Chemoselective Suzuki–Miyaura Cross-Coupling via Kinetic Transmetallation

Article abstract of DOI:10.1002/anie.201610797

Chemoselective Suzuki–Miyaura cross-coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups.

Full text of DOI:10.1002/anie.201610797

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International Edition: DOI: 10.1002/anie.201610797
German Edition: DOI: 10.1002/ange.201610797
Synthetic Methods
Chemoselective Suzuki–Miyaura Cross-Coupling via Kinetic
Transmetallation
James W. B. Fyfe, Neal J. Fazakerley, and Allan J. B. Watson*
Abstract: Chemoselective Suzuki–Miyaura cross-coupling
generally requires a designed deactivation of one nucleophile
towards transmetallation. Here we show that boronic acids can
be chemoselectively reacted in the presence of ostensibly
equivalently reactive boronic acid pinacol (BPin) esters by
kinetic discrimination during transmetallation. Simultaneous
electrophile control allows sequential chemoselective cross-
couplings in a single operation in the absence of protecting
groups.
transmetallation (Scheme 1c).[8] Accordingly, current meth-
ods to achieve chemoselectivity rely upon employing one
nucleophile that is unreactive towards transmetallation under
the prevailing reaction conditions. In particular, selective
discrimination of two arylboron nucleophiles is only achiev-
able using a suitable protecting group strategy.[9,10]
Here we report that the chemoselective cross-coupling of
two seemingly equivalently reactive aryl organoboron com-
pounds can be achieved by exploiting subtle differences in
their respective rates of transmetallation (Scheme 1d).
Elegant studies by Hartwig,[11] Amatore and Jutand,[12]
Schmidt,[13] and, recently, Denmark[14] have demonstrated the
role of oxopalladium transmetallation in the Suzuki–Miyaura
reaction.[15] As part of his seminal study, Hartwig reported
that boronic acids were observed to transmetallate ca.
45 times faster than the equivalent BPin ester using stoichio-
metric quantities of a dimeric oxopalladium complex and in
a non-competitive system.[11] Based on these data we ques-
tioned whether chemoselective cross-coupling of a boronic
acid over a BPin ester might be possible via kinetic discrim-
ination during transmetallation in a catalytic system.
Chemoselective Suzuki–Miyaura cross-coupling of multi-
nucleophile systems has emerged as a powerful synthetic
strategy for chemical synthesis.[1,2] Chemoselectivity within
systems containing two organoborons is typically achieved by
a designed deactivation: 1) Highly effective p-orbital protect-
ing group strategies developed by Burke (BMIDA)[3] and
Suginome (BDAN)[4] render one organoboron unit unreac-
tive towards transmetallation (Scheme 1a);[5,6] 2) a unique
self-activation/protection mechanism developed by both
Morken and Shibata allows chemoselectivity within geminal
and vicinal diboron compounds (Scheme 1b);[7] and 3) Crud-
den has shown that benzyl BPin species are unreactive in the
absence of specific additives, allowing selective aryl/benzyl
We initially independently assessed the relative rates of
cross-coupling of boronic acid 1a and the equivalent BPin 1b
with bromobenzene (2) under representative Suzuki–
Miyaura reaction conditions (Scheme 2a).
These initial results suggested comparable reactivity of 1a
and 1b, with both nucleophiles rapidly consumed at the same
initial rate and displaying a comparable reaction profile.
However, under identical reaction conditions in a competitive
system notable chemoselectivity was recorded (Scheme 2b).
Here, the cross-coupling of 4a was found to significantly
outcompete 1b, with ca. 9:1 selectivity exhibited in this non-
optimized system.
Accordingly, while exhibiting similar reactivity in isola-
tion, chemoselectivity can be leveraged in a competitive
system by kinetic discrimination of the nucleophiles by the
catalytically generated PdII-intermediate. Since transmetalla-
tion occurs after the rate-determining step (RDS),[16] the
overall rate is unaffected by transmetallation in the isolated
reactions (Scheme 2a) but a rate difference exists and there-
fore chemoselectivity can still be leveraged between nucleo-
philes post-RDS (Scheme 2b).[17] However, this is contingent
Scheme 1. Nucleophile-selective Suzuki–Miyaura reactions.
