Rapid multistep synthesis of 1,2,4-oxadiazoles in a single continuous microreactor sequence

Article abstract of DOI:10.1021/jo801152c

(Chemical Equation Presented) A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles from readily available arylnitriles and activated carbonyls in a single continuous microreactor sequence is described. The synthesis incorporates three s

Full text of DOI:10.1021/jo801152c

Rapid Multistep Synthesis of 1,2,4-Oxadiazoles in a Single
Continuous Microreactor Sequence
Daniel Grant, Russell Dahl, and Nicholas D. P. Cosford*
The San Diego Center for Chemical Genomics, Burnham Institute for Medical Research,
10901 North Torrey Pines Road, La Jolla, Califoria 92037
ncosford@burnham.org
ReceiVed June 5, 2008
A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles from readily available arylnitriles
and activated carbonyls in a single continuous microreactor sequence is described. The synthesis
incorporates three sequential microreactors to produce 1,2,4-oxadiazoles in ∼30 min in quantities (40-80
mg) sufficient for full characterization and rapid library supply.
Introduction
can be performed at ambient temperature in a microreactor.
Furthermore, the size of the microreactor also allows the chemist
to more easily achieve forcing conditions (high temperature and
pressure), analogous to sealed tube reactions but without the
dangers and difficulties inherently associated with this type of
chemistry.
Although examples of multistep organic transformations using
flow methods have been reported,11 these sequences involve
reagent packed columns12,13 or are broken into segments
involving workup and purification.14,15 While introduction of
reagents to a flow reaction via solid support in a packed column
allows for clean reactions without incorporation of byproduct
into the reaction stream, or involving changes in concentration,
it introduces the problem of having to renew, replace, or repack
the reagent columns as they are consumed. Recently, we have
become interested in the use of microreactors for the rapid
synthesis of focused libraries via combinations of multiple
organic transformations into single unbroken microreactor
sequences. This strategy maximizes the speed and efficiency
of synthesis by eliminating the need for handling of the
There is a continual need for the development of new
technologies that enable the rapid and efficient construction of
biologically interesting small molecules.1 The application of
automated methods to the synthesis of focused libraries2 to
populate screening collections is an important field of research,
particularly for the biopharmaceutical sector and increasingly
for the academic community.3 Reports on the use of microre-
actors (microfluidic chips) as an alternative to “in flask”
chemistry have recently started to appear in the scientific
literature.4-7 Microreactors afford efficient mixing and precise
temperature control,8 allowing the development of useful
variations of traditionally low temperature reactions such as the
Swern oxidation9 and oligosaccharide couplings,10 both of which
(1) Chighine, A.; Sechi, G.; Bradley, M. Drug Disc. Today 2007, 12, 459–
464.
(2) Deng, Z.; Chuaqui, C.; Singh, J. J. Med. Chem. 2006, 49, 490–500.
(3) Huryn, D. M.; Cosford, N. D. P. Annu. Rep. Med. Chem. 2007, 42, 401–
416.
(4) Kang, L.; Chung, B. G.; Langer, R.; Khademhosseini, A. Drug Disc.
Today 2008, 13, 1–13.
(5) Watts, P.; Wiles, C. Chem. Commun. 2007, 443–467.
(6) Garcia-Egido, E.; Spikmans, V.; Wong, S. Y. F.; Warrington, B. H. Lab
Chip 2003, 3, 73–76.
(7) Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12,
8434–8442.
(8) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151–163.
(9) Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew.
Chem., Int. Ed. 2005, 44, 2413–2416.
(10) Carrel, F. R.; Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Org. Lett.
2007, 9, 2285–2288.
(11) Schwalbe, T.; Kadzimirsz, D.; Jas, G. QSAR Comb. Sci. 2005, 24, 758–
768.
(12) Baxendale, I. R.; Giffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Synlett
2006, 427–430.
(13) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer,
G. K. Org. Lett. 2006, 8, 5231–5234.
(14) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade,
D. T. Chem. ReV. 2007, 107, 2300–2318.
(15) Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby,
S.; Tranmer, G. K. Chem. Commun. 2006, 2566–2568.
