Palladium-catalyzed stereoselective intramolecular cyclization and Suzuki coupling of N-arylsulfonyl-α-chloroenamides promoted by a γ-hydroxy group

Article abstract of DOI:10.1016/j.tet.2018.06.010

The Suzuki reaction of both (E)- and (Z)-α-chloro-γ-hydroxyenamides with benzeneboronic acid by using Pd₂(dba)₃, tBu₃P, and Cs₂CO₃ proceeded stereoselectively to afford only (E)-trisubstituted enamides. Also, palladium-catalyzed intramolecular cyclization of (E)- and (Z)-α-chloro-γ-hydroxyenamides bearing an N-arylsulfonyl group took place stereoselectively to give the corresponding (E)-2,3-dihydrobenzoisothiazole 1,1-dioxides. The γ-hyroxy group in α-chloroenamides was found to accelerate the present palladium-catalyzed carbon-carbon bond forming reactions.

Full text of DOI:10.1016/j.tet.2018.06.010

Accepted Manuscript
Palladium-catalyzed stereoselective intramolecular cyclization and Suzuki coupling of
N-arylsulfonyl-α-chloroenamides promoted by a γ-hydroxy group
Yuto Yabuuchi, Kenta Sakamoto, Tomoyuki Yoshimura, Jun-ichi Matsuo
PII:
S0040-4020(18)30677-X
10.1016/j.tet.2018.06.010
TET 29606
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 April 2018
Revised Date: 31 May 2018
Accepted Date: 5 June 2018
Please cite this article as: Yabuuchi Y, Sakamoto K, Yoshimura T, Matsuo J-i, Palladium-catalyzed
stereoselective intramolecular cyclization and Suzuki coupling of N-arylsulfonyl-α-chloroenamides
promoted by a γ-hydroxy group, Tetrahedron (2018), doi: 10.1016/j.tet.2018.06.010.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Palladium-catalyzed stereoselective intramolecular
cyclization and Suzuki coupling of N-arylsulfonyl-α-
chloroenamides promoted by a γ-hydroxy group
Leave this area blank for abstract info.
Yuto Yabuuchi, Kenta Sakamoto, Tomoyuki Yoshimura, and Jun-ichi Matsuo*
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Palladium-catalyzed stereoselective intramolecular cyclization and Suzuki coupling of
N-arylsulfonyl-α-chloroenamides promoted by a γ-hydroxy group
Yuto Yabuuchi, Kenta Sakamoto, Tomoyuki Yoshimura, and Jun-ichi Matsuo
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Suzuki reaction of both (E)- and (Z)-α-chloro-γ-hydroxyenamides with benzeneboronic acid
by using Pd2(dba)3, tBu3P, and Cs2CO3 proceeded stereoselectively to afford only (E)-
trisubstituted enamides. Also, palladium-catalyzed intramolecular cyclization of (E)- and (Z)-α-
chloro-γ-hydroxyenamides bearing an N-arylsulfonyl group took place stereoselectively to give
the corresponding (E)-2,3-dihydrobenzoisothiazole 1,1-dioxides. The γ-hyroxy group in α-
chloroenamides was found to accelerate the present palladium-catalyzed carbon-carbon bond
forming reactions.
Available online
Keywords:
α-Chloroenamide
Palladium
2009 Elsevier Ltd. All rights reserved
.
Suzuki reaction
Intramolecular cyclization
Hydroxy group
———
Corresponding author. Tel.: +81-76-234-4474; fax: +81-76-234-4474; e-mail: jimatsuo@p.kanazawa-u.ac.jp

2
Tetrahedron
ACCEPTED MANUSCRIPT
R4
R3
1. Introduction
HO R4
R3
O
Cl
α-Haloenamides are valuable synthetic intermediates for the
R1
O2S
R1
synthesis of a variety of substituted enamides by palladium-
catalyzed coupling reactions such as Suzuki1-3 and Sonogashira4,5
N
O2S
N
TiCl4
R2
R2
(Z)-5
reactions.6
Interestingly, the double bond geometry of a
method a
4
substituted enamide product sometimes varied in these coupling
reactions. For example, Hsung,7 Zhu,8 Kazmaier,9 and Iwasawa10
reported that Suzuki and Sonogashira coupling reactions of α-
chloro, α-bromo-, and α-iodoenamides gave trisubstituted or
tetra-substituted enamides without changing the geometry of the
double bonds. On the other hand, Sahoo11 and Hammond12
reported that Suzuki and Sonogashira coupling reactions of an
(E)-α-haloenamide gave a mixture of (E)- and (Z)-trisubstituted
enamides. The latter results suggested that partial isomerization
on a carbon-carbon double bond of enamides took place in
palladium-catalyzed coupling reactions. However, to the best of
our knowledge, complete isomerization of enamide geometry has
not been reported.13
1) BuLi
THF
HO R4
R4
R3
R3
Me3SiCl
MeOH
Cl
2) O
R1
O2S
OH
R1
O2S
+ (Z)-
R4
N
5
R2
(E)-5
R3
N
R2
CH2Cl2
method b
6
Scheme 2. Synthesis of α-chloro-γ-hydroxyenamides 5.
Table 1. Stereoselective synthesis of (E)-α-chloro-γ-
hydroxyenamides (E)-5 by hydrochlorination of 6.
We recently reported a new method for the synthesis of γ-
hydroxy-α-haloenamides
1 and their synthetic utility for
entry
R1
R2
R3
R4
5
yield
(%)a
88
81
46
72
74
86
86
85
82
86
71
E/Zb
palladium-catalyzed coupling reaction and cyclization to 2
(Scheme 1).14 When we studied the palladium-catalyzed coupling
and cyclization of 1 in detail, we found that the γ-hydroxy group
was important for rate acceleration of palladium-catalyzed
reactions and control of the geometry of the double bond of
products. The influence of a hydroxyl group in the Heck reaction
on regioselecivity of allylic alcohols15-20 or on stereoselective
reaction21,22 and C-H alkenylation of arenes23,24 have been
reported by other research groups, and we describe here hydroxy
group-promoted intramolecular cyclization and Suzuki coupling
of γ-hydroxy-α-chloroenamides 1.
1
2
3
4
5
6
7
8
Tol
Tol
Bn
Me
Me
Me
H
Me
tBu
Ph
iPr
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
89:11
88:12
59:41c
83:17
82:18
87:13
83:17
86:14
84:16
64:36
>99:1
H
–(CH2)4–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
Me
2-Naph
Tol
Bn
Bn
Me
2,6-
9
10
11
5j
5k
Tol
iPr2C6H3
aIsolated yield.
bDetermined by the isolated yield of each compound.
cDetermined by 1H NMR analysis.
Hydroxy group-
promoted
HO
HO
HO
Cl
Ar
Ar
O
*
*
Ar
O
O
Ar
O
O
R1 R2
O
S N
S
N
S
N
introduction
of R1 and R2
palladium-
catalyzed
reactions
Ar
1
2
3
Suzuki reactions of (E)- and (Z)-chloroenamides 5g,d,e with
benzeneboronic acid were performed by using 2 mol% of
Pd2(dba)3 and 5 mol% of tBu3P, Cs2CO3 in dioxane at 80 °C for 3
Scheme 1. Synthetic utility of α-chloro-γ-hydroxyenamide 1.
days (Table 2).
chloroenamides
It was found that both (E)- and (Z)-
gave (E)-products stereoselectively
5
7
2. Results and discussion
regardless of γ-alkyl substituents. (Z)-Products were not detected
(entries 1-6). Thus, complete isomerization of a carbon-carbon
double bond of enamides took place in the case of (E)-
chloroenamides 5 (entries 2, 4, and 6). When chloroenamides
had a primary hydroxy group at the γ-position (5e, entries 5 and
6), yields of product (E)-7e were low because the hydroxy group
was easily oxidized. In this case, formation of an aldehyde was
(Z)- and (E)-α-Chloro-γ-hydroxyenamides 5 were prepared
stereoselectively by two methods (Scheme 2). (Z)-α-Chloro-γ-
hydroxyenamides 5 were synthesized by TiCl4-mediated reaction
between ynamides 4 and ketones or aldehydes (method a).14 By
method a, only (Z)-isomers were obtained. (E)-α-Chloro-γ-
hydroxyenamides (E)-5 were synthesized by hydrochlorination of
1
ynamide 6.
