Fully automated continuous flow synthesis of highly functionalized imidazo[1,2-a] heterocycles

Article abstract of DOI:10.1021/ol902433a

[Chemical equation presented] The first continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids directly from 2-aminopyridines and bromopyruvic acid has been developed, representing a significant advance over the corresponding in-flask method. The process was applied to the multistep synthesis of imidazo[1,2-a]pyridine-2-carboxamides, including a Mur ligase inhibitor, using a two microreactor, multistep continuous flow process without isolation of intermediates.

Full text of DOI:10.1021/ol902433a

ORGANIC
LETTERS
2010
Vol. 12, No. 3
412-415
Fully Automated Continuous Flow
Synthesis of Highly Functionalized
Imidazo[1,2-a] Heterocycles
Ananda Herath, Russell Dahl, and Nicholas D. P. Cosford*
Program in Apoptosis and Cell Death Research and Conrad Prebys Center for
Chemical Genomics, Burnham Institute for Medical Research, 10901 North Torrey
Pines Road, La Jolla, California 92037
ncosford@burnham.org
Received October 21, 2009
ABSTRACT
The first continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids directly from 2-aminopyridines and bromopyruvic acid has
been developed, representing a significant advance over the corresponding in-flask method. The process was applied to the multistep synthesis
of imidazo[1,2-a]pyridine-2-carboxamides, including a Mur ligase inhibitor, using a two microreactor, multistep continuous flow process without
isolation of intermediates.
Over the past several years, high-throughput chemical
synthesis has become increasingly important because of its
potential to positively impact the drug discovery process.1-3
Two of the most common hurdles encountered in the
development of high-throughput syntheses of libraries of
complex molecules have been slow reaction times and
reliance on harsh or inconvenient reaction conditions.
Moreover, the optimization and purification of these reactions
are often time-consuming and inefficient. Automated mi-
croreactor-based (microfluidic chip) continuous flow systems
have the potential to greatly accelerate the production of
small molecule libraries.4,5 Advantages include efficient heat
transfer, enhanced reagent mixing, small reaction volumes,
and the potential to run multistep reactions in a single,
uninterrupted microreactor sequence using continuous flow
conditions.6,7 We are developing flow chemistry methods
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10.1021/ol902433a  2010 American Chemical Society
Published on Web 12/28/2009

