Synthesis and Suzuki Reactions of N-Heterocyclic Carbene Difluoro(aryl)-boranes

Article abstract of DOI:10.1021/acs.orglett.5b01101

Readily available NHC-arylboranes (NHC-BH₂Ar) are converted in high yield to stable NHC-difluoro(aryl)boranes (NHC-BF₂Ar) by treatment with 2 equiv of 1-chloromethyl-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor). In turn, the NHC-difluoro(aryl)boranes participate directly in Suzuki reactions under conditions previously used for anionic trifluoroborate salts. Accordingly, NHC-difluoroboranes are a new class of stable precursors for Suzuki reactions.

Full text of DOI:10.1021/acs.orglett.5b01101

Letter
pubs.acs.org/OrgLett
Synthesis and Suzuki Reactions of N‑Heterocyclic Carbene
Difluoro(aryl)-boranes
Swapnil Nerkar and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Readily available NHC-arylboranes (NHC-BH2Ar) are
converted in high yield to stable NHC-difluoro(aryl)boranes (NHC-
BF2Ar) by treatment with 2 equiv of 1-chloromethyl-4-fluoro-1,4-
diazonia-bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor). In
turn, the NHC-difluoro(aryl)boranes participate directly in Suzuki
reactions under conditions previously used for anionic trifluoroborate
salts. Accordingly, NHC-difluoroboranes are a new class of stable
precursors for Suzuki reactions.
he ease of handling of N-heterocyclic carbene boranes
(NHC-boranes) has facilitated the recent exploration of
Scheme 1. Formation and Proposed Suzuki Reactions of B-
Aryl NHC-Boranes
T
the reagent chemistry of this interesting class of ligated
boranes.1 NHC-boranes with B−H bonds serve as reducing
agents in both radical2 and ionic3 reactions. They are also
valuable co-initiators in photopolymerizations,4 and they are
precatalysts for borenium-catalyzed hydrogenations.5 NHC-
boryl sulfides,6,7 halides, triflates, and related species are useful
reagents.1,8 Though much of this chemistry is based on 1,3-
imidazol-2-ylidene boranes, an assortment of newer classes of
NHC-boranes also show promise.9
Furthermore, it is increasingly possible to make carbon-
substituted NHC-boranes. NHC-boranes with B−C bonds can
be made either by direct complexation of NHCs and boranes1
or by functionalization of simple NHC-boranes by catalyzed
hydroborations,10 substitutions,11 and carbene BH insertion
reactions.12 The carbon-substituted NHC-boranes formed in
these reactions often have favorable physical properties (stable,
easy to isolate), but little is presently known about their
chemistry.
Recently, we have found in collaboration with Taniguchi that
NHC-arylboranes are readily made by the hydroboration
reaction of arynes.13 In the parent example shown in Scheme
1 (eq 1), generation of benzyne from o-silyl triflate 1 and
fluoride ion14 in the presence of NHC-boranes (NHC-BH3)
results in spontaneous hydroboration to provide robust, stable
products like 2. This aryne hydroboration is so far unique to
NHC-boranes,13 which are stable enough to survive the
conditions of benzyne generation yet reactive enough to add
spontaneously to benzyne as it forms.
As a first step toward increasing the synthetic utility of
carbon-substituted NHC-boranes, we set out to bridge the gap
between NHC-borane chemistry and boronic acid chemistry.15
Within boronic acid chemistry, we targeted the Suzuki−
Miyaura reaction16,17 as job-one (Scheme 1, eq 2). Here we
report that NHC-arylboranes are readily fluorinated to give
NHC-difluoro(aryl)boranes.18 In turn, these difluoro(aryl)-
boranes are boronic acid equivalents that partner directly with
aryl bromides in Suzuki reactions under standard conditions.
After summarizing the results of the two new reactions, we
briefly compare and contrast the new NHC-difluoro(aryl)-
boranes with other common precursors for Suzuki reactions.