Many methods have been reported for
confirmed by the H NMR spectra of the crude product. After
hydrohalogenation of ynamides by using MgX2 in a wet solvent,7
TMSX and water,25,26 PPh3/H2O/CX4,11 N-oxides/halogenated
solvents,27 and syn-addition of HF.28,29 In the present study, we
used the addition of in situ formed HCl generated from Me3SiCl
and MeOH13 to ynamides 6 that were prepared by lithiation of 4
with butyllithium followed by reaction with carbonyl compounds
(method b). Method b gave a mixture of (E)- and (Z)-isomers of
5, and each isomer was isolated by column chromatography on
silica gel except 5c (Table 1). Moderate to good (E)-selectivity
was observed by method b, and steric demands of N-substituents
(R2) were found to be crucial for good (E)-selectivity (entries 9-
11).
oxidative addition of palladium (0) to 5e, a reaction of γ-hydroxy
group to the palladium (II) can give alkoxy palladium species
which might give an aldehyde and palladium hydride. In the
Suzuki coupling reaction of (Z)-5g, (E)-8, which was formed by
intramolecular cyclization, was obtained in 9% yield (entry 1). It
was also found that (E)-5g reacted more smoothly than (Z)-5g.

3
Pd(OAc)2 (10 mol%)
PtBu3 (20 mol%)
Cs2CO3 (1.2 equiv)
R4
Table 2. Suzuki reaction of (E)- and (Z)-chloroenamides 5 with
benzeneboronic acid to (E)-7.
4
HO R1
R2
ACCEPTED MANUSCRIPT
R1
R2
R
HO
Cl
dioxane, 80 °C
3 days
O2S
N
O2S
N
H
R3
R3
(Z)-5
(E)-8
HO
HO
HO
HO
Ph
O
O2S
N
O2S
O2S
O2S
N
N
N
Bn
8g: 81%
Bn
8l: 80%
Bn
8f: 31%
Bn
8m: 69%
entry
R1
R2
5
7
yield (%)a
1
2
3
4
5
6
-(CH2)5-
-(CH2)5-
iPr
iPr
H
(Z)-5g
(E)-5g
(Z)-5d
(E)-5d
(Z)-5e
(E)-5e
(E)-7g
(E)-7g
(E)-7d
(E)-7d
(E)-7e
(E)-7e
69b
90
82
71
30
25
HO
HO Me
tBu
HO Me
Me
HO
H
H
H
H
iPr
NCbz
O2S
O2S
O2S
O2S
N
N
N
N
Bn
Bn
8b: 83%
Bn
Bn
H
8n: 51%
8a: 55%
8d: 36%, (57%a)
aIsolated yield.
bCompound (E)-8 was obtained in 9% yield.
NO2
HO
HO COOMe
Me
HO
OH
O2S
O2S
O2S
O2S
N
N
N
N
Bn
Bn
8o: 58%
Bn
8p: 79%
Bn
8q: 0%c
8e: 0%, (0%b)
HO
O2S
N
Next, intramolecular cyclization of (Z)-α-chloroenamides 5
was investigated by using a catalytic amount of Pd(OAc)2
Me
8j: 56%
,
aReaction time: 7 days.
bPd2(dba)3 was used instead of Pd(OAc)2.
cReaction time: 1 day.
tBu3P, and Cs2CO3 in dioxane at 80 °C for 3 days (Table 3). It
was found that cyclization of α-chloroenamide 5 bearing a
tertiary γ-hydroxyl group proceeded smoothly to afford (E)-
cyclized products 8 except in the case giving 8q with a
carbomethoxy group. Cyclization of α-chloroenamide bearing a
secondary or a primary hydroxyl group resulted in low yields of
the desired products 8d,e. The geometry of cyclized products
Intramolecular cyclization of (E)-chloroenamides 5 was
performed under the same reaction conditions as those for
cyclization of (Z)-isomers (Table 4).9,14 Although the yields of
cyclized products 8 were lower than those with cyclization of
(Z)-chloroenamides 5, cyclization of (E)-α-chloroenamide 5 gave
only (E)-isomers of cyclized products 8. (Z)-Isomers of products
were not detected in any of the cases. These results suggested
that complete isomerization of the double bond of the enamide
moiety took place in the intramolecular cyclization of (E)-5. It
was noted that cyclized product 8k having an N-2,6-
diisopropylphenyl group was obtained in a high yield (93%). In
the cyclization to 8r, recovered chloroenamide 5r had an
unchanged E/Z ratio. Therefore, isomerization of the enamide
carbon-carbon double bond did not precede the cyclization.
1
(E)-8 was determined by similarity in the H NMR spectrum of
8d for which stereochemistry was determined by NOE
experiments. Comparison with the results giving 8a and 8b
suggested that a more sterically hindered hydroxyl group was
effective for the present cyclization. Cyclization to a p-
nitrobenzenesulfonyl group of 8p and to a 1-naphthylsulfonyl
group of 8o also took place. The decreased yield of a cyclized
product with an N-methyl group (8j, 56%) suggested that the
present cyclization proceeded more efficiently when a bulky N-
substituent was substituted. All of the obtained cyclized products
had an (E)-configuration and (Z)-isomers were not detected even
if the reaction was quenched halfway.
Table 4. Cyclization of (E)-α-chloroenamides 5.
Table 3. Intramolecular cyclization of (Z)-α-chloroenamides 5.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Pd(OAc)2 (10 mol%)
PtBu3 (20 mol%)
Cs2CO3 (1.2 equiv)
R4
4. Experimental section
R4
HO R1
R2
Cl
H
4.1. General methods
dioxane, 80 °C
3 days
O2S
O2S
N
R2
R3 OHR1
(E)-5
N
R3
All melting points were determined on Yanagimoto micro
(E)-8
melting point apparatus. Infrared spectra (IR) were recorded on
Horiba IR-710. 1H NMR spectra were recorded on a JOEL JNM
ECA600 (600 MHz) or a JOEL JNM ECS400 (400 MHz)
spectrometer at room temperature; chemical shifts (δ) are
reported in parts per million relative to tetramethylsilane.
Splitting pattern are designated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. 13C NMR spectra were
recorded on a JOEL JNM ECA600 (150 MHz) or a JOEL JNM
ECS400 (100 MHz) spectrometer with complete proton
decoupling. Chemical shifts are reported in parts per million
relative to tetramethylsilane with the solvent resonance as the
internal standard CDCl3. HRMS data were recorded on JEOL
JMS-T100TD. Analytical TLC was performed on Merck
precoated TLC plates (silica gel 60 GF254, 0.25 mm). Silica-gel
Column chromatography was carried out on silica gel 60 N
(Kanto Kagaku Co., Ltd., spherical, neutral, 63-210 ꢀm or 40-50
ꢀm). Preparative thin-layer chromatography (PTLC) was carried
out on silica gel Wakogel B-5F.
HO Me
Me
HO
HO
HO
O2S
O2S
O2S
O2S
N
N
N
N
Bn
Bn
Bn
Me
8g: 62%
8f: 37%
8a: 21%
8j: 47%
HO
HO
HO Me
Ph
HO
O2S
iPr
N
O2S
O2S
O2S
N
N
N
Me
Bn
Bn
8c: 43%a
Bn
8r: 58%b
8k: 93%
8i: 58%
aA mixture of (E)- and (Z)-chloroenamides 5c (E/Z = 10:7) was used.
bA mixture of (E)- and (Z)-chloroenamides 5r (E/Z = 1:1) was used and the reaction time was 7 days.
To clarify the effects of a γ-hydroxy group, Suzuki coupling
and intramolecular cyclization of α-chloroenamide 9 for which
the γ-hydroxy group was protected with a trimethylsilyl group
were investigated (Scheme 3). It was found that neither Suzuki
coupling nor intramolecular cyclization of (Z)-9 proceeded.30
These results suggested that the γ-hydroxy group of 5 accelerated
the present palladium-catalyzed reactions.
