Potassium trimethylsilanolate enables rapid, homogeneous suzuki-miyaura cross-coupling of boronic esters

Article abstract of DOI:10.1021/acscatal.9b04353

Herein, a mild and operationally simple method for the Suzuki-Miyaura cross-coupling of boronic esters is described. Central to this advance is the use of the organic-soluble base, potassium trimethylsilanolate, which allows for a homogeneous, anhydrous cross-coupling. The coupling proceeds at a rapid rate, often furnishing products in quantitative yield in less than 5 min. By applying this method, a >10-fold decrease in reaction time was observed for three published reactions which required >48 h to reach satisfactory conversion.

Full text of DOI:10.1021/acscatal.9b04353

Letter
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Cite This: ACS Catal. 2020, 10, 73−80
Potassium Trimethylsilanolate Enables Rapid, Homogeneous
Suzuki−Miyaura Cross-Coupling of Boronic Esters
Connor P. Delaney, Vincent M. Kassel, and Scott E. Denmark*
Roger Adams Laboratory, University of Illinois, 600 South Matthews Avenue, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: Herein, a mild and operationally simple method for the
Suzuki−Miyaura cross-coupling of boronic esters is described. Central
to this advance is the use of the organic-soluble base, potassium
trimethylsilanolate, which allows for a homogeneous, anhydrous cross-
coupling. The coupling proceeds at a rapid rate, often furnishing
products in quantitative yield in less than 5 min. By applying this
method, a >10-fold decrease in reaction time was observed for three
published reactions which required >48 h to reach satisfactory
conversion.
KEYWORDS: cross-coupling, Suzuki−Miyaura reaction, homogeneous catalysis, synthetic methods, palladium
he Suzuki−Miyaura reaction1−4 is one of the premier
To qualify as a superior alternative to existing procedures,
Tmethods for the formation of carbon−carbon bonds. this new method must satisfy several criteria: (1) all reagents
used must be inexpensive, simple to prepare, and stable, (2)
the reaction conditions must be anhydrous to avoid ester
hydrolysis and mitigate protodeboronation, (3) the procedure
must be operationally simple and robust enough to compete
with the state of the art, and (4) the conditions should effect
rapid cross-coupling at room-temperature. The first point of
optimization was the identification of a boronic ester that best
fulfills these criteria.
Advances in ligand design have allowed for successful cross-
coupling at room-temperature,5−9 cross-coupling of substrates
bearing a poor nucleofuge,9,10 as well as those involving
sterically hindered partners.11,12 However, competitive proto-
deboronation often necessitates the use of the organometallic
coupling partner in excess,13−15 and multiple strategies have
been developed to mitigate this issue. Most common is the use
of masked boronic acids such as BF3K salts,16−18 MIDA
boronates,19,20 and triolboronate salts11,21 which slowly release
the boronic acid in situ. In other cases, the reaction rate is
increased such that the desired cross-coupling outpaces the
protodeboronation reaction, either by ligand design6 or use of
a secondary transmetalation agent.12,19,22 The most robust
solution is to run Suzuki−Miyaura reactions anhydrously to
minimize protodeboronation using an insoluble, inorganic
base, as protodeboronation cannot occur in the absence of a
proton source.23−25 Although occasionally effective, this
modification introduces a new set of problems, as the particle
size, stir rate, and flask shape/size become relevant factors in
heterogeneous reactions.
Pioneering work from this laboratory demonstrated that
boronic esters are competent transmetalation partners without
the need for hydrolysis to the parent boronic acid and that the
structure of the boronic ester (in particular dimethyl and glycol
esters) has a significant effect on the rate of transmetalation.26
We sought to demonstrate this effect in catalytic systems to
illustrate that the identity of boron reagent used in the
Suzuki−Miyaura coupling can increase the rate of sluggish
reactions, thereby demonstrating the value of these reagents
beyond their use as protecting groups.
Although glycol boronic esters were attractive from a kinetic
standpoint, they were labile to column chromatography.
