Oxidative geminal functionalization of organoboron compounds

Article abstract of DOI:10.1002/anie.201206501

Excellent tolerance: Stable acylboronates equipped with N-methyliminodiacetyl (MIDA) boryl groups ([B]) were prepared by using a sequence of oxidative manipulations at the boron-bound carbon center (green in scheme). Chemoselective transformations of these acylated organoboron building blocks yielded a range of multifunctionalized boron derivatives and supplied access to valuable borylated heterocycles (see scheme). Copyright

Full text of DOI:10.1002/anie.201206501

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DOI: 10.1002/anie.201206501
Synthetic Methods
Oxidative Geminal Functionalization of Organoboron Compounds**
Zhi He, Piera Trinchera, Shinya Adachi, Jeffrey D. St. Denis, and Andrei K. Yudin*
Dedicated to Professor George A. Olah on the occasion of his 85th birthday
Organoboronic acids and their derivatives are widely utilized
building blocks in chemical synthesis.[1] The reactivity of these
molecules is due to the accessibility of the vacant p orbital at
the trivalent boron center. This Lewis acidity, however, is
a “double-edged sword”, since sp2-hybridized boron species
are often too reactive to survive chemical transformations
during late-stage functional-group manipulation. The emer-
gence of stable tetracoordinate organoboron derivatives, such
as organotrifluoroborates[2] and N-methyliminodiacetyl
(MIDA) boronates,[3] as boronic acid surrogates has opened
up new opportunities to address this problem. The corre-
sponding organoboron compounds are stable under a variety
of conditions wherein other functional groups are chemo-
selectively transformed, thereby leaving the boryl function-
ality available for downstream transformations.[4,5] The tetra-
coordinate nature of the sp3 boron center in these molecules
inhibits undesired reactions typical of trivalent organoboron
compounds.
In our recent contribution, we described the preparation
of configurationally stable a-boryl acids.[6] In the present
study, we opted to utilize the Barton radical decarboxylation,
Table 1: Preparation of MIDA a-hydroxyboronates.[a]
Starting Material
R
Product
Yield [%][b]
1a
1b
2a
2b
73
70
1c
2c
50
1d
1e
2d
2e
70
71
Recent development of MIDA boronate derived a-boryl
aldehydes/carboxylic acids[6] and their pinene analogues[7] has
further highlighted the prominent effect of sp3 boron centers
in chemoselective transformations. While functional-group
manipulations remote to the tetracoordinate boryl groups are
well-documented, geminal functionalization, particularly oxi-
dative transformation directly at the a-position of the boron
center, has remained underexplored.[4r,5g] Herein, we describe
a decarboxylative conversion of a-boryl carboxylic acids to a-
hydroxyboronates that have enabled access to stable MIDA
acylboronates through oxidation of the hydroxy group. This
new class of acylboronates was found to be suitable for
chemoselective synthesis of a range of heterocyclic boronate
building blocks. Of note is the facility with which function-
alities that are sensitive to classical lithiation–borylation
protocols (for instance, unprotected amines) can be handled
by using this new method. Our work should encourage the
development of additional examples where boron-containing
heterocycles are accessed by means other than established
metal-based approaches.
1 f
1g
1h
1i
2 f
2g
2h
2i
32
32
35
29
[a] The reactions were carried out using: step 1) a-borylcarboxylic acid
(1.0 equiv), N-hydroxypyridine-2-thione (1.2 equiv), DCC (1.2 equiv), and
DMAP (0.05 equiv) in anhydrous CH2Cl2 at 238C for 12 h; step 2) O2
bubbling, tBuSH (9.0 equiv), irradiation with 250 W tungsten-halogen
light at 238C for 2–8 h; step 3) (MeO)3P (2.0 equiv) at 238C for 2 h.
[b] Yields of isolated products after silica gel chromatography.
DCC=N,N’-dicyclohexylcarbodiimide. DMAP=4-dimethylaminopyri-
dine.
which is a well-established method to replace carboxylic acids
with other functional groups,[8,9] as a test reaction to evaluate
the feasibility of a-hydroxyboronate preparation. MIDA a-
borylcarboxylic acid 1a (Table 1, entry 1) was first converted
to the corresponding thiohydroxamate ester under standard
DCC/DMAP coupling conditions. The resulting bright-yellow
ester solution was then bubbled with O2 gas in the presence of
tBuSH while being irradiated under tungsten-halogen light.
Upon irradiation, the a-boryl radical species derived from the
photoinduced decomposition of the thiohydroxamate ester
was trapped by molecular oxygen and converted to the a-
boryl hydroperoxide intermediate. The final reductive treat-
ment of the reaction mixture with trimethylphosphite
[*] Z. He, P. Trinchera, Dr. S. Adachi, J. D. St. Denis,
Prof. Dr. A. K. Yudin
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George St. Toronto, ON, M5S 3H6 (Canada)
E-mail: ayudin@chem.utoronto.ca
[**] We would like to thank Natural Science and Engineering Research
Council (NSERC) and Canadian Institutes of Health Research
(CIHR) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206501.
