Catalyst-controlled wacker-type oxidation: Facile access to functionalized aldehydes

Article abstract of DOI:10.1021/ja411749k

The aldehyde-selective oxidation of alkenes bearing diverse oxygen groups in the allylic and homoallylic position was accomplished with a nitrite-modified Wacker oxidation. Readily available oxygenated alkenes were oxidized in up to 88% aldehyde yield and as high as 97% aldehyde selectivity. The aldehyde-selective oxidation enabled the rapid, enantioselective synthesis of an important pharmaceutical agent, atomoxetine. Finally, the influence of proximal functional groups on this anti-Markovnikov reaction was explored, providing important preliminary mechanistic insight.

Full text of DOI:10.1021/ja411749k

Communication
pubs.acs.org/JACS
Catalyst-Controlled Wacker-Type Oxidation: Facile Access to
Functionalized Aldehydes
Zachary K. Wickens, Kacper Skakuj, Bill Morandi, and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute
of Technology, Pasadena, California 91125, United States
S
* Supporting Information
alkenes to overcome their poor innate selectivity and provide
methyl ketone products in high yield (Scheme 1B).4a,b
ABSTRACT: The aldehyde-selective oxidation of alkenes
bearing diverse oxygen groups in the allylic and
homoallylic position was accomplished with a nitrite-
modified Wacker oxidation. Readily available oxygenated
alkenes were oxidized in up to 88% aldehyde yield and as
high as 97% aldehyde selectivity. The aldehyde-selective
oxidation enabled the rapid, enantioselective synthesis of
an important pharmaceutical agent, atomoxetine. Finally,
the influence of proximal functional groups on this anti-
Markovnikov reaction was explored, providing important
preliminary mechanistic insight.
However, while major advances have been made in addressing
many other classical limitations of the Wacker process,5,6 the
development of a catalyst-controlled anti-Markovnikov Wacker
oxidation has seen only preliminary success.3,7 Work in this area
has focused on aliphatic alkene model systems, and no Wacker-
type oxidation has provided reliable aldehyde selectivity across
a wide range of allylic and homoallylic functional groups.3
A general, anti-Markovnikov oxidation of readily accessible
oxygen-containing alkenes would enable efficient access to
synthetically versatile polyfunctional building blocks. Further-
more, enantioenriched allylic and homoallylic alcohol deriva-
tives can be easily prepared via established synthetic routes.8
Due to the synthetic versatility of the aldehyde functional
group,9 a reliable aldehyde-selective Wacker would enable
diverse catalytic strategies to address the historical challenge10
of anti-Markovnikov alkene functionalization.11−13
Previous efforts to prepare functionalized aldehydes via
Wacker oxidations have exploited specifically tailored directing
groups to obtain substrate-controlled anti-Markovnikov selec-
tivity.14,15 Unfortunately, this approach lacks flexibility and
requires the synthetic route to be planned around the
installation and removal of directing auxiliaries. Furthermore,
reliance upon a narrow class of directing groups can result in
inherent synthetic incompatibilities. For example, although
allylic furfoyl esters provide high substrate-derived aldehyde
selectivity, allylic stereocenters are racemized by a reversible
palladium-catalyzed rearrangement.14f Moreover, functional
groups in the homoallylic position are rarely effective at
overcoming Markovnikov’s rule.3 Thus, a catalyst-controlled
method to oxidize diverse oxygen-containing alkenes to
aldehydes remains an elusive but highly desirable tool for
organic synthesis.16
he Tsuji−Wacker oxidation is a powerful synthetic tool
Tthat provides access to carbonyls from terminal alkenes.