Furthermore, we observed competitive reduction of the aryl
halide when they were employed, likely arising from Pd-
mediated β-hydride elimination of the glycol backbone. Thus,
a search for a more stable ester that maintained the enhanced
reaction rate was initiated by comparing new boronic esters
alongside the nucleophiles we previously investigated (acid,
pin, neop, gly)26c in the stoichiometric model of trans-
metalation rate (Figure 1). Boronic esters derived from cis-
tetrahydrofuran-3,4-diol 5a, cis-cyclopentane-1,2-diol 6a, and
neopentyl glycol27 7a appeared most favorable of those
examined. Each possessed transmetalation rates significantly
higher than the parent boronic acid 3a as well as improved
stability when compared to the glycol ester 4a. Esters 6a, 7a,
and 8a exhibited non-first-order kinetics; as a result, a
numerical comparison of transmetalation rate could not be
established between these esters and 3a. However, it is clear
that they transmetalate faster than 3a. Furthermore, when
Received: October 9, 2019
Revised: November 15, 2019
© XXXX American Chemical Society
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Letter
however, the reactions were plagued by irreproducibility owing
to insolubility. An appropriate soluble base was sought to
address this issue; such a base would also be of considerable
interest in systems that utilize anhydrous conditions to
attenuate protodeboronation.
Extensive investigations on silicon-based, cross-coupling
reactions from this laboratory28−32 suggested the use of
potassium trimethylsilanolate (TMSOK) because of its low
cost and high solubility in ethereal solvents.33 Initial results
were encouraging; in a survey of three solvents and four
catalysts for the coupling of 4-bromobenzotrifluoride (9a) with
neopentyl 4-fluorophenylboronic ester (7a), the combination
of Pd−P(t-Bu)3-G3 and THF was uniquely effective (Table
1).34
Initial experiments combining the three 4-fluorophenylbor-
onic esters 5a, 6a, and 7a with 9a (Table 2) revealed a striking
dependence on stoichiometry.35 Optimal results were obtained
with 1.4 equiv of base; two of three esters furnished 10aa in
quantitative yield within 5 min at room temperature. Excesses
of TMSOK (2.0 or 3.0 equiv) resulted in reaction stalling at
low conversion.
To better differentiate the three esters, the ability of each to
transfer two different arenes, one heterocyclic (5b−7b), and
one electron deficient (5c−7c) with several aryl halides was
examined. In addition, the stability of each ester to silica gel
column chromatography and storage was evaluated, along with
their physical properties (Table 3). Esters derived from cis-3,4-
tetrahydrofurandiol and neopentyl glycol were crystalline
solids, whereas the esters derived from cis-1,2-cyclopentanediol
were oils. Of the six esters prepared, all were indefinitely bench
stable save for the cyclopentanediol ester of furan-2-boronic
acid. When combined with 9a or 11a, esters 6b and 7b each
afforded the product 10ba in quantitative yield. When these
aryl halides were combined with 5b, the product yield was
slightly diminished. However, yields of 10cb were significantly
lower, likely owing to the lesser migratory aptitude of the 3,5-
bis(trifluoromethyl)phenyl unit. In reactions with 11b, neo-
pentyl ester 7c afforded the highest yield followed by 6c and
then ester 5c. In reactions with 9b little variation in yield was
observed. From these comparisons, neopentyl glycol boronic
esters were deemed only marginally superior; however, in view
of their price36 and familiarity, these esters were selected for
development.
Figure 1. Relative rates of transmetalation for various boronic esters.
Reactions were run with 1 equiv of ester with respect to Pd and
monitored by 19F NMR against an internal standard. See the
Supporting Information for details.
Table 1. Survey of Catalyst and Solvent for the Coupling of
7a with 9a
a
yield of 10aa (%)
The foregoing preliminary studies revealed that some
reactions afforded quantitative yield in <5 min, but those
that did not proceeded in low yield or failed to react altogether.
