General method for synthesis of 2-heterocyclic N-methyliminodiacetic acid boronates

Article abstract of DOI:10.1021/ol100671v

A wide range of 2-pyridyl and other difficult-to-access heterocyclic N-methyliminodiacetic acid boronates can be readily prepared from the corresponding bromides via a new method involving direct transligation of 2-heterocyclic trialkoxyborate salts with N-methyliminodiacetic acid (MIDA) at elevated temperatures.

Full text of DOI:10.1021/ol100671v

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2314-2317
General Method for Synthesis of
2-Heterocyclic N-Methyliminodiacetic
Acid Boronates
Graham R. Dick, David M. Knapp, Eric P. Gillis, and Martin D. Burke*
Howard Hughes Medical Institute, Roger Adams Lab, UniVersity of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
burke@scs.uiuc.edu
Received March 22, 2010
ABSTRACT
A wide range of 2-pyridyl and other difficult-to-access heterocyclic N-methyliminodiacetic acid boronates can be readily prepared from the
corresponding bromides via a new method involving direct transligation of 2-heterocyclic trialkoxyborate salts with N-methyliminodiacetic
acid (MIDA) at elevated temperatures.
Most small molecules are highly modular in their constitu-
tion.1,2 To maximally harness this inherent modularity, we
aim to develop a general platform of building blocks
representing the substructural motifs that most commonly
appear in a wide range of targeted structures.3 In this regard,
a collection of air-stable and environmentally friendly
2-pyridyl building blocks represent a very important objec-
tive, as this subunit is found in many pharmaceuticals,4
natural products and/or their derivatives,5 unnatural nucle-
otides,6 fluorescent probes,7 metal-complexing ligands,8 and
materials.9
acids are notoriously unstable, which precludes their effective
utilization.10 Many different types of surrogates for 2-het-
erocyclic boronic acids have been developed, including
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10.1021/ol100671v  2010 American Chemical Society
Published on Web 04/29/2010

