Synthesis of α-Borylated Ketones by Regioselective Wacker Oxidation of Alkenylboronates

Article abstract of DOI:10.1021/acs.orglett.8b02234

As part of a program aimed at metal-catalyzed oxidative transformations of molecules with carbon-metalloid bonds, the synthesis of α-borylated ketones is reported via regioselective TBHP-mediated Wacker-type oxidation of N-methyliminodiacetic acid (MIDA)-protected alkenylboronates. The observed regioselectivity correlates with the hemilabile nature of the B-N dative bond in the MIDA boronate functional group, which allows boron to guide selectivity through a neighboring group effect.

Full text of DOI:10.1021/acs.orglett.8b02234

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α‑Borylated Ketones by Regioselective Wacker
Oxidation of Alkenylboronates
Victoria B. Corless,† Aleksandra Holownia,† Hayden Foy,‡ Rodrigo Mendoza-Sanchez,† Shinya Adachi,†
Travis Dudding,*,‡ and Andrei K. Yudin*,†
†Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6,
Canada
‡Department of Chemistry, Brock University, 1812 Sir Isaac Brock Way, St. Catherines, ON L2S 3A1, Canada
S
* Supporting Information
ABSTRACT: As part of a program aimed at metal-catalyzed oxidative
transformations of molecules with carbon−metalloid bonds, the synthesis of
α-borylated ketones is reported via regioselective TBHP-mediated Wacker-
type oxidation of N-methyliminodiacetic acid (MIDA)-protected alkenylbor-
onates. The observed regioselectivity correlates with the hemilabile nature of
the B−N dative bond in the MIDA boronate functional group, which allows
boron to guide selectivity through a neighboring group effect.
he reactivity of organoboron reagents is defined by the
oxidant (Table 1, entries 1−4). However, no oxidation of the
TLewis acidity of boron, which can attenuate the alkenyl MIDA boronates was observed. We then explored
TBHP-mediated Wacker-type oxidation using the Pd(Quinox)-
Cl2 catalyst reported by Sigman and co-workers, given its
previous success with internal systems.23 We were pleased to
observe that, although initial conversion was low, oxidation of 1a
(Table 1, entry 5) proceeded with high regioselectivity and
resulted in exclusive oxidation at the benzylic position to give 2a.
The remaining mass balance was unreacted starting material.
The same conditions were applied to pinacol boronic ester 1v
and trifluoroboronate 1w; however, both compounds were
incompatible with the reaction conditions. Decomposition was
observed in both cases after mixing with the peroxide, which
suggested that the MIDA derivative behaved as an outlier.
To rule out steric direction in the experimentally observed
regioselectivity, the reaction was repeated with R groups
possessing A values similar to those of the MIDA boronate,
which was computed to be 2.40 kcal/mol (see Supporting
Information (SI)). (E)-3-Methyl-1-phenyl-1-butene and (E)-1-
tert-butyl-2-phenylethene were subjected to the aforementioned
conditions. In the case of (E)-1-tert-butyl-2-phenylethene, only
starting material was recovered after prolonged reaction times,
with no trace of the ketone products. Oxidation of (E)-3-methyl-
1-phenyl-1-butene resulted in an approximate 10:1 mixture of
regioisomeric ketone products, with the major isomer identified
as 3-methyl-1-phenylbutan-2-one.
nucleophilicity of the C−B bond. Boronic esters are used as
key intermediates in many fundamental synthetic processes
where the nucleophilic nature of the C−B bond enables
formation of various C−C, C−O, C−S, and C−N linkages. The
N-methyliminodiacetic acid (MIDA) protecting group has seen
widespread application as it masks boron’s Lewis acidity through
a dative B−N bond, forming a stabilized tetracoordinate
boronate complex that tolerates a range of reaction con-
ditions.1−14
Given our long-standing interest in the chemistry of
amphoteric α-boryl aldehydes, we sought to develop a route
to MIDA-protected α-borylated ketones. We opted to pursue
oxidation of borylated alkenes. The Wacker−Tsuji oxidation is
an established protocol for the oxidation of terminal alkenes to
methyl ketones. Recent advances in this area have extended this
oxidative catalysis to internal alkenes, although regioselectivity is
often problematic.15−19 We therefore sought to explore the
effects of the MIDA boronate substitution in this context. A
recent study from our group determined that the hemilability of
the B−N bond modulates the reactivity of the boronate group in
boron transfer reactions.20 We were motivated to explore the
role of the MIDA ligand in influencing regioselectivity, due to
either the neighboring group effect as a result of the hemilabile
nature of the B−N bond or the electronic direction as a result of
the nucleophilic C−B bond.21,22 Herein, we report the role of
MIDA boronates in guiding the highly regioselective oxidation
of borylated alkenes to access α-borylated ketones.
