Synthesis of spiropyrrolidinyl-benzoisothiazoline derivatives by 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide

Article abstract of DOI:10.1016/j.tet.2014.10.039

The new spirocyclic compounds, spiropyrrolidinyl-benzoisothiazoline derivatives were synthesized by the 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide. The stereochemistry of 1,3-dipolar cycloaddition as well as the stereochemistry of Knoevenagel condensation of benzoisothiazole-2,2-dioxide with aldehydes were studied.

Full text of DOI:10.1016/j.tet.2014.10.039

Tetrahedron xxx (2014) 1e7
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Synthesis of spiropyrrolidinyl-benzoisothiazoline derivatives by 1,3-
dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes
and azomethine ylide
Guorui Cao, Feifei Long, Yingchun Zhao, Yu Wang, Longjiang Huang, Dawei Teng *
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2014
Received in revised form 11 October 2014
Accepted 17 October 2014
Available online xxx
The new spirocyclic compounds, spiropyrrolidinyl-benzoisothiazoline derivatives were synthesized by
the 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide. The
stereochemistry of 1,3-dipolar cycloaddition as well as the stereochemistry of Knoevenagel condensation
of benzoisothiazole-2,2-dioxide with aldehydes were studied.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
Benzoisothiazole-2,2-dioxide
Spirocyclic compound
Azomethine ylide
Spiropyrrolidinyl-benzoisothiazoline
1. Introduction
dipoles such as azomethine ylides, nitrones, and nitrile oxides. To
the best of our knowledge, there are no reports on the synthetic
Benzoisothiazole dioxides, which possess similar structure with
oxindoles, have been shown to exhibit a variety of biological ac-
tivities. Many benzoisothiazole dioxides derivatives substituted in
the C-3 position are useful pharmaceutical agents such as central
application of benzoisothiazole-2,2-dioxide-3-ylidene 5 with 1,3-
dipoles.
Herein, we demonstrate the application of a [3þ2] cycloaddi-
tion reaction toward the synthesis of novel benzoisothiazole di-
oxide derivatives. The results of our studies will lead to an
unprecedented synthesis of spiropyrrolidinyl-benzoisothiazoline
derivatives using 1,3-dipolar cycloaddition reaction of 5 with azo-
methine ylide 6.
1
nervous system stimulants and antihypertensive agents. Spi-
robenzoisothiazole dioxide derivatives inhibit the activity of
phosphotyrosine phosphatase 1B, which is suitable for the treat-
2
ment of type I and II diabetes. They are also progesterone receptor
antagonists3 and potent HIV-1 inhibitors. Although considerable
4
efforts have been made to develop efficient methods for the syn-
5
2. Results and discussion
thesis of benzoisothiazole dioxides and their derivatives, molec-
6
ular diversity is only varied on the C-3 position by alkylation and
7
Our research started with a modified literature synthesis of
benzoisothiazole-2,2-dioxide,
isothiazole-2,2-dioxide 1 was prepared by sequential N-alkylation
of 2-bromoaniline with mesyl chloride and iodomethane to afford
N,N-disubstituted aniline, which was smoothly converted to 1 un-
der sodium amide in ammonia condition. Knoevenagel condensa-
Knoevenagel condensation. As part of our effort on exploring bi-
5
c
8
1-methyl-1,3-dihydro-benzo[c]
ologically important heterocyclic and spirocyclic compounds and
inspired by the biological activities of naturally occurring spiroox-
9
indole derivatives and their synthetic intermediates, we started to
examine the 1,3-dipolar cycloadditions of benzoisothiazole-2,2-
dioxide-3-ylidene derivatives 5a, 5b, and 5c to different 1,3-
tion of
1 with aldehydes 2aej to afford a,b-unsaturated
dipolarophiles 5aej. For acetaldehyde and propylaldehyde, Knoe-
venagel condensation products 3k and 3l are obtained, the corre-
sponding dipolarophiles 5k and 5l are obtained by O-alkylation of 3
with mesyl chloride and subsequent elimination under basic con-
dition (Scheme 1).
*
Corresponding author. Tel./fax: þ86 532 68074518; e-mail address: dteng@
qust.edu.cn (D. Teng).
http://dx.doi.org/10.1016/j.tet.2014.10.039
0
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
G. Cao et al. / Tetrahedron xxx (2014) 1e7
H
N
Due to the deshielding effect of the sulfuryl group of the ben-
NH2
Br
N
MsCl
CH3I
SO2CH3
0
0
SO2CH3
zoisothiazoline ring, the chemical shift of H-2 and H-6 protons in
the phenyl ring are approximately 7.79e8.03 ppm for the Z-isomers
and 7.45e7.74 ppm for the E-isomers. These findings are in accor-
dance with the similar results of 3-substituted indolin-2-ones,
Pyridine,toluene
NaH,DMF
Br
Br
R
RCHO
0
0
where it has been demonstrated that the H-2 and H-6 protons in
the phenyl ring of 3-substituted-indolin-2-ones display a slight
NaNH2
NH3 (l)
SO2
2a-j
SO2
N
N
KOH,EtOH
10
down-field shift in the Z-isomers as compared with E-isomers.
1
The chemical shifts of the vinyl protons are approximately
5
a-j
6
.57e7.45 ppm for the Z-isomers and 6.62e7.47 ppm for the E-
RCHO K2CO3 / DMF
k, 2l
isomers. The downfield of the vinyl proton chemical shift of the E-
isomer relative to its Z-isomer (except for 5feh) is due to the vinyl
proton of the E-isomer being deshielded by the sulfuryl group of
the benzoisothiazoline ring. The results coincide with the similar
a,b-unsaturated oxindole reported by Teichert, where the vinyl
protons of the E-isomers always appear at lower field in the H
NMR spectra than the corresponding signal of the Z-isomers.
The H-4 chemical shifts of the respective Z and E isomers are
also listed in Table 1. It is clear that the shifts of compound 5g and
2
HO
MsO
R
R
R
MsCl
DBU
SO2
SO2
SO2
Et3N,DCM
toluene
N
1
N
N
11
4k, 4l
5k, 5l
3k, 3l
Scheme 1. Synthetic route of benzoisothiazole-2,2-dioxide-3-ylidene derivatives 5.
5
h move to 8.72 and 8.48 ppm, which are attributed to the hy-
Two stereoisomers of the 1-methyl-3-alkylidene-1,3-
dihydrobenzo[c]isothiazole 2,2-dioxide 5, either by direct Knoeve-
nagel condensation or by elimination of the corresponding mesy-
drogen bond between C-4 hydrogen and the oxygen of ester group
in 5g and furanyl in 5h. It means that there is a favorable electro-
static interaction between the electron-rich oxygen (possesses
and C-4 hydrogen (possesses
dꢀ)
1
lates, are found in H NMR spectra and thin-layer chromatography
dþ) (Scheme 3).
analysis. The geometrical configurations of compound 5 could be
0
partly assigned on the chemical shifts of particular proton, H-2 , H-
O
0
6
, and H-vinyl, in the molecules and confirmed using NOE analysis.
O
H
O
H
The Z configured compounds 5aef showed NOE between the proton
at the C-4 position and the vinyl proton, whereas the E-configured
0
SO2
N
compounds showed NOE between the C-4 and hydrogen at the C-2
SO2
0
1
N
(
or C-6 ) (see Scheme 2). The H NMR chemical shift of their par-
ticular protons (H-2 ,6 , H-4, and H-vinyl) are summarized in Table 1.
0
0
5
g
5
h
R
Scheme 3. Hydrogen bond between C-4 hydrogen and O-3 atom in 5g and 5h.
NOE
H
NOE
R
H
H
H
The relative ratios of the two isomers in the mixtures are de-
H
1
termined by H NMR spectral analysis or column chromatography.
