A one-pot synthesis of 3-substituted-5-carbonylmethyl-1,2,4-oxadiazoles from β-keto esters and amidoximes under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.02.005

Herein we report a high yielding one-pot 'green' synthesis of 3-substituted-5-carbonylmethyl-1,2,4-oxadiazoles from readily available β-keto esters and amidoximes under simple and convenient solvent-free conditions. No additional base is needed. The reaction likely goes through an acyl ketene intermediate.

Full text of DOI:10.1016/j.tetlet.2007.02.005

Tetrahedron Letters 48 (2007) 2231–2235
A one-pot synthesis of 3-substituted-5-carbonylmethyl-
1
,2,4-oxadiazoles from b-keto esters and amidoximes
under solvent-free conditions
*
Wu Du, Quang Truong, Hongbo Qi, Yan Guo, Harry R. Chobanian,
William K. Hagmann and Jeffrey J. Hale
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 21 December 2006; revised 1 February 2007; accepted 5 February 2007
Available online 7 February 2007
Abstract—Herein we report a high yielding one-pot ‘green’ synthesis of 3-substituted-5-carbonylmethyl-1,2,4-oxadiazoles from read-
ily available b-keto esters and amidoximes under simple and convenient solvent-free conditions. No additional base is needed. The
reaction likely goes through an acyl ketene intermediate.
Ó 2007 Elsevier Ltd. All rights reserved.
1
,2,4-Oxadiazole is a pharmaceutically important het-
promoted by bases such as NaH,12 NaOMe,13
1
4
erocycle. It can be found in many biologically active
molecules such as sphingosine-1-phosphate-1 (S1P )
receptor agonist, muscarinic agonist, serotoninergic
antagonists, inhibitors of monoamine oxidase, and
dopamine ligands. In addition, 1,2,4-oxadiazoles are
also often used as bioisosteres of esters and amides for
improved physical or biological properties. This
K CO , and condensation of malonic diesters with
2 3
1
5
amidoximes under neutral and solvent-free conditions.
1
1
2
We have ongoing interest in efficient synthesis of 1,2,4-
oxadiazoles. As an extension of our previous work,
we wish to report here an efficient one-pot synthesis of
5-b-keto-1,2,4-oxadiazoles 6 with a broader scope of
application.
3
4
5
6
includes the development of pseudopeptides by bioiso-
7
steric replacement of the amide moiety in peptides,
Beta-keto esters are important building blocks in organic
synthesis. The studies on transesterification of b-keto
esters revealed that under thermal conditions, a b-keto
ester can undergo elimination of a molecule of alcohol
which is currently under intense studies for its important
implication in peptide chemistry and peptidomimetics.
1
6
Accordingly, the synthesis of 1,2,4-oxadiazoles has
received much attention and has been the subject of
intense studies. 1,2,4-Oxadiazoles are often synthesized
by 1,3-dipolar cyclization of nitrile oxide and cyano
compounds or cyclization/dehydration of O-acyl ami-
doximes. The latter are usually derived from coupling
of carboxylic acids and amidoximes. Recently reported
TBAF catalyzed cyclization of O-acyl amidoximes
makes the latter route a popular approach to 1,2,4-
oxadiazoles. Further efforts in this area have focused
on developing more efficient one-pot synthesis of this
ring system. This includes recently published micro-
wave-assisted condensation of aryl amidoxime and aryl
to form an a-keto ketene intermediate 2. Kinetic stud-
ies showed that the sterically more hindered alcohol is
easier to be eliminated. Thus tert-butyl b-keto ester 1
is 15–20 times faster than less hindered methyl b-keto
8
1
7
ester in formation of the acyl ketene. Ketenes are a
family of highly reactive and versatile intermediate in
organic synthesis. Despite the broad application of ket-
enes in organic synthesis, the application of the a-keto
ketenes generated from b-keto esters has only been limi-
ted to transesterification to generate other b-keto esters.
Amidoxime 4 should react analogously to give transeste-
rification product O-acyl amidoxime 5, which would
then yield 5-b-keto-1,2,4-oxadiazole 6 under thermal
conditions (Scheme 1).
9
1
0
1
1
aldehyde, condensation of esters with amidoximes
*
Corresponding author. Tel.: +1 732 594 2891; fax: +1 732 594 5966;
e-mail: wu_du@merck.com
There is limited literature precedent for the synthesis of
5-b-keto-1,2,4-oxadiazoles. They are typically synthesized
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.005

