.
1H NMR (400 MHz, CDCl3):  = 7.35 (dd, J = 8.4, 7.0 Hz, 2 H), 7.29 (d, J =
7.3 Hz, 2 H), 7.23 (t, J = 7.2 Hz, 1 H), 7.15 (s, 1 H), 4.06 (s, 2 H), 2.33 (s,
3 H).
13C NMR (101 MHz, CDCl3):  = 198.2, 136.2, 129.7, 126.4, 122.5, 59.9,
31.6.
Methyl 2-[N-(4-Fluorophenyl)sulfamoyl]acetate (1k)
Yield: 1.9 g (34%); light blue solid; mp 100–102 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.56–7.22 (m, 1 H), 7.20–6.99 (m, 3 H),
3.96 (s, 2 H), 3.84 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.6, 161.3 (d, 1JC,F = 246.6 Hz), 132.0
(d, 4JC,F = 3.1 Hz), 125.4 (d, 3JC,F = 8.4 Hz), 116.6 (d, 2JC,F = 22.8 Hz), 53.5,
52.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H10FNO4SNa: 270.0207;
found: 270.0213.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H11NO3SNa: 236.0352;
found: 236.0357.
N-(4-Fluorophenyl)-2-oxopropane-1-sulfonamide (1b)
Yield: 1.48 g (95%); brown crystals; mp 87.8–88.9 °C.
1H NMR (400 MHz, CDCl3):  = 7.32–7.26 (m, 2 H), 7.11 (s, 1 H), 7.10–
6.96 (m, 2 H), 4.03 (s, 2 H), 2.35 (s, 3 H).
Methyl 4-({N-[4-(Trifluoromethyl)phenyl]sulfamoyl}methyl)ben-
zoate (1n)
13C NMR (101 MHz, CDCl3):  = 198.5, 161.3 (d, 1JC,F = 246.5 Hz), 131.9
(d, 4JC,F = 3.0 Hz), 125.3 (d, 3JC,F = 8.4 Hz), 116.5 (d, 2JC,F = 22.9 Hz), 59.6,
31.7.
19F NMR (376 MHz, CDCl3):  = –115.2.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H10FNO3SNa: 254.0258;
Yield: 460 mg (25%); white solid; mp 191–192 °C (Et2O).
1H NMR (400 MHz, acetone-d6):  = 7.95 (d, J = 8.4 Hz, 2 H), 7.67 (d, J =
8.5 Hz, 2 H), 7.49 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.3 Hz, 2 H), 4.68 (s, 2
H), 3.89 (s, 3 H).
found: 254.0257.
13C NMR (101 MHz, acetone-d6):  = 166.9, 143.1, 135.4, 132.2, 131.3,
130.3, 128.1 (d, 1JC,F = 270.7 Hz), 127.5 (q, 3JC,F = 3.8 Hz), 125.7 (q, 2JC,F
=
N-(4-Methoxyphenyl)-2-oxopropane-1-sulfonamide (1c)
32.6 Hz), 119.5, 58.3, 52.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H14F3NO4SNa: 396.0488;
Yield: 1.54 g (94%); brown crystals; mp 71.5–73.0 °C.
found: 396.0505.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804

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Synthesis
Methyl 4-{[N-(2,6-Dimethylphenyl)sulfamoyl]methyl}benzoate
(1o)
1H NMR (400 MHz, CDCl3):  = 7.61 (d, J = 8.3 Hz, 2 H), 7.41 (d, J = 8.2
Hz, 2 H), 7.12 (d, J = 8.9 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 1 H), 6.62 (s, 1 H),
4.31 (s, 2 H), 3.81 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 158.3, 134.4, 132.9, 132.0, 129.2,
124.2, 118.6, 115.4, 113.2, 57.3, 56.0.
Yield: 415 mg (29%); white solid; mp 171.5–173 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 8.04 (d, J = 8.2 Hz, 2 H), 7.54 (d, J = 8.1
Hz, 2 H), 7.17–6.98 (m, 3 H), 5.93 (s, 1 H), 4.47 (s, 2 H), 3.91 (s, 3 H),
2.41 (s, 6 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H14N2O3SNa: 325.0617;
13C NMR (101 MHz, CDCl3):  = 166.7, 137.4, 133.9, 133.0, 131.1,
found: 325.0608.
130.7, 130.1, 129.1, 128.2, 60.4, 52.4, 19.5.
N,1-Bis(4-cyanophenyl)methanesulfonamide (1v)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H19NO4SNa: 356.0927;
Yield: 0.93 g (63%) after washing with DCM; white solid; mp 237–
239 °C .
found: 356.0922.
Methyl 4-[(N-(4-Methoxyphenyl)sulfamoyl]methyl)benzoate (1p)
1H NMR (400 MHz, DMSO-d6):  = 10.55 (s, 1 H), 7.82 (d, J = 8.3 Hz, 2
H), 7.76 (d, J = 8.8 Hz, 2 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.28 (d, J = 8.8 Hz,
2 H), 4.78 (s, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 142.8, 134.7, 132.3, 132.0, 118.9,
118.5, 118.0, 111.2, 104.9, 57.2.
Yield: 0.9 g (57%); white solid; mp 121.5–123 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.99 (d, J = 8.3 Hz, 2 H), 7.37 (d, J = 8.2
Hz, 2 H), 7.12 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 6.51 (s, 1 H),
4.31 (s, 2 H), 3.90 (s, 3 H), 3.81 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.6, 157.9, 133.8, 131.0, 130.7,
130.1, 129.2, 123.8, 115.0, 57.1, 55.7, 52.4.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H11N3O2SNa: 320.0464;
found: 320.0449.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H17NO5SNa: 358.0720;
found: 358.0712.
1-(2-Cyanophenyl)-N-phenylmethanesulfonamide (1w)
Yield: 420 mg (77%); white solid; mp 141–142 °C (Et2O).
Methyl 4-{[N-(4-Cyanophenyl)sulfamoyl]methyl}benzoate (1q)
1H NMR (400 MHz, CDCl3):  = 7.72–7.60 (m, 1 H), 7.60–7.52 (m, 2 H),
7.44 (td, J = 7.4, 1.8 Hz, 1 H), 7.38–7.28 (m, 2 H), 7.23–7.17 (m, 2 H),
7.17–7.12 (m, 1 H), 7.10 (s, 1 H), 4.62 (s, 2 H).
13C NMR (101 MHz, CDCl3):  = 136.7, 133.4, 133.2, 132.2, 132.1,
129.8, 129.5, 125.3, 120.2, 117.4, 114.7, 56.4.
Yield: 430 mg (26%); white solid; mp 180–182 °C (Et2O).