SO2
SO2
In most cases, the more thermodynamically stable Z-isomer is
predominantly formed, with the exception of compound 5h
N
N
(
Table 1, Entry 8). In the condensation of furfural 2h with 1, a larger
Scheme 2. Determination of the configurations for 5aef by NOE analysis.
amount of the E-isomer was observed (E-isomer: Z-isomer¼3.4:1),
Table 1
Yields and 1H NMR chemical shift values of key protons of compound 5
6
'
R
2
'
R
CH
SO
CH
4
4
5
6
5
2
SO
2
N
6
N
7
7
5
a-f
5g-l
Entry
5
R
Isomer ratio (Z:E)a Total yield (%) NMR data chemical shift in ppm
0
0
0
0
Z-isomer H-2 ,6 E-isomer H-2 ,6 Z-isomer H-4 E-isomer H-4 Z-isomer H-vinyl E-isomer H-vinyl
1
2
3
4
5
6
7
8
9
5a
H
1.4:1
1.5:1
1:1
1.7:1
1.8:1
1:1
83
81
80
88
85
65
70
90
93
94
65
62
7.90
7.79
7.87
7.81
7.90
8.03
N/A
N/A
N/A
N/A
N/A
N/A
7.45
7.49
7.55
7.51
7.57
7.74
N/A
N/A
N/A
N/A
N/A
N/A
7.51
7.47
7.46
7.46
7.48
7.54
7.47
7.41
7.28
7.40
7.28
7.37
7.51
7.49
7.66
7.47
7.48
7.34
8.72
8.48
7.56
7.62
7.35
7.53
7.45
7.40
7.36
7.35
7.39
7.45
6.68
7.21
6.57
6.68
6.67
6.643
7.47
7.43
7.39
7.38
7.40
7.43
6.62
7.07
6.74
6.75
6.74
6.644
5b p-CH
3
5c 4-OCH
5d 4-Cl
5e 4-F
5f 4-NO
5g CO Et
5h Furan-2-yl
5i Cyclopentyl 1.7:1
5j Pentan-3-yl 2.5:1
5k CH
5l CH
3
2
2
1.5:1
1:3.4
10
11
12
3
1.8:1
1.2:1
2
CH
3
a
Determined by 1H NMR from the crude reaction mixture.
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G. Cao et al. / Tetrahedron xxx (2014) 1e7
Table 3
3
which could be due to the electrostatic repulsion between the
a
0
Synthesis of spiropyrrolidinyl-benzoisothiazoline 7ael via 1,3-dipolar cycloaddi-
sulfuryl oxygen atom of the benzoisothiazoline ring and the O-1 of
tion reactions
furan in their Z-isomer form (Scheme 4).
Ph
N
R
TFA
R
2
SO
2
MeO
N
TMS
SO
N
DCM
N
Ph
(Z) 5a-l
7a-l
6
Scheme 4. Rational for the preferred E configuration of compound 5h.
Ph
N
R
With the benzoisothiazole-2,2-dioxide-3-ylidene 5 in hand, the
1
,3-dipolar cycloaddition of 5 with azomethine ylide are conducted.
Initially, we use the mixture of E- and Z-isomer of benzoisothiazole-
,2-dioxide-3-ylidene 5d as the dipolarophile. To our surprise, only
SO2
N
2
Entry
(Z)-alkene
R
Time
Yield (%)b
one adduct 7d was observed when 5d reacted with azomethine
ylide precursor 6 in methylene chloride using trifluoroacetic acid as
the catalyst. It was indicated that Z-alkenes vanished from the
mixture and E-alkenes did not participated in the 1,3-dipolar re-
action based on thin-layer chromatography. We then use isolated E-
alkene 5d in this reaction, no product was found even in elevated
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Phenyl
4-Methylphenyl
4-Methoxyphenyl
4-Chlorophenyl
4-Fluorophenyl
4-Nitrophenyl
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
24 h
24 h
4 h
4 h
80
83
85
89
92
94
77
90
18
None
95
88
ꢁ
2
CO Et
temperature (110 C in toluene). This phenomenon is presumed to
Furan-2-yl
Cyclopentyl
Pentan-3-yl
be the effect of the steric hindrance of the sulfuryl in E-alkene. We
also studied the isomerization of Z-alkene 5d and E-alkene 5d in
various conditions, but did not found any change in thin-layer
chromatography. So Z-alkenes were isolated from the isomers
and used in the 1,3-dipolar cycloadditon reaction.
The 1,3-dipolar cycloaddition was also investigated in various
Lewis acid, solvents, and temperature conditions. The results were
summarized in Table 2. Trifluoroacetic acid proved to be the best
Lewis acid catalyst as compared to other Lewis acid catalyst (entry
10
5j
5k
5l
11
CH
CH
3
2
12
CH
3
a
Conversion of dipolarophile determined by 1H NMR.
Isolated yields.
b
proceed with bulky groups such as pentan-3-yl group (entry 10),
cycloalkyl group gave low yield (18% entry 9). For aromatic alde-
hyde derived alkenes, the substrates derived by both electronically
deficient aldehydes and electronically rich aldehydes gave high
yields (entry 1e6). Heteroaromatic aldehyde derived alkene (entry
9
e12). Dichloromethane is the suitable solvent (entry 1). The yield
of the reaction did not increase at higher concentration of tri-
fluoroacetic acid (entry 5e6), and no significant yield increasing
was found when performing this reaction at higher temperature
8
) also resulted in a high yield of the desired product.
The relative stereochemistry of the adduct 7d, 7f, and 7g were
(
entry 7, 8).
12
assigned by X-ray crystallography analysis (Fig. 1), and the ste-
reochemistry of the other products were assigned by analogy. In
general, the 1,3-dipolar reactions of alkene 5 with azomethine ylide
exhibited remarkable regiospecificity with exclusive formation of
one stereoisomer.
Table 2
a
The optimization of reaction conditions
Ph
Cl
N
catalyst
SO
2
MeO
N
TMS
SO2
Cl
N
N
Ph
(
Z)-alkene 5d
6
7d
Entry
Catalyst (equiv.)
Solvent
Temp
Time
Yield (%)b
1
2
3
4
5
6
7
8
9
1
1
1
TFA(0.1)
TFA(0.1)
TFA(0.1)
TFA(0.1)
TFA(0.2)
TFA(0.5)
TFA(0.1)
TFA(0.1)
DCM
Toluene
THF
CH CN
3
DCM
DCM
rt
rt
rt
rt
rt
4 h
8 h
8 h
8 h
5 h
5 h
8 h
8 h
8 h
8 h
8 h
8 h
89
85
80
82
89
89
86
84
59
64
32
None
rt
ꢁ
CH
3
CN
80
110
rt
rt
rt
C
C
ꢁ
Toluene
THF
Ether
Fig. 1. X-ray crystallography of compound 7d, 7f, and 7g.
TiCl
BF (0.1)
Et AlCl(0.1)
LiBr (0.1)
4
(0.1)
0
1
2
3
Toluene
3. Conclusions
2
ꢁ
CH
3
CN
80
C
a
In conclusion, we described the 1,3-dipolar cycloadditions of
benzoisothiazole-2,2-dioxide-3-ylidene derivatives to azomethine
ylides and new spirocyclic compounds, spiropyrrolidinyl-
benzoisothiazoline derivatives were synthesized. The 1,3-dipolar
cycloadditions of benzoisothiazole-2,2-dioxide-3-ylidene de-
rivatives to nitrones and nitrile oxides are under investigation and
will be reported in due course.
Reaction condition: (Z)-alkene 5d (1 mmol), 6 (1.3 mmol), solvent (2 mL).
Isolated yield.
b
The results of the 1,3-dipolar cycloaddition of Z-alkenes 5ael
with 6 were summarized in Table 3. For the aliphatic aldehyde
derived alkenes, the reaction proceed smoothly with less hindered
group such as methyl and ethyl group (entry 11 and 12), and hardly
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4
G. Cao et al. / Tetrahedron xxx (2014) 1e7
þ
þ
4
. Experimental section
(ESI-TOF ): m/z Calcd for C16
2
H16NO
2
S [(MþH) ]: 286.0902. Found:
85.0909.
