Enantioselective allylic substitutions using ketene silyl acetals catalyzed by a palladium-chiral amidine complex

Article abstract of DOI:10.1016/S0957-4166(98)00045-7

Enantioselective allylic substitutions using ketene silyl acetals 3 as a nucleophile have been explored. In the asymmetric reactions of 1,3- diphenylprop-2-enyl pivalate 2 catalyzed by the Pd(0)-chiral amidine 1 complex, excellent levels of stereocontrol

Full text of DOI:10.1016/S0957-4166(98)00045-7

Pergamon
Tetrahedron: Asymmetry 9 (1998) 741–744
Enantioselective allylic substitutions using ketene silyl acetals
catalyzed by a palladium–chiral amidine complex†
Akihito Saitoh, Kazuo Achiwa and Toshiaki Morimoto∗
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka-shi 422-8002, Japan
Received 22 December 1997; accepted 28 January 1998
Abstract
Enantioselective allylic substitutions using ketene silyl acetals 3 as a nucleophile have been explored. In the
asymmetric reactions of 1,3-diphenylprop-2-enyl pivalate 2 catalyzed by the Pd(0)–chiral amidine 1 complex,
excellent levels of stereocontrol are achieved along with good conversions, demonstrating that ketene silyl acetals
are able to expand the scope of asymmetric allylic alkylations. The present asymmetric reactions should proceed via
nucleophilic attack at the allyl terminus trans to the diphenylphosphinyl group of the amidine on the side opposite
to palladium. © 1998 Elsevier Science Ltd. All rights reserved.
Transition metal catalyzed allylic reactions using allyl compounds, alkenes and conjugated dienes have
been actively investigated as an important synthetic tool for C–C and C–X (X=H, heteroatoms) bond
formation and for mechanistic studies.1 Palladium(0)-assisted reactions are especially fruitful in the field
of organic synthesis because the reaction proceeds catalytically.1a For enantioselective allylic reactions
using palladium–chiral ligand complexes,2 a wide variety of ligands have been developed in which high
levels of asymmetric induction and mechanistic understanding have been successfully demonstrated.
As a nucleophile in the asymmetric allylic alkylations, stabilized ‘soft’ nucleophiles with electron-
withdrawing groups such as anionic species derived from malonates have generally been required. In
the aspect of synthetic strategy, we have been exploring the use of ketene silyl acetals in order to extend
the scope of asymmetric alkylations. Since ketene silyl acetals3 can be readily prepared from esters
having α-hydrogen atoms, the current approach will expand the utilization of asymmetric alkylations
in organic synthesis and play an important role in place of less stabilized ‘harder’ nucleophiles such as
anionic species of monoesters. Herein we wish to describe enantioselective allylic substitutions using
ketene silyl acetals as a nucleophile catalyzed by the Pd(0)–amidine complex4 and their mechanistic
interpretation along with the result using (S)-BINAP as a more general chiral ligand.
Ketene silyl acetals 3a–d were prepared according to the literature.5 The new P–N bidentate ligand,
phosphorus-containing chiral amidine 1,4 which demonstrated excellent enantiometric excess in the
∗
†
Corresponding author. E-mail: morimtt@ys2.u-shizuoka-ken.ac.jp
Asymmetric Reactions Catalyzed by Chiral Metal Complexes, LXXXIII.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00045-7

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A. Saitoh et al. / Tetrahedron: Asymmetry 9 (1998) 741–744
allylic alkylations using Trost’s procedure,6 was firstly applied to the present approach (Scheme 1). As
a typical procedure, allylpalladium chloride dimer and the amidine 1 were mixed in a solvent at room
temperature under argon, followed by adding (E)-1,3-diphenylprop-2-enyl pivalate 2 dissolved in the
solvent. Ketene silyl acetal was then added to the π-allyl palladium complex solution. The substituted
product thus obtained was isolated by preparative TLC.
Scheme 1.
As summarized in Table 1, the asymmetric alkylations with various ketene silyl acetals7 proceeded
under conditions catalyzed by the Pd–amidine complex in which excellent levels of enantiometric excess
were achieved.8 A reduction of the amount of catalyst did not affect the enantiometric excess significantly
(runs 1–3). The use of THF as a solvent resulted in the decrease of chemical yield and enantioselectivity
(runs 4, 6, and 10). It appeared that the steric hindrance of ketene silyl acetals at R1 and R2 affected
the chemical yields (run 5). The reaction using 3c did not proceed even if the catalyst amount and the
reaction time were increased. This result could be derived from the lower nucleophilicity of 3c compared
with alkyl-substituted 3a and 3b.
In the well-known procedure6 to generate a soft anionic nucleophile by reacting dimethyl malonate,
N,O-bis(trimethylsilyl)acetamide (BSA), and lithium acetate, the anion species would be produced
Table 1
Asymmetric allylic substitutions with ketene silyl acetals 3a–d catalyzed by palladium complex of
phosphorus-containing amidine 1a