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afforded the desired MIDA a-hydroxyboronate 2a in 73%
yield. Although compounds containing a gem-hydroxyboron
motif have been reported,[10] these molecules equipped with
a tetracoordinate boron center are unprecedented.
The successful synthesis of compound 2a prompted us to
expand the scope of the preparative procedure (Table 1). It
was found that alkyl-substituted substrates generally afforded
the desired MIDA a-hydroxyboronates in good yields. How-
ever, the starting a-borylcarboxylic acids with aryl substitu-
ents resulted in the isolation of products with low yields (29–
35%), which are possibly due to delocalization of the a-boryl
radical to the aromatic ring, thereby triggering the generation
of unidentified by-products. It is worth pointing out that,
although the carbon-centered radicals with ordinary trivalent
a-boronic ester substituents are known intermediates in
a range of reactions,[11] ours is the first report of a chemical
transformation involving a-boryl radicals connected to the sp3
boron center.
With a-hydroxyboronates in hand, we questioned the
possibility of alcohol oxidation as a general means of
accessing acylboronic compounds, a class of scarce but
highly valuable synthetic building blocks.[12] Tetracoordinate
boron centers have been shown to be stable under oxidative
conditions leading to the formation of remote aldehyde or
ketone functionalities from alcohols;[4p,5h] however, the cor-
responding oxidation at the carbon atom equipped with the
boryl group is unprecedented. To examine the feasibility of
this novel transformation, a-hydroxyboronate 2a was first
subjected to the Ley oxidation (TPAP/NMO; TPAP = tetra-
propylammonium perruthenate, NMO = 4-methylmorpho-
line N-oxide).[13] Encouragingly, the desired MIDA acylboro-
nate 3a was isolated from the reaction by using a large
amount of TPAP (50 mol%). Lower TPAP loading (e.g.
5 mol%) failed to afford the desired product. An increase in
reactiom time led to significant decomposition. The ineffi-
ciency of this process prompted us to examine milder
oxidants. To our delight, the reaction between 2a and
a stoichiometric amount of Dess–Martin periodinane[14] in
CH2Cl2 smoothly afforded the acylboronate 3a as a white
powder that was stable in air after silica gel chromatography
in 70% yield (Scheme 1). To test the generality of this process,
different a-hydroxyboronates were also subjected to the
Dess–Martin oxidation (Scheme 1). Alkyl- and aryl-substi-
tuted substrates were all tolerated and the corresponding
acylboronates were isolated in good yields. Importantly, no
oxidative cleavage of the carbon–boron bond was observed in
this process.
Scheme 1. Preparation of MIDA acylboronates through Dess–Martin
oxidation. The reactions were carried out using a-hydroxyboronate
(1.0 equiv), Dess–Martin periodinane (1.1 equiv) in CH2Cl2 at 238C for
0.5 h. All yields in parentheses are yields of isolated products after
silica gel chromatography.
Scheme 2. Transformations of MIDA acylboronates. m-CPBA=meta-
chloroperoxybenzoic acid. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
TMSOTf=trimethylsilyl trifluoromethanesulfonate.
revealing a stronger migratory aptitude of the tetracoordinate
MIDA boron center compared to alkyl or aryl substituents.
Given the fact that an analogous 1,2-boryl migration also took
place in the BF3-promoted rearrangement of oxiranyl MIDA
boronates to generate a-boryl aldehydes,[6c] the MIDA boryl
group is likely to find additional applications in organic
synthesis owing to its potential in migratory transformations.
The exposure of acylboronates 3a and 3b to strong
oxidant Br2 in dioxane/CH2Cl2 resulted in the corresponding
a-bromination products 5a and 5b in good yields with the
carbon–boron bond remaining intact. The ease of a-bromi-
nation of MIDA acylboronates attests to their enolization
capability. For further validation, the 1-(silyloxy)vinylboro-
nates 6a and 6b were synthesized by treating the starting
We next turned our attention to the stability and reactivity
of MIDA acylboronates. To test the tolerance of their carbon–
boron bonds towards chemical transformations, various
MIDA acylboronates were subjected to a range of conditions
(Scheme 2). Treatment of compounds 3c and 3 f with
m-CPBA afforded good yields of stable acyloxyboronate
products 4b and 4a, respectively. Unlike ordinary acyloxy-
boranes, which are a class of unstable strong Lewis acids,[15]
compounds 4a and 4b are stable in air and can be purified
using silica gel chromatography. These results unambiguously
indicated the occurrence of a Baeyer–Villiger transformation
that proceeded by the migration of the boryl group, thus
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acylboronates 3b and 3c with TMSOTf in the presence of
DBU.
