Transforming Suzuki-Miyaura cross-couplings of MIDA boronates into a green technology: No organic solvents

Article abstract of DOI:10.1021/ja409663q

New technology has been developed that enables Suzuki-Miyaura couplings involving widely utilized MIDA boronates to be run in water as the only medium, mainly at room temperature. The protocol is such that no organic solvent is involved at any stage; from the reaction through to product isolation. Hence, using the E factor scale as a measure of greenness, the values for these cross-couplings approach zero.

Full text of DOI:10.1021/ja409663q

Communication
pubs.acs.org/JACS
Transforming Suzuki−Miyaura Cross-Couplings of MIDA Boronates
into a Green Technology: No Organic Solvents
Nicholas A. Isley,† Fabrice Gallou,‡ 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
health, and environmental perspective.8b And just as certain
ABSTRACT: New technology has been developed that
enables Suzuki−Miyaura couplings involving widely
utilized MIDA boronates to be run in water as the only
medium, mainly at room temperature. The protocol is
such that no organic solvent is involved at any stage; from
the reaction through to product isolation. Hence, using the
E factor scale as a measure of greenness, the values for
these cross-couplings approach zero.
organic solvents have been essentially removed from use (e.g.,
benzene and CCl4), and others such as chlorinated solvents
discouraged, so is DMF apparently destined to realize a similar
fate.10 Hence, it behooves the synthesis community to work
toward not only reliance on safer solvents but also on greener
solvents. Indeed, this goal is a priority in most industrial circles,
including the Pharmaceutical Roundtable associated with the
ACS Green Chemistry Institute.11
Our efforts of late have focused on development of alternative,
nontraditional approaches to reactions that are heavily utilized by
both academic and industrial laboratories worldwide. The goal
continues to be to “get organic solvents out of organic reactions,”
utilizing nanoparticles composed of environmentally benign
amphiphiles that allow cross-couplings and related metal-
mediated reactions to take place in water and without heating
or cooling.12 In this report, we disclose new technology that
enables MIDA boronates to participate in Suzuki−Miyaura
couplings where the required release of boronic acids occurs in
water at room temperature (RT, 23 °C). Indeed, the overall
process, including workup, can be done in the complete absence
of organic solvents. Based on the most commonly employed
yardstick of Sheldon and co-workers as a measure of greenness,
therefore, these reactions take place with associated E factors
approaching zero.4b,13
s illustrated in a review by Snieckus and Colacot tracing the
A
development of Pd-catalyzed cross-coupling reactions
leading up to the Nobel Prizes in 2010, the Suzuki−Miyaura
coupling was the most heavily used among these name reactions
in the past decade, by far.1 Notwithstanding its extraordinary
popularity,2 such highly valued C−C bond-forming processes,3
typically run under homogeneous conditions, come with an
associated heavy price from the environmental perspective.
Oftentimes conditions for such couplings involve mixed,
aqueous solvent systems (that make solvent recovery costly),
excess of a coupling partner, and heat to drive reactions to
completion. Moreover, boronic acids or their boronate
derivatives may afford byproducts resulting from homocoupling
or protio-quenching.2 This material is in addition to the solvents
used that make up, in general, the vast majority of organic waste
produced by the chemical enterprise.4
One addition to the portfolio of organoboron intermediates
that has found widespread acceptance5,6 in organic synthesis
involves N-methyliminodiacetic acid (MIDA) boronates,
developed extensively by Burke.7 They offer several positive
features associated with their use, including air stability and
crystallinity, two virtues that the pharmaceutical industry, in
particular, finds appealing. With notoriously unstable 2-
heteroaromatic substituted systems, the 2-pyridyl system in
particular, slow release to their corresponding boronic acids
allows for couplings that otherwise have a history of either
limited utility or complete failure.8
Along with these properties, however, come their attendant
limitations and/or associated disadvantages that are nontrivial,
especially from the standpoint of “greenness”.4b Aside from the
typical conditions that rely on a large excess of base (5−7 equiv)
and heat (60−100 °C) to gradually release the corresponding
boronic acids and the low molarities involved (0.01−0.13 M), the
solvent systems characteristic of these couplings are partially
aqueous.8,9 In some cases, the requirement for a solvent such as
DMF makes the coupling highly undesirable from a safety,
An initial coupling involving a 1:1 stoichiometry of p-tolyl
MIDA boronate 1 and 5-bromopyrimidine was performed in
aqueous nanomicelles composed of commercially available
designer surfactant TPGS-750-M14 at RT (Scheme 1). In the
presence of palladium catalyst Pd(dtbpf)Cl2 (2 mol %), along
with Et3N (3 equiv), and over a 24 h period, the adduct could be
isolated by diluting the reaction mixture with water and filtering
off the desired product. Using this simple procedure, the
coupling product could be isolated in 82% yield in >95% purity
(by 1H NMR); alternatively, a 90% yield could be achieved using
traditional methods by filtering through a plug of silica with
organic solvent. This example was conducted on a gram scale,
achieving a 74% isolated yield using only 8 mL of H2O for the
Received: September 17, 2013
Published: November 13, 2013
© 2013 American Chemical Society
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Communication
(vitamin E TPGS). Each led to a reasonable level of conversion
under otherwise identical conditions (69−89%; see SI).
