1,1-Dichloromethyl methyl ether 452 Reagent

Another useful reagent for introduction of the carbonyl carbon is dichloromethyl methyl ether. In the presence of a hindered alkoxide base, it is deprotonated and acts as a nucleophile toward boron. Rearrangement then ensues with migration of two boron substituents. Oxidation gives a ketone. 

Scheme 9.1 describes reactions with several lithiated compounds, including dichloromethane, dichloromethyl methyl ether, phenylthiomethyl methyl ether, and phenylthioacetals. Compare the structure of these reagents and the final products for these reactions. Develop a mechanistic outline that encompasses these reactions. Discuss the features that these reagents have in common with one another and with carbon monoxide. 

The synthesis of dichloromethyl methyl ether has been included because of its usefulness as a reagent for the preparation of aromatic aldehydes (Expt 6.115). It is readily obtained by the reaction of phosphorus pentachloride in admixture with phosphorus oxychloride with methyl formate (Expt 5.71). 

Besides 11-18, several other formylation methods are known." In one of these, dichloromethyl methyl ether formylates aromatic rings with Friedel-Crafts catalysts." The ArCHClOMe compound is probably an intermediate. Orthoformates have also been used." In another method, aromatic rings are formylated with formyl fluoride HCOF and BF3." Unlike formyl chloride, formyl fluoride is stable enough for this purpose. This reaction was successful for benzene, alkylbenzenes, PhCl, PhBr, and naphthalene. Phenols can be regioselectively formylated in the ortho position in high yields by treatment with 2 equivalents of paraformaldehyde in aprotic solvents in the presence of SnCLj and a tertiary amine." Phenols have also been formylated indirectly by conversion to the aryllithium reagent followed by treatment with V-formyl piperidine." See also the indirect method mentioned at 11-23. 

A method for converting carboxylic acids under neutral conditions to the corresponding acid chlorides is available with a-halogenated ethers as reagents. Thus it has been shown that 2-chlorodioxin can give acid chlorides of a variety of acids in good yield. The method, however, has not received wide application. Instead a,a-dichloromethyl methyl ether, which can be prepared easily, has replaced other a-ha-loethers as reagents. In Table 3 some examples are listed. 

Sometimes the addition of a small amount of ZnCh as a catalyst is recommended, e.g. succinic acid is transformed to the dichloride only in the presence of this catalyst. It has to be noticed, however, that under these conditions hydrogen chloride is evolved and, therefore, acid sensitive compounds cannot be taken. Af-acylamino acid chlorides and chlorides of fully acetylated sugar acids are also obtainable in yields of 70% or more. Whereas most reagents seem to be unsuited to the preparation of acid halides of a-keto acids, dichloromethyl methyl ether is successful in this reaction (equation 10). Pyruvyl chloride can now be made in ca. 50% yield. In some examples the corresponding a,a-dibromomethyl methyl ether has also been tested. ... 

If carboxylic acid esters are readily available, they provide a convenient basis for the preparation of acid halides. Modified phosphorus halides, like 2,2,2-trichloro-l,3,2-benzodioxaphosphole can be applied successfully. This reagent forms first a 1,1-dichloroalkyl ether, which decomposes to the acid chloride (equation 16). The reaction conditions are rather drastic. For instance -butyl benzoate has to be heated for 4 h at 180 °C in order to get a 90% yield of benzoyl chloride. The only stable and isolable 1,1-dichloro ether is a,a-dichloromethyl methyl ether, which, as described above, is used as a mild reagent for the conversion of carboxylic acids to their chlorides. Similarly severe conditions are required if the chlorine or bromine adduct of triphenylphosphine is selected. This reaction may be catalyzed by BF3. It has been applied successfully to unsaturated esters and to the cleavage of lactones. 

Chiral boronic esters react with organolithium reagents to form diorganylalkoxyboranes (borinic esters). Subsequent reaction with the anion of dichloromethyl methyl ether then yields chiral ketones by rearrangement of both of the groups on boron (Scheme 42). No racemization is observed in this sequence and alkyl-, aryl- or alkynyl-lithium reagents can be used. 

Dichloromethyl methyl ether and zinc chloride cleave 38 to the 6-formate (41). With an excess of the reagent, the final product is 2,3,4-tri-0-acetyl-6-0-(dichloromethyl)-a-D-glucopyranosyl chloride.565,566... 

Alkylborinic esters, obtained from alkylboronic esters and an organometallic reagent, are converted into the corresponding ketones by the reaction with dichloromethyl methyl ether in the presence of a hindered base, followed by oxidation with hydrogen peroxide in pH 8 buffer or with anhydrous trimethylamine Ar-oxide18. 

ALKENES Allyl dimethyldithiocarbamate. Bis(t -cyclopentadienyl)niobium trihydride. Cyanogen bromide. Di-n-butylcopperlithium. a,o-Dichloromethyl methyl ether. 2,3-Dimethyl-2-butylborane. N,N-Dimethyl dichlorophosphoramide. Diphenyl diselenide. Di-n-propylcopperlithium. Ferric chloride. Grignard reagents. Iodine. Lithium phenylethynolate. Lithium 2,2,6,6-tetramethylpiperidide. Methyl iodide. o-Nitro-phenyl selenocyanate. Propargyl bromide. rra s-l-Propenyllithium. Selenium. Tetrakis(triphenylphosphine)palladium. Titanium(IH) chloride. Titanium trichloride-Lithium aluminum hydride. p-Toluenesulfonylhydrazine. Triphenylphosphine. Vinyl-copper reagents. Vinyllithium. Zinc. 

Hydroboration of a.,oi-dienes. Cyclic hydroboration of ,cu-dienes can be effected with this reagent. The initial product is often polymeric, but six- to eight-membered cyclic B-chloroboracycloalkanes can be obtained after depolymerization by distillation in good yields. The B-chloroboracycIoaikanes (2) and (3) from 1,4-pentadiene (1) were transformed into the cyclic ketones (6) and (7) by reaction with a,a -dichloromethyl methyl ether (5, 200 203) followed by oxidation. ... 

Yamato and co-workers introduced dichloromethyl methyl ether in the presence of titanium tetrachloride as a reagent for one-pot formylation followed by in situ Bradsher cyclization. In this way anthracene regioisomers 25 and 26 were obtained from diaryImethane 24 in good yield. The initially formed anthracene derivative presumably reacts with excess dichloromethyl methyl ether to yield 9- or 10-formylanthracene derivative 25 or 26. 

Peracetates of mono- and di-saccharides e.g. a-D-glucopyranose and j8-lactose) were treated with dichloromethyl methyl ether and tin(iv) chloride at room temperature to give the more stable acetylated glycosyl chlorides in high yields, and this and other uses of this reagent in carbohydrate chemistry... 

A review (in German) of dichloromethyl methyl ether as a reagent in carbohydrate chemistry outlines its use in the conversion of sugar acids into the corresponding acid chlorides. ... 

The use of a,a-dichloromethyl alkyl ethers for the conversion of carboxylic acids to acid chlorides was first reported by Heslinga et al. in 1957.4 The submitters have found that the readily available a,a-dichlo-romethyl methyl ether2 is the reagent of choice for the preparation of pyruvoyl chloride.6 This simple and economical procedure has been used in other laboratories,51213 and the submitters have applied the method to the preparation of three other a-keto acid chlorides 2-oxobutanoyl chloride (32%), 3-methyl-2-oxobutanoyl chloride (10%), and phenylglyoxylyl chloride (78%).6... 

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