9b was isolated after the TBAF desilylation. Upon standing in
solvents (e.g. DMSO, MeCN, CHCl3), the mixture sponta-
neously converted to pure compound 9b within hours, thus
further underscoring the relative instability of the acylboro-
nate unit. This could be attributed to the inefficient inter-
action between the p* orbital of the carbonyl group and the
low-lying sB–N and sB–O orbitals on the MIDA boryl sub-
stituent. The corresponding interaction between the p*
orbital of the carbonyl group and the sC–B orbital in
compound 9 contribute stronger stabilization to the system.
We further subjected 9a and 9b to the Dess–Martin
oxidation (Scheme 4A). Gratifyingly, the oxidation smoothly
afforded the desired 2-oxo-acylboronate products 10a and
10b as solids that are stable in air. The 1,2-diketo compounds
equipped with boryl groups are hitherto unknown. The X-ray
structure of 10a (Scheme 4B)[20] revealed that the bond
The facile access to a-bromocarbonyl compounds 5a and
5b encouraged us to examine their potential in downstream
transformations leading to heterocycles. We were pleased to
observe that the reaction of 5a or 5b with thioamides in DMF
at 658C afforded a range of 4-borylated thiazoles in good
yields (Table 2, entries 1–4). Replacement of thioamide with
Table 2: Preparation of MIDA thiazol-4-ylboronates.[a]
Entry
R’
R’’
Product
Yield [%][b]
1
2
3
4
5
6
PhCH2
PhCH2
Ph
Ph
PhCH2
Ph
Me
Ph
Me
Ph
NH2
NH2
7a
7b
7c
7d
7e
7 f
50
66
33
66
88
61
[a] Reactions were carried out using a-bromoacylboronate (1.0 equiv),
thioamide or thiourea (1.2 equiv) in anhydrous DMF at 658C for 6 h.
[b] Yields of isolated products after silica gel chromatography.
thiourea in the reaction also resulted in the smooth gener-
ation of thiazol-2-amine products (Table 2, entries 5–6).
Significantly, no cleavage of the boryl group was observed
in these reactions. The thiazolylboronates, which are stable in
air and difficult to obtain with established borylation method-
ologies,[16,17] are valuable building blocks for cross-coupling
reactions[18] in the synthesis of active pharmaceutical ingre-
dients.
Scheme 4. A) Synthesis of 2-oxo-acylboronates and their transforma-
tion to quinoxaline derivatives. B) Crystal structure of 10a. Thermal
ellipsoids are set at 50% probability.
Successful preparation of thiazolylboronates aroused our
curiosity to further explore new possibilities towards bory-
lated heterocyclic compounds from MIDA acylboronates and
their derivatives. We envisioned the conversion of 1-(silyl-
oxy)vinylboronates to a-hydroxyacylboronates. Upon sub-
jecting compounds 6a and 6b to the Rubottom oxidation (a
continuous treatment with m-CPBA and TBAF),[19] a-
hydroxy-a-boryl ketones 9a and 9b, respectively, were
isolated (Scheme 3). It is likely that the initially formed a-
hydroxyacylboronates 8a/b isomerized to their more stable
isomers 9a/b through a proton transfer process. Indeed, in the
case of vinylboronate 6b, a 1:1 mixture of the corresponding
a-hydroxyacylboronate 8b and the rearranged a-boryl ketone
=
length of its two C O bonds is between 1.22 and 1.23 ꢀ, thus
indicating a set of ordinary 1,2-diketone carbonyl groups. The
smooth transition of 10b to a 2-borylated quinoxaline
derivative 11 upon treatment with o-phenylenediamine
(Scheme 4A) further corroborated the potential of this class
of molecules in heterocyclic boronate synthesis. Given the
existence of quinoxaline subunits in many bioactive com-
pounds,[21] direct access of boronic acid building blocks of this
sort through 2-oxo-acylboronates is of particular importance
for medicinal chemistry research.
In summary, we have demonstrated a facile oxidative
installation of a hydroxy group geminal to the MIDA boryl
moiety through a Barton radical decarboxylation from a-
borylcarboxylic acids. The resulting a-hydroxyboronates were
subsequently transformed to a novel class of acylboronates
that are stable in air through the Dess–Martin oxidation.
These carbonyl-based building blocks are capable of generat-
ing a range of functionalized boron derivatives, including
acyloxyboranes, a-bromoacylboronates, 1-(silyloxy)vinyl-
boronates, a-hydroxy-a-boryl ketones, and 2-oxo-acylboro-
nates. Exemplified by the successful downstream preparation
of a series of borylated thiazoles and quinoxalines, MIDA
Scheme 3. Generation of a-hydroxy-a-boryl ketones. TBAF=tetra-n-
butylammonium fluoride.
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provides opportunities to synthesize boron-containing het-
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Received: August 12, 2012
Published online: October 4, 2012
Keywords: boronates · heterocyclic boronates ·
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organoboron compounds · oxidation · synthetic methods
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