Regioselective Wacker oxidation of internal alkenes: Rapid access to functionalized ketones facilitated by cross-metathesis

Article abstract of DOI:10.1002/anie.201303587

Wacka wacka: The title reaction makes use of a wide range of directing groups (DG) to enable the highly regioselective oxidation of alkenes, and occurs predictably at the distal position. Both E and Z alkenes afford valuable functionalized ketones and cross-metathesis was shown to facilitate the preparation of the starting materials. BQ=benzoquinone. Copyright

Full text of DOI:10.1002/anie.201303587

Angewandte
Chemie
DOI: 10.1002/anie.201303587
Synthetic Methods
Regioselective Wacker Oxidation of Internal Alkenes: Rapid Access to
Functionalized Ketones Facilitated by Cross-Metathesis**
Bill Morandi, Zachary K. Wickens, and Robert H. Grubbs*
Dedicated to Professor Erick M. Carreira on the occasion of his 50th birthday
Functionalized ketones are key synthetic intermediates in
target-oriented synthesis.[1] Important carbon–carbon bond-
forming processes such as the aldol or Mannich reactions have
enabled the preparation of hydroxyketones and aminoke-
tones.[2] These products are highly sought-after intermediates
in the preparation of natural products and drugs, and thus
represent key synthetic targets. Novel complementary
approaches to their synthesis are therefore in high demand.
Although alkene metathesis is a privileged carbon–carbon
forming reaction,[3] it has found only limited use in the
preparation of ketones.[4] This limitation is due to the lack of
an efficient methodology to catalyze the oxidation of internal
Scheme 1. Sequential cross-metathesis/regioselective Wacker oxidation
alkenes to carbonyls with regiocontrol. The ubiquitously
adopted palladium-catalyzed Tsuji–Wacker reaction would
be a logical tool to achieve this transformation.[5] However,
although recent advances in the field have been achieved,[6,7]
the Wacker oxidation still exhibits limited reactivity towards
internal alkenes and suffers from poor understanding of the
factors determining the regioselectivity. If those challenges
could be overcome, the synthetic power of the Tsuji–Wacker
oxidation of terminal alkenes could be translated to internal
alkenes. Such a desirable catalytic oxidation would enable
rapid access to functionalized ketones when coupled to the
carbon–carbon forming power of cross-metathesis (CM).
Herein, we report an efficient and regioselective prepa-
ration of functionalized ketones by an olefin cross-metathesis/
regioselective Wacker oxidation sequence (Scheme 1). A key
aspect of this work was the identification of a wide range of
directing groups for enabling a regioselective Wacker oxida-
tion of unsymmetrically substituted alkenes, specifically, an
oxidation which occurs predictably at the distal position.
Importantly, rapid access to the starting materials using E-
and Z-selective cross-metathesis was demonstrated. This
combined approach affords a powerful new tool for the
synthesis of versatile functionalized ketones and should find
applications in target-oriented synthesis.
for the preparation of functionalized ketones. BQ=benzoquinone.
At the outset of our investigations, we reasoned that the
allylic heteroatom placed in close proximity to the alkene
could provide an efficient handle to induce the desired
regioselectivity.[8] Previous examples of directed Wacker
oxidations of internal alkenes have been limited by low
yields, use of peroxide as oxidants, and high oxygen pressure,
and were limited in scope.[6,8] In addition, only recently have
efficient catalyst systems for the Wacker oxidation of internal
alkenes been developed.[6] In the classical Tsuji–Wacker
oxidation of terminal alkenes, phthalimide and ester directing
groups have been shown to direct an anti-Markovnikov attack
to form aldehydes from terminal alkenes.[9] Strikingly, a recent
report from Feringa and co-workers demonstrated the
inability of neutral palladium(II) complexes to oxidize
internal alkenes.[9b] Instead, internal allylic esters rearranged
to the corresponding terminal alkenes prior to oxidation. This
inherent limited reactivity of neutral palladium(II) complexes
towards internal alkenes prompted us to study our previously
reported, highly active dicationic palladium(II) system[6a] to
develop an efficient, regioselective Wacker oxidation of
unsymmetrical alkenes.
Initial preliminary experiments using an optimized sol-
vent system (DMA/MeCN/H2O) led to long reaction times
with incomplete conversion. Use of a binary solvent system
(MeCN/H2O) and acid[10] led to a much more active system
and full conversion was obtained. In contrast to the oxidation
of unfunctionalized alkenes, DMA is not necessary to prevent
isomerization in the presence of coordinating groups.[6a]
Having an efficient protocol in hand, we tested a selection
of simple monofunctionalized alkene substrates to efficiently
probe the influence of diverse groups on the regioselectivity
(Table 1). Allylic alcohol derivatives demonstrated that good
regioselectivity could be obtained using common protecting
[*] Dr. B. Morandi, Z. K. Wickens, Prof. Dr. R. H. Grubbs
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA 91125 (USA)
E-mail: rhg@caltech.edu
[**] We gratefully acknowledge financial support from the King Abdullah
University of Science and Technology Centre in Development, King
Fahd University of Petroleum and Minerals, the NSF, and the Swiss
National Science Foundation for a fellowship to B.M.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303587.
