Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

Article abstract of DOI:10.3762/bjoc.13.26

A versatile continuous-flow synthesis of highly functionalized 1,2,4-oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a single-step liquid-liquid microextraction unit to remove high boiling point polar solvents and impurities and provides the target compounds in high purity with excellent overall yields.

Full text of DOI:10.3762/bjoc.13.26

Continuous-flow synthesis of highly functionalized
imidazo-oxadiazoles facilitated by microfluidic extraction
Ananda Herath and Nicholas D. P. Cosford*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 239–246.
Cancer Metabolism & Signaling Networks Program, Sanford Burnham
Prebys Medical Discovery Institute, 10901 North Torrey Pines Road,
La Jolla, California 92037, USA
doi:10.3762/bjoc.13.26
Received: 01 October 2016
Accepted: 06 January 2017
Published: 07 February 2017
Email:
Nicholas D. P. Cosford* - ncosford@sbpdiscovery.org
This article is part of the Thematic Series "Automated chemical
synthesis".
* Corresponding author
Keywords:
Guest Editor: I. R. Baxendale
imidazo[1,2-a]pyridine; imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazole;
liquid–liquid extraction module; microreactor; 1,2,4-oxadiazole
© 2017 Herath and Cosford; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A versatile continuous-flow synthesis of highly functionalized 1,2,4-oxadiazoles starting from carboxylic acids is reported. This
process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep con-
tinuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a single-step
liquid–liquid microextraction unit to remove high boiling point polar solvents and impurities and provides the target compounds in
high purity with excellent overall yields.
Introduction
The design and execution of scalable and economically viable On the other hand, a significant challenge in flow chemistry is
processes for the preparation of biologically active small mole- the formation of insoluble intermediates in the reactor. This can
cules is a major hurdle in modern organic synthesis. The devel- often be prevented by using polar organic solvents such as
opment of batch processes that combine multiple reactions into dimethylformamide (DMF) [7-9,15]. However, the challenges
“one-pot” have been used successfully in some cases [1-6]. of removing large amounts of high boiling solvents during the
However, this approach has a number of drawbacks, primarily purification and isolation process can limit scalability and effi-
because of mutual interference between various reactive com- ciency. Furthermore, many useful synthetic reactions are
ponents. Recently, continuous-flow chemistry has emerged as a incompatible with the use of DMF as a solvent. Recently
powerful technique in organic synthesis. This is in part due to several unit operations have successfully been implemented in
the potential for integrating individual reaction steps and subse- continuous-flow syntheses to allow separations and purifica-
quent separations into a single streamlined process [7-14].
tions in a continuous fashion, such as liquid–liquid microextrac-
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Beilstein J. Org. Chem. 2017, 13, 239–246.
tion [12,16-20] or microfluidic distillation [21,22]. Herein we and drug leads including sphingosine-1-phosphate 1 (S1P1) re-
describe the utilization of liquid–liquid microextraction to facil- ceptor agonists [25-27] and metabotropic glutamate subtype 5
itate a complex, multistep flow synthesis process.
(mGlu5) receptor negative allosteric modulators (NAMs)
[25,28-30]. Most synthetic efforts toward the preparation of
Our research in the field of flow synthesis has focused on devel- these heterocyclic systems utilize a multistep, in-flask approach
oping continuous-flow chemistry methods to access complex, as illustrated by the synthesis of S1P1 agonists (Scheme 1).
drug-like molecules from readily available precursors without Thus, a typical batch synthesis entails the formation of an
isolation of intermediates. We have shown that the “tele- amidoxime by reacting an arylnitrile with hydroxylamine in the
scoping” of multiple synthetic steps into a single continuous presence of a base [29-31]. The amidoxime is then combined
process provides an efficient method for the production of with a carboxylic acid derivative in the presence of a coupling
heterocyclic compound libraries in sufficient quantities for bio- reagent. The target oxadiazole is then formed via an intramolec-
logical screening in high-throughput assay formats as well as ular cyclodehydration (Scheme 1) [27,32-34].
