A Micellar Catalysis Strategy for Suzuki-Miyaura Cross-Couplings of 2-Pyridyl MIDA Boronates: No Copper, in Water, Very Mild Conditions

Article abstract of DOI:10.1021/acscatal.7b03241

Suzuki-Miyaura (SM) cross-couplings of 2-pyridyl MIDA boronates can be successfully carried out in the complete absence of copper by attenuation of the Lewis basicity associated with the pyridyl nitrogen using selected substituents (e.g., fluorine or chlorine) on the ring. This strategy imparts additional synthetic options compared with existing approaches based on the use of Lewis acids or N-oxides. Thus, access to highly valued 2-substituted pyridyl rings via an initial Suzuki-Miyaura coupling can be followed by dehalogenation, S_NAr reactions, or a second SM coupling to arrive at 2,6-disubstituted pyridyl arrays, all run in a single pot, enabled by micellar catalysis in water. Accessing targets within drug-like space is demonstrated in a four-step, one-pot sequence. Computational data suggest that the major role being played by electron-withdrawing substituents in promoting these cross-couplings without the need for copper is to slow the rates of protodeboronation of intermediate 2-pyridylboronic acids.

Full text of DOI:10.1021/acscatal.7b03241

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2017, 7, 8331-8337
A Micellar Catalysis Strategy for Suzuki−Miyaura Cross-Couplings of
2‑Pyridyl MIDA Boronates: No Copper, in Water, Very Mild Conditions
Nicholas A. Isley,† Ye Wang,† Fabrice Gallou,‡ Sachin Handa,† Donald H. Aue,*,†
and Bruce H. Lipshutz*,†
†Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland
S
* Supporting Information
ABSTRACT: Suzuki−Miyaura (SM) cross-couplings of 2-
pyridyl MIDA boronates can be successfully carried out in the
complete absence of copper by attenuation of the Lewis basicity
associated with the pyridyl nitrogen using selected substituents
(e.g., fluorine or chlorine) on the ring. This strategy imparts
additional synthetic options compared with existing approaches
based on the use of Lewis acids or N-oxides. Thus, access to
highly valued 2-substituted pyridyl rings via an initial Suzuki−
Miyaura coupling can be followed by dehalogenation, SNAr
reactions, or a second SM coupling to arrive at 2,6-disubstituted pyridyl arrays, all run in a single pot, enabled by micellar catalysis
in water. Accessing targets within drug-like space is demonstrated in a four-step, one-pot sequence. Computational data suggest
that the major role being played by electron-withdrawing substituents in promoting these cross-couplings without the need for
copper is to slow the rates of protodeboronation of intermediate 2-pyridylboronic acids.
KEYWORDS: micellar catalysis, green chemistry, E factor, MIDA boronates, Suzuki−Miyaura
ithin the privileged family of pyridines,1 the presence of
the 2-pyridyl-substituted moiety exists in many arenas,
Scheme 1. Two Potential Roles of Cu for Suzuki−Miyaura
Cross-Couplings of 2-Pyridyl Units
W
including materials,2 biologically active natural products,3
pharmaceuticals,4 ligands,5 and fluorescent probes,6 emphasiz-
ing its broad-based occurrence. Nonetheless, 2-pyridyl organo-
metallic reagents remain notably underdeveloped with respect
to both their preparation and their use in cross-coupling
chemistry.7 Because of the Lewis basic and electronegative
nitrogen of the pyridyl unit, participation by the 2-position in a
transmetalation event onto a transition metal remains quite
challenging, as competing protioquenching is commonplace.7
Only a handful of reports have attempted to solve this difficult
issue using 2-pyridyl zincate salts,8 trialkylstannanes,9 silanes,10
or boron with various ligands or protecting groups.11 The 2-
substituent that allows pyridyl building blocks to be free-
flowing crystalline solids that can be stored on the benchtop in
air for extended periods and purifiable via flash chromatography
is the N-methyliminodiacetic acid (MIDA) boronate ligand.
