Discovery of a practical direct O2-coupled wacker oxidation with Pd[(-)-sparteine]Cl2

Article abstract of DOI:10.1021/ol061662h

The discovery of a direct O₂-coupled Wacker oxidation with use of balloon pressure of O₂ and low catalyst loading is described. Use of (-)-sparteine as a ligand on Pd prevents olefin isomerization and leads to selective formation of methyl ketones from terminal olefins in good yields. Oxidation of enantiomerically enriched substrates is reported with no observed racemization.

Full text of DOI:10.1021/ol061662h

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4117-4120
Discovery of a Practical Direct
O2-Coupled Wacker Oxidation with
Pd[(−)-sparteine]Cl2
Candace N. Cornell and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112-0850
sigman@chem.utah.edu
Received July 6, 2006
ABSTRACT
The discovery of a direct O2-coupled Wacker oxidation with use of balloon pressure of O2 and low catalyst loading is described. Use of
)-sparteine as a ligand on Pd prevents olefin isomerization and leads to selective formation of methyl ketones from terminal olefins in good
(
−
yields. Oxidation of enantiomerically enriched substrates is reported with no observed racemization.
The Wacker oxidation, wherein a terminal olefin is converted
to a methyl ketone, is an industrially and synthetically
important transformation that has been extensively studied.1,2
However, even with numerous methods available, the need
for an improved and versatile Wacker oxidation is demon-
strated in recent syntheses which required the use of 0.25
equiv to stoichometric amounts of Pd and Cu.3,4 As a specific
example, Leighton and co-workers used two Wacker oxida-
tions in their synthesis of Dolabelide D (Figure 1). While
they were able to perform these oxidations with catalytic
Pd, 25 mol % loading was required.
Figure 1. Recently reported Wacker oxidations in Leighton’s
synthesis of Dolabelide D.
(1) (a) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel,
A. Angew. Chem. 1962, 74, 93-102. For reviews on Wacker oxidations
see: (b) Takacs, J. M.; Jiang, X.-t. Curr. Org. Chem. 2003, 7, 369-396.
(c) Tsuji, J. Synthesis 1984, 369-384.
Due to the complex nature of standard Wacker reactions
(i.e., excess Cu salts and/or other cocatalysts), it is difficult
to improve the reaction conditions systematically and ration-
ally. Therefore, our goal was to eliminate the need for co-
oxidants by using a ligand on Pd, thus simplifying the method
while also providing an adjustable reaction parameter. Herein
we report the discovery and application of a direct O2-
coupled Wacker oxidation catalyzed by Pd[(-)-sparteine]-
Cl2 wherein the choice of solvent has a profound effect on
olefin isomerization and selection of terminal oxidant.
Our initial forays into developing Wacker catalysts led to
the use of tert-butyl hydroperoxide (TBHP) as the terminal
(2) For recent book chapters on Wacker oxidations see: (a) Monflier,
E.; Mortreux, A. In Aqueous-Phase Organometallic Catalysis, 2nd ed.;
Cornils, B., Herrmann, W. A., Eds.; Wiley-VHC: Weinheim, Germany,
2004; pp 481-487. (b) Hintermann, L. In Transition Metals for Organic
Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VHC: Weinheim,
Germany, 2004; Vol. 2, pp 379-388. (c) Jira, R. In Applied Homogeneous
Catalysis with Organometallic Compounds, 2nd ed.; Cornils, B., Herrmann,
W. A., Eds.; Wiley-VHC: Weinheim, Germany, 2002; Vol. 1, pp 386-
405.
(3) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126, 10264-
10266.
(4) Schmidt, D. R.; Park. P. K.; Leighton, J. L. Org. Lett. 2003, 5, 3535-
3537. For the total synthesis of Dolabelide D, see: Park, P. K.; O’Malley,
S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128, 2796-
2797.
10.1021/ol061662h CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/05/2006