4.2. (E)-N-Benzyl-N-(1-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-
4-methylbenzenesulfonamide ((E)-5a)
To a stirred solution of ynamide 6 (1.0 mmol) and methanol
(1.1 mmol) in dry CH2Cl2 (2.5 mL) was added
chlorotrimethylsilane (1.1 mmol) at room temperature, and the
resulting mixture was stirred for 2 h at room temperature. After
evaporation of volatiles, the residue was purified by column
chromatography on silica gel.
White powder. 1H NMR (400 MHz, C6D6): δ (ppm) 0.91 (3H,
s), 1.21 (3H, s), 1.89 (3H, s), 3.26 (1H, s), 3.95 (1H, d, J = 13.3
Hz), 4.90 (1H, d, J = 13.3 Hz), 5.75 (1H, s), 6.81 (2H, d, J = 8.2
Hz), 7.01-7.13 (3H, m), 7.44 (2H, d, J = 7.3 Hz), 7.78 (2H, d, J =
7.8 Hz). 13C NMR (100 MHz, C6D6): δ (ppm) 21.2, 28.7, 30.8,
52.4, 71.0, 125.6, 128.5, 128.6, 128.9, 129.8, 130.6, 134.2, 135.3,
143.3, 144.4. IR: (CHCl3, cm-1) 3569, 2981, 1361, 1164. HRMS
(DART/CHCl3): [M-OH]+ Calcd. for C19H21ClNO2S: 362.0982;
Found 362.0983.
4.3. (Z)-N-Benzyl-N-(1-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-
4-methylbenzenesulfonamide ((Z)-5a)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.24 (6H,
s), 2.17 (1H, s), 2.46 (3H, s), 4.49 (2H, s), 5.78 (1H, s), 7.25-7.38
(7H, m), 7.78 (2H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3):
δ (ppm) 21.6, 28.7, 51.1, 69.7, 125.6, 128.1, 128.2, 128.5, 129.2,
129.7, 134.5, 135.4, 142.6, 144.3. IR: (CHCl3, cm-1) 3592, 2929,
1355, 1166. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C19H21ClNO2S: 362.0982; Found 362.0979.
Scheme 3. Attempted Suzuki reaction and intramolecular
cyclization of γ-trimethylsiloxy-α-haloenamide 9.
3. Conclusion
In conclusion, we have reported that the palladium-catalyzed
Suzuki reaction and intramolecular cyclization of N-arylsulfonyl
α-chloroenamides provided (E)-phenyl-substituted enamides and
4.4. (E)-N-Benzyl-N-(1-chloro-3-hydroxy-3,4,4-trimethylpent-1-
en-1-yl)-4-methylbenzenesulfonamide ((E)-5b)
(E)-2,3-dihydrobenzoisothiazole
1,1-dioxides,
respectively.
Thus, products had the (E)-enamide moiety regardless of the
configurations of α-chloroenamides. It was also found that the
palladium-catalyzed carbon-carbon bond formation was
accelerated by a γ-hydroxy group. The products obtained will be
a useful synthetic intermediate for the synthesis of various
amines because they had two characters of an enamide and an
allylic alcohol.
White solid. 1H NMR (600 MHz, CDCl3, a mixture of two
conformers (1:0.8)): δ (ppm) 0.42 (3H, s), 0.54 (7.2H, s), 0.90
(9H, s), 1.34 (2.4H, s), 2.47 (5.4H, s), 2.73 (0.8H, s), 3.36 (1H,
s), 4.07 (1H, d, J = 13.2 Hz), 4.10 (0.8H, d, J = 13.2 Hz), 4.77
(0.8H, d, J = 13.2 Hz), 4.85 (1H, d, J = 13.2 Hz), 5.98 (0.8H, s),
6.06 (1H, s), 7.27-7.44 (12.6H, m), 7.83 (2H, d, J = 8.7 Hz), 7.86
(1.6H, d, J = 8.7 Hz). 13C NMR (150 MHz, CDCl3): δ (ppm)
21.7, 22.9, 24.9, 25.3, 38.0, 38.8, 52.2, 52.4, 77.6, 78.2, 125.3,
126.0, 128.53, 128.54, 128.6, 128.8, 128.9, 129.7, 129.8, 130.2,
130.4, 133.8, 134.2, 140.5, 140.8, 144.8. IR: (CHCl3, cm-1) 3567,

5
1
2964, 1355, 1164. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C22H27ClNO2S: 404.1451; Found 404.1443.
White solid. H NMR (600 MHz, CDCl3): δ (ppm) 1.01-1.08
ACCEPTED MANUSCRIPT
(1H, m), 1.35-1.50 (4H, m), 1.65-1.80 (3H, m), 2.47 (3H, s), 2.77
(1H, brs), 4.04 (1H, d, J = 13.1 Hz), 4.84 (1H, d, J = 13.1 Hz),
5.92 (1H, s), 7.30-7.39 (7H, m), 7.84 (2H, d, J = 8.2 Hz). 13C
NMR (150 MHz, CDCl3): δ (ppm) 21.6, 22.8, 23.4, 38.4, 41.1,
51.9, 80.4, 125.7, 128.4, 128.5, 128.6, 129.7, 130.2, 133.6, 134.4,
141.0, 144.8. IR: (CHCl3, cm-1) 3523, 2964, 1348, 1162. HRMS
(DART/CH2Cl2): [M-OH]+ Calcd. for C21H23ClNO2S: 388.1138;
Found 388.1133.
4.5. (Z)-N-Benzyl-N-(1-chloro-3-hydroxy-3,4,4-trimethylpent-1-
en-1-yl)-4-methylbenzenesulfonamide ((Z)-5b)
Colorless oil. 1H NMR (600 MHz, CDCl3): δ (ppm) 0.73 (9H, s),
1.11 (3H, s), 2.29 (1H, s), 2.46 (3H, s), 4.46 (1H, d, J = 9.2 Hz),
4.53 (1H, d, J = 9.2 Hz), 5.79 (1H, s), 7.25-7.37 (7H, m), 7.79
(2H, d, J = 5.2 Hz). 13C NMR (150 MHz, CDCl3): δ (ppm) 21.6,
22.7, 24.7, 38.9, 50.9, 76.9, 124.7, 128.1, 128.5, 129.3, 129.7,
134.6, 135.5, 140.2, 144.2. IR: (CHCl3, cm-1) 3600, 2969, 1353,
1164. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C22H27ClNO2S: 404.1451; Found 404.1450.
4.11. (Z)-N-Benzyl-N-(1-chloro-2-(1-hydroxycyclopentyl)vinyl)-
4-methylbenzenesulfonamide ((Z)-5f)
1
Colorless oil. H NMR (400 MHz, CDCl3): δ (ppm) 1.49-1.65
(4H, m), 1.67-1.82 (4H, m), 2.46 (3H, s), 4.50 (2H, s), 5.90 (1H,
s), 7.25-7.38 (7H, m), 7.78 (2H, d, J = 8.2 Hz). 13C NMR (100
MHz, CDCl3): δ (ppm) 21.6, 23.3, 40.1, 51.2, 79.7, 126.9, 128.1,
128.2, 128.5, 128.7, 129.2, 129.7, 134.6, 135.4, 141.2, 144.3. IR:
(CHCl3, cm-1) 3590, 2964, 1353, 1166. HRMS (DART/CHCl3):
[M-OH]+ Calcd. for C21H23ClNO2S: 388.1138; Found 388.1140.
4.6. N-Benzyl-N-(1-chloro-3-hydroxy-3-phenylbut-1-en-1-yl)-4-
methylbenzenesulfonamide (5c)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.16 (3H, s),
1.73 (2.1H, s), 2.472 (3H, s), 2.467 (2.1H, s), 3.26 (0.7H, s), 3.70
(1H, s), 4.05 (0.7H, d, J = 12.8 Hz), 4.11 (1H, d, J = 12.8 Hz),
4.82 (0.7H, d, J = 12.8 Hz), 4.92 (1H, d, J = 12.8 Hz), 5.97
(0.7H, s), 6.03 (1H, s), 6.88-6.94 (1.7H, m), 7.04-7.54 (18.7H,
m), 7.82 (2H, d, J = 8.2 Hz), 7.86 (1.4H, d, J = 8.2 Hz). 13C NMR
(100 MHz, CDCl3): δ (ppm) 21.7, 28.7, 29.6, 51.9, 52.2, 73.7,
74.5, 124.4, 124.96, 124.99, 126.1, 126.8, 128.0, 128.1, 128.5,
128.6, 128.67, 128.72, 128.8, 129.7, 129.8, 130.2, 130.5, 133.48,
133.53, 134.0, 134.2, 141.3, 141.8, 144.88, 144.90, 145.0, 146.9.
