Chiral Tertiary Sulfonium Salts as Effective Catalysts for Asymmetric Base-Free Neutral Phase-Transfer Reactions

Article abstract of DOI:10.1002/anie.201612328

Although chiral quaternary ammonium and phosphonium salts are commonly used for asymmetric organocatalysis, the catalytic ability of chiral tertiary sulfonium salts has yet to be demonstrated in asymmetric synthesis. Herein, we show that chiral bifunction

Full text of DOI:10.1002/anie.201612328

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612328
German Edition: DOI: 10.1002/ange.201612328
Organocatalysis
Chiral Tertiary Sulfonium Salts as Effective Catalysts for Asymmetric
Base-Free Neutral Phase-Transfer Reactions
Shiyao Liu, Keiji Maruoka, and Seiji Shirakawa*
Dedicated to Professor Shoichi Shimizu on the occasion of his 60th birthday
Abstract: Although chiral quaternary ammonium and phos-
phonium salts are commonly used for asymmetric organo-
catalysis, the catalytic ability of chiral tertiary sulfonium salts
has yet to be demonstrated in asymmetric synthesis. Herein, we
show that chiral bifunctional trialkylsulfonium salts catalyze
highly enantioselective conjugate additions of 3-substituted
oxindoles to maleimides under base-free neutral phase-transfer
conditions.
C
hiral onium salts are recognized as some of the most
reliable compounds in asymmetric synthesis (Figure 1).
[1–5]
Various types of chiral quaternary ammonium and phospho-
nium salts have been synthesized, particularly over the past
[1,2]
two decades.
These compounds have been employed as
chiral phase-transfer catalysts, and have enabled a wide
[
3]
variety of efficient enantioselective transformations. On the
other hand, the catalytic ability of chiral tertiary sulfonium
salts has yet to be demonstrated in asymmetric synthesis,
despite the utility of these chiral compounds as reagents in
[
4,5]
stereoselective reactions.
The limitations of chiral sulfo-
nium salt catalysts have been attributed mainly to the high
reactivity and instability of the compounds with acidic a-
[
6]
hydrogen atoms. The corresponding sulfonium ylides are
thought to be formed from alkylsulfonium salts under
ordinary basic phase-transfer conditions, and as a result, the
catalytic activity of the sulfonium salts is lost. To avoid this
problem and realize efficient asymmetric reactions with chiral
sulfonium salt catalysts, we became interested in a base-free
neutral phase-transfer reaction system. The formation of
sulfonium ylides from sulfonium salts can be suppressed
under base-free, neutral conditions. Under such conditions,
chiral sulfonium salt catalysts could efficiently promote
asymmetric neutral phase-transfer reactions with a high
level of enantioselectivity. Herein, we report the development
Figure 1. Chiral onium salts in organic synthesis.
[
7]
of chiral tertiary sulfonium salt catalysts for highly enantio-
selective conjugate additions under base-free neutral phase-
[
8]
transfer conditions.
To achieve highly enantioselective phase-transfer reac-
tions with chiral sulfonium salt catalysts, we employed
a binaphthyl backbone as the chiral scaffold for the synthesis
of the catalysts. The target chiral tertiary sulfonium triflates
1
–3 (Scheme 1 and Table 1) were readily prepared in a similar
[
*] S. Liu, Prof. Dr. S. Shirakawa
manner, which involved a reaction of the corresponding
binaphthol-derived arylmethyl bromide and dialkyl sulfide in
Department of Environmental Science
Graduate School of Fisheries and Environmental Sciences
Nagasaki University
1–14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
E-mail: seijishirakawa@nagasaki-u.ac.jp
Homepage: http://seijishirakawa.wix.com/greenchemistry
Prof. Dr. K. Maruoka
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612328.
Scheme 1. Synthesis of chiral sulfonium salt catalysts. Tf=trifluoro-
methanesulfonyl.
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the presence of silver triflate (see the Supporting Information
for details).
As a model reaction to examine the ability of chiral
sulfonium salts 1–3, asymmetric conjugate additions of 3-
substituted oxindoles 4 to maleimides 5 under base-free
[
9]
conditions were selected (Table 1). The reaction between 3-
phenyloxindole 4a and N-phenylmaleimide (5a) in H O/
2
[
a]
Table 1: Catalyst optimization.
Scheme 2. Control experiments.
[
b]
[c]
[d]
Entry
Catalyst
Yield [%]
d.r.
ee [%]
promoted by catalyst 2c in a H O/toluene biphasic solvent
2
1
2
3
4
5
6
7
1a
1b
2a
2b
2c
3a
3b
<5
24
31
77
64
53
15
–
–
4
mixture, the reaction did not take place in a homogeneous
70:30
86:14
88:12
92:8
88:12
74:26
[
13]
toluene system. To clarify the importance of the sulfonium
74
83
91
81
76
salt moiety on catalyst 2c, the reaction with sulfide catalyst 7
[
e]
was also examined in a H O/toluene biphasic system. Com-
2
pound 7 was not able to catalyze the present base-free neutral
phase-transfer reaction, that is, the tertiary sulfonium salt
moiety of catalyst 2c was essential in promoting the reaction.
