Condensation-Driven Assembly of Boron-Containing Bis(Heteroaryl) Motifs Using a Linchpin Approach

Article abstract of DOI:10.1021/acs.orglett.5b02741

Herein, we describe the bromomethyl acyl boronate linchpin-an enabling reagent for the condensation-driven assembly of novel bis(heteroaryl) motifs. This building block is readily accessible from commercially available starting materials. A variety of 2-a

Full text of DOI:10.1021/acs.orglett.5b02741

Letter
pubs.acs.org/OrgLett
Condensation-Driven Assembly of Boron-Containing Bis(Heteroaryl)
Motifs Using a Linchpin Approach
Shinya Adachi,† Sean K. Liew,† C. Frank Lee,† Alan Lough,† Zhi He,† Jeffrey D. St. Denis,†
Gennady Poda,‡,§ and Andrei K. Yudin*,†
†Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON M5S 3H6,
Canada
‡Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, ON
M5G 0A3, Canada
§Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada
S
* Supporting Information
ABSTRACT: Herein, we describe the bromomethyl acyl boronate
linchpin−an enabling reagent for the condensation-driven assembly of
novel bis(heteroaryl) motifs. This building block is readily accessible
from commercially available starting materials. A variety of 2-amino-
and 2-methylpyridines were reacted with MIDA-protected bromo-
methyl acylboronate to afford 2-boryl imidazo[1,2-a]pyridine and 2-
boryl indolizine derivatives, respectively, in excellent yields. Subsequent
condensation with hydroxyamidines and hydrazonamides converted
the intermediate heterocycles into novel boron-containing bis-
(heteroaryl) units characterized by high thermal stability.
ontemporary approaches to drug discovery emphasize the
need to access diverse and underexplored chemical space
imidazo[1,2-a]pyridines and indolizines, are present in a wide
range of bioactive molecules.6,7 Many of these molecules have
been extensively exploited in drug discovery and, as defined by
Evans, are often called “privileged scaffolds” based on their
ability to bind multiple protein targets.8 It was our hope to
develop a chemoselective process toward novel privileged
scaffolds with substitution patterns that cannot be easily
accessed using alternative means. We also sought to use this
technology to generate entirely new bis(heterocycle) motifs
that would accommodate boron as an integral part of the new
ring system.
To initiate our studies, we aimed to synthesize the doubly
electrophilic parent bromomethyl acylboronate building block
3,9 which was unattainable using our previous methodology.9d
Starting from commercially available 2-MIDA (N-methylimino-
diacetic acid) boryl10,11 oxirane 1,10b the epoxide was
regioselectively ring-opened with lithium bromide in the
presence of acetic acid. The crude α-bromomethyl alcohol 2
was directly subjected to Dess−Martin oxidation, which
afforded the bromomethyl acylboronate 3 in 65% overall
yield in just two steps (Scheme 1). This synthesis involves only
one purification step and can also be performed on gram scale.
Having secured a short and scalable route to 3, we pursued
heterocycle synthesis via a condensation/substitution reaction
sequence. We first experimented with 2-aminopyridine 4a
(Table 1). The reaction mixture of 3 with 4a in acetonitrile was
C
to ensure the novelty of new chemical entities (NCEs). One
way to address this challenge is to produce complex organic
molecules and synthetically manipulate their skeletons. While
this strategy has many attractive features at the drug
development stage,1 it may not be easily transferable to the
discovery of bioactive molecules due to high C-sp3 content in
many natural product-inspired frameworks. This is the reason
why fragment-based discovery approaches emphasize relatively
small, sp2-rich scaffolds that enable the discovery of promising
molecules with high ligand efficiency.2 To be relevant in drug
discovery, such strategy is likely to rely on heteroaromatics, a
well-established modality that is known to deliver drug
candidates.3
We have pursued synthetic tools to rapidly build novel
bis(heterocycle) chemotypes with unusual connectivity be-
tween the two components. We felt that such strategy must (a)
have its origin in a readily accessible amphoteric linchpin and
employ simple starting materials and (b) deliver privileged
structural end points while simultaneously facilitating access to
hitherto unexplored chemotypes. In the present manuscript, we
report a successful realization of this concept using
bromomethyl acylboronate and its use in the condensation-
based synthesis of novel bis(heteroaryl) motifs.4
Pyridine is second to only benzene as the most frequently
used ring system found in the FDA’s Orange Book of Small
Molecule Drugs.5 It is for this reason that synthetic chemists
have shown tremendous interest in the synthesis of pyridine-
containing compounds. Fused derivatives of pyridine, such as
Received: September 27, 2015
© XXXX American Chemical Society
A
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Letter
excellent yield (entry 1). The scope of this synthesis was
explored with a range of substituted 2-aminopyridines. The
reaction with 2-amino-4-methoxypyridine afforded the corre-
sponding product in high yield (6b, entry 2). Aminopyridines
containing electron-withdrawing substituents at the 3-, 4-, or 5-
position, such as trifluoromethyl, nitro, and ester groups (4c−
e), were tolerated in this process, but required longer reaction
times (entries 3−5). We found that increasing the temperature
to 80 °C allowed for a reduction of reaction time without
substantially compromising the yield of 6e. Unfortunately, the
yield of 6c was nearly halved under the same conditions. 5-
Iodo- and 3-benzyloxy-2-aminopyridines 4f,g also furnished the
corresponding products in high yields (6f,g, entries 6−7). The
reaction of 2-aminopyrimidine 4h proceeded to full conversion,
however, the product 6h decomposed during aqueous workup.