trifluoroborate salts,11 trialkoxy or trihydroxyborate salts,12
diethanolamine adducts,13 sterically bulky boronic esters,14
and boroxines.15 Important advances with 2-heterocyclic
silanolates have also recently been reported.16 However, it
remains a challenge to develop air-stable and chemically pure
2-pyridyl building blocks.17
We recently reported that 2-heterocyclic N-methylimino-
diacetic acid (MIDA) boronates can serve as stable and
highly effective surrogates for a wide range of unstable
2-heterocyclic boronic acids under “slow-release” cross-
coupling conditions.3e We also discovered that 2-pyridyl
MIDA boronate 1a is the first air-stable 2-pyridyl borane
that can be isolated in chemically pure form and is a very
convenient cross-coupling partner under modified slow-
release conditions.3e However, our preliminary synthesis of
this building block was cumbersome, low yielding, and not
scalable.3e Given the broad potential utility of 2-heterocyclic
MIDA boronates for many diverse applications,4-9 we
pursued a practical, scalable, and general method for their
synthesis. Building on the surprising discovery that 2-pyridyl
MIDA boronate 1a is stable in anhydrous DMSO even at
130 °C, we herein report that a broad range of 2-pyridyl
and other challenging-to-access heterocyclic MIDA boronates
can be prepared from the corresponding readily available
bromides via a new method involving direct transligation of
trialkoxyborate salts with MIDA at elevated temperatures
(Figure 1).
Figure 1. New method that provides access to a wide range of
2-pyridyl and other difficult-to-access MIDA boronates from the
corresponding readily available bromides.
Lithium triisopropyl 2-pyridyl borate18 3 is known to be
a useful intermediate for preparing other boronic acid
surrogates10,13 and for cross-coupling with a range of aryl
halides.12a In preliminary studies, however, we were only
able to achieve a low yield of 1a from 3.3e For example, the
dropwise addition of a freshly prepared THF solution of 3
to a stirred suspension of MIDA in DMSO at 55 °C over
1 h (Figure 2A) resulted in a very low (∼10%) and poorly
reproducible yield of 1a (Figure 2B). A major byproduct
observed in this reaction was pyridine, suggesting that
protodeborylation of the notoriously labile 2-pyridyl-boron
bond was a predominant competing pathway.
(11) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286.
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(13) (a) N-Phenyldiethanolamine 2-pyridylboronate is prepared as a
structurally undefined complex containing variable quantities of isopropyl
and N-phenyldiethanolamine groups and a stoichiometric quantity of lithium:
Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685–687. (b)
Jones, N. A.; Antoon, J. W.; Bowie, A. L.; Borak, J. B.; Stevens, E. P.
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adducts: Gravel, M.; Thompson, K. A.; Zak, M.; Be´rube´, C.; Hall, D. G. J.
Org. Chem. 2002, 67, 3–15. (d) A solid-supported diethanolamine-bound
2-pyridyl reagent has also been reported: Gros, P.; Doudouh, A.; Fort, Y.
Tetrahedron Lett. 2004, 45, 6239–6241.
Figure 2. (A) Method for the preparation of 2-pyridyl MIDA
boronate 1a from 2a via the intermediacy of triisopropoxyborate
1
salt 3. (B) Yield of 1a (via H NMR, average of two runs) as a
function of the internal reaction temperature.
With the goal of minimizing this side reaction, we initially
explored a wide range of complexation conditions involving
milder temperatures. However, as shown in Figure 2B,
reducing the temperature always resulted in even lower yields
of 1a. Prompting us to reverse our approach, we discovered
in parallel studies that 1a is surprisingly stable in hot DMSO.
For example, heating a solution of 1a in d6-DMSO at 130
°C for one hour caused no change in the 1H NMR spectrum
(see Supporting Information (SI)), which suggested that the
undesired protodeborylation observed in the transligation
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2004, 69, 2210–2212.
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Org. Lett., Vol. 12, No. 10, 2010
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reaction was occurring prior to MIDA complexation. This
led us to question whether alternatively increasing the
reaction temperature might enable a rapid transligation to
form the very stable MIDA boronate 1a prior to the
decomposition of its precursor 3. Consistent with this
hypothesis, we discovered that raising the internal temper-
ature from 55 to g115 °C resulted in a 6-fold increase in
the yield of 1a (see Figure 2B). Moreover, the procedure
proved to be highly reproducible at these elevated temper-
atures.
solid on the benchtop under air without decomposition for
more than 1 year (see SI for details).
A preliminary survey of scope has further revealed that a
wide variety of 2-pyridyl bromides can also be transformed
into the corresponding 2-pyridyl MIDA boronates using this
same methodology. Specifically, 6-, 5-, and 4-methyl-2-
pyridyl subunits appear in a wide variety of pharmaceuticals,
materials, and metal ligands, and the corresponding MIDA
boronate building blocks 1b-1d can be readily accessed on
gram-scale (entries 2-4). It would also be highly advanta-
geous in drug discovery to have access to a collection of
air-stable 2-pyridyl building blocks having both electron-
releasing and electron-withdrawing groups. Accordingly,
6-methoxy- and 6-, 5-, and 4-trifluoromethyl-2-pyridyl MIDA
boronates 1e-1h were all prepared with this same procedure
(entries 5-8). Bromo-substituted 2-pyridyl MIDA boronates
1i and 1j, each having the potential for a range of iterative
cross-coupling applications,3 were also conveniently syn-
thesized via monofunctionalization of dibromo pyridines 2i
and 2j (entries 9 and 10). Remarkably, all of these 2-pyridyl
MIDA boronates 1a-j are air- and chromatographically
stable, highly crystalline, monomeric, free-flowing solids (SI).
Table 1. Synthesis of 2-Pyridyl MIDA Boronates
Scheme 1
Importantly, all of the reagents used in this novel protocol
can be readily accessed for very low cost,20 including the
MIDA ligand. Using a new procedure involving reversed
order of reagent additions compared to that reported
previously,3f,21 MIDA can now be easily prepared on the
kilogram scale from the commodity chemicals iminodiacetic
acid, formaldehyde, and formic acid (Scheme 1, see SI for
details). Tens of thousands of metric tons of iminodiacetic
acid are produced each year as a starting material for
herbicides, surfactants, and environmental chelating re-
agents.22 Thus, this starting material is very inexpensive.23
(19) (See SI for full details.) To a stirred solution of 2-bromopyridine
(9.5 mL, 97 mmol) and triisopropyl borate (19.5 mL, 84.8 mmol) in THF
(175 mL) at -78 °C was added dropwise n-BuLi (2.5 M in hexanes, 36
mL, 90 mmol). The resulting solution was warmed to 23 °C and added
over one hour to a stirred solution of MIDA (25.4 g, 173 mmol) in DMSO
(175 mL) at 115 °C. The resulting mixture was cooled to 23 °C and filtered.
The filtrate was deacidified with solid K3PO4 (72.6 g, 342 mmol) and
concentrated in vacuo. The resulting residue was precipitated from CH3CN:
CH2Cl2:Et2O to afford 1a (11 g, 55%).
(20) 2-Bromopyridine, n-BuLi, and (i-PrO)3B can be purchased on the
kilogram scale for <$20/mol (Spectrum Chemicals, Gardena, CA, USA),
<$31/mol (Beta Pharma, New Haven, CT, USA), and <$28/mol (Matrix
Scientific, Columbia, SC, USA), respectively.
This new method was easily reproduced on the gram scale
to provide 2-pyridyl MIDA boronate 1a in 59% isolated yield
after silica gel chromatography (Table 1, entry 1). An
optimized procedure was also developed for preparing 1a
on the decagram scale without the use of chromatography.19
This highly crystalline building block has been stored as a
(21) (a) Childs, A. F.; Goldsworthy, L. J.; Harding, G. F.; King, F. E.;
Nineham, A. W.; Norris, W. L.; Plant, S. G. P.; Selton, B.; Tompsett,
A. L. L. J. Chem. Soc. 1948, 2174–2177. (b) Chase, B. H.; Downes, A. M.
J. Chem. Soc. 1953, 3874–3877
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(22) Yangong, Z. China Chem. Reporter 2005, 16 (8), 16.
(23) Iminodiacetic acid can be purchased on the kilogram scale for
<$5.50/mol (City Chemical, West Haven, CT, USA).
2316
Org. Lett., Vol. 12, No. 10, 2010

