Methoxymethyl enol ethers

A soln. of 5.0 g. ethyl 8/, 8a/ -dimethyl-l-oxo-l,2,3,4,6,7,8,8a-octahydro-2-naph-thoate in hexamethylphosphoramide added at 5° under Ng to a stirred mixture of a 60%-dispersion ofNaHin mineral oil and hexamethylphosphoramide, stirring continued 1 hr. at room temp., cooled to 5°, 1.93 g. chloromethyl methyl ether added, and stirred 2 hrs. at room temp. 5.7 g. crude methoxymethyl enol ether dissolved in ether, added rapidly with Dry Ice-cooling under argon to a stirred dark blue soln. of Li in anhydrous NH3, and stirring continued 12 min. at -33°, the b. p. of liq. NHg 2.85 g. ethyl 8/, 8ai -dimethyl-l,2,3,4,6,7,8,8a-octahydro-2j -naphthoate. Overall Y 60%. - 0-Alkylation of the startg. -keto esters occurs under the above conditions to the complete exclusion of the C-alkylated isomer. The subsequent reduction gives the less stable axial isomer. R. M. Coates and J. E. Shaw, J. Org. Chem. 35, 2597 (1970) f. e. s. ibid. 35, 2601 carboxylic acids, also from a,/ -ethylenecarboxylic acids, cf. ibid. 36, 1151 (1971). 

The double reduction of jff-ketoester methoxymethyl enol ethers (88) is reported by an American school o high-yield method for the hydro-genolysis of the /S-carbonyl function treatment with lithium in ammonia causes reduction of the conjugated double bond, elimination of methoxy-methanol, and further reduction to give the saturated ester (89). This procedure is equally effective on the corresponding /3-ketoacids. ... 

Alkoxy ketones. These ketones can be prepared by an aldol-type reaction of enol ethers with acetals catalyzed by a trityl salt. Methoxymethyl (MOM) enol ethers are more reactive than methyl enol ethers. 

As depicted in Scheme 1.1.2, the silyl ketones (S)-ll of high enantiomeric purity were converted into the Z-configured silyl enol ethers (S) -12, which were used in the aminomethylation step by treatment with dibenzyl(methoxymethyl)amine in the presence of a Lewis acid. The silylated Mannich bases S,R)-13 were obtained in excellent yields and diastereomeric excesses (de = 92-96%). Finally,... 

When the ylid derived from the oxide 7 was treated with benzaldehyde, a 2-methoxy-l,3-diene was formed. This led us to attempt a synthesis of (i) ar-turmerone by a sequence (Scheme 3) in which 7 effectively acts as an acyl anion equivalent. The required aldehyde 8 was synthesized in good yield using initially diphenyl(methoxymethyl)phosphine oxide (3), and then chlorotri-methylsilane-sodium iodide (12) to cleave the enol ether. 

This procedure consists of the synthesis of a precursor, methoxymethyl vinyl ether, an a-hydroxy enol ether, and the intramolecular hydrosilylatlon of the latter followed by oxidative cleavage of the silicon-carbon bonds. The first step, methoxymethylation of 2-bromoethanol, is based on Fujita s method.7 The second and third steps are modifications of results reported by McDougal and his co-workers. Dehydrobromination of 2-bromoethyl methoxymethyl ether to methoxymethyl vinyl ether was achieved most efficiently with potassium hydroxide pellets -9 rather than with potassium tert-butoxide as originally reported for dehydrobromination of the tetrahydropyranyl analog.10 Potassium tert-butoxide was effective for the dehydrobromination, but formed an adduct of tert-butyl alcohol with the vinyl ether as a by-product in substantial amounts. Methoxymethyl vinyl ether is lithiated efficiently with sec-butyllithium in THF and, somewhat less efficiently, with n-butyllithium in tetrahydrofuran. Since lithiation of simple vinyl ethers such as ethyl vinyl ether requires tert-butyllithium,11 metalation may be assisted by the methoxymethoxy group in the present case. 

Methoxymethylation ofp-keto esters The sodium salts of fS-keto esters on alkylation with chloromethyl methyl ether in HMPT give almost exclusively the product of O-alkylation (96-100%). Yields of O-alkylated products are lower in less polar aprotic solvents. These enol ethers are reduced with lithium in liquid ammonia to the corresponding saturated esters (23-61 % yield). The method is most efficient for reduction of a relatively hindered keto group of a p-keto ester. 

If there is a leaving group in the (i-position of the carbonyl starting material 132 during homologation by the methoxymethyl reagents 116 or 117, it is lost during the hydrolysis of the enol ether product 133 to form an enal 134. 

Selective formation of the methyl enol ether and reduction of the C(11) keto function followed by protection of the resultant alcohol as methoxymethyl ether provided (275). 

Mannich reactionsJ The reaction of methoxymethyl(dibenzyl)amine with silyl enol ethers proceeds at low temperatures in the presence of BFj-OEt A bulky silyl group at the a -position of the enol ether can serve as a stereocontrol element. 