4
.1. General
4
.2.5. (Z)-3-(4-Methoxy-benzylidene)-1-methyl-1,3-dihydro-benzo
All the reagents were purchased from TCI chemicals and local
[c]isothiazole-2,2-dioxide (Z-5c). Yield: 40%, yellow solid,
ꢁ
1
suppliers, and used without purification. All reactions were moni-
tored by TLC. Chromatography refers to open column chromatog-
raphy on silica gel (100e200 mesh).
mp:168e169 C; H NMR (500 MHz, CDCl ): d 7.87 (d, 2H, J 9.0 Hz),
3
7.46 (d, 1H, J 7.5 Hz), 7.37 (s, 1H), 7.31 (t, 1H, J 8.0 Hz), 7.00 (t, 1H, J
8.0 Hz), 6.97 (d, 2H, J 9.0 Hz), 6.68 (d, 1H, J 8.0 Hz), 3.87 (s, 3H), 3.19
13
Melting points were recorded on a RY-1 microscopic melting
3
(s, 3H); C NMR (125 MHz, CDCl ): d 161.6, 140.1,132.6,130.2,128.6,
1
apparatus and were uncorrected. H NMR spectra were recorded on
125.1, 124.7, 121.6, 119.9, 119.5, 116.9, 114.3, 109.2, 108.6, 53.3, 29.6.;
þ
þ
5
00 MHz and 13C NMR spectra were recorded on 125 MHz by using
HRMS (ESI-TOF ): m/z Calcd for C16
H16NO
3
S [(MþH) ]: 302.0851.
a Bruker Avance 500M spectrometer. Chemical shifts were reported
in parts per million ( ) relative to tetramethylsilane (TMS). Mass
Found: 302.0859.
d
spectra were performed on an Ultima Global spectrometer with an
ESI source. The X-ray single-crystal diffraction was performed on
Saturn 724þ instrument.
4.2.6. (E)-3-(4-Methoxy-benzylidene)-1-methyl-1,3-dihydro-benzo
[c]isothiazole-2,2-dioxide (E-5c). Yield: 40%, yellow solid,
ꢁ
1
mp:116e119 C; H NMR (500 MHz, CDCl
.55 (d, 1H, J 8.5 Hz), 7.39 (s, 1H), 7.32 (t, 1H, J 7.5 Hz), 6.96 (d, 2H, J
9.0 Hz), 6.86 (t, 1H, J 7.5 Hz), 6.75 (d, 1H, J 8.0 Hz), 3.88 (s, 3H), 3.20
3
): d 7.65 (d, 1H, J 8.0 Hz),
7
4
5
.2. General procedure for the preparation of dipolarophiles
ae5j
13
(s, 3H); C NMR (125 MHz, CDCl
3
):
d
161.0, 141.1, 132.6, 131.6, 131.2,
1
30.5, 130.2, 125.1, 123.5, 121.2, 114.3, 109.2, 55.3, 26.6; HRMS (ESI-
þ
þ
To a suspension of 1-Methyl-1,3-dihydro-benzo[c]isothiazole-
,2-dioxide 1 (0.37 g, 2.0 mmol) and potassium carbonate (0.41 g,
.0 mmol) in ethanol (10 mL), aldehyde 2ae2j (2.5 mmol) was
TOF ): m/z Calcd for C16
302.0857.
H16NO
3
S [(MþH) ]: 302.0851. Found:
2
3
added in one portion. Then, the resulting mixture was stirred at
reflux for 4 h. The mixture was evaporated to remove solvent under
reduced pressure. Water (20 mL) was added and the mixture was
extracted with ethyl acetate (3ꢂ10 mL). The combined organic
extracts were dried over sodium sulfate and concentrated in vacuo.
The residue was subjected to column chromatography on silica gel
4.2.7. (Z)-3-(4-Chloro-benzylidene)-1-methyl-1,3-dihydro-benzo [c]
isothiazole-2,2-dioxide (Z-5d). Yield: 55.4%, yellow solid, mp:
ꢁ
1
145e147 C; H NMR (500 MHz, CDCl
3
): d 7.81 (d, 2H, J 8.5 Hz), 7.46
(d, 1H, J 8.0 Hz), 7.40 (d, 2H, J 8.5 Hz), 7.35 (s, 1H), 7.34 (t, 1H, J
13
8.0 Hz), 7.00 (t, 1H, J 7.5 Hz), 6.69 (d, 1H, J 8.0 Hz), 3.17 (s, 3H);
C
NMR (125 MHz, CDCl ): 140.5, 136.7, 132.2, 131.9, 131.8, 131.3,
3
d
(
100e200 mesh) using petroleum/ethereethyl acetate as eluent to
130.6, 129.2, 128.9, 127.7, 121.9, 120.7, 118.9, 109.0, 26.8; HRMS (ESI-
þ
þ
afford dipolarophiles 5ae5j.
TOF ): m/z Calcd for C15
06.0361.
H13ClNO
2
S [(MþH) ]: 306.0356. Found:
3
4
2
.2.1. (Z)-3-Benzylidene-1-methyl-1,3-dihydro-benzo[c]isothiazo-le-
ꢁ
1
,2-dioxide (Z-5a). Yield: 48.4%, yellow solid, mp: 97e98 C;
H
4.2.8. (E)-3-(4-Chloro-benzylidene)-1-methyl-1,3-dihydro-benzo [c]
NMR (500 MHz, CDCl
3
): 7.90 (d, 2H, J 6.5 Hz), 7.51 (d, 1H, J 7.5 Hz),
d
isothiazole-2,2-dioxide (E-5d). Yield: 32.6%, yellow solid, mp:
ꢁ
1
7.46e7.47 (m, 3H), 7.46 (s, 1H), 7.35 (t, 1H, J 7.5 Hz), 7.03 (t, 1H, J
3
100e102 C; H NMR (500 MHz, CDCl ): d 7.51 (d, 2H, J 8.5 Hz),
13
8
.0 Hz), 6.71 (d, 1H, J 8.0 Hz), 3.19 (s, 3H); C NMR (125 MHz,
7.48e7.43 (m, 3H), 7.38 (s, 1H), 7.36e7.34 (d, 1H, J 7.5 Hz), 6.86 (t,
13
CDCl
3
):
d
140.5, 132.1, 131.4, 131.0, 130.6, 130.5, 128.9, 121.8, 120.6,
1H, J 7.5 Hz), 6.76 (d, 1H, J 8.0 Hz), 3.20 (s, 3H); C NMR (125 MHz,
þ
1
19.2, 108.9, 26.8; HRMS (ESI-TOF ): m/z Calcd for C15
H14NO
2
S
CDCl
3
):
d
141.4, 135.8, 135.1, 131.9, 129.9, 129.6, 129.2, 128.8, 128.7,
þ
þ
[(MþH) ]: 272.0745. Found: 272.0740.
126.7, 123.8, 121.4, 116.3, 109.4, 26.7; HRMS (ESI-TOF ): m/z Calcd
for C15
þ
H
13ClNO
2
S [(MþH) ]: 306.0356. Found: 306.0360.
4
2
.2.2. (E)-3-Benzylidene-1-methyl-1,3-dihydro-benzo[c]isothiazo-le-
ꢁ
1
,2-dioxide (E-5a). Yield: 34.6%, yellow solid, mp: 64e66 C;
): 7.56 (d, 2H, J 6.5 Hz), 7.51 (d, 1H, J 8.0 Hz),
.47 (s, 1H), 7.46e7.43 (m, 3H), 7.34 (t, 1H, J 7.5 Hz), 6.83 (t, 1H, J
.5 Hz), 6.75 (d, 1H, J 8.0 Hz), 3.20 (s, 3H); 13C NMR (125 MHz,
H
4.2.9. (Z)-3-(4-Fluoro-benzylidene)-1-methyl-1,3-dihydro-benzo[c]
NMR (500 MHz, CDCl
7
7
3
d
isothiazole-2,2-dioxide (Z-5e). Yield: 54.6%, yellow solid, mp:
ꢁ
1
138e140 C; H NMR (500 MHz, CDCl
3
): d 7.91e7.88 (m, 2H), 7.48
(d, 1H, J 8.0 Hz), 7.39 (s, 1H), 7.35 (t, 1H, J 8.0 Hz), 7.16e7.12 (m, 2H),
13
CDCl
3
):
d
141.3, 134.6, 132.9, 131.6, 131.4, 129.8, 128.9, 128.5, 123.9,
7.02 (t, 1H, J 7.5 Hz), 6.70 (d, 1H, J 7.5 Hz), 3.18 (s, 3H); C NMR
þ
1
C
21.3, 116.6, 109.2, 26.7; HRMS (ESI-TOF ): m/z Calcd for
(125 MHz, CDCl
3
):
d
140.5, 132.7, 132.6, 131.2, 131.0, 129.0, 128.3,
þ
þ
15
H
14NO
2
S [(MþH) ]: 272.0745. Found: 272.0743.
121.7, 120.4, 119.0, 116.2, 116.0, 108.9, 26.7; HRMS (ESI-TOF ): m/z
þ
Calcd for C15
H13FNO
2
S [(MþH) ]: 290.0651. Found: 290.0647.
