Ligand-controlled E/Z selectivity and enantioselectivity in palladium-catalyzed allylation of benzofuranones with 1,2-disubstituted allylic carbonates

Article abstract of DOI:10.1039/c3cc49338e

The first highly E- and enantioselective allylic alkylation of prochiral carbon nucleophiles with 1,2-disubstituted allylic carbonates is reported. The key to the successful development of this protocol is the ability of modular ion-paired chiral ligands

Full text of DOI:10.1039/c3cc49338e

Showcasing research from Prof. Takashi Ooi’s Laboratory,
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya,
Japan.
As featured in:
Ligand-controlled E/Z selectivity and enantioselectivity
in palladium-catalyzed allylation of benzofuranones with
1,2-disubstituted allylic carbonates
The first highly E- and enantioselective allylic alkylation of
prochiral carbon nucleophiles with 1,2-disubstituted allylic
carbonates is reported. The key is the ability of modular
ion-paired chiral ligands to simultaneously control the
E/Z selectivity and enantioselectivity.
See Takashi Ooi et al.,
Chem. Commun., 2014, 50, 4554.
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Ligand-controlled E/Z selectivity and
enantioselectivity in palladium-catalyzed
allylation of benzofuranones with
1,2-disubstituted allylic carbonates†
Cite this: Chem. Commun., 2014,
50, 4554
Received 9th December 2013,
Accepted 19th December 2013
Kohsuke Ohmatsu,a Mitsunori Itoa and Takashi Ooi*ab
DOI: 10.1039/c3cc49338e
www.rsc.org/chemcomm
The first highly E- and enantioselective allylic alkylation of prochiral
carbon nucleophiles with 1,2-disubstituted allylic carbonates is reported.
The key to the successful development of this protocol is the ability
of modular ion-paired chiral ligands to simultaneously control the
E/Z selectivity and enantioselectivity.
Precise control of stereochemistry in carbon–carbon bond-forming
reactions is a subject of fundamental importance in organic synthesis,
and has been continuously addressed in the development of a number
of synthetically valuable catalytic transformations based on the different
strategies. Among them, transition-metal-catalyzed asymmetric allylic
alkylations have been extensively studied, rendering them one of the
most powerful tools for the stereoselective construction of nascent
Scheme 1 Transition-metal-catalyzed asymmetric allylic alkylations.
In the palladium-catalyzed allylic alkylation with 1,2-disubstituted
chiral carbons at prochiral nucleophiles and/or allylic electrophiles.1 allylic substrates, the E/Z selectivity is strongly influenced by the
Depending on the substitution patterns of allylic substrates and relative stability of the syn and anti p-allyl palladium intermediates.
catalytic systems, this mode of asymmetric C–C bond connection gives The syn p-allyl complex is generally more stable than the anti counter-
rise to the multiple stereochemistries. For instance, the reactions of part because of the unfavorable 1,3-allylic strain in the anti complex.6
prochiral nucleophiles with 1-substituted or 1,3-disubstituted allylic Introduction of a substituent at the 2-position of the allylic moiety,
substrates generate two adjacent stereocenters in the product incor- however, destabilizes the syn complex through 1,2-steric repulsion
porating the 3,3-disubstituted or 1,3,3-trisubstituted (branched) allylic (Fig. 1). Therefore, the relative population of each complex is
unit and hence require the simultaneous enantio- and diastereocontrol. predominantly governed by the nature of the substituents on the
With the aim of controlling these intricate stereochemistries by a allylic component and is difficult to control by a catalyst.7 This
catalyst, several reliable methodologies have been developed.2–4 common understanding probably constitutes the prime reason
On the other hand, asymmetric allylations with 1,2-disubstituted for E- or Z-selective asymmetric allylic alkylation remaining
allylic substrates lead to the formation of enantiomeric and elusive. Herein, we demonstrate the feasibility of essentially
geometrical isomers of the product having a 1,2,3-trisubstituted ligand-controlled high E- and enantioselectivity for the first
(liner) allylic unit (Scheme 1). Despite their potential synthetic time in the palladium-catalyzed allylation of benzofuranones
relevance, however, catalytic protocols for enabling a highly E- and with 1,2-disubstituted allylic carbonates.
enantioselective allylic alkylation are very limited.5
a Institute of Transformative Bio-Molecules (WPI-ITbM), and Department of Applied
Chemistry, Graduate School of Engineering, Nagoya University, Chikusa,
Nagoya 464-8603, Japan
b CREST, Japan Science and Technology Agency (JST), Chikusa, Nagoya 464-8603,
Japan. E-mail: tooi@apchem.nagoya-u.ac.jp
† Electronic supplementary information (ESI) available: Experimental details
(including selected NMR spectra) and crystallographic data. CCDC 972631–
972633. For ESI and crystallographic data in CIF or other electronic format see
