Microwave-Assisted Synthesis of Benzoxazole-7-carboxylate Esters Using Trifluoroacetic Acid and Acetic Acid

Abstract

Existing routes to benzoxazole-7-carboxylates are low-yielding. The following letter describes a new methodology for the synthesis of benzoxazole-7-carboxylates in much improved yield using trifluoroacetic acid-acetic acid and microwave irradiation.

benzoxazoles - heterocycles - cyclisations - acylations - microwave-assisted synthesis - trifluoroacetic acid

References and Notes

<A NAME="RD19406ST-1">1</A> Goldstein SW. Dambeck PJ. J. Heterocycl. Chem.  1990,  27:  335 

<A NAME="RD19406ST-2">2</A> Kosoka T. Wakabuyashi T. Heterocycles  1995,  41:  477 

<A NAME="RD19406ST-3">3</A> Meyer V. J. Prakt. Chem.  1915,  92:  265 

<A NAME="RD19406ST-4">4</A> Razavi H. Palaninathan SK. Powers ET. Wiseman RL. Purkey HE. Mohamedmohaideen NN. Deechongkit S. Chiang KP. Dendle MTA. Sacchettini JC. Kelly JW. Angew. Chem. Int. Ed.  2003,  42:  2758 

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General Procedure for Mono-N-acyl Compounds 3: Amino phenol (1.0 equiv), benzoyl chloride (1.1 equiv), pyridinium 4-toluenesulfonate (0.26 equiv) and Et₃N (1.1 equiv) were stirred in xylene (10 mL) and heated at reflux overnight. The reaction mixture was evaporated and purified by chromatography (silica gel; 0-30% EtOAc-pentane). Combined fractions were evaporated and redissolved in EtOAc and washed with aq 2 M aq HCl solution, sat. aq NaHCO₃ and brine. The organic solution was dried (MgSO₄) and evaporated to give the desired mono-N-acylated product 3b-g.

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Representative Cyclisation Procedure for Mono-N-acylated Precursors; Methyl 2-Phenylbenzoxazole-7-carboxylate ( 5): Methyl-2-hydroxy-3-(phenylamido)- benzoate (0.15 g) was dissolved in TFA-AcOH (1:1, 3 mL), in a 5-mL microwave vial, sealed and irradiated to 200 °C for 20 min in a Biotage^TM Initiator^TM microwave. The reaction mixture was evaporated to a minimum (co-evapo-rated with toluene thrice) and purified by flash chromatog-raphy [silica gel, 0-30% Et₂O-PE (40:60)] and evaporated to give the title compound as a white powder (0.12 g; 88% conversion). ¹H NMR (400 MHz, CDCl₃): δ = 8.34 (m, 2 H), 7.99 (m, 2 H), 7.57 (m, 3 H), 7.43 (t, J = 7.8 Hz, 1 H), 4.06 (s, 3 H). MS: [ES (Waters Alliance HT LCMS system) (+ve ion)]: m/z = 254 [MH⁺].

<A NAME="RD19406ST-7">7</A> Pottorf RS. Chadha NK. Katkevics M. Ozola V. Suna E. Ghane H. Regberg T. Player MR. Tetrahedron Lett.  2003,  44:  175 

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Attempted cyclisation using one-pot conditions described by Pottorf did not give any desired product when applied to the synthesis 7-carboxy benzoxazole system.

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General Procedure for Diacylation of Amino Phenol 4: Amino phenol (1 equiv), aroyl chloride (2.1 equiv), and Et₃N (2.1 equiv) were stirred in CH₂Cl₂ for 1-4 d. For 4c-g, diacyl material can be filtered off from reaction mixture as a white precipitate. For phenyl diacyl compound 4b, the reaction mixture was then diluted with CH₂Cl₂ and washed with sat. aq NaHCO₃ solution. The organic layer was dried (MgSO₄) and evaporated to give the desired material as a white solid.

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General Procedure for Cyclisation of Diacyl Compounds 5-10: The diacylated amino phenol was suspended in TFA-AcOH in a microwave vial, sealed and irradiated to 200 °C for 20 min in Biotage^TM Initiator^TM microwave. The reaction mixture was evaporated to a minimum (co-evaporated with toluene thrice), redissolved in CH₂Cl₂ and washed with sat. NaHCO₃ solution. The organic layer was dried (MgSO₄), evaporated and purified by chromatography (if required) to give the desired benzoxazole product. ¹H NMR and MS (ES) data were consistent with those previously described.