1H NMR (400 MHz, acetone-d6):  = 9.23 (s, 1 H), 7.95 (d, J = 8.5 Hz, 2
H), 7.72 (d, J = 8.8 Hz, 2 H), 7.46 (dd, J = 8.6, 1.8 Hz, 4 H), 4.71 (s, 2 H),
3.89 (s, 3 H).
13C NMR (101 MHz, acetone-d6):  = 166.8, 143.7, 135.2, 134.5, 132.2,
131.3, 130.3, 119.4, 119.3, 107.3, 58.5, 52.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H12N2O2SNa: 295.0512;
found: 295.0498.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H14N2O4SNa: 353.0566;
found: 353.0570.
1-(2-Cyanophenyl)-N-[4-(trifluoromethyl)phenyl]methane-
sulfonamide (1x)
Yield: 680 mg (67%); white solid; mp 171–172 °C (DCM).
1-(4-Cyanophenyl)-N-[4-(trifluoromethyl)phenyl]methane-
sulfonamide (1s)
1H NMR (400 MHz, acetone-d6):  = 9.37 (s, 1 H), 7.97–7.75 (m, 1 H),
7.74–7.62 (m, 4 H), 7.61–7.55 (m, 1 H), 7.52 (d, J = 8.4 Hz, 2 H), 4.81 (s,
2 H).
Yield: 420 mg (62%); white solid; mp 146–148 °C (hexane).
1H NMR (400 MHz, CDCl3):  = 7.67–7.56 (m, 4 H), 7.41 (d, J = 8.3 Hz, 2
H), 7.29 (d, J = 8.5 Hz, 2 H), 7.21 (s, 1 H), 4.67–4.35 (m, 2 H).
13C NMR (101 MHz, acetone-d6):  = 142.8, 134.0, 133.8, 133.4, 133.3,
130.3, 127.4 (q, 3JC,F = 3.8 Hz), 125.8 (q, 2JC,F = 32.5 Hz), 125.4 (d, 1JC,F
=
13C NMR (101 MHz, CDCl3):  = 140.1, 133.5, 132.7, 131.7, 127.2 (q,
270.5 Hz), 119.4, 117.8, 115.5, 57.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H12F3N2O2SNa: 341.0566;
found: 341.0554.
1
3JC,F = 3.9 Hz), 127.0, 123.9 (q, JC,F = 271.7 Hz), 122.7, 118.9, 118.0,
113.2, 57.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H11F3N2O2SNa: 363.0386;
found: 363.0371.
1-(2-Cyanophenyl)-N-(2,6-dimethylphenyl)methanesulfonamide
(1y)
1-(4-Cyanophenyl)-N-(2,6-dimethylphenyl)methanesulfonamide
Yield: 560 mg (47%); light purple solid; mp 168–169 °C (Et2O).
(1t)
1H NMR (400 MHz, CDCl3):  = 7.36 (dd, J = 7.8, 1.4 Hz, 1 H), 7.31 (dd,
J = 7.9, 1.3 Hz, 1 H), 7.25 (td, J = 7.7, 1.4 Hz, 1 H), 7.12 (td, J = 7.6, 1.4
Hz, 1 H), 6.82–6.67 (m, 3 H), 5.97 (s, 1 H), 4.37 (s, 2 H).
13C NMR (101 MHz, CDCl3):  = 137.6, 133.3, 133.1, 132.8, 132.7,
132.3, 129.4, 129.1, 128.3, 117.6, 114.7, 58.6, 19.4.
Yield: 0.9 g (62%); light green solid; mp 156–158 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.70–7.62 (m, 2 H), 7.61–7.52 (m, 2 H),
7.19–7.06 (m, 3 H), 5.97 (s, 1 H), 4.45 (s, 2 H), 2.41 (s, 6 H).
13C NMR (101 MHz, CDCl3):  = 137.4, 134.2, 132.7, 132.6, 131.8,
129.1, 128.4, 118.4, 112.9, 60.2, 19.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H16N2O2SNa: 323.0825;
found: 323.0811.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H16N2O2SNa: 323.0825;
found: 323.0812.
1-(2-Cyanophenyl)-N-(4-methoxyphenyl)methanesulfonamide
(1z)
1-(4-Cyanophenyl)-N-(4-methoxyphenyl)methanesulfonamide
(1u)
Yield: 1.0 g (68%); light purple solid; mp 120–121 °C (Et2O).
Yield: 364 mg (60%) after washing with DCM; light purple solid; mp
134–135 °C.
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1H NMR (400 MHz, CDCl3):  = 7.74–7.66 (m, 1 H), 7.65–7.55 (m, 2 H),
7.47 (ddd, J = 7.7, 6.5, 2.3 Hz, 1 H), 7.24–7.14 (m, 2 H), 6.94 (s, 1 H),
6.90–6.83 (m, 2 H), 4.60 (s, 2 H), 3.81 (s, 3 H).
Methyl (±)-2-[(4S,5S)-5-Acetyl-2-(4-methoxyphenyl)-1,1-dioxido-
isothiazolidin-4-yl]acetate (3c)
Yield: 404 mg (98%), after column chromatography (hexane/EtOAc);
brown oil; dr = 17:1.
13C NMR (101 MHz, CDCl3):  = 157.9, 133.4, 133.2, 132.4, 132.2,
1H NMR (400 MHz, CDCl3):  = 7.25–7.17 (m, 2 H), 6.91–6.84 (m, 2 H),
4.25 (d, J = 6.9 Hz, 1 H), 3.82 (dd, J = 9.3, 7.7 Hz, 1 H), 3.77 (s, 3 H), 3.67
(s, 3 H), 3.51 (h, J = 7.4 Hz, 1 H), 3.36 (dd, J = 9.3, 7.6 Hz, 1 H), 2.71–
2.57 (m, 2 H), 2.49 (s, 3 H).
129.4, 129.1, 124.0, 117.5, 114.9, 114.6.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H14N2O3SNa: 325.0617;
found: 325.0618.
1-(2-Cyanophenyl)-N-(4-cyanophenyl)methanesulfonamide (1aa)
13C NMR (101 MHz, CDCl3):  = 195.9, 171.3, 158.8, 128.7, 125.9,
114.8, 71.6, 55.6, 52.1, 51.4, 36.7, 30.8, 30.3.
Yield: 780 mg (52%); white solid; mp 234–235 °C (Et2O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H19NO6SNa: 364.0831;
found: 364.0834.
1H NMR (400 MHz, acetone-d6):  = 9.48 (s, 1 H), 7.79 (dd, J = 7.7, 1.4
Hz, 1 H), 7.74–7.67 (m, 3 H), 7.65 (dd, J = 7.9, 1.4 Hz, 1 H), 7.59 (td, J =
7.6, 1.5 Hz, 1 H), 7.50–7.39 (m, 2 H), 4.83 (s, 2 H).
