Regiocontrolled Wacker Oxidation of Cinnamyl Azides

Article abstract of DOI:10.1021/acs.orglett.8b00344

A highly regioselective Wacker oxidation has been developed for the oxidation of cinnamyl azides. The catalytic oxidation tolerates the azide functionality, and more than 15 β-azido ketones were isolated (25-92% yield). High regioselectivity for the aryl ketone is observed in all cases. A robustness screen was conducted to determine functional group tolerance. The products of the oxidaiton can be readily diversified.

Full text of DOI:10.1021/acs.orglett.8b00344

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regiocontrolled Wacker Oxidation of Cinnamyl Azides
Angela S. Carlson, Cristian Calcanas, Ryan M. Brunner, and Joseph J. Topczewski*
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: A highly regioselective Wacker oxidation has been developed
for the oxidation of cinnamyl azides. The catalytic oxidation tolerates the azide
functionality, and more than 15 β-azido ketones were isolated (25−92%
yield). High regioselectivity for the aryl ketone is observed in all cases. A
robustness screen was conducted to determine functional group tolerance.
The products of the oxidaiton can be readily diversified.
zides are an attractive functional group due to their
versatile reactivity, which provides a distinct handle for
substrates, and classically, the ketone product is obtained.
However, chemists have struggled to deliver Wacker oxidation
methods that provide high selectivity for the oxidation of
internal alkenes. This is best illustrated by examining the
oxidation of β-methylstyrene (Scheme 2i). While styrene
A
further functionalization.1 Our laboratory has been interested in
exploiting the unique rearrangement of allylic azides.2,3 We are
therefore interested in identifying catalyzed protocols that are
compatible with an allylic azide. It would be exciting to
demonstrate the compatibility of allylic azides with ubiquitous
palladium catalysis. The Wacker oxidation, as a classic
palladium-catalyzed alkene functionalization, seemed a logical
choice for exploration. No Wacker oxidations of allylic azides
have been reported. It was not initially clear that an allylic azide
would be compatible with oxidative conditions.4,5 The azide
could react with the metal center directly and inhibit the
reaction or poison the catalyst. Allylic azides are known to
rearrange, which could further complicate the Wacker
oxidation.2,6,7 However, such a reaction could provide efficient
catalytic access to β-azido-ketones.
Scheme 2. Wacker Oxidation of Internal Alkenes
The β-azido-ketone motif has been used as a heterocycle
precursor, an intermediate for total syntheses, and a
pharmaceutical building block (Scheme 1).8−13 Additionally,
Scheme 1. β-Azido-Ketone Syntheses and Applications
oxidation affords acetophenone with near perfect selectiv-
ity,20−22 the oxidation of β-methylstyrene is only modestly
selective for phenylacetone.23,24 Recent progress has enabled
the regioselective oxidation of some internal alkenes. Most
notable are contributions from the laboratories of Grubbs and
Sigman (Scheme 2ii).24−28 We hypothesized that an allylic
azide could serve as the proximal functionality in a
regioselective oxidation. This work describes the Wacker
oxidation of cinnamyl azides using oxone as the stoichiometric
oxidant. The aryl ketone is obtained in high regioselectivity in
all cases (Scheme 2iii).
In these studies, we used a number of precautions when
working with azides. Azides are known to be potentially
explosive. No incidents were encountered in this work. Safety
shields were used for all reactions and operations, including
rotary evaporation.29 No azides were synthesized that contain
the β-azido-ketone has been used as a triplet nitrene
source.14−16 Typically, this motif is synthesized by conjugate
addition of an azide anion or by displacement of sensitive β-
halo-ketones.12,17,18
The Wacker oxidation has been widely utilized both
Received: January 30, 2018
industrially and academically.19 Terminal alkenes are excellent
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00344
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
fewer than nine carbons, which is a common rule of thumb
used for determining the stability of an azide.1,30 If working
with more than 1 g of azide, we recommend that a more
detailed safety analysis, such as TGA and DSC, be conducted
prior to scale-up.
