108
Y. Wang et al. / Tetrahedron Letters 47 (2006) 105–108
1
3
equiv. HBTU
equiv. PS-BEMP
OH
O
O
O
CH3CN, MW
1
1
+
o
NH
50 C,15 min
N
H
O
i) 3 equiv. PS-PPh3,
.5 equiv. CCl CN
MW, 100 C, 5 min.
1
3
NHNH2
o
3
ii) 2 equiv. DIEA, MW,
o
1
50 C, 15 min., THF
2
Scheme 3. Synthesis of diacyl hydrazide 3.
2
. 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. 2002, 9,
1251–1283; (d) Dzierba, C. D.; Combs, A. P. Annu. Rep.
Med. Chem. 2002, 37, 247–256.
O
O
3
1
equiv. PS-PPh3,
O
NH
N
equiv. CCl CN
N
3
N
H
CH CN, MW
1
3
o
50 C, 20 min.
3. (a) Tully, W. R.; Gardner, C. R.; Gillespie, R. J.;
Westwood, R. J. Med. Chem. 1991, 34, 2060; (b) Chen,
C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59,
1
00% conversion
95% yield
3
4
3
738; (c) Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J.
Scheme 4. Conversion of 3 to 1,3,4-oxadiazole 4 with PS-PPh
CCl CN.
3
/
Med. Chem. 2000, 35, 267–271; (d) Crimmin, M. J.;
OÕHanlon, P. J.; Rogers, N. H.; Walker, G. J. Chem. Soc.,
Perkin Trans. 1 1989, 2047; (e) Laddi, U. V.; Desai, S. R.;
Bennur, R. S.; Bennur, S. C. Ind. J. Heterocycl. Chem.
3
of the resin and evaporation of the solvents. In most
cases, a quick, simple flash silica column afforded the
desired product 1,3,4-oxadiazole in high purity.
2
002, 11, 319–322.
4
. For some recent examples, see: (a) Baxendale, I. R.; Ley,
S. V.; Martinelli, M. Tetrahedron 2005, 61, 5323–5349; (b)
Liras, S.; Allen, M. P.; Segelstein, B. E. Synth. Commun.
In summary, we have developed a rapid and efficient
method for the synthesis of 1,3,4-oxadiazoles in high
yields using readily available carboxylic acids and acid
hydrazides in one simple step under mild reaction condi-
tions. The use of solid-phase reagents in combination
with microwave heating greatly simplified the purifica-
tion process, and allowed us to quickly identify the opti-
mal reaction condition and obtain high yields and
operational efficiency. This method is not only suitable
for the preparation of either individual analogues, but
also the production of libraries using automation.
2
000, 30, 437–443; (c) Brown, B. J.; Clemens, I. R.;
Neesom, J. K. Synlett 2000, 1, 131–133; (d) Coppo, F. T.;
Evans, K. A.; Graybill, T. L.; Burton, G. Tetrahedron
Lett. 2004, 45, 3257–3260; (e) Brain, C. T.; Paul, J. M.;
Loong, Y.; Oakley, P. J. Tetrahedron Lett. 1999, 40, 3275–
3
3
278; (f) Brain, C. T.; Brunton, S. A. Synlett 2001, 3, 382–
84.
5
. (a) Tandon, V. K.; Chhor, R. B. Synth. Commun. 2001, 31,
727–1732; (b) Mashraqui, S. H.; Ghadigaonkar, S. G.;
1
Kenny, R. S. Synth. Commun. 2003, 33, 2541–2545; (c)
Bentiss, F.; Lagrenee, M.; Barbry, D. Synth. Commun.
2
001, 31, 935–938; (d) Jedlovska, E.; Lesko, J. Synth.
Commun. 1994, 24, 1879–1885.
6
7
. Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989–6992.
. Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org.
Lett. 2005, 7, 925–928.
Supplementary data
8. (a) Dutta, M. M.; Goswami, B. N.; Kataky, J. C. S. J.
Heterocycl. Chem. 1996, 23, 793–795; (b) Kosmrlj, J.;
Kocevar, M.; Polanc, S. Synlett 1996, 7, 652–654.
9
. General procedure: A Smith Process vial (0.5–2 ml) was
charged with a stir bar. To the vessel were added 0.1 mmol
of the carboxylic acid and 0.11 mmol of the acid hydrazide
in 1.5 ml dry CH CN. 0.3 mmol PS-PPh (3 mmol/g) was
References and notes
3
3
1
. For recent reviews, see: (a) Kirschning, A.; Monenschein,
H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650–
79; (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–
added to the reaction mixture, followed by 0.2 mmol
CCl CN. The reaction vessel was sealed and heated in
microwave to 150 °C for 20 min. After cooling, the
reaction vessel was uncapped and the resin was filtered
3
6
3
and washed with additional CH CN. The desired 1,3,4-
oxadiazoles were isolated by flash chromatography. All
products thus obtained were greater than 98% pure as
1
3
36; (d) Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res.
Rev. 1999, 19, 97–148; (e) Garcia, J. G. Methods Enzymol.
003, 369, 391–412.
determined by LC/MS and H NMR analysis.
10. In most cases, LC/MS analysis of the crude materials
showed the purities of the products are greater than 90%.
2