4
.2.3. (Z)-1-Methyl-3-(4-methyl-benzylidene)-1,3-dihydro-benzo[c]
isothiazole-2,2-dioxide (Z-5b). Yield: 48.6%, yellow solid, mp:
4.2.10. (E)-3-(4-Fluoro-benzylidene)-1-methyl-1,3-dihydro-benzo [c]
ꢁ
1
1
81e183 C; H NMR (500 MHz, CDCl
3
):
d
7.79 (d, 2H, J 8.5 Hz), 7.47
isothiazole-2,2-dioxide (E-5e). Yield: 30.4%, yellow solid, mp:
ꢁ
1
(
7
d, 1H, J 7.5 Hz), 7.40 (s, 1H), 7.32 (t, 1H, J 7.5 Hz), 7.26e7.25 (m, 2H),
99e101 C; H NMR (500 MHz, CDCl
3
): d 7.58e7.55 (m, 2H), 7.48 (d,
.00 (t, 1H, 7.5 Hz), 6.68 (d, 1H, J 8.0 Hz), 3.17 (s, 3H), 2.40 (s, 3H); 13
C
1H, J 7.5 Hz), 7.41 (s, 1H), 7.36 (t,1H, J 8.0 Hz), 7.17e7.14 (m, 2H), 6.85
13
NMR (125 MHz, CDCl
3
):
d
141.1, 140.3, 130.6, 130.2, 129.6, 129.3,
(t, 1H, J 7.5 Hz), 6.76 (d, 1H, J 8.0 Hz), 3.20 (s, 3H); C NMR
þ
1
21.6, 120.3, 119.3, 108.7, 26.6, 21.5; HRMS (ESI-TOF ): m/z Calcd for
(125 MHz, CDCl
3
):
d
141.4, 134.6, 131.8, 130.7, 130.6, 130.1, 129.2,
þ
þ
C
16
H
16NO
2
S [(MþH) ]: 286.0902. Found: 286.0911.
128.9, 126.6, 123.6, 121.3, 116.2, 116.0, 109.3, 26.6; HRMS (ESI-TOF ):
m/z Calcd for C15
þ
H13FNO
2
S [(MþH) ]: 290.0651. Found: 290.0649.
4.2.4. (E)-1-Methyl-3-(4-methyl-benzylidene)-1,3-dihydro-benzo [c]
isothiazole-2,2-dioxide (E-5b). Yield: 32.4%, yellow solid, mp:
4.2.11. (Z)-3-(4-Nitro-benzylidene)-1-methyl-1,3-dihydro-benzo[c]
ꢁ
1
113e115 C; H NMR (500 MHz, CDCl
3
):
d
7.62 (d, 1H, J 7.5 Hz), 7.49
isothiazole-2,2-dioxide (Z-5f). Yield: 32.5%, red solid, mp:
ꢁ
1
(
d, 2H, J 8.0 Hz), 7.46 (s, 1H), 7.36 (t, 1H, J 8.0 Hz), 7.28e7.27 (m, 2H),
199e200 C; H NMR (500 MHz, CDCl
3
): d 8.30 (d, 2H, J 8.5 Hz), 8.03
6
.87 (t, 1H, J 8.0 Hz), 6.77 (d, 1H, J 8.0 Hz), 3.22 (s, 3H), 2.42 (s, 3H);
(d, 2H, J 8.5 Hz), 7.54 (d, 1H, J 7.5 Hz), 7.44 (s, 1H), 7.42 (t, 1H, J
1
3
13
C NMR (125 MHz, CDCl
3
):
d
141.2, 140.3, 133.6, 131.8, 131.5, 129.9,
8.0 Hz), 7.06 (t, 1H, J 7.5 Hz), 6.74 (d, 1H, J 8.0 Hz), 3.20 (s, 3H);
C
129.6, 129.2, 128.7, 127.3, 123.8, 121.3, 116.7, 109.2, 26.7, 21.5; HRMS
NMR (125 MHz, CDCl ): 148.3, 141.0, 138.2, 135.4, 132.3, 131.1,
3
d
Please cite this article in press as: Cao, G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.039

G. Cao et al. / Tetrahedron xxx (2014) 1e7
5
þ
þ
þ
1
26.7, 124.0, 122.1, 121.2, 118.2, 109.2, 26.8; HRMS (ESI-TOF ): m/z
HRMS (ESI-TOF ): m/z Calcd for C14
H18NO
2
S [(MþH) ]: 264.1058.
þ
Calcd for C15
13
H N
2
O
4
S [(MþH) ]: 317.0596. Found: 317.0594.
Found: 264.1066.
4
.2.12. (E)-3-(4-Nitro-benzylidene)-1-methyl-1,3-dihydro-benzo[c]
4.2.19. (Z)-3-(2-Ethyl-butylidene)-1-methyl-1,3-dihydro-benzo[c]
isothiazole-2,2-dioxide (E-5f). Yield: 32.5%, orange solid, mp:
isothiazole-2,2-dioxide (Z-5j). Yield: 67.1%, white solid, mp:
ꢁ
1
ꢁ
1
122e124 C; H NMR (500 MHz, CDCl
3
):
d
8.33 (d, 2H, J 9.0 Hz), 7.74
89e90 C; H NMR (500 MHz, CDCl ): d 7.40 (d, 1H, J 7.5 Hz), 7.32 (t,
3
(
8
d, 2H, J 8.5 Hz), 7.43 (s, 1H), 7.41 (t, 1H, J 7.5 Hz), 7.34 (d, 1H, J
1H, J 7.5 Hz), 6.97 (t, 1H, J 7.5 Hz), 6.68 (d, 1H, J 8.0 Hz), 6.40 (d, 1H, J
11.5 Hz), 3.16 (s, 3H), 3.08e3.02 (m, 1H), 1.72e1.64 (m, 2H),
13
.0 Hz), 6.87 (t, 1H, J 8.0 Hz), 6.79 (d, 1H, J 8.0 Hz), 3.22 (s, 3H);
C
13
NMR (125 MHz, CDCl
3
): d 148.3, 141.9, 139.6, 137.4, 135.0, 132.9,
1.50e1.41 (m, 2H), 0.97 (t, 6H, J 7.5 Hz); C NMR (125 MHz, CDCl
3
):
1
31.1, 129.6, 127.9, 126.7, 124.3, 121.7, 115.7, 109.7, 26.5; HRMS (ESI-
d 139.6, 138.6, 134.0, 130.5, 121.3, 120.4, 117.9, 108.7, 42.4, 28.0, 26.4,
þ
þ
þ
þ
TOF ): m/z Calcd for C15
H
13
N
2
O
4
S [(MþH) ]: 317.0596. Found:
11.8, 11.7; HRMS (ESI-TOF ): m/z Calcd for C14
H20NO
2
S [(MþH) ]:
316.0592.
266.1215. Found: 266.1219.
4
.2.13. (Z)-(1-Methyl-2,2-dioxo-1,2-dihydro-benzo[c]isothiazol-3-
4.2.20. (E)-3-(2-Ethyl-butylidene)-1-methyl-1,3-dihydro-benzo[c]
ylidene)-acetic acid ethyl ester (Z-5g). Yield: 42%, brown solid,
isothiazole-2,2-dioxide (E-5j). Yield: 26.9%, white solid, mp:
ꢁ
1
ꢁ
1
mp:132e133 C; H NMR (500 MHz, CDCl
3
):
d
7.47e7.44 (m, 2H),
61e62 C; H NMR (500 MHz, CDCl ): d 7.62 (d, 1H, J 8.0 Hz), 7.36 (t,
3
6
3
.98 (t, 1H, J 7.5 Hz), 6.69e6.67 (m, 2H), 4.37 (q, 2H, J 7.0 Hz), 3.18 (s,
H), 1.38 (t, 3H, J 7.0 Hz); C NMR (125 MHz, CDCl ): d 162.6, 144.7,
3
1H, J 8.0 Hz), 7.02 (t, 1H, J 8.0 Hz), 6.75 (d, 1H, J 8.0 Hz), 6.44 (d, 1H, J
11.0 Hz), 3.16 (s, 3H), 2.89e2.83 (m, 1H), 1.74e1.66 (m, 2H),
13
13
142.3, 134.5, 122.7, 121.6, 116.4, 116.1, 109.1, 62.0, 27.0, 14.0; HRMS
1.55e1.47 (m, 2H), 0.95 (t, 6H, J 7.5 Hz); C NMR (125 MHz, CDCl
3
):
þ
þ
(
ESI-TOF ): m/z Calcd for C12
H14NO
4
S [(MþH) ]: 268.0644. Found:
d 141.0, 140.7, 134.7, 130.8, 124.5, 121.6, 117.5, 109.1, 42.1, 27.5, 26.6,
þ
þ
2
68.0650.
