Oxidative Cyclization of β-Hydroxyenones with Palladium(II): A Novel Entry to 2,3-Dihydro-4H-pyran-4-ones

Article abstract of DOI:10.1021/ol0361296

(Equation presented) A palladium(II)-mediated oxidative cyclization was found to be effective for the preparation of structurally diverse 2,3-dihydro-4H-pyran-4-ones from the corresponding β-hydroxyenones. Attractive features of this transformation includ

Full text of DOI:10.1021/ol0361296

ORGANIC
LETTERS
2004
Vol. 6, No. 1
91-94
Oxidative Cyclization of
â-Hydroxyenones with Palladium(II):
A Novel Entry to
2,3-Dihydro-4H-pyran-4-ones
Maud Reiter, Sandrine Ropp, and Ve´ronique Gouverneur*
UniVersity of Oxford, The Dyson Perrins Laboratory, South Parks Road,
OX1 3QY Oxford, UK
Veronique.gouVerneur@chem.ox.ac.uk
Received October 31, 2003
ABSTRACT
A palladium(II)-mediated oxidative cyclization was found to be effective for the preparation of structurally diverse 2,3-dihydro-4H-pyran-4-ones
from the corresponding â-hydroxyenones. Attractive features of this transformation include the ready availability of the starting enones, the
regiocontrol, and the easy access of enantiopure 2,3-dihydro-4H-pyran-4-one from the corresponding enantiopure enone.
The oxidation of ethylene to acetaldehyde, the so-called
Wacker process, is one of the best-known reactions catalyzed
by palladium(II).1 This transformation has proven to be a
versatile method for functionalization of olefins as exempli-
fied by the recently reported asymmetric oxidative Wacker
heterocyclization that provides an elegant entry to various
enantioenriched heterocycles.2 All these advances notwith-
standing, it is noteworthy that there have been only a few
examples of oxidative cyclization involving R,â-unsaturated
esters3 and, to the best of our knowledge, only one paper
has reported the palladium(II)-mediated oxidative cyclization
of conformationally rigidified 2-hydroxychalcones leading
to diverse flavone derivatives.4 Surprisingly, the process has
never been applied to structurally diverse â-hydroxyenones
despite the ready availability of these compounds as race-
mates or in enantiopure form. Given the enormous synthetic
potential of the corresponding 2,3-dihydro-4H-pyran-4-ones
that would be formed upon oxidative cyclization, this lack
of work in the area seems even more amazing.5 Herein we
report that the aforementioned palladium(II)-mediated trans-
formation is feasible and that it provides a rapid entry to
structurally diverse 2,3-dihydro-4H-pyran-4-ones. Our initial
studies of this process focused on developing an optimum
set of reaction conditions for the oxidative cyclization of the
â-hydroxyenone 1a (Table 1).
(1) (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ruttinger,
R.; Kojer, H. Angew. Chem. 1959, 71, 176-182. (b) Smidt, J.; Hafner, W.;
Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, J. Angew. Chem. 1962, 74, 93-
102. (c) Tsuji, J. Synthesis 1984, 369-384. (d) See also: Tsuji, J. Palladium
Reagents and Catalysts. InnoVations in Organic Synthesis; John Wiley &
Sons: New York, 1998, and references therein.
(2) (a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S. J. Am. Chem.
Soc. 1981, 103, 2318-2323. (b) Hosokawa, T.; Okuda, C.; Murahashi, S.
J. Org. Chem. 1985, 50, 1282-1287. (c) Uozumi, Y.; Kato, K.; Hayashi,
T. J. Am. Chem. Soc. 1997, 119, 5063-5064. (d) Uozumi, Y.; Kato, K.;
Hayashi, T. J. Org. Chem. 1998, 63, 5071-5075. (e) Arai, M. A.; Kuraishi,
M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907-2908. (f)
Thorarensen, A.; Palmgren, K.; Itami, K.; Backwall, J.-E. Tetrahedron Lett.
1997, 38, 8541-8544. (g) Itami, K.; Palmgren, A.; Thorarensen, A.;
Backwall, J.-E. J. Org. Chem. 1998, 63, 6466-6471. (h) Cotton, H. K.;
Verboom, R. C.; Johansson, L.; Plietker, B. J.; Backwall, J.-E. Organo-
metallics 2002, 21, 3367-3375. (i) Trend, R. M.; Ramtohul, Y. K.; Ferreira,
E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892-2895.
The key to success lies in the correct choice of catalyst,
solvent, and coreagents to favor the oxidative cyclization
(3) Auclair, S. X.; Morris, M.; Sturgess, M. A. Tetrahedron Lett. 1992,
33, 7739-7742.
(4) Kasahara, A.; Izumi, T.; Ooshima, M. Bull. Chem. Soc. Jpn. 1974,
47, 2526-2528.
(5) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407-2474.
Danishefsky, S. J.; Biolodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1380-1419. Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997,
97, 2063-2192. Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558-
3588.
10.1021/ol0361296 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/10/2003