10.1021/jo801152c CCC: $40.75
Published on Web 08/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7219–7223 7219

Grant et al.
SCHEME 1. “In Flask” Synthesis of 222
FIGURE 1. Biologically active bis-substituted oxadiazoles.
intermediates by a chemist. Once a sequence has been devel-
oped, the synthesis is simply a matter of preparing starting
material solutions and introducing them to the system. Ulti-
mately, the use of this strategy to prepare compounds whose
traditional syntheses involve long reaction times and forcing
conditions will greatly facilitate the population of previously
sparsely populated chemical space.16
Results and Discussion
The 1,2,4-oxadiazole scaffold is a class of heterocycle
commonly found in biologically active molecules. This motif
is often used as an amide or ester bioisostere17,18 and is found
in several drugs and drug leads19 including the potent S1P1
agonist 120 (Figure 1) and the metabotropic glutamate subtype
5 (mGlu5) receptor antagonist 2.21,22 The synthesis of oxadia-
zoles has typically been carried out by reacting arylnitriles with
hydroxylamine to give the amidoxime in moderate yields
(Scheme 1).21-23 Cyclization of the O-acyl amidoxime formed
from reaction of the amidoxime with an acyl chloride is
generally the most difficult and time-consuming step and often
requires sealed tube conditions and long reaction times. In an
attempt to improve on these procedures, microwave-assisted
methods for this cyclization have recently been reported.24-26
Herein we report the rapid synthesis of bis-substituted 1,2,4-
oxadiazoles from arylnitriles in a single, unbroken microreactor
sequence, utilizing three microreactors, two of which involve
superheating of the solvent. In this way, we have shortened a
multiday, multistep sequence to a highly efficient procedure
lasting less than 30 min.27
One of the chief concerns in any microfluidic experiment is the
formation of solid in the microreactor. This problem can be
exacerbated by the need to use relatively concentrated reagent
streams essential for efficiency, especially when several solutions
are combined over a multistep sequence. For these reasons, as well
as its high boiling point, DMF was selected as the solvent for our
initial studies. The arylnitriles may be introduced into the system
in concentrations of up to 1.0 M, although 0.5 M solutions provided
more uniform solubility of the arylnitriles used in these experiments.
However, the NH2OH·HCl/Hunig’s base solution cannot exceed
a concentration greater than 0.4 M because of solubility issues. In
initial experiments, LCMS analysis showed that the conversion of
nitriles to the corresponding amidoximes was complete after only
6 min at 150 °C. Similarly, the dehydrative cyclization of the O-acyl
amidoxime goes to completion in 10 min in a microreactor at 200
°C and 7.5-9.0 bar in DMF.
The integration of both of these reactions into a continuous
sequence proved challenging. Interestingly, the condensation of
the amidoxime with the acid chloride proved to be the most
problematic step. The stream containing the amidoxime, exiting
the first microreactor,28 was combined with a solution of acid
(16) Lipinski, C.; Hopkins, A. Nature 2004, 432, 955–861.
(17) Diana, G. D.; Volkots, D. L.; Nitz, T. J.; Bailey, T. R.; Long, M. A.;
Vescio, N.; Aldous, S.; Pevear, D. C.; Dutko, F. J. J. Med. Chem. 1994, 37,
2421–2436.
SCHEME 2. Continuous Microfluidic Sequence for the
Synthesis of 1,2,4-Oxadiazoles
(18) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.; Luthman,
K. J. Med. Chem. 1999, 42, 4331–4342.
(19) Zhang, H. Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.; Ollis-
Mason, K.; Qiu, L.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med.
Chem. 2005, 48, 5215–5223.
(20) Li, Z.; Chen, W.; Hale, J. J.; Lynch, C. L.; Mills, S. G.; Hajdu, R.;
Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G. J.; Chrebet, G.;
Parent, S. A.; Bergstrom, J.; Card, D.; Forrest, M.; Quackenbush, E. J.; Wickham,
L. A.; Vargas, H.; Evans, R. M.; Rosen, H.; Mandala, S. J. Med. Chem. 2005,
48, 6169–6173.