We were able to circumvent aqueous workup by replacing
triethylamine with Amberlite IRA-67, which furnished the
desired product 6h in high yield after chromatography (entry
8). The reaction of 1-aminoisoquinoline 4i with the
bromomethyl acylboronate was also performed in the presence
of Amberlite IRA-67 (entry 9).
Scheme 1. Synthesis of Bromomethyl Acylboronate 3
Table 1. Synthesis of 2-MIDA Boryl Imidazo[1,2-a]pyridines
a
and Indolizines
With our success in isolating previously inaccessible 2-
borylated imidazo[1,2-a]pyridines, we focused our attention on
the synthesis of 2-substituted indolizines.12 Expanding our
methodology of condensation-based cyclizations with 2-
alkylated pyridines was projected to furnish these difficult-to-
access products with complete regioselectivity. The reaction of
2-methylpyridines 5a−c and 2-ethylpyridine 5d with bromo-
methyl acylboronate 3 using the same protocol as the one used
with 2-aminopyridines afforded 2-MIDA boryl indolizines 7a−
d in good yields (entries 10−13). 2-Pyridylacetonitrile 5e and
ethyl-2-pyridylacetate 5f were also used to produce the
corresponding boryl indolizine 7e,f in good yields, although
an excess of the pyridine was required to achieve full conversion
(entries 14 and 15).
To the best of our knowledge, 2-boryl derivatives of
imidazo[1,2-a]pyridines and indolizines have not been reported
in the literature. This can be attributed to the regioselectivity
issues associated with conventional heterocycle borylation
strategies.13 Our condensation-based approach allows for
exclusive access to 2-borylated heterocycles that can be further
used for the construction of novel bis(aryl) motifs.
With the surging interest to incorporate boron into aromatic
structures,14 we aimed to adopt our linchpin approach toward
the synthesis of boron-containing bis(heteroaryl) systems using
condensation as the sole synthetic operation. The use of readily
available hydroxyamidines 8 and hydrazonamide 9 serves a
twofold purpose: (a) to act as a bidentate ligand to chelate
boron15,16 and (b) to fulfill the electronic requirements of
Huckel’s rule when chelated to boron to produce an aromatic
̈
heterocycle. Although 2-MIDA boryl imidazo[1,2-a]pyridines 6
were unsuitable for the reaction with 8 and 9 due to the
competing protodeboronation process, the free boronic acids of
indolizines 7a−f reacted with 8 to successfully afford novel 2-
indolizyl-oxadiazaboroles (IN-OZBs) 10 in high yields
(Scheme 2). Benzohydrazonamide 9 was also reacted with
indolizines 7a−c,e,f to produce the corresponding 2-indolizyl-
triazaboroles (IN-TZBs) 11 in good yields.
a
Unless otherwise noted the reaction was carried out under the
following conditions: bromomethyl acylboronate 3 (0.10−0.48 mmol,
1.0 equiv), 4 or 5 (1.0 equiv), Et3N (3.0 equiv), MeCN, 70 °C.
b
c
Reaction was performed at 80 °C. Amberlite IRA-67 was used
d
e
We were able to grow X-ray quality crystals of 10a and 11a.17
The X-ray structure of 10a and 11a (Figures 1 and 2) revealed
that the OZB and TZB rings are planar, further confirming
their aromatic character. In IN-OZB 10a, the OZB ring forms
dihedral angles of 28.64(19)° with the phenyl ring and
instead of Et3N. 1.2 equiv 3 was used. 2.0 equiv 5 were used.
stirred at 70 °C for 30 min, followed by the addition of
triethylamine. After aqueous workup and silica gel chromatog-
raphy, 2-MIDA boryl imidazo[1,2-a]pyridine 6a was isolated in
B
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Letter
We ran additional experiments to further understand the
stability profiles of our molecules. The melting points of 10a
and 11a are 205 and 189 °C, respectively, indicating that IN-
OZBs 10 and IN-TZBs 11 possess excellent thermal stability.
