Synthesis of a 2-(2-Trifluoroethoxyphenyl)oxazoline

Abstract

The title compound has been prepared in four steps starting from ethyl 2-fluorobenzoate. The final product as well as the intermediates are fully characterised by spectroscopic methods with the ¹H and ¹³C NMR spectra, featuring coupling to ¹⁹F being particularly informative.

1. Introduction

Among simple heterocyclic auxiliary groups, the 4,5-dihydrooxazole (or 2-oxazoline) has proved to be one of the most useful, directing ortho-metalation on an aryl ring and facilitating a wide range of subsequent synthetic transformations, many of them in an asymmetric fashion [1,2,3]. In our own work, we have studied 2-(2-benzyloxyphenyl)oxazolines and observed that, upon treatment with a strong base, they may undergo either cyclisation to afford 3-aminobenzofurans or 1,2-Wittig rearrangement. While treatment with n-BuLi/KOt-Bu generally led to direct cyclisation to benzofuran products, using n-BuLi on its own gave the Wittig rearrangement [4]. It was later found that in isomeric thiophene-based systems, products derived from either direct cyclisation or Wittig rearrangement could be obtained depending on the distance between the oxazoline and benzyloxy functions [5]. In the meantime, it was discovered that the N-butylamide group, CONHBu, is more effective in directing the Wittig rearrangement in such systems [6]. In an attempt to broaden the scope of such transformations, various alternatives to the benzyloxy substituent have been examined including trifluoroethoxy, OCH₂CF₃, and this was prepared in the N-butylbenzamide series but did not react on treatment with a strong base. As described in a review article [7], the formation of α-trifluoromethyl anions may result in a range of different reaction outcomes depending on the other groups present. In this paper, we describe the stepwise synthesis of the corresponding 2-(2-trifluoroethoxyphenyl)oxazoline 4 and full characterisation of the final product and the intermediates for the first time.

2. Results

The starting point for our synthesis was 2-fluorobenzoyl chloride which is commercially available at a reasonable cost. Simply adding this to an excess of ethanol and heating for 3 h followed by evaporation gave the ethyl ester, ethyl 2-fluorobenzoate. We have previously reported the preparation and use of this compound in studies on pyrolysis of 2-aminophenyl-substituted stabilised phosphonium ylides [8]. To introduce the 2,2,2-trifluoroethoxy group [9], a patent procedure was followed [10] involving deprotonation of 2,2,2-trifuoroethanol with potassium tert-butoxide in THF followed by addition of the ethyl 2-fluorobenzoate to afford 1 in good yield (Scheme 1). Remarkably for such a simple compound, this has not been characterised before, and so we report here its full characterisation including mp, HRMS, IR and ¹H, ¹³C and ¹⁹F NMR spectra (see Section 3 and Supplementary Materials). The NMR spectra were particularly informative with the trifluoroethoxy group giving rise to signals at δ_F −74.0, a 2H quartet at δ_H 4.41 (³J_H-F 8.0 Hz) and quartets at δ_C 123.2 (¹J_C-F 276 Hz) and 67.5 (²J_C-F 35.5 Hz). The corresponding methyl ester has been described in a patent [11] wherein it was prepared by a different method and only characterised by a melting point and elemental analysis. Alkaline hydrolysis of ester 1 using sodium hydroxide in aqueous dioxane [12] gave the corresponding carboxylic acid 2 which had a melting point in good agreement with the literature value [11] but is also characterised spectroscopically for the first time. The preparation of 2 by a different method is also described in a patent [13] but there it is only characterised by LCMS.

Scheme 1. Stepwise construction of compound 4.

In order to prepare the target oxazoline 4, the acid 2 was first converted into its acid chloride using thionyl chloride, and this was reacted directly with 2-amino-2-methylpropan-1-ol to give the previously unknown hydroxy amide 3 in moderate yield. This gave ¹H, ¹³C and ⁹F NMR spectra in agreement with expectation featuring the usual signals for OCH₂CF₃ and a broad singlet at δ_H 7.60 (NH) together with a 1H triplet at δ_H 5.20 and 2H doublet (³J 6.4 Hz) at δ_H 3.69 for CH₂OH. The final cyclisation to give the oxazoline 4 was accomplished in excellent yield by treatment with thionyl chloride, and this previously unknown compound was fully characterised. Disappointingly in terms of the original aim of the work, treatment of compound 4 with a variety of strong bases under a range of conditions led to recovery of unchanged starting material. As we previously described for the corresponding amide, 2-(2,2,2-trifluoroethoxy)-N-butylbenzamide [6], trifluoroethoxy does not undergo either direct cyclisation or Wittig rearrangement in these systems.

Interestingly, after our work had been completed and while this paper was in preparation, the 6-methyl analogue of compound 4 was reported [14], prepared by direct palladium-catalysed oxidative alkoxylation of the 2-(2-methylphenyl)oxazoline. Its spectroscopic data are in good agreement with those of 4 although the fluorine coupling has not been recognised in their interpretation.