11.8, 11.7; HRMS (ESI-TOF ): m/z Calcd for C14
66.1215. Found: 266.1218.
H20NO
2
S [(MþH) ]:
2
4
.2.14. (E)-(1-Methyl-2,2-dioxo-1,2-dihydro-benzo[c]isothiazol-3-
ylidene)-acetic acid ethyl ester (E-5g). Yield: 28%, brown solid, mp:
4.3. General procedure for the preparation of dipolarophiles
5ke5l
ꢁ
1
1
07e108 C; H NMR (500 MHz, CDCl
3
):
d
8.72 (d, 1H, J 8.0 Hz), 7.50
(
4
t,1H, J 7.5 Hz), 7.07 (t,1H, J 7.5 Hz), 6.75 (d,1H, J 8.0 Hz), 6.62 (s,1H),
.33 (q, 2H, J 7.0 Hz), 3.19 (s, 3H), 1.37 (t, 3H, J 7.0 Hz); C NMR
13
To a solution of 1-Methyl-1,3-dihydro-benzo[c]isothiazole-2,2-
dioxide 1 (0.37 g, 2.0 mmol) and aldehyde 2ke2l (2.5 mmol) in
N,N-dimethyl formamide (6 mL), potassium carbonate (0.41 g,
3.0 mmol) was added in one portion. Then, the mixture was stirred
at room temperature overnight. Water (20 mL) was added and the
mixture was extracted with ethyl acetate (3ꢂ10 mL). The combined
organic extracts were dried over anhydrous sodium sulfate and
concentrated in vacuo. The resulting crude intermediate was dis-
solved in dichloromethane (10 mL), triethylamine (0.25 g,
2.5 mmol) were added in one portion. Then mesyl chloride (0.25 g,
(
1
C
125 MHz, CDCl
3
):
d
164.0, 146.3, 142.8, 134.5, 129.9, 122.1, 118.1,
þ
15.2, 109.0, 61.7, 27.0, 14.1; HRMS (ESI-TOF ): m/z Calcd for
þ
12
H14NO
4
S [(MþH) ]: 268.0644. Found: 268.0649.
4
.2.15. (Z)-3-Furan-2-ylmethylene-1-methyl-1,3-dihydro-benzo[c]
isothiazole-2,2-dioxide (Z-5h). Yield: 20.5%, yellow solid, mp:
1
ꢁ
1
33e135 C; H NMR (500 MHz, CDCl
3
): d 7.66 (d, 1H, J 1.5 Hz), 7.41
(
d, 1H, J 7.5 Hz), 7.31 (t, 1H, J 7.5 Hz), 7.21e7.19 (m, 2H), 6.99 (t, 1H, J
7
.5 Hz), 6.68 (d, 1H, J 8.0 Hz), 6.59e6.56 (m, 1H), 3.21 (s, 3H); 13
C
ꢁ
NMR (125 MHz, CDCl
1
Calcd for C13
3
):
d
148.1, 146.0, 140.2, 130.6, 127.1, 121.5,
2.2 mmol) was added dropwise at 0 C. The mixture was stirred at
þ
19.9, 118.6, 117.6, 115.2, 113.2, 108.6, 26.6; HRMS (ESI-TOF ): m/z
room temperature for 5 h. The reaction was quenched with water
(30 mL) and the organic layer was dried over anhydrous sodium
sulfate, concentrated in vacuo, and purified by column chroma-
tography (PE:EA¼20:1).
þ
H12NO
3
S [(MþH) ]: 262.0538. Found: 262.0534.
4
.2.16. (E)-3-Furan-2-ylmethylene-1-methyl-1,3-dihydro-benzo [c]
isothiazole-2,2-dioxide (E-5h). Yield: 69.5%, orange solid, mp:
1
ꢁ
1
39e140 C; H NMR (500 MHz, CDCl
3
):
d
8.48 (d, 1H, J 8.0 Hz), 7.73
4.3.1. (Z)-3-Ethylidene-1-methyl-1,3-dihydro-benzo[c]isothiazole-
ꢁ
1
(
(
d, 1H, J 1.0 Hz), 7.40 (t, 1H, J 7.5 Hz), 7.09e7.06 (m, 2H), 6.88e6.87
2,2-dioxide (Z-5k). Yield: 41.8%, white solid, mp: 101e103 C;
NMR (500 MHz, CDCl ): 7.28 (d, 1H, J 7.5 Hz), 7.23 (t, 1H, J 8.0 Hz),
6.89 (t, 1H, J 7.5 Hz), 6.67 (q, 1H, J 7.5 Hz), 6.61 (d, 1H, J 8.0 Hz), 3.08
H
13
m, 1H), 6.75 (d, 1H, J 8.0 Hz), 6.63e6.62 (m, 1H), 3.22 (s, 3H);
C
3
d
NMR (125 MHz, CDCl
1
Calcd for C13
3
):
d
149.4, 145.7, 140.9, 131.3, 129.6, 125.8,
þ
13
21.7, 119.1, 117.0, 116.1, 113.0, 108.7, 26.7; HRMS (ESI-TOF ): m/z
3
(s, 3H), 2.29 (d, 3H, J 7.5 Hz); C NMR (125 MHz, CDCl ): d 139.6,
þ
H12NO
3
S [(MþH) ]: 262.0538. Found: 262.0531.
134.6, 130.6, 128.8, 121.5, 120.3, 117.9, 108.8, 26.4, 14.3; HRMS (ESI-
þ
þ
TOF ): m/z Calcd for C10
H12NO
2
S [(MþH) ]: 210.0589. Found:
4
.2.17. (Z)-3-Cyclopentylmethylene-1-methyl-1,3-dihydro-benzo[c]
210.0588.
isothiazole-2,2-dioxide (Z-5i). Yield: 58.6%, white solid, mp:
ꢁ
1
1
(
29e131 C; H NMR (500 MHz, CDCl
t,1H, J 8.0 Hz), 6.86 (t,1H, J 7.5 Hz), 6.57 (d,1H, J 8.0 Hz), 6.46 (d,1H,
J 11.0 Hz), 3.45e3.39 (m, 1H), 3.05 (s, 3H), 2.04e1.98 (m, 2H),
3
):
d
7.28 (d, 1H, J 7.5 Hz), 7.20
4.3.2. (E)-3-Ethylidene-1-methyl-1,3-dihydro-benzo[c]isothiazole-
ꢁ
1
2,2-dioxide (E-5k). Yield: 23.2%, white solid, mp: 54e55 C;
NMR (500 MHz, CDCl ): 7.35 (d, 1H, J 8.0 Hz), 7.31 (t, 1H, J 7.5 Hz),
6.96 (t, 1H, J 7.5 Hz), 6.74 (q, 1H, J 7.5 Hz), 6.67 (d, 1H, J 8.0 Hz), 3.14
H
3
d
13
1
d
3
.72e1.59 (m, 4H), 1.41e1.34 (m, 2H); C NMR (125 MHz, CDCl ):
139.4, 138.6, 132.1, 130.3, 121.3, 120.2, 117.7, 108.6, 39.4, 33.9, 26.3,
5.5; HRMS (ESI-TOF ): m/z Calcd for C14
64.1058. Found: 264.1065.
13
3
(s, 3H), 2.36 (d, 3H, J 7.5 Hz); C NMR (125 MHz, CDCl ): d 139.6,
þ
þ
2
2
H18NO
2
S [(MþH) ]:
134.6, 130.5, 128.7, 121.4, 120.2, 117.9, 108.7, 26.4, 14.2; HRMS (ESI-
þ
þ
TOF ): m/z Calcd for C10
10.0590.
