C O M M U N I C A T I O N S
Table 3. Reactions with Proton Sources
Scheme 1. Double Bond Geometry Controls the Configuration
and Enantiomeric Excess of Product
time
4
5
9
10
entry
R
R
′
solvent
(min)
(% ee)
(%)
6(%)
(%)
(%)
1
2
3
4
5
CO2Me Me dioxane
30 94 (94)
6
0
0
0
2
0
0
9
91
22
0
0
0
0
CO2Me
COCH3
CO2Me
COCH3
H
H
H
H
dioxane
dioxane
THF
15 90 (93) 10
15 17 (81) 83
10 71 (87) 27
THF
<5
8 (63) 92
76 14
may react more slowly in 1,4-dioxane relative to collapse to product,
so that very little proton transfer occurs between the enolate and
these proton sources. The conjecture is supported by the reaction
of 3 in 1,4-dioxane in the presence of 1 equiv of dimethyl
methylmalonate, dimethyl malonate, or acetylacetone. The reaction
with dimethyl methylmalonate was identical to that of the control.
A small amount (9%) of dimethyl allylmalonate was detected in
the run with dimethyl malonate, and the yield of byproduct 5 slightly
increased to 10%, but the enantiomeric excess of the reaction
remained high (93%) (entry 2). In entry 3, high yields of 5 (83%)
and allyl acac (91%) were detected with the loss of yield (17%)
and enantiomeric excess (81%) of the product 4. A similar trend
was observed in THF, with the addition of a significant amount of
diallyl acac also being observed. With the increase of the acidity
of the additive, the ability to intercept the solvent caged contact
ion pair relative to collapse to 4 increases. Thus the amount of
byproducts increases.
Scheme 2. Model for the Enantioselectivity of 4
Scheme 3. Proposed Mechanism for the Reaction
In summary, we report the first palladium-catalyzed asymmetric
R-allyl alkylation of acyclic ketones. The reaction proceeds under
very mild conditions and generates an R-tertiary stereogenic center
with excellent yield, regioselectivity, and enantiomeric excess. On
the basis of our experimental results, we propose an intramolecular
mechanism involving an inner sphere reductive elimination, quite
distinct from the usual behavior of π-allyl-Pd complexes. Further
investigation of the mechanism and the application of the reaction
in organic synthesis are underway.
Acknowledgment. We thank the National Science Foundation
and National Institutes of Health, GM13598, for their generous
support of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of Californias
San Francisco, supported by the NIH Division of Research
Resources.
the case of 1-mesityl-1-propenyl carbonate (entries 15 and 16); the
reaction of the E-isomer went to completion in 6 h with a
quantitative yield and 96% ee, but only trace amount of product
was detected in 16 h for the Z isomer.
The absolute configuration of 4 was determined to be S by Pd-
CaCO3-catalyzed hydrogenation of the CdC double bond and
comparison of the optical rotation of the product with the known
enantiomer.6 This result conflicts with the model of intermolecular
nucleophilic attack of the enolate on the π-allyl-Pd complex
possessing ligand 1, by which the R enantiomer is preferred.7 The
same conflict was found in our previous studies.3a In the case of
allyl enol carbonate, since the π-allyl-Pd cation is the only
counterion of the in situ generated enolate, it is likely that there is
coordination between the enolate and palladium. According to the
work of Hartwig et al., either C- or O-bound arylpalladium enolates
can undergo reductive elimination to generate the corresponding
R-aryl ketones.8 Therefore, under our reaction conditions, a
reasonable explanation invokes a shift of mechanism from a direct
attack of the enolate on the allyl moiety to an inner sphere process
of coordination and reductive elimination (Scheme 2).
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
References
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The distinctive solvent effect in favor of 1,4-dioxane may be
explained by the fact that it is much better in forming solvent caged
contact ion pairs than THF.9 The proton sources in the bulk solution,
mainly the monoalkylated product itself or trace amounts of water,
(8) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
(9) Hogen-Esch, T. E.; Smid, J. J. Am. Chem. Soc. 1965, 87, 669.
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