IR: (CHCl3, cm-1) 3544, 3033, 1348, 1164. HRMS
(DART/CH2Cl2): [M-OH]+ Calcd. for C24H23ClNO2S: 424.1138;
Found 424.1137.
4.12. (E)-N-Benzyl-N-(1-chloro-2-(1-hydroxycyclohexyl)vinyl)-4-
methylbenzenesulfonamide ((E)-5g)
1
White solid. H NMR (400 MHz, CDCl3): δ (ppm) 0.79-1.73
(10H, m), 2.47 (3H, s), 2.73 (1H, s), 4.04 (1H, d, J = 12.8 Hz),
4.85 (1H, d, J = 13.3 Hz), 5.75 (1H, s), 7.28-7.46 (7H, m), 7.84
(2H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.1,
21.2, 21.6, 25.2, 36.0, 38.1, 52.0, 71.7, 125.1, 128.41, 128.43,
128.7, 129.7, 130.3, 133.7, 134.4, 142.9, 144.8. IR: (CHCl3, cm-1)
3550, 2937, 1351, 1162. HRMS (DART/CH2Cl2): [M-OH]+
Calcd. for C22H25ClNO2S: 402.1295; Found 402.1292.
4.7. (E)-N-Benzyl-N-(1-chloro-3-hydroxy-4-methylpent-1-en-1-
yl)-4-methylbenzenesulfonamide ((E)-5d)
4.13. (E)-N-Benzyl-N-(1-chloro-2-(1-
hydroxycyclohexyl)vinyl)methanesulfonamide ((E)-5h)
Colorless crystals. mp: 125-127.5 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 0.22 (3H, d, J = 6.9 Hz), 0.64 (3H, d, J = 6.4
Hz), 1.24-1.37 (1H, m), 2.48 (3H, s), 3.26 (1H, s), 3.70-3.78 (1H,
m), 3.98 (1H, d, J = 13.3 Hz), 4.88 (1H, d, J = 13.3 Hz), 5.81
(1H, d, J = 9.6 Hz), 7.24-7.46 (7H, m), 7.82 (2H, d, J = 8.2 Hz).
13C NMR (100 MHz, C6D6): δ (ppm) 17.3, 17.9, 21.7, 32.3, 51.4,
71.9, 128.3, 128.6, 128.7, 128.9, 129.8, 129.9, 133.8, 134.5,
138.1, 144.9. IR: (CHCl3, cm-1) 3540, 2962, 1351, 1164. HRMS
(DART/CH2Cl2): [M-OH]+ Calcd. for C20H23ClNO2S: 376.1138;
Found 376.1142.
1
Colorless oil. H NMR (400 MHz, CDCl3): δ (ppm) 0.80-1.63
(10H, m), 2.33 (1H, s), 3.08 (3H, s), 4.35 (1H, d, J = 13.2 Hz),
4.81 (1H, d, J = 13.2 Hz), 5.81 (1H, s), 7.30-7.41 (3H, m), 7.45-
7.51 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.1, 21.2,
25.1, 36.0, 37.9, 38.9, 52.4, 71.7, 124.6, 128.57, 128.63, 130.3,
133.6, 143.2. IR: (CHCl3, cm-1) 3560, 2937, 1349, 1159. HRMS
(DART/CHCl3): [M-OH]+ Calcd. for C16H21ClNO2S: 326.0982;
Found 326.0977.
4.14. (E)-N-Benzyl-N-(1-chloro-2-(1-
hydroxycyclohexyl)vinyl)naphthalene-2-sulfonamide ((E)-5i)
4.8. (E)-N-Benzyl-N-(1-chloro-3-hydroxyprop-1-en-1-yl)-4-
methylbenzenesulfonamide ((E)-5e)
Colorless crystals. mp: 134.5-136 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 0.80-1.80 (10H, m), 2.68 (1H, s), 4.08 (1H, d, J
= 13.0 Hz), 4.95 (1H, d, J = 13.0 Hz), 5.79 (1H, s), 7.28-7.38
(3H, m), 7.41-7.48 (2H, m), 7.62-7.73 (2H, m), 7.95 (2H, d, J =
7.3 Hz), 8.01 (2H, d, J = 8.7 Hz), 8.52 (1H, s). 13C NMR (100
MHz, CDCl3): δ (ppm) 21.1, 21.3, 25.3, 36.1, 38.1, 52.2, 71.8,
123.5, 124.9, 127.7, 128.0, 128.5, 129.26, 129.28, 129.5, 130.3,
130.4, 132.1, 133.7, 134.4, 135.3, 143.1. IR: (CHCl3, cm-1) 3559,
2937, 1351, 1162. HRMS (DART/ CH2Cl2): [M-OH]+ Calcd. for
C25H25ClNO2S: 438.1295; Found 438.1298.
1
White powder. H NMR (400 MHz, CDCl3): δ (ppm) 2.47 (3H,
s), 3.59-3.72 (1H, m), 3.96 (2H, d, J = 12.8 Hz), 4.90 (1H, d, J =
13.8 Hz), 5.98 (1H, t, J = 7.9 Hz), 7.30-7.40 (7H, m), 7.81 (2H,
d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.7, 51.3,
58.5, 128.2, 128.6, 128.7, 129.3, 129.4, 129.9, 134.0, 134.7,
134.8, 144.8. IR: (CHCl3, cm-1) 3569, 3031, 1353. HRMS
(DART/CH2Cl2): [M-OH]+ Calcd. for C17H17ClNO2S: 334.0669;
Found 334.0674.
4.9. (Z)-N-Benzyl-N-(1-chloro-3-hydroxyprop-1-en-1-yl)-4-
methylbenzenesulfonamide ((Z)-5e)
4.15. (E)-N-(1-Chloro-2-(1-hydroxycyclohexyl)vinyl)-N,4-
dimethylbenzenesulfonamide ((E)-5j)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 2.46 (3H, s),
4.13 (2H, dd, J = 5.5 and 5.9 Hz), 4.48 (2H, s), 5.85 (1H, t, J =
5.9 Hz), 7.24-7.38 (7H, m), 7.77 (2H, d, J = 8.7 Hz). 13C NMR
(100 MHz, CDCl3): δ (ppm) 21.6, 51.2, 59.4, 127.8, 128.09,
128.11, 128.5, 128.9, 129.7, 134.2, 134.6, 135.3, 144.4. IR:
(CHCl3, cm-1) 3602, 3033, 1355, 1166. HRMS (DART/CHCl3):
[M-OH]+ Calcd. for C17H17ClNO2S: 334.0669; Found 334.0665.
1
Colorless crystals. mp: 69.5-71 °C. H NMR (400 MHz, CDCl3):
δ (ppm) 1.29-1.97 (10H, m), 2.45 (3H, s), 2.98 (3H, s), 3.41 (1H,
s), 5.84 (1H, s), 7.34 (2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4
Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.6, 22.1, 22.4,
25.4, 36.20, 36.22, 39.3, 71.5, 128.7, 129.2, 129.6, 133.1, 139.9,
144.9. IR: (CHCl3, cm-1) 3513, 2937, 1351, 1164. HRMS
(DART/CHCl3): [M-OH]+ Calcd. for C16H21ClNO2S: 326.0982;
Found 326.0984.