(21) Roppe, J.; Smith, N. D.; Huang, D.; Tehrani, L.; Wang, B.; Anderson,
J.; Brodkin, J.; Chung, J.; Jiang, X.; King, C.; Munoz, B.; Varney, M. A.; Prasit,
P.; Cosford, N. D. P. J. Med. Chem. 2004, 47, 4645–4648.
(22) Van Wagenen, B. C.; Stormann, T. M.; Moe, S. T.; Sheehan, S. M.;
McLeod, D. A.; Smith, D. L.; Isaac, M. G.; Slassi, A. Appl. P. I. WO
2002068417, NPS Pharmaceuticals, Inc., 2001.
(23) Eloy, F.; Lenaers, R. Chem. ReV. 1962, 62, 155–183.
(24) Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org. Lett. 2005, 7,
925–928.
(25) Adib, M.; Jahromi, A. H.; Tavoosi, N.; Mahdavi, M.; Bijanzadeh, H. R.
Tetrahedron Lett. 2006, 47, 2965–2967.
(26) Evans, M. D.; Ring, J.; Schoen, A.; Bell, A.; Edwards, P.; Berthelot,
D.; Nicewonger, R.; Baldino, C. M. Tetrahedron Lett. 2003, 44, 9337–9341.
(27) All microfluidic experiments were performed using a Syrris AFRICA
microfluidic apparatus.
(28) It should be noted that while the conversion of nitrile to the amidoxime
requires only 6 min, in the continuous system the time of the reaction mixture
on the final 200 °C chip dictates the flow rates for the entire system; thus, the
reaction mixture remains on the first chip for 12 min.
7220 J. Org. Chem. Vol. 73, No. 18, 2008

Multistep Synthesis of 1,2,4-Oxadiazoles
TABLE 1. Optimization of Molar Ratios for the Synthesis of 2 in
a Continuous Microreactor Sequence
TABLE 3. Microfluidic Synthesis of
3-(1,2,4-Oxadiazol-5-yl)propanoic Acids from Arylnitriles and
Succinic Anhydride
entry
2-CNPy:NH2OH/Hunig’s basea:3-CNBzCl
yieldb (%)
1
2
3
4
5
1:1:1
45
45
21
11
32
1:1.2:1.2
1:1.5:1.5
1:1:1.5
1:2:2
a 3:1 molar ratio of NH2OH·HCl to Hunig’s base. b Yield determined
by LCMS using an internal standard (chlorpromazine) added to the
arylnitrile reactant solution.
TABLE 2. Synthesis of Bis-Substituted 1,2,4-Oxadiazoles via a
Continuous Microreactor Sequence from Arylnitriles and Acyl
Chlorides
a Isolated yield of pure product after purification of crude reaction
mixture using preparative HPLC.
was submerged in an ice bath before the T-fitting. It was also
imperative that the combined streams be allowed to react at
room temperature for at least 2 min before entering the final
microreactor at 200 °C. For this purpose, a 1500 mm coil of
0.05 mm PTFE capillary tubing was placed between the T-fitting
and the final microreactor. This coil holds a volume of 250 µL
and essentially acts as a room temperature microreactor. The
final optimized microreactor sequence is shown in Scheme 2
and consists of three microreactors at three different tempera-
tures in addition to a cooling loop.
In order to optimize the molar ratio of reactants, experiments
were performed to compare the effects of various molar ratios
on yield (Table 1). We found that there was no benefit to
increasing the molar equivalents of hydroxylamine/Hunig’s base
or acid chloride in relation to arylnitrile. However, for the final
synthetic procedure we selected a ratio of 1:1.2:1.2 to offset
the loss of reagent by decomposition in the reactant reservoir.