When exposed to protic solvents such as d6-DMSO/water or
d4-methanol, IN-OZBs 10 undergo partial solvolysis to
Scheme 2. Synthesis of IN-OZBs 10 or IN-TZBs 11
1
hydroxyamidines 8, as indicated by H NMR experiments. In
contrast, IN-TZBs 11 showed high resistance toward solvolysis
under the same experimental conditions (see Supporting
Information). Our ability to fine-tune the heterocycle stability
based on the composition of the boron chelate may find
application in self-healing boronic acid based materials, where
pH based stability is the prevailing feature.18
We also assessed the potential of borylated heterocycles in
other applications. It is known that 2-boryl azacycles (e.g., 2-
pyridyl boronic acid) are unfavorable substrates for cross-
coupling due to their high propensity for protodeboronation.10c
It was recently reported that the Suzuki-type reaction of MIDA-
protected pyridyl boronic acids can be achieved in the presence
of a Buchwald palladacycle and Cu(OAc)2.10c,19 We applied
this methodology to successfully cross-couple our imidazo[1,2-
a]pyridine 6a with 4-bromobenzonitrile catalyzed by XPhos-
G3-Palladacycle (XPhos Pd G3)20 to produce biaryl 12 in 73%
yield (Scheme 3).
Scheme 3. Suzuki-Type Cross-Coupling Reaction of 2-MIDA
Boryl Imidazo[1,2-a]pyridine 6a
Figure 1. Contacts in the crystal structure of 10a.
2-MIDA boryl indolizine 7a was also transformed into the
corresponding BF3K salt 13 in 94% yield by deprotection of
MIDA followed by treatment with KHF2 (Scheme 4). Recently,
Scheme 4. Synthesis of 2-Indolizyl Potassium
Trifluoroborate
Figure 2. Contacts in the crystal structure of 11a.
26.18(17)° with the indolizine ring system, while in IN-TZB
11a the TZB ring forms dihedral angles of 14.41(6)° with the
phenyl ring and 16.71(5)° with the indolizine ring system. In
the crystal, molecules of IN-OZB 10a are linked by weak
bifurcated N---H···(N,O) hydrogen bonds to form chains along
[010]. It is apparent that the N and O atoms each participate as
hydrogen bond acceptors to the NH of a second equivalent of
the molecule. In contrast, simply swapping the O atom in the
OZB to an NH as in TZB 11a introduces a second hydrogen
bond donor in the molecule and completely changes the
intermolecular contacts in the crystal structure. It is particularly
intriguing that, of the two NH contacts on the boron atom, one
is participating in a conventional N---H···N hydrogen bond to
form chains along [010], while the other is participating in a
weak N---H···π(arene) interaction to complete a two-dimen-
sional network parallel to [001]. OZBs 10 may be viewed as
BN analogues of oxazoles and isoxazoles, while the TZBs 11
may be perceived as BN isosteres of imidazoles and pyrazoles,
all of which are frequently utilized components within bioactive
compounds.
Perrin and co-workers demonstrated that 18F-labeled com-
pounds could be used as small molecule tracers.21 Our
methodology offers a unique condensation-driven route toward
new 18F-labeled heterocyclic chemotypes.
In summary, we have outlined a strategy that applies the
previously elusive bromomethyl acylboronate toward the
construction of novel bis(heteroaryl) motifs. Our synthesis
utilizes straightforward condensation processes, offering a rare
example of a bottom-up synthesis of unexplored chemotypes.
We also demonstrate how one can run consecutive
condensation reactions using a boron-based linchpin and
obtain heteroaromatic units that are linked by C−B bonds.
This approach to build bis(heteroaryl) units leads to the
installation of boron-based heterocycles that are difficult to
procure using any other means. In addition, the condensation
protocol we describe is governed by different regiochemistry
rules compared to conventional heteroaromatic borylation
reactions. We believe that our strategy will open access to novel
C
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Letter
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because the intermolecular contacts furnished by OZB and
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The Supporting Information is available free of charge on the
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glett.5b02741.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
Crystallographic data for 10a (CIF)
Crystallographic data for 11a (CIF)
Analytical data (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ayudin@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
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We thank the Natural Science and Engineering Research
Council (NSERC) for funding. G.P. would like to acknowledge
the support of the Ontario Institute for Cancer Research and
funding from the Government of Ontario. The authors wish to
acknowledge NSERC and the Canadian Foundation for
Innovation, Project Number 19119, and the Ontario Research
Fund for funding of the Centre for Spectroscopic Investigation
of Complex Organic Molecules and Polymers.
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