The functional group tolerance, versatility, and reliability of this
transformation have led to its broad adoption within the
synthetic community.1 The regioselectivity of the Tsuji−
Wacker oxidation is substrate-controlled,2 and methyl ketone
products are typically favored in accord with Markovnikov’s
rule.1b,c However, this innate regioselectivity is sensitive to both
proximal coordinating groups and the steric environment
around the alkene.3 Thus, the ratio of aldehyde to ketone
products formed from oxidation of functionalized substrates
can be challenging to predict a priori (Scheme 1A).2,3 Sigman
and co-workers recently developed a Wacker-type oxidation
system that delivered catalyst-controlled ketone selectivity.2,4
This system was employed in the oxidation of functionalized
Scheme 1. (A) Tsuji−Wacker Conditions Provide a
Substrate-Dependent Mixture of Aldehydes and Ketones;
(B) Catalyst-Controlled Solutions to Markovnikov and Anti-
Markovnikov Regioselectivity in Wacker-Type Oxidations
We recently developed a nitrite-modified Wacker-type
catalyst system capable of reversing the innate Markovnikov
selectivity exhibited by aliphatic alkenes.7d Thus, we set out to
evaluate whether Lewis basic oxygen functional groups would
interfere with or enhance the aldehyde selectivity of the
reaction. In addition to its synthetic value, we anticipated that
this line of inquiry would also provide key mechanistic insight
into this newly developed nitrite-modified Wacker process.
A series of alkene-containing phenyl ether substrates of
varying chain length were subjected to both nitrite-modified
Received: November 18, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Wacker conditions and Tsuji−Wacker conditions to evaluate
the influence of proximal oxygen-containing functional groups
on the regioselectivity (Figure 1). The high anti-Markovnikov
Table 1. Influence of Oxygen Functionality on Wacker
Oxidations
a
Figure 1. Influence of phenoxy group proximity on regioselectivity in
Wacker-type oxidations. (Conditions A) Blue:7d PdCl2 (PhCN)2 (12
mol %), CuCl2·H2O (12 mol %), AgNO2 (6 mol %), t-BuOH/MeNO2
(15:1), rt, O2 (1 atm), 6 h. (Conditions B) Red:1b PdCl2 (10%), CuCl
(1 equiv), DMF/H2O (7:1), rt, O2 (1 atm), 24 h.
a
b
0.5 mmol of alkene (0.0625 M), 5 h. Yield of isolated aldehyde
c
selectivity exhibited by an unbiased substrate (1-dodecene)
under nitrite-modified Wacker conditions was markedly
enhanced as the ether moiety approached the alkene (Figure
1). Exceptional aldehyde selectivity (>90%) was observed with
both the allylic (n = 1) and homoallylic phenyl ether (n = 2),
despite the significant difference in the innate regioselectivity of
the two substrates under Tsuji−Wacker conditions. Moreover,
substrates bearing a distal ether functional group (n = 3)
retained the high regioselectivity observed in the unfunction-
alized systems. These encouraging results are consistent with a
catalyst-controlled process in which the selectivity is further
enhanced by proximal heteroatoms. Following this preliminary
success, we sought to optimize the reaction conditions. With
oxygenated alkenes, NaNO2 proved to be an effective and
inexpensive source of nitrite. This result stands in contrast to
our previous work with aliphatic substrates, where it was found
that AgNO2 enhanced the rate and selectivity.7d
To be a general catalyst-controlled methodology to access
functionalized aldehydes, the high anti-Markovnikov selectivity
must not be dependent on specific directing groups. With this
in mind, we examined a collection of substrates bearing
different oxygen-containing functional groups in both the allylic
or homoallylic position under the optimized conditions (Table
1). The oxidation of these substrates took place with high
aldehyde selectivity (89−96%), allowing the aldehyde product
to be isolated in prepartively useful yields (64−88%),
irrespective of the nature of the oxygen-containing functional
group. In particular, alkyl, aryl and silyl ethers, as well as acetyl
esters, were all well tolerated. For comparison, each substrate
was additionally subjected to Tsuji−Wacker conditions to
determine its innate selectivity. In contrast to the high anti-
Markovnikov selectivity observed across the series under
nitrite-modified Wacker conditions, the innate selectivity varied
greatly as a function of substrate. The excellent aldehyde
selectivity provided by the nitrite-modified Wacker oxidation of
homoallylic substrates is particularly notable due to their high
innate Markovnikov selectivity (≥80% ketone selective).