[*] J. W. B. Fyfe, Dr. A. J. B. Watson
Department of Pure and Applied Chemistry, University of Strathclyde
Glasgow, G1 1XL (UK)
E-mail: allan.watson.100@strath.ac.uk
on
ensuring
inhibition
of
pinacol
equilibration
(Scheme 3).[18,19]
Competitive coupling of the in situ generated BPin-
derived boronic acid erodes selectivity and thus must be
controlled in order to exploit any natural kinetic advantage
(see below). Fortunately, however, diol transfer can be
controlled by the basic media typically used for Suzuki–
Miyaura reactions,[18,20] allowing optimization of this nascent
Dr. N. J. Fazakerley
GlaxoSmithKline, Medicines Research Centre
Stevenage, SG1 2NY (UK)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610797.
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Temperature was important for reaction efficiency, with
708C optimum over a 1 h timeframe.[21] As predicted, the
choice of reaction medium was crucial to both efficiency and
selectivity.[21] Of the inorganic bases known to be effective in
limiting boron speciation processes,[18,19] K3PO4 was most
effective.[21] A solvent survey found 1,4-dioxane offered
improved selectivity vs. THF (entry 1 vs. entry 2).[21] Lastly,
there was a notable correlation between conversion/selectiv-
ity and the quantity of H2O added to the system (entries 2–5).
Limiting the quantity of H2O to 5 equiv (entry 2) provided
a robust and highly selective system, while selectivity rapidly
decreased as H2O increased (entries 3–5). Importantly, in
order to rule out any effects of the p-Me substituent, the
corresponding experiment using Ph-B(OH)2 and p-tol-BPin
was conducted, affording comparable results (95:5 3:5).[21]
Excesses of H2O negatively impacted selectivity in this
system due to competing processes arising from the formation
of a visibly biphasic system at > 20 equiv H2O.[20] 1) Equili-
bration increased as H2O increased, thereby reducing selec-
tivity due to the formation of a competing boronic acid from
the BPin component (see Scheme 3). 2) Introduction of
a bulk basic aqueous phase promotes phase transfer of
boronic acid from the organic phase to the aqueous as its
cognate boronate.[19] Assuming a largely organic phase bound
Pd catalyst,[15,20] this lowers the concentration of boronic acid
available for transmetallation in the organic phase, instead
requiring a contra-thermodynamic transfer of boronic acid
boronate from the aqueous phase to the organic,[15,20] and
thereby negatively impacting both reaction efficiency and
selectivity. Spectroscopic investigations supported these
hypotheses, the key solution events are shown in Scheme 4.
Scheme 2. Independent and competitive cross-couplings of boronic
acid (1a/4a) vs. BPin (1b) with aryl bromide 2. Determined by HPLC
analysis.
Scheme 3. Equilibration in a boronic acid/BPin system.
system (Table 1; see the Supporting Information for full
details of the investigation of all variables).
Scheme 4. Key events affecting chemoselectivity: phase transfer (A)
and equilibration (B).
Under reaction-like conditions (i.e., in the absence of Pd
catalyst and aryl halide) using restricted quantities of H2O
(98/2 1,4-dioxane/H2O), the formation of a bulk aqueous
phase is prevented and, consequently, phase transfer of
boronic acid to the aqueous (A, Scheme 4) is restricted. In
contrast, in a highly biphasic medium (50/50 1,4-dioxane/
H2O), boronic acid phase transfer was observed to begin
immediately (< 5 min). The BPin species were not observed
to undergo phase transfer, consistent with previous stud-
ies.[19,21]
Table 1: Chemoselective cross-coupling of B(OH)2 vs. BPin. Optimiza-
tion.
Entry
H2O [equiv]
Solvent
Conv. 3:5 [%][a]
1
2
3
4
5
5
5
20
50
100
THF
6:76
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0:100
12:80
28:68
30:58
In addition, under optimum (low H2O) conditions, diol
equilibration (B, Scheme 4) was inhibited, maintaining ca.
95% integrity of the initial system (16.4:1 B(OH)2:BPin after
[a] Determined by HPLC analysis. See the Supporting Information.[21]
2
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10 min). However, under biphasic conditions, equilibration
Electron-rich boronic acids delivered greater efficiency over
was much more significant (2:1 B(OH)2:BPin within 10 min).