A working hypothesis identifies three factors: (1) the previous
observation that ≥2.0 equiv of TMSOK was detrimental
(Table 2), (2) the failure of substrates with lesser migratory
aptitude (Table 3), and (3) the extraordinary rate of reaction
(Figure 2). It appears the reaction stalls when the base is
present in excess of boronic ester; however, for many
substrates, a substantial quantity of base is consumed by the
time the entire portion is added owing to the rate of reaction.
To support this hypothesis, the rate at which the room-
temperature cross-coupling of 7a and 9a occurs under these
conditions was determined (Figure 2). We employed our
rapid-injection NMR apparatus (RI-NMR)37 to obtain a
kinetic profile of the reaction. After 6 s (the minimum time
required to adequately mix the sample), the reaction was
observed to be >50% complete, with full conversion achieved
in under 60 s (Figure 2). Thus, to retain reactivity for sluggish
THF
dioxane
DME
Pd-XPhos-G3
Pd-P(t-Bu)3-G3
PEPPSI IPr
<5
100
0
<5
50
0
0
<5
0
Pd[P(t-Bu)3]2
0
0
0
a
Yield of 10aa obtained by 19F NMR against an internal standard.
Reactions run on 0.10 mmol scale using 1.20 equiv of boronic ester
7a.
neopentyl and pinacol esters 7a and 8a were combined with
palladium hydroxide dimer 1, the rate of transmetalation was
substantially faster in the presence of excess ester. On the basis
of these data, the neopentyl, cyclopentanediol, and THF-diol
esters were selected for further investigation. Additional details
on the stoichiometric studies using these esters are available in
the Supporting Information.
Next, a search for an optimal base was conducted. Guided by
the previously reported results,26 CsOH·H2O was tested;
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Table 2. Study of TMSOK Stoichiometry
a
yield of 10aa (%)
boronic ester
base source
time
1.2 equiv
1.4 equiv
2.0 equiv
3.0 equiv
7a
7a
7a
6a
5a
Oakwood35
Gelest
Gelest
Gelest
5 min
5 min
1 h
5 min
5 min
96
96
100
88
100
100
100
100
12
100
25
21
8
23
31
38
8
Gelest
54
<5
20
a
See footnote a in Table 1. Reactions run on 0.25 mmol scale using 1.20 equiv of boronic ester.
Table 3. Comparison of Coupling Efficiency, Stability, and
Physical State of Six Boronic Esters
Figure 2. Rapid-injection NMR reaction profile. Concentration of
10aa obtained by 19F NMR against an internal standard. Reaction run
on 0.16 mmol scale using 1.20 equiv of boronic ester.
Table 4. Development of a Portionwise Addition Protocol
a b
,
for Challenging Substrates
entry
base addition method
yield (%)
1
2
3
4
5
1.4 equiv added in one portion
1.4 equiv added dropwise over 15 s
1.0 equiv added in one portion
1.0 equiv, followed by 0.4 equiv at 45 min
0.9 equiv, followed by 0.5 equiv at 45 min
52 31
45 39
80
98
98
1
0
1
a
Recovery determined by subjecting 150 mg of each ester to silica gel
b
a
column chromatography (3.0 cm column, 30 g silica gel). Yield of
Reactions run in triplicate on 0.25 mmol scale using 1.20 equiv of
10ba and 10cb obtained by 19F NMR against an internal standard.
b
boronic ester 7a. Yield of 10ac obtained by 19F NMR against an
Reactions run on a 0.25 mmol scale using 1.20 equiv of boronic ester.
internal standard.
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a
Table 5. Reaction Scope of Neopentylboronic Esters
a
b
Reactions with 1.00 mmol of aryl halide with 1.2 equiv of boronic ester. Yields of isolated product after column chromatography. Product was
c
d
e
f
further purified to analytical purity, see the Supporting Information. Pinacol ester used. Concentration was 0.4 M. 4 mol % catalyst used. 1.04
equiv of boronic ester used.
reaction partners, the slow or portionwise addition of base was
investigated (Table 4).
