High enantioselectivity in rhodium-catalyzed allylic alkylation of 1-substituted 2-propenyl acetates

Article abstract of DOI:10.1021/ol0343562

(Matrix presented) Rhodium-catalyzed asymmetric allylic alkylation of 1-substituted 2-propenyl acetates with dimethyl malonate proceeded with high enantioselectivity in the presence of cesium carbonate as a base and a rhodium catalyst generated from Rh(dp

Full text of DOI:10.1021/ol0343562

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1713-1715
High Enantioselectivity in
Rhodium-Catalyzed Allylic Alkylation of
1-Substituted 2-Propenyl Acetates
Tamio Hayashi,* Atsushi Okada, Toshimasa Suzuka, and Motoi Kawatsura
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received February 28, 2003
ABSTRACT
Rhodium-catalyzed asymmetric allylic alkylation of 1-substituted 2-propenyl acetates with dimethyl malonate proceeded with high enantioselectivity
in the presence of cesium carbonate as a base and a rhodium catalyst generated from Rh(dpm)(C H ) (dpm ) dipivaloylmethanato) and a
2
4 2
chiral phosphino-oxazoline whose basic skeleton is axially chiral binaphthyl to give branch alkylation products in greater than 90% ee.
Palladium-catalyzed asymmetric allylic alkylation is one of
the most frequently examined asymmetric reactions catalyzed
by transition metal complexes because of its easy manipula-
tion, high catalytic activity, and high enantioselectivity.1
Recently, other transition metals, including molybdenum2 and
iridium3 have also been reported to catalyze the asymmetric
alkylation. In the reaction, which proceeds through mono-
substituted π-allyl intermediates, the regioselectivity in
forming a branch chiral isomer is higher with molybdenum
and iridium catalysts than with palladium catalysts. Rhodium
catalysts4 have some unique features in the allylic alkylation
reactions. Recently, Evans has reported5 that the regiochem-
istry and the stereochemistry of the starting allylic esters are
conserved in the allylic substitution products. Namely, the
rhodium-catalyzed substitution takes place at the carbon
substituted with the leaving group with net retention of
configuration. It seems that the high regio- and stereospeci-
ficity in the rhodium-catalyzed system are not compatible
with the catalytic asymmetric synthesis using a chiral
rhodium catalyst, and as a result, there have been very few
reports on the use of chiral rhodium catalysts for the
asymmetric allylic substitution reactions.6 We succeeded in
the rhodium-catalyzed asymmetric allylic alkylation with
(2) (a) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104. (b)
Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141. (c) Kaiser, N.-F. K.;
Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. Angew. Chem., Int.
Ed. 2000, 39, 3596. (d) Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky,
P. Tetrahedron Lett. 2001, 42, 509. (e) Trost, B. M.; Dogra, K.; Hachiya,
I.; Emura, T.; Hughes, D. L.; Krska, S.; Reamer, R. A.; Palucki, M.; Yasuda,
N.; Reider, P. J. Angew. Chem., Int. Ed. 2002, 41, 1929. See also: Lloyd-
Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 462.
(3) (a) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025.
(b) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741. (c) Bartels, B.;
Garcia-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. Inorg. Chem. 2002,
2569. See also: Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120,
8647.
(1) For reviews: (a) Trost, B. M.; Chulbom, L. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; VCH: New York, 2000; p 593. (b) Pfaltz,
A.; Lautens, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, Chapter
24. (c) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (d)
Hayashi, T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993; p 325. (e) Frost, C. G.; Howarth, J.; Williams, J. M. J.
Tetrahedron: Asymmetry 1992, 3, 1089.
(4) (a) Tsuji, J.; Minami, I.; Shimidzu, I. Tetrahedron Lett. 1984, 25,
5157. (b) Minami, I.; Shimidzu, I.; Tsuji, J. J. Organomet. Chem. 1985,
296, 269. (c) Takeuchi, R.; Kitamura, N. New J. Chem. 1998, 659.