Table 1. Optimization Studiesa
entry
Pd source (mol %)
co-oxidant (mol %)
additive (10 mol %)
solvent
conversion (%)
1
2
3
4
5
6
7
8
9
PdCl2 (10)
PdCl2 (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
benzoquinone (400)
benzoquinone (400)
benzoquinone (400)
none
none
none
Na2HPO4
none
DME
DME
DME
DME
DME
DME
DME
DME
DME
toluene
100
90
50
20
73
7
0
60 (89c)
1
0
Pd(TFA)2 (5)
Pd(OAc)2 (5)
PdCl2 (10)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
PdCl2 (10)
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
b
Na2CO3
Na2HPO4
none
PdCl2 (10)
Pd(TFA)2 (5)
b
10
Na2CO3
pyridined
a All reactions were carried out with 1 atm of O2 at 50 °C for 20 h. b Performed with 200 mol %. c Conversion after 40 h. d Performed with 20 mol %.
rather than the direct Michael addition.6 The effect of various
reaction parameters (catalyst, solvent, co-oxidant, additives
such as base or salts, solvent) on the conversion of a repre-
sentative enone into the corresponding adduct was examined
(Table 1). The oxidative cyclization of enone 1a, readily
prepared by an aldol reaction of 3-penten-2-one with hydro-
cinnamaldehyde in 79% isolated yield, was first attempted
under the conditions traditionally applied for a Wacker-type
oxidation using palladium(II) chloride/copper(I) chloride/
oxygen in DME. Under these conditions, all the starting
material was converted into the desired product 2a (entry
1). The absence of Na2HPO4 resulted in slightly lower con-
version (90%) (entry 2). Substituting PdCl2 for Pd(TFA)2
or Pd(OAc)2 while keeping all other parameters constant
induced a marked decrease in the conversion (entries 3 and
4). It was also found that the use of the organic oxidant
benzoquinone in place of CuCl was not beneficial, indepen-
dent of the Pd source and the additive (entries 5-7). A
catalytic Pd(II) oxidation using O2 as the sole stoichiometric
oxidant was also attempted (entry 8). Gratifyingly, this
reaction delivered the desired product albeit with reduced
conversion (60%) after 20 h. The conversion could be
improved to 89% by leaving the reaction for 40 h. For this
transformation, the presence of 10 mol % Na2HPO4 was
essential (entry 9). Finally, we investigated the possibility
of promoting the cyclization of 1a into 2a using the reaction
conditions applied by Stoltz et al. for the Pd-catalyzed
aerobic cyclization of phenol-alkenes.2i We found that under
these conditions, no product was formed (entry 10).
Under our optimized conditions, the oxidative cyclization
of various substituted â-hydroxyenones now occurs smoothly
(Table 2).
(E)-1a, which was completely converted into the desired
product 2a after only 4 h at 50 °C. After purification, 2a
was isolated in 79% yield (entry 1). Changing the geometry
of the enone did not affect the transformation, as 2a could
also be obtained from the enone (Z)-1a with a chemical yield
of 59% (entry 2). The reaction does not tolerate the presence
of a substituent on the vinylic carbon adjacent to the carbonyl
group. Indeed, the presence of a methyl group on this position
is sufficient to suppress the reaction, with only starting
material being recovered after 20 h at 50 or 80 °C (entry 3).
This result is in agreement with the lack of reactivity
observed for MeCOCMedCH2 toward the intermolecular
palladium(II)-catalyzed acetalization with alcohols or diols.7
In contrast, the preparation of 1-substituted 2,3-dihydro-4H-
pyran-4-ones such as 2a and 2c-f was successful, the
isolated yields typically ranging from 43 to 86%. In this
series, the phenyl-substituted â-hydroxy enone 1e was the
least reactive since the initial stage of this transformation
involves disruption of the conjugated system between the
carbonyl and phenyl group; this reaction therefore required
an extended reaction time to afford 2e in an isolated chemical
yield of 43% (entry 6). In contrast, the 1-alkyl 2,3-dihydro-
4H-pyran-4-ones were all prepared with chemical yields
superior to 75%. For substrate 1g possessing an unsubstituted
terminal enone functionality, a side product identified as the
acyclic reduced enone 3 was also formed (entry 8). A similar
side product has not been observed with the other substrates.
We have also successfully applied the methodology for
the preparation of hepialone (()-2h, a natural pheromonal
component of the male moth, isolated from Hepialus hecta
L. (entry 9).8 Interestingly, we have not detected the for-
mation of a Michael adduct for any of the substrates studied
herein. With the success of the oxidative cyclization on
It became quickly apparent that the reaction times could
be significantly reduced for some substrates such as the enone
(7) Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S. J. Org. Chem.
1987, 52, 1758-1764.
(6) For conversion of enones into â-benzyloxy ketones or â-amido
ketones, see: Hosokawa, T.; Shinohara, T.; Ooka, Y.; Murahashi, S. Chem.
Lett. 1989, 11, 2001-2004. Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001,
3, 25-28.
(8) For other multistep syntheses of 2h, see for example: (a) Dreeâen,
S.; Schabbert, S.; Schaumann, E. Eur. J. Org. Chem. 2001, 245-251. (b)
Uchino, K.; Yamagiwa, Y.; Kamikawa, T.; Kubo, I. Tetrahedron Lett. 1985,
26, 1319-1320.
92
Org. Lett., Vol. 6, No. 1, 2004