The generality of the reaction was probed through a substrate
scope, the results of which are displayed in Scheme 1. Alkenes
substituted with aliphatic R groups (1d−f,n,p) and aromatic
rings bearing electron-donating groups (1g−i) were converted
to the corresponding ketones with good conversion and high
selectivity. Oxidation of aliphatic alkenes was achieved at a lower
To the best of our knowledge, there have been no reports
wherein a metal-catalyzed oxidation has been performed on a
boron-containing alkene, delivering an oxygenated end point
with preservation of the C−B bond. We initially attempted the
synthesis of desired α-borylated ketones using PdCl2 and
Pd(OAc)2 catalysts and molecular oxygen or TBHP as the
Received: July 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02234
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
additive
solvent
temperature (°C)
yield (%)
1
2
3
4
5
6
7
Pd(OAc)2 (5 mol %)
Pd(OAc)2 (5 mol %)
PdCl2 (5 mol %)
Pd(OAc)2 (5 mol %)
Pd(Quinox)Cl2 (5 mol %)
Pd(Quinox)Cl2 (10 mol %)
Pd(Quinox)Cl2 (15 mol %)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
TBHP
TBHP
TBHP
TFA
CuCl2
CuCl2
DMF/H2O 7:1
DMF/H2O 7:1
DMF/H2O 7:1
DMF
CH2Cl2
CH2Cl2
50
50
50
rt
rt
rt
0
0
0
0
AgSbF6 (12.5 mol %)
AgSbF6 (15 mol %)
AgSbF6 (20 mol %)
20 (11)
65 (58)
75 (70)
TBHP
CH2Cl2
rt
a
b
Reactions were carried out using 0.10 mmol 1a (0.1 M) and monitored for 18 h. TBHP (70% aq) was used (12 equiv). Determined by 1H NMR
analysis (isolated yields are given in parentheses).
products in terminal alkenes following Markovnikov’s rule.23−28
No aldehyde was observed when 3,3-dimethylbut-1-ene was
subjected to the same reaction conditions. Additionally,
oxidation of allyl MIDA boronate (Scheme 1, 1t) resulted in
the Markovnikov ketone product (Scheme 1, 2t). This reversal
in regioselectivity as a result of direct boronate substitution was
somewhat unexpected in light of previous studies23,25,26,29 but
supported our initial hypothesis.
Scheme 1. Substrate Scope for the Synthesis of α-Borylated
Ketones
The selectivity of the TBHP-mediated Wacker oxidation of
alkenyl MIDA boronates was investigated by DFT analysis at the
B3LYP/Lan2DZ (IEFPCM = dichloromethane) level of theory
using Gaussian 09.30 Emerging from these calculations were
transition states TS(Ph)-I and TS(Ph)-II, which correspond to the
lowest-energy α- and β-carbon addition modes of the peroxide
to the coordinated alkene 1a (see Figure 1 and SI). Transition
state structures in which the MIDA ligand was coordinated to
the palladium center through a Pd−O interaction could not be
located. The relative free energy barriers of TS(Ph)-I and TS(Ph)
-
II were computed to be 15.0 and 19.8 kcal/mol, respectively.
TS(Ph)-I was favorable by 1.9 kcal/mol relative to starting
reagents and the Pd(Quinox) catalyst, which is consistent with
the observed experimental β-selectivity.
Contributing to this energetic difference was a steric contact
between the alkene and tert-butyl group of TBHP in TS(Ph)-II as
seen by a H···H distance of 2.31 Å (Figure 1) and noncovalent
interaction plots (see SI). In addition to sterics, computational
analysis discerned underlying electronic factors contributing to
α- versus β-selectivity. NBO analysis revealed stabilizing donor−
acceptor orbital interactions amounting to 16.7 kcal/mol
involving electron donation from a d-orbital of Pd and the C−
Pd σ bond to a p-orbital of boron in TS(Ph)-I (Figure 2). Also
a
10 mol % of Pd(Quinox)Cl2 and 12 mol % of AgSbF6 were used.
b
c
NMR yield. Decomposition observed.
10 mol % catalyst loading, likely due to decreased steric
congestion in the catalyst’s coordination sphere. For more
hindered alkenes, a decrease in conversion, though not in
selectivity, was observed. Meta-substituted phenyl rings
(1h,k) showed a decrease in conversion relative to that of
their para analogues. Ortho substitution (1i,m) was not
tolerated. For alkenes bearing electron-deficient aromatic rings
(1j−l), a decrease in conversion was also observed,24 though the
reaction still proceeded with high regioselectivity. For alkenes
1c,i,m,o,r,s,u, the oxidation did not proceed at all, most likely
due to a high degree of steric congestion around the alkene.
Interestingly, when vinyl MIDA boronate (Scheme 1, 1q) was
subjected to the TBHP-mediated Wacker-type conditions, the
oxidation resulted in formation of the α-boryl aldehyde (anti-
Markovnikov product) with no trace of the acyl boronate
(Markovnikov product). The Pd(Quinox)Cl2 reportedly
operates under catalyst control, yielding single regioisomeric
products in electronically biased alkenes and methyl ketone
present was a smaller in magnitude donor−acceptor σ(C−B)
→
d(Pd)* interaction, which provided 2.7 kcal/mol of stabilization.
