Palladium-catalyzed intramolecular hydroalkylation of unactivated olefins with dialkyl ketones

Article abstract of DOI:10.1021/ol034879+

(Matrix presented) Treatment of 3-butenyl heptyl ketone with substoichiometric amounts of PdCl₂(CH₃CN)₂ (10 mol%), HCl (0.1 equiv), and CuCl₂ (0.3 equiv) in dioxane at 70°C for 12 h in a sealed tube formed 2-hexylcyclohexanone in 77% isolated yield. A number of alkyl 3-butenyl ketones underwent hydroalkylation under these conditions to form 2-substituted cyclohexanones in moderate to good yield.

Full text of DOI:10.1021/ol034879+

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2699-2701
Palladium-Catalyzed Intramolecular
Hydroalkylation of Unactivated Olefins
with Dialkyl Ketones
Xiang Wang, Tao Pei, Xiaoqing Han, and Ross A. Widenhoefer*
Duke UniVersity, P. M. Gross Chemical Laboratory,
Durham, North Carolina 27708-0346
rwidenho@chem.duke.edu
Received May 20, 2003
ABSTRACT
Treatment of 3-butenyl heptyl ketone with substoichiometric amounts of PdCl2(CH CN)2 (10 mol %), HCl (0.1 equiv), and CuCl2 (0.3 equiv) in
3
dioxane at 70 °C for 12 h in a sealed tube formed 2-hexylcyclohexanone in 77% isolated yield. A number of alkyl 3-butenyl ketones underwent
hydroalkylation under these conditions to form 2-substituted cyclohexanones in moderate to good yield.
The direct addition of the R-C-H bond of a dialkyl ketone
across the CdC bond of an unactivated olefin (hydroalky-
lation) is a transformation of considerable synthetic potential,
but for which no effective procedure exists. For example,
intramolecular hydroalkylation of γ-, δ-, ꢀ-, or ú-alkenyl alkyl
ketones occurs thermally but requires temperatures of g350
°C.1 Radical-mediated olefin hydroalkylation occurs under
relatively mild conditions but suffers from poor site selectiv-
ity for radical generation, poor product selectivity, and slow
chain transfer.2 Lewis acid-catalyzed intramolecular olefin
hydroalkylation occurs at room temperature but suffers from
limited generality, is restricted to activated methylene
compounds, and involves carbocationic intermediates.3 Tran-
sition metal-catalyzed hydroalkylation has been restricted to
the addition of activated methylene compounds to reactive
unsaturated groups such as allenes,4 alkynes,5 and conjugated
dienes.6
We recently reported the hydroalkylation of 3-butenyl
â-diketones catalyzed by PdCl2(CH3CN)2 (1) to form 2-acyl-
cyclohexanones (eq 1),7,8 which represent the first examples
of the transition metal-catalyzed hydroalkylation of unacti-
vated olefins with carbon nucleophiles.9-11 Unfortunately,
efficient hydroalkylation was initially restricted to â-dike-
tones, which are g1011 more acidic and possess an equilib-
rium enol content g108 greater than do to dialkyl ketones.12,13
Through our efforts to expand the scope of palladium-
catalyzed hydroalkylation, we noted that the reactivity of
alkenyl â-keto esters toward 1 increased significantly in the
presence of Me3SiCl, which we attributed to the in situ
generation of a reactive silyl enol ether.14 For example, the
(5) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem.
1996, 61, 2699.
(6) Goddard, R.; Hopp, G.; Jolly, P. W.; Kruger, C.; Mynott, R.; Wirtz,
C.J. Organomet. Chem. 1995, 486, 163.
(7) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290.
(8) For examples of the palladium-catalyzed oxidative alkylation of
alkenyl â-diketones, see: Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2003, 125, 648.
(1) (a) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1. (b) Moinet, G.;
Brocard, J.; Conia, J. M. Tetrahedron Lett. 1972, 4461.
(2) (a) Julia, M. Acc. Chem. Res. 1971, 4, 386. (b) Curran, D. P. Synthesis
1988, 417, 489. (c) Giese, B. Radicals in Organic Synthesis: Formation
of Carbon-Carbon Bonds; Pergamon Press: New York, 1986. (d) Jasperse,
C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 1237.
(3) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1982, 21, 96.
(4) (a) Trost, B. M.; Gerusz, V. J. J. Am. Chem. Soc. 1995, 117, 5156.
(b) Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am. Chem. Soc. 1994, 116,
6019.
(9) Transition metal-catalyzed olefin hydroarylation10 and alkenylation11
via C-H bond activation has also been reported.
(10) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Lenges, C. P.;
Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616. (c) Lim, Y. G.; Kim, Y.
H.; Kang, J. B. J. Chem. Soc., Chem. Commun. 1994, 2267. (d) Jordan, R.
F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778.
10.1021/ol034879+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003