4.10. (E)-N-Benzyl-N-(1-chloro-2-(1-hydroxycyclopentyl)vinyl)-
4-methylbenzenesulfonamide ((E)-5f)

6
Tetrahedron
4.16. (Z)-N-(1-Chloro-2-(1-hydroxycyclohexyl)vinyl)-N,4-
m), 4.48 (2H, s), 5.10 (2H, s), 5.69 (1H, s), 7.23-7.41 (12H, m),
ACCEPTED MANUSCRIPT
7.76 (2H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm)
dimethylbenzenesulfonamide ((Z)-5j)
21.6, 36.0, 39.5, 51.1, 67.1, 68.8, 127.4, 127.8, 128.0, 128.1,
128.3, 128.5, 128.6, 129.2, 129.8, 134.3, 135.2, 136.8, 139.8,
144.5, 155.1. IR: (CHCl3, cm-1) 3585, 3012, 1689, 1355, 1166.
HRMS (DART/CHCl3): [M-OH]+ Calcd. for C29H32ClN2O5S:
537.1615; Found 537.1614.
1
Colorless oil. H NMR (400 MHz, CDCl3): δ (ppm) 1.20-1.88
(10H, m), 2.44 (3H, s), 2.47 (1H, s), 2.99 (3H, s), 6.15 (1H, s),
7.32 (2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.4 Hz). 13C NMR (100
MHz, CDCl3): δ (ppm) 21.6, 21.7, 21.9, 25.1, 35.6, 37.30, 37.34,
70.7, 128.1, 129.6, 127.0, 134.2, 137.7, 144.3. IR: (CHCl3, cm-1)
3588, 2938, 1355, 1168. HRMS (DART/CHCl3): [M-OH]+
Calcd. for C16H21ClNO2S: 326.0982; Found 326.0989.
4.22. (Z)-N-Benzyl-N-(1-chloro-2-(1-
hydroxycyclohexyl)vinyl)naphthalene-1-sulfonamide ((Z)-5o)
Yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 0.98-1.56
(10H, m), 2.12 (1H, s), 4.67 (2H, s), 5.58 (1H, s), 7.22-7.31 (5H,
m), 7.53-7.72 (3H, m), 7.95 (1H, d, J = 7.8 Hz), 8.12 (1H, d, J =
8.2 Hz), 8.34 (1H, d, J = 6.4 Hz), 8.78 (1H, d, J = 8.2 Hz). 13C
NMR (100 MHz, CDCl3): δ (ppm) 21.7, 24.9, 36.9, 50.8, 70.6,
124.1, 125.1, 126.1, 127.0, 128.1, 128.3, 128.4, 128.7, 128.9,
129.2, 131.5, 133.4, 134.2, 134.5, 135.1, 141.2. IR: (CHCl3, cm-1)
3586, 2937, 1350, 1162. HRMS (DART/ CH2Cl2): [M-OH]+
Calcd. for C25H25ClNO2S: 438.1295; Found 438.1299.
4.17. (E)-N-(1-Chloro-2-(1-hydroxycyclohexyl)vinyl)-N-(2,6-
diisopropylphenyl)-4-methylbenzenesulfonamide ((E)-5k)
1
White powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.17 (6H,
d, J = 6.4 Hz), 1.30 (6H, d, J = 6.9 Hz), 1.32-1.56 (4H, m), 1.60-
1.74 (6H, m), 2.42 (1H, s), 2.47 (3H, s), 3.15-3.26 (2H, m), 6.06
(1H, s), 7.22 (2H, d, J = 7.8 Hz), 7.32-7.41 (3H, m), 7.83 (2H, d,
J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.67, 21.74,
24.4, 24.7, 25.2, 29.0, 37.2, 70.8, 125.1, 128.8, 129.4, 129.8,
130.1, 132.2, 134.1, 136.4, 144.5, 150.1. IR: (CHCl3, cm-1) 3585,
2935, 1353, 1164. HRMS (DART/ CH2Cl2): [M-OH]+ Calcd. for
C27H35ClNO2S: 472.2077; Found 472.2080.
4.23. (Z)-N-Benzyl-N-(1-chloro-2-(1-hydroxycyclohexyl)vinyl)-4-
nitrobenzenesulfonamide ((Z)-5p)
1
4.18. (Z)-N-Benzyl-N-(1-chloro-2-(1-hydroxy-4-
Yellow powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.10-1.63
phenylcyclohexyl)vinyl)-4-methylbenzenesulfonamide ((Z)-5l)
(10H, m), 2.04 (1H, s), 4.55 (2H, s), 5.80 (1H, s), 7.28-7.38 (5H,
m), 8.09 (2H, d, J = 8.4 Hz), 8.40 (2H, d, J = 8.4 Hz). 13C NMR
(100 MHz, CDCl3): δ (ppm) 21.7, 24.9, 36.9, 51.5, 70.8, 124.3,
125.0, 128.5, 128.7, 129.2, 129.3, 133.7, 142.5, 144.3, 150.4. IR:
(CHCl3, cm-1) 3592, 2938, 1535, 1349, 1172. HRMS
(DART/CH2Cl2): [M-OH]+ Calcd. for C21H22ClN2O4S: 433.0989;
Found 433.0989.
Yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.46-1.56 (2H,
m), 1.59-1.67 (2H, m), 1.77-1.90 (4H, m), 2.10(1H, s), 2.37-2.46
(1H, m), 2.46 (3H, s), 4.50 (2H, s), 5.75 (1H, s), 7.14-7.22 (3H,
m), 7.23-7.38 (9H, m), 7.79 (2H, d, J = 8.2 Hz). 13C NMR (100
MHz, CDCl3): δ (ppm) 21.6, 28.4, 36.2, 43.3, 51.1, 69.8, 125.9,
126.0, 126.8, 128.11, 128.14, 128.3, 128.5, 129.2, 129.7, 134.5,
135.4, 142.3, 144.3, 146.9. IR: (CHCl3, cm-1) 3590, 2929, 1355,
1166. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C28H29ClNO2S: 478.1608; Found 478.1602.
4.24. N-Benzyl-N-(3-hydroxy-3,4,4-trimethylpent-1-yn-1-yl)-4-
methylbenzenesulfonamide (6b)
Colorless crystals. mp: 96.5-97.5 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 0.87 (9H, H), 1.29 (3H, s), 1.70 (1H, s), 2.45
(3H, s), 4.47 (2H, s), 7.22-7.37 (7H, m), 7.76 (2H, d, J = 8.4 Hz).
13C NMR (100 MHz, CDCl3): δ (ppm) 21.6, 24.7, 25.0, 38.3,
55.3, 74.2, 75.0, 127.7, 128.3, 128.5, 128.9, 129.7, 134.4, 134.5,
144.6. IR: (CHCl3, cm-1) 3604, 2969, 2244, 1367, 1168. HRMS
(DART/CH2Cl2): [M+H]+ Calcd. for C22H28NO3S: 386.1790;
Found 386.1794.
4.19. (Z)-N-Benzyl-N-(1-chloro-2-(1-hydroxy-4-
phenylcyclohexyl)vinyl)-4-methylbenzenesulfonamide ((Z)-5l’, a
diastereomer of (Z)-5l))
Yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.14 (1H, dt, J
= 3.2 and 11.0 Hz), 1.18 (1H, dt, J = 3.2 and 11.0 Hz), 1.51 (2H,
dt, J = 3.7 and 9.6 Hz), 1.69 (2H, d, J = 11.4 Hz), 2.06 (2H, d, J
= 11.4 Hz), 2.37-2.46 (1H, m), 2.45 (3H, s), 2.53 (1H, s), 4.54
(2H, s), 5.99 (1H, s), 7.06 (2H, d, J = 7.3 Hz), 7.17-7.38 (10H,
m), 7.80 (2H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ
(ppm) 21.6, 30.6, 38.3, 43.1, 51.0, 70.7, 126.1, 126.9, 127.7,
128.1, 128.3, 128.6, 129.2, 129.8, 134.6, 135.4, 139.2, 144.4,
146.1. IR: (CHCl3, cm-1) 3585, 2937, 1353, 1166. HRMS
(DART/CHCl3): [M-OH]+ Calcd. for C28H29ClNO2S: 478.1608;
Found 478.1602.
