Zinc-Catalyzed Alkyne-Carbonyl Metathesis of Ynamides with Isatins: Stereoselective Access to Fully Substituted Alkenes

Article abstract of DOI:10.1021/acs.joc.9b02350

A zinc-catalyzed intermolecular alkyne-carbonyl metathesis reaction of ynamides with isatins followed by an amide to ester conversion has been developed, which produces the indolone derivatives with a fully substituted alkene species in good to high yields. The salient features of this reaction include the following: mild reaction conditions, an inexpensive zinc catalyst, a broad substrate scope, the excellent regiocontrol and stereoselectivity, and amenable to the gram scale.

Full text of DOI:10.1021/acs.joc.9b02350

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Article
Zinc-Catalyzed Alkyne-Carbonyl Metathesis of Ynamides with
Isatins: Stereoselective Access to Fully Substituted Alkenes
Chaoqun Ao, Xiaohan Yang, Shikun Jia, Xinfang Xu, Yanqiu Yuan, Dan Zhang, and Wenhao Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02350 • Publication Date (Web): 08 Nov 2019
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Zinc-Catalyzed Alkyne-Carbonyl Metathesis of Ynamides with
Isatins: Stereoselective Access to Fully Substituted Alkenes
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Chaoqun Ao, Xiaohan Yang, Shikun Jia, Xinfang Xu, Yanqiu Yuan, Dan Zhang,* and
Wenhao Hu*
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Email: zhangdan5@mail.sysu.edu.cn; huwh9@mail.sysu.edu.cn
O
NHTs
Z
O
Ts
N
R1
Zn(OTf)2
(20 mol%)
O
O
Z
Ar
O
DCE, 40 o
C
R1
OH
N
R3
Ar
N
R3
30 examples
52%~>95% yields
Z = linker
Inexpensive zinc catalyst & good yields
Excellent regiocontrol & stereoselectivity
Unique indolones installed with a fully substituted alkene species
Mild reaction conditions, general scope & amenable to gram scale
Alkyne-carbonyl metathesis/amide to ester interconversion cascade
ABSTRACT: A zinc-catalyzed intermolecular alkyne-carbonyl metathesis reaction of
ynamides with isatins followed by an amide to ester interconversion has been
developed, which produces the indolone derivatives with a fully substituted alkene
species in good to high yields. The salient features of this reaction include mild
reaction conditions, inexpensive zinc catalyst, broad substrate scope, excellent
regiocontrol and stereoselectivity, and amenable to gram scale.
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INTRODUCTION
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The olefin metathesis1 and the analogous carbonyl-olefin metathesis2 reactions are
two of the most significant and widely used strategies for the construction of
carbon–carbon double bonds, which have been extensively investigated and employed
in the last two decades. The impact of these methods can be highlighted by their
extraordinary use in the synthesis of carbocyclic or heterocyclic natural products and
pharmaceuticals.3 On the other hand, the alkyne-carbonyl metathesis,4 although
discovered more than sixty years ago by Büchi under irradiation,5 is far less
developed. Recently, this methodology has attracted the attention of the synthetic
community that could serve as an efficient and atom-economic alternative to the
Wittig reaction by the straightforward construction of -unsaturated carbonyls. In
this context, photoinduced,5,6 Lewis acid7-13 or Brønsted acid-catalyzed,14
gold-catalyzed,15 and other catalytic16 alkyne-carbonyl metathesis reactions have been
reported. Furthermore, these attractive methods have been incorporated and explored
in the total synthesis of natural products and complex molecules.17 Among these
advances, we noted that the use of toxic and/or expensive transition-metal catalysts is
inevitable in the most of the intermolecular alkyne–carbonyl metathesis reactions, and
the photoinduced version provides the desired alkenes as two inseparable isomers.6
Thus, the construction of conjugated carbonyl compounds using the alkyne-carbonyl
metathesis reaction with readily available materials in the presence of an
environmentally friendly and inexpensive catalyst would be of significant importance
in organic synthesis. 9
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In continuation of our research program on multi-component reactions (MCRs) via
electrophilic trapping of active ylide/zwitterionic intermediates,18 recently, Liu19 and
we20 have found that the gold carbene species, which is generated from catalytic
alkyne oxidation,21 could be introduced to this model of reaction through the
Mannich- or aldol-type additions, independently (Scheme 1a). Encouraged by these
results, we became interested in the using of ynamide as a non-diazo carbene
precursor for the development of this type of multi-component reactions (Scheme 1b,
path a). However, under our previous reported conditions,20b only decomposition of
ynamide 1a was observed and the electrophile N-methyl isatin 2a remained intact in
the presence of gold catalyst and an oxidant at room temperature in DCE
(1,2-dichloroethane). When replacing the gold catalyst with Zn(OTf)2, which was
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reported as an effective promotor in the oxidative ynamide transformation by Ye,22
the (Z)-tetra-substituted alkene 3aa that formed through an alkyne-carbonyl
metathesis/amide to ester interconversion cascade was obtained in 50% yield (Scheme
1c, path b), rather than the nucleophilic addition product.23 With regard to the fact that
the selective synthesis of fully substituted alkenes remains a challenging task in
organic synthesis by classical carbonyl olefination,24 herein, we reported an
environmentally friendly zinc-catalyzed alkyne-carbonyl metathesis reaction of
ynamides with isatins under mild reaction conditions, and the resulting amide
products with a tethered hydroxyl group could convert to the ester analogues
spontaneously. Notably, these generated 3-alkenyloxindole derivatives are useful
building blocks in the synthesis of many natural alkaloids and are privileged scaffolds
in biologically active molecules.
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Scheme 1. Catalytic alkyne oxidative cyclization vs alkyne-carbonyl
metathesis.
(a) Previous work: Au-catalyzed alkyne oxidative cyclization/ylide interception
O
Mannich-type
addition
NHAr1
Ar2
[Au]
O
imines
O
HO
HO
OH
OH
[Au]
[O]
O
O
[Au]
O
OH
isatins
O[Au]
H
O
non-diazo carbene precursor
Aldol-type
addition
Ar
N
R
(b) The reaction of ynamides with isatins
Ts
Ts
N
Ts
N
N
O
O[M]
R1
O
[M]/[O]
E
E
H
(designed)
path a
O
H
[M]
O
H
O
R1
R1
Ts
N
R1
Ts
TsHN
O
HO
O
OH
N
O
R1
R1
R1
Ar
N
O
O
HO
O
path b
Zn(OTf)2
Ts
O
isatins
(observed)
This work
Ar
N
Ar
N
R2
N
R2
R2
I
3
4
RESULTS AND DISCUSSION
To optimize the conditions of metathesis reaction of ynamide 1a with isatin 2a, a
variety of metal catalysts were initially investigated in DCE at 40 oC (Table 1, entries
1-12). To our delight, (Z)-3-alkenyloxindole 3aa was isolated in 88% yield using 20
mol% of Zn(OTf)2 (Table 1, entry 8). Inferior results were obtained with other metal
catalysts. ZnBr2, ZnCl2, and FeCl3 could also promote the metathesis reaction with
moderate to high yields (entries 9-11). In the case with Ni(OTf)2, 3aa was generated
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in 8% yield combined with the amide product 4aa in 40% yield (entry 4). Screening
of the solvents revealed that comparable high yields were achieved when the reactions
were conducted in dichloromethane, ethyl acetate or toluene (entries 13-15), but no
reaction occurred in the tetrahydrofuran (entry 16). Further investigation of the
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o
reaction temperature showed that high conversions could be realized from -10 C to
o
60 C (entries 17-19), however, the amide to ester interconversion was hampered at
lower temperature (entry 17) or in the absence of 4Å molecular sieves (entry 20).
Therefore, the optimized reaction conditions was identified as the use of inexpensive
o
Zn(OTf)2 as catalyst in DCE at 40 C (entry 8). The molecular structures of 3aa and
4aa were inferred from X-ray diffraction analysis of their analogues 3ac and 4la,
respectively.25
Table 1. Optimization of the Reaction Conditionsa
O
O
O
Ph
Ph
Ts
N
O
O
N
conditions
Ts
NHTs
OH
O
O
N
Ph
N
N
OH
1a
2a
4aa
3aa
T
(oC)
40
40
40
40
40
40
40
40
40
40
40
80
40
40
40
40
-10
rt
yield (%)b
3aa/4aa
74/-
entry
catalyst
solvent
1
2
In(OTf)3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
EA
Fe(OTf)2
Yb(OTf)3
Ni(OTf)2
Cu(OTf)2
Sc(OTf)3
Mg(OTf)2
Zn(OTf)2
ZnBr2
73/-
3
57/-
4
8/40
5
13/-
6
31/-
7
nr/-
>95(88)c/-
8
9
55/-
10
11
12
13
14
15
16
17
18
19
20e
21f
ZnCl2
60/-
FeCl3
41/-
15d/-
AgSbF6
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
87/-
85/-
toluene
THF
86/-
nr/-
DCE
DCE
DCE
DCE
DCE
17/82
94/5
86(78)c/-
40/41
90(82)c/-
60
40
40
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aReaction conditions: 1a (0.22 mmol), 2a (0.2 mmol), activated 4Å molecular sieves (200 mg) and
5
6
b
metal catalyst (20 mol%) in DCE (6.0 mL) at corresponding temperature. Yields determined by
proton NMR of the crude reaction mixture using 4-nitrobenzaldehyde as the internal standard.
7
8
9
d
o
cData in parentheses are the isolated yields. No reaction occurred at 40 C, and the reaction was
conducted at 80 oC with most of the material 1a decomposed into complex mixture. eThe reaction
was conducted in the absence of 4Å molecular sieves. fThe reaction was conducted with 10 mol%
Zn(OTf)2. nr = no reaction, DCE = 1,2-dichloroethane, DCM = dichloromethane, EA = ethyl
acetate, THF = tetrahydrofuran.
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Under the optimized reaction conditions, we first explored the feasibility of the
reaction with a variety of substituted isatins, and the results are summarized in Table
2. A variety of N-protected isatins with different substituents on the benzene moiety
or the nitrogen atom all reacted with ynamide 1a efficiently, giving the corresponding
products 3aa-3an in 52%->95% yield. For the 4-susbtituted isatins, due to the steric
hindrance, higher reaction temperature is necessary to ensure the high conversion, and
these products were obtained in relatively lower yields (3aj and 3ak). Notably, in the
reaction using the propargyl protected isatin 2m, only the ynamide served as the yne
addend to take part in the reaction to give product 3am in 92% yield. It is worth
mentioning that the installation of a protecting group at the nitrogen atom of isatins is
indispensable according to the reported formal alkyne-carbonyl metathesis with alkali
metal ynamidates by Ma,16c however, the N-unprotected isatin worked smoothly
under current conditions, delivering the corresponding product 3ao in 79% yield.
