Phenol Alkylation using Cs2CO3 as base

[Rhodium]

Facile Synthesis of Alkyl Phenyl Ethers Using Cesium Carbonate
Jong Chan Lee, Jong Yeob Yuk, Sung Hye Cho
Synthetic Communications, 25(9), 1367-1370 (1995)

Abstract
A highly efficient alkylation method of phenols using alkyl halide/cesium carbonate/acetonitrile system is described.

The conversion of phenols to phenyl ethers is an important transformation in organic synthesis and numerous methods have been reported to achieve this goal. However, the reaction of alkylating agents with the phenoxide ions were conventionally required aqueous or phase-transfer catalytic conditions^1,2. ln general the bases employed in those conditions were limited to NaH, NaOH, and K₂CO₃. These bases low solubilities in organic solvents often required somewhat longer reaction times and harsh conditions. More soluble tetraalkylammonium fluorides were used for alkylation, however, their hygroscopic nature is highly undesirable³.

Cesium salts assisted cyclization reaction has been often provided higher yields than the methods of using the other alkali metal alternatives^4,5.

To extend applicability of cesium salts and for the search of facile alkylating method, we report in this paper the results on the alkylation of various phenols by use of cesium carbonate as a base. The reaction of a range of substituted phenols with alkyl halides in CH₃CN at 80°C in the presence of cesium carbonate were studied. The results are summarized in the Table.

In the methylation process, methyl iodide exhibited better yields than dimethyl sulfate and the Cs₂CO₃/CH₃I/CH₃CN system gave higher yields than the K₂CO₃/CH3I/acetone combination as illustrated in the Table (entry 2, 3). The latter results clearly demonstrated that the use of cesium carbonate leads to improvements in yields compared to the potassium carbonate for the phenyl ether formation. Similarly, allylation and benzylation of phenols were carried out in the Cs₂CO₃/CH₃CN system. As an alkylating agent, allyl bromide and benzyl bromide were used for allylation and benzylation respectively which provided very high yields for the most cases. Alkylations were completed smoothly within a few hours (4-5h). In the each of alkylation process, phenyl ethers were obtained as a single product. Isolated yields obtained in this study were always comparable or higher than previously reported methods. The high solubility of cesium carbonate in acetonitrile and loose ion-pair formation of phenoxides with cesium cation could be the reasons of these extraordinary high yields of alkylation in non-aqueous system.

ln conclusion, we have developed a facile and efficient alkylation method of phenols in high yields with reagent combination of alkyl halide/Cs₂CO₃ in CH₃CN.

Experimental Section

General Procedure

The alkyl halide (5.0 equiv.) was added to a solution of phenol (0.10 g, 1.06 mmol) and Cs₂CO₃ (2.0 equiv.) in 40 mL of acetonitrile. The mixture was refluxed for 5h and the solvent was removed in vacuo. The residue was dissolved in diethyl ether (2 x 100 mL), washed with water (3 x 30 mL) and the combined ethereal layers were dried over MgSO₄, and evaporated. The residue was chromatographed on a short silica gel column with ethyl acetate as eluent to give, after evaporation of ethyl acetate, the pure phenyl ether.



References
[1] Furniss, B. S., Hannaford, A. J., Smith, P. W. G., Tatchell, A. R., "Vogel's Textbook of Practical Organic Chemistry", 5th ed. Longman Scientific & Technical, NY, 1989, pp 984-988.
[2] Ussel, M., Schmidt., S. Neumann, B., Synthesis, 382 (1986)
[3] Miller, J. M., So, K. H., Clark, J. H., Can. J. Chem., 57, 1887 (1979)
[4] Sone, T., Sato, K., Ohba, Y., Bull. Chem. Soc. Jpn., 63, 838 (1989)
[5] Mitchell, D. K. and Sauvage, V., Angew. Chem., 100, 985 (1988)