2-(3-Bromophenyl)imidazo[2,1-b]oxazole

Abstract

The microwave-assisted reaction of 2-nitroimidazole with 3-bromophenacyl bromide in the presence of potassium carbonate as a base and dimethylformamide as a solvent afforded 2-(3-bromophenyl)imidazo[2,1-b]oxazole. The formation of this compound was explained via a domino mechanism comprising an initial N-alkylation reaction of the imidazole substrate, followed by the base-promoted deprotonation of the position adjacent to the carbonyl to give an enolate anion that finally cyclizes via an intramolecular S_NAr reaction, with the loss of the nitro group as potassium nitrite. Then, the proposed 1-(3-bromophenacyl)-2-nitroimidazole intermediate could be isolated by reducing the reaction time and was shown to be a precursor of the imidazo[2,1-b]oxazole final product.

1. Introduction

Heterocyclic structures with bridgehead nitrogen atoms are very important in diversity-oriented libraries, and therefore, finding new synthetic approaches for their construction is an important goal in organic synthesis. The imidazo[2,1-b]oxazole framework is relevant to the preparation of organic electroluminescent device materials [1] and is present in a variety of pharmaceutically interesting compounds with activities such as p38 MAP kinase inhibition [2], RAF kinase inhibition [3], androstane receptor agonism [4], inhibition of the RAFs-MEK1/2-ERK1/2 signalling pathway in triple-negative breast cancer cells [5], MAP kinase inhibition [6] and TFG-β inhibition [7], among others. Moreover, a dihydro derivative of the imidazo[2,1-b]oxazole skeleton is the pharmacophoric fragment of the recently approved antitubercular drug delamanid (Deltyba^®), useful against multiresistant tuberculosis [8].

The method employed for the synthesis of the imidazo[2,1-b]oxazole nucleus is almost universally based on the reaction of 2-aminoisoxazoles with phenacyl halides followed by cyclization in the presence of titanium(IV) chloride [9], which works well but has the disadvantage of requiring a fuming, corrosive and toxic catalyst, which additionally has low stability. In this context, here, we describe an alternative approach to imidazo[2,1-b]oxazole derivatives, based on the treatment of 2-nitroimidazole, a commercially available reagent, with a phenacyl bromide derivative in the presence of a mild base.

2. Results and Discussion

As shown in Scheme 1, the microwave irradiation of 2-nitroimidazole (150 °C, 2 h) with 3-bromophenacyl bromide in dimethylformamide containing suspended potassium carbonate afforded compound 4. This product presumably arises from a domino process starting with an initial N-alkylation to give 1, followed by the base-promoted deprotonation of position α to the carbonyl to give enolate 2 and its final cyclization by an intramolecular S_NAr reaction, via intermediate 3, with the final loss of the nitro group as potassium nitrite. This pathway was confirmed by the isolation of a mixture of 1 and 4 when the reaction was performed under milder conditions (150 °C and 1 h), which was transformed into 4 by increasing the reaction time.

The structural assignment of compound 4 was based on the following spectral observations: (a) the absence of signals due to the phenacyl side chain (methylene signal in ¹H-NMR, carbonyl signal in ¹³C-NMR and IR); (b) the absence of IR absorption bands due to the nitro group; (c) the downfield displacement of the imidazole protons associated with the loss of the electron-withdrawing nitro group; (d) the appearance of a singlet for one proton at 7.54 ppm, ascribed to the oxazole moiety. Spectral assignments were assisted by ¹³C-¹H HMBC correlation experiments, the most representative of which are shown in Scheme 2. Copies of these spectra can be found in the Supporting Information. Moreover, a high-resolution mass spectral measurement of compound 4 was consistent with the proposed structure.