Rehybridization of boron to sp3 by this ligand results in these
desired attributes and is remarkably effective in Suzuki−
Miyaura (SM) cross-couplings via a slow-release mechanism.12
One challenging aspect associated with 2-pyridyl MIDA
boronate-mediated cross-couplings is the elevated levels of
copper required in the reaction mixture.11 Although reports on
copper-only-catalyzed SM cross-couplings are known,13
copper’s role in palladium-catalyzed cross-couplings of 2-
pyridyl systems is still poorly understood (Scheme 1). While
recent work provided evidence that copper additives affect the
rate of protodeboronation of 2-pyridyl systems under atypical
cross-coupling conditions (i.e., in the absence of Pd and aryl
halide),14 it has also been thought to assist in the trans-
metalation step to palladium via an initially formed 2-
pyridylcopper species.11 Although some 2-pyridylcopper
species have been isolated and upon exposure to the reaction
conditions do lead to the desired product, such a species has
never been directly implicated in the reaction.11,15 Given that
copper is used at sub- to stoichiometric levels (i.e., noncatalytic
amounts), not only for palladium-catalyzed SM cross-couplings
of 2-pyridyl boryl,11 2-pyridyl thiomethyl,16 and other systems17
but also in Stille9 and Hiyama10 2-pyridyl cross-couplings as
well, we hypothesized early on18 that copper may act as a Lewis
acid toward the pyridyl nitrogen. This might be favored over
the corresponding N-to-Pd bonding that would otherwise
remove Pd from the catalytic cycle and slow the overall
coupling, as is oftentimes observed with Lewis basic
Received: September 21, 2017
Revised: October 23, 2017
© XXXX American Chemical Society
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heterocyclic coupling partners. This is analogous to recent
reports of iridium-catalyzed pyridyl C−H borylation, where the
catalytic activity of iridium is impacted when Ir is bound to a
pyridyl center.19 Thus, on the basis of the rich history of
pyridyl-based directing group chemistry involving both Cu and
Pd,20 we moved forward with our hypothesis that copper might
act as a Lewis acid, freeing up Pd to allow cross-coupling to take
place.
literature.22 After the cross-coupling event, the halogenated
product can be used as a coupling partner en route to 2,6-
disubstituted pyridines, can participate in SNAr reactions, or
may simply be removed, a process amenable to a one-pot
sequence. The resulting technology fulfills several of “The 12
Principles of Green Chemistry,”23 including (1) the use of a 1:1
ratio of the two coupling partners, (2) a benign reaction
medium, (3) mild conditions, and (4) catalytic use of Pd, along
with micellar catalysis.24 The substrate scope is notably broad,
using either aryl/heteroaryl chlorides or bromides. In certain
cases, no organic solvent (including purification) is necessary, as
the desired product can simply be filtered and collected. In
other cases, the crude material can be filtered through a pad of
silica gel to obtain the product in high purity. Lastly,
preliminary computational data also provide support for the
hypothesis that placement of a halogen at selected sites on the
pyridyl ring does indeed lower the rate of protodeboronation
after in situ generation of the boronic acid.
To discourage palladium from interacting at the pyridyl
nitrogen in the absence of copper, we initially envisioned a
substituent on the pyridine ring that could be easily removed or
utilized for subsequent reactions and that would inductively
attenuate the basicity at nitrogen. Placing the substituent at the
6-position might also provide steric hindrance at the nitrogen
center, with both effects hypothetically weakening N−Pd
bonding and aiding in the desired cross-coupling without
reliance on copper. Moreover, each newly substituted pyridine
would also, after a cross-coupling, provide a new series of
pyridyl analogues of potential interest. Such an approach would
be complementary to the use of the corresponding N-oxide, as
recently reported in related couplings.21 This new strategy,
however, would uniquely offer further options for synthetic
planning if the group could not only be easily removed but also
serve as a handle for downstream functionalization(s). As this
study progressed, it was found that substituents at the 6-
position attenuated the rate of release of the MIDA ligand and,
more importantly, attenuated the rates of protodeboronation,
which can otherwise lead to reduced yields of coupled products
(Scheme 2).
