Efficient approach for the design of effective chiral quaternary phosphonium salts in asymmetric conjugate additions

Article abstract of DOI:10.1039/c3sc22130j

An efficient approach for the design of chiral quaternary phosphonium bromides as chiral phase-transfer catalysts was demonstrated. A catalyst library of phosphonium salts with various structures was readily constructed using commercially available chiral phosphines as catalyst precursors, and an optimized catalyst was successfully applied to highly enantioselective conjugate additions under base-free phase-transfer conditions with low catalyst loading.

Full text of DOI:10.1039/c3sc22130j

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Efficient approach for the design of effective chiral
quaternary phosphonium salts in asymmetric conjugate
additions†
Cite this: DOI: 10.1039/c3sc22130j
*
Seiji Shirakawa, Atsuyuki Kasai, Takashi Tokuda and Keiji Maruoka
An efficient approach for the design of chiral quaternary phosphonium bromides as chiral phase-transfer
catalysts was demonstrated. A catalyst library of phosphonium salts with various structures was readily
constructed using commercially available chiral phosphines as catalyst precursors, and an optimized
catalyst was successfully applied to highly enantioselective conjugate additions under base-free phase-
transfer conditions with low catalyst loading.
Received 3rd December 2012
Accepted 26th February 2013
DOI: 10.1039/c3sc22130j
www.rsc.org/chemicalscience
Fig. 1. As a model reaction to examine the catalyst ability of
these phosphonium salts, asymmetric conjugate addition of
Introduction
During more than the last two decades, asymmetric phase-
transfer catalysis based on the use of structurally well-dened
chiral quaternary ammonium salts has become a topic of great
scientic interest, and a variety of chiral quaternary ammonium
salts have been developed as reliable catalysts for asymmetric
phase-transfer reactions.1 On the other hand, only a few exam-
ples of chiral quaternary phosphonium salts2 as chiral phase-
transfer catalysts have been reported, with quite limited
success,3–5 and hence the development of new effective chiral
quaternary phosphonium salts is an important challenge in
organocatalytic chemistry.6 Our approach for the discovery of
effective chiral quaternary phosphonium salts relies on the use
of commercially available chiral phosphine compounds7 as
catalyst precursors. This approach allows facile construction of
a catalyst library of chiral quaternary phosphonium salts with
various structures. Here we wish to report a new and efficient
approach for the design of effective chiral quaternary phos-
phonium salts based on the use of a commercially available
chiral phosphine library (Fig. 1) in asymmetric conjugate
additions under base-free phase-transfer conditions8 with low
catalyst loading (0.1 mol%).
3-substituted oxindole 10 to acrolein was selected (Table 1),
because of high synthetic utility of the resulting conjugate
adduct 11 in the construction of attractive tricyclic structures
Results and discussion
A catalyst library of chiral quaternary phosphonium salts with
various structures was readily constructed by benzylation of
corresponding commercially available phosphines as shown in
Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic
Chemistry, Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto, 606-8502, Japan. E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81-
75-753-4041; Tel: +81-75-753-4041
† Electronic supplementary information (ESI) available: Experimental details and
characterization data for new compounds. See DOI: 10.1039/c3sc22130j
Fig. 1 Library of chiral quaternary phosphonium salts.
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Table 1 Screening of catalyst librarya
Entry
Catalyst
Yieldb (%)
eec (%)
Fig. 2 Proposed working model of bifunctional catalyst 9.
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
13
5
5
9
18
97
96
96
8
8
2
6
4
(Scheme 2). A wide variety of arylmethyl bromides were employed
to prepare a catalyst library of type 9 with various electronic and
steric environments, and the prepared catalysts 9a–9p were
applied to asymmetric conjugate addition of 3-phenyloxindole
10a with acrolein under base-free phase-transfer conditions.14
The catalysts of type 9 generally promoted the reaction efficiently
1
À25
26
69
9a
a
Reaction conditions: 10a (0.050 mmol), acrolein (0.15 mmol) in the
presence of catalyst (1 mol%) in H2O (1.0 mL)/mesitylene (1.0 mL) at
b
c
0
ꢀC for 24 h. Yield of isolated product. Determined by chiral
HPLC analysis.
(Scheme 1).3b,9 Although many examples of asymmetric conju-
gate additions of 3-substituted oxindoles have recently been
reported,10 examples of asymmetric conjugate addition to
acrolein have been quite limited, despite the high synthetic
utility of the adduct 11.3b,5f
We initially examined the screening of chiral bisphospho-
nium salts 1–4 as phase-transfer catalysts under base-free