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Table 1: Initial scope of directing groups.[a]
Entry
1
Substrate
Product
Yield [%][b]
71
Sel.[c]
9:1
2
80
ꢀ20:1
3
4
5
80
80
83
ꢀ20:1
6.5:1
10:1
Scheme 2. Preparation and further screening of directing groups
enabled by cross-metathesis.
6
7
70
72
ꢀ20:1
ꢀ20:1
terminal unbranched allyl phthalimide offers dramatically
reduced regioselectivity compared to the branched allyl
phthalimide in the Tsuji–Wacker oxidation (6:4).[12] The
branched allylic phthalimide similarly afforded the product
with high regioselectivity and thus provides access to secon-
dary aminoketones. Overall, both branched and linear
protected amine and alcohol substrates enable a regioselective
Wacker oxidation to be performed.
Despite recent progress in the oxidation of internal
alkenes, Z alkenes have proven either inert or prone to
positional isomerization in Wacker-type oxidations.[13] Since
many olefination reactions produce either Z alkenes or
a mixture of both Z and E isomers, we sought to probe the
effect of alkene geometry upon the oxidation.[14] To this end, it
was critical to access the desired starting materials as
stereochemically pure Z isomers to clearly understand the
underlying isomeric dependence on the reaction outcome. We
thus exploited a new class of chelated ruthenium alkene
metathesis catalysts which exhibit exquisite kinetic control to
access the corresponding Z substrates (Scheme 3).[15]
[a] 1 mmol alkene, MeCN/H2O (7:1), 16 h. [b] Yield of isolated product.
[c] Sel.=distal oxidation/proximal oxidation. Determined by 1H NMR
analysis. DG=directing group. Bz=benzoyl, Ts=4-toluenesulfonyl.
groups, such as benzyl (Bn; 9:1). Introduction of a benzoate
group increased the regioselectivity to greater than or equal
to 20:1. This result is particularly interesting in light of
potential known side reactions of allylic esters, such as the
well-established palladium-catalyzed allylic substitution and
rearrangement.[11] For example, the recent report from
Feringa and co-workers shows a strong preference for allylic
rearrangement over oxidation of internal alkenes.[9b]
A
branched allylic benzoate afforded a similar excellent result
and thus bodes well for the use of more elaborated substrates
(entry 3). We then explored the ability of homoallylic
functionalities to direct the oxidation reaction, since the
corresponding oxidation products are not readily accessible
by traditional carbon–carbon forming processes. Synthetically
viable regiocontrol for the distal oxidation product was
obtained with up to greater than or equal to 20:1 selectivity
(entries 4–6). Interestingly, this approach is not limited to
protected alcohols, as an b,g-unsaturated methyl ester
afforded the distal oxidation product (entry 6). An allylic
NHTs group gave the corresponding aminoketone derivative
in high regioselectivity, thus expanding the reaction scope to
nitrogen-derived directing groups (entry 7).
We were pleased to find that the chelated catalyst could
cleanly prepare the desired Z substrates from allyl benzoate
and allyl phthalimide in good yields and greater than 95%
With a regioselective Wacker oxidation of internal
alkenes in hand, we sought to illustrate the power of
a combined cross-metathesis/regioselective Wacker sequence
in the preparation of hydroxy- and aminoketones (Scheme 2).
Moreover, the coupling with cross-metathesis presented an
opportunity to further probe the predictability of the
regiocontrol using other directing groups. An allylic carbon-
ate and two allylic phthalimides (a common amine protecting
group) were readily accessed using the Grubbs–Hoveyda
second-generation catalyst (1). The linear substrates afforded
high regiocontrol for the distal oxidation product in the
subsequent Wacker oxidation. This control is critical, as the
Scheme 3. Demonstration of an efficient regioselective Wacker oxida-
tion of Z substrates enabled by Z-selective cross-metathesis. THF=te-
trahydrofuran.
2
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Z selectivity. These two products were then smoothly trans-
formed into the corresponding ketones in high regioselectiv-
ity and yield, comparable to the results obtained for the
E isomers. These results thus establish that the efficiency of
our oxidation protocol towards E alkenes also applies to
Z alkenes.
With an interest in further probing the synthetic utility of
the metathesis/regioselective Wacker sequence, we explored
this strategy in the context of the bioactive, polyfunc-
tionalized alkene starting material capsaicin (Scheme 4a).[16]
Scheme 5. Qualitative study of inductive effects on the relative rate
and regioselectivity using both a) intermolecular and b) intramolecular
competition experiments. Yield is that of the isolated product.
tionally, an allylic OBn was tested to uncover the effect of this
group on the relative rate. The benzyl group is more electron-
donating than the acyl substituents previously tested. This
OBn substrate was oxidized with an increased rate and gave
lower selectivity, and is thus consistent with the inductive
trend previously observed. To further probe the effect of
electron density on the relative oxidation rate, an intra-
molecular competition experiment using a substrate bearing
both an allylic OBn and an allylic 4-NO2-BzO was performed.
