Kita Esterification

• General Characteristics

Under the conditions developed by Kita, esters are synthesized from the corresponding alcohols and carboxylic acids using a ruthenium catalyst and ethynyl ethyl ether as a dehydrating agent. The reaction proceeds cleanly under mild conditions, thus workup and purification are made easy.

These conditions have also been used to synthesize acid anhydrides, amides, and macrolactones.

• General References

• Wasserman, H. H.; Wharton, P. S. J. Am. Chem. Soc. 1960, 82, 661. DOI: 10.1021/ja01488a042
• Kita, Y.; Akai, S.; Ajimura, N.; Yoshigi, M.; Tsugoshi, T.; Yasuda, H.; Tamura, Y. J. Org. Chem. 1986, 51, 4150. doi: 10.1021/jo00372a010
• Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. Synlett 1993, 273. DOI: 10.1055/s-1993-22428
• Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J. Chem. Soc. Perkin Trans. 1 1993, 2999. doi:10.1039/P19930002999
• Trost, B. M.; Chisholm, J. D. Org. Lett. 2002, 4, 3743. doi: 10.1021/ol026726c
• Ohba, Y.; Takatsuji, M.; Nakahara, K.; Fujioka, H.; Kita, Y. Chem. Eur. J. 2009, 15, 3526. doi: 10.1002/chem.200801548

Reviews

• Kita, Y.; Akai, S. Chem. Rec. 2004, 4, 363. doi:10.1002/tcr.20027
• Parenty, A.; Moreau, X.; Campagne, J.-M.  Chem. Rev. 2006, 106, 911. DOI: 10.1021/cr0301402

• History

The reaction was developed by Professor Yasuyuki Kita and his colleagues in 1986 (then at Osaka University).

• Reaction Mechanism

Ethynyl ethyl ether is activated by the ruthenium catalyst and reacts with carboxylic acid. The resulting 1-ethoxyvinyl ester is then activated by Brønsted acid and attacked by alcohol, giving ester product and eliminating ethyl acetate.

• Examples

The total synthesis of amphidinolide A.^[1]

An example in optimization of macrolactonization conditions^[2]: The Kita conditions afforded the desired product in this case where other commonly used conditions such as the Yamaguchi and the Corey-Nicolaou conditions did not work as well.

• Experimental Procedure

Macrolactonization^[2]

Under nitrogen atmosphere, ethoxyacetylene (21 uL, 0.30 mmol) was slowly added to the solution of [RuCl₂(p-cymene)]₂ (1.2 mg, 1.99 umol) in acetone (0.5 mL) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 5 min and 13-hexyloxacyclotridecan-2-one (30 mg, 0.098 mmol) in acetone (0.5 mL) was slowly added to the solution at 0 ℃. The resulting mixture was stirred at room temperature for 1 h. Ru was filtered through short neutral SiO₂ pad column eluted by EtOAc. The residue was concentrated in vacuo. The ethoxyvinyl ester (EVE) (quant., >95% purity based on ¹H NMR analysis) was used without further purification.

The crude EVE was diluted with DCE (10 mL) and slowly added by syringe pump to the highly diluted p-TsOH (0.05 M in DCE/CH₃CN 1:1, 0.2 mL, 0.01 mmol) solution in DCE (30 mL) over 10 h at 80 ℃. The reaction mixture was stirred at 80 ℃ for additional 1 h and cooled to room temperature. Et₃N (ca. 0.012 mmol) was added and the mixture was concentrated in vacuo. Purification of the residue by SiO2 column chromatography (hexane/Et2O 20:1) gave the desired maclolactone product (18 mg, 64%) as a colorless oil.

• Experimental Tips

• References

1. (a) Trost, B. M.; Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420. DOI: 10.1021/ja027883+ (b) Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028.DOI: 10.1021/ja049292k
2. Ohba, Y.; Takatsuji, M.; Nakahara, K.; Fujioka, H.; Kita, Y. Chem. Eur. J. 2009, 15, 3526. doi: 10.1002/chem.200801548

• Related Reactions

• Related Books

• External Links

esterification, ruthenium catalyst