conditions (Table 1). Attempted reaction of 3-phenyloxindole
10a and acrolein in H2O/mesitylene11 under the inuence of
catalysts 1–4 (1 mol%) at 0 ꢀC for 24 h afforded a conjugate
adduct 11a in low yields and enantioselectivities (entries 1–4).
Next we examined chiral monophosphonium salts 5–9a.
Although catalysts 5 and 6 showed low reactivities (entries 5 and
6), BINAP-7c and MOP-derived12 lipophilic monophosphonium
salts 7–9a efficiently promoted the reaction to afford the
product 11a in high yields (entries 7–9). Among these catalysts,
the hydroxy group-possessing bifunctional catalyst 9a showed
good enantioselectivity (69% ee, entry 9).8,13 The benecial effect
of a hydroxy group in bifunctional catalyst 9 may be explained
by hydrogen-bonding interaction between this motif and the
enolate anion derived from oxindole 10 (A in Fig. 2),8b,c,13a,d or
the carbonyl oxygen of acrolein (B in Fig. 2).13b,e,h
The structure of catalyst 9 was further optimized by the
introduction of various arylmethyl groups on the phosphorus
Scheme 1 Synthetic utility of conjugate adduct 11.
Scheme 2 Optimization of catalyst structure in 9.
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(92–99% yields, except for catalyst 9p: 57% yield), and some
characteristic features of the aryl moiety (Ar) of catalyst 9 follow:
(1) introduction of electron-withdrawing groups at meta posi-
tions increased the enantioselectivity (9c, g, h, l); (2) use of ortho-
substituents caused a decrease in enantioselectivity (9b, n, p); (3)
the steric effect of substituents did not improve the enantiose-
lectivity (9j, k, n); (4) introduction of nitro groups as a strong
electron-withdrawing group at 3,5-positions gave highest enan-
tioselectivity (9l, 90% ee).
Methyl-substituted catalyst 9q was also examined (Scheme
2), and the adduct 11a was obtained with low enantioselectivity.
It should be noted that chiral quaternary phosphonium salt 12,
which was an effective catalyst for asymmetric conjugate addi-
tions of 3-aryloxindoles to methyl vinyl ketone and acrolein
under phase-transfer conditions with base additive at low
temperature (À60 ꢀC),3b gave the adduct 11a in mꢀoderate
enantioselectivity under mild base-free conditions at 0 C.
With the effective chiral quaternary phosphonium salt in
hand, we studied the substrate generality of the asymmetric
conjugate addition of various 3-aryloxindoles to acrolein under
base-free phase-transfer conditions (Scheme 3). To demonstrate
the practicability of the present reaction, only 0.1 mol% of
Scheme 4 Asymmetric conjugate additions of 3-phenyloxindole 10a to vinyl
ketones.
Scheme 5 Asymmetric sulfenylation of 3-aryloxindole 10h.
chiral catalyst 9l was used in these asymmetric conjugate
additions. The introduction of electron-withdrawing and elec-
tron-donating substituents to both the oxindole core and the
3-aryl group (10a–10i) uniformly gave the products (11a–11i) in
excellent yields (92–99% yields) with high enantioselectivities
(88–91% ee) at low catalyst loading. Unfortunately, 3-methyl-
oxindole showed low reactivity under the similar reaction
conditions.15
Asymmetric conjugate additions of 3-phenyloxindole 10a to
vinyl ketones3b,5f,16 under base-free phase-transfer conditions in
the presence of catalyst 9l were also examined (Scheme 4), and
conjugate adducts 13a and 13b were obtained with high enan-
tioselectivities (90% ee). It should be noted that these reactions
under homogeneous conditions in mesitylene without H2O
proceeded very sluggishly, indicating that the coexistence of
H2O is essential to promote the reaction efficiently.8
To further expand the synthetic utility of quaternary phos-
phonium salts 9, we also examined the asymmetric sulfenyla-
tion of 3-aryloxindole 10h under base-free phase-transfer
conditions (Scheme 5).17 Although the reaction with catalyst 9l
gave a product 14 in moderate enantioselectivity, catalyst 9h
improved the enantioselectivity to give the sulfenylation
product 14 in high yield with good enantioselectivity.
Conclusions
In summary, we have demonstrated a new and efficient
approach for the design of chiral quaternary phosphonium
bromides as chiral phase-transfer catalysts. A catalyst library
with various structures has readily been constructed using
Scheme 3 Asymmetric conjugate additions of 3-aryloxindoles to acrolein.
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commercially available chiral phosphines as catalyst precur-
sors. The optimized catalyst has successfully been applied to
hitherto difficult highly enantioselective conjugate additions of
3-aryloxindoles to acrolein under base-free phase-transfer
conditions with low catalyst loading. Further application of the
catalyst library to other asymmetric reactions is currently
underway by our group.
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Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
tic Research from JSPS and MEXT (Japan).
¨
in Asymmetric Catalysis, ed. A. Borner, Wiley-VCH,
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