2232
W. Du et al. / Tetrahedron Letters 48 (2007) 2231–2235
O
O
O
O
O
tBuOH
R'OH
-
O
C
R'
R
R
O
R
O
3
2
1
HO
N
H N
2
R"
4
O
O
O
O N
-
H O
2
R
O
N
H N
R
N
R"
2
R"
5
6
Scheme 1.
1
8
from 2,2,6-trimethyl[1,3]dioxin-4-one, a-cyanoketone
in entry 7 that 8g was prepared in 84% yield. Functional
groups such as sulfone and benzyl ether were also toler-
ated under the reaction conditions as shown in entries 8
and 9. The oxadiazole products were prepared in 92%
and 84%, respectively.
1
9
through a multi-step sequence, by TBAF promoted
cylization/dehydration of O-acyl amidoxime, or by
reaction of amidoxime with diketene in the presence of
NaOMe. The latter approach yielded 3-acetomethyl-
,2,4-oxadizaoles in one-pot. However, the drawback
1
0
2
0
1
is that diketene is volatile, difficult to handle, and its
scope of application is very limited: only methyl ketone
can be made from diketene. The synthesis of 5-aceto-
methyl-1,2,4-oxadiazoles from ethyl acetoacetate was
also minimally explored either in the presence of
In addition to substituted amidoximes, various b-keto
esters are also good substrates. As shown in entries
10–12, methyl and ethyl b-keto esters worked well in this
reaction. Ethyl ester 7b yielded oxadiazole 8j in 69%
yield while methyl ester 7c yielded oxadiazole 8k in
87% yield. These two reactions also showed that substit-
uents at 2 and 3 positions of the b-keto ester are toler-
ated in this reaction. Selectivity can also be achieved
among two esters from the b-keto ester substrate. As
shown in entry 12, among the two ester groups of 7d
only the one b to the ketone is reactive in the reaction.
Thus the reaction of diester 7d and phenyl amidoxime
yielded oxadiazole mono ester product 8l in 70% yield.
The selective activation of ester group by b-ketone
allows a very efficient synthesis of ester containing
1,2,4-oxadiazole products that would otherwise take
longer steps to make.
NaOMe, or under extensive heating in toluene.22
However, both conditions gave low yields of the
oxadiazole products.
21
Herein we report a convenient, high yielding, and ‘green’
synthesis of 5-b-keto-1,2,4-oxadiazoles by heating a
b-keto ester and an amidoxime under solvent-free condi-
tions. The procedure is very simple: 1 equiv of amid-
oxime was mixed with 2 equiv of b-keto ester in a vial.
The mixture was then heated to 120–140 °C for 2–4 h.
After the reaction was complete, the brown reaction
mixture was applied to a silica gel column and purified
2
3
by flash chromatography. When solid reactants were
used, the solid melted upon heating to give a homo-
geneous reaction mixture. The results are summarized
in Table 1.
The solvent-free conditions likely contribute to the high
efficiency of this reaction in two ways: driving the reac-
tion toward the desired oxadiazole product by removing
other volatile products and favored entropy effect by
achieving high concentration of amidoxime reactants.
In addition to the oxadiazole product, a molecule of
alcohol and a molecule of water are also generated
according to the proposed mechanism. Removal of these
side products becomes easier under the solvent-free con-
ditions, and thus facilitates completion of the reaction.
The subsequent addition of an amidoxime to the acyl
ketene intermediate is an intermolecular reaction. It is
also significantly accelerated by the high concentration
of the amidoxime achieved under the solvent-free
conditions.
This one-pot procedure works well for a wide range of
substrates. Various substituted amidoximes were reacted
with t-butyl acetoacetate and gave excellent yield of the
desired oxadiazole products. As shown in entries 1–3,
the electron withdrawing or donating group on the phen-
yl ring did not affect the reaction. All three reactions
gave almost quantitative yields. In entry 4, oxadiazole
8
d containing an electron deficient heterocycle was pre-
pared in 84% yield. In addition, this one-pot procedure
is simple and efficient. The reaction conditions are also
very mild. As shown in entry 5, the methyl ester in ami-
doxime 4e survived the reaction in which only the t-
butyl ester reacted with 4e and gave 95% yield of 8e.
Similarly in entry 6, the ethyl ester group of 4f remained
inert in the reaction that gave 88% yield of 8f. Such
chemoselectivity is hard to achieve under previously
reported conditions involving bases such as NaH,
NaOMe, and K CO . Amidoximes bearing a simple
In summary, we report here a high yielding one-pot syn-
thesis of 5-carbonylmethyl-1,2,4-oxadiazoles from read-
ily available b-keto esters and amidoximes under simple
and convenient solvent-free conditions. The reaction
likely goes through an acyl ketene intermediate. The
conditions are mild and a wide range of functional
groups can be tolerated. The reaction is also selective:
2
3
alkyl group also worked well in this reaction, as shown