Methyl (±)-(4S,5S)-4-(2-Methoxy-2-oxoethyl)-2-phenylisothiazoli-
dine-5-carboxylate 1,1-Dioxide (3d)
13C NMR (101 MHz, acetone-d6):  = 143.5, 143.4, 134.4, 134.0, 133.9,
133.5, 133.2, 133.1, 130.4, 117.8, 115.5, 107.5, 57.5.
Yield: 251 mg (77%), after column chromatography (EtOAc/DCM); dr =
8:1; yield: 170 mg (52%), after additional crystallization from Et2O; dr
= >20:1 white solid; mp 118.5–120 °C (Et2O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H11N3O2SNa: 320.0464;
found: 320.0462.
1H NMR (400 MHz, CDCl3):  = 7.39 (t, J = 7.7 Hz, 2 H), 7.36–7.27 (m, 2
H), 7.24 (t, J = 7.3 Hz, 1 H), 4.20 (d, J = 7.4 Hz, 1 H), 4.09–3.98 (m, 1 H),
3.93 (s, 3 H), 3.74 (s, 3 H), 3.64–3.36 (m, 2 H), 2.81 (dd, J = 16.6, 6.1 Hz,
1 H), 2.71 (dd, J = 16.6, 6.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 171.0, 164.6, 136.8, 129.6, 126.2,
121.9, 66.8, 53.9, 52.3, 50.5, 36.4, 31.9.
Sultams 3; General Procedure
To a suspension of K2CO3 (1.2 equiv) in DMF (5 mL) was added the
corresponding sulfonamide 1 (1–1.2 mmol, 1 equiv). The mixture was
stirred for 10 min, and then methyl 4-bromocrotonate (2a; 1.1 equiv)
or (E)-1-[(3-bromoallyl)sulfonyl]-4-methylbenzene (2b; 1.1 equiv)
was added in one portion. The mixture was stirred at 0, 25, 35 or 55
°C until full consumption of sulfonamide (0.5–20 h, TLC: SiO2, eluent:
n-hexane/EtOAc 75:25). After full conversion, DMF was evaporated in
vacuo and the residue was partitioned between EtOAc and H2O, and
the aqueous phase was extracted with EtOAc (3 × 10 mL). The com-
bined organic phases were washed sequentially with aq 1 M HCl (2 ×
15 mL), H2O (3 × 10 mL) and brine (2 × 20 mL), dried (Na2SO4), filtered,
concentrated, and purified by column chromatography on silica gel or
by crystallization.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H17NO6SNa: 350.0669;
found: 350.0603.
Methyl (±)-(4S,5S)-4-(2-Methoxy-2-oxoethyl)-2-(4-methoxy-
phenyl)isothiazolidine-5-carboxylate 1,1-Dioxide (3e)
Yield: 304 mg (84%), after column chromatography (EtOAc/DCM) +
crystallization from Et2O; white solid; mp 93.5–95.5 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.25 (d, J = 9.0 Hz, 2 H), 6.89 (d, J = 9.0
Hz, 2 H), 4.13 (d, J = 7.4 Hz, 1 H), 3.97–3.84 (m, 4 H), 3.79 (s, 3 H), 3.71
(s, 3 H), 3.59–3.45 (m, 1 H), 3.42 (dd, J = 9.3, 7.6 Hz, 1 H), 2.76 (dd, J =
16.6, 7.0 Hz, 1 H), 2.67 (dd, J = 16.6, 7.2 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 171.1, 164.9, 158.8, 128.9, 125.9,
114.9, 66.5, 55.6, 53.9, 52.2, 51.5, 36.7, 32.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H19NO7SNa: 380.0774;
found: 380.0779.
Methyl (±)-2-[(4S,5S)-5-Acetyl-1,1-dioxido-2-phenylisothiazoli-
din-4-yl]acetate (3a)
Yield: 361 mg (96%), after column chromatography (hexane/EtOAc);
brown oil; dr = 16:1.
1H NMR (400 MHz, CDCl3):  = 7.40–7.34 (m, 2 H), 7.30–7.25 (m, 2 H),
7.22 (t, J = 7.3 Hz, 1 H), 4.30 (d, J = 7.3 Hz, 1 H), 3.93 (dd, J = 9.0, 7.4 Hz,
1 H), 3.70 (s, 3 H), 3.53 (h, J = 7.2 Hz, 1 H), 3.48–3.41 (m, 1 H), 2.71 (dd,
J = 16.5, 7.3 Hz, 1 H), 2.64 (dd, J = 16.5, 6.9 Hz, 1 H), 2.52 (s, 3 H).
Methyl (±)-(4S,5S)-4-(2-Methoxy-2-oxoethyl)-2-(p-tolyl)isothiazo-
lidine-5-carboxylate 1,1-Dioxide (3f)
13C NMR (101 MHz, CDCl3):  = 195.7, 171.2, 136.7, 129.6, 126.2,
122.0, 72.0, 52.2, 50.3, 36.4, 30.8, 30.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H17NO5SNa: 334.0725;
found: 334.0726.
Yield: 156 mg (46%), after column chromatography (EtOAc/DCM) +
crystallization from Et2O; white solid; mp 88–90 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.30–6.97 (m, 4 H), 4.15 (d, J = 7.6 Hz, 1
H), 4.04–3.83 (m, 4 H), 3.71 (s, 3 H), 3.56–3.36 (m, 2 H), 2.77 (dd, J =
16.6, 6.7 Hz, 1 H), 2.67 (dd, J = 16.6, 7.1 Hz, 1 H), 2.33 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 171.0, 164.7, 136.5, 134.0, 130.2,
122.7, 66.7, 53.9, 52.3, 50.8, 36.6, 32.0, 21.0.
Methyl (±)-2-[(4S,5S)-5-Acetyl-2-(4-fluorophenyl)-1,1-dioxidoiso-
thiazolidin-4-yl]acetate (3b)
Yield: 374 mg (94%), after column chromatography (hexane/EtOAc);
brown oil.
1H NMR (400 MHz, CDCl3):  = 7.30–7.21 (m, 2 H), 7.09–7.01 (m, 2 H),
4.29 (d, J = 7.2 Hz, 1 H), 3.86 (t, J = 9.2 Hz, 1 H), 3.68 (s, 3 H), 3.52 (h, J =
7.3 Hz, 1 H), 3.39 (t, J = 9.2 Hz, 1 H), 2.74–2.58 (m, 2 H), 2.50 (s, 3 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H19NO6SNa: 364.0825;
found: 364.0818.
