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groups (entries 3 and 4) were significantly better candidates than
their electron-rich or neutral carboxylic acids (entries 1 and 2).
To demonstrate the efficiency of this method, we also reacted
cinnamic acid as well as salicylic acid (entries 5 and 6) with acid
hydrazides to give the corresponding oxadiazoles, which were
not easily accessible by previous methods, in high yields. As can
be seen from the Table 2, aliphatic carboxylic acids were also con-
verted in good yields to the corresponding oxadiazoles (entries 8
and 10). In addition, the optically active oxadiazoles were also pre-
pared (entry 9) by this method, with no racemization being ob-
served by chiral GC analysis.19
In conclusion, we have developed an inexpensive, efficient,
straightforward, and common method for the synthesis of oxazo-
lines and oxadiazoles from various carboxylic acids using cyanuric
chloride. The reaction is carried out in one-pot and is operationally
simple and gives products with high yields and purity. Moreover,
this process is amenable to scale-up.
Acknowledgment
We thank Professor Paul Floreancig, University of Pittsburgh, for
helpful discussions.
15. Gossage, R. A.; Sadowy, A. L. Lett. Org. Chem. 2005, 2, 25–28.
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19. In a typical procedure, the carboxylic acid (0.43 mmol, 1 equiv) and cyanuric
chloride (1.3 mmol, 3 equiv) were dissolved in CH2Cl2 (5 ml) in an open test
tube. Pyridine (0.86 mmol, 2 equiv) was added dropwise, a white suspension
was formed on vortexing occasionally. After 15 min acid hydrazide (1.2 mmol,
3 equiv) was added (portionwise) followed by indium (0.13 mmol, 0.30 equiv)
at room temperature. The reaction mixture was occasionally shaken on a
vortex mixer at room temperature until formation of oxadiazoles was
completed as determined by TLC and GC–MS analysis. (S)-2-Phenyl-5-(2-
phenylpropyl)-[1,3,4]oxadiazole (Table 2, entry 9). 1H NMR (600 MHz, CDCl3):
References and notes
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d
7.98(d, J = 7.4 Hz, 2H), 7.54–7.48 (m, 3H), 7.34–7.28 (m, 4H), 7.25(t,
J = 7.4 Hz, 1H), 3.42(m, 1H), 3.22 (dd, J = 12.0 Hz, 2H), 1.43(d, J = 6.0 Hz, 3H);
TM
GC–FID: (Chiraldex , 50 °C, 5 min, 2 °C/min to 160 °C, 10 min.), tR: 16.81 min
(99% ee). ½a D
260 °C, 5 min, 40 °C/min to 300 °C, 10 min), tR: 11.95 min. MS (EI) m/z
(relative intensity): 264 (M+ꢀ
52), 249 (24), 160 (60), 105 (100).2-(2,2-
ꢀ
+8.23 (c 0.10, EtOH); GC: (HP-5, 50 °C, 2 min, 20 °C/min to
,
Diphenylethyl)-5-methyl-[1,3,4]oxadiazole (Table 2, entry 10). 1H NMR
(600 MHz, CDCl3): d 7.38–7.18 (m, 10H), 4.52 (m, 1H), 3.05 (d, J = 6.0 Hz,
2H), 2.45 (s, 3H); GC: (HP-5, 50 °C, 2 min, 20 °C/min to 260 °C, 5 min, 40 °C/
min to 300 °C, 10 min), tR: 11.85 min. MS (EI) m/z (relative intensity): 264
(M+ꢀ, 45), 180 (10), 167 (100), 152 (25).2-(2,2-Diphenylethyl)-4,4-dimethyl-4,5-
dihydrooxazole (Table 1, entry 10). 1H NMR (600 MHz, CDCl3): d 7.30–7.18 (m,
10H), 4.51 (m, 1H), 3.93 (s, 2H), 3.04 (d, J = 6.0 Hz, 2H), 1.05 (s, 6H); GC: (HP-
5, 50 °C, 2 min, 20 °C/min to 260 °C, 5 min, 40 °C/min to 300 °C, 10 min), tR:
11.20 min. MS (EI) m/z (relative intensity): 279 (M+ꢀ, 8), 264 (35), 167 (100),
152 (25), 77 (10).
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