3
any notable byproducts (entry 13). Other reactants with ortho-
substituents at phenyl ring (1b, 1e, 1h, 1j, 1p) or electrically
unfavorable reactants (1e-g, 1j-l) proceeded smoothly to
produce the corresponding 1,2,4-oxadiazoles with high yields.
Among the reactants examined, 1h and 1s were reported to give
only moderate to poor yields (2h: 77%, 2s: <5%) when 0.1eq
TBAF was used.7f Products with potentially reactive functional
groups in R2 such as alkyl chloride (2u) and ester (2v) could
also be obtained in moderate yields; albeit increased catalyst
loading was needed. Unfortunately, reactants with ester (1t) and
β−keto (1w) functionality gave no desired products. In the
case of 1t, almost no reaction occurred probably due to the
weaker electrophilicity of its carbonyl carbon. 1w also showed
low reactivity and gave just a small amount of benzamidoxime
as a byproduct.11 Interestingly, by decreasing the amount of
catalyst (0.05 eq) and reaction time (1 min), 1,2,4-oxadiazole
with silyl ether in R2 (2x) was successfully obtained (entry 24)
with suppression of silyl cleavage (12% HPLC yield of
desilylated 1,2,4-oxadiazole). When 1M THF solution of TBAF
was used under the same condition (0.05 eq of TBAF, 1 min) in
place of TBAH, the main product was the desilylated 1,2,4-
oxadiazole (76% HPLC yield) rather than 2x (18% HPLC yield).
a0.5 eq of TBAH was used.
b1.0 eq of TBAH was used.
c0.05 eq of TBAH was used and the reaction time was 1 min.
dTBS = tert-butyldimethylsilyl
In conclusion, we found that TBAH could be used as an
efficient catalyst for base catalyzed cyclizations of 1,2,4-
oxadiazoles from O-acylamidoximes. Various 3,5-substituted
1,2,4-oxadiazoles could be obtained in good yields utilizing
TBAH. Reaction times were reduced compared with those of
TBAF and this catalyst was compatible with a wider range of
functionality. Finally, due to the absence of fluoride in this
system, this method is free from the concern regarding
corrosion of reaction vessels, enabling large-scale synthesis of a
wide range of pharmaceutical drugs, agricultural chemicals or
compounds important in material applications.
Acknowledgments
We would like to express our gratitude to our colleagues,
Keiko Bando, Yuko Taoka and Junetsu Igarashi for their
analytical supports.
References and notes
1.
2.
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T. J. Med. Chem. 2012, 55, 1817-1830.
Table 3. Reaction of Various O-Acylamidoximes 1
TBAH
(0.1 eq, 40% w/w aqueous solution)
(a) Clitherow, J. W.; Beswick, P.; Irving, W. J.; Scopes, D. I. C.;
Barnes, J. C.; Clapham, J.; Brown, J. D.; Evans, D. J.; Hayes, A.
G. Bioorg. Med. Chem. Lett. 1996, 6, 833-838; (b) Andersen, K.
E.; Lundt, B. F.; Jørgensen, A. S.; Braestrup, C. Eur. J. Med.
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Chem. 1995, 60, 3112-3120; (d) Naka, T.; Kubo, K. Curr. Pharm.
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T.; Bailey, R. T.; Long, M. A.; Vescio, N.; Aldous, S.; Peveur, D.
C.; Dutko, F. J. J. Med. Chem. 1994, 37, 2421-2436; (f) Borg, S.;
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2697.
N
O
NH2
N
O
R2
R1
R1
R2
N
O
THF (0.4 M), r.t., 10 min
1a-x
2a-x
Entry
R1
R2
Product
Isolated
yield %
1
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2b
2c
2d
2e
2f
95
93
>99
>99
94
90
97
>99
89
94
96
99
80
99
95
96
95
95
89
0
2
2-MeOC6H4
3
3-MeOC6H4
4
4-MeOC6H4
5
2-NO2C6H4
6
3-NO2C6H4
7
4-NO2C6H4
o-tolyl
Me
2g
2h
2i
3.
4.
(a) Diana, G. D.; Nitz, T. J. U.S. Patent US 5464848, 1995; (b)
Fromtling, R. A.; Castañer, J. Drugs Fut. 1997, 22, 40-44.
(a) Lanier, M.; Luo, Z.; Moorjani, M.; Tellew, J. E.; Williams, J.
P.; Zhang, X. PCT Int. Appl. WO 2006044958, 2006; (b) Tellew,
J. E.; Lanier, M.; Moorjani, M. et al, Bioorg. Med. Chem. Lett.
2010, 20, 7259 -7264.
Carbone, M.; Li, Y.; Irace, C.; Mollo, E.; Castelluccio, F.; Di
Pascale, A.; Cimino, G.; Santamaria, R.; Guo, Y. W.; Gavagnin,
M. Org. Lett. 2011, 13, 2516-2519.
8
9
10
11
12
13a
14
15
16
17
18
19
20
21a
22b
23
24c
Me
2j
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
o-tolyl
Me
2k
2l
5.
6.
Me
Me
2m
2n
2o
2p
2q
2r
2s
(a) Agneeswari, R.; Tamilavan, V.; Song, M.; Kang, J. W.; Jin, S.
H.; Hyun, M. H. J. Polym. Sci., Part A: Polym. Chem. 2013, 51,
2131-2141; (b) Parra, M.; Hidalgo, P.; Carrasco, E.; Barbera, J.;
Silvino, L. Liq. Cryst. 2006, 33, 875-882; (c) Jung, J. C.; Choi, E.
J. Angew. Macromol. Chem. 1992, 197, 73-82.
Me
Me
Me
7.
(a) Tiemann, F.; Kruger, P. Chem. Ber. 1884, 17, 1685-1698; (b)
Ooi, N. S.; Wilson, D. A. J. Chem. Soc., Perkin Trans. 2. 1980,
1792-1799; (c) Tabei, K.; Kawashima, E.; Takada, T.; Kato, T.
Chem. Pharm. Bull. 1982, 30, 336-340; (d) Chiou, S.; Shine, H. J.
J. Heterocyclic Chem. 1989, 26, 125-128; (e) Liang, G. B.; Feng,
D. D. Tetrahedron Lett. 1996, 37, 6627-6630; (f) Gangloff, A. R.;
Litvak, J.; Shelton, E. J.; Sperandio, D.; Wang, V. R.; Rice, K. D.
Tetrahedron Lett. 2001, 42, 1441-1443.
Ph
Ph
4-Py
Ph
tBu
Ph
OMe
2t
Ph
CH2Cl
2u
2v
2w
2x
64
76
0
Ph
8.
9.
(a) Yarovenko, V. N.; Zavarzin, I. V.; Krayushkin, M. M. Russ.
Chem. Bull. 1986, 35, 1106; (b) Augustine, J. K.; Akabote, V.;
Hegde, S. G.; Alagarsamy, P. J. Org. Chem. 2009, 74, 5640-5643.
(a) Buscemi, S.; Pace, A.; Vivona, N. Tetrahedron Lett. 2000, 41,
7977-7981; (b) Zhang, Y. X.; Sasaki, K.; Hirota, T. J. Heterocycl.
Chem. 1999, 36, 787-791; (c) Suwiński, J.; Świerczek, K.;
CH2CO2Me
CH2COMe
CH2OTBSd
Ph
Ph
86
Ph