In the reaction of mesityl bromide with 7a, addition of a
THF solution of TMSOK, either in a single bolus or dropwise
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a
a
Table 6. Cross-Coupling of Nonfluorinated Arenes
Table 7. Improving the Rate of Known Reactions
a
Reactions with 1.00 mmol of aryl halide with 1.2 equiv of boronic
ester. Yields of isolated product after column chromatography.
b
Product was further purified to analytical purity, see the Supporting
c
Information. 0.44 M concentration.
over 15 s gave variable and unsatisfactory yields (entries 1 and
2). Decreasing the quantity of base to 1.0 equiv restored
reaction reproducibility (entry 3) but did not proceed to
completion within 3 h. Addition of 1.0 equiv of TMSOK
solution followed by an additional 0.4 equiv after 45 min
provided sufficient base to achieve full conversion (entry 4).
Ultimately, we chose to use 0.9 equiv of TMSOK followed by
0.5 equiv after 45 min (entry 5) to accommodate the
possibility of using 1.0 equiv of ester.38
With optimized conditions fully developed, the generality of
the TMSOK-promoted cross-coupling was explored with a
series of neopentyl boronic esters and 9a (Table 5a). In
general, reactions were complete in 5 min affording product in
excellent (>90%) yield. Reactions using electron-rich partners
such as 4-methoxyphenyl-, 3,4,5-trimethoxyphenyl-, and 3,4-
methylenedioxyphenylboronic ester or electronically neutral
partners such as 4-fluorophenyl-, 2-naphthyl-, and 1-
naphthylboronic ester furnished the respective products in
>90% yield in under 5 min. Electron-deficient nucleophiles
such as 4-cyano-, 4-trifluoromethyl-, 4-sulfonyl-, and 3,5-
bis(trifluoromethyl)phenylboronic esters required slightly
extended reaction times to reach completion but also afforded
>90% yields. Protodeboronation prone heterocycles such as 2-
furyl, 2-thienyl, 2-(4-cyano)thienyl, and n-Boc-pyrrolyl-2-
boronic ester gave excellent yields as well, with all but 10qa
proceeding to completion in less than 5 min. The neopentyl
ester of 2-pyridylboronic acid proved too unstable for effective
isolation; however, the pinacol ester of 6-substituted
pyridylboronic acids such as 6-trifluoromethyl-2-pyridyl-
boronic ester and 6-methoxy-2-pyridylboronic ester were
effectively cross-coupled at slightly elevated temperatures and
extended reaction times. Boronic esters bearing unobtrusive
groups such as 2-fluorophenyl- and 2-trifluoromethoxyphenyl
boronic ester reacted in 5 and 30 min, respectively, each in
>90% yield. The more encumbered 2-methylphenylboronic
ester was successfully cross-coupled in 94% yield after 30 min.
However, mesitylboronic ester was cross coupled in only 40%
yield after 3 h, using 4.0 mol % catalyst.
a
Reactions with 1.00 mmol of aryl halide. Yields of isolated product
after column chromatography.
Next, the electrophile scope and functional group compat-
ibility were examined by combining a series of aryl halides with
7a (Table 5b). Electron deficient aryl halides were excellent
partners, leading to complete reaction in <5 min. 4-
Nitrophenyl bromide (9g) reacted successfully, and secondary
amides were competent without protection, as was 4-bromo-
acetophenone (9e). 4-Ethoxycarboxyphenyl bromide (9d)
reacted rapidly and did not suffer saponification; however,
methyl esters undergo competitive demethylation. Electron
rich aryl halides that retard the rate of oxidative addition were
equally competent; 4-bromodiphenyl ether (9h) and 4-
bromoanisole (9i) both reacted in quantitative yield in <5 min.
Amines were compatible under these conditions; tertiary
amine-containing aryl bromide 9j gave an excellent yield. Some
nitrogen heterocycles were compatible; 6-trifluoromethyl-2-
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Letter
bromopyridine reacted quantitatively in <5 min, and 2-
bromopyridine reacted quantitatively in 15 min.