follow-up confirmatory studies. We previously reported a
method for the preparation of 1,2,4-oxadiazoles in an uninter- For our initial studies on the development of a flow synthesis of
rupted continuous-flow sequence using arylnitriles and acyl 1,2,4-oxadiazoles we focused on the reaction of N-hydroxynico-
chloride precursors [9]. We also reported the flow synthesis of tinimidamide with 3-bromobenzoic acid (Table 1). Screening a
highly functionalized imidazo[1,2-a]heteroaryl derivatives from variety of reaction conditions using a single microreactor we
readily available starting materials in a single continuous found that the combination of EDC/HOBt/DIPEA (1:1:1) for
process [7]. We now report an efficient continuous-flow proce- 10 min at 150 °C provided the best conditions for complete
dure for the synthesis of 1,2,4-oxadiazoles directly from aryl- conversion of 3-bromobenzoic acid to the corresponding 1,2,4-
nitriles and carboxylic acid derivatives. We further demonstrate oxadiazole derivative (Table 1, entry 5). The use of N,N-
the incorporation of this procedure into a continuous, three- dimethylformamide (DMF) as a solvent resulted in competitive
microreactor method for the highly efficient preparation of a amide formation from the decomposition product of DMF at
diverse library of imidazo-oxadiazole derivatives. Moreover, high temperature. In order to prevent this we switched to N,N-
this continuous-flow method was successfully combined with a dimethylacetamide (DMA) as the solvent.
single-step liquid–liquid microextraction unit to remove high
boiling point polar solvents and impurities.
We next focused our efforts on combining this optimized oxadi-
azole ring-closure procedure with our previously reported flow
synthesis of amidoximes by the reaction of hydroxylamine with
Results and Discussion
Historically the 1,2,4-oxadiazole scaffold has been used by me- precursor aryl- and heteroarylnitriles (Table 2). These two reac-
dicinal chemists as a ubiquitous bioisosteric replacement of tions were successfully perfomed in flow with slight modifica-
amide and ester functionalities in a wide variety of biologically tions to the reaction conditions to generate a variety of 1,2,4-
active compounds [23,24]. This motif is found in several drugs oxadiazoles (Table 2). Reactions of arylnitriles having electron-
Scheme 1: In-flask (batch) preparation of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles (S1P1 agonists) [27].
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Table 1: Optimization of the flow synthesis of 1,2,4-oxadiazoles.
Entry
T [°C]
Product Ratio 2a:2ba
1
2
3
4
5
50
75
0:100b
3:97
100
125
150
18:82
80:20
99:1
aCompound ratios were determined using LC–MS (see Figure S1 in Supporting Information File 1). bCompound 2a was not observed.
donating (Table 2, entry 7) or electron-withdrawing groups assembled as shown in Table 3. The first reaction, the forma-
(Table 2, entries 1, 2, 4 and 8) proceeded efficiently in good to tion of imidazo[1,2-a]pyridine-2-carboxylic acid, was per-
excellent overall yields. Additionally, a range of aliphatic and formed in a 1000 μL reactor (glass chip) at 100 °C. The acid
aromatic acids were tolerated under these reaction conditions to exiting the first reactor was combined with EDC/HOBt/DIPEA
produce the corresponding oxadiazoles in high yields. Several (1:1:1) in a T-mixer. The synthesis of amidoxime was achieved
advantages of this methodology compared to our previously re- by placing a second reactor (250 μL glass chip) in a heated sili-
ported flow synthesis should be noted. First, this method is cone oil bath at 100 oC. The product stream was next intro-
more facile because no cooling step is necessary before flowing duced into a third reactor (1000 μL) and mixed with the stream
into the second microreactor. Secondly, many more carboxylic exiting from the T-mixer at 150 oC. Initial studies suggested
acid derivatives are readily available (purchased or easily syn- that premixing of acid and coupling reagent was efficient and
thesized) than acyl chlorides allowing access to greater diver- provided better yields. The substrate scope of this continuous
sity. Finally, this method is easily adapatable to the synthesis of flow method is shown in Table 3. Thus, this flow method
compounds with increasing complexity, as shown by our next delivers a diverse array of drug-like heterocycles in good
set of experiments.
overall yields.