4.25. N-Benzyl-N-((1-hydroxycyclohexyl)ethynyl)-4-
methylbenzenesulfonamide (6g)
1
Colorless crystals. mp: 91-92 °C. H NMR (400 MHz, CDCl3): δ
(ppm) 1.02-1.30 (3H, m), 1.36-1.60 (5H, m), 1.69-1.77 (2H, m),
1.96 (1H, s), 2.45 (3H, s), 4.48 (2H, s), 7.24-7.34 (7H, m), 7.75
(2H, d, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.6,
23.2, 25.0, 39.9, 55.3, 68.9, 74.7, 78.0, 127.7, 128.3, 128.4,
128.9, 129.7, 134.4, 134.5, 144.6. IR: (CHCl3, cm-1) 3592, 2937,
2240, 1365, 1108. HRMS (DART/CH2Cl2): [M+H]+ Calcd. for
C22H26NO3S: 384.1633; Found 384.1636.
4.20. (Z)-N-Benzyl-N-(1-chloro-2-(4-hydroxytetrahydro-2H-
pyran-4-yl)vinyl)-4-methylbenzenesulfonamide ((Z)-5m)
Yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.52-1.62 (2H,
m), 1.65-1.76 (2H, m), 2.47 (3H, s), 3.35-3.47 (2H, m), 3.67-3.77
(2H, m), 4.49 (2H, s), 5.74 (1H, s), 7.25-7.38 (7H, m), 7.78 (2H,
d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.6, 37.1,
51.1, 63.5, 68.1, 127.3, 128.1, 128.3, 128.6, 129.2, 129.8, 134.4,
135.3, 140.1, 144.5. IR: (CHCl3, cm-1) 3603, 2927, 1355, 1166,
1091. HRMS (DART/CH2Cl2): [M-OH]+ Calcd. for
C21H23ClNO3S: 404.1087; Found 404.1079.
4.26. N-Benzyl-N-((1-hydroxycyclohexyl)ethynyl)naphthalene-2-
sulfonamide (6i)
Colorless needles. mp: 91.5-92.5 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 1.01-1.27 (3H, m), 1.31-1.57 (5H, m), 1.69-1.78
(2H, m), 1.91 (1H, s), 4.55 (2H, s), 7.24-7.31 (5H, m), 7.59-7.72
(2H, m), 7.80-7.86 (1H, m), 7.90-8.00 (3H, m), 8.42 (1H, s). 13C
NMR (100 MHz, CDCl3): δ (ppm) 23.2, 25.0, 39.9, 55.5, 69.0,
74.8, 78.0, 122.5, 127.7, 127.9, 128.4, 128.5, 128.9, 129.2, 129.3,
129.4, 129.5, 131.9, 134.2, 134.3, 135.2. IR: (CHCl3, cm-1) 3590,
2937, 2240, 1361, 1168. HRMS (DART/CH2Cl2): [M+H]+ Calcd.
for C25H26NO3S: 420.1633; Found 420.1634.
4.21. Benzyl (Z)-4-(2-((N-benzyl-4-methylphenyl)sulfonamido)-2-
chlorovinyl)-4-hydroxypiperidine-1-carboxylate ((Z)-5n)
Yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.52-1.61 (4H,
m), 2.31(1H, s), 2.46 (3H, s), 3.23-3.40 (2H, m), 3.46-3.63 (2H,

7
1
4.27. N-((1-Hydroxycyclohexyl)ethynyl)-N,4-
dimethylbenzenesulfonamide (6j)
Yellow solid. H NMR (400 MHz, CDCl3): δ (ppm) 1.31 (6H,
ACCEPTED MANUSCRIPT
s), 2.49 (3H, s), 4.74 (2H, s), 5.07 (1H, s), 7.24-7.43 (6H, m),
7.77 (1H, d, J = 7.6 Hz), 8.66 (1H, s). 13C NMR (100 MHz,
CDCl3): δ (ppm) 22.2, 31.5, 44.0, 69.6, 116.0, 120.7, 127.2,
127.6, 128.7, 129.0, 129.6, 130.4, 130.7, 133.0, 135.2, 143.5. IR:
(CHCl3, cm-1) 3590, 3029, 1365. HRMS (DART/CHCl3): [M-
OH]+ Calcd. for C19H20NO2S: 326.1215; Found 326.1211.
1
Colorless oil. H NMR (400 MHz, CDCl3): δ (ppm) 1.14-1.30
(1H, m), 1.40-1.72 (7H, m), 1.83-1.92 (2H, m), 2.10 (1H, s), 2.46
(3H, s), 3.06 (3H, s), 7.36 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J =
8.4 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.6, 23.3, 25.1,
39.2, 40.0, 68.9, 72.3, 79.4, 127.8, 129.7, 133.1, 144.8. IR:
(CHCl3, cm-1) 3590, 2938, 2240, 1365, 1170. HRMS
(DART/CH2Cl2): [M+H]+ Calcd. for C16H22NO3S: 308.1320;
Found 308.1324.
4.32. (E)-2-Benzyl-3-(2-hydroxy-2,3,3-trimethylbutylidene)-5-
methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8b)
Yellow solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 0.75 (9H, s),
1.34 (3H, s), 2.48 (3H, s), 4.62 (1H, d, J = 16.8 Hz), 4.90 (1H, d,
J = 16.8 Hz), 5.18 (1H, s), 7.22-7.43 (6H, m), 7.77 (1H, d, J = 8.0
Hz), 8.75 (1H, s). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.2,
22.5, 24.7, 39.3, 44.2, 114.9, 120.7, 126.9, 127.7, 128.8, 129.1,
129.7, 130.6, 132.6, 135.4, 143.4. IR: (CHCl3, cm-1) 3600, 2967,
1299. HRMS (DART/CHCl3): [M-OH]+ Calcd. for C22H26NO2S:
368.1684; Found 368.1680.
4.28. N-(2,6-Diisopropylphenyl)-N-((1-
hydroxycyclohexyl)ethynyl)-4-methylbenzenesulfonamide (6k)
Colorless crystals. mp: 143.5-145 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 1.13 (6H, d, J = 6.9 Hz), 1.17 (6H, d, J = 6.9
Hz), 1.42-1.71 (8H, m), 1.81-1.90 (2H, m), 2.00 (1H, s), 2.48
(3H, s), 2.98-3.11 (2H, m), 7.17 (2H, d, J = 7.8 Hz), 7.32-7.39
(3H, m), 7.86 (2H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3):
δ (ppm) 21.7, 23.1, 23.3, 25.1, 25.2, 28.9, 39.9, 69.0, 72.9, 79.0,
124.5, 128.2, 129.5, 129.9, 133.4, 135.1, 144.8, 148.3. IR:
(CHCl3, cm-1) 3592, 2937, 2238, 1361, 1170. HRMS
(DART/CH2Cl2): [M+H]+ Calcd. for C27H36NO3S: 454.2416;
Found 454.2421.
4.33. (E)-2-Benzyl-3-(2-hydroxy-2-phenylpropylidene)-5-methyl-
2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8c)
1
White powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.58 (3H,
s), 2.04 (1H, s), 2.20 (3H, s), 4.76 (1H, d, J = 16.5 Hz), 4.94 (1H,
d, J = 16.5 Hz), 5.43 (1H, s), 7.13-7.28 (6H,m), 7.30-7.44 (3H,
m), 7.46 (2H, d, J = 7.3 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.78 (1H,
s). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.7, 37.0, 44.0, 73.0,
115.4, 120.3, 124.9, 126.8, 127.3, 127.8, 128.1, 128.2, 128.8,
129.3, 130.1, 130.7, 133.8, 135.1, 143.2, 147.0. IR: (CHCl3, cm-1)
3598, 3029, 1303. HRMS (DART/CH2Cl2): [M-OH]+ Calcd. for
C24H22NO2S: 388.1372; Found 388.1371.
4.29. N-Benzyl-N-ethynylnaphthalene-1-sulfonamide (6o)
1
White solid. H NMR (400 MHz, CDCl3): δ (ppm) 2.74 (1H, s),
4.54 (2H, s), 7.16-7.27 (5H, m), 7.53 (1H, t, J = 7.8 Hz), 7.59-
7.71 (2H, m), 7.94 (1H, d, J = 7.8 Hz), 8.11 (1H, d, J = 8.2 Hz),
8.30 (1H, d, J = 7.8 Hz), 8.80 (1H, d, J = 8.2 Hz). 13C NMR (100
MHz, CDCl3): δ (ppm) 54.7, 60.9, 75.7, 124.0, 125.2, 127.2,
128.3, 128.41, 128.44, 128.5, 128.6, 128.9, 131.3, 133.2, 134.0,
134.3, 135.4. IR: (CHCl3, cm-1) 3315, 2138, 1363, 1168. HRMS
(DART/CH2Cl2): [M+H]+ Calcd. for C19H16NO2S: 322.0902;
Found 322.0911.