We hypothesized that NHC-dihalo(aryl)boranes would
liberate boronic acids on exposure to water. In practice, this
reaction occurred easily, indeed too easily, for boryl iodides,
bromides, and chlorides as shown by the results in Scheme 2.
Treatment of NHC-phenylborane 3 with diiodine (1 equiv),
dibromine (1 equiv), or N-chlorosuccinimide (NCS, 2 equiv)
resulted in rapid formation of the corresponding NHC-
dihaloboranes 4−6 as assessed by 11B NMR spectroscopy.8,13
The iodide 4 and bromide 5 were very sensitive to water,
quickly liberating phenylboronic acid 7 (PhB(OH2), as assessed
by 11B NMR spectroscopy) and the corresponding imidazolium
halide salt (as assessed by 1H NMR spectroscopy). The
dichloroborane 6 was more stable, yet still gradually produced
phenylboronic acid 7 over a few hours on exposure to water at
25 °C.
Received: April 15, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01101
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Scheme 2. Halogenation Reactions of an NHC-
Phenylborane
Scheme 3. Selectfluor Difluorination Reactions
These rapid halogenation reactions are potentially useful for
making boronic acids from NHC-boranes. However, boronic
acids themselves16d are often not the preferred precursors for
Suzuki reactions. Instead, stable precursors such as pinacol
boranes, trifluoroborate salts, and MIDA boronates (MIDA is
N-methyliminodiacetate) are commonly used because they are
easy to handle.19
We found the sweet spot between stability for ease of
handling and reactivity in Suzuki reactions with NHC-
difluoro(aryl)boranes. We recently described several such
difluoroboranes that had promising stability but were not
convenient to prepare.18 We now find that NHC-difluoro-
(aryl)boranes can be easily made by reaction of NHC-
arylboranes with Selectfluor.20,21
trifluoroborates (Pd(OAc)2 and a carbonate base in meth-
anol).22 We varied only the base, looking at both cesium
carbonate (Cs2CO3) and potassium carbonate (K2CO3). Both
worked, but the former gave faster conversions in scouting
reactions (see Supporting Information) so it was selected for
the scope study.
In the typical reaction shown in entry 1 of Table 1, a
methanol solution of 8 (1 equiv), 4-bromobenzonitrile 14a (1
Table 1. Suzuki Coupling Reactions of 8 with Aryl Bromides
In a typical example, reaction of 3 with 2 equiv of Selectfluor
at room temperature in acetonitrile cleanly provided difluor-
oborane 8 in 1.5 h as followed by 11B NMR spectroscopy (4.6
ppm, t, JBF = 62.4 Hz). Simple evaporation of the acetonitrile
and direct purification of the crude product by automated flash
chromatography provided the robust difluoroborane 8 as a
white solid (mp 80−83 °C) in 83% yield. This is a significant
improvement over the prior fluorination procedure (Ph3CBF4,
PhOH),18 both in practice (Selectfluor is cheaper and easier to
handle than Ph3CBF4) and in outcome (Ph3CBF4 often
provides side products). Unlike the other dihaloboranes 4−6,
difluoroborane 8 is stable to exposure to water for long periods
at room temperature and even on heating (as long as base is
excluded).
Reaction of 3 with only 1 equiv of Selectfluor provided
mainly difluoroborane 8 with only a small resonance observed
for the corresponding monofluoroborane (NHC-BHFPh, at
−11 ppm). For this representative double fluorination reaction
at least, the second fluorination step is faster than the first one.
Scheme 3 shows the structures of several other NHC-
difluoro(aryl)boranes made by reactions with Selectfluor along
with reaction times and isolated yields. We varied both the
NHC-borane ylidene substituent while keeping the B-
substituent as phenyl (9−11; 72−87% yield), and the B-
substituent while keeping the NHC-borane as 1,3-dimethyli-
midazol-2-ylidene (12, 68% yield, and 13, 81% yield).