Specifically, mole per mole, iminodiacetic acid is more than
five times cheaper than n-BuLi.20,23 MIDA is also completely
biodegradable,24 thus making MIDA boronates a very
environmentally friendly alternative to the corresponding
organostannanes.17 Finally, the highly crystalline and air-
stable nature of MIDA boronates greatly facilitates their
isolation, purification, and storage, making them highly
attractive intermediates. Given all of these features, this new
method stands to provide practical access to a wide range
of 2-heterocyclic and other types of very useful MIDA
boronate building blocks with an array of important applica-
tions. In fact, several of the new building blocks reported
herein are already commercially available.25
We have also preliminarily explored the potential of this
new protocol to provide access to other types of very
challenging-to-access heterocyclic boranes. For example,
thiazole subunits appear in many pharmaceuticals, ligands,
fluorescent probes, and materials, as well as a wide range of
NRPS-derived natural products.1,5c,26,27 However, the cor-
responding boronic acids again suffer from substantial
stability issues.26,27 Using an unoptimized version of this
same protocol, 5-thiazolyl MIDA boronate 5 was accessed
from the corresponding bromide 4, and this new heterocyclic
borane also proved to be indefinitely air-stable (SI, structure
confirmed by X-ray crystallography, Scheme 2).
Scheme 3
MIDA boronate 7 (structure confirmed by X-ray crystal-
lography), and this new building block has also proven to
be indefinitely air-stable (SI).
In summary, we have developed a practical, scalable, and
cost-effective method for preparing a wide range of previ-
ously challenging-to-access heterocyclic MIDA boronates
involving direct transligation of the corresponding readily
accessible triisopropoxyborate salts. Importantly, this new
method completely avoids the intermediacy of boronic acids.
In several cases, the building blocks described herein
represent the first examples of the corresponding heterocyclic
boranes that can be isolated as air-stable materials in
chemically pure form. This methodology and the novel
MIDA boronates that it can access stand to have a highly
enabling impact on the synthesis of a wide range of
pharmaceuticals, natural products, and materials.
Acknowledgment. We gratefully acknowledge the NSF
(CAREER 0747778) and Bristol-Myers Squibb for funding
and Aldrich for reagents. D.M.K. is an NIH CBI Training
Grantee, E.P.G. is a BMS Graduate Fellow, and M.D.B. is
a HHMI Early Career Scientist, Beckman Young Investiga-
tor, Sloan Research Fellow, Dreyfus New Faculty Awardee,
Bristol-Myers Squibb Unrestricted Grant in Synthetic Or-
ganic Chemistry Awardee, Eli Lilly Grantee, Amgen Young
Investigator, and AstraZeneca Excellence in Chemistry
Awardee.
Scheme 2
As a final example, 2-pyrazine subunits are very important
in medicinal chemistry and many other applications.28
However, to the best of our knowledge, there are no
previously reported examples of air-stable 2-pyrazinyl borane
building blocks. As shown in Scheme 3, using the standard
conditions described above, 2-bromopyrazine 6 was ef-
fectively transformed into the corresponding 2-pyrazinyl
Supporting Information Available: Procedures and
characterization for all new compounds as well as spectral
and X-ray crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL100671V
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