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Multi-step Rapid Synthesis of 1,2,4-Oxadiazoles

Release time:2019-10-09 17:27:29


Heterocyclic compounds containing a 1,2,4-oxadiazole parent ring are commonly found in biologically active compounds, which are commonly used as bioisosteres of amides or esters and have been found in several drugs and Among the lead compounds are the receptor agonist 1 of S1P1 and the metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2 (Fig. 1).

 Figure 1: Bioactive oxadiazole disubstituted compounds
The synthesis method of 1,2,4-oxadiazoles is mainly by reacting an aromatic nitrile with hydroxylamine to form ammonia oxime, and then reacting with an acid chloride to form an amide, and finally cyclizing to obtain a target compound (Fig. 2), and cyclization It is the most difficult and time-consuming step in all reaction steps, and usually requires a long-term reaction in a sealed tube.

Figure 2: Method of conventional synthesis 2
Daniel Grant et al. used a continuous flow microchannel reactor to rapidly and efficiently synthesize 1,2,4-oxadiazole compounds, and designed a microchannel reactor experimental device through reasonable experimentation (Fig. 3).

Figure 3: Continuous flow microchannel reactor unit for the synthesis of 1,2,4-oxadiazoles
On this basis, the authors used aramid and acid chloride to disubstituted the 1,2,4-oxadiazole parent ring to synthesize a series of compounds containing 1,2,4-oxadiazole parent ring (Figure 4).
Figure 4: Results of disubstituted 1,2,4-oxadiazole parent rings in a continuous flow microchannel reactor using aramid and acid chloride
A series of carboxylic acid compounds containing a 1,2,4-oxadiazole parent ring were synthesized using aramid and succinic anhydride (Fig. 5).
Figure 5: Synthesis of a carboxylic acid compound containing a 1,2,4-oxadiazole parent ring in a continuous flow microchannel reactor using an aromatic nitrile and succinic anhydride
From the above data, it can be seen that the author used a continuous flow microchannel reactor to explore a new method for rapidly and efficiently synthesizing a compound containing 1,2,4-oxadiazole, which would require a lot of The reaction time in days and many steps was shortened to only tens of minutes, and it was proved that with this method, a desired library of small molecule heterocyclic compounds can be quickly established in a short time.
References: J. Org. Chem. 2008, 73, 7219–7223