Moreover, N-Boc isatin as a substrate also resulted in N-H product 3ao in 58% yield,
in which N-Boc deprotection occurred probably promoted by the Lewis acid.
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Table 2. Substrate Scope of Isatins 2a
5
6
7
8
O
O
Ph
Ts
Zn(OTf)2, 20 mol%
N
O
Ar
O
NHTs
4Å MS, DCE, 40 °C
overnight
N
Ar
O
Ph
OH
R
N
R
2a-o
1a
9
3
10
11
12
13
14
15
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O
O
O
Ph
Ph
Ph
O
O
O
Cl
Br
NHTs
NHTs
NHTs
O
O
O
N
N
N
3aa
3ab
3ac
, 77%
, 88%
, 75%
O
O
Ph
Ph
O
O
O
O
F
R
NHTs
NHTs
N
N
3ae
R = Me,
, 79%
3ad
, 60%
O
3ac
, CCDC: 1901127
3af
R = OMe, , 86%
O
O
Ph
Ph
Ph
O
O
O
O
NHTs
NHTs
NHTs
O
O
N
N
N
Br
Cl
Cl
Br
b
3ag
3ah
, 88%
, >95%
O
3ai
, 68%
O
O
Ph
Ph
Ph
Cl
O
O
O
O
O
NHTs
NHTs
NHTs
O
N
N
N
Bn
b
b
, .>95%,b Z/E = 5:1
3aj
3ak
3al
, 65%
O
, 52%
O
O
Ph
Ph
Ph
O
O
O
O
NHTs
O
NHTs
NHTs
O
N
N
N
H
Ph
c
d
3an
, 93%
3am
3ao
, 79% (58% )
, 92%
aReaction conditions: 1a (0.22 mmol), 2 (0.2 mmol), Zn(OTf)2 (14.5 mg, 20 mol%), and
o
activated 4Å molecular sieves (200 mg) in DCE (6.0 mL) at 40 C overnight, and the yields are
given in isolated yields. bThe reaction was carried out at 80 oC. cThe reaction was carried out at 80
oC with 1.2 equivalent of 1a.d N-Boc isatin was used as the substrate.
Next, a set of ynamides 1 was examined for this metathesis reaction with isatin 2a
(Table 3). Aryl ynamides bearing both electron-donating and electron-withdrawing
groups as well as a methyl group at either the para-, meta-, or ortho-position of the
benzene ring proceeded smoothly, yielding products 3ba-3ha with consistently high
yields and stereoselectivities. Although the steric effect showed an obvious influence
on the yield (3ha), the reaction appeared to be quite general with respect to a wide
variety of functional groups. The thienyl, naphthyl, terminal, and alkyl alkynes were
then examined to prove the generality of this transformation. It was observed that the
reaction produced the desired products in good to high yields (3ia-3la). Higher
temperature was used to facilitate the amide to ester interconversion in the case with
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the alkyl-substituted alkyne 1l, and the corresponding amide product 4la could be
isolated in 42% yield under the standard condition at 40 oC, which was confirmed by
X-ray diffraction analysis and identified as one of the key intermediates in this
cascade proecess.25 Likewise, the variations of the linkage on the ynamides were also
well-tolerated for this protocol, which provide good yields (3ma-3pa). Especially, the
chirality on this motif was not affected at all under current conditions (3na and 3oa).
To demonstrate the scalability and the practicality of the current method, a gram scale
reaction was carried out, in which 1.45 g of 3ga was isolated in 92% yield with
reduced catalyst loading (note b).
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Table 3. Substrate Scope of Ynamides 1a
O
R1
O
Ts
Zn(OTf)2, 20 mol%
R'2
N
R2
O
4Å MS, DCE, 40 °C
N
R1
O
overnight
N
1b-p
2a
3
R
O
Me
3ba
R = F,
, 90%
, 86%
O
3ca
R = Cl,
O
NHTs
3da
R = OMe,
R = CF3,
, 73%
3ea
O
O
NHTs
, 92%
, 91%
N
O
3fa
R = Me,
N
b
3ga
, 95% (92%,1.45 g)
Me
O
O
S
O
O
O
O
NHTs
NHTs
NHTs
O
O
O
N
N
N
3ha
3ia
, 70%
O
3ja
, 67%
O
, 93%
O
H
Ph
O
O
O
O
NHTs
NHTs
NHTs
O
O
N
N
N
d
, 63%,c Z/E = 6:1
O
, 80%
O
3ma
, 79%
3ka
3la
O
Ph
Ph
Ph
H
(R) NHTs
N
O
O
O
O
O
NHTs
(R)
S
O
O
O
Ar
N
N
N
3oa, 85%, 99% eee
3pa
, Ar = 4-MeOC6H4, 94%
e
3na
, >95%, 87% ee
aReaction conditions: 1 (0.22 mmol), 2a (0.2 mmol), Zn(OTf)2 (14.5 mg, 20 mol%), and
o
activated 4Å molecular sieves (200 mg) in DCE (6.0 mL) at 40 C overnight, and the yields
are given in isolated yields. bThe reaction was carried out on a 3.2 mmol scale with 10 mol%
c
d
of Zn(OTf)2. The reaction was conducted with 1.5 equivalent of 1k. The reaction was
o
conducted at 80 C, and the corresponding amide product 4la was isolated in 42% yield
combined with 3la in equal amount when the reaction was conducted at 40 oC. eThe reactions
were conducted with 1n in 87% ee or 1o in 99% ee.
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Scheme 2. Control Experiments
5
6
7
8
O
Ph
O
standard
conditions
Ts
N
O
H
NHTs
O
(a)
O
Ph
O
N
N
O
O
9
5
2a
3aa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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O
Ph
O
standard
conditions
Ts
N
Ts
N
O
O
O
(b)
(c)
Bn
Ph
Ph
Bn
N
N
6
2a
2a
7
16/18O
O
Ph
Ts
N
Zn(OTf)2
(20 mol%)
O
NHTs
N
DCE, 40 °C
+ H218O
>95% conv.
O
OH
N
1a
18O not detected)
16/18O
3aa
(
16/18O
Ph
Ts
N
standard
conditions
O
NHTs
(d)
O
Ph
>95% conv.
O
N
OH
N
(
18O = 19.1 %)
2a
(
18O = 20.5 %)
3aa
1a
Ts
N
Zn(OTf)2
(20 mol%)
Ph
O
Ts
N
O
(e)
O
4Å MS, DCE
80 °C, 36 h
O
N
Ph
N
3qa
, 40 %
1q
2a
Ts
O
N
Ph
Ph
with or without
OH
Zn(OTf)2 (20 mol%)
O
O
NHTs
(f)
4Å MS, DCE, 40 °C
overnight
O
O
N
N
3aa
with Zn(OTf)2, >95% yield
without Zn(OTf)2, NR
4aa
To gain insight into the reaction mechanism, a series of control experiments were
carried out. Firstly, ester 5 and amide 6 were prepared and subjected to the standard
reaction conditions in the presence of isatin 2a, respectively. However, the
corresponding alkene products 3aa or 7 was not obtained (Scheme 2a and 2b). These
results exclude the ester 5 or its amide analogues 6, which was reported to be
generated via catalytic alkyne hydration,19a as the possible intermediate in current
reaction. Further investigations with isotopic-labeling experiments, either conducted
18
18
the model reaction in the presence of H2 O (Scheme 2c) or with O labeling isatin
(Scheme 2d), clearly indicated that the oxygen atom in the newly created carbonyl
group of 3aa is from isatin. Furthermore, ynamide 1q without the tethered hydroxyl
group also provided the corresponding metathesis product 3qa albeit only in 40%
o
yield at higher reaction temperature (Scheme 2e, 80 C), which indicates that the
reaction is facilitated by the hydroxyl species on the alkynes, most probably by
coordination of the hydroxyl group with zinc catalyst, and promoting the
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intermolecular reaction via a formal intramolecular version. In addition, the amide
product 4aa could fully convert to 3aa in the presence of zinc catalyst (Scheme 2f),
which is a practical and mild method for the esterification of amides.26
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On the basis of the above results and the known chemistry of the alkyne-carbonyl
metathesis reaction,4-16 a proposed reaction pathway is depicted in Scheme 3. The
reaction is initiated by the coordination of the carbonyl groups on the isatins with the
oxophilic zinc-salt. Then nucleophilic attack of the -carbon of the ynamides to the
activated carbonyl group of isatins, followed by intramolecular cyclization through a
keteniminium ion intermediate A leads to the oxetene intermediate B.17d In this stage,
the tethered hydroxyl group on the ynamide might also coordinate with the zinc
catalyst, which facilitates the intermolecular addition thought a formal intramolecular
version. The subsequent electrocyclic ring-opening of the resulting unstable oxetane
intermediate delivers the -unsaturated carbonyl product 4, which could be isolated
and confirmed by X-ray diffraction analysis.25 The intramolecular amide to ester
interconversion promoted by the same zinc catalyst occurs spontaneously in one-pot
under the current conditions, producing the ester analogues 3 via C and regenerating
the zinc catalyst for next catalytic cycle. The regioselectivity in this alkyne-carbonyl
metathesis reaction is controlled by electronic bias of the ynamide species, and the syn
selectivity is presumably governed by the tridentate zinc-coordination model in the
ring-opening event. During the electrocyclic ring-opening, the three carbonyl “O”
coordinate with the Zn catalyst,27 so that the configuration of the oxetene intermediate
is fixed, thereby preferentially delivering the (Z)-olefin product.
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Scheme 3. Proposed reaction mechanism
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O
NHTs
O
Zn(OTf)2
Ar
O
R
N
O
2
9
Ts
N
Ar
O
N
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OH
R
Amide-Ester
Exchange
R
3
1
Ts
Ts
H
N
N
C
O
R
O
H
O
O
Zn(OTf)2
Ar
O
Ar
O
Zn(OTf)2
N
N
A
C
Alkyne-Carbonyl
Metathesis
Ts
N
H
O
R
O
Zn(OTf)2
Ar
O
4
N
B
CONCLUSIONS
In summary, we have developed a zinc-catalyzed intermolecular alkyne-carbonyl
metathesis/amide to ester interconversion cascade process for the library synthesis of
indolone derivatives with a fully substituted alkene species in good to high yields. The
attractive features of this procedure are the mild reaction conditions, high
atom-economy, broad substrate scope, excellent regiocontrol and stereoselectivity,
use of inexpensive and environmentally friendly catalyst. Moreover, this protocol can
directly introduce an acrylate functionality on the C-3 position of the indolone unit,
which would be a useful tool for the synthesis of biologically active molecules.