Methyl (±)-(4S,5S)-2-(2,6-Dimethylphenyl)-4-(2-methoxy-2-oxo-
ethyl)isothiazolidine-5-carboxylate 1,1-Dioxide (3g)
13C NMR (101 MHz, CDCl3):  = 195.7, 171.2, 161.2 (d, 1JC,F = 246.6 Hz),
132.3 (d, 4JC,F = 3.0 Hz), 125.2 (d, 3JC,F = 8.5 Hz), 116.4 (d, 2JC,F = 22.8 Hz),
71.6, 52.2, 50.9, 36.5, 30.8, 30.3.
Yield: 153 mg (61%) after column chromatography (EtOAc/DCM) +
crystallization from Et2O; white solid; mp 117.5–119 °C (Et2O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H16FNO5SNa: 352.0631;
found: 352.0629.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804

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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.20–7.12 (m, 1 H), 7.12–7.02 (m, 2 H),
4.20 (d, J = 9.1 Hz, 1 H), 3.91 (s, 3 H), 3.90–3.83 (m, 1 H), 3.71 (s, 3 H),
3.67–3.55 (m, 1 H), 3.49–3.27 (m, 1 H), 2.84 (dd, J = 16.6, 6.0 Hz, 1 H),
2.70 (dd, J = 16.6, 7.5 Hz, 1 H), 2.40 (s, 3 H), 2.39 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.42–7.20 (m, 2 H), 7.20–6.92 (m, 2 H),
4.18 (d, J = 7.6 Hz, 1 H), 3.97 (dd, J = 9.1, 7.1 Hz, 1 H), 3.93 (s, 3 H), 3.73
(s, 3 H), 3.64–3.49 (m, 1 H), 3.49–3.42 (m, 1 H), 2.80 (dd, J = 16.6, 6.8
Hz, 1 H), 2.70 (dd, J = 16.6, 7.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 171.1, 164.9, 140.6, 139.9, 132.4,
129.4, 129.2, 65.3, 53.8, 52.2, 50.6, 36.4, 32.5, 18.9, 18.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H21NO6SNa: 378.0982;
found: 378.0971.
13C NMR (101 MHz, CDCl3):  = 171.0, 164.7, 161.3 (d, 1JC,F = 246.6 Hz),
132.5 (d, 4JC,F = 3.0 Hz), 125.2 (d, 3JC,F = 8.5 Hz), 116.5 (d, 2JC,F = 22.9 Hz),
66.5, 53.9, 52.3, 51.1, 36.5, 32.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H16FNO6SNa: 368.0575;
found: 368.0568.
Methyl (±)-(4S,5S)-2-(4-Chlorophenyl)-4-(2-methoxy-2-oxoethyl)-
isothiazolidine-5-carboxylate 1,1-Dioxide (3h)
Methyl (±)-2-[(4S,5S)-1,1-Dioxido-2-phenyl-5-(p-tolyl)isothiazoli-
din-4-yl]acetate (3l)
Yield: 180 mg (50%), after column chromatography (EtOAc/DCM) +
crystallization from Et2O; white solid; mp 124–126 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.39–7.31 (m, 2 H), 7.24–7.17 (m, 2 H),
4.17 (d, J = 7.7 Hz, 1 H), 3.97 (dd, J = 8.8, 6.8 Hz, 1 H), 3.91 (s, 3 H), 3.72
(s, 3 H), 3.58–3.41 (m, 2 H), 2.79 (dd, J = 16.6, 6.4 Hz, 1 H), 2.68 (dd, J =
16.6, 7.2 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.9, 164.5, 135.4, 131.8, 129.7,
123.2, 66.7, 54.0, 52.3, 50.5, 36.3, 31.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H16ClNO6SNa: 384.0279;
found: 384.0272.
Yield: 45 mg (38%), after column chromatography (EtOAc/DCM);
brown solid; mp 133–135 °C.
1H NMR (400 MHz, CDCl3):  = 7.40–7.33 (m, 4 H), 7.32–7.28 (m, 2 H),
7.28–7.23 (m, 2 H), 7.20–7.11 (m, 1 H), 4.24 (d, J = 12.1 Hz, 1 H), 4.05
(dd, J = 8.9, 6.9 Hz, 1 H), 3.63 (s, 3 H), 3.59 (t, J = 9.2 Hz, 1 H), 3.46–3.32
(m, 1 H), 2.60 (dd, J = 16.3, 4.3 Hz, 1 H), 2.46 (dd, J = 16.3, 9.3 Hz, 1 H),
2.39 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 170.9, 140.1, 138.0, 130.0, 129.9,
129.5, 125.6, 124.6, 119.5, 68.6, 52.1, 50.5, 35.5, 34.8, 21.4.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H21NO4SNa: 382.1083;
found: 382.1101.
Methyl (±)-(4S,5S)-2-(4-Cyanophenyl)-4-(2-methoxy-2-oxoethyl)-
isothiazolidine-5-carboxylate 1,1-Dioxide (3i)
Methyl (±)-4-[(4S,5S)-4-(2-Methoxy-2-oxoethyl)-1,1-dioxido-2-
phenylisothiazolidin-5-yl]benzoate (3m)
Yield: 125 mg (36%), after column chromatography (EtOAc/DCM) +
crystallization from Et2O; white solid; mp 133–135.5 °C (Et2O).
Yield: 330 mg (82%), after crystallization from Et2O; white solid; mp
201–202 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.64 (d, J = 8.8 Hz, 2 H), 7.30 (d, J = 8.9
Hz, 2 H), 4.26 (d, J = 8.3 Hz, 1 H), 4.09 (q, J = 5.5 Hz, 1 H), 3.92 (s, 3 H),
3.73 (s, 3 H), 3.52 (qd, J = 8.3, 6.0 Hz, 2 H), 2.89–2.77 (m, 1 H), 2.69
(dd, J = 16.9, 7.1 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.8, 163.8, 141.4, 133.6, 119.0,
118.6, 107.9, 66.7, 54.1, 52.4, 49.5, 35.7, 31.5.
1H NMR (400 MHz, CDCl3):  = 8.12 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 8.5
Hz, 2 H), 7.48–7.33 (m, 2 H), 7.33–7.27 (m, 2 H), 7.23–7.11 (m, 1 H),
4.35 (d, J = 11.8 Hz, 1 H), 4.07 (dd, J = 9.0, 6.9 Hz, 1 H), 3.94 (s, 3 H),
3.75–3.53 (m, 4 H), 3.48–3.32 (m, 1 H), 2.58 (dd, J = 16.3, 4.7 Hz, 1 H),
2.49 (dd, J = 16.3, 8.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.7, 166.5, 137.6, 134.0, 131.6,
130.4, 130.1, 129.6, 125.1, 120.0, 68.4, 52.5, 52.2, 50.5, 35.6, 35.2.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H16N2O6SNa: 375.0621;
found: 375.0615.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H21NO6SNa: 426.0982;
found: 426.0987.