for transformations that are either not possible or highly
inefficient using in-flask chemistry. This will enable the rapid
synthesis of highly functionalized, drug-like small molecules
in high purity and on a scale sufficient for evaluation in
multiple biological assays. We previously reported the
preparation of 1,2,4-oxadiazoles from arylnitriles and acti-
vated carbonyls in a single continuous flow sequence.7a We
now report the efficient, multistep, continuous flow synthesis
of diverse, highly functionalized imidazo[1,2-a] heterocycles
directly from commercially available starting materials.
The imidazo[1,2-a] heterocyclic scaffold is found in
compounds with anticancer, antiviral, and antimicrobial
activities and in modulators of the nervous system.8,9
Typically, the synthesis of imidazo[1,2-a] heterocycles
requires long reaction times and high temperatures, limiting
the accessibility of these biologically important structures.10
Direct condensation of 2-bromopyruvic acid with 2-ami-
nopyridines to generate imidazo[1,2-a]pyridine-2-carboxylic
acids is inefficient due to competing decarboxylation of the
product at high temperatures. Therefore, stepwise protocols
are generally used for the formation of imidazopyridine
carboxylic acid derivatives. For example, in a typical in-
flask procedure, ethyl bromopyruvate is condensed with
2-aminopyridine (Scheme 1).
Scheme 1. In-Flask Preparation of
Imidazo[1,2-a]pyridine-2-carboxylic Acids and
Imidazo[1,2-a]pyridine-2-carboxamides
The product ester is isolated and subjected to saponification
to provide the product.11 Naturally, each in-flask step
involves workup and purification of the intermediates. Herein
we report the first continuous flow synthesis of imidazo[1,2-
a]pyridine-2-carboxylic acids from 2-aminopyridines and
bromopyruvic acid using a single microreactor to enable the
rapid synthesis of these compounds. We further demonstrate
the incorporation of this procedure into a continuous, two
microreactor method for the highly efficient preparation of
a diverse library of amide derivatives.
Focusing initially on the flow synthesis of imidazo[1,2,a]
heterocyclic acids, we screened a variety of substrates and
reaction conditions using a single microreactor and found
that the use of a catalytic amount of p-toluenesulfonic acid
(PTSA) (0.25 equiv) efficiently provided the desired
products from 2-aminopyridines (1.0 equiv) and bromopy-
ruvic acid (1.2 equiv) in dimethylformamide (DMF) at
125 °C. Although previous in-flask studies reported the use
of protic solvents for the synthesis of this class of hetero-
cycles, DMF was selected due to its high boiling point and
excellent solubilizing properties. The 2-aminopyridine (0.5
M) and bromopyruvic acid (0.5 M) were introduced into the
microreactor, and PTSA was either flowed in via a separate
channel or premixed with the bromopyruvic acid. Reaction
monitoring by LCMS analysis showed that the conversion
of bromopyruvic acid to the corresponding imidazo[1,2-a]-
pyridine-2-carboxylic acid derivative was complete within
10 min in a preheated microreactor at 125 °C and 4.0 bar.
Under these conditions, a series of imidazo[1,2-a]pyridine-
2-carboxylic acids were efficiently synthesized in moderate
to high yields (Table 1).
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for the treatment of cancer.12 Our single-step synthesis that
provides the product in 63% yield constitutes a major
improvement over the reported two-step, in-flask procedure
to afford the product in 22% overall yield.
Table 1. Flow Synthesis of Imidazo[1,2-a]heteroaryl-2-carboxylic
Acids
To demonstrate the utility of the newly developed meth-
odology, our next goal was to develop a continuous flow
method to access imidazo[1,2-a]pyridine-2-carboxamides in
a single, uninterrupted process directly from readily available
starting materials. Optimization studies showed that a
combination of EDC/HOBt/DIPEA (1:1:2) for 10 min at 75
°C were the best conditions for complete conversion of the
imidazoheterocyclic acids to the corresponding amide deriva-
tives. Initial efforts to directly combine these two reactions
using two microreactors were unsuccessful. Experimentation
with a variety of reaction conditions demonstrated that
removal of PTSA from the first reaction and the separate
additions of solutions of EDC/HOBt (1:1) and amines/DIPEA
(1:1) were necessary to achieve conversion. The major
reaction competing with the amidation is the nucleophilic
addition of the amine to EDC. Thus, to compensate for this
side reaction the amidation reactions were performed using
an excess of base and amine. The final optimized conditions
employed were: (i) 1.2 equiv of bromopyruvic acid, (ii) a
residence time on the first microreactor of 20 min and a
temperature 100 °C, and (iii) the stream containing the
imidazo[1,2-a]pyridine-2-carboxylic acid exiting the first
microreactor was combined with a solution of EDC/HOBt
and amines/DIPEA in a second microreactor at 75 °C for
10 min (Figure 1).
a Isolated yield based on 1 after purification of a crude reaction mixture
using preparative HPLC. Reactions were performed on 0.45 mmol scale.
sized (Table 1). Reactions of 2-aminopyridines having
electron-donating (Table 1, entry 1) or electron-withdraw-
ing groups (Table 1, entries 2 and 4) proceeded efficiently
with moderate to excellent yields. Notably, functionalized
2-aminopyridines underwent cyclization leading to chloro-
(Table 1, entries 2, 5), bromo- (Table 1, entry 7), hydroxy-
(Table 1, entry 6), and amino- (Table 1, entry 5) substituted
imidazo[1,2-a]pyridine-2-carboxylic acids. One intriguing
observation was that this new method can be used to generate
free amine or hydroxyl group-containing imidazopyridine
carboxylic acids in an efficient manner, without the need to
use protecting groups. The product in Table 1, entry 4 is
notable since it is a dicarboxylic acid that is monoprotected
as the ester, allowing selective functionalization of the free
acid in subsequent synthetic transformations. Additionally,
the new flow method can be applied to the synthesis of other
imidazoheterocyclic scaffolds such as pyrimidines (Table 1,
entry 3), thiazoles (Table 1, entry 8), and benzothiazoles
(Table 1, entry 9). Significantly, the product in Table 1, entry
9 is a key intermediate for the preparation of AB530, a
recently disclosed FLT3 kinase inhibitor under evaluation
Figure 1. Continuous flow sequence for the synthesis of imi-
dazo[1,2-a]pyridine-2-carboxamides.
Several aspects of this new continuous flow process are
noteworthy. First, this is the first example of the synthesis
of imidazo[1,2-a]heteroaryl-2-carboxamides in a single con-
tinuous process, directly from readily available starting
materials (i.e., 2-aminopyridines and bromopyruvic acid). As
noted previously, the in-flask synthesis of these compounds
involves multiple reaction steps involving workup and
purification of multiple intermediates,13 often requiring the
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414
Org. Lett., Vol. 12, No. 3, 2010