A. Saitoh et al. / Tetrahedron: Asymmetry 9 (1998) 741–744
743
directly from dimethyl malonate. In the reaction using the BSA, the formation of carbomethoxy ketene
1
methyltrimethylsilyl acetal 3d could not be detected by H NMR.9 This observation suggests that the
BSA does not work as a silylating agent to form 3d but reacts as a base.6
The current reaction could proceed by a nucleophilic attack of the ketene silyl acetal on the π-
allyl complex through an interaction of π-orbitals between the π-allyl and the carbon–carbon double
bond of the ketene silyl acetal. Another possible path is a nucleophilic attack of pivalate anion to the
silyl group. The reactions using 3d might be induced by the latter case because a good conversion
was achieved in spite of the lower nucleophilicity due to the attached electron-withdrawing group.
The absolute configuration of methyl 2,2-dimethyl-3,5-diphenylpent-4-enoate 4a was determined by
comparing HPLC peaks of 4a with those of the reference S sample10 derived from (3R)-methyl 2-
carbomethoxy-3,5-diphenylpent-4-enoate 4d as depicted in Scheme 2. The absolute configuration of 3-
(1-carbomethoxycyclohexyl)-1,3-diphenyl-1-propene 4b was suggested to have the same S configuration
as that of 4a by similarity of elution order in the HPLC analysis. The present asymmetric allylations using
ketene silyl acetals could proceed through the complex 7 as a major path in which the nucleophilic attack
proceeded from the side opposite the palladium11 and was induced predominantly at the allyl terminus
trans to the diphenylphosphinyl group (Scheme 3).4
Scheme 2.
Scheme 3.
In order to extend the present approach, the asymmetric allylic alkylation of 2 catalyzed by a Pd(0)–(S)-
BINAP complex was conducted using 3a under the same conditions as that of run 2 in Table 1. The
reaction using dichloromethane as a solvent afforded the alkylated product 4a having the S configuration
in 89% yield (65% e.e.). It was demonstrated that the asymmetric reaction proceeded on a level with
that using the amidine ligand in terms of conversion. The enantioselectivity was moderate although the
reactivity of ketene silyl acetal was confirmed.
In summary, we have developed a useful route to excellent levels of enantioselective alkylations along
with good conversion using ketene silyl acetals as nucleophiles and the new type of chiral ligand,
phosphorus-containing amidine. The process could be applied to the Pd(0) catalyst coordinated with
another type of chiral ligand. Further efforts are currently in progress with respect to other asymmetric
reactions using the amidine ligand, the modification of amidine ligand, and the extension of the present
process using ketene silyl acetals to practical applications such as total syntheses of natural products.

