Synthesis and Reaction of the First Oxazol-4-ylboronates: Useful Reagents for the Preparation of the Oxazole-Containing Biaryl Compounds

Abstract

The first oxazol-4-ylboronates were prepared from the corresponding 4-bromo- and 4-trifluoromethanesulfonyloxy-oxazoles. The Suzuki coupling using the resulting boron reagents with various aryl halides, including benzene, pyridine, oxazole and thiazole rings, in the presence of palladium catalyst proceeded to produce the oxazole-containing biaryl compounds in moderate to good yields.

oxazoles - oxazol-4-ylboronates - Suzuki coupling - biaryl compounds - palladium-catalyzed cross-coupling

References and Notes

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<A NAME="RU30705ST-12">12</A>

Preparation of 2-Phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole ( 2).
A suspension of Pd₂(dba)₃·CHCl₃ (120 mg, 0.13 mmol) and tricyclohexylphosphine (220 mg, 0.78 mmol) in 1,4-dioxane (60 mL) was stirred for 30 min at r.t. under Ar. Bis(pinacolato)diboron (1.46 g, 5.7 mmol), 2-phenyl-4-tri-fluoromethanesulfonyloxyoxazole (1, 1.53g, 5.2 mmol) and KOAc (769 mg, 7.8 mmol) were successively added to the resulting solution. After being at reflux for 2 h, the reaction mixture was diluted with Et₂O (300 mL). The resulting mixture was washed with H₂O (100 mL) and then dried over Na₂SO₄. Concentration of the solvent in vacuo gave a residue, which was purified by silica gel column chromato-graphy (hexane-EtOAc, 20:1 to 1:1) to give 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (2). After recrystallization from hot hexane, pure 2 (1.06 g, 75%) was obtained as colorless needles; mp 124-125 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.38 (12 H, s), 7.44 (3 H, m), 8.07 (1 H, s), 8.14 (2 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 24.8, 84.3, 126.9, 127.3, 128.6, 130.4, 148.0, 162.8; IR (neat) 2996, 2973, 1567, 1363, 1319, 1081, 692 cm^-1. HRMS (EI): m/z calcd for C₁₅H₁₈BNO₃ [M⁺]: 271.1380; found: 271.1374.

<A NAME="RU30705ST-13A">13a</A> Prager RH. Smith JA. Weber B. Williams CM. J. Chem. Soc., Perkin Trans. 1  1997,  2665 

<A NAME="RU30705ST-13B">13b</A>

The method reported in ref. 13a is inconvenient to synthesize 3. We developed the alternative method to prepare bromide 3 from benzoyl chloride and propargylamine as follows (Scheme [3] ).

<A NAME="RU30705ST-14">14</A>

Preparation of 5-Methyl-2-phenyl-4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)oxazole ( 4).
n-BuLi in n-hexane (1.58 M, 0.42 mL, 0.67 mmol) was added to a stirred solution of 4-bromo-5-methyl-2-phenyl-oxazole (3, 144 mg, 0.65 mmol) in THF (3 mL) at -78 °C under Ar. After 30 min, triisopropylborate (0.17 mL, 0.73 mmol) was added to the resulting solution and stirred for 1 h at the same temperature. The reaction mixture was allowed to warm to r.t. and stirred for 1 h. Pinacol (86 mg, 0.73 mmol) and glacial AcOH (42 µL, 0.73 mmol) were added to the resulting solution and the resulting mixture was stirred for 1 h. The reaction mixture was diluted with Et₂O (30 mL) and washed with H₂O (10 mL) and then dried over Na₂SO₄. Concentration of the solvent in vacuo gave a residue, which was purified by silica gel column chromatography (hexane-EtOAc, 1:1) to give 5-methyl-2-phenyl-4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)-oxazole (4). After recryst-allization from hot hexane, pure 4 (95 mg, 55%) was obtained as colorless needles; mp 108-109 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.36 (12 H, s), 2.56 (3 H, s), 7.41 (3 H, m), 8.10 (2 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 11.8, 24.9, 83.9, 126.5, 127.6, 128.5, 129.9, 160.1, 161.0. IR (neat): 2979, 1593, 1407, 1382, 1317, 1141, 1085, 1050, 696 cm^-1. HRMS (EI): m/z calcd for C₁₆H₂₀BNO₃ [M⁺]: 285.1536; found: 285.1532.

<A NAME="RU30705ST-15">15</A>

Although both K₂CO₃ and K₃PO₄ worked well in the coupling reaction of 2 with bromobenzene, we chose K₂CO₃ as a base for further applications due to its milder basicity.

<A NAME="RU30705ST-16">16</A>

General Procedure of the Suzuki Coupling [Synthesis of 2,4-Diphenyloxazole ( 5)]. A solution of 2 (60 mg, 0.22 mmol), bromobenzene (23 µL, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (13 mg, 11 µmol) and K₂CO₃ (92 mg, 0.66 mmol) in DMF (1 mL) was heated at 100 °C for 30 min under Ar. The reaction mixture was diluted with Et₂O (30 mL) and washed with H₂O (10 mL) and then dried over Na₂SO₄. Concentration of the solvent in vacuo gave a residue, which was purified by silica gel column chromatography (hexane-EtOAc, 20:1) to give 2,4-diphenyloxazole (5, 43 mg, 88%) as a white solid. All characterization data of 5 were compatible with the literature. [13]

<A NAME="RU30705ST-17">17</A> Self-coupling reaction of the borane reagent 2 occurred to give 2,2′-diphenyl-4,4′-bioxazole in ca. 20% yield. This undesired event sometimes happened in slow Suzuki reaction, see: Moreno-Mañas M. Pérez M. Pleixats R. J. Org. Chem.  1996,  61:  2346