It is possible to release boronic acids from the difluoro-
(aryl)boranes by heating with water and base (see Supporting
Information), but it is easier to use them directly in Suzuki
reactions. To this end, we tried Molander and Bialatto’s
conditions for low palladium loading in reactions of potassium
a
b
Isolated yield after flash chromatography. Small amounts of methyl
esters 14e and 15e resulting from Cannizzaro reactions with the
solvent were also formed.
equiv), Pd(OAc)2 (1 mol %), and cesium carbonate (Cs2CO3,
3 equiv) was refluxed for 3 h. Standard workup and flash
chromatography provided 4-phenylbenzonitrile 15a in 87%
yield.
Entries 2−7 in Table 1 show the results of additional Suzuki
coupling reactions of the partner NHC-difluoro(aryl)borane 8
with assorted aryl bromides 14b−g under the same conditions.
B
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Letter
All of the reactions produced good yields of Suzuki coupling
products 14b−g (68−84%) over the course of 1−4 h. Reaction
progress can be monitored by standard TLC analysis.
Table 2 shows examples of Suzuki reactions of the other
difluoroboranes 9−13, this time all with 4-bromobenzonitrile
bode well for future applications in boronic acid chemistry,
both in and beyond Suzuki reactions.
Finally, third, the fluorination of NHC-boranes provides an
entry to boronic acid chemistry that differs from current stable
precursors. The other main classes of stable Suzuki precursors
shown in Figure 1, potassium trifluoroborates,24 pinacol
boranes, and MIDA boronates,25 usually come from precursors
in the boronic acid oxidation state. These are in a way
protecting groups.
Table 2. Suzuki Reactions with NHC-Difluoro(aryl)boranes
Figure 1. Comparing and contrasting stable precursors for Suzuki
reactions.
NHC-difluoro(aryl)boranes differ because they are produced
by fluorination, not functional group exchange. Thus, the run
up to Suzuki chemistry in the NHC-borane approach is based
on low oxidation states of boron. The stability of both the
parent NHC-boranes and their difluoro derivatives coupled
with their access from reduced boron chemistry will in the long
run provide added flexibility in diverse synthetic settings
including multistep total synthesis and selective cross coupling
reactions.
In summary, we have bridged the budding chemistry of
NHC-boranes with well established boronic acid chemistry by a
two-step sequence of fluorination and Suzuki reaction.
Currently, the simplest N-heterocyclic carbene, 1,3-dimethyli-
midazol-2-ylidene, looks attractive for this chemistry because it
is readily available and has a relatively low molecular weight (96
g mol−1). Looking beyond Suzuki reactions, the observations
suggest that substituted NHC-difluoro(aryl)boranes may serve
as boronic acid precursors or equivalents in other types of
reactions as well.
a
Isolated yield after flash chromatography.
14a. Again Molander’s conditions for trifluoroborate couplings
were used with Cs2CO3, and isolated yields of products 15a, 16,
and 17 are uniformly good, 68−84%. Analysis of several crude
1
products by H NMR spectroscopy showed resonances of the
1,3-dimethylimidazolium salt by protonation of the NHC. This
salt and the inorganic products are readily removed by silica gel
filtration.
What happens to the difluoro(aryl)boranes under the
reaction conditions is currently unclear, but we speculate that
they mimic other Suzuki precursors by slowly producing either
boronates or reactive equivalents of boronates throughout the
course of the reaction.22,23
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, compound characterization data, and
copies of NMR spectra of all products. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01101.
The significance of this preliminary work is 3-fold. First, the
immediate goal to build a bridge between NHC-borane
chemistry and Suzuki chemistry has been met. Second, the
bridge is built upon NHC-difluoro(aryl)boranes. These neutral
compounds, usually white solids, are convenient to chromato-
graph, easy to identify, largely insoluble in water, and soluble in
a wide range of organic solvents. These favorably properties
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: curran@pitt.edu.
Notes
The authors declare no competing financial interest.
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Letter
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ACKNOWLEDGMENTS
■
We thank the National Science Foundation and the National
Institutes of Health for support. We thank Prof. Tsuyoshi
Taniguchi (Kanazawa University) and Dr. Emmanuel Lacote
̂
(CNRS and University of Lyon) for helpful discussions.
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