Furthermore, deuteration experiments were performed with
[a] Reaction conditions: 4a (0.070 mmol), 5a (0.084 mmol), catalyst
(
5 mol%, 0.0035 mmol), H O (2.0 mL)/toluene (0.2 mL), 258C, 16 h.
2
1
[b] Yield of isolated product 6aa. [c] Determined by H NMR and HPLC
3
-phenyloxindole 4a. Treatment of 4a with catalyst 2c in
analysis. [d] Determined by HPLC analysis on a chiral stationary phase.
e] Reaction time: 24 h. Boc=tert-butoxycarbonyl.
[
toluene (10:1) was run in the presence of catalyst 1a or 1b
5 mol%) at 258C for 16 h. Whereas methoxy-substituted
catalyst 1a afforded only a trace amount of product 6aa
entry 1), the bifunctional catalyst 1b with a hydroxy group
(
(
promoted the reaction to give 6aa in moderate yield, albeit
with low enantioselectivity (4% ee; entry 2). These results
suggested that a bifunctional catalyst design was beneficial to
the reaction. Encouraged by this result, we next examined
bifunctional sulfonium salts 2, which also possess a urea group
[
10]
(
entries 3–5). To our delight, phenylurea-substituted cata-
lyst 2a gave the product 6aa in good diastereo- and
enantioselectivity (74% ee; entry 3). Further tuning of the
urea moiety on catalyst 2 improved both the yield and the
stereoselectivity (entries 4 and 5), and the highest levels of
diastereo- and enantioselectivity were achieved with catalyst
[11,12]
2
c (91% ee; entry 5).
Changes in the alkyl groups on the
sulfonium moiety (catalysts 3) did not improve the results
(
entries 6 and 7).
Several control experiments were performed to clarify the
mechanism of the present reaction (Scheme 2). We first
examined the effect of H O on the base-free neutral phase-
2
transfer reaction. Whereas this reaction was efficiently
Scheme 3. Proposed catalytic cycle.
2
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[
a]
a D O/toluene biphasic system at
Table 2: Scope and limitation.
2
5
8C for 2 h returned deuterated 3-
phenyloxindole, [D]-4a, in quanti-
tative yield. However, in the
absence of a catalyst, [D]-4a was
obtained in only 8% yield. These
results completely agree with pre-
vious observations for base-free
neutral phase-transfer reactions
with quaternary ammonium and
phosphonium salt catalysts, and
indicate that the reaction proceeds
via a sulfonium enolate interme-
1
2
[b]
[c]
[d]
Entry
1
4
X
R
5
R
Product Yield [%]
d.r.
ee [%]
4a
4a
4a
4a
4b
4b
4c
4d
4e
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
4-Me-C H
4-Me-C H
3-Me-C H
4-F-C H
Bu
5a Ph
5b 4-MeO-C H
5c 4-CF -C H
5d Me
5a Ph
6aa
6ab
6ac
6ad
6ba
6bc
6ca
6da
6ea
6 fa
6ga
6gc
6ha
6ia
64
42
60
17
45
54
28
59
<5
46
81
70
66
61
73
66
85
56
92:8
91
[
[
[
e]
f]
e]
2
3
4
5
6
7
8
9
0
1
2
3
4
86:14 86
87:13 86
89:11 86
85:15 83
85:15 83
83:17 88
90:10 83
6
4
3
6
4
6
4
4
4
[f]
5c 4-CF -C H
3 6
6
4
[
7h,i]
diate.
5a Ph
5a Ph
5a Ph
5a Ph
5a Ph
5c 4-CF -C H
5a Ph
5a Ph
6
Based on these observations,
a catalytic cycle for the present
reaction was proposed (Scheme 3).