oxidant and catalyst 5 (Pd(IiPr)(OTs)2) employing an N-
heterocyclic carbene ligand in the conversion of styrenes to
acetophenone derivatives.5 When evaluating decene as a
substrate under these reaction conditions, oxidation is ob-
served but a mixture of regiomeric ketones is formed due to
rapid olefin isomerization (Scheme 1). Substrate isomeriza-
methylstyrene was submitted to the reaction conditions with
Pd[(-)-sparteine]Cl2 as the catalyst. The formation of 4′-
methylacetophenone is observed in high selectivity and GC
yield (eq 1).
Scheme 1. Decene Oxidation with in Situ Formed
Pd(IiPr)(OTs)2 (5) and TBHP(aq) in MeOH
On the basis of this success, Pd[(-)-sparteine]Cl2 was then
evaluated as a catalyst for decene oxidation with TBHP(aq)
in MeOH. Unfortunately, low chemo- and regioselectivity
was again observed. Therefore, we decided to evaluate DMF
as a solvent which, classically, has been shown to increase
olefin miscibility and enhance selective methyl ketone
formation.1b,c,6a Surprisingly, no conversion of decene was
observed in DMF with catalytic Pd[(-)-sparteine]Cl2 and
TBHP(aq), but decene isomerization had been eliminated, even
upon heating to 70 °C for 24 h. On the basis of this obser-
vation, N-methyl-2-pyrrolidinone (NMP) and N,N-dimeth-
ylacetamide (DMA) were evaluated as solvents. To our
delight, conversion of decene to 2-decanone was observed
with no detectable olefin isomerization over the course of
the reaction with use of 5 mol % Pd[(-)-sparteine]Cl2 at 70
°C (eq 2).
tion is common with general Wacker conditions. For
example, oxidation of terminal straight chain aliphatic
alkenes with 10 mol % PdCl2, 2 equiv of CuCl in 7 to 1
DMF to H2O under an O2 atmosphere leads to 3-10%
formation of isomeric carbonyl compounds.1c,6 The relative
selectivity for methyl ketone formation is not neccessarily
reflective of the high rate of olefin isomerization. Tang and
co-workers have shown the rate of olefin isomerization is
over 30-fold greater than the rate of olefin oxidation, but
the terminal olefin reacts significantly faster than internal
olefins, leading mainly to methyl ketone formation.6b Under
our current reaction conditions, the catalytic system promotes
oxidation of all olefin isomers, leading to the production of
2-, 3-, and 4-decanone.
Upon scaling, catalyst decomposition was observed based
on a black precipitate and diminished conversions, prompting
several control experiments with unanticipated results. TBHP
is not necessary for oxidation of the olefin, but enhances
the reaction rate and selectivity (Table 1, entries 1 vs 4). An
To improve the selectivity for methyl ketone formation,
dative ligands, counterions, and solvents were probed. Initial
evaluation of pyridine and Et3N as ligands on Pd, commonly
used in Pd-catalyzed aerobic alcohol oxidations,7 did not
promote the Wacker oxidation and initially led us away from
investigating other dative amine ligands. However, our recent
report profiling the propensity for Pd[(-)-sparteine]Cl2 to
form stable monocationic species in solution,8 and the
observed olefin activation with Pd[(-)-sparteine]Cl2 in
hydroalkoxylation reactions9 and oxidative acetal formation,10
led us to evaluate this bidentate amine ligand under our
Wacker-type oxidation conditions with TBHP. Thus, 4-
Table 1. Discovery of a Direct O2-Coupled
Pd[(-)-sparteine]Cl2-Catalyzed Wacker Oxidation of Decene
(5) Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 2796-
2797.
(6) (a) Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241-
243. (b) Tang, H. G.; Sherrington, D. C. J. Mol. Catal. 1994, 94, 7-17. (c)
Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39,
8765-8768.
(7) For reviews on Pd-catalyzed aerobic alcohol oxidations see: (a)
Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221-229. (b)
Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420. (c) Stoltz, B. M.
Chem. Lett. 2004, 33, 362-367. (d) Muzart, J. Tetrahedron 2003, 59, 5789-
5816.
entry
∆ conditions
% convn
% GC yield
1
2
3
4
5
6
7
8
9
std
no Pd
N2
99
0
63
46
94
0
17
33
8
89b
89
55
59
no TBHPa
no TBHPa/N2
Pd(CH3CN)2/a/O2
O2
21
99(9 h)
98(9 h)
95(6.5 h)
74(6.5 h)
Pd(CH3CN)2/no TBHPa/O2
no TBHPa/O2
(8) Mueller, J. A.; Cowell, A.; Chandler, B. D.; Sigman, M. S. J. Am.
Chem. Soc. 2005, 127, 14817-14824.
(9) Gligorich, K. M.; Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc.
2006, 128, 2794-2795.
a H2O added. b At 4 h, 80% convn >60% of remaining SM was internal
olefin isomers, but only product was 2-decanone.
(10) Balija, A. M.; Stowers, K. J.; Schultz, M. J.; Sigman, M. S. Org.
Lett. 2006, 8, 1121-1124.
4118
Org. Lett., Vol. 8, No. 18, 2006

