Asymmetric allylation of unsymmetrical 1,3-diketones using a BINAP-palladium catalyst

Article abstract of DOI:10.1021/ol034665s

(Matrix presented) The chiral palladium complex generated in situ from [Pd(η³-allyl)Cl]₂ and (R)-BINAP is a good catalyst for the catalytic asymmetric allylation of 1,3-diketones. The reaction provided chiral 2,2-dialkyl-1,3-diketones with 64-89% ee in high yields (13 examples). Enantiomeric excesses are strongly affected by the γ-substituent of the allylic substrates. A variety of unsymmetrical 1,3-diketones were alkylated with cinnamyl acetate in good enantioselectivities via use of the BINAP-palladium catalyst (77-89% ee).

Full text of DOI:10.1021/ol034665s

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2177-2179
Asymmetric Allylation of Unsymmetrical
1,3-Diketones Using a BINAP−Palladium
Catalyst
,†
,‡
Ryoichi Kuwano,* Kei-ichi Uchida,‡ and Yoshihiko Ito*
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, and Department of Synthetic
Chemistry & Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
rkuwascc@mbox.nc.kyushu-u.ac.jp
Received April 19, 2003
ABSTRACT
The chiral palladium complex generated in situ from [Pd(η3-allyl)Cl]2 and (R)-BINAP is a good catalyst for the catalytic asymmetric allylation
of 1,3-diketones. The reaction provided chiral 2,2-dialkyl-1,3-diketones with 64−89% ee in high yields (13 examples). Enantiomeric excesses
are strongly affected by the γ-substituent of the allylic substrates. A variety of unsymmetrical 1,3-diketones were alkylated with cinnamyl
acetate in good enantioselectivities via use of the BINAP−palladium catalyst (77−89% ee).
Highly enantioselective formation of a quaternary chiral
carbon center is an important goal in organic synthetic
chemistry.1 Alkylation of 2-substituted 1,3-diketones is one
of the synthetic approaches for the formation of quaternary
carbons. However, enantioselective versions of the alkylation
have so far been regarded as difficult, probably due to the
steric and electronic similarities of the two carbonyl groups
of the 1,3-diketones.2-4
presence of a chiral palladium catalyst. Efficient enantio-
selective allylations for creation of a chiral carbon center
on a soft nucleophile have only been achieved with dif-
ficulty.3,5 The prochiral 1,3-diketone enolate is generally
believed to be located far from the chiral ligand in the
transition state of the nucleophlic attack on the chiral (η3-
allyl)palladium intermediate.
Previously, we reported a highly enantioselective allylation
of prochiral nucleophiles, R-acetamido-â-ketoesters.6 In the
asymmetric reaction, a BINAP-palladium complex was the
most enantioselective catalyst for the preparation of R-amino
acids bearing a quaternary chiral R-carbon with up to 95%
ee. To evaluate the BINAP-palladium catalyst for the
This paper reports an enantioselective alkylation of
unsymmetrical 1,3-diketones using allylic acetates in the
† Kyushu University.
‡ Kyoto University.
(1) For recent reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388-401. (b) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591-4597.
(2) Fiaud, J. C. Tetrahedron Lett. 1975, 3495-3496.
(3) (a) Fiaud, J. C.; Hibon de Gournay, A.; Larcheveque, M.; Kagan, H.
B. J. Organomet. Chem. 1978, 154, 175-185. (b) Hayashi, T.; Kanehira,
K.; Tsuchiya, H.; Kumada, M. J. Chem. Soc., Chem. Commun. 1982, 1162-
1164. (c) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org.
Chem. 1988, 53, 113-120. (d) Sawamura, M.; Nagata, H.; Sakamoto, H.;
Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586-2592.
(4) Enantioselective Michael reactions of unsymmetrical 1,3-diketones:
(a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240-11241. (b) Christoffers, J.; Mann, A. Chem. Eur. J. 2001, 7, 1014-
1027.
(5) (a) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118,
3309-3310. (b) Sawamura, M.; Nakayama, Y.; Tang W.-M.; Ito, Y. J.
Org. Chem. 1996, 61, 9090-9096. (c) Trost, B. M.; Radinov, R.; Grenzer,
E. M. J. Am. Chem. Soc. 1997, 119, 7879-7880. (d) Trost, B. M.; Ariza,
X. J. Am. Chem. Soc. 1999, 121, 10727-10737. (e) Brunel, J. M.; Tenaglia,
A.; Buono, G. Tetrahedron: Asymmetry 2000, 11, 3585-3590. (f) Nakoji,
M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 3329-
3331. (g) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem.
2002, 67, 7418-7423.
(6) (a) Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236-3237.
(b) Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1, 837-839.
10.1021/ol034665s CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003

