Rapid and efficient synthesis of 1,2,4-oxadiazoles utilizing polymer-supported reagents under microwave heating

Article abstract of DOI:10.1021/ol050007r

(Chemical Equation Presented) 1,2,4-Oxadiazoles can be rapidly and efficiently synthesized from a variety of readily available carboxylic acids and amidoximes using either method A or method B. The use of commercially available polymersupported reagents c

Full text of DOI:10.1021/ol050007r

ORGANIC
LETTERS
2
005
Vol. 7, No. 5
25-928
Rapid and Efficient Synthesis of
,2,4-Oxadiazoles Utilizing
9
1
Polymer-Supported Reagents under
Microwave Heating
†
Ying Wang,* Reagan L. Miller, Daryl R. Sauer, and Stevan W. Djuric
High-Throughput Organic Synthesis Group, Global Pharmaceutical Research and
DeVelopment, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-6113
wang.ying@abbott.com
Received January 3, 2005
ABSTRACT
1,2,4-Oxadiazoles can be rapidly and efficiently synthesized from a variety of readily available carboxylic acids and amidoximes using either
method A or method B. The use of commercially available polymer-supported reagents combined with microwave heating resulted in high
yields and purities of the product 1,2,4-oxadiazoles in an expeditious manner.
Polymer-assisted solution-phase (PASP) synthesis, which
uses either polymeric reagents or scavenger resins, has
become a prevalent method for the rapid generation and
purification of solution-phase chemical libraries in the
by conventional methods, easy reaction optimization, and
no residual functionality from bead attachment in the final
product. All of these features are important factors to
consider in a high-throughput organic synthesis environment
for the rapid generation of compounds.
2
1
pharmaceutical industry in recent years. In PASP synthesis,
excess polymer-supported reagents can be used to drive a
reaction to completion and can then be easily removed by
filtration after completion of the reaction. This ultimately
results in shorter synthesis times and higher purities of the
compounds produced. Unlike solid-phase synthesis, all of
the advantages associated with solution-phase chemistry can
be exploited, such as monitoring the reaction in real time
As part of our ongoing program to develop efficient and
robust methods for the preparation of libraries of biologically
interesting compounds from readily available building blocks,
we turned our attention to 1,2,4-oxadiazoles. 1,2,4-Oxa-
diazoles have often been described as bioisosteres for amides
(2) For some of the recent examples, see: (a) Storer, P. I.; Takemoto,
T.; Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem. Eur.
J. 2004, 10, 2529-2547. (b) Storer, R. I.; Takemoto, T.; Jackson, P. S.;
Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 2521-2525. (c) Nicolaou, K.
C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao,
G. Q. J. Am. Chem. Soc. 2000, 122, 9968-9976. (d) Jaunzems, J.; Hofer,
E.; Jesberger, M.; Sourkouni-Argirusi, G.; Kirschning, A. Angew. Chem.,
Int. Ed. 2003, 42, 1166-1170. (e) Rademann, J.; Smerdka, J.; Jung, G.;
Grosche, P.; Schmid, D. Angew. Chem., Int. Ed. 2001, 40, 381-385. (f)
Sauer, D. R.; Kalvin, D.; Phelan, K. M. Org. Lett. 2003, 5, 4721-4724.
(g) Wang, Y.; Sauer, D. R. Org. Lett. 2004, 6, 2793-2796.
†
Department of Chemistry, University of Wisconsin-Madison.
(1) For recent reviews, see: (a) Kirschning, A.; Monenschein, H.;
Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650-679. (b) Ley, S. V.;
Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom,
D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3815-4195. (c) Parlow, J. J.; Devraj, R. V.; South,
M. S. Curr. Opin. Chem. Biol. 1999, 3, 320-336. (d) Drewry, D. H.; Coe,
D. M.; Poon, S. Med. Res. ReV. 1999, 19, 97-148.
1
0.1021/ol050007r CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/10/2005