Ether cleavage. Silica gel on which oxalic acid is deposited hydrolyzes enol ethers. This reagent is useful for converting 3-methoxy-2,5(10)-diene steroids (Birch reduction products of A-aromatic steroids) into the corresponding 5(10)-en-3-ones. For the cleavage of other ethers in methanol, the silica-alumina gel (prepared by the sol-gel method) is very valuable. The ease of deprotection follows the order TMS > 1 -methyl-1 -methoxyethyl 1 -ethoxyethyl > THP methoxymethyl. 

Besides the fully unsaturated 5 f-l,4-dioxepin (45), the unsaturated 1,4-dioxepins, 6,7-dihydro-5Ef-l,4-dioxepin (46), and 2,3-dihydro-5 f-l,4-dioxepin (47), incorporate either the structural feature of an enediol ether or an enol ether. One general method for the preparation of seven-membered rings of type (46) involves ring expansion thus, treatment of 2-(methoxymethyl)-l,3-dioxane with dodecylbenzenesulfonic acid in vacuum gas oil at 250 °C and simultaneous distillation gave (46) with 69% conversion and 84% selectivity. Several 6,6-disubstituted derivatives (49), which have found interest as intermediates for agrochemicals, drugs, and plastics, have analogously been... 

Anion Trap. Besides formation of silyl enol ethers, TMSCl has also been applied to trap other oxide anions to form the desired trimethylsilyl derivatives. For example, reaction of ethyl 4-phenylbutanoate with l,l-dichloroethylUthium, which was generated from 1,1-dichloroethane and LDA, produced exclusively the mixed acetal as expected in 86% yield in the presence of TMSCl (eq 44). Without TMSCl, the reaction gave the corresponding ketone as the final product. However, the yield is rather low and the ketone was obtained in only 16% (eq 45). When the same reaction run with methoxymethyl 4-phenylhutanoate, it... 

Anhydro-3,4,5,7-tetra-0-(methoxymethyl)-D-gluco-hept-l-enitol (16) is prepared from tetra(methoxymethylether) of 6-D-gluconolactone. The carbonyl function of lactone is olefinated with dimethyltitanocene to provide enol ether (Scheme 31.16). 

The initial olefination was accomplished using the Wittig olefination conditions developed by Corey (NaH/DMSO) to afford E/Z mixtures of enol ethers. The enol ethers undergo hydrolysis to the corresponding aldehydes upon treatment with 5% aqueous HF in acetonitrile. Modest degrees of stereoselectivity were observed. The ability of fluoride to mediate the hydrolysis of the (trimethylsilyl)ethoxymethyl moiety may provide opportunities not available when (methoxymethyl)triphenylphosphonium salts are employed. However, it should be noted that Zbiral and Schonauer reported that hydrolysis could not be realized with the use of tetrabutylammonium formate or triethylamine 2HF. 

One-carbon homologation of a ketone to an a,/8-unsaturated aldehyde can be accomplished by formation of the requisite enol ether using methoxymethyl-enetriphenylphosphorane (Scheme 25). Alternatively, the lithioenamino-phosphonate (15) can be used to effect the same conversion [equation (24]. ... 

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). In similar fashion, silyl enol ethers give ketones (eq 12), allyl-silanes afford homologated alkenes (eq 13), and stannylalkynes are converted to propargyl ethers. ... 

Lithium naphthalenide (prepared from lithium and 1.33 equivalents of naphthalene) also reductively cleaves benzyl ethers [Scheme 4.143],262 Some functionalities survive the reaction conditions like carbon-carbon double bonds, benzene rings, THP ethers, stlyl ethers and methoxymethyl ethers. A ketone group can be present but its prior conversion to an enolate is necessary. A similar transformation, but with a catalytic amount of naphthalene, has been reported.263 Although allyl ethers are also cleaved by the procedure, the selective deprotec-... 

Many functional groups are stable under conditions for the alkylation of pseudoephedrine glycinamide enolates, including aryl benzenesulfonate esters (eq 18), rert-butyl carbamate and rerf-butyl carbonate groups (eq 19), tert-butyldimethylsilyl ethers, benzyl ethers, ferf-butyl ethers, methoxymethyl ethers, and alkyl chlorides. The stereochemistry of the alkylation reactions of pseudoephedrine glycinamide and pseudoephedrine sarcosinamide is the same as that observed in alkylations of simple A(-acyl derivatives of pseudoephedrine. 

Modified Ghugaev reaction. The Li-salt of (l-phenylcyclohexyl)methoxymethyl-carbinol, prepared from the carbinol with phenyllithium in ether according to J. Weinstock and F. G. Bordwell, Am. Soc. 77, 6706 (1955), allowed to react with GS2 then with methyl iodide, and the resulting crude S-methyl xanthate heated 4.5 hrs. at 190-195°crude 1-phenylcyclohexylacetaldehyde enol methyl ether. Y 64%.—This is one step in a multistep conversion of acids with a-quaternary G-atoms into j -subst. acetaldehyde derivatives. F. e. s. J. W. Wilt and B.H. Philip, J. Org. Ghem. 24, 616 (1959). 

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