Stereo-Selective Synthesis of 5-Norbornene-2-exo-carboxylic Acid—Rapid Isomerization and Kinetically Selective Hydrolysis


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.

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Kanao, M. , Otake, A. , Tsuchiya, K. and Ogino, K. (2012) Stereo-Selective Synthesis of 5-Norbornene-2-exo-carboxylic Acid—Rapid Isomerization and Kinetically Selective Hydrolysis. International Journal of Organic Chemistry, 2, 26-30. doi: 10.4236/ijoc.2012.21005.

1. Introduction

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 [7]. In the case of photoresist monomer synthesis, endo-isomer provides undesired lactone by intramolecular cycloaddition to result in a low yield of desired photoresist monomer [8]. As can be seen in the two examples, exo-selective synthesis of norbornene carboxylic acid derivatives is of importance from the practical viewpoint.

Some of exo-selective syntheses of norbornene derivatives have been reported. Gouverneur et al. reported asymmetric Diels-Alder reaction by using antibody catalyst [9]. Fraile reported asymmetric Diels-Alder reaction of furan with chiral acrylate [10]. Avenoza and Kawamura reported asymmetric Diels-Alder reaction of cyclopentadiene and chiral dienophile [11,12]. Because of high cost of these reactions, practically pure exo-isomer is obtained by removing of endo-isomer through lactonization [13, 14]. Previously we reported exo-selective synthesis of 5-norbornene-2-carboxylic acid from endo-rich carboxylate in order to investigate the effect of endo/exo ratio on performance of photoresist prepared from tert-butyl 5- norbornene-2-carboxylate [15]. High exo-content and yield of the product cannot be explained only by exoselective hydrolysis as reported by of Niwayama and Hiraga [16]. As the plausible mechanism, we proposed that hydrolysis should be carried out accompanying with endo/exo isomerization.

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.

2. Experiment

2.1. Materials

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 [15]. The ratio of endo/exo was determined as 80/20 by 1H-NMR and HPLC. Sulfuric acid was obtained from Aldrich. Tetrahydrofuran (THF) was purchased from Wako Pure Chemical Industries. Ltd., and dehydrated by distillation under nitrogen with sodium/benzophenone. All other materials were purchased from Wako Pure Chemical Industries. Ltd. and used without any further purification unless otherwise mentioned.

2.2. General Procedure for Synthesis of exo-Rich 5-Norbornene-2-carboxylic acid (NBCA)

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.

2.3. Synthesis of exo-Rich Methyl 5-Norbornene-2-carboxylate (MNBC)

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%). 

2.4. Characterization

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.

3. Results and Discussion

Figure 1 shows 1H-NMR spectrum of MNBC synthesized via a conventional Diels-Alder cycloaddition reaction as a starting material. The mole ratio of endo/exo was determined as 80/20. In order to obtain 5-norbornene-2-exo-carboxylic acid (exo-NBCA), isomerization from endo-isomer to exo-isomer is required. As MNBC has an active proton at α-position of carbonyl group, the corresponding carbanion can be generated by elimination of the proton in basic conditions. In general, carbanion has sp3-type trigonal pyramid structure, and low activation barrier for the inversion of this geometry. By utilizing the continuous inversion, the mixture comprising mainly endo-isomer of MNBC can be isomerized to corresponding endo/exo mixture of which ratio is ruled by thermodynamic equilibrium under basic conditions.

Conflicts of Interest

The authors declare no conflicts of interest.


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