EXPERIMENTAL SECTION
General. All reactions were carried out in oven-dried glassware. The solvents were
dried and degassed by standard methods. Metal catalysts used in this reaction were
purchased from commercial sources and used without further purification. Isatin
derivatives were prepared according to previously published procedure and had
physical and spectral properties identical to those earlier reported.28 Flash column
chromatography was performed using silica gel (300-400 mesh). Analytical thin-layer
chromatography was performed using glass plates pre-coated with 200-300 mesh
silica gel impregnated with a fluorescent indicator (254 nm). H NMR and C{1H}
NMR spectra were recorded in CDCl3 on a 400/500 MHz spectrometer; chemical
shifts are reported in ppm with the solvent signals as reference, and coupling
constants (J) are given in Hertz. The peak information is described as: s = singlet, br =
1
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broad, d = doublet, t = triplet, q = quartet, m = multiplet, comp = composite signals.
High-resolution mass spectra (HRMS) were recorded on a commercial apparatus (ESI
Source).
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General Procedure for the Synthesis of Ynamides 1.
Synthesis of 1a, 1b and 1e-1g29: To a 100-mL oven-dried flask containing a magnetic
stirring bar, and bromoalkyne (4.4 mmol, 1.2 equiv) in toluene (25 mL), DMEDA
.
(0.16 mL, 1.48 mmol, 0.4 equiv), FeCl3 6H2O (0.2 g, 0.74 mmol, 0.2 equiv), K2CO3
(1.02 g, 7.4 mmol, 2.0 equiv), and amide (3.7 mmol, 1.0 equiv) were added in
o
sequence. The reaction mixture was refluxing at 90 C in an oil bath for 12 h. Then,
the reaction mixture was cooled to room temperature, filtered and washed with diethyl
ether. The filtrate was concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (eluted with petroleum ether/ethyl acetate =
5:1- 3:1) to give the pure products 1a, 1b and 1e-1g.
Synthesis of 1c, 1d, 1h-1j, and 1l-1p30: To a 50-mL oven-dried Three-neck- flask
containing a magnetic stirring bar, bromoalkyne (4.4 mmol, 1.2 equiv), amide (3.7
.
mmol, 1.0 equiv), 1,10-phenanthroline (0.133 g, 0.74 mmol, 0.2 equiv), CuSO4 5H2O
(0.092 g, 0.37 mmol, 0.1 equiv), K2CO3 (1.02 g, 7.4 mmol, 2.0 equiv), and anhydrous
toluene (15 mL) were added in sequence under argon atmosphere. The reaction
o
mixture was stirred at 80 C in an oil bath for 12 h under these conditions. After
completion (monitored by TLC), the crude reaction mixture was cooled to room
temperature, filtered and the residue was washed with diethyl ether. The filtrate was
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (eluted with petroleum ether/ethyl acetate = 5:1- 3:1) to
give the pure products 1c, 1d, 1h-1j, and 1l-1p.
1k was prepared according to previously published procedure and had physical and
spectral properties identical to those earlier reported.31
N-(2-hydroxyethyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1a). Pale yellow
1
oil, 1.04 g, 89% yield. H NMR (500 MHz, CDCl3) (δ, ppm) 7.86 (d, J = 8.1 Hz, 2H),
7.39 – 7.34 (comp, 4H), 7.32 – 7.27 (comp, 3H), 3.90 (m, 2H), 3.59 (t, J = 5.3 Hz,
2H), 2.45 (s, 3H), 2.04 (t, J = 6.0 Hz, 1H).The spectral data match those previously
reported.22
N-((4-fluorophenyl)ethynyl)-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide
(1b).
Pale yellow oil, 1.11 g, 90% yield. 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.84 (d, J =
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3.57 (t, J = 5.4 Hz, 2H), 2.67 – 2.55 (m, 1H), 2.43 (s, 3H). C{1H} NMR (100 MHz,
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CDCl3) (δ, ppm) 162.3 (d, J = 249.3 Hz), 145.1, 134.1, 133.6 (d, J = 8.6 Hz), 129.9,
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127.8, 118.5 (d, J = 3.5 Hz), 115.6 (d, J = 22.0 Hz), 81.7, 69.6, 59.8, 53.9, 21.7. F
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NMR (376 MHz, CDCl3) δ -111.2. HRMS (TOF MS ESI+) calculated for
C17H17NO3FS+ [M + H]+: 334.0908, found 334.0904.
N-((4-chlorophenyl)ethynyl)-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (1c).
Yellow oil, 0.44 g, 34% yield.1H NMR (500 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 8.4
Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.33 – 7.10 (m, 4H), 3.95 – 3.82 (m, 2H), 3.58 (t, J
= 5.3 Hz, 2H), 2.45 (s, 3H), 2.29 – 2.18 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ
145.1, 134.1, 134.0, 132.6, 129.9, 128.7, 127.8, 121.0, 82.9, 69.8, 60.0, 54.0, 21.7.
HRMS (TOF MS ESI+) calculated for C17H17NO3ClS+ [M + H]+: 350.0612, found
350.0621.
N-(2-hydroxyethyl)-4-methyl-N-((4-(trifluoromethyl)phenyl)ethynyl)benzenesulfonami
de (1d). Pale yellow oil, 0.79 g, 56% yield. 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.85
(d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1
Hz, 2H), 3.91 (q, J = 5.6 Hz, 2H), 3.61 (t, J = 5.3 Hz, 2H), 2.45 (s, 3H), 2.31 – 2.24
(m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.3, 134.1, 131.1, 120.0, 127.9 (d, J =
267.5 Hz), 127.8, 125.2 (q, J = 3.7 Hz). 122.6, 84.6, 70.1, 60.0, 53.9, 21.7. 19F NMR
(376 MHz, CDCl3) δ -62.7. HRMS (TOF MS ESI+) calculated for C18H17NO3F3S+ [M
+ H]+: 384.0876, found 384.0876.
N-(2-hydroxyethyl)-N-((4-methoxyphenyl)ethynyl)-4-methylbenzenesulfonamide (1e).
Pale yellow oil, 0.99 g, 78% yield. 1H NMR (500 MHz, CDCl3) (δ, ppm) 7.84 (d, J =
8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.4 Hz,
2H), 3.87 (q, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.56 (t, J = 5.4 Hz, 2H), 2.49 – 2.46 (m,
13
1H), 2.43 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ 159.6, 144.9, 134.2, 133.5,
129.8, 127.8, 114.3, 114.0, 80.6, 70.4, 59.9, 55.3, 54.0, 21.7. HRMS (TOF MS ESI+)
calculated for C18H20NO4S+ [M + H]+: 346.1108, found 346.1105.
N-(2-hydroxyethyl)-4-methyl-N-(p-tolylethynyl)benzenesulfonamide (1f). Pale yellow
oil, 1.08 g, 89% yield. 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 8.4 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 3.93 –
3.81 (m, 2H), 3.56 (t, J = 5.4 Hz, 2H), 2.64 – 2.50 (m, 1H), 2.42 (s, 3H), 2.32 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 144.9, 138.2, 134.2, 131.6, 129.9, 129.1, 127.8,
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119.3, 81.3, 70.7, 59. 9, 54.0, 21.7, 21.5. HRMS (TOF MS ESI+) calculated for
C18H20NO3S+ [M + H]+: 330.1158, found 330.1150.
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N-(2-hydroxyethyl)-4-methyl-N-(m-tolylethynyl)benzenesulfonamide (1g). Pale yellow
oil, 1.12 g, 92% yield.1H NMR (400 MHz, CDCl3) (δ, ppm) 7.85 (d, J = 8.3 Hz, 2H),
7.35 (d, J = 8.0 Hz, 2H), 7.23 – 7.14 (comp, 3H), 7.11 – 7.04 (m, 1H), 3.88 (q, J = 5.4
Hz, 2H), 3.57 (t, J = 5.3 Hz, 2H), 2.43 (s, 3H), 2.30 (comp, 4H). 13C{1H} NMR (100
MHz, CDCl3) (δ, ppm) 144.9, 138.0, 134.2, 132.0, 129.9, 128.9, 128.5, 128.2, 127.8,
122.3, 81.7, 70.9, 60.0, 54.0, 21.7, 21.2. HRMS (TOF MS ESI+) calculated for
C18H20NO3S+ [M + H]+: 330.1158, found 330.1148.
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N-(2-hydroxyethyl)-4-methyl-N-(o-tolylethynyl)benzenesulfonamide (1h). Pale yellow
oil, 0.94 g, 77% yield. 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.86 (d, J = 8.3 Hz, 2H),
7.35 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.23 – 7.13 (m, 2H), 7.16 – 7.06 (m,
1H), 3.91 (q, J = 5.8 Hz, 2H), 3.61 (t, 2H), 2.44 (s, 3H), 2.36 (s, 3H), 2.18 – 2.10 (m,
13
1H). C{1H} NMR (100 MHz, CDCl3) (δ, ppm) δ 145.0, 139.7, 134.3, 131.4, 129.9,
129.5, 127.9, 127.8, 125.6, 122.3, 85.7, 69.8, 60.0, 54.1, 21.7, 20.8. HRMS (TOF MS
ESI+) calculated for C18H20NO3S+ [M + H]+: 330.1158, found 330.1152.
N-(2-hydroxyethyl)-4-methyl-N-(thiophen-2-ylethynyl)benzenesulfonamide
(1i).
o
Brown solid, mp 73.8-74.6 C. 0.65 g, 54% yield. 1H NMR (400 MHz, CDCl3) (δ,
ppm) 7.84 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.27 (dd, J = 5.2, 1.1 Hz, 1H),
7.17 (dd, J = 3.6, 1.2 Hz, 1H), 6.96 (dd, J = 5.2, 3.6 Hz, 1H), 3.93 – 3.79 (m, 2H),
3.58 (t, J = 5.8, 4.8 Hz, 2H), 2.46 (s, 3H), 2.17 – 2.07 (m, 1H). 13C{1H} NMR (100
MHz, CDCl3) (δ, ppm) 145.1, 134.2, 133.3, 129.9, 128.1, 127.8, 127.1, 122. 5, 85.5,
+
64.2, 60.0, 54.1, 21.7. HRMS (TOF MS ESI+) calculated for C15H16NO3S2 [M + H]+:
322.0566, found 322. 0562.
