Tandem Chemoselective Suzuki-Miyaura Cross-Coupling Enabled by Nucleophile Speciation Control

Article abstract of DOI:10.1002/anie.201504297

Control of boronic acid speciation is presented as a strategy to achieve nucleophile chemoselectivity in the Suzuki-Miyaura reaction. Combined with simultaneous control of oxidative addition and transmetalation, this enables chemoselective formation of two C-C bonds in a single operation, providing a method for the rapid preparation of highly functionalized carbogenic frameworks.

Full text of DOI:10.1002/anie.201504297

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International Edition: DOI: 10.1002/anie.201504297
German Edition: DOI: 10.1002/ange.201504297
Sequential Cross-Coupling
Tandem Chemoselective Suzuki–Miyaura Cross-Coupling Enabled by
Nucleophile Speciation Control**
Ciaran P. Seath, James W. B. Fyfe, John J. Molloy, and Allan J. B. Watson*
Abstract: Control of boronic acid speciation is presented as
a strategy to achieve nucleophile chemoselectivity in the
Suzuki–Miyaura reaction. Combined with simultaneous con-
trol of oxidative addition and transmetalation, this enables
À
chemoselective formation of two C C bonds in a single
operation, providing a method for the rapid preparation of
highly functionalized carbogenic frameworks.
T
he Suzuki–Miyaura reaction is the primary method for Pd-
À
catalyzed cross-coupling, accounting for over 40% of C C
bond constructions in the pharmaceutical industry alone.[1,2]
Chemoselective control of this reaction is currently limited to
single mechanistic events, focusing on either the electrophile
or nucleophile independently.[3] Electrophile selectivity has
been thoroughly demonstrated by exploiting the well-defined
principles of oxidative addition (I > Br> Cl, etc.; Sche-
me 1a)[4,5] while nucleophile selectivity has been achieved
through the use of inert (protected) boronic acid derivatives
(Scheme 1b(i))[6] or a geminal/vicinal diboron self-activation
mechanism (Scheme 1b(ii)).[7] Despite these advances, gen-
eral nucleophile chemoselectivity remains elusive. Reactions
Scheme 1. Approaches to chemoselective Suzuki–Miyaura cross-cou-
pling. Cat =catalyst, MIDA=N-methyliminodiacetic acid, OA=oxida-
tive addition, PG=protecting group, Pin=pinacolato, TM=transme-
talation.
À
are therefore limited to only one selective C C bond forming
event,[8] with sequential chemoselective cross-coupling ach-
ieved only through separate reactions.[3,6n,9] Establishing
simultaneous electrophile and nucleophile selectivity to
Tandem chemoselective Suzuki–Miyaura cross-coupling
was initially explored using the benchmark reaction of phenyl
BPin 1, 4-bromophenyl BMIDA 2, and aryl chloride 3
(Table 1). The reaction design plan required three distinct
chemoselective events to cooperate simultaneously. 1) Cross-
coupling of 1 and 2 to produce the expected biaryl BMIDA
intermediate 4,[6r,10] based upon selective oxidative addition of
2 vs. 3 and transmetalation of 1 vs. 2; 2) formation of BPin 6
from the BMIDA intermediate and 5 via control of speci-
ation;[10] and 3) cross-coupling of 6 with 3 to deliver 7a.
Control of these events represented a significant challenge.
Chemoselective oxidative addition can be capricious and
reaction/catalyst dependent[4a,5]—premature reaction of 1 and
3 would deliver 8. Hydrolysis of 2 must be controlled to avoid
premature transmetalation of the latent boronic acid and
uncontrolled oligomerization, leading to 9.[10,11] However, this
must be levied against the requirement of aqueous base to
facilitate effective cross-coupling[12] and ensure effective
speciation manipulation.[10]
À
allow successive C C bond-forming events in a single reac-
tion remains unsolved.
Recently, we demonstrated that boron speciation can be
controlled during Suzuki–Miyaura cross-coupling to enable
chemoselective and quantitative ligand exchange in situ.[10]
Here we report that boron speciation, oxidative addition, and
transmetalation can be simultaneously controlled to enable
À
two chemoselective Suzuki–Miyaura C C bond formations in
a single catalytic process (Scheme 1c). This provides a simple
yet powerful solution to achieving nucleophile chemoselec-
tivity and enables the rapid and efficient synthesis of high-
value products.
[*] C. P. Seath, J. W. B. Fyfe, J. J. Molloy, Dr. A. J. B. Watson
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde
295 Cathedral Street, Glasgow, G1 1XL (UK)
E-mail: allan.watson.100@strath.ac.uk
Initial evaluation of a catalyst system based on our
previous work failed to deliver the desired triaryl product 7a;
the reaction produced only the formal homologation adduct 6
with aryl chloride 3 returned, indicating problematic oxida-
tive addition with this less reactive electrophile (entry 1).
Moving to a more activated catalyst system (Pd(OAc)2,
SPhos;[13,14] entry 2) provided low conversion to 7a with the
[**] We thank the Carnegie Trust for a PhD Scholarship (CPS), the
EPSRC UK National Mass Spectrometry Facility at Swansea
University for analyses, and GlaxoSmithKline for chemical resour-
ces.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504297.
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Table 1: Reaction development.
Entry
Catalyst[a]
K3PO4
[equiv]
H2O
[equiv]
7a:6:8 [%][b]
1
2
3
4
5
6
7
8
[PdCl2(dppf)][c]
3
3
3
3
4
4
4
5
5
5
0:100:0
17:42:4
35:23:11
53:4:25
88:0:0
41:0:24
25:13:0
80:0:11
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
10
20
20
30
40
20
[a] 4 mol% Pd, 8 mol% ligand. [b] Determined by HPLC analysis.
[c] 4 mol%.