Fig. 1 syn and anti p-allyl Pd complexes leading to the E- or Z-product.
DOI: 10.1039/c3cc49338e
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Table 1 Optimization of the ligand structure and reaction conditions for
asymmetric allylation of benzofuranone 1a with 1,2-disubstituted allylic
carbonate E-2aa
the E-isomer but with a low to moderate enantiomeric excess
(entries 2 and 3). These results prompted us to pursue the
modification of the chiral anion component of the ligand 4
with regard to the structural feature of 3,30-aromatic substitu-
tents (Ar1). Interestingly, reduction of the steric demand by
removal of the 2,6-dimethyl groups from Ar1 (4c) led to a
significant improvement in both E/Z- and enantioselectivities;
further, the installation of a 2-methyl-4-methoxyphenyl group
(4d) enabled even higher levels of geometrical and enantio-
control, although the chemical yield of 3a was substantially
diminished (entries 4 and 5). This reactivity problem was overcome
by switching the 4-chlorophenyl phosphorous substituent (Ar2) of
the ammonium phosphine component of 4d to a 4-trifluoromethyl-
phenyl group (4e) without detrimental impact on the selectivity
profile (entry 6). Finally, we succeeded in the quantitative isolation of
geometrically almost pure E-3a with 94% ee by using mesitylene in
place of toluene under otherwise identical conditions (entry 7).
With the optimized ligand structure and reaction conditions
in hand, we explored the substrate scope of the present E- and
enantioselective allylic alkylation of benzofuranones. The repre-
sentative results are shown in Table 2. The reactions of various
3-substituted benzofuranones with allylic carbonate E-2a gave the
corresponding allylated products (3b–3e) in excellent yield with
good-to-high E- and enantioselectivity (entries 1–4). Introduction
of an electron-donating or electron-withdrawing substituent
into the 5- or 6-position of benzofuranone did not affect the
stereochemical outcome (entries 5–7). The synthetically useful
levels of geometrical and enantiocontrol appeared feasible with
allylic carbonates possessing other electron-withdrawing substi-
tuents such as ethyl ester, dimethyl phosphonate, or nitrile at the
Entry
Ligand
Yieldb (%)
E/Zc
1 : 1
eed (%)
1
2
3
4
5
6
7e
PPh3
4a
99
88
96
35
44
99
99
—
12
50
79
93
92
94
1.5 : 1
2.5 : 1
6.7 : 1
9.4 : 1
11 : 1
4b
4c
4d
4e
4e
Table 2 Substrate scopea
>20 : 1
a
Unless otherwise noted, reactions were carried out on 0.2 mmol of 1a
with 1.0 equiv. of 2a under the influence of Pd2(dba)3ꢀCHCl3 (Pd 2.5 mol%)
and ligand (5 mol%) in toluene/H2O at room temperature for 24 h.
b
c
Combined yield of E-3a and Z-3a. The E/Z ratio was determined by
1H NMR (400 MHz) analysis of crude product. Enantiomeric excess of the
E-isomer was indicated, which was analyzed by chiral HPLC. The reaction
d
Yieldb
(%)
eed
(%)
e
Entry 1 (R1, R2)
2 (R3, R4)
3
E/Zc
was performed in mesitylene/H2O (20 : 1) instead of toluene/H2O.
1e, f
2
3
1b (Me, H)
1c (iBu, H)
1d (CH2OMe, H) 2a
1e (CH2CO2Et, H) 2a
1f (Bn, 5-OMe)
1g (Bn, 5-Cl)
1h (Bn, 6-Me)
1a (Bn, H)
1a
2a (CO2 Bu, Me)
2a
3b 90
3c 93
3d 90
3e 92
3f 91
3g 99
3h 90
3i 76
>20 : 1 91
>20 : 1 90
10 : 1 88
12 : 1 90
>20 : 1 93
>20 : 1 97
14 : 1 92
7.0 : 1 90
8.7 : 1 85
10 : 1 91
3.8 : 1 45
t
Our initial studies focused on examining the effect of a ligand on
the stereoselectivity of the alkylation with 1,2-disubstituted allylic
electrophiles. For this purpose, 3-benzylbenzofuranone 1a8,9 and
E-1,2-disubstituted allylic carbonate E-2a were selected as model
substrates, and the reaction was attempted in the presence of
Pd2(dba)3ꢀCHCl3 and PPh3 as a ligand in toluene/H2O (20:1 volume
ratio) at room temperature (Table 1, entry 1). After stirring for 24 h,
the desired allylated product 3a was obtained quantitatively in an
E/Z ratio of 1 : 1, revealing the intrinsic geometrical preference of this
allylation. Then, the reaction was performed using ion-paired chiral
4
5
2a
2a
2a
6e
7
8
2b (CO2Et, Me)
2c [PO(OMe)2, Me] 3j 88
9e
10e
11
1a
1a
2d (CN, Me)
3k 89
3l 79
t
2e (CO2 Bu, Et)
a
Unless otherwise noted, reactions were carried out on 0.2 mmol of 1
with 1.0 equiv. of 2 under the influence of Pd2(dba)3ꢀCHCl3 (Pd 2.5 mol%)
and 4e (5 mol%) in mesitylene/H2O at room temperature. For reaction
ligands10–15 4a and 4b, which exhibited high stereocontrolling time, see ESI. Isolated yield of E-3. The E/Z ratio was determined by
b
c
1H NMR (400 MHz) analysis of the crude product. Enantiomeric
d
ability in the previously reported allylation of benzofuranones
e
excess of the E-3, which was analyzed by chiral HPLC. The reaction was
conducted at 10 1C. The reaction was performed using Pd2(dba)3ꢀCHCl3
with simple 1-substituted allylic carbonates;8 the conversion to
f
3a was smooth, with a slight inclination for the formation of (Pd 5 mol%) and 4e (10 mol%).
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´
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rigorous and simultaneous control of E/Z selectivity and enantio-
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