Methyl (±)-(4S,5S)-4-(2-Methoxy-2-oxoethyl)-2-[4-(trifluoro-
methyl)phenyl]isothiazolidine-5-carboxylate 1,1-Dioxide (3j)
Yield: 178 mg (45%), after column chromatography (EtOAc/DCM) +
crystallization from Et2O; white solid; mp 100.3–102 °C (hex-
ane/Et2O).
Methyl (±)-4-{(4S,5S)-4-(2-Methoxy-2-oxoethyl)-1,1-dioxido-2-
[4-(trifluoromethyl)phenyl]isothiazolidin-5-yl}benzoate (3n)
Yield: 307 mg (65%), after crystallization from Et2O; white solid; mp
189–190 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.62 (d, J = 8.5 Hz, 2 H), 7.35 (d, J = 8.5
Hz, 2 H), 4.23 (d, J = 8.2 Hz, 1 H), 4.14–4.00 (m, 1 H), 3.92 (s, 3 H), 3.73
(s, 3 H), 3.60–3.43 (m, 2 H), 2.82 (dd, J = 16.8, 5.6 Hz, 1 H), 2.70 (dd, J =
16.7, 6.9 Hz, 1 H).
1H NMR (400 MHz, CDCl3:  = 8.13 (d, J = 8.3 Hz, 2 H), 7.62 (d, J = 8.5
Hz, 2 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 4.40 (d, J =
12.4 Hz, 1 H), 4.12 (dd, J = 8.9, 6.8 Hz, 1 H), 3.94 (s, 3 H), 3.64 (s, 4 H),
3.54–3.29 (m, 1 H), 2.59 (dd, J = 16.5, 4.4 Hz, 1 H), 2.48 (dd, J = 16.5,
8.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.5, 166.4, 141.0, 132.9, 132.0,
130.5, 130.2, 126.8 (q, 3JC,F = 3.7 Hz), 126.1 (q, 2JC,F = 33.1 Hz), 124.2 (q,
1JC,F = 271.5 Hz), 117.9, 68.4, 52.5, 52.3, 50.0, 35.1, 34.7.
2
13C NMR (101 MHz, CDCl3):  = 170.9, 164.1, 140.4, 127.2 (q, JC,F
=
32.9 Hz), 126.8 (q, 3JC,F = 3.7 Hz), 124.0 (q, 1JC,F = 271.7 Hz), 119.7, 66.8,
54.1, 52.4, 49.9, 36.0, 31.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H16F3NO6SNa: 418.0543;
found: 418.0530.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H20F3NO6SNa: 494.0856;
found: 494.0859.
Methyl (±)-(4S,5S)-2-(4-Fluorophenyl)-4-(2-methoxy-2-oxo-
ethyl)isothiazolidine-5-carboxylate 1,1-Dioxide (3k)
Yield: 2.08 g (83%), 7.3 mmol scale, obtained pure after crystallization
from Et2O; white solid; mp 116–118 °C (Et2O).
Methyl (±)-4-[(4R,5R)-2-(2,6-Dimethylphenyl)-4-(2-methoxy-2-
oxoethyl)-1,1-dioxidoisothiazolidin-5-yl]benzoate (3o)
Yield: 240 mg (56%), after crystallization from Et2O; white solid; dr =
8:1.
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1H NMR (400 MHz, CDCl3):  = 8.11 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 8.4
Hz, 2 H), 7.21–7.14 (m, 1 H), 7.13–7.06 (m, 2 H), 4.36 (d, J = 12.7 Hz, 1
H), 4.10–3.76 (m, 4 H), 3.64–3.51 (m, 4 H), 3.49–3.37 (m, 1 H), 2.62–
2.36 (m, 8 H).
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 8.4 Hz, 2 H), 7.71–7.48 (m, 4
H), 7.34 (d, J = 8.5 Hz, 2 H), 4.42 (d, J = 12.2 Hz, 1 H), 4.12 (dd, J = 8.9,
6.9 Hz, 1 H), 3.72–3.57 (m, 4 H), 3.50–3.30 (m, 1 H), 2.58 (dd, J = 16.5,
4.6 Hz, 1 H), 2.49 (dd, J = 16.5, 8.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.8, 166.6, 140.6, 139.9, 134.0,
132.8, 131.5, 130.3, 130.2, 129.3, 129.2, 52.4, 52.1, 51.1, 35.5, 35.4,
18.8, 18.8.
13C NMR (101 MHz, CDCl3):  = 170.4, 140.8, 133.6, 133.0, 130.9, 126.9
(q, JC,F = 3.8 Hz), 126.4 (q, JC,F = 33.1 Hz), 124.1 (q, JC,F = 271.7 Hz),
118.2, 118.0, 114.3, 68.2, 52.4, 50.0, 35.0, 34.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H25NO6SNa: 454.1295;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H17F3N2O4SNa: 461.0753;
found: 454.1304.
found: 461.0769.
Methyl (±)-4-[(4S,5S)-4-(2-Methoxy-2-oxoethyl)-2-(4-methoxy-
Methyl (±)-[(4S,5S)-5-(4-Cyanophenyl)-2-(2,6-dimethylphenyl)-
phenyl)-1,1-dioxidoisothiazolidin-5-yl]benzoate (3p)
1,1-dioxidoisothiazolidin-4-yl]acetate (3t)
Yield: 260 mg (62%), after crystallization from Et2O; white solid; mp
133–135 °C (Et2O).
Yield: 250 mg (63%), after crystallization from Et2O; white solid; mp
194–196 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 8.11 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.3
Hz, 2 H), 7.29 (d, J = 9.0 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 4.32 (d, J =
11.1 Hz, 1 H), 3.99 (dd, J = 9.1, 7.2 Hz, 1 H), 3.93 (s, 3 H), 3.80 (s, 3 H),
3.60 (s, 3 H), 3.56 (t, J = 9.0 Hz, 1 H), 3.47–3.27 (m, 1 H), 2.58 (dd, J =
16.2, 5.0 Hz, 1 H), 2.51 (dd, J = 16.3, 8.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.8, 166.5, 158.3, 134.8, 131.5,
130.4, 130.0, 129.8, 124.7, 114.9, 68.0, 55.6, 52.4, 52.2, 51.7, 36.0,
35.7.
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.4
Hz, 2 H), 7.22–7.15 (m, 1 H), 7.14–7.08 (m, 2 H), 4.38 (d, J = 12.3 Hz, 1
H), 3.93 (dd, J = 8.4, 6.9 Hz, 1 H), 3.60 (s, 3 H), 3.59–3.37 (m, 2 H), 2.55
(dd, J = 16.3, 4.4 Hz, 1 H), 2.50–2.30 (m, 7 H).