anaerobic atmosphere (N2) leads to significantly decreased
methyl ketone formation (entry 3). In contrast, a pure O2
atmosphere leads to an increase in reaction rate and does
not compromise selectivity (entry 7). Complete removal of
TBHP and use of a balloon atmosphere of O2 resulted
in the discovery of a direct O2-coupled Wacker oxidation
with no observable olefin isomerization by GC (entry 9).
(-)-Sparteine as a ligand also plays a significant role, as
Pd(CH3CN)2Cl2 promotes significant isomerization of the
substrate during the reaction and Pd metal precipitates from
the mixture, but unlike our previous system, methyl ketone
is the only product observed (entries 6 and 8). It should be
noted that Kaneda and co-workers have recently reported a
similar system using catalytic Pd(CH3CN)2Cl2 in DMA/H2O
mixtures that requires 6 atm of O2.11
Having discovered a system with promising scope, we now
wanted to challenge the system with substrates substituted
at the allylic or homoallylic position. The substrates were
chosen to not only model those employed by Leighton and
co-workers (Figure 1), but to probe functional group toler-
ance of the system further. Dihydromyrcenol (6), which
contains allylic substitution and a tertiary alcohol, was
successfully oxidized to the corresponding methyl ketone
(Table 3, entry 1). Upon scaling this transformation to 7.5
Table 3. Wacker Oxidation of Allylic and Homoallylic
Substituted Olefins
Optimization of the reaction conditions for a direct O2-
coupled Pd[(-)-sparteine]Cl2-catalyzed Wacker oxidation led
to the use of 1 mol % Pd[(-)-sparteine]Cl2 with 0.2 M
substrate in a 4:1 DMA:H2O mixed solvent system under
balloon pressure O2 with vigorous stirring at 70 °C (Table
2). Increasing the concentration of H2O enhances the reaction
Table 2. Initial Scope of the Pd[(-)-sparteine]Cl2-Catalyzed
Direct O2-Coupled Wacker Oxidation
a Average isolated yield of multiple experiments. b 2.5 mol
%
Pd-[(-)-sparteine]Cl2. c 7.5 mmol scale. d 8:1 DMA:H2O. e 1.0 mol %
Pd[(-)-sparteine]Cl2. f 5.0 mol % Pd-[(-)sparteine]Cl2, 80 °C, 0.15 M.
mmol from a standard 0.8 mmol scale, a slight enhancement
in isolated yield was obtained (entry 2). Oxidation of the
homoallylic alcohol 7 again showcases that olefin oxidation
is preferred in this system even in the presence of an activated
benzylic alcohol (entry 3). The predominant byproducts of
the oxidation with 7 are Wacker cyclization isomers.
Therefore, the homoallylic silyl and PMB protected alcohols
were evaluated and led to good yields (entries 4 and 5). It
should be noted that even though the catalyst is chiral, no
kinetic resolution of the racemic substrates is observed. An
allylic ether, known to be a problematic substrate in Wacker
oxidations,3,12 was also evaluated. Though only a 34% yield
was achieved with substrate 10 (an intermediate in Crimmins’
and co-workers’ synthesis of Ophirin B),3 the potential for
significant improvement over current methods employing
stoichiometric Hg, Pd, and Cu is still noteworthy.
a Average isolated yield of multiple experiments. b Isolated yield re-
flects purity of SM (internal olefins). c 6:1 DMA:H2O. d 2.0 mol %
Pd[(-)-sparteine]Cl2. e 2.5 mol % Pd-[(-)sparteine]Cl2.
rate, but must also be balanced with substrate miscibility
and catalyst stability. Balloon pressure air is tolerated with
a decreased concentration of H2O to avoid catalyst decom-
position (6:1 DMA:H2O) (entry 2). The chemoselectivity is
highlighted by evaluating a substrate containing an olefin
and a primary alcohol where olefin oxidation occurs in
preference to alcohol oxidation, even though Pd[(-)-spar-
teine]Cl2 is known to oxidize alcohols at elevated temper-
atures (entry 4).7,8 By evaluating cis-4-decene (entry 5), the
chemoselectivity of this method is further showcased in that
both olefin isomerization and internal olefin oxidation are
eliminated. Additionally, both a methyl ester and acetal
functional group were tolerated (entries 6 and 7).
Similar enantiomerically enriched substrates were evalu-
ated to determine if racemization occurs under the current
Wacker conditions.13 Enantiomerically enriched substrate
(S)-7 was converted to the corresponding methyl ketone in
a slightly diminished yield but no racemization is observed
(12) Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim,
T.-H. J. Org. Chem. 1995, 60, 4678-4679.
(13) Enantiomercially enriched 1-hydroxy-1-phenyl-3-butanone was
synthesized by using the method reported in: Lee, J.-Y.; Miller, J. J.;
Hamilton, S. S.; Sigman, M. S. Org. Lett. 2005, 7, 1837-1839.
(11) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481-485.
Org. Lett., Vol. 8, No. 18, 2006
4119