N-(2-hydroxyethyl)-4-methyl-N-(naphthalen-2-ylethynyl)benzenesulfonamide
(1j).
o
Brown solid, mp 92.1-93.8 C. 0.65 g, 48% yield. 1H NMR (500 MHz, CDCl3) (δ,
ppm) 7.91 – 7.84 (comp, 3H), 7.81 – 7.71 (comp, 3H), 7.50 – 7.43 (m, 2H), 7.39 (d, J
= 8.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 3.93 (q, J = 5.5 Hz,2H), 3.62 (t, J = 5.2 Hz,
2H), 2.43 (s, 3H), 2.27 – 2.20 (m, 1H).13C{1H} NMR (125 MHz, CDCl3) (δ, ppm)
145.0, 134.2, 133.0, 132.6, 131.0, 129.9, 128.3, 128.0, 127.9, 127.8, 127.6, 126.6,
126.6, 119.8, 82.3, 71.3, 60.1, 54.1, 21.7. HRMS (TOF MS ESI+) calculated for
C21H20NO3S+ [M + H]+: 366.1158, found 366.1158.
N-ethynyl-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (1k). Colorless solid, mp
1
< 50 oC. 0.56 g, 64% yield. H NMR (400 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 8.3 Hz,
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2H), 7.37 (d, J = 8.0 Hz, 2H), 3.85 (q, J = 5.9 Hz, 2H), 3.60 – 3.39 (m, 2H), 2.78 (s,
1H), 2.46 (s, 3H), 2.06 – 1.89 (m, 1H). The spectral data match those previously
reported.31
N-(hept-1-yn-1-yl)-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (1l). Colorless oil,
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0.17 g, 15% yield. H NMR (500 MHz, CDCl3) (δ, ppm) 7.80 (d, J = 8.3 Hz, 2H),
7.34 (d, J = 8.1 Hz, 2H), 3.91 – 3.74 (m, 2H), 3.47 – 3.44 (m, 2H), 2.45 (s, 3H), 2.25
(t, J = 7.0 Hz, 2H), 1.84 (t, J = 6.4 Hz, 1H), 1.48 (m, 2H), 1.37 – 1.24 (m, 4H), 0.97 –
0.83 (m, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 144.5, 134.4, 129.7, 127.8,
13
72. 9, 70.6, 60.1, 53.9, 31.0, 28.5, 22.1, 21.6, 18.4, 13.9. HRMS (TOF MS ESI+)
calculated for C16H24NO3S+ [M + H]+: 310.1471, found 310.1471.
N-(3-hydroxypropyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1m). Pale red
oil, 0.73 g, 60% yield. 1H NMR (500 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 7.9 Hz, 2H),
7.36 (comp, 4H), 7.28 (comp, 3H), 3.76 (q, J = 5.8 Hz, 2H), 3.54 (t, J = 6.8 Hz, 2H),
2.44 (s, 3H), 2.22 – 2.12 (m, 1H), 1.94 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) (δ,
ppm) 144.9, 134.2, 131.4, 129.9, 128.3, 127.9, 127.6, 122.7, 82.2, 70.7, 58.8, 48.6,
30.7, 21.7. HRMS (TOF MS ESI+) calculated for C18H20NO3S+ [M + H]+: 330.1158,
found 330.1153.
(R)-N-(2-hydroxypropyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1n). Pale
1
yellow oil, 1.08 g, 89% yield, 87% ee. H NMR (500 MHz, CDCl3) (δ, ppm) 7.85 (d,
J = 8.3 Hz, 2H), 7.39 – 7.31 (comp, 4H), 7.31 – 7.23 (comp, 3H), 4.23 – 4.08 (m, 1H),
3.47 (dd, J = 13.4, 8.1 Hz, 1H), 3.31 (dd, J = 13.3, 3.7 Hz, 1H), 2.44 (s, 3H), 2.36 (d,
J = 3.8 Hz, 1H), 1.25 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) (δ, ppm)
145.0, 134.2, 131.4, 129.9, 128.3, 128.0, 127.8, 122.5, 82.6, 70.6, 65.8, 58.8, 21.7,
20.1. HRMS (TOF MS ESI+) calculated for C18H20NO3S+ [M + H]+: 330.1158, found
330.1150. HPLC conditions for determination of enantiomeric excess: Chiral IA, λ =
254 nm, hexane : 2-propanol = 90:10, flow rate = 1.0 mL/min, tmajor = 11.2 min, tminor
= 12.4 min.
(R)-N-(1-hydroxypropan-2-yl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1o).
1
Reddish brown oil, 0.4 g, 32% yield, 99% ee. H NMR (500 MHz, CDCl3) (δ, ppm)
7.87 (d, J = 8.3 Hz, 2H), 7.39 – 7.33 (comp, 4H), 7.31 – 7.27 (comp, 3H), 4.29 – 4.15
(m, 1H), 3.77 – 3.61 (m, 1H), 3.61 – 3.48 (m, 1H), 2.44 (s, 3H), 1.98 – 1.88 (m, 1H),
1.10 (d, J = 6.8 Hz, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 144.8, 135.4,
13
131.3, 129.8, 128.3, 127.9, 127.7, 122.7, 78.8, 73.0, 64.4, 58.3, 21.7, 14.9. HRMS
(TOF MS ESI+) calculated for C18H20NO3S+ [M + H]+: 330.1158, found 330.1157.
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HPLC conditions for determination of enantiomeric excess: Chiral IA, λ = 254 nm,
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hexane : 2-propanol = 95:5, flow rate = 1.0 mL/min, tmajor = 24.6 min, tminor = 26.7
min.
N-(2-hydroxyethyl)-4-methoxy-N-(phenylethynyl)benzenesulfonamide
(1p).
Pale
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yellow oil, 0.34 g, 27% yield. H NMR (500 MHz, CDCl3) (δ, ppm) 7.91 (d, J = 8.9
Hz, 2H), 7.40 – 7.31 (m, 2H), 7.31 – 7.21 (comp, 3H), 7.02 (d, J = 9.0 Hz, 2H), 4.01 –
3.88 (m, 2H), 3.88 (s, 3H), 3.59 (t, J = 5.2 Hz, 2H), 2.19 – 2.00 (m, 1H). C{1H}
13
NMR (125 MHz, CDCl3) (δ, ppm) 163.9, 131.4, 130.1, 128.7, 128.3, 128.0, 122.5,
114.4, 82.2, 70.8, 60.1, 55.7, 54.0. HRMS (TOF MS ESI+) calculated for
C17H17NO4SNa+ [M + Na]+: 354.0771, found 354.0762.
General Procedure for the Catalytic Alkyne-Carbonyl Metathesis. To a 10-mL
oven-dried vial containing a magnetic stirring bar, isatin 2 (0.2 mmol, 1.0 equiv),
Zn(OTf)2 (14.5 mg, 20 mol%), and activated 4Å molecular sieves (200 mg), was
added a solution of ynamides 1 (0.22 mmol, 1.1 equiv) in DCE (6.0 mL). The
o
resulting reaction mixture was stirred overnight at 40 C in an oil bath. When the
reaction was completed (monitored by TLC), the solvent was evaporated in vacuo and
the crude residue was purified by flash column chromatography on silica gel without
additional treatment (hexanes/ethyl acetate = 8:1 to 3:1) to afford the pure products 3.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-phe
o
1
nylacetate (3aa). Yellow solid, mp 160.5-161.3 C. 83.7 mg, 88% yield. H NMR
(500 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 7.6 Hz, 2H), 7.49 (comp, 5H), 7.34 – 7.15 (m,
3H), 6.83 (d, J = 7.9 Hz, 1H), 6.79 – 6.69 (m, 2H), 6.26 (t, J = 6.3 Hz, 1H), 4.34 (t, J
= 4.8 Hz, 2H), 3.49 – 3.37 (m, 2H), 3.28 (s, 3H), 2.40 (s, 3H). C{1H} NMR (125
13
MHz, CDCl3) (δ, ppm) 167.6, 166.7, 144.1, 143.1, 141.0, 137.5, 133.2, 130.7, 130.1,
129.6, 129.3, 127.9, 127.2, 125.9, 123.6, 122.4, 120.4, 108.6, 64.7, 42.2, 26.2, 21.5.
HRMS (TOF MS ESI+) calculated for C26H25N2O5S+ [M + H]+: 477.1479, found
477.1483.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(5-chloro-1-methyl-2-oxoindolin-3-yliden
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1
e)-2-phenylacetate (3ab). Yellow solid, mp 184.0-184.8 C. 76.5 mg, 75% yield. H
NMR (500 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 7.9 Hz, 2H), 7.57 – 7.46 (m, 5H), 7.33
– 7.24 (m, 3H), 6.78 (d, J = 8.3 Hz, 1H), 6.76 – 6.70 (m, 1H), 6.19 (t, J = 6.3 Hz, 1H),
4.36 (t, J = 4.8 Hz, 2H), 3.60 – 3.39 (m, 2H), 3.29 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3) (δ, ppm) 167.2, 166.3, 143.2, 142.6, 142.6, 137.4, 132.6, 130.6,
130.4, 129.6, 129.4, 127.8, 127.8, 127.1, 125.0, 123.7, 121.7, 109.5, 64.9, 42.1, 26.4,
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21.5. HRMS (TOF MS ESI+) calculated for C26H24ClN2O5S+ [M + H]+: 511.1089,
found 511.1091.
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o
e)-2-phenylacetate (3ac). Yellow solid, mp 197.5-198.2 C. 85.3 mg, 77% yield. H
NMR (500 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 8.3 Hz, 2H), 7.56 – 7.48 (comp, 5H),
7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 1.9 Hz, 1H), 6.74
(d, J = 8.3 Hz, 1H), 6.18 (t, J = 6.2 Hz, 1H), 4.38 – 4.34 (m, 2H), 3.43 (td, J = 5.9, 4.2
Hz, 2H), 3.29 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.2,
166.2, 143.2, 143.0, 142.7, 137.4, 133.3, 132.6, 130.6, 129.6, 129.4, 127.8, 127.1,
126.5, 124.8, 122.2, 115.1, 110.0, 64.9, 42.1, 26.3, 21.5. HRMS (TOF MS ESI+)
calculated for C26H24BrN2O5S+ [M + H]+: 555.0584, found 555.0586.