or esters as a result of the increased hydrolytic and metabolic
stability of the ring. They have been incoporated into mus-
carinic agonists, benzodiazepine receptor agonists, serotonin-
reagents including polymer-supported coupling reagents. The
reactions were conveniently monitored by LC/MS analysis
in all cases, and it was observed that the use of microwave
heating greatly reduced the reaction screening and optimiza-
tion time. Among the conditions studied, we found that using
3
ergic (5-HT
3
) antagonists, and antirhinovirals. In addition,
4
they have also been used as dipeptide mimics. These
applications make this heterocycle an important structural
motif in drug discovery programs.
8
PS-Carbodiimide /HOBt for the coupling reagents gave good
conversion to 1,2,4-oxadiazole 3 under microwave heating.
The optimal reaction conditions are shown in Scheme 2,
whereby 1,2,4-oxadiazole 3 was isolated in 83% yield.
Several methods have been reported for the synthesis of
5
1
,2,4-oxadiazoles. Among those, the condensation of amid-
oximes with carboxylic acids in the presence of a coupling
reagent was considered to be particularly attractive (Scheme
1). A wide variety of structurally diverse carboxylic acids
Scheme 2. Synthesis of 1,2,4-Oxadiazole 3 with
PS-Carbodiimide/HOBt under Microwave Heating
Scheme 1. Synthesis of 1,2,4-Oxadiazoles from Carboxylic
Acids and Amidoximes
are readily available, which is beneficial for the development
of SAR in medicinal chemistry studies. Amidoximes are
often either commercially available or easily accessible by
reaction of nitriles with hydroxylamines. Our aim was to
quickly develop a convenient, robust, and high-yielding
reaction protocol for the synthesis of 1,2,4-oxadiazoles,
which would also be highly amenable for automation.
High-speed microwave synthesis has attracted a substantial
Interestingly, under conventional heating conditions, O-
acylamidoxime 4 was formed exclusively within 2 h at 40
°C with PS-Carbodiimide/HOBt and could be isolated in high
yield (Scheme 3). Further heating of the reaction mixture at
85 °C for another 24 h afforded the cyclized 1,2,4-oxadiazole
3
in 70% yield. Thus, under microwave heating conditions,
a higher conversion of 1,2,4-oxadiazole 3 was obtained in a
much shorter reaction time.
6
amount of attention in recent years. It has been demonstrated
that the use of microwave heating can dramatically shorten
reaction times, increase product purities and yields, and allow
precise control of reaction parameters.
Scheme 3. Synthesis of 1,2,4-Oxadiazole under Conventional
Initially, our studies commenced by heating carboxylic
Thermal Heating Condition
7
acid 1 and amidoxime 2 under microwave conditions at
different temperatures using various solvents and coupling
(3) (a) Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.; Hadley,
M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.; Wadsorth, H. J.; Wyman,
P. J. J. Med. Chem. 1991, 34, 2726-2735. (b) Watjen, F.; Baker, R.;
Engelstoff, M.; Herbert, R.; Macleod, A.; Knight, A.; Merchant, K.;
Moseley, J.; Saunder, J.; Swain, C. J.; Wong, E.; Springer, J. P. J. Med.
Chem. 1989, 32, 2282-2291. (c) Swain, C. J.; Baker, R.; Kneen, C.;
Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, M.; Stanton,
J.; Watling, K. J. J. Med. Chem. 1991, 34, 140-151. (d) Diana, G. D.;
Volkots, D. L.; Hitz, 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.
(
4) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.;
Luthman, K. J. Med. Chem. 1999, 42, 4331-4342.
5) For some examples, see: (a) Deegan, T. L.; Nitz, T. J.; Cebzanov,
D.; Pufko, D. E.; Porco, J. A., Jr. Bioorg. Med. Chem. Lett. 1999, 9, 209-
12. (b) Evans, M. D.; Ring, J.; Schoen, A.; Bell, A.; Edwards, P.; Berthelot,
(
2
D.; Micewonger, R.; Baldino, C. R. Tetrahedron Lett. 2003, 44, 9337-
9
2
3
341. (c) Poulain, R. F.; Tartar, A. L.; Deprez, B. P. Tetrahedron Lett.
001, 42, 1495-1498. (d) Liang, G.; Feng, D. D. Tetrahedron Lett. 1996,
7, 6627-6630. (e) Romdhane, A.; Gharbi, R.; Mighri, Z. Heterocycl.
However, when the electron-deficient amidoxime 5 was
used (Table 1), the PS-Carbodiimide/HOBt method failed
to give the desired product 6 despite prolonged heating in
the microwave. It has been reported that 1,2,4-oxadiazoles
can be obtained by heating carboxylic acids and amidoximes
Commun. 2004, 10, 151-156. (5f) Barrett, A. G. M.; Cramp, S. M.; Roberts,
R. S.; Zecri, F. J. Comb. Chem. High Throughput Screening 2000, 3 (2),
1
31-138.
6) For some recent reviews, see: (a) Kappe, C. O. Angew. Chem., Int.
(
Ed. 2004, 43, 6250-6284. (b) Kappe, C. O. Curr. Opin. Chem. Biol. 2002,
6
, 314-320. (c) Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med. Chem.
(7) All microwave reactions were performed on an Emrys Optimizer
(Personal Chemistry, http://www.personalchemistry).
(8) Argonaut Technologies, http://www.argotech.com
2
002, 9, 1251-1283. (d) Dzierba, C. D.; Combs, A. P. Annu. Rep. Med.
Chem. 2002, 37, 247-256.
926
Org. Lett., Vol. 7, No. 5, 2005

