Palladium Catalysis
6343 – 6352
205.0, 202.1, 157.7, 138.2, 40.5, 35.5, 31.6, 29.5, 24.1, 21.6 ppm; IR (neat):
n˜ =1662, 1626 cmꢀ1 (C=O); elemental analysis calcd (%) for C11H16O2: C
73.30, H 8.95; found: C 73.16, H 9.01.
vent for the oxidative alkylation of 4-pentenyl b-dicarbonyl com-
pounds.
[17] Similar products are formed in the palladium-mediated cyclization
of 2-diazo-3-oxo-6-heptenoates: D. F. Taber, J. C. Amedio, R. G.
Sherrill, J. Org. Chem. 1986, 51, 3382.
The remaining 2-acyl-2-cyclohexenones in Table 1 were synthesized by
employing a procedure analogous to that described for the cyclization of
4 with CuCl2 as the terminal oxidant (procedure A) or that described for
7 through slow addition of the substrate (procedure B). Cyclization of 15
and each of the 4-pentenyl b-keto esters depicted in Table 2 employed a
procedure similar to that described above for the cyclization of 7 with
the exception that the b-keto esters were cyclized at 708C.
[18] J. Christoffers, J. Org. Chem. 1998, 63, 4539.
[19] The selectivities quoted here refer to the ratio of oxidative alkyla-
tion:hydroalkylation products and therefore differ from the selec-
tivities quoted in Table 1, which refer to the ratio of the desired oxi-
dative alkylation product to all isomerized starting materials.
[20] This approach was based on the following three assumptions: 1) hy-
droalkylation and oxidative alkylation share the same initial steps
ꢀ
and occur by means of the same C C bond forming process, 2) the
mechanism of hydroalkylation was invariant of the b-dicarbonyl
moiety, and 3) b-hydride elimination is rapid and reversible, but
olefin displacement is irreversible. This last assumption was estab-
lished for the palladium-catalyzed hydroalkylation of 3-butenyl b-di-
ketones.[13,14]
Acknowledgement
We acknowledge the NSF (CHE-03–04994) for support of this research.
R.W. thanks the Camille and Henry Dreyfus Foundation and Glaxo-
SmithKline for unrestricted financial assistance.
[21] Isotopomers of b-keto ester 15 were employed in preference to iso-
topomers of b-diketone 4 as we were unable to isolate sufficient
amounts of the corresponding isotopomers of 6 for the 13C NMR
analysis required to establish regiochemistry.
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[22] These reactions also contained an equivalent of Me3SiCl, which im-
proves the yield and selectivity for the cyclohexanone product;[22b,c]
for example, reaction of 15 with a catalytic amount of 2 (5 mol%)
in the presence of both CuCl2 and Me3SiCl (2 equiv) led to the isola-
tion of 16 in 72% yield and cyclohexenone 17 in 15% yield;[22b,d]
a
full discussion of the role of Me3SiCl in the palladium-catalyzed hy-
droalkylation of alkenyl ketones is provided elsewhere;[22d] b) T. Pei,
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[23] The exclusive incorporation of deuterium into the exocyclic methyl
group of 16-CH2D was established by the 1:1:1 triplet at d=
21.0 ppm (JCD =19.2 Hz, isotope shift=251 ppb) in the 13C NMR
[6] a) L. S. Hegedus, Angew. Chem. 1988, 100, 1147; Angew. Chem. Int.
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5, 369.
spectrum and by the 1:1:1 triplet of doublets at d=1.02 ppm (JHD
2.2 Hz, JHH =6.8) in the H NMR spectrum.
=
1
ꢀ
[24] Loss of deuterium from the DCl released in C C bond formation
was also observed in the palladium-catalyzed cyclization of 3,3-di-
deuterio-7-octene-2,4-dione.[13,14]
[25] The enolic deuteron of 16-2,6[D2] was presumably lost during isola-
tion. Furthermore, a small amount of HCl is generated through the
minor oxidative alkylation pathway during the palladium-catalyzed
cyclization of 15-3,3[D2].
[26] The exclusive incorporation of deuterium into the C6 position of 16-
6[D1] was established by the 1:1:1 triplet at d=40.8 ppm (J=
18.6 Hz, isotopic shift=334 ppb) in the 13C NMR spectrum.
[27] As an alternative to the formation of intermediate VII from IV, col-
lapse of the enol of IV could displace an anionic palladium chloride
species that could then deprotonate the cationic cyclohexenone in-
termediate to form a Pd(H)Cl species and free 2-cyclohexenone. We
thank a reviewer for suggesting this mechanism.
[9] a) L. S. Hegedus, in Transition Metals in the Synthesis of Complex
Organic Molecules, University Science Books, Mill Valley, CA, 1999,
Chapter 7.2, pp. 188–204; b) L. S. Hegedus, in Organometallics in
Synthesis (Ed.: M. Schlosser), Wiley, Chichester, 1994, Chapter 5.3.1,
pp. 388–399.
[28] HCl is generated in the conversion of 4-8[D1] to III-[D1], DCl is
generated by reduction of the Pd(D)Cl species generated in the con-
version of III-[D1] to 5a.
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[11] See also: a) J. FranzØn, J.-E. Bäckvall, J. Am. Chem. Soc. 2003, 125,
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[29] Data was collected in this manner to avoid potential complications
arising from scrambling of the allylic positions.
[30] Under equilibrium conditions, deuterium tends to accumulate in the
position of higher stretching frequency,[31] and for this reason, inter-
mediate III-CD2 would form in preference to III-CHD. However,
because equilibrium isotope effects are typically not large, detecta-
ble amounts of III-CHD and hence 12a-CHD would be formed if
conversion of III to IV were reversible under reaction conditions.
[31] M. Wolfsberg, Acc. Chem. Res. 1972, 5, 225.
[12] T. Pei, R. A. Widenhoefer, J. Am. Chem. Soc. 2001, 123, 11290.
[13] H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125, 2056.
[14] H. Qian, R. A. Widenhoefer, Organometallics, 2004, 23, in press.
[15] A portion of these results have been communicated: T. Pei, X.
Wang, R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125, 648.
[16] Use of hydrated CuCl2 led to the formation of chlorinated byprod-
ucts. 1,2-Dichloroethane (DCE) proved superior to dioxane as a sol-
[32] H. Kurosawa, T. Majima, N. Asada, J. Am. Chem. Soc. 1980, 102,
6996.
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Chem. Eur. J. 2004, 10, 6343 – 6352
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6351