Exploiting the modularity of ion-paired chiral ligands for palladium-catalyzed enantioselective allylation of benzofuran-2(3 H)-ones

Article abstract of DOI:10.1021/ja312125a

A highly enantioselective allylation of benzofuran-2(3H)-ones is achieved under Pd catalysis by taking full advantage of the structural modularity of ion-paired chiral ligands.

Full text of DOI:10.1021/ja312125a

Communication
pubs.acs.org/JACS
Exploiting the Modularity of Ion-Paired Chiral Ligands for Palladium-
Catalyzed Enantioselective Allylation of Benzofuran-2(3H)‑ones
Kohsuke Ohmatsu,† Mitsunori Ito,† Tomoatsu Kunieda,† and Takashi Ooi*,†,‡
†Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya, 464-8603, Japan
‡Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, 464-8602, Japan
S
* Supporting Information
the precise control of anionic nucleophilic species. Herein, we
ABSTRACT: A highly enantioselective allylation of
benzofuran-2(3H)-ones is achieved under Pd catalysis by
taking full advantage of the structural modularity of ion-
paired chiral ligands.
report the successful realization of this unique possibility through
the development of the first highly enantioselective allylation of
benzofuran-2(3H)-ones.
Chiral benzofuran-2(3H)-ones possessing a quaternary stereo-
center at their C-3 positions are important building blocks for a
variety of natural products and potential pharmaceuticals.9,10
Accordingly, the establishment of an efficient catalytic method
for the asymmetric construction of this class of molecular
architecture is much sought after and several notable
contributions to fulfill this synthetic demand have been reported
to date.11 However, an enantioselective alkylation has never been
developed despite its potential as a reliable yet straightforward
strategy. In this study, we decided to pursue the development of a
Pd-catalyzed protocol by the utilization of ion-paired chiral
ligands with the expectation that they would be advantageous for
the rapid identification of an optimal structure that allows the
corresponding Pd complex to achieve rigorous enantiofacial
discrimination of the prochiral enolate ions generated from 3-
substituted benzofuran-2(3H)-ones. To this end, we first set out
to examine the reaction of 3-benzylbenzofuranone 3a with the
synthetically attractive functionalized allylic methyl carbonate 4a
as a model system (Table 1).12−15 An initial attempt with a
catalyst prepared in situ from tris(dibenzylideneacetone)-
dipalladium [Pd2(dba)3] and ion-paired chiral ligand 1 in
toluene/H2O (v/v = 20:1) at rt for 1 h resulted in the formation
of the desired product 5a in 79% isolated yield, albeit with low
enantioselectivity (entry 1). It is essential to note that O-
monoalkylated binaphthol was concurrently obtained, which
indicates that the binaphtholate ion of 1 reacted with the allyl-
Pd(II) intermediate during the course of the catalytic cycle. The
intervention of this process could lead to the loss of
stereocontrolling ability of the catalyst, which would account
for the observed low ee value. Although this phenomenon
manifested the drawback of the first-generation ligand 1, we
conceived it to be overcome toward expanded applicability by
harnessing the modularity of the ion-paired ligand. This notion
prompted us to attenuate the nucleophilicity of the chiral anion
component of the ligand. After a screening of readily available
chiral anions,16 ligand 2a having octahydrobinaphthol-derived
chiral phosphate17−19 was revealed to be a promising candidate
for promoting the reaction with high stereoselectivity (entry 2).
Optimizations then focused on modification of the chiral anion
of 2 with regard to the structural feature of the 3,3′-substituents
he design and synthesis of chiral ligands is inarguably a
T
subject of central importance in the development of
transition-metal-catalyzed stereoselective transformations be-
cause the chiral ligands play a crucial role in governing the
reactivity and stereocontrolling ability of the corresponding
metal complexes.1 While much research has led to the discovery
of broadly applicable ligands and their fruitful synthetic
applications, adding a new entry to the list of such privileged
ligand structures remains a great challenge, primarily owing to
the enormous difficulty of ligand design from first principles.
