C O M M U N I C A T I O N S
Table 1. Enantioselective R-Alkylation of Ketones with Ethylene,
generated by the reaction of 5 and ethylene undergoes copper- and
palladium-catalyzed C-C bond forming reactions in high overall
yield and with high stereoselectivity. We previously noted also for
an R-substituted zinc homoenolate such stereochemical stability of
a stereogenic center next to a carbonyl group.10
Propene, and Styrenea
The zinc enamide 3c reacts with ethylene to generate (R)-2-
ethylcyclohexanone (93.6% ee), and this selectivity is opposite to
that obtained in the alkylation of its lithium enamide with ethyl
iodide in THF at -78 °C, which gave (S)-2-ethylcyclohexanone
with 79.4% ee.2 The sense of the selectivity in the former reaction
may be explained by a six-centered transition state shown below,11
and that of the latter reaction needs a different way of reasoning.
Supporting Information Available: Details of the experimental
procedure, and characterization and physical data of products (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron
2002, 58, 2253.
(2) (a) Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger,
M. J. J. Am. Chem. Soc. 1981, 103, 3081. (b) Meyers, A. I.; Williams, D.
R.; White, S.; Erickson, G. W. J. Am. Chem. Soc. 1981, 103, 3088.
(3) Rodriguez, A. L.; Bunlalsananusorn, T.; Knochel, P. Org. Lett. 2000, 2,
3285.
(4) (a) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. Engl. 1997, 36,
2491. (b) Nakamura, E.; Kubota, K. J. Org. Chem. 1997, 62, 792. (c)
Nakamura, E.; Kubota, K.; Sakata, G. J. Am. Chem. Soc. 1997, 119, 5457.
(d) Nakamura, E.; Kubota, K. Tetrahedron Lett. 1997, 38, 7099.
(5) (a) Nakamura, M.; Hara, K.; Hatakeyama, T.; Nakamura, E. Org. Lett.
2001, 3, 3137. (b) Nakamura, M.; Hara, K.; Sakata, G.; Nakamura, E.
Org. Lett. 1999, 1, 1505. (c) Nakamura, E.; Sakata, G.; Kubota, K.
Tetrahedron Lett. 1998, 39, 2157. (d) Kubota, K.; Isaka, M.; Nakamura,
M.; Nakamura, E. J. Am. Chem. Soc. 1993, 115, 5867. (e) Lorthiois, E.;
Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63, 2442.
a N denotes an amino-alcohol group specified by the coding in Scheme
1. b Addition reaction was carried out in an autoclave under an ethylene
atmosphere (20-30 atm) at 40-60 °C for 24 h. c ee values were determined
by GC analysis. d-f Based on the starting imine and determined by GC
analysis by using decane,d undecane,e and tridecanef as an internal standard.
g Isolated yield. h The data in parentheses refer to the yield and selectivity
determined for the ketone product obtained after 5-10 min of hydrolysis.
i Regioselectivity was >99:1. j Propene atmosphere (8 atm), 60 °C for 48
h. k 1.5 equiv of styrene, 70 °C for 48 h.
(6) Racemization of the chiral center took place even under the best current
hydrolysis conditions, which is not due to epimerization of the final ketone
product but due to that of an imine intermediate.
Chart 1. Products (17-20) of the Electrophilic Trapping of the
γ-Zincioimine Intermediate In-Situ Generated by Coupling of
Enamide 5 and Ethylenea
(7) Enantioselective three-component coupling of 4-methylenecyclohexanone
enamide 5, ethylene, and ethyl 2-(bromomethyl)acrylate: An imine
precursor to 5a (2.09 g, 10.0 mmol) was added slowly to an ethereal
solution of mesityllithium (10.0 mmol) at 0 °C. Zinc chloride (ether
solution, 10.0 mmol) at 0 °C and then methyllithium (ether solution, 10.0
mmol) at -78 °C were added. Hexane (20 mL) was added, and the reaction
mixture was heated at 45 °C for 30 min to remove ether under dry nitrogen
stream. The reaction mixture was pressurized with ethylene (30 atm) and
stirred for 24 h at 60 °C. After release of excess ethylene, tetrahydrofuran
(20 mL), CuBr‚SMe2 (2.06 g, 10.0 mmol), and ethyl 2-(bromomethyl)-
acrylate (2.42 mL, 20.0 mmol) were added at -78 °C. The reaction
mixture was stirred at 0 °C for 6 h and then hydrolyzed with acetic acid
buffer (20 mL). Purification by silica gel chromatography gave the desired
R-alkylated ketone (2.15 g, 86% yield, 89.6% ee). The amino ether chiral
auxiliary can be recovered in >70% yield.
a (a) Allyl bromide (2 equiv)/CuBr‚SMe2 (20 mol %), (b) â-bromostyrene
(2 equiv, >99.9%E)/Pd(PPh3)4 (5 mol %), (c) iodobenzene (2 equiv)/
Pd(PPh3)4 (5 mol %), (d) ethyl-2-(bromomethyl)acrylate (2 equiv)/
CuBr‚SMe2 (1 equiv).
(8) Both isomers may be of nearly equal energies, but only the zinc enamide
can take part in the addition reaction.
The organozinc intermediate containing an imine functionality
such as 3 was found to be very stable under the reaction condition
of 40-60 °C in terms of its chemical and stereochemical integrity
likely because of its chelate structure. On the other hand, such an
intermediate still shows the chemical reactivities characteristic of
an organozinc species (Chart 1). For instance, the intermediate
(9) The reaction is general for 1-alkenes but produces a mixture of diastereo-
mers as to the newly formed C-C bond. The stereochemical issue still
remains to be resolved to make this extension synthetically useful.
(10) Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 1, 155.
(11) Hirai, A.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2000, 122,
11791.
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