Scheme 1. Preparation and Oxidative Cyclization of (S)-1a
into (S)-2a
Table 2. Oxidative Cyclization of â-Hydroxy Enones
Scheme 2. Proposed Mechanism for the Cyclization of 1g
a Unoptimized yield.
racemic â-hydroxyenones, we could then investigate the
stereochemical integrity of enantiopure enone 1a upon oxi-
dative cyclization into the corresponding 2,3-dihydro-4H-
pyran-4-one 2a (Scheme 1).
Enone 1a was prepared in three steps from the ketoester
4 using as the key step a Baker’s yeast-mediated catalytic
asymmetric reduction to afford the â-hydroxy ester (S)-5.9
Functional group manipulation of (S)-5 afforded the enone
(S)-1a with an overall yield of 56% and an enantiomeric
excess of 97%. Under our optimized cyclization conditions,
we found that the desired product was formed with an enan-
tiomeric excess of 97% thereby proving that this palladium-
(II)-mediated oxidative cyclization occurs with no detectable
racemization.
Although the exact details of the mechanism are unclear,
a plausible proposal for the oxidative cyclizations reported
herein is presented in Scheme 2.
Initial alkene binding to the electrophilic PdCl2 could lead
to a π-alkene-palladium complex, which could activate the
enone toward intramolecular nucleophilic attack. The latter
process would lead to a palladium(II) enolate being formed,
which could coordinate to palladium either through the
carbon atom (σ-alkyl) or through the oxygen (η3-oxoallyl).10
Subsequent â-hydride elimination would produce HPdX,
which would eliminate HX and allow Pd0 to reenter the
catalytic cycle after oxidation by molecular oxygen and CuCl.
The dibasic disodium hydrogen phosphate probably acts as
a proton scavenger. We did not observe the formation of a
Michael adduct. Such a species could be formed by proto-
(10) (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T. J.
Am. Chem. Soc. 1979, 101, 494-496. (b) Albeniz, A. C.; Catalina, N. M.;
Espinet, P.; Redon, R. Organometallics 1999, 18, 5571-5576. (c) Sodeoka,
M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648-2649. (d)
Sodeoka, M.; Tokunoh, R.; Miyazaki, F.; Hagiwara, E.; Shibasaki, M. Synlett
1997, 463-466. (e) Vicente, J.; Abad, J. A.; Chicote, M. T.; Abrisqueta,
M. D.; Lorca, J. A.; Ramirez de Arellano, M. C. Organometallics 1998,
17, 1564-1568.
(9) Athanasiou, N.; Smallridge, A. J.; Trewhella, M. A. J. Mol. Catal.
B: Enzym. 2001, 11, 893-896.
Org. Lett., Vol. 6, No. 1, 2004
93

nolysis of the cyclic palladium enolate. In this catalytic
cycle, it is possible that ligand exchange can occur prior to
â-hydride elimination, allowing transfer of a palladium-hy-
dride species onto the starting enone upon reductive elimina-
tion. This new C-bound palladium enolate can undergo
protonolysis to afford the reduced acyclic enone 3. This
second pathway can account for the formation of the side
product 3 observed upon cyclization of enone 1g and could
be regarded as a palladium-catalyzed disproportionation of
the reactant 1g.
In conclusion, we have developed a palladium-mediated
route to structurally diverse 2,3-dihydro-4H-pyran-4-ones.
These compounds are more often prepared using a concerted
or stepwise hetero-Diels-Alder (HDA) reaction of aldehydes
with Danishefsky’s dienes catalyzed by various Lewis acids.
The stepwise HDA reactions of carbonyl compounds present
similarities with our approach, as both strategies involve a
â-hydroxyenone as the key intermediate. Interestingly, the
oxidation state of carbons 2 and 3 within the products is
established within the starting dienes for the HDA route,
whereas in our approach, the oxidation state of these two
carbons is addressed in the cyclization step. Therefore, with
this novel palladium(II)-mediated cyclization process in hand,
â-hydroxy-enones such as 1a-h can now be regarded as
common precursors for the preparation of both the corre-
sponding tetrahydro-4H-pyrano-4-ones via a Michael addi-
tion process and the 2,3-dihydro-4H-pyran-ones using a
Wacker-type oxidative cyclization. Efforts to expand the
scope of the process to other heterocycles are ongoing in
our laboratory.
Acknowledgment. This work was generously supported
by The Leverhulme Trust (grant to S.R.) and the EPSRC
(grant to M.R.). The authors also thank Dr. J.M. Brown
(Dyson Perrins Laboratory, Oxford) for very helpful discus-
sions on the reaction mechanism.
Supporting Information Available: Experimental details
for all substrates 1a-h and reaction products 2a-h. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0361296
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Org. Lett., Vol. 6, No. 1, 2004