Over the past decade, the supramolecular approach to this
important problem has proven to be effective by the elaboration
of multicomponent chiral ligands and catalysts, which rely on the
use of noncovalent interactions for the spontaneous assembly of
relatively simple molecular components.2−4 The inherent
modularity of multicomponent ligands allows for the expeditious
construction of structurally diverse and meaningful catalyst
libraries, thus facilitating the identification of not only the
optimal system for a particular asymmetric reaction but also a
novel class of catalyst with promising generality.5 However, the
actual reaction manifold that has been explored in the application
of this emerging strategy is still very limited. We recently
introduced a conceptually new multicomponent chiral ligand, an
ion-paired chiral ligand of type 1 (Figure 1),6 assembled from an
achiral cationic ammonium−phosphine hybrid ligand and a
chiral binaphtholate ion through electrostatic interaction.7,8 By
exploiting the multitude of combinations created by the
ammonium phosphines and chiral acids, this ion-paired ligand
could serve as a powerful tool for developing hitherto difficult
asymmetric bond-forming reactions, particularly those involving
Figure 1. General concept of ion-paired chiral ligands (left) and first-
generation ligand 1 (right).
Received: November 5, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja312125a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Evaluation of Ion-Paired Chiral Ligands for
Asymmetric Alkylation of Benzofuranone 3a with Allylic
Carbonate 4
Table 2. Substrate Scope of Asymmetric Alkylation of
Bezofuranones 3 with Functionalized Allylic Carbonate 4b
a
a
b
cd
,
entry
1
3 (R1, R2)
5
% yield
% ee
3b (CH2i-Pr, H)
3c (i-Pr, H)
5c
5d
5e
5f
92
81
94
90
99
95
90
94
91
90
89
91
e
2
3
4
5
6
3d [(CH2)2CO2Me, H]
3e (Bn, 5-OMe)
3f (Bn, 5-Cl)
5g
5h
3g (Bn, 6-OMe)
a
Conditions: 0.20 mmol of 3 and 0.20 mmol of 4b in the presence of
Pd2(dba)3·CHCl3 (Pd 2.5 mol %) and 2c (5 mol %) in toluene (2.0
b
mL)/H2O (0.1 mL) at rt unless otherwise noted. Isolated yield of 5.
c
d
Ee of 5 was determined by chiral HPLC analysis. Absolute
stereochemistry of 5g has been established by X-ray crystal analysis
(see Figure 2 and Supporting Information (SI) for details), and the
stereochemistry of the remaining examples were assumed by analogy.
e
Conducted with 0.40 mmol of 4b (2 equiv) in the presence of
c
Pd2(dba)3·CHCl3 (Pd 5 mol %) and 2c (10 mol %).
entry
ligand
additive
4
% yield
% ee
b
1
2
3
4
5
6
7
8
1
none
none
none
none
none
6
4a
4a
4a
4a
4b
4b
4b
4b
79
22
80
The absolute configuration of the allylated product 5g was
determined to be S by single-crystal X-ray diffraction analysis
(Figure 2). The synthetic utility of this class of chiral scaffold,
b
2a
2b
2c
2c
78
b
68
82
b
91
90
b
99
92
d
P(4-Cl-C6H4)3
P(4-Cl-C6H4)3
8
14
<1
d
7
30
<1
d
6
43
−19
a
Conditions: 0.20 mmol of 3a and 0.20 mmol of 4 in the presence of
Pd2(dba)3·CHCl3 (Pd 2.5 mol %), ligand (5 mol %), and additive (2.5
b
mol %) in toluene (2.0 mL)/H2O (0.1 mL) at rt for 1 h. Isolated
c
d
yield. Determined by chiral HPLC analysis. NMR yield.
Figure 2. ORTEP diagram and derivatization of allylated bezofuranone
5g (calculated hydrogens are omitted for clarity).