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2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(5-fluoro-1-methyl-2-oxoindolin-3-yliden
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o
e)-2-phenylacetate (3ad). Yellow solid, mp 165.4-166.2 C. 59.4 mg, 60% yield. H
NMR (500 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 7.8 Hz, 2H), 7.57 – 7.43 (comp, 5H),
7.29 (d, J = 8.0 Hz, 2H), 6.98 (td, J = 8.8, 2.5 Hz, 1H), 6.75 (dd, J = 8.6, 4.2 Hz, 1H),
6.48 (dd, J = 8.9, 2.5 Hz, 1H), 6.22 (t, J = 6.2 Hz, 1H), 4.34 (t, J = 4.7 Hz, 2H), 3.47 –
3.37 (m, 2H), 3.28 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) (δ, ppm)
167.3, 166.5, 158.6 (d, J = 239.8 Hz), 143.1, 142.5, 140.21 (d, J = 1.8 Hz), 137.4,
132.6, 130.5, 129.6, 129.4, 127.7, 127.2, 125.5 (d, J = 2.9 Hz), 121.4 (d, J = 9.1 Hz),
117.0 (d, J = 24.1 Hz), 111.3 (d, J = 26.5 Hz), 109.0 (d, J = 8.3 Hz), 64.9, 42.1, 26.4,
21.5. 19F NMR (376 MHz, CDCl3) δ -120.1. HRMS (TOF MS ESI+) calculated for
C26H24FN2O5S+ [M + H]+: 495.1384, found 495.1386.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1,5-dimethyl-2-oxoindolin-3-ylidene)-2-
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phenylacetate (3ae). Yellow solid, mp 179.5-180.4 oC. 77.3 mg, 79% yield. H NMR
(500 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 7.9 Hz, 2H), 7.49 (comp, 5H), 7.28 (d, J =
8.1 Hz, 2H), 7.07 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.56 (s, 1H), 6.30 (t, J
= 6.2 Hz, 1H), 4.33 (t, J = 4.7 Hz, 2H), 3.41 (q, J = 5.3 Hz, 2H), 3.26 (s, 3H), 2.40 (s,
13
3H), 2.09 (s, 3H). C{1H} NMR (125MHz, CDCl3) (δ, ppm) 167.8, 166.7, 143.1,
142.0, 140.7, 137.5, 133.3, 131.8, 131.1, 130.1, 129.6, 129.2, 128.0, 127.2, 126.1,
124.4, 120.4, 108.3, 64.7, 42.2, 26.2, 21.5, 21.1. HRMS (TOF MS ESI+) calculated
for C27H27N2O5S+ [M + H]+: 491.1635, found 491.1639.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(5-methoxy-1-methyl-2-oxoindolin-3-ylid
ene)-2-phenylacetate (3af). Yellow solid, mp 171.2-172.0 oC. 87.0 mg, 86% yield. 1H
NMR (400 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 8.2 Hz, 2H), 7.49 (comp, 5H), 7.28 (d,
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J = 8.0 Hz, 2H), 6.81 (dd, J = 8.5, 2.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 6.32 (d, J =
2.8 Hz, 2H), 4.42 – 4.26 (m, 2H), 3.52 (s, 3H), 3.41 (td, J = 5.9, 4.1 Hz, 2H), 3.25 (s,
3H), 2.40 (s, 3H).13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.6, 166.5, 155.4,
143.1, 141.1, 138.0, 137.5, 133.1, 130.2, 129.6, 129.3, 127.9, 127.2, 126.3, 121.2,
115.7, 110.4, 109.0, 64.8, 55.5, 42.2, 26.3, 21.5. HRMS (TOF MS ESI+) calculated
for C27H27N2O6S+ [M + H]+: 507.1584, found 507.1587.
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2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(6-bromo-1-methyl-2-oxoindolin-3-yliden
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e)-2-phenylacetate (3ag). Yellow solid, mp 182.9-183.7 C. 98.0 mg, 88% yield. H
NMR (500 MHz, CDCl3) (δ, ppm) 7.82 (d, J = 7.8 Hz, 2H), 7.48 (comp, 5H), 7.28 (d,
J = 7.9 Hz, 2H), 6.99 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.13
(t, J = 6.3 Hz, 1H), 4.34 (t, J = 4.8 Hz, 2H), 3.52 – 3.34 (m, 2H), 3.26 (d, J = 1.2 Hz,
13
3H), 2.41 (s, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.4, 166.6, 145.1,
143.2, 141.7, 137.4, 132.9, 130.4, 129.6, 129.4, 127.8, 127.1, 125.3, 125.0, 124.6,
124.6, 119.3, 112.1, 64.9, 42.1, 26.4, 21.5. HRMS (TOF MS ESI+) calculated for
C26H24BrN2O5S+ [M + H]+: 555.0584, found 555.0584.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(7-chloro-1-methyl-2-oxoindolin-3-yliden
o
e)-2-phenylacetate (3ah). Yellow solid, mp 156.7-157.7 C. 100.0 mg, >95% yield.
1H NMR (500 MHz, CDCl3) (δ, ppm) 7.82 (d, J = 7.8 Hz, 2H), 7.56 – 7.39 (comp,
5H), 7.29 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 6.78 – 6.55 (m, 2H), 6.13 (t, J
= 6.3 Hz, 1H), 4.34 (t, J = 4.8 Hz, 2H), 3.65 (s, 3H), 3.50 – 3.27 (m, 2H), 2.41 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.4, 167.0, 143.2, 142.3, 139.8, 137.4,
132.9, 132.8, 130.3, 129.6, 129.4, 127.7, 127.1, 124.8, 123.1, 123.1, 122.1, 116.2,
64.9, 42.2, 29.8, 21.5. HRMS (TOF MS ESI+) calculated for C26H24ClN2O5S+ [M +
H]+: 511.1089, found 511.1090.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(6-chloro-1-methyl-2-oxoindolin-3-yliden
o
e)-2-phenylacetate (3ai). The reaction was conducted at 80 C. Yellow solid, mp
164.6-165.4 oC. 70.0 mg, 68% yield. 1H NMR (500 MHz, CDCl3) (δ, ppm) 7.82 (d, J
= 7.8 Hz, 2H), 7.56 – 7.38 (comp, 5H), 7.28 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 1.4 Hz,
1H), 6.76 – 6.71 (m, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.14 (t, J = 6.2 Hz, 1H), 4.34 (t, J
13
= 4.8 Hz, 2H), 3.47 – 3.32 (m, 2H), 3.26 (s, 3H), 2.40 (s, 3H). C{1H} NMR (125
MHz, CDCl3) (δ, ppm) 167.4, 166.7, 145.1, 143.2, 141.5, 137.4, 136.6, 132.9, 130.35,
129.6, 129.4, 127.8, 127.1, 124.9, 124.4, 122.4, 118.8, 109.3, 64.9, 42.2, 26.4, 21.5.
HRMS (TOF MS ESI+) calculated for C26H24ClN2O5S+ [M + H]+: 511.1089, found
511.1088.
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o
e)-2-phenylacetate (3aj). The reaction was conducted at 80 C. Yellow solid, mp
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141.3-142.1 oC. 66.8 mg, 65% yield. H NMR (500 MHz, CDCl3) (δ, ppm) 7.81 (d, J
= 7.9 Hz, 2H), 7.43 – 7.35 (comp, 3H), 7.32 (d, J = 7.3 Hz, 2H), 7.30 – 7.23 (comp,
3H), 6.90 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.11 (t, J = 6.1 Hz, 1H), 4.34
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(s, 2H), 3.50 – 3.37 (m, 2H), 3.31 (s, 3H), 2.40 (s, 3H). C{1H} NMR (125 MHz,
CDCl3) (δ, ppm) 168.1, 167.0, 146.1, 144.0, 143.2, 137.3, 135.6, 131.2, 130.7, 130.1,
129.6, 129.0, 128.5, 127.1, 125.2, 124.4, 118.9, 106.8, 64.7, 42.1, 26.6, 21.5. HRMS
(TOF MS ESI+) calculated for C26H24ClN2O5S+ [M + H]+: 511.1089, found 511.1090.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(4-bromo-1-methyl-2-oxoindolin-3-yliden
o
e)-2-phenylacetate (3ak). The reaction was conducted at 80 C. Yellow solid, mp
1
118.0-121.1 oC. 58.0 mg, 52% yield. H NMR (500 MHz, CDCl3) (δ, ppm) 7.81 (d, J
= 7.8 Hz, 2H), 7.39 (comp, 3H), 7.32 (d, J = 4.8 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H),
7.16 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.11 (t, J =
6.1 Hz, 1H), 4.35 (s, 2H), 3.40 (q, J = 5.4 Hz, 2H), 3.30 (s, 3H), 2.40 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) (δ, ppm) 168.1, 167.1, 146.4, 143.6, 143.2, 137.4, 135.7,
131.2, 130.2, 129.6, 129.2, 128.8, 128.6, 127.1, 125.1, 121.1, 119.0, 107.3, 64.7, 42.1,
26.5, 21.5. HRMS (TOF MS ESI+) calculated for C26H24BrN2O5S+ [M + H]+:
555.0584, found 555.0586.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-benzyl-2-oxoindolin-3-ylidene)-2-phen
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ylacetate (3al). Yellow oil, 106.1 mg, >95% yield. (Z): H NMR (400 MHz, CDCl3)
(δ, ppm) 7.78 (d, J = 8.3 Hz, 2H), 7.50 (comp, 5H), 7.40 – 7.26 (comp, 6H), 7.19 –
7.12 (comp, 3H), 6.81 – 6.65 (m, 2H), 6.25 (t, J = 6.3 Hz, 1H), 4.96 (s, 2H), 4.37 (t, J
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= 5.5Hz, 2H), 3.42 (td, J = 6.0, 4.3 Hz, 2H), 2.34 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) (δ, ppm) 167.7, 166.8, 143.3, 143.1, 141.4, 137.3, 135.4, 133.2, 130.7, 130.2,
129.8, 129.6, 129.3, 129.0, 127.9, 127.6, 127.1, 125.7, 123.7, 122.5, 120.5, 109.6,
64.9, 44.0, 42.2, 21.5. (E): 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.69 (d, J = 8.3 Hz,
2H), 7.56 – 7.51 (comp, 5H), 7.33 – 7.26 (comp, 9H), 7.24 – 7.21 (m, 2H), 4.88 –
4.78 (m, 1H), 4.09 (t, J = 5.3 Hz, 2H), 3.57 (s, 2H), 3.29 – 3.09 (m, 2H), 2.41 (s, 3H).
HRMS (TOF MS ESI+) calculated for C32H29N2O5S+ [M + H]+: 553.1792, found
553.1791.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(2-oxo-1-(prop-2-yn-1-yl)indolin-3-ylide
o
ne)-2-phenylacetate (3am). The reaction was conducted at 80 C with 1.2 equivalent
o
1
of 1a. Yellow solid, mp 188.3-189.5 C. 92.8 mg, 92% yield. H NMR (400 MHz,
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CDCl3) (δ, ppm) 7.94 – 7.77 (m, 2H), 7.49 (s, 5H), 7.29 (d, J = 7.9 Hz, 3H), 7.04 (d, J
= 7.8 Hz, 1H), 6.85 – 6.69 (m, 2H), 6.04 (t, J = 6.2 Hz, 1H), 4.56 (d, J = 2.5 Hz, 2H),
4.42 – 4.29 (m, 2H), 3.49 – 3.32 (m, 2H), 2.40 (s, 3H), 2.31 (t, J = 2.5 Hz, 1H).