mass balance consisting mainly of 6 as well as 8, the product of
reaction of 1 + 3, indicating a lack of electrophile chemo-
selectivity. Lowering the reaction temperature to avoid
premature engagement of 3 led to lower overall conversion
(see Supporting Information (SI)). A systematic evaluation of
the stoichiometric relationship between K3PO4 (a range of
bases were evaluated, see SI) and H2O revealed that cross-
coupling efficiency could be directly influenced by the
medium without resorting to specific tailoring of the cata-
lyst.[5] Increasing the quantity of H2O increased the overall
conversion (i.e., improved engagement of 3) but also led to
extensive oligomerization due to poor speciation control
(entries 3 and 4). This could be mitigated by increasing the
quantity of K3PO4,[10] which provided excellent levels of
conversion to 7a (entry 5). Further increases in H2O led to
oligomerization giving increased 9 (entries 6 and 7), which
could again be tempered by increasing the quantity of K3PO4
(entry 8). Accordingly, these results further demonstrate that
in addition to speciation control, cross-coupling efficiency can
also be directly influenced by relatively minor adjustments to
the composition of the reaction medium.[1c] A survey of
various catalyst systems with the optimum biphase composi-
tion did not provide any further improvement in the chemical
yield (see SI).
It is important to note that the optimized reaction is
effective with equal stoichiometries of 1, 2, and 3, i.e., the
chemoselectivity and yield are not statistically prejudiced
through use of impractical and uneconomical stoichiometries
of any component or by tailoring (e.g., electronic or steric
bias) of the nucleophile.[9] The reaction rates are harmonized
such that BPin 1 reacts only with aryl bromide 2, speciation
control delivers BPin 6 at a rate that avoids oligomerization or
competition with 1,[10b] and 6 reacts only with aryl chloride 3.
With our optimum reaction conditions in hand, the scope
of the tandem cross-coupling protocol was explored
(Scheme 2). The general concept was also readily transferred
Scheme 2. Chemoselective tandem Suzuki–Miyaura cross-coupling
using conjunctive haloaryl BMIDA components. Isolated yields of pure
products.
to a modified system using dihaloarenes as conjunctive bis-
electrophiles in combination with two differentiated boronic
acid-derived nucleophiles (Scheme 3). In this process, the
slightly less active DavePhos[14,15] ligand was found to be more
suitable. The reaction efficiencies between the two comple-
mentary processes are comparable, for example, the prepa-
ration of 7a is produced in 82% and 91% yield, respectively
(Scheme 2 vs. Scheme 3). This synthetic flexibility provides an
array of diverse product scaffolds in a single operation and
enhances scope based on the wider selection of available
reaction components.
A broad range of coupling partner was accommodated in
both protocols, including useful functionality on the BPin,
BMIDA, and aryl chloride components, such as ethers, esters,
fluorides, nitriles, ketones, olefins, and heterocyclic residues.
Notably, heteroaryl and alkenyl BMIDA, which must prog-
ress via the protodeboronation prone parent boronic
acids,[6e, 16] were effectively incorporated. Yields were typically
high and synthetically useful, especially when the number of
individual processes is considered.
In a departure from exploiting the standard reactivity
profiles of the electrophile (i.e., Br> Cl), we sought to further
demonstrate the potential of tandem chemoselective Suzuki–
Miyaura cross-coupling by utilizing specific reactivity gradi-
ents of dibromo or dichloro electrophiles (Scheme 4). For
À
example, tandem C C bond formation was possible using 2,4-
dichloropyrimidine to deliver 8a in 70% yield.[17] The
increased lability of alkenyl electrophiles vs. aryl electrophiles
allows chemoselective cross-coupling of 1,b-dibromostyrene
to provide 8b in 79% yield.[18] Similarly, sp2/sp3 electrophile
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Scheme 5. Synthesis of BET bromodomain inhibitor 14 by tandem
sp2–sp2/sp2–sp3 Suzuki–Miyaura cross-coupling.
The synthetic applicability of our protocol was further
exemplified in the rapid synthesis of the BET bromodomain
inhibitor 14 (Scheme 5).[20] Chemoselective sp2–sp2 cross-
coupling of conjunctive bromoaryl BMIDA 9 and dimethyl
isoxazole BPin 10, delivers intermediate BMIDA 11, which is
converted to the reactive BPin derivative 12 in situ via
speciation control. This then engages benzyl chloride in an
2
3
À
sp –sp C C bond formation to provide the key core structure
13 in 70% yield. Oxidation and reduction delivers 14.
In conclusion, we have shown that oxidative addition,
boron speciation, and transmetalation can be chemoselec-
tively and simultaneously controlled to enable tandem
Scheme 3. Chemoselective tandem Suzuki–Miyaura cross-coupling
using conjunctive dihalide components. Isolated yields of pure prod-
ucts. Ac=acetyl.
À
Suzuki–Miyaura C C bond formation in a single operation.
This method provides a simple solution to the nucleophile
selectivity issue within Suzuki–Miyaura cross-coupling and
demonstrates the power of chemoselective cross-coupling to
access highly functionalized carbogenic frameworks.
Keywords: boron · chemoselectivity · cross-coupling ·
palladium · speciation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9976–9979
Angew. Chem. 2015, 127, 10114–10117
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Received: May 11, 2015
Published online: July 1, 2015
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