(Ar1) by using well-established procedures; this uncovered that
the introduction of the 2,6-dimethyl-4-methoxyphenyl group
(2c) enabled a satisfactory level of stereochemical control (entry
4). Finally, we assessed the effect of the identity of allylic methyl
carbonate 4 on the reactivity and selectivity and found that the
alkylation proceeded smoothly with 4b bearing tert-butoxycar-
bonyl functionality to give 5b quantitatively with 92% ee (entry
5). To confirm the importance of ion pairing between the
ammonium−phosphine hybrid ligand and the chiral phosphate
ion in this stereocontrol, we also attempted the reaction with
tris(4-chlorophenyl)phosphine as a ligand in the presence of
either chiral phosphoric acid 6 or benzyltrimethylammonium
phosphate 7 under otherwise identical conditions, which gave
rise to racemic 5b in low yield (entries 6 and 7). Furthermore, the
use of achiral phosphinobenzylammonium bromide 8 with chiral
phosphoric acid 6 led to the production of 5b with low
enantioselectivity (entry 8).20
Using optimal ligand 2c, the scope of the benzofuranone
nucleophile 3 in the Pd-catalyzed asymmetric alkylation with 4b
was briefly investigated. As listed in Table 2, various C(3)
substituents, including a functionalized one, were accommo-
dated and high enantioselectivities were uniformly observed
(entries 1−3). This allylation is also applicable to 5- or 6-
substituted benzofuranones with a similar degree of enantiocon-
trol (entries 4−6).
besides as a building block of natural products with a C(3)-
quaternary benzofuranone core, can be illustrated by productive
structural reorganization through the simultaneous utilization of
the furanone and α,β-unsaturated carbonyl functionalities. For
instance, treatment of 5g with sodium methoxide triggered the
ring opening and subsequent intramolecular oxy-Michael
addition took place stereoselectively to afford benzopyran
derivative 9 in 91% yield (dr = 14:1) without the loss of
enantiomeric purity.
Next, we examined the feasibility of extending the present
system to reactions with simple allylic carbonates. Thus, the
allylation of 3a with cinnamyl methyl carbonate 4c was carried
out in a similar manner using 2c as a ligand. However, the
reaction was rather slow, and the product 5i was isolated in 79%
yield with insufficient enantioselectivity (Table 3, entry 1). This
result could be ascribed to the significant change in the structure
and electronic property of the allyl-Pd(II) intermediate; hence,
we undertook further optimization of the ligand 2, which showed
that the structural manipulation of the ammonium−phosphine
component could provide a viable solution for realizing higher
catalytic efficiency and stereoselectivity. For reactivity enhance-
ment, replacement of the 4-chlorophenyl substituent on
phosphorus (Ar2) with the more electron-withdrawing 4-
B
dx.doi.org/10.1021/ja312125a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Optimization of Ion-Paired Chiral Ligands for
Asymmetric Alkylation of Benzofuranone 3a with Cinnamyl
Carbonate 4c
Table 4. Substrate Scope of Asymmetric Alkylation of
a
Bezofuranones 3 with Allylic Carbonates 4
a
%
%
cd
,
b
entry
3 (R1, R2)
3a (Bn, H)
4 (R3)
5
yield
ee
1
2
3
4
5
6
4d (4-MeC6H4)
5j
95
98
97
93
91
93
98
95
91
93
93
91
82
92
92
94
80
90
91
96
97
90
93
93
91
92
3a (Bn, H)
4e (β-Naph)
5k
5l
3a (Bn, H)
4f (2-thienyl)
3a (Bn, H)
4g (H)
4c
5m
5n
5o
5p
5q
5r
3h (Me, H)
3b (CH2i-Pr, H)
3c (i-Pr, H)
4c
e
7
e
4c
8
3i (c-Hex, H)
3d [(CH2)2CO2Me, H]
3e (Bn, 5-OMe)
3j (Bn, 5-Me)
3f (Bn, 5-Cl)
3g (Bn, 6-OMe)
4c
9
4c
10
11
12
13
4c
5s
4c
5t
4c
5u
5v
4c
b
c
entry
ligand
% yield
% ee
a
Conditions: 0.20 mmol of 3 and 0.20 mmol of 4 in the presence of
1
2
2c
2d
2d
2e
2f
79
97
94
96
99
89
84
85
88
78
95
3
Pd2(dba)3·CHCl3 (Pd 2.5 mol %) and 2f (5 mol %) in toluene (2.0
b
mL)/H2O (0.1 mL) at rt unless otherwise noted. Isolated yield of 5.
d
c
d
3
Ee of 5 was determined by chiral HPLC analysis. Absolute
d
4
configuration of the product 5n was determined after conversion to
d
the known compound (see SI for details), and the stereochemistries of
5
d
e
the remaining examples were assumed by analogy. Performed in the
6
10
presence of Pd2(dba)3·CHCl3 (Pd 5 mol %) and 2f (10 mol %) at rt.
