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

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(OR)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 H and C nuclear magnetic resonance (NMR) spectroscopy and electrospray ionization coupled to tandem mass spectrometric (ESI MS/MS) data.

The preparation of the series of 5-(2-(trifluoromethylheteroaryl)ethyl)-1,3,4-oxadiazole-2-thiol 7b-d was carried out using a simple one-pot procedure that involves reacting the respective hydrazide 3 with CS 2 under strong basic conditions followed by acidification with HCl solution, as already described in the literature. 24,25Using an adaptation of the experimental methodology described by El-Din Mohamed et al. 7 led to products 7a-d at excellent yields.
The functionalization of 1,3,4-oxadiazole-2-thiols by alkylation and acylation reactions of the -SH group is not as common in the literature as one would expect.Hence, for this reason, and also because such a procedure may result in compounds with a broad potential spectrum of pharmacological activities, we decided to conduct such studies.To this end, we carried out alkylation reactions with 2-bromoacetophenone and acylation reactions with acetyl anhydride and trichloroacetyl chloride of the series 7b-d, as summarized in Scheme 3, using adaptations of experimental methodologies described in the literature. 26,27he characterization data of all of the synthesized compounds are given in the Experimental section.All of the newly synthesized compounds gave satisfactory analyses for the proposed structures, which were confirmed based on their 1D / 2D NMR (nuclear magnetic resonance) and HRMS (high resolution mass spectrometry) spectral data.For all series of biheterocyclic products, a multiplet due to an ethylene chain spacer between 3-4 ppm was observed in the 1 H NMR spectra, and the shape varied from a singletlike signal to two well-defined triplets (see Supplementary Information).In the 13 C NMR spectra are characteristic for all series of the product isolated the signals from ethylene spacer at d 22 and 32 ppm and at compatible chemical shifts, the signals as quartets from the carbons coupling to the fluorine atoms.
Here, we specifically described the synthesis of (trifluoromethylheteroaryl)propanoyl hydrazides (3a-d) and their cyclocondensation with trialkyl orthoformates and carbon disulfide as an efficient protocol for the preparation of diverse, novel 5(2)-[2-(trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles (4-10) at good yields.These compounds are interesting structural analogs to central nervous system chemical mediators, making them good subjects for the study of biological activity.Furthermore, heterocyclic imine nitrogens may be interesting modulators of the electronic characteristics of metals in compounds used in luminescent devices.

Synthesis of 8b and 8c
A solution of 2-bromoacetophenone (3 mmol) in CHCl 3 (5 mL) was added dropwise to a stirred and cooled (to 0 °C) solution of the respective compound 7 (3 mmol) and Et 3 N (3 mmol) in CHCl 3 (15 mL).The reaction mixture was stirred for 1 h and then was poured into water.The organic layer was separated and washed with water (10 mL × 2).The organic layer was dried over Na 2 SO 4 , and then the solvent was removed under vacuum and the solid products were identified.A portion was recrystallized from CHCl 3 / hexane solutions for elemental analysis experiments.(15 mL).The reaction mixture was stirred for 1 h, poured into water, and then the organic layer was separated and washed with water (10 mL × 4).The organic layer was dried over Na 2 SO 4 , the solvent was removed under vacuum, and the solid products were identified.A portion was recrystallized from CHCl 3 / hexane solutions for elemental analysis experiments.Vol.28

Table 3 .
Optimization of the reaction conditions between N-acylhydrazone a Isolated product 12b.