In summary, we have described an efficient four-step synthesis of the oxazoline 4 with full spectroscopic characterisation of the final product and the intermediates 1–3 for the first time.

3. Experimental Section

3.1. General Experimental Details

Melting points were recorded on a Reichert hot-stage microscope (Reichert, Vienna, Austria) and are uncorrected. IR spectra were recorded using the ATR technique on a Shimadzu IRAffinity 1S instrument. NMR spectra were obtained using Bruker AVII 400 or AVIII 500 instruments (Bruker, Billerica, MA, USA). Spectra were run in CDCl₃ with internal Me₄Si as the reference for ¹H and ¹³C and external CFCl₃ for ¹⁹F. Chemical shifts are reported in ppm to high frequency of the reference, and coupling constants are in Hz. ¹⁹F spectra were run with ¹H decoupling. NMR spectra were processed using iNMR reader, version 6.3.3 (Mestrelab Research, Santiago de Compostela, Spain). Ethyl 2-fluorobenzoate was prepared by cautious addition of 2-fluorobenzoyl chloride (Fluorochem) to an excess of ethanol followed by evaporation.

3.2. Ethyl 2-(2,2,2-Trifluoroethoxy)benzoate 1

Following a literature procedure [10], potassium tert-butoxide (6.77 g, 60.3 mmol) was added to a stirred 0 °C solution of 2,2,2-trifluoroethanol (6.02 g, 60.2 mmol) in dry THF (150 mL). After stirring at 0 °C for 30 min, a solution of ethyl 2-fluorobenzoate (5.05 g, 30.0 mmol) in dry THF (20 mL) was added dropwise and the reaction mixture was allowed to warm to rt for 6 h. Further 2,2,2-trifluoroethanol (3.02 g, 30.2 mmol) and potassium tert-butoxide (3.44 g, 30.7 mmol) were added and, after stirring at rt for a further 16 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between water (100 mL) and Et₂O (100 mL), the two layers were separated, and the aqueous layer was re-extracted with Et₂O (2 × 100 mL). The combined organic layers were dried and evaporated to give 1 (5.54 g, 74%) as a colourless solid which was used without further purification; mp 39–42 °C; IR (ATR): ν_max/cm⁻¹ 1686, 1645, 1603, 1452, 1385, 1277, 1152, 1101, 1061, 968, 866, 752 and 691; ¹H NMR (500 MHz): δ 7.85 (1 H, dd, J 7.5, 2.0, 6-H), 7.48 (1 H, ddd, J 8.5, 7.5, 1.8, 4-H), 7.13 (1 H, td, J 7.5, 1.0, 5-H), 6.97 (1 H, dd, J 8.5, 1.0, 3-H), 4.41 (2 H, q, J_HF 8.0, CH₂CF₃), 4.37 (2 H, q, J 7.0, CH₂CH₃) and 1.38 (3 H, t, J 7.0, CH₃); ¹³C NMR (125 MHz): δ 165.9 (C, C=O), 156.7 (C, C–O), 133.4 (CH, Ar), 132.0 (CH, Ar), 123.2 (C, q, J_CF 276, CF₃), 122.8 (CH, Ar), 122.3 (C, Ar), 115.5 (CH, Ar), 67.5 (CH₂, q, J_CF 35.5, CH₂CF₃), 61.2 (CH₂CH₃) and 14.1 (CH₃); ¹⁹F NMR (470 MHz): δ_F −74.0; HRMS (NSI): found, 249.0732. C₁₁H₁₂F₃O₃ (M + H) requires 249.0733.

3.3. 2-(2,2,2-Trifluoroethoxy)benzoic acid 2

A solution of sodium hydroxide (2.23 g, 55.8 mmol) in water (40 mL) was added to a stirred solution of ethyl 2-(2,2,2-trifluoroethoxy) benzoate 1 (9.21 g, 37.1 mmol) in 1,4-dioxane (90 mL), and the reaction mixture was heated under reflux for 2 h. After cooling to rt, the reaction mixture was concentrated in vacuo, and the residue was dissolved in water (150 mL) and washed with Et₂O (50 mL). The aqueous layer was acidified to pH 1 by the addition of 2 M HCl before being extracted with Et₂O (2 × 100 mL). After drying and evaporation of the combined organic layers, the residue was recrystallised (EtOAc/hexane) to give 2 (6.15 g, 75%) as colourless crystals; mp 83–85 °C (lit. [11] 85–86.5 °C); IR (ATR): ν_max/cm⁻¹ 1682, 1603, 1487, 1462, 1414, 1269, 1225, 1152, 1059, 961, 883, 858, 768, 702, 669 and 648; ¹H NMR (400 MHz): δ 8.12 (1 H, dd, J 7.8, 1.8, 6-H), 7.59 (1 H, ddd, J 8.4, 7.4, 1.8, 4-H), 7.22 (1 H, ddd, J 7.8, 7.4, 1.0, 5-H), 7.04 (1 H, dd, J 8.4, 1.0, 3-H) and 4.53 (2 H, q, J_HF 8.0, CH₂); ¹³C NMR (125 MHz): δ 169.2 (C, C=O), 157.3 (C, C–O), 134.9 (CH, Ar), 133.3 (CH, Ar), 123.3 (CH, Ar), 123.0 (q, J_CF 277, CF₃), 120.0 (C, Ar), 115.5 (CH, Ar) and 67.6 (q, J_CF 35.8, CH₂); ¹⁹F NMR (376 MHz): δ_F −73.8.