3. Materials and Methods

General experimental information. All reagents (Sigma Aldrich, Fischer, Alpha Aesar) and solvents (Scharlau, Fischer, SDS) were of commercial quality and were used as received. The reactions were performed on an Anton Paar Monowave 400 instrument and monitored using thin-layer chromatography on aluminium plates coated with silica gel and fluorescent indicator (Macherey-Nagel Xtra SIL G/UV254). Compounds were purified via silica gel column chromatography, using the conditions specified in each case. Melting points were determined using a Stuart Scientific apparatus, SMP3 Model, and were uncorrected. Infrared spectra were recorded with an Agilent Cary630 FTIR spectrophotometer (Agilent, Madrid, Spain) working by attenuated total reflection (ATR), with a diamond accessory for solid and liquid samples. NMR spectroscopic data were recorded using a Bruker Avance 250 spectrometer operating at 250 MHz for ¹H NMR and 63 MHz for ¹³C NMR (Bruker, Madrid, Spain) maintained by the NMR facility of Universidad Complutense (Unidad de Resonancia Magnética Nuclear, Madrid, Spain); chemical shifts are given in ppm and coupling constants in Hertz. High-resolution mass measurements were performed on a MALDI TOF/TOF Bruker Ultraflex instrument (Bruker, Madrid, Spain) at the Mass Spectrometry facility at Universidad Complutense (Unidad de Espectrometría de Masas, Madrid, Spain).

Synthesis of 2-(3-bromophenyl)imidazo[2,1-b]oxazole (4). A suspension of K₂CO₃ (1.1 mmol), 3′,2-dibromoacetophenone (1 mmol) and 2-nitroimidazole (1 mmol) in DMF (2 mL) was placed in a microwave tube and was then irradiated at 150 °C for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL) and extracted twice with saturated LiCl aqueous solution. The organic layer was dried with anhydrous Na₂SO₄ and filtered, and the solvent was removed under reduced pressure. The solid residue was suspended in MeOH (2 mL) and filtered, affording 155 mg of compound 4 as a pale brown solid (71%). Alternatively, compound 4 could be purified via silica gel chromatography using as mobile phase ethyl acetate-CH₂Cl₂ (2:1). Mp: 107–108 °C; ¹H NMR (250 MHz, CDCl₃) δ 7.78 (t, J = 1.7 Hz, 1H), 7.61–7.55 (m, 1H), 7.54 (s, 1H), 7.49 (ddd, J = 8.0, 1.7, 1.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H) ppm. ¹³C NMR (63 MHz, CDCl₃) δ 155.4, 148.6, 132.2, 131.2, 130.7, 129.6, 126.9, 123.3, 122.5, 107.8, 106.2 ppm. IR (neat, cm⁻¹): 1624.2, 1549.3, 1440.6, 1277.4, 1117.0, 770.9, 689.1 cm⁻¹. HRMS (MALDI-TOF): calcd. for C₁₁H₇BrN₂O [M+1]⁺: 262.9815 (⁷⁹Br) and 264.9794 (⁸¹Br); found: 262.9809 (⁷⁹Br) and 264.9788 (⁸¹Br) [M⁺ + 1].

Mechanistic control experiment. The same reaction was performed at 150 °C for 1 h. Then, the solvent was removed, and the solid residue was chromatographed on silica gel using a 2:1 ethyl acetate-CH₂Cl₂ mixture as a mobile phase, affording 199 mg of compound 4 (62%) and 55 mg of compound 1 (21%).

1-(3-Bromophenyl-2-(2-nitro-1H-imidazol-1-yl)ethan-1-one (1)

Mp: 104–105 °C; ¹H NMR (250 MHz, CDCl₃) δ 8.10 (t, J = 1.7 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.25 (d, 1H, J = 1.2 Hz), 7.09 (d, J = 1.2 Hz, 1H), 5.84 (s, 2H) ppm. ¹³C NMR (63 MHz, CDCl₃) δ 188.9, 156.2, 137.7, 135.5, 131.3, 130.9, 128.9, 126.8, 126.7, 123.6, 55.8. ppm. HRMS (MALDI-TOF): calcd. for C₁₁H₈BrN₃O₃ [M+1]⁺, 309.9822 (⁷⁹Br) and 311.9801 (⁸¹Br); found, 309.9819 (⁷⁹Br) and 311.9801(⁸¹Br). IR (neat, cm⁻¹): 1700.5, 1483.3, 1353.1, 1215.4, 771.4, and 673.8 cm⁻¹.

4. Conclusions

The treatment of 2-nitroimidazole under microwave irradiation with a phenacyl halide derivative in the presence of potassium carbonate as a base and in dimethylformamide as a solvent provided a new, efficient entry into the imidazo[2,1-b]oxazole framework from very simple starting materials and reagents.