13C NMR (101 MHz, CDCl3):  = 170.6, 140.5, 139.8, 134.6, 132.8,
132.6, 130.9, 129.4, 129.3, 118.2, 113.8, 66.5, 52.2, 51.0, 35.4, 35.3,
18.8, 18.8.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H22N2O4SNa: 421.1192;
found: 421.1203.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H23NO7SNa: 456.1087;
found: 456.1106.
Methyl (±)-2-[(4S,5S)-5-(4-Cyanophenyl)-2-(4-methoxyphenyl)-
Methyl (±)-4-[(4S,5S)-2-(4-Cyanophenyl)-4-(2-methoxy-2-oxo-
1,1-dioxidoisothiazolidin-4-yl]acetate (3u)
ethyl)-1,1-dioxidoisothiazolidin-5-yl]benzoate (3q)
Yield: 350 mg (88%), after crystallization from Et2O; white solid; mp
157–159 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.4
Hz, 2 H), 7.31 (d, J = 9.0 Hz, 2 H), 6.94 (d, J = 9.0 Hz, 2 H), 4.35 (d, J =
10.9 Hz, 1 H), 4.01 (dd, J = 9.3, 7.3 Hz, 1 H), 3.82 (s, 3 H), 3.64 (s, 3 H),
3.58 (t, J = 9.0 Hz, 1 H), 3.44–3.29 (m, 1 H), 2.66–2.36 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 170.5, 158.4, 135.4, 132.7, 130.6,
129.3, 124.8, 118.1, 114.9, 113.6, 67.6, 55.5, 52.1, 51.6, 35.9, 35.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H20N2O5SNa: 423.0985;
found: 423.0973.
Yield: 250 mg (58%), after crystallization from Et2O; white solid; mp
159–161 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 8.13 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.9
Hz, 2 H), 7.56 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.9 Hz, 2 H), 4.43 (d, J =
12.7 Hz, 1 H), 4.13 (dd, J = 8.9, 6.7 Hz, 1 H), 3.94 (s, 3 H), 3.69–3.56 (m,
4 H), 3.56–3.27 (m, 1 H), 2.58 (dd, J = 16.6, 4.2 Hz, 1 H), 2.46 (dd, J =
16.6, 9.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.4, 166.3, 141.9, 133.7, 132.3,
132.1, 130.6, 130.2, 118.8, 117.5, 106.8, 68.4, 52.5, 52.4, 49.8, 34.8,
34.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H20N2O6SNa: 451.0934;
found: 451.0917.
Methyl (±)-2-[(4S,5S)-2,5-Bis(4-cyanophenyl)-1,1-dioxidoisothi-
azolidin-4-yl]acetate (3v)
Yield: 240 mg (61%), after crystallization from Et2O; white solid; mp
157–159 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.77 (d, J = 8.3 Hz, 2 H), 7.66–7.50 (m, 4
H), 7.29 (d, J = 8.9 Hz, 2 H), 4.45 (d, J = 12.5 Hz, 1 H), 4.13 (dd, J = 8.9,
6.9 Hz, 1 H), 3.66 (s, 4 H), 3.54–3.27 (m, 1 H), 2.58 (dd, J = 16.6, 4.4 Hz,
1 H), 2.49 (dd, J = 16.6, 8.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.3, 141.7, 133.7, 133.1, 133.0,
130.9, 118.7, 118.0, 117.6, 114.4, 107.1, 68.1, 52.4, 49.7, 34.7, 34.4.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H17N3O4SNa: 418.0832;
found: 418.0837.
Methyl (±)-2-[(4S,5S)-5-(4-Cyanophenyl)-1,1-dioxido-2-phenyliso-
thiazolidin-4-yl]acetate (3r)
Yield: 210 mg (57%), after crystallization from Et2O; white solid; mp
159–161 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 8.4 Hz, 2 H), 7.68–7.57 (m, 2
H), 7.39 (dd, J = 8.7, 7.2 Hz, 2 H), 7.34–7.28 (m, 2 H), 7.20 (td, J = 7.2,
1.2 Hz, 1 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.06 (dd, J = 9.1, 7.0 Hz, 1 H),
3.77–3.52 (m, 4 H), 3.52–3.31 (m, 1 H), 2.58 (dd, J = 16.4, 5.0 Hz, 1 H),
2.51 (dd, J = 16.4, 8.4 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 170.5, 137.4, 134.7, 132.9, 130.8,
129.7, 125.4, 120.3, 118.2, 113.9, 68.1, 52.3, 50.5, 35.6, 35.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H19N2O4SNa: 371.1060;
found: 371.1057.
Methyl (±)-2-[(4S,5S)-5-(2-Cyanophenyl)-1,1-dioxido-2-phenyliso-
thiazolidin-4-yl]acetate (3w)
Yield: 380 mg (79%), after crystallization from Et2O; white solid; mp
168–169 °C (Et2O).
Methyl (±)-2-{(4S,5S)-5-(4-Cyanophenyl)-1,1-dioxido-2-[4-(triflu-
oromethyl)phenyl]isothiazolidin-4-yl}acetate (3s)
Yield: 295 mg (67%), after crystallization from Et2O; white solid; mp
188–190 °C (Et2O).
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804

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1H NMR (400 MHz, CDCl3):  = 7.85 (dd, J = 7.7, 1.0 Hz, 1 H), 7.81–7.67
(m, 2 H), 7.55 (td, J = 7.7, 1.2 Hz, 1 H), 7.47–7.36 (m, 2 H), 7.36–7.29
(m, 2 H), 7.23–7.15 (m, 1 H), 4.80 (d, J = 11.3 Hz, 1 H), 4.09 (dd, J = 9.1,
7.1 Hz, 1 H), 3.67 (t, J = 9.2 Hz, 1 H), 3.63 (s, 3 H), 3.44–3.30 (m, 1 H),
2.64–2.57 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 170.4, 137.2, 133.5, 133.4, 133.3,
130.0, 129.9, 129.5, 125.4, 120.7, 116.9, 115.1, 65.8, 52.2, 50.5, 36.3,
35.7.
1H NMR (400 MHz, CDCl3):  = 7.91–7.69 (m, 3 H), 7.65 (d, J = 8.9 Hz, 2
H), 7.59 (td, J = 7.5, 1.4 Hz, 1 H), 7.32 (d, J = 8.9 Hz, 2 H), 4.87 (d, J =
12.3 Hz, 1 H), 4.15 (dd, J = 8.9, 6.9 Hz, 1 H), 3.71 (t, J = 9.4 Hz, 1 H), 3.65
(s, 3 H), 3.54–3.32 (m, 1 H), 2.68–2.41 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 170.3, 141.7, 133.8, 133.7, 133.7,
131.5, 130.6, 130.0, 118.7, 117.9, 116.8, 115.5, 107.2, 65.9, 52.5, 49.9,
35.3, 35.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H17N3O4SNa: 418.0832;
found: 418.0829.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H20N2O5SNa: 423.0985;
found: 423.0981.
