Total Synthesis of Six 3,4-Unsubstituted Coumarins

In this article we describe a new methodology for the total synthesis of 3,4-unsubstituted coumarins from commercially available starting materials. Six examples were prepared, including five naturally occurring coumarins—7-hydroxy-6,8-dimethoxy-coumarin (isofraxidin), 7-hydroxy-6-methoxycoumarin (scopoletin), 6,7,8-trimethoxy-coumarin, 6,7-dimethoxycoumarin (scoparone), and 7,8-dihydroxycoumarin (daphnetin) and one synthetic coumarin, 7-hydroxy-6-ethoxycoumarin. Moreover, five important o-hydroxybenzaldehyde intermediates were also obtained, namely 2,4-dihydroxy-3,5-dimethoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 5-ethoxy-2,4-dihydroxy-benzaldehyde, 2-hydroxy-3,4,5-trimethoxybenzaldehyde, and 2-hydroxy-4,5-dimethoxy-benzaldehyde. The method developed herein involves just three or four steps and allows for the rapid synthesis of these important molecules in excellent yields. This is the first synthesis of 6,7,8-trimethoxycoumarin and 7-hydroxy-6-ethoxycoumarin.


Results and Discussion
Coumarins 1, 2, and 3 were synthesized from simple starting materials (Scheme 1). The hydroxyl group was protected using pivaloyl chloride [27] to give the corresponding products in 100% yield. These compounds were then iodinated in 80%, 77%, 80% yields, respectively, using N-iodo-succinimide [28,29], followed by hydrolysis using cuprous oxide, pyridine-2-aldoxime, tetrabutylammonium bromide, and cesium hydroxide [30]. The resulting o-hydroxybenzaldehydes were finally reacted with ethyl (triphenylphosphoranylidene) acetate in N,N-diethylaniline, forming coumarins 1, 2, and 3 as described above [26].  Protection of the hydroxyl groups using pivaloyl chloride and iodination of the resulting compounds proceeded as expected, but hydrolysis of the iodo-compounds 30 and 31 failed to afford the desired products 32 and 33. It was presumed that both electronic effects and steric hindrance of the three methoxy groups and the hydroxyl group at the ortho position of 30 and 31 affected the success of these reactions.

Experimental
All solvents and commercially available reagents were purchased from the suppliers and used without further purification. 1 H-NMR and 13 C-NMR spectra were recorded using Bruker DPX 500 (Bruker, Billerica, MA, USA) and 300 spectrometers, respectively. Spectra were recorded in CDCl 3 and DMSO solutions and chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as the standard. IR spectra were recorded on an Infinity Spectrum One spectrophotometer (Shimadzu, Kyoto, Japan). Mass spectra (Applied Biosystems, Toronto, Canada) were recorded on an Agilent 1100 Series VS (ES, 4000 V) mass spectrometer. Melting points were measured using a Büchi B-450 apparatus (Shanghaishenguang, Shanghai, China). Flash chromatography was performed with ACROS silica gel (particle size 0.030-0.040 mm, pore diameter ca. 6 nm) using a glass column.

General Procedure for the Synthesis of Coumarins 1-6
The appropriate o-hydroxybenzaldehyde (1 mmol) and ethyl(triphenylphosphoranylidene) acetate (1.2 mmol) were dissolved in N,N-diethylaniline (1.5 mL) and the resulting mixture was stirred under a N 2 atmosphere and reflux for 15 min. The solvent was removed under reduced pressure (1 mmHg, 52 °C) and the resulting brown oil was purified by column chromatography (petroleum ether-ethyl acetate, 3:1).

General Procedure for the Synthesis of Compounds 10-12
The corresponding phenol (3 mmol) was dissolved in dichloromethane (5 mL) and 4-dimethylamiopyridine (0.1 mmol) was added. The reaction was stirred for 0.5 h before addition of pivaloyl chloride (6 mmol) followed by dropwise addition of triethylamine (6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction solution was poured into dichloromethane (100 mL) and washed with saturated sodium chloride solution (2 × 100 mL) and saturated sodium bicarbonate solution (2 × 100 mL). The organic phase was collected, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was removed in vacuo to obtain compounds 10-12.

General Procedure for the Synthesis of 13, 21, 22.
The appropriate benzaldehyde (3 mmol) was dissolved in acetonitrile (5 mL) and N-iodosuccinimide (6 mmol) was added. Trifluoroacetic acid (0.3 μmol) was then added dropwise and the reaction mixture was heated under reflux for 6 h. After cooling to room temperature, the reaction solution was quenched by the addition of sodium sulfite (3 mmol) and stirred for five minutes. Subsequently, CH 2 Cl 2 (100 mL) was added and the solution was extracted with saturated sodium chloride solution (3 × 100 mL). The organic phase was collected, dried over anhydrous magnesium sulfate, and filtered, and the solvent was removed in vacuo. Column chromatography (petroleum ether-ethyl acetate, 40:1) afforded the corresponding iodinated compound.

General Procedure for the Synthesis of 14 and 15
The appropriate benzaldehyde (3 mmol) was dissolved in methanol (20 mL) and N-iodosuccinimide (6 mmol) was added. Trifluoromethanesulfonic acid (6 mmol) was then added dropwise and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched by the addition of sodium sulfite and the reaction mixture was stirred for five minutes. Subsequently, dichloromethane (100 mL) was added and the solution was extracted with saturated sodium chloride solution (3 × 100 mL). The organic phase was collected, dried over anhydrous magnesium sulfate, and filtered; then, the solvent was removed in vacuo. Column chromatography (petroleum ether-ethyl acetate, 40:1) afforded the corresponding iodinated compound.