For the reaction to proceed, the
6
4
–
–
1
1
1
1
1
4 f 5-Me Ph
87:13 83
88:12 90
96:4
92:8
88:12 83
89:11 84
90:10 86
89:11 84
4g 5-F
4g 5-F
4h 6-Cl
4i 7-F
4i 7-F
4j 5-F
4k 5-F
4k 5-F
Ph
Ph
Ph
Ph
Ph
4-Me-C
4-F-C H
4-F-C
[
[
[
f]
f]
f]
93
88
3
6
4
4
4
H O/toluene biphasic solvent mix-
2
ture was indispensable. When the
reaction was carried out in toluene
15
16
5c 4-CF -C H
6ic
6ja
6ka
6kc
3
6
without H O, the reversible reac-
6
H
4
5a Ph
5a Ph
5c 4-CF
2
1
1
7
8
tion with oxindole 4a and sulfo-
nium salt 2c to form sulfonium
enolate Awas not favored owing to
the facile protonation of sulfonium
enolate A with in situ generated
TfOH. On the other hand, when
the reaction was performed in the
6
4
4
6
H
3
-C
6
H
92:8
85
[a] Reaction conditions: 4 (0.070 mmol), 5 (0.084 mmol), 2c (5 mol%, 0.0035 mmol), H O (2.0 mL)/
toluene (0.2 mL), 258C, 24 h. [b] Yield of isolated product 6. [c] Determined by H NMR and HPLC
analysis. [d] Determined by HPLC analysis on a chiral stationary phase. [e] Reaction time: 16 h. [f] At
2
1
0
8C.
H O/toluene biphasic solvent
2
system, the generated TfOH was moved into the aqueous
phase. Consequently, contact between sulfonium enolate A
and TfOH was suppressed, and the formation of sulfonium
enolate A was promoted. The urea moiety of catalyst 2c
interacted with maleimide 5a via hydrogen bonds, thus
returning a well-organized complex B. It is noteworthy that
hydrogen-bonding interactions between the a-hydrogen
In summary, we have successfully demonstrated that
chiral tertiary sulfonium salt catalysts can promote asymmet-
ric reactions with
a high level of enantioselectivity.
Binaphthyl-modified bifunctional sulfonium salts bearing
a urea group were efficient catalysts for the asymmetric
conjugate addition of 3-substituted oxindoles to maleimides
under base-free neutral phase-transfer conditions. To the best
of our knowledge, this is the first example of a highly
enantioselective reaction catalyzed by a chiral tertiary
sulfonium salt.
[14]
atoms of the trialkylsulfonium salt moiety on catalyst 2c
and the substrates may also be important in organizing the
[
15]
transition-state structure. A highly stereoselective conju-
gate addition then occurred to give intermediate C. Proto-
nation of intermediate C by TfOH, which was generated
during the reaction of sulfonium triflate 2c with oxindole 4a, Acknowledgements
afforded product 6aa with regeneration of sulfonium salt
catalyst 2c.
Having proposed a plausible catalytic cycle, we examined
the generality of the asymmetric conjugate addition with
various 3-substituted oxindoles 4 and maleimides 5 under
base-free neutral phase-transfer conditions (Table 2). Not
only N-aryl maleimides (5a–5c) but also N-alkyl maleimides
This work was partially supported by a Grant-in-Aid for
Scientific Research (C) from the JSPS, the Cooperative
Research Program of “Network Joint Research Center for
Materials and Devices”, and The Naito Foundation.
(5d) were found to be suitable substrates for the reaction to Conflict of interest
give products 6 with high enantioselectivities (86–91% ee;
entries 1–4). Furthermore, a wide variety of 3-aryl oxindoles 4
with electron-withdrawing and -donating substituents on both
the 3-aryl group and the oxindole core were also applicable,
and uniformly gave high diastereo- and enantioselectivities
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · ion pairs · organocatalysis ·
phase-transfer catalysis · sulfur
[
16]
(
83–93% ee; entries 5–18).
Unfortunately, 3-alkyl oxin-
doles, such as a 3-butyloxindole 4e, showed low reactivity in
this reaction system (entry 9).
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[
11] Remaining starting materials 4a and 5a were observed after the
reaction.
[
[
12] Longer reaction times did not improve the yield.
13] The effect of the amount of water was also examined
[16] Reactions on larger scale (x10, 0.70 mmol) gave similar results
(Scheme S2).
(
Scheme S1).
[
14] a) S. Kaneko, Y. Kumatabara, S. Shimizu, K. Maruoka, S.
Shirakawa, Chem. Commun. 2017, 53, 119; see also: b) S.
Shirakawa, S. Liu, S. Kaneko, Y. Kumatabara, A. Fukuda, Y.
Omagari, K. Maruoka, Angew. Chem. Int. Ed. 2015, 54, 15767;
Manuscript received: December 20, 2016
Revised: March 7, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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Angewandte
Communications
Chemie
Communications
Organocatalysis
S. Liu, K. Maruoka,
S. Shirakawa*
&&&& — &&&&
Chiral Tertiary Sulfonium Salts as
Effective Catalysts for Asymmetric Base-
Free Neutral Phase-Transfer Reactions
Sulfonium catalyst: Whereas chiral qua-
ternary ammonium and phosphonium
salts are commonly used for asymmetric
organocatalysis, chiral tertiary sulfonium
salts have not been employed for such
purposes. It is now shown that chiral
bifunctional trialkylsulfonium salts cata-
lyze the enantioselective conjugate addi-
tion of 3-substituted oxindoles to male-
imides under base-free neutral phase-
transfer conditions.
6
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!