To demonstrate the utility of the newly developed methodology, Although this multistep continuous-flow method allowed the
our next goal was to incorporate a carboxylic acid synthesis step construction of complex molecules rapidly without the need for
into the flow process. As noted above, we previously reported purification and isolation of intermediates, lower flow rates and
the continuous-flow synthesis of imidazo[1,2-a]pyridine-2- small reactors limited the scalability of the method. As noted
carboxylic acids in a single, uninterrupted process directly from previously, the use of high boiling point solvents, such as
readily available starting materials. We hypothesized that incor- DMA, are less attractive during scale-up due to the difficulty of
porating this step into our new oxadiazole synthesis would removal of these solvents during purification. Consequently the
provide access to diverse imidazo[1,2-a]pyridin-2-yl-1,2,4- current method is limited to small scale library synthesis. There-
oxadiazoles of biological importance [27]. The flow platform fore, our next goal was to convert this microfluidic procedure to
we were using, the Syrris AFRICA® flow system, is limited to a sequence that would deliver compounds on a larger scale. To
two heated reactors. To overcome this issue a third reactor was this end, we first focused our attention on increasing the
placed in a heated silicone oil bath and a flow system was throughput of the reaction by using the larger tubing and tube
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Beilstein J. Org. Chem. 2017, 13, 239–246.
Table 2: Synthesis of 1,2,4-oxadiazoles via a continuous microreactor sequence from arylnitriles and carboxylic acids.
Entry
1
Compound
Yield (%)a
81
Entry
5
Compound
Yield (%)a
69
2
3
4
53
75
88
6
7
8
80
78
69
aIsolated yield after chromatographic purification of the crude reaction mixture.
reactors available in the Vapourtec R series flow system. We throughput of ~0.5 g/h. To demonstrate the utility of this new
also increased the flow rate to maintain a residence time of method we synthesized the mGlu5 NAM (Table 2, entry 3) on a
12 min in the third reactor (Scheme 2). Next, a microfluidic gram scale in high yield (3.5 g, 70%). With the same optimized
liquid–liquid extraction module (the AFRICA® FLLEX) was flow method we also synthesized 5-(6-bromoimidazo[1,2-
incorporated at the end of the flow sequence to remove the high a]pyridin-2-yl)-3-(4-chlorophenyl)-1,2,4-oxadiazole on a gram
boiling point solvent (DMA). Initial studies using a single scale (2 g, 42%) rapidly and efficiently (Scheme 3).
microreactor and dichloromethane as the organic extraction
phase demonstrated proof-of-concept that the microfluidic ex- Several advantages of this methodology compared to the stan-
traction could be used in the oxadiazole flow synthesis proce- dard batch synthesis should be noted. First, a fully automated
dure (see Supporting Information File 1). However, the opti- flow method permits the rapid construction of libraries of
mized method employs the introduction of toluene and water highly functionalized oxadiazole derivatives. Second,
into the microfluidic extraction module to efficiently remove imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, a scaffold with
the DMA and avoid the use of a halogenated solvent, as shown activity as S1P1 agonists, are prepared directly from commer-
in Scheme 2 and Scheme 3. The reaction mixture exiting from cially available building blocks in a single continuous process
the third reactor is mixed with water and toluene using an without isolating intermediates. As noted previously, the stan-
external pump before entering the phase separation device. On a dard in-flask (batch) synthesis of these compounds involves
preparative scale using this flow reaction setup, the desired multiple reaction steps requiring work-up and purification of
oxadiazole derivatives were obtained in good yield with a several intermediates. Furthermore, liquid–liquid microextrac-
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Beilstein J. Org. Chem. 2017, 13, 239–246.
Table 3: Continuous-flow process for the synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles.
Entry
1
Compound
Yield (%)a
46
Entry
7
Compound
Yield (%)a
59
2
3
32
44
8
9
35
35
4
5
42
55
10
11
29
20
6
59
12
25
aIsolated yield after chromatographic purification of the crude reaction mixture.
tion removes high boiling point solvent and impurities from the Conclusion
product. Finally, this new process with liquid–liquid extraction In summary, we have developed a telescoped continuous-flow
allows easy scale-up and eliminates the tedious high boiling method for the synthesis of diversely substituted imidazo[1,2-
point solvent removal step.
a]pyridine-2-yl-1,2,4-oxadiazole derivatives directly from com-
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Beilstein J. Org. Chem. 2017, 13, 239–246.