Under these conditons, the isolated yield of the entire sequence
(45%) is comparable to the reported “in flask” yield22 and
corresponds to an average yield of 76% per step. A typical 35
min run involves the collection of 3.5 mL of reaction mixture,
i.e., 0.5 mmol of product. Upon isolation by HPLC, this provides
40-80 mg of purifed product depending on yield and formula
weight. The generality of this sequence was demonstrated by
the synthesis of a number of bis-substituted 1,2,4-oxadiazoles
(Table 2). The isolated yields over the multistep synthesis ranged
from 40% to 63% and the conditions were applicable to a variety
of scaffolds. For example, heteroaryl and arylnitriles, both
electron deficient and electron rich, reacted with aroyl, het-
eroaroyl, or alkanoyl chlorides to form the corresponding
oxadiazole.
a Isolated yield of pure product after purification of crude reaction
mixture using preparative HPLC.
The same microfluidic sequence also proved applicable to
the preparation of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propanoic ac-
ids. In this case succinic anhydride was used in place of the
acyl chloride reagent (Table 3). The reaction proceeded under
similar conditions, although DMA was used as a solvent in place
of DMF, due to competitive formation of the dimethyl amide.
chloride (1.0 M) in a T-fitting before the combined streams
entered the microreactor at 200 °C (Scheme 2). After initial
attempts proved unsuccessful, subsequent experimentation
showed that the stream exiting the first microreactor must be
cooled before meeting the acyl chloride stream. This was
accomplished by insertion of a 600 mm loop of capillary which
J. Org. Chem. Vol. 73, No. 18, 2008 7221

Grant et al.
146.0, 148.3, 169.5, 174.9. LRMS (ESI): m/z calcd for C18H10N4O
(M + H)+ 299.09, found 298.95.
Ostensibly, this was the result of the slight decomposition of
DMF at high temperature.
5-Piperonyl-3-(pyridin-3′-yl)-1,2,4-oxadiazole (12). A sample
of the reaction mixture (2.0 mL) was collected, and this was purified
using preparative HPLC to provide the title compound as a white
solid (40 mg, 47%). Mp: 192-195 °C. 1H NMR (300 MHz,
CDCl3): δ 6.14 (s, 2H), 7.01 (d, J ) 8.4 Hz, 1H), 7.57 (dd, J )
4.8, 7.8 Hz, 1H), 7.67 (dd, J ) 2.8, 8.4 Hz, 1H), 8.55 (dt, J ) 3.0,
7.8 Hz), 8.83 (dd, J ) 2.5, 5.4 Hz, 1H), 9.44 (s, 1H). 13C NMR
(75 MHz, CDCl3): δ 102.4, 108.3, 109.3, 117.9, 124.3, 124.4, 136.1,
147.8, 148.7, 150.9, 152.1, 166.7, 175.3. HRMS (ESI): m/z calcd
for C14H9N3O3 (M + H)+ 268.0717, found 268.0720.
Conclusion
We have described the rapid and efficient synthesis of 1,2,4-
oxadiazoles in a continuous microreactor sequence. In this way,
a multiday, multistep preparative procedure has been shortened
to a matter of minutes, demonstrating proof-of-concept for the
rapid synthesis of focused libraries of small molecule hetero-
cycles based on this scaffold.
5-(Furan-2-yl)-3-(isoquinolin-3-yl)-1,2,4-oxadiazole (13). A
sample of the reaction mixture (3.0 mL) was collected, and this
was purified using preparative HPLC to provide the title compound
Experimental Section
1
as a white solid (64 mg, 51%). Mp: 178-180 °C. H NMR (300
General Procedure for Synthesis of 1,2,4-Oxadiazoles in a
Continuous Microfluidic System. Streams of the arylnitrile (32.5
µL/min, 0.5 M, DMF) and a solution of NH2OH ·HCl (0.4 M, DMF)
and diisopropylethylamine (1.2 M, DMF) (47.5 µL/min) were
combined in a 1000 µL chip at 150 °C. The reaction mixture was
then cooled by flowing through 60 mm of capillary submerged in
an ice bath before meeting the electrophile (20.0 µL/min, 1.0 M,
DMF) in a simple T-fitting. Following the T-fitting, the reaction
mixture flowed through 1500 mm of capillary before entering the
final 1000 µL chip at 200 °C. The stream exiting the chip was
collected after passing though the back pressure regulator. This
sequence was carried out with the back pressure maintained between
7.5 and 8.5 bar. The reaction mixture was then evaporated to remove
the solvent before being dissolved in 1.5 mL of DMF and purified
by preparative HPLC. Note: Due to conversion of product car-
boxylic acids (11, 12, and 13) to the corresponding dimethylamides
ostensibly from byproduct of DMF decomposition at high temper-
ature, reactions in which succinic anhydride is used as electrophile
were carried out in DMA.