use of strong Lewis acids.14 Second, until now, the acces-
sibility of these amides was limited due to the lack of
applicable methodologies to generate various amides using
commercially available starting materials. Finally, since this
method involves the introduction of amines in the final step,
it provides a convenient handle for further derivitization of
the products, and a wide variety of amides are accessible
simply by changing the amines.
hydroxyl (Table 2, entry 10) containing amides can be
synthesized efficiently. The tolerance of free amine and free
hydroxyl groups is particularly noteworthy since previous
syntheses of this type of scaffold were initially only
achievable in a stepwise manner.15 Finally, to demonstrate
the utility of the new method, we synthesized compound 3,
a Mur ligase inhibitor with potential antibacterial activity.16
The in-flask synthesis of this compound was reported to
proceed in 16.4% overall yield over two steps. Using our
continuous flow method, compound 3 was prepared in a
single step in 46% yield (Scheme 2).
This novel continuous flow method tolerates a wide range
of amines such as primary (Table 2, entries 3 and 7-12),
Table 2. Direct Multistep Synthesis of
Imidazo[1,2-a]pyridine-2-carboxamides from 1 and 2
Scheme 2
.
Continuous Flow Preparation of Mur Ligase
Inhibitor 3
In summary, we have developed novel continuous flow
methods for the synthesis of imidazo[1,2-a]pyridine-2-
carboxylic acids and imidazo[1,2-a]pyridine-2-carboxamides
using readily available starting materials and standard,
commercially available reagents. This work documents the
first highly efficient synthesis of imidazo[1,2-a]pyridine-2-
carboxylic acids and amides directly from 2-aminopyridines
and bromopyruvic acids. Furthermore, the continuous flow
nature of our synthesis enables the facile scale-up of these
compounds, which is highly advantageous for drug discovery.
We anticipate that these advances will facilitate the rapid
synthesis of these biologically important scaffolds. Further
exploration of the reactivity features of the process and
applications to focused library synthesis of complex biologi-
cally active molecules is in progress.
a Isolated yield based on 1 after purification of the crude reaction mixture
using preparative HPLC. Reactions were performed on a 0.38 mmol scale.
Acknowledgment. This work was supported by National
Institutes of Health grant nos. HG005033, GM079590, and
GM081261.
secondary (Table 2, entries 4 and 5), aryl (Table 2, entry 1),
heteroaryl (Table 2, entry 2), and heterocyclic (Table 2, entry
5). It is noteworthy that comparatively unreactive 3-ami-
nopyridine couples efficiently (Table 2, entry 2). Addition-
ally, amino acid derivatives can directly couple efficiently
to introduce further complexity to the final products (Table
2, entry 6). Furthermore, different imidazo[1,2-a]heterocar-
boxamides such as thiazoles and pyrimidines can be accessed
efficiently. Moreover, free amines (Table 2, entry 9) and free
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds including
1H, 13C NMR spectra and MS data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902433A
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