Although TPGS-1000 and TPGS-750-M afforded comparable
results, the former surfactant contains natural vitamin E and,
therefore, is far more expensive than is TPGS-750-M.
Scheme 1. Initial Coupling Between a MIDA Boronate and a
Heteroaryl Bromide
Several combinations of aryl MIDA boronates and aryl
bromides, in the same 1:1 ratio, were then exposed to these
conditions to assess the scope of this mild cross-coupling process.
Most biaryl products illustrated in Scheme 2 were formed in high
isolated yields, regardless of the electronic nature of the
substituent(s) on either ring. By contrast, use of the free boronic
acid, e.g., leading to product 10, afforded only a 73% yield vs 89%
using the corresponding MIDA boronate. Coupling of an N-
sulfonylindole bearing a MIDA boronate at the 3-position was
unexpectedly sluggish, requiring mild heating to 40 °C just to
form 12 in 56% yield. Changing the nature of the coupling
partner with the 3-MIDA boronate to p-bromoanisole, likewise,
led to biaryl 13 in a modest 44% yield. The corresponding 2-
MIDA boronate, however, showed no such problem, leading
upon filtration to the desired biaryl 11 in 90% isolated yield.
Aryl/heteroaryl chlorides are also amenable to coupling under
these conditions. In some cases (9, 15, 16) an increase in catalyst
loading to 4 mol % was necessary to achieve full conversion
(Scheme 3). Initial trails using 2 mol % catalyst led to biaryl 15 in
filtration procedure; hence, an E factor of 6.5 if water is
considered as waste.
Reaction variables were screened using an alkenyl MIDA
boronate, where the desired product 2 was isolated in 75% yield
(Scheme 2). The yield of coupling product 2 could be increased
Scheme 2. Representative Cross-Couplings of MIDA
Boronates and Aryl/Heteroaryl Bromides in Water at RT
Scheme 3. Representative Cross-Couplings of MIDA
Boronates and Aryl/Heteroaryl Chlorides in Water at RT
a
1
Isolated yield after filtration; determined to be >95% pure by H
b
c
NMR. Two mol % Pd catalyst. Purified by column chromatography
via Biotage. Performed in an oil bath at 40 °C.
d
a
Isolated yield after filtration; product determined to be >95% pure by
b
1H NMR. The free boronic acid derivative was used (1 equiv).
c
d
Reaction was performed in an oil bath at 40 °C. Purified by column
only 45% yield, the remaining mass being unreacted starting
materials. Attempts to use an excess of either partner leading to
products 9 and 15 had little overall impact. Heterocyclic
chlorides bearing electronically neutral, deactivated, and
activated cases participate smoothly. A product such as biaryl
14 is attractive as it possesses two functional groups available for
further manipulation.
Interestingly, there is no reported study on couplings of aryl
bromides with MIDA boronates. Nonetheless, the underlying
presumption is oftentimes that since aryl chlorides react to afford
good isolated yields of biaryls, such will be the case with aryl
bromides. However, we have previously observed, e.g., that
conditions telescoped for Miyaura borylations of chlorides do
not translate to bromides,8c and this situation appears to apply as
well to MIDA boronates. As illustrated in Table 1, the coupling
chromatography via Biotage.
to 92% using additional MIDA boronate (1.2 equiv). Inorganic
bases (e.g., Na2CO3 or K2CO3) led to <5% of the product. Other
organic bases such as triisobutylamine were totally unproductive.
Triethylamine, therefore, was chosen for further studies given
both its low cost and effectiveness. Unlike traditional MIDA
boronate couplings oftentimes run in organic media at low
molarities (e.g., 0.07 M),8 a global concentration of 0.5 M was
characteristic of all couplings preformed in these nanoreactors.
Reactions could also be run at 1.0 M with similar yields, but on a
small scale they were more difficult to monitor. Commercially
available surfactants other than TPGS-750-M were evaluated,
including Triton X-100, Brij 35, Solutol H15, and TPGS-1000
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Table 1. Comparison Reactions Conducted at RT for 24 h
Scheme 5. Synthesis of the Biaryl Core within Valsartan
reaction under micellar conditions involving an aryl bromide
gave a high yield of product 7. Switching to literature
conditions8a as to the source of Pd, ligand and solvent (aqueous
dioxane) gave poor results (27%). Even by increasing the amount
of Pd, ligand, and base, as prescribed for aryl chlorides in a
dioxane/water mix,8a only a modest yield (60%) was obtained.