Scheme 3. Robustness Screen
Initial efforts focused on identifying a highly reactive catalyst
(Table 1). We were inspired by the observations of Grubbs that
a
Table 1. Optimization of the Wacker Oxidation
b
entry
[Pd]
AgX
additive(s)
yield (%)
1
2
3
4
5
6
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
0
33
39
18
40
73
51
59
71
67
80
AgOTf
AgSbF6
AgBF4
AgNO3
AgNO3
BQ
c
7
BQ, KNO3
BQ
8
9
BQ, KNO3
BQ
d
10
AgNO3
AgNO3
e
11
BQ
a
a
Reaction conditions: substrate (60 μmol), naphthalene standard (12
A = additive % remaining; S = starting material % remaining; P =
product % formed. Reported values determined by GC−FID analysis.
A and S were determined based on a single point calibration. P was
calibrated by linear regression. Values reported are the average of
duplicate trials. Benzaldehyde was observed as the major product. 4-
Phenyl-2-butanone was observed as the major product.
μmol), [Pd] (6 μmol, 10 mol %), AgX (15 μmol, 25 mol %),
benzoquinone (12 μmol, 20 mol %), Oxone (180 μmol, 3 equiv),
water (50 μL), MeCN (400 μL), under air, room temperature.
b
b
c
Conversion and yield were determined by calibrated GC−FID
analysis. Reactions were run in duplicate, and the average value is
c
reported. Reaction was conducted with 1.2 equiv of benzoquinone
d
and no Oxone. Reaction was run using double the volume of water
e
(100 μL). Oxone was added portionwise.
the reaction beyond those represented below (Scheme 4),
without the need to synthesize numerous substrates. The full
test set, plus a few additional additives, is shown in Scheme 3.
Several of the functional groups were well tolerated, including a
free alcohol (3a), nitrile (3b), ketone (3c), heterocycle (3d),
alkyl halide (3e), and aryl halide (3f). Readily oxidized
functional groups, such as aniline (3g), furan (3h), pyrrole
(3i), and benzaldehyde (3j), were degraded. Acetal 3l
hydrolyzed to benzaldehyde. Terminal alkenes (3m) under-
went Wacker oxidation faster than the cinnamyl azide, and
alkynes inhibited the reaction (3n and 3o). Additionally, as
would be expected for an electrophilic metal center, good
ligands inhibited the catalysts (3p−q). In some cases, these
limitations could be overcome. For instance, 2,6-lutidine (3r)
was not as strong of an inhibitor, and acetanilide (3s) was
tolerated even though aniline was not.
A variety of substrates were examined (Scheme 4). The
cinnamyl azides are directly available from commercial
benzaldehydes.33 Cinnamyl azide was oxidized in comparable
yield to the model substrate (2b). Other electronically neutral
or methylated aryl rings provided acceptable yields (2c−f).
Double ortho-substitution was tolerated, and ketone 2g was
isolated in moderate yield. More electron-rich aryl rings were
the preferred substrates (2h−n). Even though benzyl acetal 3l
was hydrolyzed, the BOM acetal present in 2n was compatible
with the reaction. Halogenated arenes showed variable
compatibility with the Wacker oxidation (2o−r). A more
electron deficient aryl ring provided a diminished yield (2s).
We did not observe the α-azido ketone isomer in any of these
reactions.
“ligand free” cationic palladium complexes could achieve the
desired oxidation.26 Preliminarily, Pd(PhCN)2Cl2 was used as a
convenient precatalyst, and a variety of silver salts were added
(entries 1−5). Chloride ions exhibit strong coordination, and
no Wacker oxidation was observed with the precatalyst alone
(entry 1). Oxidation of the azide to the corresponding
cinnamaldehyde was observed as a background reaction.4,5
However, in the presence of silver(I) salts, the desired Wacker
oxidation was observed (entries 2−5). Presumably, halogen
abstraction generates a more reactive cationic palladium ion in
situ. The conversion and yield increased with all of the
examined noncoordinating counterions. This suggests the
formation of solvated Pd2+(MeCN)4 and a presumed leveling
effect under the aqueous conditions. The addition of catalytic
quantities of benzoquinone was advantageous (entry 5 vs 6).