(5) (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b)
Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (c) Evans,
P. A.; Kennedy, L. J. Org. Lett. 2000, 2, 2213. (d) Evans, P. A.; Kennedy,
L. J. J. Am. Chem. Soc. 2001, 123, 1234. (e) Evans, P. A.; Robinson, J. E.
J. Am. Chem. Soc. 2001, 123, 4609.
10.1021/ol0343562 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/17/2003

high enantioselectivity by a rational modification of the
reaction conditions and fine-tuning of the ligands on the
rhodium.
First, we examined the rhodium-catalyzed allylic alkylation
of racemic 1-phenyl-2-propenyl acetate (1) in the presence
of a chiral rhodium catalyst coordinated with (S)-i-Pr-phox
((S)-2a)7,8 under one of the standard conditions used for the
palladium-catalyzed reactions (Scheme 1). As it was expected
enantioselectivity was this low, the formation of the nonra-
cemic product indicates that the stereospecificity is not
perfect, which is probably due to the equilibration between
regio- and diastereoisomeric allyl-rhodium intermediates.
Considering that a longer lifetime of the allyl intermediate
will give us a chance for higher enantioselectivity, we
examined a stoichiometric reaction of a rhodium complex
that was generated by mixing Rh(acac)((S)-i-Pr-phox) (6)9
with racemic acetate 110,11 (Scheme 2). After the complex
Scheme 1
Scheme 2
was kept in THF at 40 °C for 30 min, dimethyl sodiomalo-
nate was added to give (R)-4 in 71% ee and 5 in a ratio of
87:13. It follows that the catalytic reaction will produce the
branch isomer 4, whose enantiomeric purity is as high as
71% if the lifetime of the allyl intermediate in the catalytic
reaction is sufficiently long. Slow addition of the nucleophile
over 48 h to the solution containing the 3a/(S)-i-Pr-phox (2a)
catalyst and acetate 1 (entry 2) or the reaction in a high
dilution condition (entry 3) gave (R)-4 in 66% ee, the ee
value being close to that observed in the stoichiometric
reaction. Thus, the enantioselectivity became higher with the
from the high stereospecificity reported by Evans, the
enantioselectivity was low. Typically, the reaction of 1 (0.40
mmol) with dimethyl sodiomalonate (1.6 mmol) in the
presence of 5 mol % Rh(acac)(C2H4)2 (3a) and (S)-2a in THF
(2.0 mL) at 40 °C for 12 h gave 90% yield of the allylic
alkylation product, which consists of regioisomers 4 and 5
in a ratio of 89:11, and the branch isomer 4 was obtained in
36% ee of the (R)-isomer (entry 1 in Table 1). Although the
Table 1. Rhodium-Catalyzed Asymmetric Allylic Alkylation of Acetate 1 with Dimethyl Malonatea
entry
ligand L*
[Rh]
solvent
base
yield (%) of 4 and 5b
ratio of 4:5c
% ee 4d
1
2e
3f
4
5
6
7
8
9
10
11
12
13g
14
15
(S)-2a
(S)-2a
(S)-2a
(S)-2a
3a (acac)
3a (acac)
3a (acac)
3a (acac)
3a (acac)
3a (acac)
3a (acac)
3b (dpm)
3c (hfac)
3d (dbm)
3a (acac)
3b (dpm)
3b (dpm)
3c (hfac)
3d (dbm)
THF
THF
THF
THF
NaH
NaH
NaH
90
63
79
91
97
93
95
98
59
76
94
94
73
64
75
89:11
87:13
90:10
91:9
87:13
96:4
87:13
97:3
79:21
89:11
96:4
36 (R)
66 (R)
66 (R)
45 (R)
59 (R)
73 (S)
58 (R)
90 (S)
58 (S)
67 (S)
87 (S)
97 (S)
97 (S)
81 (S)
87 (S)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
(S)-2a
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
(S,R)-2b
(S,S)-2c
(S,R)-2b
(S,R)-2b
(S,R)-2b
(S,R)-2b
(S,R)-2b
(S,R)-2b
(S,R)-2b
(S,R)-2b
98:2
99:1
92:8
97:3
a All reactions were carried out with allyl acetate 1 (0.40 mmol), dimethyl malonate (1.6 mmol), base (1.6 mmol), and 5 mol % rhodium catalyst generated
from a rhodium precursor 3 and a chiral ligand 2 in 2.0 mL of a solvent at 40 °C for 12 h under nitrogen. b Isolated yield by silica gel chromatography
(hexane/ethyl acetate ) 5:1). c Determined by 1H NMR analysis of a crude reaction mixture. d Determined by HPLC analysis with a chiral stationary phase
column (Chiralcel OJ (hexane/2-propanol ) 93:7)). e Slow addition of dimethyl sodiomalonate over 48 h. f High dilution in 20 mL of THF for 40 h. g Catalyst
) 1 mol %.
