Chloromethyl Methyl Ether1

MeOCH2Cl

[107-30-2]  · C2H5ClO  · Chloromethyl Methyl Ether  · (MW 80.51)

(used for the protection of alcohols, phenols, acids, amines, b-keto esters and thiols. A one-carbon synthon for alkylation of aromatics and active methylene derivatives)

Alternate Name: methoxymethyl chloride; MOMCl.

Physical Data: bp 55-57 °C; d 1.060 g cm-3.

Solubility: sol nearly all organic solvents.

Form Supplied in:  available as a technical grade liquid.

Preparative Methods: besides the original method2 which uses HCl, formalin, and methanol, MOMCl can be prepared from methoxyacetic acid3 or methylal (Dimethoxymethane).4

Handling, Storage, and Precautions: MOMCl is an OSHA-regulated carcinogen and depending on the method of preparation may contain bis(chloromethyl) ether, which is a more potent carcinogen. This reagent should be handled in a fume hood.

Protection of Alcohols.

Treatment of an alcohol with MOMCl and i-Pr2NEt (0 °C, 1 h -> 25 °C, 8 h, 86% yield)5 is the most commonly employed procedure for introduction of the MOM group. Formation of the sodium alkoxide and reaction with MOMCl is also very effective.6 This method is particularly useful for the protection of the enol of b-keto esters.7 Because of the carcinogenicity of MOMCl, a number of methods for the introduction of the MOM group have been developed which do not rely on the chloride. The methods are all based on the use of CH2(OMe)2 with various catalysts such as P2O5,8 Me3SiI,9 Nafion H,10 CH2=CHCH2SiMe3/TMSOTf/P2O5,11 FeCl3,12 Montmorillonite clay (H+),13 or TsOH/LiBr.14 In the last case, 1,3-diols give methylene acetals. It is often difficult to achieve monoprotection of 1,3-diols but some success has been recorded, as illustrated in eqs 1-3.15-17

In the orthoester route when unsymmetrical diols are used, the most hindered alcohol is protected, in contrast to the normal methods which are expected to protect the least hindered alcohol. Diols capable of forming a stannylene derivative are efficiently monoprotected (eq 3).17

Cleavage of MOM Ethers.

Since the MOM group is an acetal, it can be cleaved using acid hydrolysis. In general, aqueous acid in an organic cosolvent has proven to be effective.18-21 Use of the weak acid Pyridinium p-Toluenesulfonate in refluxing t-BuOH or 2-butanone is particularly effective for cleavage of MOM ethers of allylic alcohols.22 MEM ethers are also cleaved under these conditions. Eq 4 shows that a MOM group can be cleaved with anhydrous Trifluoroacetic Acid in the presence of an acetonide which is normally cleaved with aqueous acid.23

Catecholborane halides, particularly the bromide (B-Bromocatecholborane), are effective reagents for the cleavage of MOM ethers. The bromide cleaves the following groups in the order: MOMOR &AApprox; MEMOR > t-Boc > Cbz &AApprox; t-BuOR > BnOR > allylOR > t-BuO2CR &AApprox; secondary alkylOR > BnO2CR > primary alkylOR >> alkylO2CR. The t-butyldimethylsilyl (TBDMS) group is stable to this reagent. The chloride is less reactive and thus may be more useful for achieving selectivity in multifunctional substrates. Yields are generally >83%.24 A variety of other boron based reagents have been developed which are useful for MOM ether cleavage. The use of Bromobis(isopropylthio)borane (eq 5)25 has the advantage that 1,2- and 1,3-diols do not give formyl acetals as is sometimes the case in cleaving MOM groups with neighboring hydroxyl groups.26 The reagent also cleaves MEM groups and under basic conditions affords the i-PrSCH2OR derivatives. With Bromodimethylborane, MEM and MTM ethers are also cleaved, but esters are not affected.27

Bromotrimethylsilane, a reagent similar to but not as powerful as Iodotrimethylsilane, will cleave MOM ethers as well as acetonide, THP, trityl, and t-BuMe2Si groups, but the reagent will not cleave esters, methyl and benzyl ethers, t-butyldiphenylsilyl ethers, and amides. One example is shown in eq 6.28

Boron Trifluoride Etherate in the presence of Thioanisole,29 Magnesium Bromide in the presence of butanethiol,30 Triphenylcarbenium Tetrafluoroborate,31 and Lithium Tetrafluoroborate32 are also useful for cleavage of the MOM group. The action of lithium tetrafluoroborate is unique (eq 7) and the mechanism for cleavage is not well understood.