4.34. (E)-2-Benzyl-3-(2-hydroxy-3-methylbutylidene)-5-methyl-
2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8d)
Yellow solid. 1H NMR (400 MHz, C6D6): δ (ppm) 0.64 (3H, d, J
= 6.9 Hz), 0.75 (3H, d, J = 6.9 Hz), 0.99 (1H, brs), 1.38-1.52
(1H, m), 1.86 (3H,s), 4.20-4.31 (1H, m), 4.51 (1H, d, J = 16.5
Hz), 4.67 (1H, d, J = 16.5 Hz), 4.81 (1H, d, J = 8.2 Hz), 6.60
(1H, d, J = 8.2 Hz), 7.00 (1H, d, J = 7.8 Hz), 7.07 (2H, dd, J =
7.3 and 7.8 Hz), 7.35 (2H, d, J = 7.3 Hz), 7.43 (1H, d, J = 8.2
Hz), 7.66 (1H, s). 13C NMR (100 MHz, C6D6): δ (ppm) 14.6,
18.8, 19.0, 21.6, 32.8, 54.5, 74.3, 121.5, 125.8, 128.3, 128.5,
128.7, 129.5, 132.6, 135.6, 136.3, 136.4, 136.8, 142.4. IR:
(CHCl3, cm-1) 3600, 2962, 1305. HRMS (DART/ CH2Cl2): [M-
OH]+ Calcd. for C20H22NO2S: 340.1371; Found 340.1370.
4.30. (E)-N-Benzyl-N-(3-hydroxy-1-phenylprop-1-en-1-yl)-4-
methylbenzenesulfonamide (7e)
A mixture of enamide 5 (0.30 mmol), PhB(OH)2 (0.33 mmol),
Pd2(dba)3 (6 ꢀmol), PtBu3 (15 ꢀmol), Cs2CO3 (0.36 mmol), and
dioxane (0.6 mL) was placed in 2.0 mL vial with a screw cap
under Ar atmosphere. The mixture was stirred at 80 °C for three
days, cooled to room temperature, and diluted with diethyl ether.
The resulting mixture was filtered through a pad of Celite and the
filtrate was concentrated. The crude product was purified by
PTLC.
4.35. (E)-2-Benzyl-3-((1-hydroxycyclopentyl)methylene)-5-
methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8f)
1
Yellow oil. H NMR (400 MHz, CDCl3): δ (ppm) 2.45 (3H, s),
Yellow solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.36 (1H, s),
1.40-1.52 (2H, m), 1.65-1.83 (4H, m), 1.90-2.00 (2H, m), 2.49
(3H, s), 4.75 (2H, s), 5.14 (1H, s), 7.24-7.44 (6H, m), 7.77 (1H,
d, J = 8.0 Hz), 8.52 (1H, s). 13C NMR (100 MHz, CDCl3): δ
(ppm) 22.2, 23.0, 42.1, 44.1, 79.5, 114.8, 120.7, 127.2, 127.6,
128.7, 129.1, 130.3, 130.8, 133.9, 135.3, 143.5. IR: (CHCl3, cm-1)
3586, 2954, 1375. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C21H22NO2S: 352.1371; Found 352.1376.
4.04 (2H, d, J = 7.3 Hz), 4.74 (2H, s), 5.75 (1H, t, J = 7.3 Hz),
6.93-6.98 (2H, m), 7.08-7.15 (2H, m), 7.20-7.35 (8H, m), 7.73
(2H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.6,
52.4, 59.6, 127.7, 127.8, 128.1, 128.3, 128.7, 128.9, 129.1, 129.4,
129.6, 134.9, 136.1, 137.0, 139.3, 143.7. IR: (CHCl3, cm-1) 3602,
3031, 1344. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C23H22NO2S: 376.1371; Found 376.1369.
4.31. (E)-2-Benzyl-3-(2-hydroxy-2-methylpropylidene)-5-methyl-
2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8a)
4.36. (E)-2-Benzyl-3-((1-hydroxycyclohexyl)methylene)-2,3-
dihydronaphtho[2,3-d]isothiazole 1,1-dioxide (8i)
A mixture of enamide (0.2 mmol), Pd(OAc)2 (20 µmol),
PtBu3 (40 µmol), Cs2CO3 (0.24 mmol) and dioxane (0.4 mL)
was placed in 2.0 mL vial with a screw cap under Ar
atmosphere. The mixture was stirred at 80 °C for three days,
cooled to room temperature, and diluted with diethyl ether.
The resulting mixture was filtered through a pad of Celite and
the filtrate was concentrated. The crude product was purified
by PTLC.
1
White powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.00-1.15
(2H, m), 1.22-1.36 (2H, m), 1.54-1.75 (5H, m), 1.75-1.85 (2H,
m), 4.84 (2H, s), 5.08 (1H, s), 7.28 (1H, d, J = 7.3 Hz), 7.34 (2H,
t, J = 7.3 Hz), 7.44 (2H, d, J = 7.3 Hz), 7.60-7.67 (2H, m), 7.96-
8.04 (2H, m), 8.41 (1H, s), 9.37 (1H, s). 13C NMR (100 MHz,
CDCl3): δ (ppm) 22.8, 25.2, 39.4, 44.2, 71.2, 114.2, 121.5, 124.4,
127.2, 127.6, 128.3, 128.7, 128.75, 128.81, 129.8, 130.0, 130.8,

8
Tetrahedron
132.3, 132.6, 134.9, 135.2. IR: (CHCl3, cm-1) 3588, 2937, 1301.
4.42. (E)-2-Benzyl-3-((1-hydroxycyclohexyl)methylene)-2,3-
ACCEPTED MANUSCRIPT
HRMS
(DART/
CH2Cl2):
[M-OH]+
Calcd.
for
dihydronaphtho[2,1-d]isothiazole 1,1-dioxide (8o)
C25H24NO2S:402.1528; Found 402.1529.
1
White powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.00-1.16
4.37. (E)-3-((1-Hydroxycyclohexyl)methylene)-2,5-dimethyl-2,3-
dihydrobenzo[d]isothiazole 1,1-dioxide (8j)
(2H, m), 1.23-1.36 (2H, m), 1.50-1.80 (7H, m), 4.88 (2H, s), 5.19
(1H, s), 7.29 (1H, d, J = 7.3 Hz), 7.35 (2H, t, J = 7.3 Hz), 7.46
(2H, d, J = 7.3 Hz), 7.66 (1H, t, J = 7.3 Hz), 7.74 (1H, t, J = 7.3
Hz), 7.95 (1H, d, J = 7.8 Hz), 8.04 (1H, d, J = 8.7 Hz), 8.48 (1H,
d, J = 8.2 Hz), 8.93 (1H, d, J = 9.2 Hz). 13C NMR (100 MHz,
CDCl3): δ (ppm) 22.7, 25.0, 40.0, 44.1, 71.2, 116.6, 123.5, 124.7,
125.0, 127.2, 127.6, 128.1, 128.20, 128.24, 128.4, 128.8, 128.9,
132.7, 132.8, 133.4, 135.3. IR: (CHCl3, cm-1) 3586, 1937, 1299.
1
White powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.39-1.57
(4H, m), 1.69-1.90 (7H, m), 2.48 (3H, s), 3.04 (3H, s), 5.09 (1H,
s), 7.35 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 8.4 Hz), 8.69 (1H,
s). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.2, 22.7, 25.3, 26.1,
39.5, 70.8, 113.7, 120.4, 129.4, 129.5, 130.5, 130.6, 134.6, 143.3.
IR: (CHCl3, cm-1) 3588, 2937, 1301. HRMS (DART/ CH2Cl2):
[M-OH]+ Calcd. for C16H20NO2S: 290.1215; Found 290.1214.