Chemoselective transmetallation of boronic acid over
BPin takes place with high fidelity. The principal determinant
for chemoselectivity is therefore the generation of a mixture
of boronic acids as a result of diol equilibration. In the
optimized system (low H2O), diol equilibration takes place
more slowly. As the boronic acid is consumed by cross-
coupling, equilibration is further suppressed, i.e., chemo-
selectivity is assisted by Le Chatelierꢀs principle.
With optimized conditions for selective cross-coupling in
a model system, we sought to evaluate the generality of the
procedure by varying the structure of the boronic acid, BPin,
and bromide coupling partners in an equistoichiometric
system (Scheme 5). High selectivity was observed in all
cases with cross-coupling favoring the boronic acid, leaving
the BPin unreacted. Importantly, selectivity was unaffected
by steric (e.g., ortho-substituted compounds) or electronic
composition. Crossover experiments demonstrated that selec-
tivity was not influenced by specific combinations of boronic
acid and BPin partners—chemoselectivity was independent
of the functionality of the boron coupling partner (e.g. 7a–9a
vs. 7b–9b). Importantly, the mass balance was generally
returned starting material, with some protodeboronation
observed in specific cases.[22] Reactions were halted at 1 h
and the yields represent the efficiency of the boronic acid
coupling over this time frame; however, increasing the
reaction time did not negatively affect chemoselectivity.
those comparatively electron-poor, in agreement with pre-
vious studies.[1a,10]
Having demonstrated the generality of our protocol, we
sought to explore the utility of this process, specifically
through subsequent use of the unreacted BPin component.
Our first goal was to determine the integrity of the Pd catalyst
following the initial coupling. Simply adding a second aryl
bromide to the reaction mixture after the initial coupling was
complete allowed coupling of the unreacted aryl BPin to
produce pairs of selectively cross-coupled products in one pot
without the need for intermediate isolation or renewal of the
catalyst (Scheme 6). Reaction efficiency was generally > 80%
Scheme 6. One-pot sequential chemoselective coupling. Isolated
yields.
À
per C C bond formation, with the same efficiency trend
displayed for electronic variation as noted for Scheme 5. The
undesired coupling products were not observed. Residual aryl
halide could be observed but unreacted organoboron com-
pounds were not recovered, likely due to protodeborona-
tion.[22]
In order to fully probe the power of this methodology, we
sought to combine chemoselective transmetallation of the
organoboron nucleophile with chemoselective discrimination
of the electrophile, i.e., chemoselective oxidative addi-
tion.[18b,23] This would establish the first complete chemo-
selective control over two of the three key mechanistic
processes of the Suzuki–Miyaura reaction. Using the reac-
tivity gradient afforded by dihaloarenes, a one-pot sequential
chemoselective Suzuki–Miyaura reaction was enabled with-
out the requirement for any in situ modification of the
reaction conditions (temperature change, sequential addi-
tion) or reactants (protecting group removal, boron species
interconversion) (Scheme 7).
A change to the more active catalyst system of Pd(OAc)2
and DavePhos was required in order to engage the less
reactive aryl chloride, while a short screen of base and water
equivalents revealed optimum conversion could be achieved
using 4 equiv of K3PO4 with 15 equiv of H2O. Under these
Scheme 5. Chemoselective cross-coupling of B(OH)2 vs. BPin. Isolated
yields of the desired B(OH)2 coupled product.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: boron · chemoselectivity · cross-coupling ·
palladium · transmetallation
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À
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Acknowledgements
This work was supported by the EPSRC. We thank the
EPSRC UK National Mass Spectrometry Facility at Swansea
University for analyses and GlaxoSmithKline for PhD
studentship (J.W.B.F.) along with financial support and
chemical resources. We thank Dr. J. Redmond (Glaxo-
SmithKline) for helpful discussions.
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4
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Manuscript received: November 4, 2016
Final Article published: && &&, &&&&
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Communications
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J. W. B. Fyfe, N. J. Fazakerley,
A. J. B. Watson*
&&&& — &&&&
Set phases to stun: Chemoselective
Suzuki–Miyaura cross-coupling can be
achieved by kinetic discrimination of
boronic acids and BPin esters during
transmetallation. Simultaneous electro-
phile control allows sequential chemo-
selective cross-couplings in a single
operation in the absence of protecting
groups.
Chemoselective Suzuki–Miyaura Cross-
Coupling via Kinetic Transmetallation
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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