Strategies for the Efficient Synthesis of Biheterocyclic 5-[2-(Trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles from Levulinic Acid

Malavolta, Juliana L.; Frigo, Leandro M.; Moura, Sidnei; Flores, Darlene C.; Flores, Alex F. C.

doi:10.21577/0103-5053.20170056

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Articles • J. Braz. Chem. Soc. 28 (11) • Nov 2017 • https://doi.org/10.21577/0103-5053.20170056 copy

Strategies for the Efficient Synthesis of Biheterocyclic 5-[2-(Trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles from Levulinic Acid

Authorship SCIMAGO INSTITUTIONS RANKINGS

The synthesis of 5-[2-(trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles derived from levulinic acid is reported. Cyclocondensations [4 + 1] between four different 5-[2-(trifluoromethylheteroaryl)propionylhydrazides derived from methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4-heptenoate obtained from levulinic acid, and electrophilic orthoesters RC(OR¹)₃ (where R = H, Me, Ph) and CS₂ were carried out in a mild medium. Good yields (69-96%) of isolated products were obtained. The structures of the new ethylene-spaced biheterocycles were characterized using ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy and electrospray ionization coupled to tandem mass spectrometric (ESI MS/MS) data.

Keywords:
heterocycles; oxadiazoles; pyrimidines; pyrazoles; levulinic acid

entry	Solvent	Ratio 3c:orthoacetate	Temperature / ºC	time / h	Yield / %
1	ethanol	1:1	78	24	-^a a Mixture of 5c and starting reagents, 3:7.
2	ethanol	1:3	78	24	52
3	orthoacetate	1:10	100	16	95
4	orthoacetate	1:6	80	12	92
5	orthoacetate	1:3	80	16	92

entry	Precursor	Methodology	Product	Yield / %	Reference
1	11b	N-acylhydrazone oxidation with chloramine-T	11b	-	²⁸28 Murti, Y.; Mehrotra, V.; Pathak, D.; Int. J. Drug Discovery 2011, 2, 659.
2	11b	N-acylhydrazone oxidation with TCCA	12b	79	²⁹29 Pore, D. M.; Mahadik, S. M.; Desai, U. V.; Synth. Commun. 2008, 38, 3121.
3	13b	SOCl₂ N-acetylhydrazide dehydration	13b	-	³⁰30 Mickevicius, V.; Vaickeliooniene, R.; Sapijanskaite, B.; Chem. Heterocycl. Compd. 2009, 45, 215. The procedure described was applied to N'-acetyl-3-(2-phenyl-6-trifluoromethylpyrimidin-4-yl)propanehydrazide (13b) obtained from acetylation of 3b.

entry	11b:TCCA ratio	time / min	Yield^a a Isolated product 12b. / %
1	1:1	60	79
2	1:1	30	76
3	1:1	10	76
4	1:0.5	10	71
5	1:0.25	10	64
6	1:0.25	20	64
7	1:0.25	60	70

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