Notably, the selectivity was independent of the innate
product. Selectivity (aldehyde/ketone) obtained by 1H NMR analysis
of the unpurified reaction mixture. Reaction conditions:1b 0.1 mmol
d
of alkene, PdCl2 (10 mol %), CuCl (1 equiv), DMF/H2O (7:1,
e
0.125M), rt (20−25 °C), run to ≥95% conversion. Yield determined
f
by 1H NMR analysis of the unpurified reaction mixture. AgNO2 used
in place of NaNO2.
selectivity, clearly demonstrating catalyst-controlled regioselec-
tivity.
The success of this reaction with challenging, innately
ketone-selective homoallylic alcohol derivatives led to the
exploration of how the steric properties of this class of
substrates influences reactivity and selectivity (Table 2). Having
demonstrated that such substrates perform similarly in the
reaction irrespective of the substituent on oxygen, a benzyl
group was selected as a representative protecting group.
Variation at the α-position of the ether provided no significant
effect on yield or selectivity (Table 2, entries 1 and 2). Bulkier
substrates required an increased reaction time and replacement
of NaNO2 with the more active AgNO2 to provide an
analogous yield and selectivity (entries 4−9).
In order to assess the applicability of the process on a larger
scale, the reaction was attempted on a 4-g scale with a reduced
catalyst loading (eq 1). The reaction was 92% aldehyde
selective, delivering 71% of the aldehyde product. This result
suggests that the reaction will be readily amenable to producing
significant quantities of the desired aldehyde products.
A catalyst-controlled anti-Markovnikov Wacker oxidation
combined with established enantioselective methodologies
enables a powerful strategy to access versatile enantioenriched
building blocks. To demonstrate the utility of this synthetic
approach, we targeted atomoxetine, a norepinephrine reuptake
B
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Journal of the American Chemical Society
Communication
rates of functionalized and unfunctionalized substrates were
obtained in a series of one-pot intermolecular competition
experiments (Figure 2). Both functionalized substrates
Table 2. Influence of Steric Profile on Aldehyde-Selective
Wacker
a
Figure 2. Relative rates of oxidation to aldehyde as a function of
substrate under nitrite-modified Wacker conditions (see Table 1 for
conditions).
exhibited a substantial increase in the rate of aldehyde
formation relative to the unfunctionalized 1-dodecene. We
suspect that coordination of the Lewis basic oxygen atom to
palladium increases the rate since inductive effects would be
mitigated as the oxygen atom is moved further from the alkene.
To further probe the role of the oxygen atom, allylic and
homoallylic aryl ethers of varied electronic profiles were
prepared and evaluated under the reaction conditions.
Inductive effects have recently been demonstrated to play a
major role in determining regioselectivity in palladium-
catalyzed processes.5f,19 Interestingly, under the nitrite-modified
Wacker conditions, the aldehyde selectivity and rate are only
subtly influenced by electronic variation (Figure 3). The
a
b
0.5 mmol of alkene (0.0625 M), 5 h. Yield of isolated aldehyde
c
product. Selectivity (aldehyde/ketone) obtained by 1H NMR analysis
of the unpurified reaction mixture. 0.1 mmol of alkene, PdCl2 (10
d
mol %), CuCl (1 equiv), DMF/H2O (7:1, 0.125 M), rt (20−25 °C),
1
run to ≥95% conversion (24 h). Selectivity determined by H NMR
e
f
analysis. Yield determined by 1H NMR analysis. Isolated as an
g
inseparable mixture of aldehyde and ketone. 24 h reaction time
inhibitor approved for the treatment of attention deficit
disorder (Scheme 2).17 At the outset, one potential concern
a
Scheme 2. Synthesis of Atomoxetine
Figure 3. Selectivity and relative rates of oxidation to aldehyde as a
function of the substrate’s electronic properties under nitrite-modified
Wacker conditions (see Table 1 for conditions; 10 min reaction time).