a
Conditions: 0.20 mmol of 3a and 0.20 mmol of 4c in the presence of
Pd2(dba)3·CHCl3 (Pd 2.5 mol %) and ligand (5 mol %) in toluene
b
(2.0 mL)/H2O (0.1 mL) at rt for 5 h unless otherwise noted. Isolated
c
d
yield. Determined by chiral HPLC analysis. Conducted at 10 °C for
nucleophile 3, a series of C(3)-substituted benzofuranones were
employable, constantly affording the corresponding alkylated
products 5 of excellent enantiomeric purity (entries 5−9),
although a higher catalyst loading and reaction temperature were
required for substrates with sterically demanding appendages
such as the 3-isopropyl and 3-cyclohexyl groups (entries 7 and 8).
Also, the presence of a 5- or 6-substituent scarcely affected the
stereochemical outcome of this successful alkylation (entries
10−13).
In conclusion, we have developed a catalytic and highly
enantioselective allylation of 3-substituted benzofuran-2(3H)-
ones for the first time through the identification of a new yet
optimal ion-paired ligand featuring chiral phosphate in
combination with an achiral or a chiral ammonium phosphine.
This study not only offers a vital method for the construction of
quaternary stereocenters at the 3-position of benzofuranones
with rigorous enantiocontrol but also clearly demonstrates the
vast potential of the modular ion-paired chiral ligand for the
development of transition-metal-catalyzed asymmetric bond-
forming reactions.
48 h.
trifluoromethylphenyl group (2d) was beneficial (entry 2). This
observation allowed us to perform the reaction at a lower
temperature (10 °C), which resulted in a slight increase in the
enantioselectivity without a detrimental effect on the reactivity
profile (entry 3). More importantly, installation of chirality on
the benzylic carbon of the ammonium−phosphine moiety was
found to be associated with the stereocontrolling ability of the
corresponding Pd catalyst. Although diminished enantioselec-
tivity was observed with ligand 2e, a pairing of the (R)-phosphate
ion and (R)-1-(2-phosphinophenyl)ethylammonium ion (a
mismatched chiral anion−cation combination) (entry 4), critical
improvement in the stereoselectivity was attained with
diastereomeric ligand 2f, consisting of (S)-configured ammo-
nium phosphine (a matched combination) (entry 5).21−23
Noteworthy was that the attempted reaction with (S)-
ammonium phosphine paired with achiral phosphate ion 10 as
a ligand yielded 5i in a nearly racemic form (entry 6). These
results suggest that the chiral anion itself has a pivotal role in the
asymmetric induction.
Subsequent experiments were conducted to explore the
generality of this asymmetric allylation protocol, and the
representative results are shown in Table 4.24 With respect to
the allylic carbonate electrophile 4, the incorporation of different
substituents, including fused aromatic and heteroaryl rings, was
well tolerated (entries 1−3). In this catalytic system,
unsubstituted allyl methyl carbonate also appeared to be a
good candidate for an electrophilic partner (entry 4). With
ASSOCIATED CONTENT
* Supporting Information
Representative experimental procedures, analytical data for new
compounds, and crystallographic data for 5g. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
tooi@apchem.nagoya-u.ac.jp
■
C
dx.doi.org/10.1021/ja312125a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(h) Li, X.; Xue, X.-S.; Liu, C.; Wang, B.; Tan, B.-X.; Jin, J.-L.; Zhang, Y.-
Y.; Dong, N.; Cheng, J.-P. Org. Biomol. Chem. 2012, 10, 413. (i) Wang,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Funding Program for Next
Generation World-Leading Researchers and Program for
Leading Graduate Schools “Integrative Graduate Education
and Research Program in Green Natural Sciences” in Nagoya
University.
(14) This type of reactive electrophiles has been relatively underused
for catalytic asymmetric synthesis despite their utilities, for example, in
view of γ-functionalization of α,β-unsaturated carbonyl compounds. For
a review, see: Green, J. R. Synlett 2012, 1271.
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(17) Metal salts of chiral phosphoric acids have been used as
asymmetric catalysts: Inanaga, J.; Furuno, H.; Hayano, T. Chem. Rev.
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(18) Chiral phosphoric acids have been widely used as efficient
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́
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