A. R. Gangloff et al. / Tetrahedron Letters 42 (2001) 1441–1443
1443
R'
O
N
R'
O
N
H +
N
N
R'
F -
F -
R'
O
N
O
N
O
H
N
HO
-O
R
R
N
R
4
H
F -
H
2
H
3
R
F -
5
Scheme 1.
at 23°C, but the addition of TBAF dramatically
increased the rate of dehydration. This suggests TBAF
plays a role in both steps of the cyclocondensation
reaction.
3. (a) Quadrelli, P.; Invernizzi, A. G.; Falzoni, M.;
Caramella, P. Tetrahedron 1997, 53, 1787–1796; (b) Yu,
Y.; Watanabe, N.; Ohno, M.; Eguchi, S. J. Chem. Soc.,
Perkin Trans. 1 1995, 1417–1421; (c) Yu, Y.; Fujita, H.;
Ohno, M.; Eguchi, S. Synthesis 1995, 498–500; (d) Nei-
dlein, R.; Li, S. Synth. Commun. 1995, 25, 2379–2394.
4. (a) Korbonits, D.; Horvath, K. Heterocycles 1994, 37,
2051–2068; (b) Chiou, S.; Shine, H. J. J. Heterocycl. Chem.
1989, 26, 125–128; (c) Kayukova, L. A.; Praliev, K. D.;
Zhumadildaeva, I. S.; Klepikova, S. G. Chem. Heterocycl.
Compd. (NY) 1999, 35, 630–631; (d) Ooi, N. S.; Wilson, D.
A. J. Chem. Soc., Perkin Trans. 2 1980, 1792–1799; (e)
Andersen, K. E.; Lundt, B. F.; Joergensen, A. S.;
Braestrup, C. Eur. J. Med. Chem. 1996, 31, 417–425.
5. Hebert, N.; Hannah, A. L.; Sutton, S. C. Tetrahedron Lett.
1999, 40, 8547–8550.
The work presented here demonstrates a straightfor-
ward and mild procedure for the efficient synthesis of
3,5-disubstituted-1,2,4-oxadiazoles using tetrabutylam-
monium fluoride. A variety of acylators (acid chlorides
and anhydrides) and nitriles (both aliphatic and aro-
matic) can be used to expand the scope of substituents
around the oxadiazole ring, particularly those substi-
tuents which would not survive the more basic
conditions or higher temperatures required by other
oxadiazole syntheses. The mild conditions described
make this procedure especially amenable towards appli-
cation to solid support.
6. Pless, J. J. Org. Chem. 1974, 39, 2644–2646.
7. All new compounds were characterized fully by mp, 1H
and 13C NMR, and mass spectrometry. General proce-
dure: 3-Methyl-5-phenyl-[1,2,4]oxadiazole (3s). Hydroxyl-
amine (50% by weight in H2O, 5.0 mL, 76 mmol) and
acetonitrile (1 mL, 19 mmol) were combined in EtOH (100
mL) and heated to reflux for 1 h. The reaction was cooled
to 23°C and then conc. in vacuo to give N-hydroxy-
acetamidine (1, R=Me) as a white solid, 5.58 g (99%),
mp=136–138°C. N-Hydroxy-acetamidine (1, R=Me) (222
mg, 3.0 mmol) was placed in CH2Cl2 (5 mL) and cooled to
0°C. i-Pr2NEt (1.0 mL, 6.0 mmol) was added, followed by
slow dropwise addition of benzoyl chloride (450 mL, 3.9
mmol) in CH2Cl2 (2 mL). After 1 h at 0°C, the mixture
was allowed to warm to 23°C and was stirred overnight.
The reaction was poured into EtOAc and washed with
water and brine, then dried (MgSO4) and conc. in vacuo.
The crude material was crystallized from EtOAc/hexanes
to give O-benzoyl-acetamidoxime (2s, R=Me, R%=ben-
zoyl) as a white solid, 371 mg (69%), mp=115–116°C.
O-Benzoyl-acetamidoxime (356 mg, 2.0 mmol) was placed
under argon and THF (5 mL) was added. n-Bu4NF (1 M
in THF, 200 mL, 0.2 mmol) was added dropwise and the
reaction was stirred at 23°C for 48 h. The mixture was
poured into EtOAc and washed with water and brine. The
organic layer was dried (MgSO4) and conc. in vacuo. The
material was crystallized from EtOAc/hexanes to give 3-
methyl-5-phenyl-[1,2,4]oxadiazole (3s) as a white solid, 288
mg (90%), mp=58°C. 3g Obtained as a white solid. 1H
NMR (270 MHz, CDCl3) l 7.91, 7.80, 7.65, 2.67; 13C
NMR (68 MHz, CDCl3) l 177.08, 166.19, 149.09, 132.72,
131.73, 131.38, 124.44, 12.39; MS (m/e) 208 (MH+); mp
55–57°C. 3m Obtained as a colorless oil. 1H NMR (300
MHz, CDCl3) l 8.08, 7.45, 1.48; 13C NMR (75 MHz,
CDCl3) l 186.1, 168.0, 130.8, 128.6, 127.3, 127.1, 33.5,
28.3; MS (m/e) 203 (MH+).
Acknowledgements
We thank Mitch Lee for analytical support on the
project. We also thank Dr. Michael Venuti for his
mentorship and helpful discussions.
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