The product from the oxidation of the most electron-rich
position (distal to the 4-NO2-BzO) group), was oxidized with
a remarkable greater than 20:1 regioselectivity. This outcome
supplements the results of the intermolecular experiments
and demonstrates that protecting-group selection can enable
selective oxidation, even when potentially competing direct-
ing groups are proximal to the alkene. Benzoyl and benzyl
groups are orthogonal protecting groups, and thus, this result
will have significant implications in target-oriented synthesis.
Overall, although we initially anticipated the regioselectivity
might be chelation controlled, the observed rate and selec-
tivity trend indicates that the regioselectivity of the process
has a significant inductive component.[19,20] An inductive
model is also consistent with the selectivity obtained with the
more electron-withdrawing benzoate as compared to the
homoallylic benzyl-protected alcohol and will provide a guide
to the selectivity of other Wacker-type oxidations.[21] For
example, Sigman and co-workers recently demonstrated
strong directing effects with allylic substituents in the
oxidation of internal alkenes by a coordinatively saturated
palladium catalyst in combination with peroxide oxidants.[6d]
Further studies will be necessary to fully elucidate the origin
of the regioselectivity in Wacker-type processes.
Scheme 4. Applications of the novel synthetic sequence to a polyfunc-
tionalized target as well as in the selective functionalization of a seed
oil derivative.
We were delighted to see that both steps worked in good
yields, and the regioselectivity of the Wacker step proved to
be as high as in the more simple examples. No interference
with the directing ability of the benzoate moiety was
observed, thus validating the potential of this strategy for
complex-molecule functionalization. We envisioned this
methodology could also enable rapid generation of function-
alized molecules from inexpensive and renewable seed oil
derivatives (Scheme 4b).[17] Oleyl alcohol could be selectively
transformed into two substituted allylic benzoate substrates
using the catalyst 1. The two intermediates could further be
oxidized in high selectivity to the corresponding ketones
under our standard oxidation conditions.
Finally, we explored the origin of regioselectivity of our
protocol. We took advantage of the synthetic flexibility
offered by the benzoate aromatic moiety to qualitatively
study the electronic effects of the substituents on the reaction
outcome. Competition experiments were performed between
the allylic benzoate derivative and the corresponding 4-NO2
and 4-MeO derivatives. The relative rates are shown in
Scheme 5, with a rate following the order of NO2 < H < MeO.
This long-range electronic effect suggests the significant
buildup of a positive charge in the transition state.[18] Addi-
In conclusion, we have described a new synthetic strategy
to regioselectively access complex ketone products from
simple starting materials. A wide range of functionalized
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alkenes were established as efficient substrates for a regiose-
lective Wacker oxidation of internal alkenes, thus producing
valuable synthetic intermediates (hydroxyketones, aminoke-
tones, ketoesters). Efficiency of our regioselective Wacker
oxidation protocol was demonstrated using both E and
Z isomers prepared by cross-metathesis. Application to the
functionalization of a bioactive natural product and seed oil
derivatives showcased the potential of this cross-metathesis/
regioselective Wacker strategy in target-oriented synthesis.
An intriguing long-range inductive dependence was shown by
competition experiments and has important implications for
future applications. Overall, the high functional-group toler-
ance of both the cross-metathesis step and the Wacker
oxidation, combined with the predictable regioselectivity of
the oxidation step, holds great promise in the wide adoption
of this strategy in organic synthesis.
Received: April 27, 2013
Revised: June 9, 2013
Published online: && &&, &&&&
[11] a) This result emphasizes the need for further mechanistic study
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9038; b) Handbook of Organopalladium Chemistry for Organic
Synthesis (Ed.: E.-I. Negishi), Wiley, Hoboken, 2002.
Keywords: ketones · metathesis · oxidation · palladium ·
regioselectivity
.
[12] See ref. [7].
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4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Angewandte
Chemie
Communications
Synthetic Methods
B. Morandi, Z. K. Wickens,
R. H. Grubbs*
&&&& — &&&&
Regioselective Wacker Oxidation of
Internal Alkenes: Rapid Access to
Functionalized Ketones Facilitated by
Cross-Metathesis
Wacka wacka: The title reaction makes
use of a wide range of directing groups
(DG) to enable the highly regioselective
oxidation of alkenes, and occurs predict-
ably at the distal position. Both E and
Z alkenes afford valuable functionalized
ketones and cross-metathesis was shown
to facilitate the preparation of the starting
materials. BQ=benzoquinone.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!