Similar donor−acceptor orbital interactions were not present in
TS(Ph)-II. Nucleophilic attack at the β-carbon of TS(Ph)-I was
also accompanied by electrons from the double bond being
shuttled toward the MIDA boronate, resulting in a buildup of
electron density at the α-carbon. Consistent with this were the
computed NBO charges of −0.778e and −0.613e at the α-
carbon of TS(Ph)-I and its precomplex (PC(Ph)-I), respectively.
From these results, it is apparent that the boron of MIDA
contributes to the preorganization of reaction components
through a stereoelectronic neighboring group effect, yielding
single regioisomeric products. To eliminate the possibility that
regioselectivity is attained as a result of benzylic attack of the
nucleophile, calculations were carried out using vinyl MIDA
boronate, and similar results were obtained (see SI).
B
DOI: 10.1021/acs.orglett.8b02234
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Finally, to rule out a reaction pathway in which α- versus β-
regioselective addition is directed through complete decoordi-
nation of the MIDA ligand, TS(Ph,O)-I was computed to be the
preferred mode of addition (Figure 3). Surprisingly, TS(Ph,O)-I
Figure 3. TS(Ph,O)-I involving regioselective direction as a result of the
hemilabile nature of the MIDA B−N dative bond.
was 7.4 kcal/mol lower in energy than TS(Ph)-I. The most
striking feature of this structure is a cooperative H-bond
bridging the TBHP, hydroxyl bound boron, and protonated N
atom. The competitiveness of this addition mode, nevertheless,
is unlikely given that the computed barrier for water-promoted
MIDA opening of borylated alkene 1a was ∼22.6 kcal/mol. This
value is also consistent with the ∼26.1 kcal/mol reported barrier
for water-promoted MIDA opening in the absence of a proximal
intramolecular donor group.31
In summary, we report a highly selective route to MIDA-
protected α-borylated ketones from borylated alkenes. The
palladium-catalyzed TBHP-mediated Wacker oxidation of
MIDA alkenylboronates is thought to proceed through the
well-defined oxypalladation mechanism, previously established
by Sigman and co-workers.24 Computational analysis indicates
Figure 1. Lowest-energy transition states for the regioselective attack of
the TBHP nucleophile at the α- and β-carbon.
Figure 2. NBO analysis showing stabilizing donor−acceptor orbital interactions in TS(Ph)-I between boron and palladium, resulting in regioselective
attack of the peroxide at the β-carbon.
C
DOI: 10.1021/acs.orglett.8b02234
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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effect derived from the hemilabile nature of the MIDA B−N
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the boron atom. Ultimately, this directing group effect guides
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This method was applied to a number of borylated alkenes and
provides a mild and facile route to α-boryl ketones. Given the
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boronate will have a similar directing effect in other settings.
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ASSOCIATED CONTENT
* Supporting Information
■
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ACS Publications website at DOI: 10.1021/acs.orglett.8b02234.
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Experimental procedures and characterization of prod-
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AUTHOR INFORMATION
Corresponding Authors
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■
2011, 133, 8317−8325.
(25) Michel, B. W.; McCombs, J. R.; Winkler, A.; Sigman, M. S.
Angew. Chem., Int. Ed. 2010, 49, 7312−7315.
*E-mail: tdudding@brocku.ca.
*E-mail: ayudin@chem.utoronto.ca.
ORCID
(26) McCombs, J. R.; Michel, B. W.; Sigman, M. S. J. Org. Chem. 2011,
76, 3609−3613.
(27) Sigman, M. S.; Michel, B. W. Aldrichimica Acta 2011, 44, 55−75.
(28) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S. J.
Am. Chem. Soc. 2009, 131, 6076−6077.
Travis Dudding: 0000-0002-2239-0818
Andrei K. Yudin: 0000-0003-3170-9103
Notes
(29) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S. J.
Am. Chem. Soc. 2009, 131, 6076−6077.
The authors declare no competing financial interest.
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Houk, K. N.; Leach, A. G.; Cheong, P. H.-Y.; Burke, M. D.; Lloyd-Jones,
G. C. Nat. Chem. 2016, 8, 1067−1075.
ACKNOWLEDGMENTS
■
A.K.Y. acknowledges financial support from the Natural Science
and Engineering Research Council (NSERC). T.D. acknowl-
edges financial support from the Natural Science and Engineer-
ing Research Council (NSERC) Discovery grant (2014-04410).
The authors would like to thank Ms. Joanne Tan for her
synthetic contributions, and Dr. Darcy Burns and the NMR staff
at the University of Toronto for their assistance.
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DOI: 10.1021/acs.orglett.8b02234
Org. Lett. XXXX, XXX, XXX−XXX