(±)-1-[(4S,5R)-1,1-Dioxido-2-phenyl-4-(tosylmethyl)isothiazoli-
Methyl (±)-2-{(4S,5S)-5-(2-Cyanophenyl)-1,1-dioxido-2-[4-(triflu-
din-5-yl]ethan-1-one (3ab)
oromethyl)phenyl]isothiazolidin-4-yl}acetate (3x)
Yield: 295 mg (60%); white solid; dr = ?16:1, crystallization from tolu-
ene/Et2O; yield: 449 mg (92%); white solid; dr = ?19:1, HPLC.
1H NMR (400 MHz, CDCl3):  = 7.81 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 7.9
Hz, 2 H), 7.42 (t, J = 7.7 Hz, 2 H), 7.28–7.14 (m, 3 H), 4.91 (d, J = 8.7 Hz,
1 H), 3.92 (dd, J = 9.6, 7.5 Hz, 1 H), 3.71–3.59 (m, 3 H), 3.36–3.22 (m, 1
H), 2.44 (s, 3 H), 2.36 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 195.2, 144.9, 136.6, 135.6, 130.0,
129.4, 127.8, 125.5, 120.9, 70.7, 56.1, 48.8, 30.7, 28.6, 21.1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H21NO5S2Na: 430.0759;
found: 430.0763.
Yield: 250 mg (57%, after crystallization from Et2O; white solid; mp
130–132 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.82 (dd, J = 8.2, 1.3 Hz, 1 H), 7.80–7.70
(m, 2 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.57 (td, J = 7.6, 1.3 Hz, 1 H), 7.37 (d,
J = 8.5 Hz, 2 H), 4.85 (d, J = 12.0 Hz, 1 H), 4.15 (dd, J = 9.0, 7.0 Hz, 1 H),
3.72 (t, J = 9.2 Hz, 1 H), 3.64 (s, 3 H), 3.51–3.38 (m, 1 H), 2.63–2.52 (m,
2 H).
13C NMR (101 MHz, CDCl3):  = 170.4, 140.7, 133.7, 133.7, 132.2,
3
1
130.4, 130.1, 126.8 (q, JC,F = 3.8 Hz), 126.8 (q, JC,F = 271.6 Hz), 126.4
(q, 2JC,F = 33.1 Hz), 118.5, 116.9, 115.4, 66.0, 52.4, 50.1, 35.7, 35.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H17F3N2O4SNa: 461.0753;
found: 461.0739.
(±)-1-[(4S,5R)-2-(4-Fluorophenyl)-1,1-dioxido-4-(tosylmethyl)iso-
thiazolidin-5-yl]ethan-1-one (3bb)
Yield: 340 mg (66%); white solid; crystallization from Et2O; dr = 13:1.
Methyl (±)-2-[(4S,5S)-5-(2-Cyanophenyl)-2-(2,6-dimethylphenyl)-
1,1-dioxidoisothiazolidin-4-yl]acetate (3y)
1H NMR (400 MHz, CDCl3):  = 7.87–7.70 (m, 2 H), 7.51 (d, J = 8.0 Hz, 2
H), 7.28 (d, J = 6.6 Hz, 4 H), 4.91 (d, J = 8.4 Hz, 1 H), 3.90 (dd, J = 9.7, 7.5
Hz, 1 H), 3.69–3.58 (m, 3 H), 3.34–3.24 (m, 1 H), 2.44 (s, 3 H), 2.36 (s, 3
H).
Yield: 210 mg (53%), after crystallization from Et2O; white solid; mp
159–161 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.93 (d, J = 8.0 Hz, 1 H), 7.84–7.65 (m, 2
H), 7.54 (td, J = 7.6, 1.1 Hz, 1 H), 7.23–7.15 (m, 1 H), 7.12 (d, J = 7.4 Hz,
2 H), 4.81 (d, J = 12.2 Hz, 1 H), 3.98 (dd, J = 8.3, 6.8 Hz, 1 H), 3.70–3.42
(m, 5 H), 2.57–2.34 (m, 8 H).
13C NMR (101 MHz, CDCl3):  = 170.5, 140.5, 140.0, 133.5, 133.5,
132.9, 132.8, 130.0, 129.9, 129.4, 129.4, 129.1, 117.0, 115.6, 64.3, 52.3,
51.0, 36.4, 35.6, 18.8, 18.8.
13C NMR (101 MHz, CDCl3):  = 195.3, 160.1 (d, 1JC,F = 243.3 Hz), 144.9,
3
2
135.6, 132.7, 130.0, 127.8, 124.21 (d, JC,F = 8.6 Hz), 116.3 (d, JC,F
=
22.8 Hz), 70.4, 56.2, 49.4, 30.7, 28.7, 21.1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H20FNO5S2Na: 448.0665;
found: 448.0670.
(±)-1-[(4S,5R)-2-(4-Methoxyphenyl)-1,1-dioxido-4-(tosylmeth-
yl)isothiazolidin-5-yl]ethan-1-one (3cb)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H22N2O4SNa: 421.1192;
found: 421.1209.
Yield: 328 mg (62%); white solid; crystallization from toluene; dr =
13:1.
Methyl (±)-2-[(4S,5S)-5-(2-Cyanophenyl)-2-(4-methoxyphenyl)-
1H NMR (400 MHz, CDCl3):  = 7.84–7.79 (m, 2 H), 7.50 (d, J = 8.0 Hz, 2
H), 7.25–7.17 (m, 2 H), 7.02–6.95 (m, 2 H), 4.79 (d, J = 8.0 Hz, 1 H),
3.83 (dd, J = 9.8, 7.6 Hz, 1 H), 3.77 (s, 3 H), 3.66 (dd, J = 6.8, 2.6 Hz, 2
H), 3.59 (dd, J = 9.8, 8.2 Hz, 1 H), 3.38 (qd, J = 7.8, 6.3 Hz, 1 H), 2.44 (s,
3 H), 2.37 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 195.4, 157.9, 144.9, 135.7, 130.0,
128.6, 127.8, 124.9, 114.7, 70.3, 56.3, 55.33, 49.8, 30.7, 28.6, 21.1.