13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.4, 165.8, 143.2, 142.2, 141.7, 137.3,
133.0, 130.8, 130.3, 129.6, 129.3, 127.9, 127.2, 125.4, 123.7, 122.8, 120.4, 109.6,
76.4, 72.8, 64.8, 42.2, 29.3, 21.5. HRMS (TOF MS ESI+) calculated for
C28H25N2O5S+ [M + H]+: 501.1479, found 501.1481.
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nylacetate (3an). Yellow solid, mp 182.9-183.7 C. 101.2 mg, 93% yield. H NMR
(400 MHz, CDCl3) (δ, ppm) δ 7.66 – 7.56 (comp, 6H), 7.56 – 7.47 (comp, 6H), 7.25 –
7.19 (m, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.92 – 6.71 (m, 3H), 5.94 (t, J = 6.4 Hz, 1H),
4.53 – 4.25 (m, 2H), 3.40 – 3.29 (m, 2H), 2.38 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) (δ, ppm) δ 167.6, 166.3, 144.2, 142.9, 141.8, 137.0, 133.8, 133.2, 130.7,
130.3, 129.8, 129.5, 129.4, 128.5, 127.9, 127.2, 126.7, 125.7, 123.9, 122.9, 120.4,
110.0, 65.1, 42.1, 21.5. HRMS (TOF MS ESI+) calculated for C31H26N2O5SNa+ [M +
Na]+: 561.1455, found 561.1449.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(2-oxoindolin-3-ylidene)-2-phenylacetate
o
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(3ao). Yellow solid, mp 210.5-211.1 C. 73.0 mg, 79% yield. H NMR (500 MHz,
CDCl3) (δ, ppm) 8.75 (s, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.52 – 7.44 (comp, 5H), 7.25
(d, J = 8.0 Hz, 2H), 7.20 – 7.14 (m, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 3.7 Hz,
2H), 6.48 (t, J = 6.1 Hz, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.40 (q, J = 5.6 Hz, 2H), 2.34 (s,
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3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 168.2, 167.7, 143.3, 141. 9, 140.8,
137.0, 133.2, 130.9, 130.1, 129.7, 129.3, 127.9, 127.2, 126.5, 123.7, 122.1, 120.9,
110.9, 64.4, 42.3, 21.5. HRMS (TOF MS ESI+) calculated for C25H23N2O5S+ [M +
H]+: 463.1322, found 463.1321.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(4-fluorophenyl)-2-(1-methyl-2-oxoindoli
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n-3-ylidene)acetate (3ba). Yellow solid, mp 94.3-95.8 C. 89.3 mg, 90% yield. H
NMR (500 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 7.9 Hz, 2H), 7.50 (dd, J = 8.3, 5.3 Hz,
2H), 7.32 – 7.24 (comp, 3H), 7.18 (t, J = 8.4 Hz, 2H), 6.84 (d, J = 7.9 Hz, 1H), 6.82 –
6.75 (m, 2H), 6.25 (t, J = 6.2 Hz, 1H), 4.34 (t, J = 4.8 Hz, 2H), 3.51 – 3.37 (m, 2H),
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3.28 (s, 3H), 2.40 (s, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.6, 166.6,
164.7, 162.7, 144.2, 143.1, 139.8, 137.4, 131.0, 130.2 (d, J = 8.4 Hz), 129.6, 129.1 (d,
J = 3.6 Hz), 127.1, 126.2, 123.0 (d, J = 121.6 Hz), 120.2, 116.5 (d, J = 21.9 Hz).
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108.8, 64.9, 42.2, 26.2, 21.5. 19F NMR (470 MHz, CDCl3) δ -109.6. HRMS (TOF MS
ESI+) calculated for C26H24FN2O5S+ [M + H]+: 495.1384, found 495.1386.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(4-chlorophenyl)-2-(1-methyl-2-oxoindol
o
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in-3-ylidene)acetate (3ca). Yellow solid, mp 97.1-99.6 C. 88.6 mg, 86% yield. H
NMR (400 MHz, CDCl3) (δ, ppm) δ 7.82 (d, J = 8.3 Hz, 2H), 7.60 – 7.41 (m, 4H),
7.38 – 7.15 (m, 3H), 6.90 – 6.72 (comp, 3H), 6.21 (t, J = 6.2 Hz, 1H), 4.39 – 4.24 (m,
2H), 3.47 – 3.37 (m, 2H), 3.28 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3)
δ 167.4, 166.5, 144.2, 143.1, 139.5, 137.4, 136.3, 131.6, 131.1, 129.6, 129.5, 127.1,
126.3, 123.6, 122.5, 120.1, 108.8, 64.9, 42.2, 26.3, 21.5. HRMS (TOF MS ESI+)
calculated for C26H24ClN2O5S+ [M + H]+: 511.1089, found 511.1085.
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2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-(4-(t
rifluoromethyl)phenyl)acetate (3da). Yellow solid, mp 165.8-166.2 oC. 80.0 mg, 73%
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yield. H NMR (400 MHz, CDCl3) (δ, ppm) δ 7.83 (d, J = 8.0 Hz, 2H), 7.76 (d, J =
8.1 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.36 – 7.23 (comp, 3H), 6.92 – 6.76 (m, 2H),
6.66 (d, J = 7.6 Hz, 1H), 6.21 (t, J = 6.2 Hz, 1H), 4.50 – 4.20 (m, 2H), 3.56 – 3.35 (m,
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2H), 3.29 (s, 3H), 2.40 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ 167.1, 166.4,
144.4, 143.2, 138.9, 137.4, 136.9, 132.0 (q, J = 32.8 Hz), 131.3, 129.6, 128.5, 127.0,
126.9, 126.3 (q, J = 3.7 Hz), 123.7 (q, J = 270.6 Hz), 123.6, 122.6, 120.5, 108.9, 65.1,
42.1, 26.3, 21.5. 19F NMR (376 MHz, CDCl3) δ -62.8. HRMS (TOF MS ESI+)
calculated for C27H24F3N2O5S+ [M + H]+: 545.1353, found 545.1351.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(4-methoxyphenyl)-2-(1-methyl-2-oxoind
olin-3-ylidene)acetate (3ea). Yellow solid, mp 98.8-100.2 oC. 93.0 mg, 92% yield. 1H
NMR (500 MHz, CDCl3) (δ, ppm) 7.82 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H),
7.27 (d, J = 7.7 Hz, 3H), 7.09 – 6.95 (m, 3H), 6.89 – 6.76 (m, 2H), 6.30 (t, J = 6.1 Hz,
1H), 4.34 (t, J = 4.7 Hz, 2H), 3.87 (s, 3H), 3.40 (q, J = 5.3 Hz, 2H), 3.27 (s, 3H), 2.39
(s, 3H). 13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 168.0, 166.9, 161.2, 144.0, 143.1,
141.2, 137.4, 130.5, 129.8, 129.6, 127.1, 125.1, 124.9, 123.3, 122.3, 120.6, 114.6,
108.6, 64.6, 55.5, 42.2, 26.2, 21.5. HRMS (TOF MS ESI+) calculated for
C27H27N2O6S+ [M + H]+: 507.1584, found 507.1590.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-(p-t
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olyl)acetate (3fa). Yellow solid, mp 147.1-148.0 C. 89.4 mg, 91% yield. H NMR
(500 MHz, CDCl3) (δ, ppm) 7.83 (d, J = 7.8 Hz, 2H), 7.46 – 7.34 (m, 2H), 7.36 – 7.21
(comp, 5H), 6.90 (d, J = 7.6 Hz, 1H), 6.87 – 6.77 (m, 2H), 6.28 (t, J = 6.2 Hz, 1H),
4.33 (t, J = 4.7 Hz, 2H), 3.41 (q, J = 5.3 Hz, 2H), 3.28 (s, 3H), 2.43 (s, 3H), 2.40 (s,
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3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.8, 166.8, 144.1, 143.1, 141.3,
140.6, 137.4, 130.6, 130.2, 129.9, 129.6, 128.0, 127.2, 125.4, 123.5, 122.4, 120.5,
108.6, 64.7, 42.2, 26.2, 21.5, 21.5. HRMS (TOF MS ESI+) calculated for
C27H27N2O5S+ [M + H]+: 491.1635, found 491.1628.
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2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-(m-t
olyl)acetate (3ga). Yellow solid, mp 82.8-83.8 oC. 93.0 mg, 95% yield. 1H NMR (500
MHz, CDCl3) (δ, ppm) 7.83 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.31 – 7.23
(comp, 6H), 6.83 (d, J = 7.9 Hz, 1H), 6.81 – 6.75 (m, 2H), 6.29 (t, J = 6.2 Hz, 1H),
4.34 (t, J = 4.8 Hz, 2H), 3.41 (q, J = 5.4 Hz, 2H), 3.28 (s, 3H), 2.50 – 2.27 (comp, 6H).
13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.7, 166.8, 144.1, 143.1, 141.3, 139.2,
137.4, 133.1, 130.9, 130.7, 129.6, 129.1, 128.2, 127.2, 125.7, 125.0, 123.6, 122.4,
120.5, 108.6, 64.7, 42.2, 26.2, 21.5, 21.4. HRMS (TOF MS ESI+) calculated for
C27H27N2O5S+ [M + H]+: 491.1635, found 491.1636.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-(o-t
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olyl)acetate (3ha). Yellow solid, mp 157.9-158.7 C. 66.0 mg, 67% yield. H NMR
(400 MHz, CDCl3) (δ, ppm) 7.86 (d, J = 8.0 Hz, 2H), 7.43 – 7.38 (m, 1H), 7.37 – 7.25
(m, 6H), 6.84 (d, J = 7.8 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.33 (t, J = 6.3 Hz, 1H),
6.21 (d, J = 7.6 Hz, 1H), 4.45 – 4.21 (m, 2H), 3.44 (dt, J = 6.3, 3.1 Hz, 2H), 3.31 (s,
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3H), 2.42 (s, 3H), 2.32 (s, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.4,
166.4, 143.9, 143.1, 140.3, 137.4, 136.0, 132.9, 130.8, 130.7, 129.6, 129.6, 127.3,
127.1, 126.9, 126.8, 123.4, 122.9, 120.7, 108.5, 64.7, 42.2, 26.2, 21.5, 19.5. HRMS
(TOF MS ESI+) calculated for C27H27N2O5S+ [M + H]+: 491.1635, found 491.1640.