3.4. N-(1-Hydroxy-2-methylpropan-2-yl)-2-(2,2,2-trifluoroethoxy)benzamide 3

A solution of thionyl chloride (3.7 mL, 6.03 g, 50.7 mmol) and 2-(2,2,2-trifluoroethoxy)benzoic acid 2 (5.50 g, 25.0 mmol) in toluene (50 mL) was heated under reflux for 3 h and then evaporated to give 2-(2,2,2-trifluoroethoxy)benzoyl chloride as a pale yellow oil which was used without further purification. A solution of 2-(2,2,2-trifluoroethoxy)benzoyl chloride (25.0 mmol) in CH₂Cl₂ (50 mL) was added dropwise to a solution of 2-amino-2-methylpropan-1-ol (4.46 g, 50.0 mmol) in CH₂Cl₂ (50 mL) stirred at 0 °C. After the addition, the mixture was stirred at rt for 18 h and then poured into water. The organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (50 mL). The combined organic extracts were washed with 2M HCl (50 mL), 2M NaOH (50 mL) and water (50 mL). Drying and evaporation gave 3 (3.95 g, 54%) as a colourless oil which crystallised on standing and was used without further purification; mp 49–52 °C; IR (ATR): ν_max/cm⁻¹ 3416, 3354, 1638, 1541, 1487, 1452, 1285, 1229, 1157, 1107, 1059, 1040, 978, 864, 750, 689 and 579; ¹H NMR (400 MHz): δ 8.17 (1 H, dd, J 8.0, 2.0, 6-H), 7.60 (1 H, br s, NH), 7.48 (1 H, ddd, J 8.4, 7.4, 2.0, 4-H), 7.19 (1 H, ddd, J 8.0, 7.4, 1.0, 5-H), 6.88 (1 H, dd, J8.4, 1.0, 3-H), 5.20 (1 H, t, J6.4, OH), 4.49 (2 H, q, J_HF 8.0, CH₂CF₃), 3.69 (2 H, d, J 6.4, CH₂OH) and 1.38 (6 H, s, CH₃); ¹³C NMR (125 MHz): δ 165.1 (C, C=O), 154.4 (C, C–O), 133.0 (CH, Ar), 132.7 (CH, Ar), 123.2 (CH, Ar), 122.9 (4ry, q, J_CF 276, CF₃), 122.6 (C, Ar), 111.9 (CH, Ar), 70.9 (CH₂OH), 66.0 (q, J_CF 35.9, CH₂CF₃), 56.6 (C, C(CH₃)₂) and 24.7 (2 × CH₃); ¹⁹F NMR (376 MHz): δ −73.5; HRMS (NSI): found, 292.1158. C₁₃H₁₇F₃NO₃ (M + H) requires 292.1155.

3.5. 4,4-Dimethyl-2-(2-(2,2,2-trifluoroethoxy)phenyl)-4,5-dihydrooxazole 4

Thionyl chloride (1.2 mL, 1.96 g, 16.5 mmol) was added to a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(2,2,2-trifluoroethoxy)benzamide 3 (3.70 g, 12.7 mmol) in CH₂Cl₂ (120 mL), and the mixture was stirred at rt for 18 h. The mixture was washed with 2M NaOH (50 mL) and water (50 mL) and then dried and evaporated to give 4 (3.31 g, 95%) as a colourless oil; IR (ATR): ν_max/cm⁻¹ 2970, 2901, 1649, 1493, 1452, 1285, 1242, 1157, 1065, 1038, 964, 862, 752 and 691; ¹H NMR (500 MHz): δ 7.74 (1 H, dd, J 7.5, 1.8, 6-H), 7.42 (1 H, ddd, J 8.3, 7.5, 1.8, 4-H), 7.12 (1 H, td, J 7.5, 1.0, 5-H), 7.00 (1 H, dd, J 8.3, 1.0, 3-H), 4.40 (2 H, q, J_HF 8.0, CH₂CF₃), 4.10 (2 H, s, oxazoline CH₂) and 1.39 (6 H, s, CH₃); ¹³C NMR (125 MHz): δ 160.3 (C, C=N), 156.4 (C, C–O), 132.1 (CH, Ar), 131.3 (CH, Ar), 123.3 (C, q, J_CF 277, CF₃), 123.1 (CH, Ar), 120.1 (C, Ar), 116.4 (CH, Ar), 79.1 (oxazoline CH₂), 68.1 (q, J_CF 35.3, CH₂CF₃), 67.7 (C, C(CH₃)₂) and 28.3 (2 × CH₃); ¹⁹F NMR (470 MHz): δ −74.1; HRMS (NSI): found, 274.1047. C₁₃H₁₅F₃NO₂ (M + H) requires 274.1049.