MHz, CDCl3): δ 6.70 (dd, J ) 1.5, 3.3 Hz, 1H), 7.49 (dd J ) 1.2,
3.3 Hz, 1H), 7.71-7.84 (m, 3H), 7.99 (d, J ) 7.8 Hz, 1H), 8.09
(d, J ) 8.4 Hz, 1H), 8.67 (s, 1H), 9.43 (s, 1H). 13C NMR (75 MHz,
CDCl3): 112.9, 117.3, 121.4, 127.8, 128.1, 129.2, 129.7, 131.5,
136.0, 140.0, 140.4, 147.1, 153.6, 168.2, 169.1. HRMS (ESI): m/z
calcd for C15H9N3O2 (M + H)+ 264.0767, found 264.0773.
5-Phenyl-3-(pyrazin-2-yl)-1,2,4-oxadiazole (14).32 A sample of
the reaction mixture (3.0 mL) was collected, and this was purified
using preparative HPLC to provide the title compound as a white
solid (48 mg, 45%). Mp: 143-145 °C. 1H NMR (300 MHz,
CDCl3): δ 7.54-7.67 (m, 3H), 8.28 (d, J ) 7.8 Hz, 2H), 8.76 (d,
J ) 2.5 Hz, 1H), 8.80 (s, 1H), 8.46 (d, J ) 1.2 Hz, 1H). 13C NMR
(75 MHz, CDCl3): 123.9, 128.6, 129.5, 133.5, 142.7, 144.7, 145.1,
146.7, 167.3, 177.1. HRMS (ESI): m/z calcd for C12H8N4O (M +
H)+ 225.0771, found 225.0770.
5-Cyclopentyl-3-(pyrimidin-2-yl)-1,2,4-oxadiazole (15). A sample
of the reaction mixture (2.0 mL) was collected, and this was purified
using preparative HPLC to provide the title compound as a colorless
crystal (45 mg, 57%). Mp: 67-69 °C. 1H NMR (300 MHz, CDCl3):
δ 1.72-1.89 (m, 2H), 2.06-2.23 (m, 2H), 3.48 (p, J ) 8.1 Hz,
1H), 7.47 (t, J ) 4.8 Hz, 1H), 8.98 (d, J ) 4.8 Hz, 2H). 13C NMR
(75 MHz, CDCl3): δ 25.9, 31.8, 37.4, 122.3, 156.5, 158.2, 167.7,
185.4. HRMS (ESI): m/z calcd for C11H12N4O (M + H)+ 217.1084,
found 217.1085.
5-(3-Cyanophenyl)-3-(pyridin-2-yl)-1,2,4-oxadiazole (2).21,22
A sample of the reaction mixture (3.0 mL) was collected, and this
was purified using preparative HPLC to provide the title compound
1
as a white solid (54 mg, 45%). Mp: 148-149 °C. H NMR (300
MHz, CDCl3): δ 7.55 (dd, J ) 4.8, 7.8 Hz, 1H), 7.75 (t, J ) 7.8
Hz, 1H), 7.92-8.00 (m, 2H), 8.27 (d, J ) 8.4 Hz, 1H), 8.53 (d, J
) 7.8 Hz, 1H), 8.61 (s, 1H), 8.90 (dd, J ) 0.9, 4.8 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 114.2, 117.6, 123.8, 125.5, 126.3, 130.5,
132.0, 132.4, 136.2, 138.0, 145.8, 150.5, 169.0, 174.7. LRMS (ESI):
m/z calcd for C14H8N4O (M + H)+ 249.08, found 248.95.
