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K. K. D. Amarasinghe et al. / Tetrahedron Letters 47 (2006) 3629–3631
Table 1. Representative examples of the synthesis of 1,2,4-oxadiazoles
38
N
O
N
O
N
Compound
#
R1
R2
Yield
(%)a
N
N
O
O
N
NHBoc
3a
3b
3c
3d
3e
3f
Benzyl
Benzyl
Methyl
4-Methylphenyl
Methyl
4-Methylphenyl
Methyl
4-Methylphenyl
Methyl
91
77
95
65
86
90
62
O2N
N
N
7
6
4-Methylbenzyl
4-Methylbenzyl
4-Methoxyphenyl
4-Methoxyphenyl
tert-Butylpropionate
Figure 1. Additional examples of 1,2,4-oxadiazoles.
3g
doximes has been developed. This method tolerates a
variety of functional groups on both reaction partners
and gives 3,5 disubstituted 1,2,4-oxadiazoles in moder-
ate to excellent yields.
a Purified products.
R2
O
N
O
N
OR4
OH
Acknowledgements
N
K2CO3 (2.2 equiv)
R3
R3
+
OR4
R2
NH2
The authors would like to thank Dr. Jennifer Tinsley for
her assistance in preparing this manuscript.
toluene, reflux
(6-12 h)
O
N
O
5
2
4
N
(2.2 equiv)
R2
References and notes
Scheme 2. Synthesis of bis-1,2,4-oxadiazoles.
1. Diana, G. D.; Volkots, D. L.; Nitz, T. J.; Baily, T. R.;
Long, M. A.; Vescio, N.; Aldous, S.; Pevear, D. C.;
Dutko, F. J. Med. Chem 1994, 37, 2421–2436.
2. Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.;
Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42,
4331–4342.
Table 2. Representative examples of the synthesis of bis-1,2,4-
oxadiazoles 5
Entry Compound R2
R3
R4
Yield
(%)a
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. Med. Chem. 1991, 34,
2726–2735; (b) Suzuki, T.; Uesaka, H.; Hamajima, H.;
Ikami, T. Chem. Pharm. Bull. 1999, 47, 876–879.
4. 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, 140–151.
5. (a) Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.;
Macleod, A.; Knight, A.; Merchant, K.; Moseley, J.;
Saunders, J.; Swain, C. J.; Wong, E.; Springer, J. P. J.
Med. Chem. 1989, 32, 2282–2291; (b) Williams, J. P.;
Lavrador, K. Comb. Chem. HighThroughput Screen. 2000,
3, 43–50.
1
2
3
4
5
6
7
8
9
5a
5a
5b
5c
5d
5e
5f
Methyl
Methyl
Ethyl
Methyl
H
H
H
Methyl 75
Ethyl 64
Ethyl 64
Benzyl Ethyl 69
Benzyl Ethyl 68
Benzyl Ethyl 67
Benzyl
4-Fluorobenzyl
3-(Thiophene)methyl Benzyl Ethyl 40
Methoxyethyl Benzyl Ethyl 73
Cyclopropylmethyl Benzyl Ethyl 40
4-methoxyphenyl Benzyl Ethyl 83
5g
5h
5i
10
a Purified products.
oxime to give bis-1,2,4-oxadiazole 5a in comparable
yields (Table 2, entries 1 and 2). A variety of functional-
ized amidoximes, including aliphatic, aromatic, hetero-
cyclic and protected alcohols, participated in this
reaction to give bis-1,2,4-oxadiazoles in moderate to
good yields. Moreover, this method was amenable to
the use of microwave irradiation. For example, micro-
wave irradiation of a mixture of dimethyl malonate,
acetamide oxime and K2CO3 in toluene at 180 ꢁC for
10 min yielded 72% of 5a.11 Additionally, we used this
method to synthesize tris-1,2,4-oxadiazole 6 in 42% yield
and the reaction tolerated the presence of a nitro group
in the phenyl ring (Fig. 1).10 Reaction of L-Boc-Phe-
OMe with acetamide oxime in the presence of K2CO3
in refluxing toluene for 6 h yielded oxadiazole 7 in
72% yield with complete racemization of the chiral cen-
ter, as determined by 19F analysis of its Mosher’s amide
(Fig. 1).
6. Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.;
Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J. Med. Chem.
1993, 36, 2886–2890.
7. Chiou, S.; Shine, H. J. J. Heterocyclic Chem. 1989, 26,
125–128.
8. Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.;
Wang, V. R.; Rice, K. D. Tetrahedron Lett. 2001, 42,
1441–1443, and references cited therein.
9. General procedure: To a solution of methyl phenylacetate
(100 mg, 0.67 mmol) in toluene (3 mL) was added acet-
amide oxime (104 mg, 1.4 mmol) followed by K2CO3
(193 mg, 1.4 mmol). The reaction mixture was stirred at
reflux for 6 h. The reaction mixture was cooled to room
temperature, diluted with EtOAc (25 mL) and washed
successively with water (2 · 10 mL) and brine (1 · 10 mL).
The organic phase was dried (Na2SO4), filtered and
concentrated. The residue was chromatographed on SiO2
(0–20% EtOAc in hexane) to give 106 mg of 3a as a
colorless oil (91%).
10. All new compounds were fully characterized by 1H and
13C NMR, and mass spectrometry. Characterization data
1
In summary, a general, practical method of synthesizing
1,2,4-oxadiazoles from carboxylic acid esters and ami-
for a few selected compounds (3a): H NMR (300 MHz,
CDCl3) d 2.40 (s, 3H), 4.22 (s, 2H), 7.29–7.39 (m, 5H); 13
C