asymmetric allylation of 1,3-diketones, the reaction of
2-acetylcyclohexanone with allyl acetate in the presence of
KO(t-Bu) and 1 mol % [Pd(η3-C3H5)Cl]-(R)-BINAP catalyst
in toluene (Scheme 1) was conducted. The reaction at -60
Table 2. Catalytic Asymmetric Allylation of 1,3-Diketones
with Cinnamyl Acetatea
Scheme 1
°C produced (S)-2-acetyl-2-allylcyclohexanone with 64% ee
in 82% yield.
The BINAP-palladium catalyst promoted alkylations with
γ-substituted allylic acetates as well as allyl acetate (Table
1). No formation of a regioisomeric side product was
Table 1. Catalytic Asymmetric Alkylations of
2-Acetylcyclohexanone with Allylic Acetatesa
entry
R
temp, °C
yield, %b
ee, %c
a Reactions were conducted at -60 °C in 2.5 mL of toluene for 24 h.
1,3-Diketones/cinnamyl acetate (0.5 mmol)/KO(t-Bu)/[Pd(η3-C3H5)Cl]2/
(R)-BINAP ) 120/100/120/0.5/1.05. b Isolated yield. c Determined by chiral
HPLC analysis.
1
2
3
4
5
C3H7
-30
-30
-60
-60
-60
79
65
99
87
87
64
65
85
83
84
cyclo-C6H11
Ph
p-MeO-C6H4
p-CF3-C6H4
pionyl substrate (entry 6) proceeded with selectivity similar
to that of the 2-acetyl substrate (Table 1, entry 3). Acyclic
1,3-diketones were alkylated with cinnamyl acetate in the
presence of the BINAP-palladium catalyst and yielded the
corresponding chiral 2,2-dialkyl-1,3-diketones with over 80%
ee (entries 7 and 8).
The cinnamyl group of the products given in Table 2 can
readily convert into a carboxymethyl group (Scheme 2). After
selective protection of cyclohexanone with cyclic ketal,3c
oxidative cleavage of the C-C double bond with NaIO4-
RuO2 catalyst7 provided the corresponding carboxylic acid.
The acid was isolated as a methyl ester after esterification
with (trimethylsilyl)diazomethane8 in a good yield. This
result demonstrates that cinnamyl acetate in the present
asymmetric allylation can work as a synthon of a carboxy-
a Reactions were conducted in 2.5 mL of toluene for 24 h. 2-Acetyl-
cyclohexanone/allylic acetate (0.5 mmol)/KO(t-Bu)/[Pd(η3-C3H5)Cl]2/
BINAP ) 120/100/120/0.5/1.05. b Isolated yield. c Determined by chiral
HPLC or GC analysis.
observed. Aromatic γ-substituents yielded chiral products
with a higher enantiomeric excess than aliphatic ones (entries
3-5 vs 1 and 2). The highest selectivity [85% ee (S)] in
this series was achieved with cinnamyl acetates (entry 3).
No reaction of prenyl, methallyl, and 1,3-diphenyl-2-propenyl
acetates occurred under the reaction conditions.
The scope of 1,3-diketones in the BINAP-palladium-
catalyzed allylation is extensive, as shown in Table 2. The
highest enantioselectivity (89% ee) was observed in the
reaction of 2-acetyl-4,4-dimethylcyclohexanone (entry 1).
Substrates with a five-, seven-, and eight-membered ring
underwent alkylation with cinnamyl acetate at a high level
of enantioselectivity (entries 3-5). The reaction of a 2-pro-
(7) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936-3938.
(8) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475-1478.
2178
Org. Lett., Vol. 5, No. 12, 2003

available. This method will allow organic chemists to use
the asymmetric allylation of prochiral nucleophiles without
synthesizing specialized chiral ligands. Pursuit of the origin
of the enantioselectivity in the asymmetric allylation is in
progress.
Scheme 2
Acknowledgment. This work was partly supported by
the Novartis Foundation (Japan) for the Promotion of Science
and a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
methyl group, which can be further transformed into various
functional groups.
In conclusion, we developed a new protocol of enantio-
selective allylation of various unsymmetrical 1,3-diketones
by a BINAP-palladium catalyst, which is commercially
OL034665S
Org. Lett., Vol. 5, No. 12, 2003
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