5-Phenyl-3-(pyridin-2-yl)-1,2,4-oxadiazole (10).29-31 A sample
of the reaction mixture (3.0 mL) was collected, and this was purified
using preparative HPLC to provide the title compound as a white
solid (48 mg, 45%). Mp: 128-130 °C. 1H NMR (300 MHz,
CDCl3): δ 7.48 (ddd, J ) 1.4, 4.8, 7.8 Hz, 1H), 7.56-7.65 (m,
3H), 7.91 (dt, J ) 2.0, 7.8 Hz, 1H), 8.26 (d, J ) 8.0 Hz, 1H), 8.32
(d, J ) 6.8 Hz, 2H), 8.87 (d, J ) 4.8 Hz, 1H). 13C NMR (75 MHz,
CDCl3): 176.8, 169.0, 150.7, 146.7, 137.3, 133.2, 129.4, 128.6,
125.8, 124.3, 123.5. HRMS (ESI): m/z calcd for C13H9N3O (M +
H)+ 224.0818, found 224.0821.
5-(3-Cyanophenyl)-3-(4-fluorophenyl)-1,2,4-oxadiazole (16). A
sample of the reaction mixture (3.0 mL) was collected, and this
was purified using preparative HPLC to provide the title compound
1
as a white solid (80 mg, 63%). Mp: 197-198 °C. H NMR (300
MHz, CDCl3): δ 7.21-7.27 (m, 2H), 7.75 (t, J ) 7.8 Hz, 1H),
7.93 (dt, J ) 1.0, 7.8 Hz, 1H), 8.18-8.23 (m, 2H), 8.46 (dt, J )
1.0, 7.5 Hz, 1H), 8.55 (t, J ) 1.5 Hz, 1H). 13C NMR (75 MHz,
CDCl3): 114.1, 116.3, 116.6, 117.7, 122.87, 122.90, 125.8, 130.0,
130.1, 130.5, 131.9, 132.2, 136.0, 163.4, 166.7, 168.7, 174.0. HRMS
(ESI): m/z calcd for C15H8FN3O (M + H)+ 266.0724, found
266.0719.
3-(4-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazole (17).33 A sample
of the reaction mixture (3.0 mL) was collected, and this was purified
using preparative HPLC to provide the title compound as a white
solid (46 mg, 40%). Mp: 98-99 °C. 1H NMR (300 MHz, CDCl3):
δ 3.92 (s, 3H), 7.07 (d, J ) 8.7 Hz, 2H), 7.55-7.64 (m, 3H), 8.15
(d, J ) 9.0 Hz, 2H), 8.25 (d, J ) 8.4 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ 55.7, 114.5, 119.7, 124.7, 128.4, 129.3, 129.4, 132.9,
162.2, 168.9, 175.7. LRMS (ESI): m/z calcd for C15H12N2O2 (M +
H)+ 253.1, found 252.95.
5-(3-Cyanophenyl)-3-(quinolin-2-yl)-1,2,4-oxadiazole (11).22 A
sample of the reaction mixture (3.0 mL) was collected, and this
was purified using preparative HPLC to provide the title compound
1
as a white solid (90 mg, 63%). Mp: 153 °C dec. H NMR (300
MHz, CDCl3): δ 7.69 (t, J ) 7.2 Hz, 1H), 7.76 (t, J ) 8.1 Hz,
1H), 7.85 (t, J ) 7.2 Hz, 1H), 7.95 (d, J ) 7.8 Hz, 2H), 8.33 (d,
J ) 8.7 Hz, 1H), 8.39-8.43 (m, 2H), 8.58 (d, J ) 7.8, 1H), 8.66
(s, 1H). NMR (75 MHz, CDCl3): δ 114.2, 117.7, 120.4, 125.5,
127.9, 128.5, 129.2, 130.5, 130.6, 130.8, 132.2, 132.5, 136.2, 137.9,
3-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)propanoic Acid
(18). A sample of the reaction mixture (3.0 mL) was collected,
and this was purified using preparative HPLC to provide the title
compound as a colorless crystal (54 mg, 46%). Mp: 135-137 °C.