1714
Org. Lett., Vol. 5, No. 10, 2003

lower concentration of the nucleophile, which should prolong
the lifetime of the allyl-rhodium intermediates.12
nato ligand will give us a further chance for higher selectivity.
Of the â-diketonato ligands examined, dipivaloylmethanato
(dpm) ligand gave the best results. The reaction of acetate 1
with Cs2CO3 and dimethyl malonate in the presence of a
rhodium catalyst generated from Rh(dpm)(C2H4)2 (3b) and
(S,R)-2b in dioxane gave 98% yield of (S)-4 (90% ee) and
5 in a 97:3 ratio (entry 8). The enantioselectivity was further
improved (up to 97% ee) by carrying out the reaction in
toluene with the rhodium catalyst of 3b/(S,R)-2b (entry 12).
The regioselectivity in giving 4 is also higher (4:5 ) 98:2).
With the rhodium catalyst precursors 3c and 3d coordinated
with hfac and dbm, respectively, the enantioselectivity was
not higher than that with the acac-rhodium catalyst 3a (entries
9, 10, 14, and 15).
Although slow addition or high dilution conditions in-
creased the enantioselectivity, these methods are not con-
venient from a practical point of view because the reaction
requires a longer reaction time and the yields are generally
not sufficiently high. The use of cesium carbonate Cs2CO3
as a base in place of sodium hydride brought about higher
enantioselectivity (entries 4 and 5).13 The higher enantiose-
lectivity may be related to the weaker basicity of Cs2CO3,
which will keep the concentration of the nucleophile lower,
resulting in a longer lifetime of the allyl-rhodium intermedi-
ates. The reaction with phosphino-oxazoline ligand (S,R)-
axial-phox (2b),14 whose basic skeleton is axially chiral
binaphthyl, was found to be more enantioselective than that
with (S)-i-Pr-phox (2a). The reaction of acetate 1 with cesium
carbonate and dimethyl malonate in dioxane in the presence
of rhodium catalyst 3a/(S,R)-axial-phox (2b) gave (S)-4 in
73% ee and 5 in a ratio of 96:4 (entry 6).
Using Rh(dpm)(C2H4)2 (3b) and (S,R)-2b as a catalyst in
toluene for the allylic alkylation with Cs2CO3 and dimethyl
malonate, a high enantioselectivity ranging between 94 and
97% ee was observed for 1-(substituted phenyl)-2-propenyl
acetates 7a-c (Scheme 3). The enantioselectivity was also
One of the characteristic features of the rhodium catalysts
used here is that they have an acetylacetonato-type ligand
in addition to the phox ligand 2, which cannot be incorpo-
rated into the palladium catalysts due to the limitation of
coordination number. Thus, modification of the acetylaceto-
Scheme 3
(6) To the best of our knowledge, there has been only one report
describing the use of a chiral rhodium catalyst: Selvakumar, K.; Valentini,
M.; Pregosin, P. S. Organometallics 1999, 18, 4591.