1,1-dioxidoisothiazolidin-4-yl]acetate (3z)
Yield: 380 mg (79%), after crystallization from Et2O; white solid; mp
106–108 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.86 (d, J = 8.1 Hz, 1 H), 7.78–7.66 (m, 2
H), 7.53 (td, J = 7.6, 1.2 Hz, 1 H), 7.37–7.28 (m, 2 H), 7.03–6.81 (m, 2
H), 4.76 (d, J = 10.6 Hz, 1 H), 4.02 (dd, J = 9.3, 7.4 Hz, 1 H), 3.80 (s, 3 H),
3.61 (d, J = 7.3 Hz, 4 H), 3.43–3.30 (m, 1 H), 2.74–2.48 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 170.7, 158.6, 134.3, 133.6, 133.5,
130.0, 130.0, 129.4, 125.4, 117.1, 115.1, 115.0, 65.6, 55.7, 52.3, 51.8,
37.0, 36.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H23NO6S2Na: 460.0864;
found: 460.0866.
Ethyl (±)-(4S,5R)-2-Phenyl-4-(tosylmethyl)isothiazolidine-5-car-
boxylate 1,1-Dioxide (3d′b)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H20N2O5SNa: 423.0985;
found: 423.0981.
Yield: 419 mg (80%), after column chromatography (hexane/DCM);
colorless oil; dr = 6.4:1.
Methyl (±)-2-[(4S,5S)-5-(2-Cyanophenyl)-2-(4-cyanophenyl)-1,1-
dioxidoisothiazolidin-4-yl]acetate (3aa)
Yield: 240 mg (51%), after column chromatography; white glassy solid.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804

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A. Klochkova et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.86–7.82 (m, 2 H), 7.54–7.48 (m, 2 H),
7.45–7.39 (m, 2 H), 7.27–7.20 (m, 3 H), 4.72 (d, J = 9.4 Hz, 1 H), 4.22
(qd, J = 7.1, 1.4 Hz, 2 H), 3.96 (dd, J = 9.7, 7.3 Hz, 1 H), 3.83 (dd, J = 14.5,
6.2 Hz, 1 H), 3.74–3.61 (m, 2 H), 3.30–3.18 (m, 1 H), 2.44 (s, 3 H), 1.21
(t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 163.6, 145.7, 136.5, 135.5, 130.4,
129.6, 128.2, 126.3, 121.9, 66.3, 63.5, 57.9, 50.1, 30.5, 21.8, 14.1.
(4) Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gut, J.; Rosenthal,
P. J. Bioorg. Med. Chem. Lett. 2006, 16, 4115.
(5) Wroblewski, T.; Graul, A.; Castañer, J. Drugs Fut. 1998, 23, 365.
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HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H23NO6S2Na: 460.0864;
found: 460.0857.
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Methyl (E)-4-{[N-Phenyl-1-(p-tolyl)methyl]sulfonamido}but-2-
enoate (4l)
A solution of methyl (E)-4-bromobut-2-enoate (188 mg, 1.05 mmol)
in DMF (10 mL) was added to a mixture of sulfonamide 1l (261 mg, 1
mmol) and K2CO3 (207 mg, 1.5 mmol) in DMF (15 mL). After stirring
for 24 h at r.t., the reaction mixture was poured into 5% aq HCl (50
mL) and extracted with DCM (2 × 25 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated in vacuo to give the
crude product, which was crystallized from Et2O to give the pure title
compound; yield: 260 mg (72%); white solid; mp 119–120 °C (Et2O).
1H NMR (400 MHz, CDCl3):  = 7.41–7.33 (m, 2 H), 7.33–7.27 (m, 5 H),
7.21 (d, J = 7.8 Hz, 2 H), 6.65 (dt, J = 15.7, 5.8 Hz, 1 H), 5.80 (dt, J = 15.7,
1.7 Hz, 1 H), 4.25 (s, 2 H), 4.14 (dd, J = 5.8, 1.8 Hz, 2 H), 3.68 (s, 3 H),
2.38 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.2, 142.8, 139.2, 139.1, 130.8,
129.7, 129.6, 128.1, 127.9, 125.5, 123.5, 57.6, 52.6, 51.7, 21.4.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H21NO4SNa: 382.1083;
found: 382.1081.
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51, 2681.
Funding Information
This research was supported by the grant of the President of the Rus-
sian Federation project no. МK-1073.2020.3.
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(МK-1
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2
0
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3)
(16) Yan, J.; Cheo, H. W.; Teo, W. K.; Shi, X.; Wu, H.; Idres, S. B.; Deng,
L. W.; Wu, J. J. Am. Chem. Soc. 2020, 142, 11357.
(17) (a) Pan, Z.; Wang, S.; Brethorst, J. T.; Douglas, C. J. J. Am. Chem.
Soc. 2018, 140, 3331. (b) Song, B.; Yu, C. B.; Ji, Y.; Chen, M. W.;
Zhou, Y. G. Chem. Commun. 2017, 53, 1704. (c) Tao, Y.;
Gilbertson, S. R. Chem. Commun. 2018, 54, 11292.
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Synth.Commun. 2002, 32, 2877. (b) Gilleron, P.; Wlodarczyk, N.;
Houssin, R.; Farce, A.; Laconde, G.; Goossens, J.-F.; Lemoine, A.;
Pommery, N.; Henichart, J.-P.; Millet, R. Bioorg. Med. Chem. Lett.
2007, 17, 5465.
Acknowledgment
We thank the Research Center for Magnetic Resonance, Center for X-
ray Diffraction Methods and the Center for Chemical Analysis and
Materials Research of Saint Petersburg State University Research Park
for obtaining the analytical data.
Supporting Information
(19) (a) Zang, Q.; Javed, S.; Hill, D.; Ullah, F.; Bi, D.; Porubsky, P.;
Neuenswander, B.; Lushington, G. H.; Santini, C.; Organ, M. G.;
Hanson, P. R. ACS Comb. Sci. 2012, 14, 456. (b) Rolfe, A.;
Samarakoon, T. B.; Hanson, P. R. Org. Lett. 2010, 12, 1216.
(20) Grosheva, D. S.; Rassadin, V. A.; Sokolov, V. V. Eur. J. Org. Chem.
2015, 1355.
(21) CCDC 2036644 (3e) and CCDC 2036645 (3r) contain the supple-
mentary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/structures.
(22) (a) Rassadin, V. A.; Tomashevskii, A. A.; Sokolov, V. V.; Potekhin,
A. A. Chem. Heterocycl. Compd. 2008, 44, 474. (b) Reddy, M. V.;
Mallireddigari, M. R.; Pallela, V. R.; Cosenza, S. C.; Billa, V. K.;
Akula, B.; Subbaiah, D. R.; Bharathi, E. V.; Padgaonkar, A.; Lv, H.;
Gallo, J. M.; Reddy, E. P. J. Med. Chem. 2013, 56, 5562.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1343-9451. Crystallographic data and cop-
ies of NMR spectra are included.
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© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1795–1804