Scheme 2: Gram-scale synthesis of mGlu5 NAM by continuous flow in combination with microfluidic extraction.
Scheme 3: Gram-scale synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazole S1P1 agonist scaffold by continuous flow combined with microfluidic
extraction.
mercial nitriles, aminopyridine carboxylic acids and hydroxyl- instrument. Chemical shifts of 1H NMR spectra were recorded
amine. Moreover, we demonstrated that a liquid–liquid in parts per million (ppm) on the δ scale from an internal stan-
microextraction unit can be utilized to remove high polar water dard of residual CDCl3 (7.24 ppm). Chemical shifts of
soluble solvents and impurities from products. This scalable 13C NMR spectra were recorded in ppm from the central peak
method provides the desired oxadiazole derivatives at a rate of of CDCl3 (77.0 ppm) on the δ scale. High-resolution ESI–TOF
≈0.5 g/h and represents a significant advantage over batch syn- mass spectra were acquired from the Mass Spectrometry Core
thesis. We anticipate that these advances will facilitate the rapid at the Sanford Burnham Prebys Medical Discovery Institute
synthesis of these biologically important compounds.
(Orlando, Florida). LC–MS analyses were carried out on a
Shimadzu LC–MS 2010 Series LC System with a Kromasil 100
5 micron C18 column (50 × 2.1 mm i.d.). Continuous-flow
Experimental
All reagents were used as received unless otherwise noted. 1H (microreactor) experiments were carried out using a Syrris
and 13C spectra were obtained in CDCl3 at room temperature, AFRICA apparatus or a Vapourtec R Series Flow Chemistry
unless otherwise noted, on a JEOL (JNM-CS400) 400 MHz System.
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Beilstein J. Org. Chem. 2017, 13, 239–246.
General procedure for the optimization of the
flow synthesis of 1,2,4-oxadiazoles (Table 1)
residue was purified via automated flash chromatography
(SiO2) to afford the desired product (CombiFlash® Rf, 12g flash
The reaction was conducted in a glass reactor consisting of a column). The solvent gradient was 90% hexane to 50% ethyl
1.0 mL retention unit and three inlets. Streams of EDC/HOBt/ acetate over 15 min at a flow rate of 15 mL/min.
DIPEA (1:1:1, 25 μL/min, 0.6 M, DMA), acid/DIPEA (1:1,
25 μL/min, 0.5 M, DMA) and a solution of amidoximes
Supporting Information
(25 μL/min, 0.5 M, DMA) were combined in the glass reactor at
different temperatures for 10 min of residence time. Reactions
LC traces for optimization of oxadiazole synthesis
were monitored by LC–MS analysis and showed that the
(Table 1), details of liquid–liquid microextraction with
conversion of the 3-bromobenzoic acid to the corresponding
FLLEX module including LC traces, general and detailed
1,2,4-oxadiazole was optimal at 150 °C (Table 1, entry 5).
synthetic procedures with full characterization data for
compounds, and 1H NMR and 13C NMR spectral traces of
all compounds.
General procedure for the synthesis of 1,2,4-
oxadiazoles via a continuous microreactor
sequence from arylnitriles and acids
Supporting Information File 1
Experimental data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-26-S1.pdf]
(Table 2)
A solution of ArCN/NH2OH·HCl/DIPEA (1.05:1:3, 0.4 M,
DMA) was introduced to a glass microreactor (250 μL) heated
at 100 °C. The stream exiting from the first reactor was
combined with streams of the acid/DIPEA (1:1, 25.0 μL/min, Acknowledgements
0.5 M, DMA) and EDC/HOBt/DIPEA (1:1:1, 25 μL/min, The authors thank Drs. Dhanya Panickar, Douglas Sheffler and
0.6 M, DMA) in a second glass reactor (1.0 mL) at 150 °C for Peter Teriete for their help editing the manuscript. This work
15 min of residence time. This reaction was carried out with a was supported by National Institutes of Health grant nos.
back pressure of 4.0 bar. The reaction mixture was mixed with HG005033, GM079590, and GM081261.
excess water and extracted three times with dichloromethane.
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