H12NO
2
S [(MþH) ]: 210.0589. Found:
2
4.2.18. (E)-3-Cyclopentylmethylene-1-methyl-1,3-dihydro-benzo [c]
isothiazole-2,2-dioxide (E-5i). Yield: 34.4%, white solid, mp:
4.3.3. (Z)-1-Methyl-3-propylidene-1,3-dihydro-benzo[c]isothiazo-le-
ꢁ
1
ꢁ
1
8
1
8
6e88 C; H NMR (500 MHz, CDCl
3
):
d
7.56 (d, 1H, J 8.0 Hz), 7.35 (t,
2,2-dioxide (Z-5l). Yield: 33.8%, white solid, mp: 105e107 C;
NMR (500 MHz, CDCl ): 7.37 (d, 1H, J 8.0 Hz), 7.31 (t, 1H, J 8.0 Hz),
6.97 (t, 1H, J 7.5 Hz), 6.68e6.63 (m, 2H), 3.15 (s, 3H), 2.83e2.77 (m,
H
H, J 8.0 Hz), 7.02 (t, 1H, J 7.5 Hz), 6.74 (d, 1H, J 8.0 Hz), 6.60 (d, 1H, J
.5 Hz), 3.31e3.24 (m, 1H), 3.16 (s, 3H), 2.06e2.04 (m, 2H),
3
d
.82e1.71 (m, 4H), 1.57e1.54 (m, 2H); 13C NMR (125 MHz, CDCl
):
140.9, 132.9, 130.6, 124.5, 121.5, 117.4, 109.0, 39.2, 33.2, 26.5, 25.5;
2H), 1.26e1.22 (m, 3H); C NMR (125 MHz, CDCl
13
1
3
3
): d 139.7, 135.1,
d
133.3, 130.5, 121.4, 120.3, 117.8, 108.7, 26.4, 22.0, 13.5; HRMS
Please cite this article in press as: Cao, G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.039

6
G. Cao et al. / Tetrahedron xxx (2014) 1e7
þ
þ
(
2
ESI-TOF ): m/z Calcd for C11
H
14NO
2
S [(MþH) ]: 224.0745. Found:
6.62 (d, 1H, J 8.0 Hz), 4.00e3.93 (m, 2H), 3.88 (d, 1H, J 11.5 Hz), 3.75
(t, 1H, J 9.5 Hz), 3.58 (t, 1H, J 10.0 Hz), 3.47 (d, 1H, J 11.5 Hz), 3.26 (t,
24.0741.
13
3
1H, J 8.5 Hz), 2.69 (s, 3H); C NMR (125 MHz, CDCl ): d 141.2, 138.4,
4
2
.3.4. (E)-1-Methyl-3-propylidene-1,3-dihydro-benzo[c]isothiazo-le-
133.2, 130.2, 129.7, 128.6, 128.5, 127.8, 127.6, 127.3, 125.9, 123.3,
ꢁ
1
þ
,2-dioxide (E-5l). Yield: 28.2%, white solid, mp: 63e65 C; H NMR
): 7.53 (d,1H, J 7.5 Hz), 7.36 (t,1H, J 7.5 Hz), 7.02 (t,
H, J 7.5 Hz), 6.74 (d, 1H, J 8.0 Hz), 6.64 (t, 1H, J 7.5 Hz), 3.17 (s, 3H),
122.5, 109.7, 73.0, 59.9, 58.4, 55.7, 55.0, 26.8; HRMS (ESI-TOF ): m/z
þ
(
500 MHz, CDCl
3
d
Calcd for C24H24ClN
2
O
2
S [(MþH) ]: 439.1247. Found: 439.1257.
1
2
d
13
0
0
0
.71e2.65 (m, 2H), 1.28e1.22 (m, 3H); C NMR (125 MHz, CDCl
3
):
4.4.5. (3 R*,3S*)-1-methyl-1 -benzyl-3 -(4-fluorophenyl)-spiro-[2,1-
0
140.8, 137.1, 135.1, 133.9, 130.7, 124.7, 121.6, 109.0, 26.6, 22.3, 13.0;
benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7e). Yield: 92%, white
þ
þ
ꢁ
1
HRMS (ESI-TOF ): m/z Calcd for C11
Found: 224.0740.
H14NO
2
S [(MþH) ]: 224.0745.
solid, mp:101e102 C; H NMR (500 MHz, CDCl
7.5 Hz), 7.40e7.29 (m, 5H), 7.12 (t, 1H, J 7.5 Hz), 6.90e6.80 (m, 4H),
.61 (d, 1H, J 8.0 Hz), 3.99e3.93 (m, 2H), 3.87 (d, 1H, J 11.5 Hz),
3.77e3.74 (m,1H), 3.57 (t,1H, J 9.5 Hz), 3.47 (d,1H, J 11.5 Hz), 3.27 (t,
3
): d 7.46 (d, 2H, J
6
4
.4. General procedure for the preparation of
13
spiropyrrolidinyl-benzoisothiazoline 7aei, 7k, and 7l
3
1H, J 8.0 Hz), 2.67 (s, 3H); C NMR (125 MHz, CDCl ): d 141.0, 138.2,
1
30.3, 129.6, 128.6, 128.4, 127.2, 125.8, 123.2, 122.4, 114.3, 114.1,
þ
To a solution of alkene 5 (0.3 mmol) and 6 (0.092 g, 0.39 mmol)
in dichloromethane (1 mL), trifluoroacetic acid (1M in 0.03 mL of
dichloromethane, 0.03 mmol) was added dropwise. Then the
mixture was stirred for 4e12 h at room temperature. Water (10 mL)
was added and the mixture was extracted with ethyl acetate
109.6, 72.9, 59.8, 58.1, 55.7, 54.7, 26.7; HRMS (ESI-TOF ): m/z Calcd
for C24
þ
H24FN
2
O
2
S [(MþH) ]: 423.1543. Found: 423.1549.
0
0
0
4.4.6. (3 R*,3S*)-1-methyl-1 -benzyl-3 -(4-nitrophenyl)-spiro-[2,1-
0
benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7f). Yield: 94%, white
solid, mp: 176e177 C; H NMR (500 MHz, CDCl ): d 7.99 (d, 2H, J
8.5 Hz), 7.45e7.35 (m, 6H), 7.29 (t, 1H, J 7.5 Hz), 7.15 (t, 1H, J 7.5 Hz),
7.08 (d, 1H, J 9.0 Hz), 6.63 (d, 1H, J 8.0 Hz), 3.98e3.91 (m, 2H),
3.89e3.83 (m, 2H), 3.58 (t,1H, J 9.5 Hz), 3.45 (d,1H, J 11.5 Hz), 3.29 (t,
ꢁ
1
(
3ꢂ5 mL). The combined organic extracts were dried over anhy-
3
drous sodium sulfate and concentrated in vacuo. The residue was
subjected to column chromatography on silica gel (100e200 mesh)
using petroleum ethereethyl acetate as eluent to afford
spiropyrrolidinyl-benzoisothiazoline 7aei, 7k, and 7l.
13
1H, J 8.0 Hz), 2.69 (s, 3H); C NMR (125 MHz, CDCl
3
): d 147.2, 142.7,
1
40.9, 130.0, 129.6, 128.6, 128.5, 127.4, 125.6, 123.2, 122.7, 122.5,
0
0
0
þ
4
.4.1. (3 R*,3S*)-1-methyl-1 -benzyl-3 -phenyl-spiro-[2,1-benzis-oth-
109.6, 72.9, 59.7, 58.6, 55.7, 55.0, 53.4, 26.4; HRMS (ESI-TOF ): m/z
Calcd for C24
0
þ
iazole-3,4 -pyrrolidin]-2,2-dioxide (7a). Yield: 80%, white solid, mp:
H N
24 3
O
4
S [(MþH) ]: 450.1488. Found: 450.1480.