The same trend holds with aryl chlorides, leading to biaryls 15
and 16.
could be obtained in water at RT uneventfully in 92% isolated
yield. 2-Chlorobenzonitrile can also be utilized as a coupling
partner, albeit with mild heating to 40 °C, to arrive at 17 in
essentially quantitative isolated yield.
Lastly, a 2-pyridyl MIDA boronate has been tested to
determine whether this class of particularly challenging coupling
partners might be amenable to micellar catalysis. The 2-pyridyl
subunit is especially common in pharmaceuticals,18 natural
products,19 and materials.20 Although only a single example (18;
Scheme 6) has as yet been screened, it reacted with remarkable
Following filtration of the diluted reaction mixture leading to
product isolation, the aqueous filtrate can be recycled. As
illustrated in Scheme 4, once an initial coupling is completed
Scheme 4. Sequence for Organic Solvent-Free Suzuki−
Miyaura Reactions: Couple/Filter/Recycle
Scheme 6. Preliminary Examples Using a 2-Pyridyl MIDA
Boronate in Suzuki−Miyaura Couplings in Water
a
b
The coupling partner was the corresponding aryl bromide. Isolated
yield after filtration; product determined to be >95% pure by 1H
NMR. The coupling partner was the corresponding aryl chloride.
c
facility with both an electron-rich and -poor aryl halide. Biaryls 19
and 20 were formed in good isolated yields using stoichiometric
amounts of each partner, in water at 40 °C. By contrast, the
traditional method includes 0.5 equiv of copper in the pot,21 an
alcohol additive, an excess of MIDA boronate, and is run in DMF
at 100 °C.8b
In summary, nanoreactors composed of an engineered
surfactant in water enable Suzuki−Miyaura couplings involving
MIDA boronates to be run efficiently in the complete absence of
organic solvents using a simple couple/filter/recycle sequence.
The huge excesses of heavy, inorganic bases in reaction mixtures
consisting of water and organic solvents that require heating in
these traditional couplings can now be replaced by very mild and
green conditions. Further studies on couplings involving a variety
of 2-pyridyl MIDA boronates of high relevance to the
pharmaceutical industry are in progress and will be reported in
due course.
(e.g., to give 5, 6, or 7; additional substrates in SI), each product
can be isolated by the dilution/filtration protocol. Upon addition
of TPGS-750-M so as to bring its level back to 2 wt %, the
aqueous solution could be recycled to regenerate biaryls 5 and 7,
which were again isolated using the same dilution/filtration
sequence. Clearly, the palladium catalyst must be retained in the
aqueous phase, in all likelihood assisted by the MIDA salt acting
as ligand.15,16 Each of these products was formed with an
associated E factor close to zero.
One application of this green chemistry focuses on the sartan
family of drugs, e.g., valsartan (Diovan), which is therapeutically
useful in treating congestive heart failure and high blood pressure
(Scheme 5).17 The biaryl core is a common intermediate and
should be derivable from a cross-coupling between 4-tolyl MIDA
boronate and 2-bromobenzonitrile. Indeed, biaryl product 17
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2011, 76, 5061 and references therein. (d) Lipshutz, B. H.; Ghorai, S.;
Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovskiy, A. J. Org.
Chem. 2011, 76, 4379.
(13) (a) Lipshutz, B. H.; Isley, N. A.; Fennewald, J. C.; Slack, E. D.
Angew. Chem., Int. Ed. 2013, 52, 10592 and references therein. (b) Our E
factor calculations take organic solvent only into consideration as waste.
(14) Aldrich catalog numbers 733857 and 763918.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
lipshutz@chem.ucsb.edu
■
(15) Report of MIDA acting as a ligand on palladium: Smith, B. B.;
Sawyer, D. T. Inorg. Chem. 1968, 7, 1526.
(16) Catalyst is clearly soluble within the surfactant solution only with
the addition of MIDA. Moreover, the Pd content within the product was
nearly 8 times lower if MIDA was employed in the filtration procedure
compared to its free boronic acid derivative. Details and pictures in SI.
(17) (a) Pandarus, V.; Desplantier-Giscard, D.; Gingras, G.; Beland, F.;
Ciriminna, R.; Pagliaro, M. Org. Process Res. Dev. 2013, in press, DOI:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support provided by the NIH (GM 86485) is warmly
acknowledged with thanks.
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