yield of the palladium-catalyzed conversion of methyl 3-oxo-
6-heptenoate to 2-carbomethoxycyclohexanone increased
from 21 to 91% upon addition of Me3SiCl to the reaction
mixture (eq 2). Here we report that continued study in this
area has led to the identification of HCl as the active
promoter in palladium-catalyzed, silane-mediated hydroalky-
lation and to the development of the first effective transition
metal-catalyzed procedure for the hydroalkylation of an
unactivated olefin with a simple dialkyl ketone.
Table 1. Cyclization of Alkenyl R-Aryl Ketones Catalyzed by
1 (10 mol %) in the Presence of Me3SiCl (2-3 equiv) and
CuCl2 (1 equiv) at 70 °C in Dioxane
The pKa and Kenol/ketone of R-aryl ketones lie roughly
midway between the corresponding values for â-keto esters
and dialkyl ketones,12,13 and for this reason, we initially
focused our attention on the cyclization of alkenyl R-aryl
ketones. Surprisingly, a number of R-aryl 3-butenyl and
4-pentenyl ketones underwent efficient intramolecular hy-
droalkylation under conditions similar to those employed for
the cyclization of alkenyl â-keto esters, albeit under more
forcing conditions (Table 1). For example, treatment of
benzyl 3-butenyl ketone (2) with a catalytic amount of 1
(10 mol %) in the presence of Me2SiCl2 (2.5 equiv) and
CuCl2 (1 equiv) at 70 °C for 18 h led to isolation of 2-phenyl
cyclohexanone in 78% yield (Table 1, entry 1).15 Unfortu-
nately, this silane-mediated protocol required a 2- to 3-fold
excess of the chlorosilane and failed in the case of both
electron-rich R-aryl ketones and dialkyl ketones. For ex-
ample, attempted cyclization of 3-butenyl heptyl ketone (3)
or 1-(4-methoxyphenyl)-5-hexene-2-one (4) employing these
conditions gave the desired cyclohexanone in e15% GC
yield.
We initially hypothesized that Me3SiCl promoted the
palladium-catalyzed hydroalkylation of alkenyl ketones via
in situ formation of a reactive silyl enol ether.14 To test this
assumption and gain insight into the role of the chlorosilane
in palladium-catalyzed hydroalkylation, a dioxane-d8 solution
of 2, Me3SiCl, and 1 (0.1 equiv) was analyzed by 1H NMR
spectroscopy. In contrast to our expectations, no evidence
for formation of the silyl enol ether of 2 was obtained, and
instead, partial hydrolysis of Me3SiCl with adventitious
a Dichlorodimethylsilane employed in place of Me3SiCl. b Thermody-
namic isomer ratio g50:1.
moisture generated a mixture of hexamethyldisiloxane and
HCl. On the basis of this observation, we considered that
perhaps HCl, rather than Me3SiCl, was the active promoter
of palladium-catalyzed olefin hydroalkylation. Consistent
with this hypothesis, treatment of 2 with substoichiometric
amounts of 1 (10%), HCl (0.1 equiv), and CuCl2 (0.3 equiv)
in a sealed tube for 12 h at 70 °C led to the isolation of
2-phenylcyclohexanone in 79% yield (Table 2, entry 1).16
Identification of HCl as the active promoter in the
palladium-catalyzed hydroalkylation of 2 was significant
because the procedure based on this knowledge proved to
be effective for the hydroalkylation of alkyl alkenyl ketones
(Table 2). Noteworthy was the formation of a quaternary
carbon atom in the cyclization of 3-butenyl cyclohexyl ketone
(Table 2, entry 7). Likewise, a 3-butenyl methyl ketone,
which is ∼100-fold less acidic than an ethyl ketone,
underwent intramolecular hydroalkylation in moderate yield
(Table 2, entry 12). This silane-free procedure was also
effective for the intramolecular hydroalkylation of electron-
rich R-aryl ketones such as 4 (Table 2, entry 6).
(11) (a) Trost, B. M.; Imi, K.; Davies, I. W. J. Am. Chem. Soc. 1995,
117, 5371. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2001, 123, 2685.
(12) pKa values for 2,4-pentanedione, ethyl acetoacetate, benzyl methyl
ketone, and ethyl methyl ketone in DMSO are 13.3, 14.2, 19.9, and 24.8,
respectively. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(13) Kenol/ketone values for 2,4-pentanedione, ethyl acetoacetate, benzyl
methyl ketone, and ethyl methyl ketone are 3.2, 0.9, 8 × 10-5, and 5 ×
10-9, respectively. Guthrie, J. P. Can. J. Chem. 1979, 57, 1177.
(14) Pei, T.; Widenhoefer, R. A. Chem. Commun. 2002, 650.
On the basis of deuterium-labeling experiments, we have
proposed a mechanism for the palladium-catalyzed hy-
droalkylation of an alkenyl ketone involving attack of the
pendant enol on the palladium-complexed olefin of I to form
2700
Org. Lett., Vol. 5, No. 15, 2003

