POLISH JOURNAL OF CHEMISTRY
(FORMERLY ROCZNIKI CHEMII)
65, 1433 (1991)

On reactivity of methoxymethyl acetate towards alcohols and phenols,

J. Krol, G. Grynkiewicz, A. Kutner, Polish J. Chem., 65, 1433, (1991)

Institute of Pharmaceutical Industry, Rydygiera 8, 01-793 Warszawa

      Acetal exchange reactions are recognized as convenient transformations, particularly useful in the area of protecting group chemistry ¹⁾. Methoxymethyl acetate (acetoxymethoxymethane, 1), which is an easily available reagent, constitutes the simplest non-symmetrical acetal ²⁾, which can be regarded as a model of glycosyl (hemiacetal) ester. Compounds with such functional groups configuration are of considerable significance in the carbohydrate synthesis methodology. Moreover, compound 1 can be regarded as a prospective reagent for insertion of methoxymethyl or acetoxymethyl group via the substitution at the acetal carbon atom. Preparations of methoxymethyl ethers from alcohols and formaldehyde dimethyl acetal under acidic conditions was described to proceed effectively only with the use of a large excess of the acetal ^3-6). We have reasoned that the presence of an acetoxy substituent, as a better leaving group, in the molecule of the reagent should facilitate the reaction of the acetal exchange and allow to substantially reduce required excess of the reagent.

      In this paper we describe the use of methoxymethyl acetate as a protecting agent for alcohols and phenols.

EXPERIMENTAL

      ¹H NMR spectra were recorded on a Bruker WP 100 SY spectrometer in CDCl₃ with TMS as an internal standard. Chemical shifts are given in δ values. IR spectra were taken on a Specord 75 IR spectrophotometer as films of oily substances or in KBr pellets. Melting points were determined in capillaries and were not corrected. TLC was performed using silica gel precoated aluminium sheets and solvent system A, hexane - ethyl acetate 7:3 or B, benzene - ethyl acetate 95:5. Acetoxymethoxymethane, (1) was prepared according to the known procedure ²⁾. The catalyst mixture ZnCl₂-Et₂O-CH₂Cl₂ was obtained by the known method ⁷⁾ from 1.00 g (7.34 mmole) of anhydrous ZnCl₂, 1.61 g (21.7 mmole) of Et₂O and CH₂Cl₂ added up to a total volume of 5 ccm.

Screening of catalysts. General procedure

      Acetoxymethoxymethane, (1, 0.2 ccm, 2 mmole) and given catalyst (1 mmole; in case of SnCl₄ 0.2 mmole was used) were added to the stirred solution of p-nitrobenzyl alcohol (0.153g, 1 mmole) in 5 ccm of dichloromethane. The stirring was continued ar toom temperature overnight and the reaction was monitored by TLC using solvent system A. On completion of the reaction, the mixture was washed with 10 ccm of 10% aq. NaHCO₃ and brine and dried over anhydrous Na₂SO₄. Solvents were removed under reduced presuure. The yield of methoxymethyl ether formed was calculated from the intensities of methoxy- and aromatic protons signals in the ¹H NMR spectrum.

Reactions of acetoxymethoxymethane, (1) with alcohol or phenol (2). General procedure

      A mixture of ZnCl₂-Et₂O-CH₂Cl₂ (1 ccm) followed by 1 ccm (10 mmole) of 1 were added to the solution of the hydroxyl compound 2 (1 mmole) in 5 ccm of dry dichloromethane vigorously stirred at room temperature. The stirring was continued until the hydroxylic substrate (2) was consumed (TLC, solvent system A). The mixture was then washed with 15 ccm of 10% aq. NaHCO₃. Traces of unreacted phenols 2 were removed with 30 ccm of 5% NaOH. The aqueous layer was washed with 5 ccm of CH₂Cl₂. Combined organic layers were dried over anh. Na₂SO₄ and evaporated. Column chromatography on silica gel in hexane - ethyl acetate gave the respective methoxymethyl ethers 3 in the form of colorless or slightly yellow oils, except the methoxymethyl ether of cholesterol, which was obtained as white crystals.

Methoxymethyl ether of p-nitrobenzyl alcohol 3.1

      Analysis:

      For C₉H₁₁O₄N (197.19) - Calcd.: 54.8% C, 7.1% H;      Found: 54.8% C, 7.1% H.

      IR: 3080, 2950, 1600, 1520, 1350, 1150, 1105, 1050, 970, 915, 850, 735 cm^-1.

Methoxymethyl ether of cholesterol 3.2

      Analysis:

      For C₂₉H₅₀O₂ (430.69) - Calcd.: 80.9% C, 11.7% H;      Found: 80.7% C, 11.5% H.

      TLC, solvent system B, R_f =0.56 (Lit. ⁸ ): 0.58).

      IR: 2950, 1460, 1370, 1150, 1100, 1030 cm^-1.

Methoxymethyl ether of phenol 3.3

      Analysis:

      For C₈H₁₀O₂ (138.16) - Calcd.: 69.5% C, 7.3% H;      Found: 69.6% C, 7.5% H.

      IR: 3050, 2960, 2910, 2830, 1590, 1480, 1210, 1140, 1070, 990, 910, 740 cm^-1.

Methoxymethyl ether of 3,4-dichlorophenol 3.4

      Analysis:

      For C₈H₈O₂Cl₂ (207.05) - Calcd.: 46.4% C, 3.9% H;      Found: 46.7% C, 4.0% H.

      IR: 3100, 2980, 2920, 2850, 1595, 1475, 1260, 1220, 1160, 1140, 1090, 1000, 920, 865 cm^-1.

Methoxymethyl ether of 4-carbomethoxyphenol 3.5

      Analysis:

      For C₁₀H₁₂O₄ (196.20) - Calcd.: 61.2% C, 6.2% H;      Found: 61.1% C, 6.2 H.

      IR: 3060, 2980, 2950, 2900, 2830, 1700, 1590, 1420, 1270, 1140, 1090, 980, 840, 750 cm^-1.

RESULTS AND DISCUSSION

      Initial screening of the catalysts, given in Table 1 has shown that zinc chloride etherate is a mild, yet sufficiently active catalyst of the acetal exchange.

Table 1

^a Molar ratio of the alcohol to 1 was 1:2
^b Estimated by ¹H NMR                      

      Zinc chloride etherate in comparison to other catalysts in Table 1 gives much better yields of the corresponding ether, and is also more convenient to handle. Representative examples of alcohols and phenols protected with the use of this catalyst are shown in Table 2.

Table 2

^aCalculated for the isolated product.

      It was found that the tenfold molar excess of acetoxymethoxymethane (1) over alcohol (2) was necessary to get the best yield of respective ethers for the shortest reaction time. The optimum molar ratio of the catalyst to the alcohol was found to be within the range from 1.2:1 to 2:1. However, the reaction time and yield of ether varied considerably for different hydroxylic substrates. This might be attributed to the different electron density at the hydroxylic oxygen atom.

      In summary, methoxymethyl acetate (acetoxymethoxymethane) in the presence of ZnCl₂ etherate (or other Lewis acid) in CH₂Cl₂ at rt is a good reagent for the protection of certain alcohols or phenols with moderate to good yields. Studies on the use of acetoxymethoxymethane for the protection of other natural and synthetic alcohols and phenols is under way in our laboratory.

Acknowledgements

      The assistance of W. Jakubowski, M.Sc. in recording analytical data is gratefully acknowledged. We thank Mrs. M. Lisik for performing elemental analyses. The work was supported in part by the grant CPBR 11.5 from the Polish National Cancer Program.

Received January 5th, 1990.

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