Protection of alcohols and phenols with methoxymethyl acetate.

On reactivity of methoxymethyl acetate towards alcohols and phenols

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

1. Methoxymethyl acetate, H3C-CO-O-CH2-O-CH3 can be used as a protecting reagent for alcohols and phenols at room temperature.

   
   
   

2. Protected compounds are their methoxymethyl ethers. For example phenol, C6H5OH gives the protected derivative at room temperature in 81% yield. This reaction is completed in 16 hrs, and zinc chloride etherate catalyses it. The best solvent is dichloromethane:
   
   

   

   
   
   

   In similar conditions 4-nitrobenzyl alcohol gives the corresponding ether at rt in 76% yield. The reaction is completed in 3 hrs:
   
   

   

   
   
   

   Also substituted phenols, for example 3,4-dichlorophenol and 4-carbomethoxyphenol give the corresponding ethers in 66% and 68% yield, respectively. Conditions are similar: (use of zinc chloride etherate in dichloromethane).

   
   
   

   Zinc chloride (an example of a Lewis acid) etherate in dichloromethane is a mild yet sufficiently active catalyst of the acetal exchange in all cases.

   
   
   

   One can also use other Lewis acid, for example stannic or aluminum chlorides.

   
   
   

   The tenfold molar excess of methoxymethyl acetate over alcohol or phenol gives the best yields of respective ethers for the shortest reaction time.

   
   
   

   For deprotection of MOM ethers see Frequently Asked Questions (below).

   
   
   

   In summary, methoxymethyl acetate (acetoxymethoxymethane) in the presence of zinc chloride etherate in dichloromethane at room temperature is a promising agent for protection of alcohols and phenols with moderate to good yields.

   
   
   

   See also: An acetyl-protected hydroxyl group as the regioselective control element.

   
   

FREQUENTLY ASKED QUESTIONS

Q:
Please, give me the reference where the synthesis of methoxymethyl acetate is reported?

A:
Its synthesis was described in JACS, see: HUGHES W. B., KLEENE R. D., J. Am. Chem. Soc., 76, 5131 (1954).

Q:
Is this reagent (MOMOAc) commercially available? If yes, please tell me the name of the supplier.

A:
Yes, it is. Merck offers it. Please, refer to the item number 8.18404.0100.
Sigma-Aldrich will sell methoxymethyl acetate too.

Q:
Do you know if the MOMOAc is toxic?

A:
MOMOAc is not so toxic as methoxymethyl chloride, MOMCl which is carcinogenic - according to the Federal Register, 39, 3757 (1974), but I recommend gloves and goggles to reduce risk.

Q:
How sensitive are the reagents towards air and moisture?

A:
ZnCl2 etherate and methoxymethyl acetate are sensitive towards moisture, but the procedure requires no special handling of the reaction mixture. I did all the protections in Erlenmeyer flasks with a ground glass stopper, always added a magnetic stirring bar to each flask.

Q:
How to remove the methoxymethyl group?

A:
Standard removal procedure is described at: Acetals

For a simple and efficient deprotecting method see also: Adam Shih-Yuan Lee, Yi-Jung Hu and Shu-Fang Chu, "A Simple and Highly Efficient Deprotecting Method for Methoxymethyl and Methoxyethoxymethyl Ethers and Methoxyethoxymethyl Esters", Tetrahedron, 2001, 57, 2121-2126.

See also: Hideyoshi Miyake, Masahiro Fujimura, Takatsugu Tsumura and Mitsuru Sasaki, "Solvolysis of Benzyl Alcohols and Ethers in 1,2-Diols and Application to a Deprotection of Benzyl Ether-type Protecting Groups", Chemistry Letters, Vol. 35, Number 7 (2006), Page 778 (The Chemical Society of Japan).

How to easily regenerate phenols by the acid hydrolysis (2M H2SO4 in ethanol, reflux, 3 hrs) of the methoxymethylated compounds to the corresponding phenols, see: K. D. Bartle, R. L. Edwards, D. W. Jones, and I. Mir, J. Chem. Soc., pp. 411 - 419 (1967).

And how to regenerate a synthetic steroid alcohol: (19E)-3α-Hydroxy-20-oxo-5β-pregnan-19-al 19-{O-[(methoxycarbonyl)methyl]oxime} by the acid hydrolysis (35% aqueous HClO4 at 60^oC for 2 hrs in benzene-methanol, or 3M H2SO4 in methanol) of its methoxymethyl ether, see: Ivan Černý, Vladimír Pouzar, Martin Hill, Helena Havlíková and Richard Hampl, Steroids Volume 71, Issue 2, February 2006, Pages 120-128.

Q:
What is the mechanism of protection?

A:
The mechanism of protection is S_N2, nucleophilic substitution bimolecular. At least I believe so.
The nucleophile is the hydroxyl group of an alcohol or phenol residue, and the leaving molecule is acetic acid. This hypothesis is supported by subsequent reaction of either methoxymethyl ether with an alcohol (consecutive reactions). This produces a formal (R-O-CH2-O-R, where R is an alcoholic radical). The leaving molecule is methanol. I isolated both formals and elucidated their structures by ¹H-NMR.

On the contrary, none of the three phenols gave a formal.

It is well known that the electron density on the alcoholic oxygen atom is much greater than that on the phenolic one, and this is the reason why these phenols give no trace of formal.

Acetic acid is much more acidic than methanol. Its pKa value is 4.8, whereas the pKa value of methanol is 15.5 at room temperature. Therefore, the CH3COO^- anion is relatively stable compared to the CH3O^- ion. So we expected that it will be the much better leaving group than the latter. And this is the reason why methoxymethyl acetate is the better protecting agent than formaldehyde dimethyl acetal (methylal, CH3-O-CH2-O-CH3). Moreover, the -O-CO-CH3 substituent has much stronger negative inductive effect than the -O-CH3 one. It attracts electrons more strongly. This facilitates the nucleophile attack on the -CH2- group.

The S_N2 hypothesis still needs experimental verification. The mechanism of protection may be, on the contrary S_N1, nucleophilic substitution unimolecular, in which the CH3COO^- anion leaves before the RO group bonds, where R is an alcoholic or phenolic radical. This mechanism is far less probable because the carbocation CH3-O-CH2⁺, which would form in the first step is not branched. In all such cases the S_N2 mechanism has been favoured over the latter.

Read the full version of this article in Polish J. Chem.