When benzoquinone was used as the stoichiometric oxidant,
the yield was diminished (entry 7). Furthermore, control
experiments revealed that silver is not necessary (entry 8) and
that the nitrate ion is beneficial (entry 8 vs 9). Lastly, the
procedure could be further optimized by reducing the amount
of water used as a cosolvent and by adding the oxone
portionwise to slow the background oxidation (entry 10 vs 11).
The final procedure was conducted on the benchtop and uses
readily available materials.
To determine the functional group tolerance of this Wacker
oxidation, the robustness screen advocated by Glorius was
performed (Scheme 3).31,32 The additive approach provided
the ability to rapidly assess the impact of functional groups on
B
DOI: 10.1021/acs.orglett.8b00344
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Substrate Scope of Azide-Directed Wacker Oxidation
a
Yields are of isolated and purified material. Values reported are the average of duplicate trials.
Conducting a Wacker oxidation on aliphatic azides was
complicated by the Winstein rearrangement of allylic azides
(Scheme 5).2,6,7 The equilibrium mixture of azides 4 and 5 was
Scheme 6. Gram-Scale Reaction and Diversification of
Products
Scheme 5. Wacker Oxidation on Equilibrating Azide
uses Oxone as the stoichiometric oxidant. A robustness screen
was conducted, which defines the limitations of this method.
Many substrates provide a high yield of the ketone product, and
this procedure can be conducted on a gram scale.
subjected to the reaction conditions. This reaction afforded an
acceptable yield of ketone 6, which was contaminated with
small quantities of the regioisomer 7. Azide 5 provided
aldehyde 8. Aldehyde 8 is not stable under the reaction
conditions, and a number of over oxidized products were
observed.
ASSOCIATED CONTENT
■
S
* Supporting Information
This procedure was easily conducted on a gram scale
(Scheme 6). The β-azido-ketone was readily diversifiable. The
ketone could be selectively reduced to provide alcohol 9.
Allylation of the ketone was successful without azide
elimination and afforded alcohol 10. A click reaction afforded
triazole 11.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00344.
Experimental procedures and characterization data
(PDF)
In conclusion, we developed a Wacker oxidation for cinnamyl
azides that provides the aryl ketone in excellent selectivity. This
procedure demonstrates the compatibility of allylic azides with
palladium catalysis. The procedure is conducted under air and
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jtopczew@umn.edu.
C
DOI: 10.1021/acs.orglett.8b00344
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(27) DeLuca, R. J.; Edwards, J. L.; Steffens, L. D.; Michel, B. W.;
Qiao, X.; Zhu, C.; Cook, S. P.; Sigman, M. S. J. Org. Chem. 2013, 78,
1682.
(28) Liu, B.; Jin, F.; Wang, T.; Yuan, X.; Han, W. Angew. Chem., Int.
Ed. 2017, 56, 12712.
Joseph J. Topczewski: 0000-0002-9921-5102
Notes
The authors declare no competing financial interest.
(29) See the Supporting Information for details.
(30) Brase, S.; Banert, K. In Organic Azides: Synthesis and
̈
Applications; John Wiley & Sons, Ltd., 2010.
(31) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597.
(32) Gensch, T.; Teders, M.; Glorius, F. J. Org. Chem. 2017, 82,
9154.
(33) Goswami, P. P.; Suding, V. P.; Carlson, A. S.; Topczewski, J. J.
Eur. J. Org. Chem. 2016, 2016, 4805.
ACKNOWLEDGMENTS
■
Financial support was provided by the University of Minnesota
and The American Chemical Society’s Petroleum Research
Fund (PRF No. 56505-DNI1). This research was supported by
the National Institute of General Medical Sciences of the
National Institutes of Health under Award No. R35GM124718.
We also acknowledge NIH Shared Instrumentation Grant No.
S10OD011952.
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DOI: 10.1021/acs.orglett.8b00344
Org. Lett. XXXX, XXX, XXX−XXX