ꢁ
1
1
(
(
2
3
(
46e147 C; H NMR (500 MHz, CDCl
d, 1H, J 7.5 Hz), 7.39e7.34 (m, 3H), 7.29 (t, 1H, J 7.5 Hz), 7.18e7.12
m, 4H), 6.91 (d, 2H, J 7.0 Hz), 6.61 (d, 1H, J 7.5 Hz), 4.01e3.94 (m,
3
): d 7.47 (d, 2H, J 7.5 Hz), 7.42
0
0
0
4.4.7. (3 S*,3S*)-1-methyl-1 -benzyl-3 -methoxycarbonyl-spiro-[2,1-
benziso-thiazole-3,4 -pyrrolidin]-2,2-dioxide (7g). Yield: 77%, white
solid, mp:132e133 C; H NMR (500 MHz, CDCl ): d 7.38 (d, 2H, J
7.5 Hz), 7.33e7.25 (m, 5H), 7.02 (t, 1H, J 7.5 Hz), 6.68 (d, 1H, J 8.0 Hz),
4.14e4.03 (m, 2H), 3.87e3.80 (m, 2H), 3.67 (d, 1H, J 10.5 Hz), 3.46 (t,
0
ꢁ
1
H), 3.88 (d, 1H, J 11.5 Hz), 3.81e3.77 (m, 1H), 3.61 (t, 1H, J 9.5 Hz),
3
13
.49 (d, 1H, J 11.5 Hz), 3.31 (t, 1H, J 8.0 Hz), 2.62 (s, 3H); C NMR
): 141.2, 138.4, 134.6, 129.6, 128.8, 128.7, 128.5,
125 MHz, CDCl
3
d
1
2
4
27.5, 127.3, 126.4, 123.3, 122.5, 109.9, 73.2, 60.0, 58.4, 55.9, 55.5,
1H, J 8.5 Hz), 3.35 (t, 1H, J 8.0 Hz), 3.28 (t, 1H, J 9.0 Hz), 3.12 (s, 3H),
þ
þ
13
7.0; HRMS (ESI-TOF ): m/z Calcd for C24
05.1637. Found: 405.1634.
H
25
N
2
O
2
S [(MþH) ]:
3.10 (s, 1H), 1.12 (t, 3H, J 7.0 Hz); C NMR (125 MHz, CDCl
3
):
d
169.4,
140.7, 137.9, 129.6, 128.5, 128.4, 127.3, 125.7, 123.7, 121.8, 108.6, 70.5,
þ
6
C
1.2, 60.7, 59.2, 54.5, 53.4, 27.1,13.7; HRMS (ESI-TOF ): m/z Calcd for
0
0
0
þ
4.4.2. (3 R*,3S*)-1-methyl-1 -benzyl-3 -(4-methylphenyl)-spiro-[2,1-
21
H
25
N
2
O
4
S [(MþH) ]: 401.1535. Found: 401.1533.
0
benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7b). Yield: 83%, white
ꢁ
1
0
0
0
solid, mp: 139e140 C; H NMR (500 MHz, CDCl
.5 Hz), 7.60 (s, 2H), 7.44 (s, 3H), 7.38 (t, 1H, J 7.5 Hz), 7.20 (t, 1H, J
.5 Hz), 6.91 (d, 2H, J 7.5 Hz), 6.63 (d, 1H, J 8.0 Hz), 6.56 (d, 2H, J
.0 Hz), 4.55 (d, 1H, J 11.0 Hz), 4.47e4.38 (m, 2H), 4.27 (d, 1H, J
3.5 Hz), 4.09 (s, 1H), 4.03 (t, 1H, J 11.0 Hz), 3.93 (s, 1H), 2.56 (s, 3H),
.23 (s, 3H); 13C NMR (125 MHz, CDCl
): 141.1, 138.0, 130.7, 130.3,
3
):
d
7.66 (d, 1H, J
4.4.8. (3 R*,3S*)-1-methyl-1 -benzyl-3 -(furan-2-yl)-spiro-[2,1-
0
7
7
7
1
benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7h). Yield: 90%, white
ꢁ
1
solid, mp:122e123 C; H NMR (500 MHz, CDCl
3H), 7.35e7.30 (m, 3H), 7.25 (t, 1H, J 7.5 Hz), 7.22 (s, 1H), 7.08 (t, 1H, J
7.5 Hz), 6.67 (d, 1H, J 8.0 Hz), 6.27e6.26 (dd, 1H, J 2.0 Hz, J 1.0 Hz),
6.10 (d, 1H, J 3.0 Hz), 3.94 (t, 1H, J 9.0 Hz), 3.88 (s, 2H), 3.74 (d, 1H, J
3
): d 7.41e7.38 (m,
1
2
2
3
d
13
129.9, 129.4, 128.4, 128.1, 126.7, 124.1, 123.8, 122.1, 110.7, 72.1, 60.2,
11.0 Hz), 3.35 (d, 2H, J 9.0 Hz), 3.26 (d,1H, J 10.5 Hz), 2.92 (s, 3H);
C
þ
5
4.8, 54.1, 53.3, 27.9, 21.0; HRMS (ESI-TOF ): m/z Calcd for
NMR (125 MHz, CDCl ): 149.7, 141.5, 140.8, 129.4, 128.5, 128.4,
3
d
þ
C
25 27
H N
2
O
2
S [(MþH) ]: 419.1793. Found: 419.1798.
127.2, 126.9, 123.4, 122.2, 110.4, 109.3, 108.0, 71.1, 59.7, 59.5, 56.1,
þ
þ
4
8.1, 26.9; HRMS (ESI-TOF ): m/z Calcd for C22
H
23
N
2
O
3
S [(MþH) ]:
0
0
0
4
.4.3. (3 R*,3S*)-1-methyl-1 -benzyl-3 -(4-methoxyphenyl)-spiro-
395.1429. Found: 395.1434.
0
[2,1-benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7c). Yield: 85%,
ꢁ
1
0
0
0
white solid, mp: 169e170 C; H NMR (500 MHz, CDCl
H, J 7.5 Hz), 7.39e7.33 (m, 3H), 7.32e7.26 (m, 2H), 7.11 (t, 1H, J
.5 Hz), 6.84 (d, 2H, J 8.5 Hz), 6.67 (d, 2H, J 9.0 Hz), 6.61 (d, 1H, J
.0 Hz), 3.99e3.92 (m, 2H), 3.86 (d, 1H, J 11.5 Hz), 3.74 (m, 4H), 3.56
t, 1H, J 9.5 Hz), 3.45 (d, 1H, J 11.5 Hz), 3.27 (t, 1H, J 9.0 Hz), 2.66 (s,
3
):
d
7.45 (d,
4.4.9. (3 R*,3S*)-1-methyl-1 -benzyl-3 -cyclopentyl-spiro-[2,1-
0
2
7
8
(
benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7i). Yield: 18%, white
solid, mp: 129e131 C; H NMR (500 MHz, CDCl ): d 7.42 (d, 2H, J
ꢁ
1
3
8.0 Hz), 7.34e7.23 (m, 4H), 7.17 (d, 1H, J 7.5 Hz), 6.97 (t, 1H, J 7.5 Hz),
6.65 (d, 1H, J 8.0 Hz), 3.92e3.86 (m, 2H), 3.74 (d, 1H, J 11.0 Hz), 3.27
(s, 1H), 3.13 (s, 3H), 3.03 (s, 1H), 2.62e2.57 (m, 1H), 2.50e2.44 (m,
13
3
3
H); C NMR (125 MHz, CDCl ): d 158.7, 141.1, 138.4, 129.8, 129.4,
1
5
28.5, 128.4, 127.1, 126.4, 123.2, 122.3, 112.7, 109.7, 73.0, 59.9, 58.3,
1H), 1.73e1.69 (m, 1H), 1.45e1.41 (m, 1H), 1.38e1.26 (m, 5H),
þ
13
6.0, 55.0, 54.8, 27.0; HRMS (ESI-TOF ): m/z Calcd for C25
H N
27 2
O
3
S
0.98e0.90 (m, 1H), 0.38e0.34 (m, 1H); C NMR (125 MHz, CDCl
3
):
þ
[(MþH) ]: 435.1742. Found: 435.1748.
d
141.2,138.0,129.4,128.7,127.2,124.9,123.5,121.9,108.8, 72.6, 59.5,
þ
5
8.2, 56.7, 39.2, 33.5, 30.1, 29.7, 26.6, 25.1, 24.3; HRMS (ESI-TOF ):
0
0
0
þ
4
.4.4. (3 R*,3S*)-1-methyl-1 -benzyl-3 -(4-chlorophenyl)-spiro-[2,1-
m/z Calcd for C23
H
29
N
2
O
2
S [(MþH) ]: 397.1950. Found: 397.1957.