(7) (a) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769. (b)
Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566. (c) Dawson,
G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993,
34, 3149.
(8) For reviews: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336. (b) Helmchen, G. J. Organomet. Chem. 1999, 576, 203. (c)
Williams, J. M. J. Synlett 1996, 705.
high for acetates 7d and 7e, which are substituted with
1-naphthyl and an alkyl substituent, respectively, at the
R-position of the allyl acetate, to give the corresponding
branch products 8 in greater than 90% ee.
To summarize, we succeeded in asymmetric allylic alky-
lation with high enantioselectivity in the rhodium-catalyzed
reaction. The low concentration of the malonate nucleophile
increased the enantioselectivity of the catalytic reaction by
keeping the long lifetime of allyl-rhodium intermediates,
which causes equilibration between the isomeric rhodium
intermediates. A fine-tuning of the chiral rhodium catalysts
by modification of the â-diketonato ligand enhanced the
enantioselectivity up to 97% ee.
(9) Generated by mixing Rh(acac)(C2H4)2 with (S)-i-Pr-phox in THF.
31P NMR (THF): δ 51.7 (d, J ) 206.8 Hz). 1H NMR (toluene-d8): δ 0.59
(d, J ) 6.8 Hz, 3H), 0.96 (d, J ) 7.1 Hz, 3H), 1.83 (s, 3H), 2.25 (s, 3H),
3.38 (dsep, J ) 3.0, 6.9 Hz, 1H), 3.86 (dd, J ) 10.0, 8.6 Hz, 1H), 4.08 (dd,
J ) 8.6, 4.4 Hz, 1H), 5.58 (ddd, J ) 10.0, 4.4, 3.0 Hz, 1H), 5.63 (s, 1H),
7.18 (t, J ) 7.5 Hz, 1H), 7.25 (d, J ) 7.5 Hz, 1H), 7.27-7.30 (m, 3H),
7.34-7.41 (m, 3H), 7.50 (t, J ) 8.0 Hz, 1H), 8.01-8.07 (m, 2H), 8.10-
8.17 (m, 3H).
(10) 31P NMR spectra of a mixture of 6 and 1 showed the generation of
two major species in a ratio of 56:44. 31P NMR (THF): δ 46.6 (d, J )
143.6 Hz) for the major isomer and δ 40.7 (d, J ) 148.6 Hz) for the minor
isomer.
(11) For a recent example of the study on the structure of the
corresponding palladium complexes coordinated with the phosphino-
oxazoline ligand and monosubstituted π-allyl ligands, see: Kollmar, M.;
Steinhagen, H.; Janssen, J, P.; Goldefuss, B.; Makubivsjata, S. A.; Va´zquez,
J.; Rominger, F.; Helmchen, G. Chem. Eur. J. 2002, 8, 3103.
(12) (a) Concept of extending the lifetime of a metal allyl intermediate
using slow addition has been described (ref 1). (b) Effects of halide ions
on the stereospecificity in rhodium-catalyzed allylic etherification have been
reported: Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882.
(13) Cesium carbonate has been used for the palladium-catalyzed
asymmetric allylation forming a quaternary chiral center in nucleophiles:
Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed. 2002,
41, 3492.
(14) (a) Ogasawara, M.; Yoshida, K.; Kamei, H.; Kato, K.; Uozumi, Y.;
Hayashi, T. Tetrahedron Asymmetry 1998, 9, 1779. (b) Imai, Y.; Zhang,
W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron Lett. 1998, 39, 4343. (c)
Selvakumar, K.; Valentini, M.; Wo¨rle, M.; Pregosin, P. S.; Albinati, A.
Organometallics 1999, 18, 1207. (d) Ogasawara, M.; Yoshida, K.; Hayashi,
T. Heterocycles 2000, 52, 195.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0343562
Org. Lett., Vol. 5, No. 10, 2003
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