Protection of Phenols.

The reaction of MOMCl with a phenol under phase-transfer conditions works well to give phenolic MOM ethers33 and will selectivity protect a phenol in the presence of an alcohol.34 The more classical Williamson ether synthesis35 also provides excellent results, but may require the addition of a crown ether to enhance the nucleophilicity of the phenolate anion.36 As in the case of alcohol protection, alternatives using methylal have been developed for phenol protection which do not rely on the carcinogenic MOMCl.37 Phenolic silyl ethers can be converted directly to MOM ethers by reaction with TASF (Tris(dimethylamino)sulfonium Difluorotrimethylsilicate) and MOMCl.38

Cleavage of Phenolic MOM Ethers.

Again, mild acid37,39 is used for cleavage, but other alternatives such as Sodium Iodide/acetone/cat. HCl/50 °C,40 Diphosphorus Tetraiodide/CH2Cl2/0 °C -> rt,41 or TMSBr/CH2Cl242 are also effective.

Protection of Thiols.

Lithium43 and potassium44 thiolates react with MOMCl to form the thioethers. The use of MOMCl can be avoided by the reaction of the zinc thiolate with methylal.45

Protection of Acids.

The reaction of MOMCl with an acid in the presence of a base affords the MOM ester.46-48 As with the thiols, the zinc carboxylate reacts with methylal to afford the MOM ester.49 MOM esters are quite acid sensitive and are unstable to silica gel chromatography.50 The MOM ester is easily cleaved with acid, MgBr2,51 or Me3SiBr containing a trace of MeOH.52

Protection of Amine Derivatives.

Heterocyclic amines and amides are protected as their MOM derivatives by reaction of the amine or amide with MOMCl in the presence of a base such as Diisopropylethylamine,53 Sodium Hydride,54 LiH, Potassium t-Butoxide,55 or Sodium Hydroxide.56 These derivatives are cleaved with Hydrogen Chloride/EtOH53 or Boron Tribromide.55 To hydrolyze scopolamine without formation of the rearranged product (1) it was necessary to protect the amine nitrogen as the methoxy-methochloride as illustrated in eq 8.57

Use in C-C Bond-Forming Reactions.

Since MOMCl is an excellent electrophile it readily reacts with enolates58 and other carbanions59 and thus serves as an easily handled one-carbon synthon. Friedel-Crafts alkylation with MOMCl and a Lewis acid such as Tin(IV) Chloride,60 Titanium(IV) Chloride,61 Zinc Chloride,62 and Aluminum Chloride63 or Acetic Acid64 is a common method for introduction of a chloromethyl group onto an aromatic nucleus (eqs 9 and 10).60,64 The reaction is quite general and tolerates a broad range of functionality.

Alkenes react in a similar fashion giving methoxymethyl derivatives, but in this case the intermediate carbenium ion is trapped with methoxide or another nucleophile such as a nitrile to afford the methyl ether or amide in a Ritter-like reaction (eq 11).65 In similar fashion, silyl enol ethers give ketones (eq 12),66,67 allylsilanes afford homologated alkenes (eq 13),68 and stannylalkynes are converted to propargyl ethers.69

MOMCl can be converted to the Grignard reagent or the lithium reagent and used to introduce one carbon by nucleophilic attack on ketones and esters.70 These reagents are best prepared in methylal.71


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Peter G. M. Wuts

The Upjohn Co., Kalamazoo, MI, USA



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