Experimental procedures and characterization data for
all new compounds along with copies of the NMR
spectra (PDF)
Silyl protected phenols (9n) and anilines (9k) were
compatible as well. Highly encumbered aryl bromides
underwent cross-coupling readily. Mesityl bromide (9c) gave
excellent yield in only 3 h, and the extremely encumbered
2,4,6-triisopropyl-bromobenzene was successfully cross-
coupled in good yield. Aryl chlorides were also competent;
4-chlorobenzonitrile reacted cleanly, and the 2-substituted aryl
chloride 11q could be cross-coupled in only 30 min, albeit in
75% yield. Finally, benzyl chloride 11s cross-coupled
effectively without ether formation with TMSOK.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sdenmark@illinois.edu.
ORCID
■
Scott E. Denmark: 0000-0002-1099-9765
Notes
The authors declare no competing financial interest.
Several additional combinations of nonfluorinated substrates
were tested (Table 6). Aldehydes were not compatible but the
protected aldehyde 9t did couple with 7k in 87% yield.
Styrenyl bromide 9u was coupled with 7b in 94% yield.
Neopentyl 4-tert-butylphenylboronic ester 7w was successfully
combined with 9v to furnish 10wv in 90% yield after
crystallization of the product as the HCl salt. Finally, the
ethyl ester of indomethacin (10w) was methylated in 97%
yield using neopentyl methylboronic ester.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health (Grant
GM R35 127010) for generous financial support. We also
thank the UIUC SCS support facilities (microanalysis, mass
spectrometry, and NMR spectroscopy) for their assistance. Dr.
Gerald Larson (Gelest) is thanked for a generous gift of
TMSOK. We also acknowledge Dr. Andy A. Thomas for
obtaining rate profiles for the boronic acid, glycol ester,
neopentyl ester, and pinacol ester in our initial investigations.
To challenge the state of the art, it was deemed crucial to
demonstrate that these modifications are applicable to other
systems. Several published reactions were identified that take
>48 h to proceed to satisfactory conversion which were then
executed under the conditions developed herein (Table 7).
The reaction of methylboronic acid and bromide 9x catalyzed
by Pd(OAc)2/P(2-Tol)3 provides 10xx in 68% yield after 312
h.39 By substituting the neopentyl ester for the boronic acid
and using TMSOK as the base, 10xx was produced in 91%
yield after only 16 h. The cross-coupling of pyridyl bromide 9y
and phenylboronic acid catalyzed by Pd(PPh3)4 is run for 72 h
to obtain 10yy in 51% yield.40 With the modifications
described above, the product was obtained in 92% yield after
5 h. Finally, the coupling of bromide 9z with cyclo-
propylboronic acid was investigated under catalysis by
Pd(OAc)2/P(c-Hex)3, which furnished product 10zz in 73%
yield after 50 h.41 Substituting with TMSOK and neopentyl
cyclopropylboronic ester gave a lower yield owing to
competitive protodehalogenation. Switching to the THF-3,4-
diol ester suppressed this side reaction and afforded 10zz in
72% yield after 3 h. These examples demonstrate that by
simply using a boronic ester in place of the acid, using TMSOK
as a base, and a compatible solvent system (ethereal,
anhydrous solvents), the rate of cross-coupling is increased
in a variety of catalytic systems; the catalyst/ligand for each
system has not been changed. As such, we posit that this is a
general advance that can provide benefits complementary to
other improvements in ligand design.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.9b04353.
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(35) The discrepancy between Tables 1 and 2 occurs because
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79
DOI: 10.1021/acscatal.9b04353
ACS Catal. 2020, 10, 73−80

ACS Catalysis
Letter
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NOTE ADDED IN PROOF
■
During the processing of this manuscript, two related papers
appeared in ACS Catalysis (DOI: 10.1021/acscatal.9b03667
and 10.1021/acscatal.9b03666), which also describe anhy-
drous, base-activated Suzuki−Miyaura cross-couplings albeit at
significantly higher temperatures than we report.
80
DOI: 10.1021/acscatal.9b04353
ACS Catal. 2020, 10, 73−80