On the basis of an early observation25 that a methoxy group
at the 6-position of a 2-pyridyl MIDA boronate permitted
cross-coupling to occur without copper, alternative substituents
were investigated in efforts to mimic its role. A variety of 2-
B(MIDA)-pyridyl derivatives were synthesized (Scheme 4 and
Scheme 4. Reactions of 6-Fluoro-, 3-Fluoro-, and 6-Phenoxy-
2-pyridyl MIDA Boronates with Aryl/Heteroaryl Chlorides
and Bromides
Scheme 2. “Attenuation” Strategy To Avoid the Use of
Copper in 2-Pyridyl MIDA Boronate SM Cross-Couplings
Herein we report the development of this strategy using a
fluorine or chlorine residue at the 6-position of 2-B(MIDA)-
pyridyl systems, which allows these long-sought cross-couplings
to take place in the complete absence of copper (Scheme 3).
Examples of SM couplings using such 6-halo-2-pyridyl MIDA
boronates, to our knowledge, are not to be found in the
Scheme 3. Summary of Substituents That Eliminate the
Need for Cu in 2-Pyridyl SM Cross-Couplings
the Supporting Information), including 6-fluoro and 6-chloro
derivatives, anticipating that the halogens might be removed or
utilized after the initial cross-coupling. We were delighted to
find that each halo derivative led to clean couplings without
copper. The established conditions were found to be 4 mol %
Pd(dtbpf)Cl2 with DIPEA as the base in 2 wt % TPGS-750-M/
H2O at 45 °C using a 1:1 ratio of the two coupling partners
(Scheme 4). Although the reaction does proceed at room
temperature, protodeboronation occurs occasionally (1, 3) in
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competition with cross-coupling. A wide range of functional
groups are compatible, including cyano (4, 9), aldehyde (8),
ketone (11), thioether (14), and ester (13). A variety of
heterocycles, including quinoxaline (3), pyrazine (6), pyridine
(11), pyrimidine (12, 19), thioazole (18), and pyrazole (16),
also smoothly participate under these conditions. Noteworthy
is the high yield achieved for 1-bromo-2-chlorobenzene, where
the selectivity for coupling of the bromide is nearly quantitative
to give product 17. Use of the 6-phenoxy group also enables a
copperless coupling, but in situ protodeboronation was
observed to be far more rapid compared with reactions of 6-
methoxy- and 6-fluoro derivatives.
Scheme 6. Coupling/Dehalogenation Reactions under
Micellar Catalysis Conditions
These same conditions apply as well to 6-chloro-2-pyridyl
MIDA boronates. Thus, as with the 6-fluoro analogues, a
variety of functional groups are tolerated, including a free
aniline (26), nitro groups (25, 28), a heteroaryl chloride (21),
aldehydes (23, 29), a cyano group (22), and a benzyl-protected
phenol (29) (Scheme 5). Heterocycles such as pyridine (21,
Scheme 5. Substrate Scope in Couplings of 6-Chloro-2-
pyridyl MIDA Boronates with Aryl/Heteroaryl Bromides
ester (34). 6-Chloropyridines react under the same conditions,
with some reactions taking place at room temperature (e.g., to
afford 35) and in the presence of thiophene (36) and free-
indole (37) functionalities.