2-((4-methylphenyl)sulfonamido)ethyl-(E)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-(thi
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ophen-2-yl)acetate (3ia). Yellow solid, mp 114.6-115.4 C. 67.6 mg, 70% yield. H
NMR (400 MHz, CDCl3) (δ, ppm) 7.82 (d, J = 8.0 Hz, 2H), 7.61 – 7.53 (m, 1H), 7.45
– 7.37 (m, 2H), 7.34 – 7.25 (m, 3H), 7.17 (dd, J = 5.1, 3.6 Hz, 1H), 6.92 – 6.81 (m,
2H), 6.19 (t, J = 6.1 Hz, 1H), 4.40 – 4.34 (m, 2H), 3.41 (q, J = 5.4 Hz, 2H), 3.27 (s,
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3H), 2.40 (s, 3H). C{1H} NMR (100 MHz, CDCl3) (δ, ppm) 167.3, 166.6, 144.2,
143.1, 137.4, 134.3, 133.9, 131.1, 130.2, 129.8, 129.6, 128.0, 127.1, 125.9, 123.4,
122.5, 120.3, 108.7, 64.9, 42.1, 26.2, 21.5. HRMS (TOF MS ESI+) calculated for
+
C24H23N2O5S2 [M + H]+: 483.1043, found 483.1046.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-(nap
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hthalen-2-yl)acetate (3ja). Yellow solid, mp 153.7-154.5 C. 98.1 mg, 93% yield. H
NMR (500 MHz, CDCl3) (δ, ppm) 8.04 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.93 (d, J =
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8.0 Hz, 1H), 7.91 – 7.83 (comp, 3H), 7.69 – 7.52 (comp, 3H), 7.35 – 7.28 (comp, 3H),
6.97 – 6.82 (m, 2H), 6.74 (t, J = 7.7 Hz, 1H), 6.47 – 6.20 (m, 1H), 4.38 (t, J = 4.5 Hz,
2H), 3.54 – 3.41 (m, 2H), 3.33 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
(δ, ppm) 167.7, 166.8, 144.2, 143.1, 141.0, 137.4, 133.8, 133.1, 130.8, 130.4, 129.6,
129.1, 128.6, 127.9, 127.9, 127.6, 127.2, 127.0, 125.9, 125.1, 123.7, 122.5, 120.4,
108.7, 64.8, 42.2, 26.3, 21.5. HRMS (TOF MS ESI+) calculated for C30H27N2O5S+ [M
+ H]+: 527.1635, found 527.1635.
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2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)acetate
(3ka). The reaction was conducted with 1.5 equivalent of 1k. Yellow solid, mp
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139.5-141.2 oC. 50.4 mg, 63% yield. (Z): H NMR (500 MHz, CDCl3) (δ, ppm) 7.82
(d, J = 7.8 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.32 – 7.19 (m,
2H), 7.06 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.65 (s, 1H), 6.48 (t, J = 6.3 Hz,
1H), 4.35 (t, J = 4.9 Hz, 2H), 3.53 – 3.32 (m, 2H), 3.25 (s, 3H), 2.40 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) (δ, ppm) 165.4, 165.1, 143.8, 143.0, 137.6, 133.3, 131.7,
129.6, 127.1, 122.8, 121.6, 121.1, 121.0, 108.7, 64.5, 42.2, 26.2, 21.5. (E): 1H NMR
(500 MHz, CDCl3) (δ, ppm) 8.47 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.51 –
6.97 (comp, 4H), 6.79 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 4.88 (t, J = 6.5 Hz, 1H), 4.28
(t, J = 5.3 Hz, 2H), 3.36 (s, 2H), 3.23 (d, J = 12.2 Hz, 3H), 2.40 (d, J = 4.1 Hz, 3H).
HRMS (TOF MS ESI+) calculated for C20H21N2O5S+ [M + H]+: 401.1166, found
401.1173.
2-((4-methylphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)heptan
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oate (3la). The reaction was conducted at 80 C. Yellow solid, mp 110.4-111.2 C.
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75.2 mg, 80% yield. H NMR (500 MHz, CDCl3) (δ, ppm) 7.81 (d, J = 8.0 Hz, 2H),
7.48 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.08 (t, J =
7.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.23 (t, J = 6.1 Hz, 1H), 4.41 – 4.32 (m, 2H),
3.39 (q, J = 5.4 Hz, 2H), 3.23 (s, 3H), 2.81 – 2.68 (m, 2H), 2.38 (s, 3H), 1.63 (t, J =
7.9 Hz, 2H), 1.45 – 1.39 (m, 2H), 1.38 – 1.32 (m, 2H), 0.90 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 169.2, 166.5, 144.6, 143.9, 143.0, 137.6,
130.0, 129.5, 127.1, 125.0, 123.9, 122.7, 121.1, 108.7, 64.3, 42.2, 31.8, 31.7, 26.7,
26.1, 22.4, 21.4, 13.9. HRMS (TOF MS ESI+) calculated for C25H31N2O5S+ [M + H]+:
471.1948, found 471.1947.
3-((4-methylphenyl)sulfonamido)propyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-ph
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enylacetate (3ma). Yellow solid, mp 165.3-166.2 C. 77.4 mg, 79% yield. H NMR
(400 MHz, CDCl3) (δ, ppm) 7.91 – 7.68 (m, 2H), 7.63 – 7.37 (comp, 5H), 7.26 (comp,
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3H), 6.91 – 6.70 (m, 3H), 5.75 (t, J = 6.5 Hz, 1H), 4.39 – 4.18 (m, 2H), 3.27 (s, 3H),
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3.19 – 3.05 (m, 2H), 2.40 (s, 3H), 2.01 – 1.82 (m, 2H). C{1H} NMR (100 MHz,
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CDCl3) (δ, ppm) 168.1, 166.7, 144.3, 143.0, 141.3, 137.8, 133.3, 130.7, 130.1, 129.6,
129.2, 128.0, 127.0, 125.7, 123.5, 122.3, 120.4, 108.6, 63.8, 40.5, 28.0, 26.2, 21.5.
HRMS (TOF MS ESI+) calculated for C27H27N2O5S+ [M + H]+: 491.1635, found
491.1632.
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(R)-1-((4-methylphenyl)sulfonamido)propan-2-yl-(Z)-2-(1-methyl-2-oxoindolin-3-ylid
ene)-2-phenylacetate (3na). Yellow oil, 95.6 mg, >95% yield, 87% ee. 1H NMR (500
MHz, CDCl3) (δ, ppm) 7.84 (d, J = 8.0 Hz, 2H), 7.49 (s, 5H), 7.28 (d, J = 8.4 Hz, 3H),
6.83 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 2H), 6.53 – 6.31 (m, 1H), 5.10 (td, J =
6.8, 2.5 Hz, 1H), 3.53 – 3.40 (m, 1H), 3.30 (s, 3H), 3.19 – 3.06 (m, 1H), 2.40 (s, 3H),
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1.24 (d, J = 6.5 Hz, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.3, 166.8,
144.1, 143.0, 141.3, 137.5, 133.3, 130.7, 130.1, 129.6, 129.3, 127.8, 127.1, 125.6,
123.6, 122.4, 120.4, 108.7, 71.3, 47.3, 26.3, 21.5, 17.5. HRMS (TOF MS ESI+)
calculated for C27H27N2O5S+ [M + H]+: 491.1635, found 491.1642. HPLC conditions
for determination of enantiomeric excess: Chiral IA, λ = 254 nm, hexane :2-propanol
= 85:15, flow rate = 1.0 mL/min, tmajor = 28.6 min, tminor = 31.3 min.
(R)-2-((4-methylphenyl)sulfonamido)propyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-
2-phenylacetate (3oa). Yellow solid, mp 142.4-143.7 oC. 84.0 mg, 85% yield, 99% ee.
1H NMR (500 MHz, CDCl3) (δ, ppm) 7.77 – 7.71 (m, 2H), 7.50 – 7.46 (m, 3H), 7.44
– 7.41 (m, 2H), 7.32 – 7.27 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 7.8 Hz, 1H),
6.82 – 6.76 (m, 2H), 6.08 (d, J = 6.4 Hz, 1H), 4.22 (dd, J = 11.3, 3.4 Hz, 1H), 4.04
(dd, J = 11.3, 6.5 Hz, 1H), 3.74 – 3.62 (m, 1H), 3.31 (s, 3H), 2.29 (s, 3H), 1.28 (d, J =
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6.7 Hz, 3H). C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.6, 166.6, 144.2, 142.8,
140.8, 138.3, 133.1, 130.8, 130.1, 129.4, 129.2, 127.9, 127.0, 125.9, 123.6, 122.4,
120.4, 108.7, 67.6, 49.2, 26.3, 21.4, 19.2. HRMS (TOF MS ESI+) calculated for
C27H27N2O5S+ [M + H]+: 491.1635, found 491.1632. HPLC conditions for
determination of enantiomeric excess: Chiral IA, λ = 254 nm, hexane : 2-propanol =
85:15, flow rate = 1.0 mL/min, tmajor = 27.2 min, tminor = 39.5 min.
2-((4-methoxyphenyl)sulfonamido)ethyl-(Z)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-ph
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enylacetate (3pa). Yellow solid, mp 109.9-110.7 C. 92.5 mg, 94% yield. H NMR
(500 MHz, CDCl3) (δ, ppm) 7.88 (d, J = 8.8 Hz, 2H), 7.49 (s, 5H), 7.26 (m,1H), 6.95
(d, J = 8.8 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.78 – 6.73 (m, 2H), 6.23 (t, J = 5.2 Hz,
1H), 4.68 – 4.24 (q, J = 5.0 Hz, 2H), 3.84 (s, 3H), 3.49 – 3.34 (m, 2H), 3.28 (s, 3H).
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13C{1H} NMR (125 MHz, CDCl3) (δ, ppm) 167.7, 166.7, 162.7, 144.1, 141.0, 133.2,
132.1, 130.8, 130.1, 129.3, 129.2, 127.9, 125.9, 123.6, 122.4, 120.4, 114.1, 108.6,
64.7, 55.6, 42.2, 26.2. HRMS (TOF MS ESI+) calculated for C26H25N2O6S+ [M + H]+:
493.1428, found 493.1426.
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(Z)-N-(2-hydroxyethyl)-2-(1-methyl-2-oxoindolin-3-ylidene)-2-phenyl-N-tosylacetami
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de (4aa). The reaction was conducted at -10 C. Yellow solid, mp 161.2-162.8 C.
78.1 mg, 82% yield. 1H NMR (500 MHz, CDCl3) (δ, ppm) 7.99 – 7.69 (m, 2H), 7.52
(comp, 3H), 7.34 – 7.19 (m, 3H), 7.06 (d, J = 7.7 Hz, 3H), 6.86 – 6.63 (m, 2H), 4.16 –
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3.96 (m, 2H), 3.88 (s, 1H), 3.80 – 3.64 (m, 2H), 3.13 (s, 3H), 2.36 (s, 3H). C{1H}
NMR (125 MHz, CDCl3) (δ, ppm) 168.2, 166.5, 144.8, 133.0, 130.3, 130.3, 130.2,
130.1, 129.8, 129.5, 128.9, 128.1, 123.3, 122.2, 121.0, 108.4, 59.9, 49.2, 26.0, 21.6.