Finally, no racemization is observed in the conversion of an
allylic ether to the corresponding carbonyl (entry 4).
Table 4. Wacker Oxidation of Enantiomerically Enriched
In summary we have discovered a ligand modulated direct
O2-coupled Wacker oxidation that operates at ambient
pressures of O2. The substrate scope and chemoselectivity
of the system is highlighted by the functional group tolerance
and ability to oxidize enantiomerically enriched substrates
with no racemization. Discovery of a direct O2-coupled
Wacker oxidation will allow the first mechanistic studies on
a Wacker oxidation that does not require additives to be
performed. This and further evaluation of the potential utility
of this direct O2-coupled Wacker oxidation method are
currently underway.
Substrates
Acknowledgment. This work is supported by the Na-
tional Institute of Health (NIGMS RO1 GM3540). M.S.S.
thanks the Dreyfus Foundation (Teacher-Scholar) and Pfizer
for their support. We are grateful to Johnson Matthey for
the gift of various Pd salts.
a Average isolated yield of multiple experiments. b 1.0 mol % Pd-[(-)-
sparteine]Cl2. c 4.1 mmol scale. d 5.0 mol % Pd-[(-)sparteine]Cl2, 80 °C,
0.15 M.
(Table 4, entry 1). Both the PMB and TBS protected alcohols
were excellent substrates for the Wacker oxidation with
>80% isolated yields and no racemization (entries 2 and 3).
The relatively low catalyst loadings (compared to 25%) and
elimination of co-oxidants vastly improves the practicality
of Wacker oxidations of protected homoallylic alcohols.
Supporting Information Available: Experimental pro-
cedures and characterization data for products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061662H
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