8
9
ered that both MP-carbonate and PS-BEMP afforded a
much better conversion than DIEA. Near quantitative
conversion of carboxylic acid 1 to 1,2,4-oxadiazole 6 was
obtained with 1 equiv of HBTU and 3 equiv of PS-BEMP
in acetonitrile at 160 °C for 15 min under microwave heating
Table 1. Synthesis of 1,2,4-Oxadiazole with HBTU Using
Different Bases
(Table 1, entry 4). The reaction worked much better in
acetonitrile than in DMF and other solvents. For solubility
reasons, up to 20% DMF could be added to the reaction
system as a cosolvent without compromising the yield. This
is particularly desirable in an automation format where most
of the reagents are added through liquid delivery lines. The
PS-BEMP resin could be easily filtered off upon completion
of the reaction.
entry
base
DIEA
K2CO3
MP-Carbonate
PS-BEMP
conversion (%)a
1
2
3
4
40
<10
70
95
The HBTU/PS-BEMP protocol worked well with a range
of amidoximes, affording good to excellent yield of the
corresponding 1,2,4-oxadiazoles (Table 2, entries 1-7,
method A). In only two cases that we have studied, less than
satisfactory yields were obtained (Table 2, entries 8 and 9),
where the starting materials and the intermediate O-acyl-
amidoximes were both observed in the LC/MS analysis after
the reaction.
a
1
Conversion was determined by LC/MS and crude H NMR.
in the presence of HBTU and N,N-diisopropylethylamine
DIEA). Indeed, under microwave heating conditions, 1,2,4-
5b
(
oxadiazole 6 was formed as judged by LC/MS analysis,
although the conversion was low (Table 1, entry 1). Attempts
to improve the conversion by exploring higher temperatures,
prolonged heating, and other solvents in the microwave
uniformly failed. We then investigated the use of several
bases including polymer-supported bases. These results are
summarized in Table 1. To our delight, we quickly discov-
It is known that 1,2,4-oxadiazoles can generally be
synthesized from amidoximes and carboxylic acid chlo-
1
0
rides. However, this method is not very attractive at first
glance. Acid chlorides are relatively reactive and thus hard
Table 2. Synthesis of 1,2,4-Oxadiazoles from Carboxylic Acids and Amidoximes with Method A or Method B
a
Isolated yields after purification. b Conversion is determined by crude LC/MS or H NMR. c Not determined.
1
Org. Lett., Vol. 7, No. 5, 2005
927