1H NMR (300 MHz, CDCl3): 3.04 (t, J ) 7.2 Hz, 2H), 3.28 (t, J
(29) Lehmann, A. WO2004SE01819 20041207 (Astrazeneca AB, Swed.; NPS
Pharmaceuticals, Inc., 2007.
(30) Paudler, W. W.; Kuder, J. E. J. Org. Chem. 1967, 32, 2430–2433.
(31) Gardiner, E. M.; Duron, S. G.; Massari, M. E.; Severance, D. L.; Semple,
J. E. PCT/US, PCT/US2006/026242 (Kalypsys, Inc., USA), 2007.
(32) Pancechowska-Ksepko, D.; Foks, H.; Janowiec, M.; Zwolska-Kwiek,
Z. Acta Pol. Pharm. 1986, 43, 211–217.
(33) Zhou, T.; Chen, Z.-C. Synth. Commun. 2002, 32, 887–891.
7222 J. Org. Chem. Vol. 73, No. 18, 2008

Multistep Synthesis of 1,2,4-Oxadiazoles
) 7.2 Hz, 2H), 3.90 (s, 3H), 7.01 (d, J ) 8.7 Hz, 2H), 8.01 (d, J
) 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): 22.0, 29.0, 55.6, 114.5,
119.3, 129.3, 162.2, 168.2, 176.5, 178.0. HRMS (ESI): m/z calcd
for C12H12N2O4 (M + H)+ 249.0870, found 249.0972.
3-(3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl)propanoic Acid (19).
A sample of the reaction mixture (3.0 mL) was collected, and this
was purified using preparative HPLC, carried out on only 2.5 mL
of the reaction mixture due to solubility issues, to provide the title
compound as a colorless crystal (48 mg, 45%). Mp: 156-157 °C.
1H NMR (300 MHz, CDCl3): 3.03 (d, J ) 7.5 Hz, 2H), 3.28 (d, J
) 7.5 Hz, 2H), 7.63 (d, J ) 8.7 Hz, 2H), 7.96 (d, J ) 9.0 Hz, 2H).
13C NMR (75 MHz, DMSO): 27.2, 35.3, 130.5, 130.9, 134.4, 137.8,
172.2, 178.2,185.5. HRMS (ESI): m/z calcd for C11H9BrN2O3 (M
+ H)+ 296.9869, found 296.9873.
MHz, DMSO): 2.89 (t, J ) 6.9 Hz, 2H), 3.24 (t, J ) 6.9 Hz, 2H),
7.82 (t, J ) 8.1 Hz, 1H), 7.89 (t, J ) 7.8 Hz, 1H), 8.21 (d, J ) 8.7
Hz, 1H), 8.24 (d, J ) 9.0 Hz, 1H), 8.59 (s, 1H), 9.46 (s, 1H). 13C
NMR (75 MHz, DMSO): 27.2, 35.3, 126.2, 133.1, 133.3, 134.3,
134.7, 137.0, 140.6, 145.0, 158.8, 173.3, 178.3, 185.2. HRMS (ESI):
m/z calcd for C14H11N3O3 (M + H)+ 270.0873, found 270.0875.
Acknowledgment. This work was supported by Grant Nos.
GM079590 and GM081261, awarded by the National Institute
of General Medical Sciences, Department of Health and Human
Services.
Supporting Information Available: Additional experimental
1
procedures; H and 13C NMR spectra of oxadiazoles 2 and
3-(3-(Isoquinol-3-yl)-1,2,4-oxadiazol-5-yl)propanoic Acid (20). A
sample of the reaction mixture (3.5 mL) was collected, and this
was purified using preparative HPLC to provide the title compound
10-20. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
as a white solid (93 mg, 62%). Mp: 210 °C dec. H NMR (300
JO801152C
J. Org. Chem. Vol. 73, No. 18, 2008 7223