The 6-chloro group within the initial product can also be
subjected to a second SM cross-coupling without any additional
palladium being added to the reaction vessel (Scheme 7). More
Scheme 7. One-Pot Access to 2,6-Disubstituted Pyridines
Using Micellar Catalysis
28), pyrimidine (22), and thiophene (27) could all be
successfully cross-coupled. One particularly interesting aspect
of these conditions is that no homocoupling of the B(MIDA)-
pyridyl system was observed in either the presence or the
absence of the aryl halide coupling partner. Moreover, the
chloride at the 6-position remained intact, as oxidative addition
was observed only with the aryl/heteroaryl bromide coupling
partner.
To complement our nanomicelle-enabled couplings, micellar
conditions were also newly developed for removal of both the
fluoride and chloride groups via nickel-catalyzed hydro-
dehalogenation. Following the SM cross-coupling, the nickel
catalyst, ligand, base, and hydride source can be added directly
to the reaction vessel to smoothly afford the desired
dehalogenated pyridyl ring. A number of reactions were
demonstrated in which an initial coupling of either a 6-chloro-
or 6-fluoro-2-B(MIDA)-pyridine with an aryl/heteroaryl bro-
mide could be followed by removal of the 6-halogen, both at 45
°C (Scheme 6). Catalytic conditions for hydrodefluorination of
2-fluoropyridines are unknown; nonetheless, this reduction
could not only be effected under these conditions but done so
with 100% selectively in the presence of Ar−F bonds, as in 33.
Defluorination occurs readily in the presence of an activated
base, in addition to an arylboronic acid, is all that is needed to
promote the second coupling. Representative diarylated
products derived from insertion of functionalized aryl bromide
partners at both the 2- and 6-positions on the pyridyl ring
include products 38, 39, and 40, which were formed in good
overall yields.
While traditional SNAr reactions involving 2-fluoropyridyl
systems typically take place in organic solvents (e.g., DMF),26
the 6-fluoro residue is susceptible to subsequent nucleophilic
attack in the same aqueous reaction mixture (Scheme 8). Upon
completion of the initial cross-coupling, addition of K3PO4
along with, e.g., an amine nucleophile leads to displacement
reaction products 41, 42, and 43.
Given the prominent role played by 2,6-disubstituted
pyridines in pharmaceuticals and agrochemicals (see the
examples in Figure 1), we endeavored to demonstrate access
to such structures using our micellar technology at each step in
a synthesis, in this case of a known antagonist.27 Beginning with
6-chloro-2-B(MIDA)-pyridine, two successive SM cross-cou-
plings gave product 44 (Scheme 9). Without isolation, a zinc-
mediated nitro group reduction28 yielded the free amine, to
which was added benzoyl chloride at room temperature to
afford the desired product 45 in a four-step, one-pot sequence
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Scheme 8. One-Pot Sequence Involving a Second-Stage SNAr
Coupling
Scheme 10. Expanded Substrate Scope of Substituted 2-
Pyridyl MIDA Boronates Coupled with Aryl/Heteroaryl
Bromides
Figure 1. Examples of biologically active 2,6-disubstituted pyridines.
Scheme 9. One-Pot, Four-Step Sequence Leading to a Drug
Analogue
material. As shown previously (vide supra), product 53 could
be dehalogenated to afford the final product 54.
To further demonstrate additional functional group compat-
ibility with couplings of 6-chloro-2-pyridyl MIDA boronates
under micellar conditions, various heterocycles were added to
the reaction mixture, as this has been established as an effective
and quick tool for such an assessment.21a,29 For the system
shown (Scheme 11), no additional products beyond the desired
Scheme 11. Doping of the Reaction Mixture with
Heterocyclic Fragments To Demonstrate Additional
Functional Group Compatibility
in 52% overall yield. To ensure that the reaction mixture
remained semihomogeneous, EtOAc as a cosolvent was added
to the reaction vessel after both SM cross-couplings, leading to
full conversion for the two subsequent reactions. After
completion of this four-step, one-pot reaction, more EtOAc
was added to effect in flask extraction of the product.