Scheme 1
Table 2. Cyclization of R-Aryl and Alkyl 3-Butenyl Ketones
Catalyzed by 1 (10 mol %) in the Presence of CuCl2 (0.3 equiv)
and HCl (0.1 equiv) at 70 °C in Dioxane in a Sealed Tube
palladium olefin intermediate I can presumably undergo
cyclization and because enolization of an R-aryl ketone or
dialkyl ketone is slow in the absence of an acid catalyst,18
we propose that HCl facilitates the palladium-catalyzed
hydroalkylation of alkenyl ketones by catalyzing enolization
of the palladium olefin intermediate I.
In summary, we have identified HCl as the active promoter
in palladium-catalyzed, silane-mediated hydroalkylation and
have developed the first effective procedure for the hy-
droalkylation of an unactivated olefin with a dialkyl ketone
based on this knowledge. We are currently working toward
the identification of more effective methods for promoting
enolization of alkenyl ketones and toward expanding the
scope of palladium-catalyzed hydroalkylation with respect
to ring size and substitution.
Acknowledgment. Acknowledgment is made to the NSF
(CHE-03-04994) for support of this research. R.W. thanks
the Camille and Henry Dreyfus Foundation, the Alfred P.
Sloan Foundation, DuPont, and GlaxoSmithKline for finan-
cial assistance. Academic year support for T.P. and X.W.
has been provided by Duke University in the form of a
Charles R. Hauser Fellowship and Burroughs Wellcome
Fellowship, respectively.
the palladium cyclohexyl species II (Scheme 1).17 Isomer-
ization of II via iterative â-hydride elimination/addition
forms the metastable palladium enolate species III, which
undergoes protonolysis to form the cyclohexanone with
regeneration of 1 (Scheme 1). All available evidence points
to C-C bond formation (I f II, Scheme 1) as the turnover-
limiting step of catalysis. Because only the enol tautomer of
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds and
cyclohexanones. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) CuCl2 stabilized the Pd(II) catalyst with respect to reduction/
decomposition. Cyclization in the absence of CuCl2 led to incomplete
conversion.14
OL034879+
(16) Me3SiCl also served as an effective source of HCl in this
transformation. No reaction was observed in the absence of 1.
(17) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056.
(18) Keefe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport,
Z., Ed.; John Wiley & Sons: New York, 1990; pp 451-453.
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