to store and handle. In addition, compared to the diverse
array of carboxylic acids, very few carboxylic acid chlorides
are readily available, which makes it difficult to perform
thorough SAR studies in a medicinal chemistry setting. One
way to solve this problem is to convert the carboxylic acids
to the corresponding carboxylic acid chlorides, preferably
in situ. Among the many reported procedures, the use of
In the process of developing the HBTU/PS-BEMP method,
we were also delighted to find that carboxylic acid chlorides
generated in situ with PS-PPh /CCl CN reacted in a facile
3 3
manner with a variety of amidoximes to generate the
corresponding 1,2,4-oxadiazoles (Scheme 4). THF was found
3
to be the best solvent for both steps. The PS-PPh resin from
the first step did not interfere with the second step in our
hands. Thus, the reaction can be performed in one pot in
THF without the need for filtration. After the carboxylic acid
chloride was generated in situ, amidoxime and DIEA were
added and the reaction mixture was heated in the microwave
at 150 °C for 15 min to afford the desired 1,2,4-oxadiazole
in high yield (Table 2, method B). In many cases, the
conversion was quantitative and only the desired product and
a small amount of excess amidoxime were observed in the
11
3 3
PS-PPh /CCl CN is particularly attractive (Scheme 4). The
Scheme 4. Synthesis of 1,2,4-Oxadiazoles by in Situ
Fromation of Carboxylic Acid Chlorides13
1
crude LC/MS and H NMR analysis. This one-pot two-step
reaction was found to be quite general and worked on a
variety of alkyl and aryl carboxylic acids and amidoximes.
In most cases, the isolated yield was more than 85%. In most
expamples, either the HBTU/PS-BEMP or the PS-PPh
CCl CN method gave good yields of the desired products
Table 2, entries 1-7). Of particular note, however, are two
3
/
3
(
examples (Table 2, entries 8 and 9), where method B afforded
the desired products with much higher conversion and
isolated yields.
reaction is easy to perform under mild reaction conditions
and can be easily adapted to automation. In addition, PS-
PPh
found that under microwave heating conditions, usually at
00 °C for 5 min, a variety of carboxylic acid chlorides can
be easily obtained in situ from diverse carboxylic acids with
3
can be easily filtered off after the reaction. We have
In summary, we have developed two microwave-enhanced,
rapid, and efficient methods for the synthesis of 1,2,4-
oxadiazoles. Both methods use readily available solid-phase
reagents that not only result in higher yields but also greatly
simplify the purification process. Additionly, the use of
microwave technology allowed us to quickly identify optimal
reaction conditions with reaction times reduced from hours
to minutes. Both methods are suitable for the preparation of
either individual analogues or the production of libraries
using automated protocols.
1
12
nearly quantitative yields.
(
9) 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-
phosphorine, polymer-bound; http://www.sigmaaldrich.com
10) (a) Korbonits, D.; Horvath, K. Heterocycles 1994, 37, 2051-2068.
b) Mathvink, R. J.; Barritta, A. M.; Candelore, M. R.; Cascieri, M. A.;
(
(
Deng, L.; Tota, L.; Strader, C. D.; Wyvratt, M. J.; Fisher, M. H.; Weber,
A. E. Bioorg. Med. Chem. Lett. 1999, 9, 1869-1874.
(11) (a) Jang, D. O.; Park, D. J.; Kim, J. Tetrahedron Lett. 1999, 40,
5
323-5326. (b) Buchstaller, H.; Ebert, H. M.; Anlauf, U. Synth. Commun.
Supporting Information Available: General experiment
details and characterizations of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
2
001, 31, 1001-1005.
(
12) Unpublished results.
13) Partial conversion to 1,2,4-oxadiazoles was observed with 3 equiv
(
of PS-DIEA or PS-Carbonate. Comparable yields of 1,2,4-oxadiazoles were
obtained when 3 equiv of PS-BEMP was used in place of DIEA.
OL050007R
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Org. Lett., Vol. 7, No. 5, 2005