0
benzisothiazole-3,4 -pyrrolidin]-2,2-dioxide (7d). Yield: 89%, white
solid, mp:169e171 C; H NMR (500 MHz, CDCl
ꢁ
1
0
0
0
3
):
d
7.47 (d, 2H, J
4.4.10. (3 R*,3S*)-1-methyl-1 -benzyl-3 -methyl-spiro-[2,1-benzi-so-
0
7.5 Hz), 7.41e7.27 (m, 5H), 7.15e7.11 (m, 3H), 6.86 (d, 2H, J 8.5 Hz),
thiazole-3,4 -pyrrolidin]-2,2-dioxide (7k). Yield: 95%, white solid,
Please cite this article in press as: Cao, G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.039

G. Cao et al. / Tetrahedron xxx (2014) 1e7
7
ꢁ
1
mp:108e110 C; H NMR (500 MHz, CDCl
7
1
3
):
d
7.40 (d, 2H, J 7.5 Hz),
3. Collins, M. A.; Mackner, V. A.; Wrobel, J. E.; Edwards, J. P.; Jones, T. K.; Tegley, C.
M.; Zhi, L. US 6,339,098, 2002.
.34e7.23 (m, 4H), 7.20 (d, 1H, J 7.5 Hz), 7.02 (t, 1H, J 7.5 Hz), 6.72 (d,
H, J 8.0 Hz), 3.88e3.81 (m, 2H), 3.67 (d, 1H, J 11.0 Hz), 3.23 (d, 1H, J
1.0 Hz), 3.12 (s, 3H), 3.06 (t, 1H, J 9.0 Hz), 2.89 (t, 1H, J 9.0 Hz),
3
.68e2.63 (m, 1H), 1.21 (d, 3H, J 7.0 Hz); C NMR (125 MHz, CDCl ):
141.2, 138.6, 129.3, 128.6, 128.4, 127.1, 125.6, 123.4, 122.2, 109.1,
2.4, 59.7, 58.6, 46.2, 26.6, 12.0, 11.9; HRMS (ESI-TOF ): m/z Calcd
4
. Baker, D. C.; Mayasundai, A.; Mao, J.; Johnson, S. C.; Yan, S. PCT Int. Appl. WO
,000,004,004A1, 2000. Baker, D. C.; Mayasundai, A.; Mao, J.; Johnson, S. C.; Yan,
S. Chem. Abstr. 2000, 132, 122613s.
2
1
2
d
13
5. (a) Wojciechowski, K. Heterocycles 2002, 57, 1717e1740; (b) Liu, Z. P.; Takeuchi,
Y. Heterocycles 2002, 56, 693e709; (c) Skorcz, J. A.; Suh, J. T. US 3,472,843, 1969.
(d) Collins, M. A.; Mackner, V. A.; Wrobel, J. E.; Edwards, J. P.; Jones, T. K.; Tegley,
þ
7
C. M.; Zhi, L. US 6,339,098, 2002. (e) Chrostowska, A.; Gracian, F.; Sotiropoulos,
J. M.; Genevieve, P. G.; Wojciechowski, K. Eur. J. Org. Chem. 2000, 313e318; (f)
Bunnett, J. F.; Kato, T.; Flynn, R. R.; Skorcz, J. A. J. Org. Chem. 1963, 28, 1e6; (g)
Katohgi, M.; Togo, H.; Yamaguchi, K.; Yokoyama, M. Tetrahedron 1999, 55,
14885e14900; (h) Wojciechowski, K.; Siedlecka, U.; Modrzejewska, H.; Ko-
si nꢀ ski, S. Tetrahedron 2002, 58, 7583e7588; (i) Rayabarapu, D. K.; Zhou, A.; Jeon,
þ
for C19
23
H N
2
O
2
S [(MþH) ]: 343.1480. Found: 343.1482.
0
0
0
0
4
.4.11. (3 R*,3S*)-1-methyl-1 -benzyl-3 -ethyl-spiro-[2,1-benziso-thi-
azole-3,4 -pyrrolidin]-2,2-dioxide (7l). Yield: 88%, white solid,
1
K. O.; Samarakoon, T.; Rolfe, A.; Siddiqui, H.; Hanson, P. R. Tetrahedron 2009, 65,
ꢁ
mp:104e106 C; H NMR (500 MHz, CDCl
3
):
d 7.54e7.52 (m, 2H),
3180e3188.
7
1
1
.46 (d, 2H, J 7.5 Hz), 7.42e7.40 (m, 3H), 7.35 (t, 1H, J 8.0 Hz), 7.09 (t,
H, J 7.5 Hz), 6.74 (d, 1H, J 8.0 Hz), 4.41e4.33 (m, 3H), 4.16e4.09 (m,
H), 3.89e3.85 (m, 1H), 3.33e3.28 (m, 1H), 3.16 (s, 3H), 2.86e2.83
m,1H),1.90e1.87 (m,1H),1.24e1.22 (m,1H), 0.75 (t, 3H, J 7.5 Hz); C
NMR (125 MHz, CDCl
6. (a) Kosi nꢀ ski, S.; Wojciechowski, K. Eur. J. Org. Chem. 2000, 1263e1270; (b)
Skorcz, J. A.; Suh, J. T. J. Heterocycl. Chem. 1972, 9, 219e223; (c) Wojciechowski,
K. Tetrahedron 1993, 49, 10017e10026; (d) Modrzejewska, H.; Wojciechowski,
K. Tetrahedron 2005, 61, 8848e8854; (e) Wojciechowski, K. Synth. Commun.
1997, 27, 135e144; (f) Lancaster, M.; Smith, D. J. H. J. Chem. Soc., Chem. Commun.
1980, 471e472.
7. (a) Wr oꢀ bel, Z. Tetrahedron 2001, 57, 7899e7907; (b) Wojciechowski, K. Mole-
cules 1996, 1, 51e56.
13
(
3
):
d
141.2,129.3,128.7,128.4,127.3,123.4,122.2,
þ
1
09.0, 72.5, 59.7, 58.4, 56.5, 29.7, 26.5, 20.0, 13.3; HRMS (ESI-TOF ):
þ
m/z Calcd for C20
H
N O
25 2 2
S [(MþH) ]: 357.1637. Found: 357.1633.
8. (a) Hong, H.; Huang, L. J.; Teng, D. W. Chin. Chem. Lett. 2011, 9, 1009e1012; (b)
Huang, L. J.; Teng, D. W. Chin. Chem. Lett. 2011, 5, 523e526.
9
. (a) Chen, X. H.; Wei, Q.; Luo, S. W.; Xiao, H.; Gong, L. Z. J. Am. Chem. Soc. 2009,
Acknowledgements
1
2
31, 13819e13825; (b) Onishi, T.; Sebahar, P. R.; Williams, R. M. Tetrahedron
004, 60, 9503e9515; (c) Onishi, T.; Sebahar, P. R.; Williams, R. M. Org. Lett.
2003, 5, 3135e3137; (d) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,
22, 5666e5667; (e) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
Financial support from Qingdao University of Science & Tech-
nology doctoral research funding (12010101) is gratefully
acknowledged.
1
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186e3189; (f) Ashimori, A.; Bachand, B.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477e6487; (g) Ed-
mondson, S. D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1138e1140; (h)
Edmondson, S. D.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem.
Soc. 1999, 121, 2147e2155; (i) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6500e6503.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.039.
10. (a) Marbel, C. S.; Hiers, G. S. In Organic Syntheses Collective; Blatt, A. H., Ed.;Coll.
Vol. 1; Willey: New York, NY, 1941; Coll. Vol. 1, p 327; (b) Ankati, H.; Akubathini,
S. K.; Kamila, S.; Mukherjee, C.; D’Mello, S. R.; Biehl, E. R. Open Org. Chem. J.
2
009, 3, 1e10; (c) Zhou, F. S.; Zheng, J. B.; Dong, X. C.; Zhang, Z. W.; Zhao, L. L.;
References and notes
Sha, X. Y.; Li, L.; Wen, R. Lett. Org. Chem. 2007, 4, 1e5.
1
1. Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477e3480.
12. CCDCe1004300 (7d), CCDCe1004302 (7f) and CCDCe1004301 (7g) contain the
supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
1. (a) Skorcz, J. A.; Suh, J. T.; Judd, C. I. US 3,704,299, 1972. (b) Skorcz, J. A.; Suh, J. T.;
Judd, C. I. US 3,725,426, 1973. (c) Collins, M. A.; Mackner, V. A.; Wrobel, J. E.;
Edwards, J. P.; Jones, T. K.; Tegley, C. M.; Zhi, L. US 6,339,098, 2002.
2. Petry, S.; Baringhaus, K.-H.; Tennagels, N.; Mueller, G. US 20,050,070,533 A1,
2005.
Please cite this article in press as: Cao, G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.039