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A. Saitoh et al. / Tetrahedron: Asymmetry 9 (1998) 741–744
References
1. Recent review articles and books on transition metal-catalyzed organic synthesis via π-allyl complexes, see: (a) Tsuji,
J. Transition Metals in Organic Synthesis Kagaku Dojin, Japan, 1997. (b) Tsuji, J. Palladium Reagents and Catalysts,
Innovations in Organic synthesis John Wiley, New York, 1995, p. 290. (c) Godleski, S. A. Comprehensive Organic Synthesis
Vol 4, Pergamon, Oxford, 1991, p. 585. (d) Trost, B. M. Angew. Chem. Int. Ed. Engl. 1989, 28, 1173. (e) Tsuji, J.; Minami,
I. Acc. Chem. Res. 1987, 20, 140. (f) Heck, R. F. Palladium Reagents in Organic Synthesis Academic Press, New York,
1985. For the mechanistic understanding on palladium-catalyzed allylations, see: (g) Trost, B. M.; Weber, L.; Strege, P. E.;
Fullerton, T. J.; Dietsche, T. J. J. Am. Chem. Soc. 1978, 100, 3426. (h) Trost, B. M.; Verhoeven, T. R. ibid. 1978, 100, 3435.
(i) Akermark, B.; Backvall, J. E.; Lowenborg, A.; Zetterberg, K. J. Organomet. Chem. 1979, 166, C33. (j) Trost, B. M.;
Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730. (k) Hayashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. ibid. 1983,
105, 7767. (l) Mackenzie, P. B.; Whelan, J.; Bosnichi, B. ibid. 1985, 107, 2046.
2. General reviews on palladium-catalyzed asymmetric allylic alkylations, see: (a) Trost, B. M.; Van Vranken, D. L. Chem.
Rev. 1996, 96, 395. (b) Williams, J. M. J. Synlett 1996, 705. (c) Hayashi, T. In Catalytic Asymmetric Synthesis, Ed. Ojima,
I., VCH, Weinheim, 1993. (d) Pfalts, A. Acc. Chem. Res. 1993, 26, 339. (e) Reiser, O. Angew. Chem. Int. Ed. Engl. 1993, 32,
547. (f) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (g) Consiglio, G.; Waymouth,
R. Chem. Rev. 1989, 89, 257.
3. Organic synthesis using ketene silyl acetals was well compiled by Kita et al., see: Kita, Y.; Tamura, O.; Tamura, Y. J. Synth.
Org. Chem. 1986, 1118.
4. Saitoh, A.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1997, 8, 3567.
5. Ketene methyltrimethylsilyl acetal 3c (R4=Me3) was prepared as a 7:3 mixture with a C-silylated compound, methyl
trimethylsilylacetate. Carbomethoxy ketene methyltrimethylsilyl acetal 3d tends to be hydrolyzed easily. Therefore the
hydrolyzed product, dimethyl malonate was removed by distillation just before conducting the asymmetric reaction. Articles
referring to the preparation of ketene silyl acetals, see: (a) Ainsworth, C.; Chen, F.; Kuo, Y.-N. J. Organomet. Chem. 1972,
46, 59. (b) Rathke, M. W.; Sullivan, D. F. Synth. Commun. 1973, 3, 67. (c) Kita, Y.; Haruta, J.; Segawa, J.; Tamura, Y.
Tetrahedron Lett. 1979, 4311.
6. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143.
7. Asymmetric alkylations of cycloalkenediol derivatives using disilylamide having a ketene silyl acetal skeleton were shown
in a previous paper. The silylated nucleophile was employed in order to reduce the dissociation of bisphosphine ligand from
the palladium by an amide anion which was initially used as a nucleophile, see: Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui,
S.; Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016.
8. Analytical data for the alkylated products. 4a: 1H NMR (270 MHz, CDCl3) δ: 1.18 (s, 3H), 1.23 (s, 3H), 3.60 (s, 3H), 3.75
(d, 1H, J=9.6 Hz), 6.45 (d, 1H, J=15.8 Hz), 6.60 (dd, 1H, J=9.6, 16.2 Hz), 7.21–7.41 (m, 10H); GCMS (EI) m/z 294 (M+);
263; 233; 205; 193; 116. 4b: 1H NMR (270 MHz, CDCl3) δ: 1.22–1.33 (m, 6H), 1.52–1.63 (m, 4H), 3.50 (d, 1H, J=10.8
Hz), 3.57 (s, 3H), 6.41 (d, 1H, J=16.2 Hz), 6.65 (dd, 1H, J=9.9, 15.5 Hz), 7.14–7.37 (m, 10H); GCMS (EI) m/z 334 (M+);
303; 275; 193; 116. 4d: 1H NMR (270 MHz, CDCl3) δ: 3.52 (s, 3H), 3.71 (s, 3H), 3.95 (d, 1H, J=10.9 Hz), 4.27 (dd, J=8.6,
10.9 Hz, 1H), 6.33 (dd, 1H, J=8.2, 15.8 Hz), 6.48 (d, 1H, J=15.8 Hz), 7.20–7.33 (m,10H); GCMS (EI) m/z 324 (M+); 293;
265; 232; 206; 193; 116.
9. Dimethyl malonate (1.644 mmol), BSA (1.644 mmol), and lithium acetate (0.0273 mmol) in 2 ml of dichloromethane
were stirred at room temperature under argon for 1.5 h. The volatiles were removed in vacuo immediately. The 1H
NMR spectrum of the residue was measured, followed by comparison of the spectrum with that of carbomethoxy ketene
methyltrimethylsilyl acetal 3d.
10. Krapcho’s condition is available to prepare (3S)-methyl 3,5-diphenylpent-4-enoate 5, see: (a) Krapcho, A. P.; Lovery, A. J.
Tetrahedron Lett. 1973, 957. (b) Krapcho, A. P.; Jahngen Jr., E.; Lovery, A. J. ibid. 1974, 1091. (c) Morimoto, Y.; Shirahama,
H. Tetrahedron 1996, 52, 10631.
11. Among preceding articles related to palladium-catalyzed allylations without focusing on the enantioselective reaction, a
study using allyl acetate and ketene silyl acetal to yield α-allylated carboxylic acid esters and cyclopropane derivatives
was found. The addition of silyl enolate from the side opposite the metal was proposed, see: (a) Carfagna, C.; Mariani,
L.; Musco, A.; Sallese, G. J. Org. Chem. 1991, 56, 3924. (b) Carfagna, C.; Galarini, R.; Musco, A.; Santi, R. J. Mol.
Catal. 1992, 72, 19. Tsuji et al. explored palladium-catalyzed reactions of allyl carbonates with ketene silyl acetals. It was
demonstrated as a reaction mechanism that the reaction proceeded through the formation of π-allylpalladium complex by
the oxidative addition of allyl carbonate, followed by decarboxylation and the addition of enolate anion to the metal, see:
(c) Tsuji, J.; Takahashi, K.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984, 25, 4783. Iron complexes for the reaction of
allyl acetate with ketene silyl acetal, see: (d) Enders, D.; Frank, U.; Fey, P.; Jandeleit, B.; Lohray, B. B. J. Org. Chem. 1996,
519, 147.