W. Du et al. / Tetrahedron Letters 48 (2007) 2231–2235
2233
Table 1.
O
O
HO
O
O N
R3
N
R1
O
+
R1
R4
N
R2
H N
2
R4
R2
7
4
8
Entry
1
7
4
8
Yield (%)
O
O
HO
O
O N
N
O
N
100
99
98
84
95
88
84
H N
Ph
2
7
a
4a
8a
HO
O
O N
N
N
H N
N
2
3
4
5
6
7
7a
7a
7a
7a
7a
7a
2
O
O
8
b
4
b
HO
O
O N
N
H N
2
CF3
CF3
4
c
8c
HO
N
CF3
O
O N
N
CF
3
H N
2
N
N
8
d
4
d
HO
N
O
O N
H N
N
2
O
CO Me
2
O
8
e
4
e
HO
O
O N
N
O
O
N
H2N
O
N
O
8
f
4
f
HO
O
O
N
N
H N
2
8
g
4
g
HO
O
O
N
O
O
S
N
O O
S
N
8
9
7a
H N
2
92
F
F
4
h
8h
HO
O
O N
N
OBn
OBn
7a
N
84
H N
2
8
i
4
i
(continued on next page)

2234
W. Du et al. / Tetrahedron Letters 48 (2007) 2231–2235
Table 1 (continued)
Entry
7
4
8
Yield (%)
O
O
O
O N
O
O
N
1
0
1
4f
O
69
8
j
7
b
HO
O
O
N
O
O N
O
H N
N
N
1
2
N
87
70
7
c
8k
8l
4
j
O
O
O
O
O
3
O N
12
EtO
OEt
4a
EtO
N
3
7
d
only the esters that are b to a carbonyl and capable of
forming acyl ketene intermediate are reactive. Unlike
many 1,2,4-oxadiazole syntheses that require bases, no
additional reagents are needed under these conditions.
Thus the purification process is much simplified and sol-
vent waste is eliminated, and the reaction is cost efficient
and environmentally friendly. Further studies on this
topic will be reported in due course.
Long, M. A.; Vescio, N.; Aldous, S.; Pevear, D. C.;
Dutko, F. J. J. Med. Chem. 1994, 37, 2421.
. Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.;
Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42,
7
4
331.
8
9
. Hemming, K. J. Chem. Res., Synop. 2001, 6, 209.
. Liang, G.-B.; Feng, D. D. Tetrahedron Lett. 1996, 37,
6
627.
1
0. Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.;
Wang, V. R.; Rice, K. D. Tetrahedron Lett. 2001, 42,
1
441.
1
1. Adib, M.; Jahromi, A. H.; Tavoosi, N.; Mahdavi, M.;
Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47, 2965.
2. (a) Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.;
Macleod, A. M.; Merchant, K. J.; Showell, G. A.;
Saunders, J.; Herbert, R. H.; Freedman, S. B.; Harley,
E. A. J. Med. Chem. 1990, 33, 2690; (b) Swain, C. J.;
Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward,
E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling, K.
J. Med. Chem. 1991, 34, 140.
Acknowledgment
1
The authors wish to thank Dr. Shrenik K. Shah for
helpful discussions and valuable comments on the
manuscript.
References and notes
13. Sauerberg, P.; Kindtler, J. W.; Nielsen, L.; Sheardown, M.
J.; Honore, T. J. Med. Chem. 1991, 34, 687.
14. Amarasinghe, K. K. D.; Maier, M. B.; Srivastava, A.;
Gray, J. L. Tetrahedron Lett. 2006, 47, 3629.
15. Du, W.; Hagmann, W. K.; Hale, J. J. Tetrahedron Lett.
2006, 47, 4271.
1
. 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.