HRMS (TOF MS ESI+) calculated for C26H25N2O5S+ [M + H]+: 477.1479, found
477.1481.
(Z)-N-(2-hydroxyethyl)-2-(1-methyl-2-oxoindolin-3-ylidene)-N-tosylheptanamide
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(4la). The reaction was conducted at 40 C. Yellow solid, mp 132.9-134.6 C. 39.5
mg, 42% yield. 1H NMR (500 MHz, CDCl3) (δ, ppm) 7.54 (d, J = 7.4 Hz, 3H), 7.35 (t,
J = 7.8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.9 Hz, 2H), 6.75 (d, J = 7.8 Hz,
1H), 4.34 – 4.06 (m, 3H), 3.77 (td, J = 8.1, 3.9 Hz, 1H), 3.49 (s, 1H), 3.11 – 2.95 (m,
1H), 2.81 (s, 3H), 2.74 – 2.57 (m, 1H), 2.32 (s, 3H), 1.90 – 1.74 (m, 1H), 1.75 – 1.64
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(m, 1H), 1.52 – 1.45 (m, 2H), 1.41 – 1.32 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). C{1H}
NMR (125 MHz, CDCl3) (δ, ppm) 169.8, 165.4, 144.3, 143.6, 135.7, 129.8, 128.8,
128.7, 124.4, 123.3, 122.8, 121.2, 108.0, 59.5, 50.0, 33.6, 32.1, 27.3, 25.4, 22.3, 21.5,
14.0. HRMS (TOF MS ESI+) calculated for C25H30N2O5SNa+ [M + Na]+: 493.1768,
found 493.1769.
General Procedure for the gram-scale synthesis. To a 25-mL oven-dried
round-bottom flask with a magnetic stirring bar, 1g (1.16 g, 3.52 mmol, 1.1 equiv),
isatin 2a (515.4 mg, 3.2 mmol, 1.0 equiv), Zn(OTf)2 (116.3 mg, 10.0 mol%),
activated 4Å molecular sieves (500 mg), and DCE (17 mL) were added in sequence at
room temperature. Then, the resulting reaction mixture was stirred overnight at 40 oC.
When the reaction was completed (monitored by TLC), the solvent was evaporated in
vacuo and the residue was recrystallized directly from DCM/PE to afford 1.45 g pure
3ga as yellow solid (92% yield).
Synthesis of 5: To a 100-mL oven-dried round-bottom flask with a magnetic stirring
bar, N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (1.07 g, 5.0 mmol, 1.0 equiv)
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TEA (1.2 equiv) at 0 C, and the reaction mixture was stirred under these conditions
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for 4 h. After completion (monitored by TLC), the mixture was diluted with DCM and
poured onto water. The aqueous phase was extracted with DCM (30 mL × 2), the
organic extracts were combined and dried over Na2SO4. The solvent was evaporated
in vacuo after filtration, and the residue was purified by column chromatography on
silica gel (eluted with petroleum ether/ethyl acetate = 6:1- 3:1) to give 0.96 g pure
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product 5 in 58% yields. White solid, mp 58.0-59.6 C. H NMR (400 MHz, CDCl3)
(δ, ppm) 7.71 (d, J = 8.3 Hz, 2H), 7.45 – 7.10 (comp, 7H), 5.06 (t, J = 6.0 Hz, 1H),
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4.08 (t, J = 5.3 Hz, 2H), 3.56 (s, 2H), 3.19 (q, J = 5.7 Hz, 2H), 2.42 (s, 3H). C{1H}
NMR (100 MHz, CDCl3) (δ, ppm) 171.4, 143.7, 136.9, 133.6, 129.8, 129.2, 128.7,
127.3, 127.0, 63.2, 42.1, 41.0, 21.6. HRMS (TOF MS ESI+) calculated for
C17H20NO4S+ [M + H]+: 334.1108, found 334.1106.
Control Experiment (a): To a 10-mL oven-dried vial containing a magnetic stirring
bar, 2a (8.1 mg, 0.05 mmol, 1.0 equiv), Zn(OTf)2 (3.6 mg, 20 mol%), and activated
4Å molecular sieves (50 mg), was added a solution of 5 (17.4 mg, 0.05 mmol, 1.0
equiv) in DCE (1.0 mL). After addition, the reaction mixture was stirred overnight at
o
o
40 C, and additional 12 h at 80 C in an oil bath. Then the reaction mixture was
filtered and concentrated in vacuo. The residue was subjected to 1H NMR analysis in
CDCl3 without any additional treatment. Most of the starting materials 5 and 2a
remained intact (see Figure S1).
Control Experiment (b): To a 10-mL oven-dried vial containing a magnetic stirring
bar, 2a (8.1 mg, 0.05 mmol, 1.0 equiv), Zn(OTf)2 (3.6 mg, 20 mol%), and activated
4Å molecular sieves (50 mg), was added a solution of 632 (18.9 mg, 0.05 mmol1.0
equiv) in DCE (1.0 mL). After addition, the resulting reaction mixture was stirred
o
o
overnight at 40 C in an oil bath, and additional 12 h at 80 C. Then the reaction
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mixture was filtered and concentrated in vacuo. The residue was subjected to H
NMR analysis in CDCl3 without any additional treatment. Most of the starting
materials 6 and 2a remained intact (see Figure S2).
Isotope-labeled experiment (c): To a 10-mL oven-dried vial containing a magnetic
stirring bar, 2a (16.1 mg, 0.1 mmol, 1.0 equiv), Zn(OTf)2 (7.3 mg, 20 mol%), and
activated 4Å molecular sieves (100 mg), was added a solution of ynamide 1a (34.6
18
mg, 0.11 mmol, 1.1 equiv) and H2 O (2.0 μL) in DCE (3.0 mL). The resulting
reaction mixture was stirred overnight at 40 oC in an oil bath. When the reaction was
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completed (monitored by TLC), the crude mixture was subjected to high-resolution
mass spectra (HRMS) analysis, and no molecular weight of 3aa-18O was detection
(see Figure S3).
Synthesis of 2a-18O: To a 10-mL oven-dried vial containing a magnetic stirring bar,
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2a (16.1 mg, 0.1 mmol), TsOH (3.4 mg, 20 mol%), H2 O (3.0 μL), and anhydrous
MeCN (2.0 mL) were added in sequence, and the reaction mixture was stirred at room
temperature for 4 h. Then, the crude reaction mixture was filtered and concentrated
under reduced pressure, and the crude reaction mixture was subjected to
high-resolution mass spectra (HRMS) analysis (see Figure S4 for HRMS, and Figure
S5 for EIC analysis; 20.5% of 2a-18O was detected). The obtained product used in the
next step without purification.
Isotope-labeled experiment (d): To a 10-mL oven-dried vial containing a magnetic
stirring bar, the 2a-18O, Zn(OTf)2 (3.6 mg, 20 mol%), and activated 4Å molecular
sieves (50 mg), was added a solution of ynamide 1a (34.6 mg, 0.11 mmol) in DCE
(3.0 mL). The resulting reaction mixture was stirred overnight at 40 oC in an oil bath.
When the reaction was completed (monitored by TLC). Then the solvent was
concentrated under reduced pressure, and the crude reaction mixture was subjected to
high-resolution mass spectra (HRMS) analysis (see Figure S6 for HRMS, and Figure
S7 for EIC analysis, and 19.1% of 3aa-18O was detected).
Control Experiment (e): To a 10-mL oven-dried vial containing a magnetic stirring
bar, isatin 2a (32.2 mg, 0.2 mmol, 1.0 equiv), Zn(OTf)2 (14.5 mg, 20 mol%), and
activated 4Å molecular sieves (200 mg), was added a solution of ynamide 1q (85.5
mg, 0.3 mmol, 1.5equiv) in DCE (6.0 mL). The resulting reaction mixture was stirred
o
at 80 C for 36 h. When the reaction was completed (monitored by TLC). Then the
solvent was evaporated in vacuo and the residue was purified by flash column
chromatography on silica gel (hexanes/ethyl acetate = 10:1 to 3:1) without additional
treatment to afford 35.7 mg pure products 3qa in 40% yields. Yellow solid, mp
188.2-189.7 C. 1H NMR (500 MHz, CDCl3) (δ, ppm) 7.72 (comp, 3H), 7.60 – 7.40
o
(comp, 4H), 7.35 – 7.17 (comp, 3H), 7.04 (d, J = 7.8 Hz, 1H), 6.77 (t, J = 7.4 Hz, 2H),
3.27 (s, 3H), 3.14 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) (δ, ppm)
166.4, 144.6, 130.4, 130.4, 130.3, 130.2, 130.1, 129.5, 129.0, 129.0, 128.3, 128.2,
128.1, 123.2, 121.9, 108.2, 26.0, 21.7. HRMS (TOF MS ESI+) calculated for
C25H22N2O4SNa+ [M + Na]+: 469.1192, found 469.1193.
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Control Experiment (f): To two 10-mL oven-dried vials containing a magnetic
stirring bar respectively, 4aa (23.8 mg, 0.05 mmol), Zn(OTf)2 (3.6 mg, 20 mol% or
none), activated 4Å molecular sieves (50 mg), and DCE (1.0 mL) were added in
sequence at room temperature. Then, the resulting reaction mixture was stirred
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overnight at 40 C in an oil bath. Then the reaction mixture was filtered and
concentrated in vacuo. The residue was subjected to proton NMR analysis in CDCl3
without any additional treatment (see Figure S8). In the case with Zn(OTf)2, all the
starting material 4aa was converted to 3aa (see Figure S8, the third spectrum). In the
case without Zn(OTf)2, most of the starting material 4aa remained intact (see Figure
S8, the fourth spectrum).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at http://pubs.acs.org.
Figures for control experiments、copies of NMR spectra and HPLC chromatograms
of chiral compounds (PDF)
X-ray crystal data for 3ac (CIF)
X-ray crystal data for 4la (CIF)
AUTHOR INFORMATION
Corresponding Authors
*Email: zhangdan5@mail.sysu.edu.cn. (D. Z)
*Email: huwh9@mail.sysu.edu.cn. (W. H.)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support for this research from the National Natural Science Foundation of China (Nos.
21602148 and 21901259), National Science & Technology Major Project “Key New
Drug Creation and Manufacturing Program” of China (2018ZX09711002-006), and
The Program for Guangdong Introducing Innovative and Entrepreneurial Teams (No.
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2016ZT06Y337) is greatly acknowledged.
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