To demonstrate that these conditions are also amenable to
more highly substituted 2-B(MIDA)-pyridyl arrays, additional
complexes were prepared and subjected to the same Pd-
catalyzed cross-couplings to arrive at products 46−53 and 55
(Scheme 10). It is worth mentioning that when aryl or alkynyl
substituents were placed para to the B(MIDA) residue, a
significant amount of the starting 2-B(MIDA)-pyridyl complex
remained unreacted, suggesting that release of the MIDA ligand
is quite slow under these conditions. Thus, for examples leading
to moderate yields (e.g., 48, 49, 50, 52), some of the 2-
B(MIDA)-pyridyl starting material could be recovered intact. In
general, the yields of the desired biaryl products were good,
albeit in some cases they are based on recovered starting
material (BRSM). If desired, the reaction yield can be increased
(e.g., 51) by adding additional Ar−Br and base after 24 h to
fully consume the remaining 2-B(MIDA)-pyridyl starting
coupling product were observed via GC−MS in addition to the
added material. Heterocycles containing oxazole, thiazole,
piperidine, morpholine, acridine, and free indole did not affect
conversion to the biaryl product. On the other hand, in the
presence of N-methylimidazole, only 25% conversion took
place, while with benzimidazole or benzotriazole present, only a
trace of product, at most, was observed.
Another attractive aspect of using 6-halo-2-B(MIDA)-
pyridines under micellar catalysis conditions is that simple
filtration of the aqueous reaction mixture leads directly to biaryl
products, as demonstrated previously using aryl-B(MIDA)
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complexes (Scheme 12).25 Thus, on the basis of organic
solvents involved in the overall process, the E factor30 using this
1
Scheme 13. (top) H NMR Studies of 2-B(MIDA)-pyridyl
Complexes in D2O; (bottom) Relative Rates of Release of
the MIDA Ligands of Various 2-B(MIDA)-pyridyl
Complexes in D2O
Scheme 12. Examples Using 6-Fluoro-2-B(MIDA)-pyridine
in Organic-Solvent-Free Suzuki−Miyaura Reactions
procedure is zero, as no organic solvent is used at any time.
After the reaction, only minimal amounts of recyclable water
are used to isolate solid product(s) in high yield and purity
1
(>95%, as determined by H NMR spectroscopy).
To gain insight as to why fluorine and other inductively
electron-withdrawing substituents at the 6-position allow the
cross-coupling to occur without copper in the pot, we
considered three possible explanations: (1) that an electron-
withdrawing substituent, as in 6-fluoro-2-B(MIDA)-pyridine,
might weaken binding to palladium and promote trans-
metalation by opening a coordination site on palladium, (2)
that attenuation of the rate of release of the MIDA ligand
would lead to slow release of the boronic acid to help prevent
competitive protodeboronation, and (3) that direct attenuation
of the rates of protodeboronation would promote cross-
coupling. For explanation (1), however, it is not clear whether
prior binding to the pyridyl nitrogen would cause any problem
in attachment of pyridyl group of the boronic acid onto
palladium.12c,31 To investigate the role of pyridyl binding, we
note that experimental gas-phase and solution basicities are
substantially reduced by inductively electron-withdrawing
substituents.32 Furthermore, density functional theory calcu-
lations for 2-B(MIDA)-pyridine show that it can bind to
palladium competitively with a water ligand and that 6-fluoro-2-
B(MIDA)-pyridine binds with a 4.0 kcal/mol less favorable free
energy in toluene (see the Supporting Information for details).
The second possibility for how a 6-fluoropyridyl substituent
could function is by affecting the rate of MIDA hydrolysis.
coupling, as their slower MIDA release rate reduces the
amount of protodeboronation-prone boronic acid in the pot at
any given time, though it is not clear that such an effect would
be important enough by itself to be effective.
The best explanation, however, is the third one above, that
added copper or a 6-fluoro or other electron-withdrawing
substituent can promote transmetalation by directly reducing
the rates of protodeboronation of 2-pyridylboronic acids.