HRMS
(DART/CHCl3):
C25H24NO2S:402.1528; Found 402.1520.
[M-OH]+
Calcd.
for
4.38. (E)-2-(2,6-Diisopropylphenyl)-3-((1-
hydroxycyclohexyl)methylene)-5-methyl-2,3-
dihydrobenzo[d]isothiazole 1,1-dioxide (8k)
4.43. (E)-2-Benzyl-3-((1-hydroxycyclohexyl)methylene)-5-nitro-
2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8p)
1
Yellow powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.04-1.18
1
White amorphous. H NMR (400 MHz, CDCl3): δ (ppm) 1.11
(2H, m), 1.22-1.40 (2H, m), 1.55-1.75 (7H, m), 4.81 (2H, s), 5.25
(1H, s), 7.24-7.44 (5H, m), 8.02 (1H, d, J = 8.7 Hz), 8.39 (1H,
dd, J = 1.8 and 8.7 Hz), 9.88 (1H, d, J = 1.8 Hz). 13C NMR (100
MHz, CDCl3): δ (ppm) 22.6, 25.0, 39.8, 44.5, 71.3, 118.3, 122.1,
124.6, 125.3, 127.2, 128.0, 129.0, 130.79, 130.84, 134.5, 137.5,
150.5. IR: (CHCl3, cm-1) 3586, 2937, 1536, 1317. HRMS
(DART/CHCl3): [M-OH]+ Calcd. for C21H21N2O4S: 397.1222;
Found 397.1229.
(6H, d, J = 6.9 Hz), 1.29 (6H, d, J = 6.9 Hz), 1.33-1.84 (11H, m),
2.53 (3H, s), 2.99-3.11 (2H, m), 4.68 (1H, s), 7.31 (2H, d, J = 7.3
Hz), 7.40-7.51 (2H, m), 7.78 (1H, d, J = 7.8 Hz), 8.79 (1H, s).
13C NMR (100 MHz, CDCl3): δ (ppm) 22.2, 22.3, 24.2, 25.1,
25.3, 28.8, 39.2, 70.8, 120.8, 124.8, 125.1, 128.4, 129.6, 130.7,
130.9, 131.1, 135.7, 143.2, 151.5. IR: (CHCl3, cm-1) 3592, 2933,
1297. HRMS (DART/CH2Cl2): [M-OH]+ Calcd. for C27H34NO2S:
436.2310; Found 436.2310.
4.44. (E)-2-Benzyl-3-(3-hydroxy-4-methylpentan-2-ylidene)-5-
methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8r)
4.39. (E)-2-Benzyl-3-((1-hydroxy-4-
phenylcyclohexyl)methylene)-5-methyl-2,3-
dihydrobenzo[d]isothiazole 1,1-dioxide (8l)
Colorless oil. 1H NMR (400 MHz, C6D6): δ (ppm) 0.60 (3H, d, J
= 6.9 Hz), 0.99 (3H, d, J = 6.4 Hz), 1.54-1.65 (1H, m), 1.81
(3H,s), 1.87 (3H, s), 4.41 (1H, d, J = 13.7 Hz), 4.44 (1H, d, J =
20.6 Hz), 4.60 (1H, d, J = 15.1 Hz), 6.54 (1H, d, J = 7.8 Hz),
6.90-7.00 (3H, m), 7.13 (1H, s), 7.15-7.23 (2H, m), 7.38 (1H, d, J
= 7.8 Hz). 13C NMR (100 MHz, C6D6): δ (ppm) 17.9, 18.1, 21.6,
35.6, 44.4, 71.5, 109.4, 121.5, 126.7, 127.8, 129.0, 129.9, 131.2,
131.7, 134.6, 136.1, 143.8. IR: (CHCl3, cm-1) 3598, 2962, 1326.
HRMS (DART/CH2Cl2): [M-OH]+ Calcd. for C21H24NO2S:
354.1528; Found 354.1532.
1
Yellow powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.40-1.55
(3H, m), 1.65-1.75 (2H, m), 1.88-2.06 (4H, m), 2.49 (3H, s), 4.76
(2H, s), 5.03 (1H, s), 7.16-7.45 (11H, m), 7.77 (1H, d, J = 7.8
Hz), 8.70 (1H, s). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.3,
29.0, 38.7, 43.3, 44.1, 69.6, 116.8, 120.7, 126.1, 126.8, 127.2,
127.6, 128.4, 128.7, 129.2, 129.5, 130.4, 130.7, 133.1, 135.3,
143.5, 146.8. IR: (CHCl3, cm-1) 3592, 2927, 1301. HRMS
(DART/CH2Cl2): [M-OH]+ Calcd. for C28H28NO2S: 442.1841;
Found 442.1837.
4.45. (Z)-N-Benzyl-N-(1-chloro-2-(1-
((trimethylsilyl)oxy)cyclohexyl)vinyl)-4-
methylbenzenesulfonamide (9)
4.40. (E)-2-Benzyl-3-((4-hydroxytetrahydro-2H-pyran-4-
yl)methylene)-5-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-
dioxide (8m)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) -0.05 (9H, s),
1.10-1.35 (4H, m), 1.39-1.57 (4H, m), 1.72-1.85 (2H, m), 2.46
(3H, s), 4.51 (2H, s), 5.87 (1H, s), 7.21-7.37 (7H, m), 7.77 (2H,
d, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 20.7, 21.6,
22.3, 25.2, 38.1, 51.0, 73.8, 126.0, 128.0, 128.1, 128.5, 129.1,
129.6, 135.0, 135.6, 141.6, 144.1. IR: (CHCl3, cm-1) 2937, 1353,
1164, 840. HRMS (DART/CHCl3): [M-OTMS]+ Calcd. for
C22H25ClNO2S: 402.1295; Found 402.1294.
Yellow powder. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.78 (4H,
t, J = 5.0 Hz), 2.49 (3H, s), 3.18 (1H, t, J = 5.0 Hz), 3.21 (1H, t, J
= 5.0 Hz), 3.75 (1H, t, J = 5.0 Hz), 3.78 (1H, t, J = 5.0 Hz), 4.78
(2H, s), 5.00 (1H, s), 7.28-7.42 (6H, m), 7.78 (1H, d, J = 8.2 Hz),
8.62 (1H, s). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.2, 39.8,
44.1, 64.3, 68.4, 113.4, 120.8, 127.1, 127.9, 128.6, 128.9, 129.2,
130.5, 131.0, 133.6, 135.0, 143.6. IR: (CHCl3, cm-1) 3590, 2962,
1382, 1099. HRMS (DART/CHCl3): [M-OH]+ Calcd. for
C21H22NO3S: 368.1320; Found 368.1324.
4.41. Benzyl (E)-4-((2-benzyl-5-methyl-1,1-
dioxidobenzo[d]isothiazol-3(2H)-ylidene)methyl)-4-
hydroxypiperidine-1-carboxylate (8n)
Acknowledgement
This work was supported by JSPS KAKENHI Grant Number
15K07855.
1
Yellow powder. H NMR (400 MHz, CDCl3): δ (ppm) 1.61-1.79
(4H, m), 2.48 (3H, s), 3.11-3.25 (2H, m), 3.48-3.58 (2H, m), 4.75
(2H, s), 4.93 (1H, s), 5.10 (2H, s), 7.21-7.43 (11H, m), 7.77 (1H,
d, J = 7.8 Hz), 8.61 (1H, s). 13C NMR (100 MHz, CDCl3): δ
(ppm) 22.2, 38.5, 40.3, 44.1, 67.1, 69.0, 113.1, 120.9, 127.1,
127.8, 128.0, 128.5, 128.6, 128.8, 129.2, 130.5, 131.1, 133.7,
134.9, 136.7, 143.7, 155.1. IR: (CHCl3, cm-1) 3590, 3029, 1691,
1363. HRMS (DART/CHCl3): [M-OH]+ Calcd. for C29H29N2O4S:
501.1848; Found 501.1846.
Supplementary Material
Supplementary data related to this article can be found at .

9
References and notes
ACCEPTED MANUSCRIPT
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