Simple and efficient stereo-selective synthesis of exo-5-norbornene-2-carboxylic acid (NBCA) is reported. Preliminary studies on base promoted isomerization of methyl 5-norbornene-2-carboxylate (MNBC) revealed that rapid isomerization was accomplished with sodium tert-butoxide (tBuONa), and the exo-content at the equilibrium was ca. 60%. The hydrolyses of endo-rich MNBC ( endo/exo = 80/20) under various conditions were carried out. The exo selectivity for resulting NBCA was improved when the hydrolysis was conducted with equimolar water at room temperature in the presence of the stronger base (tBuONa) ( endo/exo: 18/82). Whereas the use of excess amount of water led to rapid and non-selective hydrolysis affording high endo content of the product. The plausible reaction mechanism involving rapid equilibrium of thermodynamic isomerization and kinetically preferred hydrolysis of exo ester is proposed.
5-Norbornene-2-carboxylic acid and its derivatives are important as intermediates of pharmaceutically and biologically active compounds and monomers for advanced polymeric materials. 2-Substituted norbornene compounds can be conventionally obtained by Diels-Alder cycloaddition between cyclopentadiene and acrylic compounds. It is well-known that Diels-Alder cycloaddiotion is endoselective due to secondary orbital overlap, and the selectivity is enhanced by Lewis acid [1,2]. Polynorbornenes, which can be synthesized by vinyl polymerization or ring-opening metathesis polymerization (ROMP) of norbornene derivatives, show high thermal stability and transparency, and are useful for optical applications such as optical fibers, disk, lens and displays [3,4]. Norbornene derivatives are also useful as monomers or intermediates for photoresist materials [5,6]. Exo-isomer of norbornene carboxylic ester shows higher reactivity in living ROMP than endo-isomer [
Some of exo-selective syntheses of norbornene derivatives have been reported. Gouverneur et al. reported asymmetric Diels-Alder reaction by using antibody catalyst [
In this paper, various experimental parameters includeing reaction solvent, temperature, type of base, and the amount of water were optimized in order to afford simple and efficient synthetic method for exo-norbornene carboxylic acid, and confirm our hypothesis about exo-selective hydrolysis.
5-Norbornene-2-carboxylate (MNBC) and tert-butyl 5- norbornene-2-carbocylate (tBNBC) were synthesized via conventional Diels-Alder cycloaddition reaction according to the previous work [
THF solution of base (1 mol/L) was charged into a twonecked flask equipped with a dropping funnel under nitrogen atmosphere. MNBC (exo; 20%, 0.4 mol/L) was added into the flask and stirred at room temperature for 3 h. One or ten equivalents of deionized water diluted with THF was added into the reaction mixture dropwise, and the reaction was continued for 24 h at predetermined temperature. In order to complete the hydrolysis, excess amount of deionized water was added. The reaction mixture was stirred for 1 h at room temperature and was neutralized with acetic acid until pH was adjusted to 7.5. The excess solvent was removed under reduced pressure. After the addition of 35% HCl until pH was adjusted to 2.0, the reaction mixture was extracted with toluene three times. Toluene was removed under reduced pressure, and the product was dried in vacuo over night to give NBCA.
5-Norbornene-2-carboxylic acid (9.40 g, 68 mmol, exo; 72), methanol (8.30 mL, 0.20 mol), dichloromethane (20 mL) and 98%-sulfuric acid (0.28 mL, 5.0 mmol) were added into 100 mL-three-necked flask. The mixture was heated and refluxed for 17 h, and cooled to room temperature. After addition of deionized water, the reaction mixture was extracted with dichloromethane and the extract was washed with sat. NaHCO3aq. The solvent was removed under reduced pressure to give methyl 5-norbornene 2-carboxylate (9.63 g, 93%, exo; 75%).
1H-NMR spectra were obtained on a JEOL ECX-500 instrument at 500 MHz. The ratio of endoand exo-isomers of MNBC, NBCA, and tBNBC were determined from peak intensities of each isomer by 1H-NMR in chloroform-d at 25˚C. The ratio of MNBC and NBCA were also determined by HPLC; JASCO C-Net II/ADC system, UV-detector; JASCO UV-2075 (224 nm), column; SC PEGASIL ODS-2352 (4.6 mm i.d., 18 cm), eluent; distilled water/methanol = 4/6 (1 mL/min), pH was adjusted to 3 by phosphate buffer, retention time; exo-isomer 7.4 min, endo-isomer 8.6 min. The ratio determined by HPLC was calibrated by NMR.