Recent experimental and computational results provide critical
insights into the rates at which aryl/heteroaryl boronic acids
undergo protodeboronation in acidic, neutral, and basic
aqueous dioxane solution.14 The proposed mechanisms suggest
that protodeboronation of 2-pyridylboronic acid is fastest in the
pH range 4−11. In these experiments, addition of cupric
chloride (0.10 M) slowed protodeboronation of 2-pyridylbor-
onic acid more than 20-fold. This provides the best explanation
for how copper salts permit cross-coupling to occur in good
yields prior to a protodeboronation side reaction. The 6-
trifluoromethyl and 6-methoxy derivatives were also observed
to protodeborylate at a reduced rate, suggesting an inductive
effect that could be related to how the 6-fluoro and other
substituents function. In detailed calculations on the mecha-
nism for protodeborylation of the 6-fluoroboronic acid, we
indeed predict that this reaction should occur at a substantially
slower rate than with the parent boronic acid.34
In summary, new technology has been developed that allows
use of stoichiometric amounts of 2-pyridyl MIDA boronates as
coupling partners in Suzuki−Miyaura cross-coupling reactions
with aryl halides to be run under environmentally responsible
micellar catalysis conditions. In particular, excessive amounts of
copper, elevated reaction temperatures, large excesses of heavy
base, and use of DMF as solvent are literature reaction
parameters that have all been favorably mitigated. Most notably,
the need for a copper salt as an additive in these reactions has
been eliminated by altering the substituent at the 6-position of
the pyridine ring to slow the rate of protodeboronation under
basic conditions. Key to this success was the judicious choice of
either fluorine or chlorine on the pyridyl ring. This approach
adds considerable flexibility for secondary same-pot (1) facile
removal via a newly developed hydrodehalogenation based on
1
Several 2-pyridyl-B(MIDA) complexes were examined by H
NMR spectroscopy, each in a solution of D2O, to determine
their relative stabilities in an aqueous environment, as 2-
pyridylboronic acid complexes (Scheme 13, top) were
previously reported to be unstable in water.7e We were
surprised to find that this conversion worked as well as it did
in water, since previously reported studies were strictly
anhydrous.11 Recent work has elucidated mechanisms for
MIDA hydrolysis under neutral and basic conditions to form
boronic acids in aqueous THF.33 The relative rates of release of
the MIDA ligand in D2O were examined for different pyridyl
complexes. As illustrated in Scheme 13 (bottom), both the 6-
fluoro-2-B(MIDA)-pyridine derivative and the 6-chloro-2-
B(MIDA)-pyridine analogue had significantly slower conver-
sions to their corresponding boronic acids compared with both
the parent 2-B(MIDA)-pyridine and the 5-methyl-2-B(MIDA)-
pyridine analogue. These data suggest an explanation for why
the 6-halopyridyl analogues successfully undergo cross-
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moiety. The electron-withdrawing substituents act primarily by
mimicking the effect of copper, which functions by slowing the
rates of protodeboronation of intermediate 2-pyridylboronic
acids. This strategy may prove to be general in other transition-
metal-catalyzed reactions using 2-pyridyl organometallic
reagents.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.7b03241.
■
S
Experimental procedures, analytical data, copper release
rate studies, and NMR spectra (PDF)
Computational and mechanistic results (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: aue@chem.ucsb.edu.
*E-mail: lipshutz@chem.ucsb.edu.
■
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47, 4695−4698. (b) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003,
ORCID
Bruce H. Lipshutz: 0000-0001-9116-7049
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support provided by Novartis and the NSF
(SusChEM 1561158) is warmly acknowledged. We are also
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for Scientific Computing at the CNSI and MRL (NSF MRSEC
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of palladium provided by Johnson Matthey (Dr. Thomas
Colacot) and selected chemicals supplied by MilliporeSigma are
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