a
(i) [Ir(COD)Cl]2 (1 mol %), (R,R,R)-(3,5-dioxa-4-phospha-cyclo-
hepta[2,1-a;3,4-a′]dinaphthalen-4-yl)bis(1-phenylethyl)amine (2 mol
%), THF, 50 °C, 16 h; (ii) PdCl2(PhCN)2 (10%), CuCl2·2H2O
(10%), AgNO2 (5%), t-BuOH/MeNO2 (15:1), O2 (1 atm), rt, 5 h;
(iii) NaBH3CN (2 equiv), MeNH3Cl (excess), rt, 24 h.
minimal inductive influence is consistent with an apolar, radical-
type addition.20−22 We have previously suggested a radical
mechanism to explain the anti-Markovnikov selectivity in light
of preliminary mechanistic experiments.23,24 In addition to
illustrating the minimal inductive influence on alkene oxidation,
these experiments suggest that electronic modulation does little
to enhance or mitigate the coordinating influence of the Lewis
basic oxygen functional groups.
In summary, this anti-Markovnikov, nitrite-modified Wacker
oxidation provides a facile route for the preparation of
functionalized aldehydes from a wide variety of oxygenated
alkenes. The reliability and versatility of the methodology bodes
well for its immediate application in target-oriented synthesis.
The potential of the transformation was illustrated in the rapid,
enantioselective synthesis of atomoxetine. Finally, key sub-
strate-derived influences on the regioselectivity were explored,
which provided important mechanistic information regarding
the interplay between catalyst and substrate control, which will
guide ongoing mechanistic evaluation of this important process.
with this approach was whether the stereocenter proximal to
the alkene would racemize under the nitrite-modified reaction
conditions. To test the viability of this route, cinnamyl alcohol
derivative A was transformed into chiral allylic ether B via a
highly enantioselective iridium-catalyzed allylic substitution
reaction.18 Upon treatment of B with the anti-Markovnikov
Wacker conditions, the corresponding aldehyde, C, was
produced in good yield. Subsequent derivatization via reductive
amination demonstrated that the targeted drug, D, could be
accessed without loss of enantiopurity over the course of the
synthetic sequence. The success of this strategy, particularly the
retention of stereochemical information at the allylic position,
showcases that the nitrite-modified Wacker oxidation is
compatible with well-established asymmetric methods and
provides access to valuable synthetic products in a modular,
catalytic manner.
To provide a foundation for further mechanstic study, we
next probed the substrate-derived factors that enhance the
catalyst-controlled aldehyde selectivity. To this end, the relative
C
dx.doi.org/10.1021/ja411749k | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368−3398.
(b) Hintermann, L. Top. Organomet. Chem. 2010, 123−155.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(12) Substrate-controlled aldehyde-selective Wacker oxidations have
been coupled to catalytic reductions to enable both formal anti-
Markovnikov hydration and hydroamination processes: (a) Dong, G.;
Teo, P.; Wickens, Z. K.; Grubbs, R. H. Science 2011, 333, 1609−1612.
(b) Bronner, S. M.; Grubbs, R. H. Chem. Sci. 2014, 5, 101−106.
(13) For selected examples of progress in anti-Markovnikov
functionalization: (a) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608−5609.
(b) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
2702−2703. (c) Hamilton, D. S.; Nicewicz, D. A. J. Am. Chem. Soc.
2012, 134, 18577−18580. (d) Nguyen, T. M.; Nicewicz, D. A. J. Am.
Chem. Soc. 2013, 135, 9588−9591. (e) Zhu, S.; Niljianskul, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746−15749.
AUTHOR INFORMATION
Corresponding Author
rhg@caltech.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Gordon and Betty
Moore Foundation, the NSF, and the Swiss National Science
Foundation for a fellowship to B.M.
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