16. Witzeman, J. S.; Nottingham, W. D. J. Org. Chem. 1991,
56, 1713.
2
. (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. Med. Chem. 1991, 34,
17. Witzeman, J. S. Tetrahedron Lett. 1990, 31, 1401.
18. Boehme, T. M.; Augelli-Szafran, C. E.; Hallak, H.;
Pugsley, T.; Serpa, K.; Schwarz, R. J. Med. Chem. 2002,
45, 3094.
2726; (b) Suzuki, T.; Uesaka, H.; Hamajima, H.; Ikami, T.
Chem. Pharm. Bull. 1999, 47, 876.
19. Cho, S. Y.; Ahn, J. H.; Ha, J. D.; Kang, S. K.; Baek, J. Y.;
Han, S. S.; Shin, E. Y.; Kim, S. S.; Kim, K. R.; Cheon, H.
G.; Choi, J.-K. Bull. Korean Chem. Soc. 2003, 24, 1455.
20. Tabei, K.; Kawashima, E.; Takada, T.; Kato, T. Chem.
Pharma. Bull. 1982, 30, 336.
21. Yale, H. L.; Spitzmiller, E. R. J. Heterocycl. Chem. 1978,
15, 1373.
22. Kocevar, M.; Stanovnik, B.; Tisler, M. J. Heterocycl.
Chem. 1982, 19, 1397.
23. Experimental procedure: t-Butyl acetoacetate 7a (160 mg,
1 mmol) and amidoxime 4h (116 mg, 0.5 mmol) were
mixed in a vial. The reaction mixture was then heated in
an oil bath at 120 °C for 2 h. TLC showed completion of
3
. Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders,
J.; Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.;
Watling, K. J. Med. Chem. 1991, 34, 140.
. Harfenist, M.; Heuser, D. J.; Joyner, C. T.; Batchelor, J.
F.; White, H. L. J. Med. Chem. 1996, 39, 1857.
. Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.;
Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J. Med. Chem.
4
5
1
993, 36, 2886.
. (a) Lima, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005,
2, 23; (b) Andersen, K. E.; Lundt, B. F.; Joergensen, A.
6
1
S.; Braestrup, C. Eur. J. Med. Chem. 1996, 31, 417; (c)
Diana, G. D.; Volkots, D. L.; Nitz, T. J.; Bailey, T. R.;

W. Du et al. / Tetrahedron Letters 48 (2007) 2231–2235
2235
the reaction. The brown mixture was then purified by
flash chromatography on silica gel to give product 8h
133.5, 131.65, 131.58, 116.77, 116.59, 83.31, 53.37, 53.1,
41.3, 29.9, 21.4.
(
137 mg) as a white solid in 92% yield. The proton NMR
showed that 8h is a mixture of the ketone form (8h) and
O
O N O O
OH
O
O
S
O
N
0
the enolate form (8h ) in a ratio of 4:1 in CDCl
3
(Fig. 1).
, 500 MHz) d 7.85
2H, m), 7.22 (2H, m), 4.55 (2H, s), 4.08 (2H, s), 2.29
S
1
N
N
H NMR of the ketone form: (CDCl
3
(
(
F
F
1
8h'
3H, s). H NMR of the enolate form: (CDCl
3
, 500
8h
MHz) d 7.85 (2H, m), 7.22 (2H, m), 5.49 (1H, s), 4.52
1
3
Figure 1.
The spectroscopic data of other oxadiazole products are
consistent with their structures.
(
2H, s), 2.08 (3H, s). C NMR of the mixture of both
the ketone and the enolate form (CDCl , 125 MHz) d
98.3, 176.4, 174.3, 171.7, 167.2, 165.2, 161.4, 158.7,
3
1