1,1-Dimethoxyethane

[534-15-6]  · C4H10O2  · 1,1-Dimethoxyethane  · (MW 90.12)

(reagent for diol protection1 and condensation reactions8)

Alternate Name: acetaldehyde dimethyl acetal.

Physical Data: mp -113.2 °C; bp 64.5 °C; d 0.850 g cm-3.

Solubility: sol most organic solvents.

Handling, Storage, and Precautions: flammable liquid.

Diol Protection.

1,1-Dimethoxyethane used for the protection of diols as acetals of acetaldehyde can offer advantages over the more commonly employed acetonide protection using 2,2-Dimethoxypropane or Acetone. The acetonides tend to prefer the formation of five-membered rings and thus offer some selectivity for 1,2-diol over 1,3-diol protection. This selectivity is switched for the O-ethylidene derivatives. This is believed to result from an elimination of an axial methyl group in the chair conformations of the O-ethylidene compounds.1 This is illustrated in the ethylidenation (eq 1) of L-sorbose. The use of acetaldehyde for this transformation is ineffective.2 The product of the acetonation of L-sorbose is shown for comparison purposes. Similar selectivity has been observed in the protection of steganone (eq 2).3 Although a new stereocenter is created and there is the possibility of generating a mixture of stereoisomers, the one with the equatorial methyl group is usually preferred.

Mixed acetals of acetaldehyde can be prepared by reaction of 1,1-dimethoxyethane with another alcohol under acid catalysis. If the alcohol is a tertiary allylic one (eq 3), the mixed acetal loses methanol to form the enol ether which then undergoes a Claisen rearrangement.4

The reaction of the bis(trimethylsilyloxy)pyrimidine (eq 4) in the presence of Titanium(IV) Chloride and the acetal produces the a-methoxyethyluracil in 62% yield.5

Cyanotrimethylsilane reacts with 1,1-dimethoxyethane (eq 5) to afford 2-methoxypropanenitrile in 73% yield if catalyzed by Boron Trifluoride Etherate6 and in 63% yield if catalyzed by Zinc Iodide.7

Condensation Reactions.

The dimethyl acetal of acetaldehyde serves as a useful surrogate for Acetaldehyde in a number of Lewis acid mediated condensation reactions.8 Vinyl ethers are especially receptive partners in these reactions. Methyl vinyl ether reacts to produce the 3-methoxy acetal (eq 6) in 60% yield. This product is also accompanied by 18% of an addition product derived from further reaction of the vinyl ether with the methoxy acetal. The relative reactivity of this acetal as well as a number of other acetals has been reported.9

Trimethylsilyl enol ethers couple with the acetal in an aldol-type reaction to afford b-methoxy carbonyl compounds. These reactions can be effected by the use of a number of different Lewis acids. Some of the Lewis acids that have been employed are TiCl4, Tin(IV) Chloride, Zinc Bromide, Triphenylmethyl Perchlorate or hexachloroantimonate, and Trimethylsilyl Trifluoromethanesulfonate. The silyloxy diene (eq 7) on treatment with the acetal in the presence of either SnCl4 or ZnBr2 provides the aldol product in 62% and 63% yield, respectively.10 The bis(thiomethyl)silyloxy diene (eq 8) when treated with trityl perchlorate condenses with 1,1-dimethoxyethane to provide the b-methoxy ketone in 61% yield.11

Stereoselectivity.

A TiCl4-catalyzed reaction of the silyloxy diene (eq 9) with the acetal results in a 57:43 (E):(Z) mixture of products in 51% yield. These products are derived from attack at the g-position of the carbonyl system.12

The reaction of the silyl enol ether of t-butyl acetoacetate, trimethylsilyl triflate, and the dimethyl acetal (eq 10) affords a 1:1 mixture of stereoisomers in 90% yield.13

The enol ether derived from (R)-hexahydromandelic acid (eq 11) produces the aldol product in good yield. The products were reduced with Lithium Aluminum Hydride for the determination of the enantiomeric excesses. If the reaction is catalyzed by Me3SiOTf, the product after reduction has an ee of 60% and an erythro:threo ratio of 9:1. Catalysis by Ph3CSbCl6 results in an increase in the ee to 98%, but the erythro:threo ratio drops to 4:1.14

Allylic and allenic stannanes also couple with 1,1-dimethoxyethane. Treatment of the tributylallenylstannane with TiCl4 and the acetal (eq 12) yields a 56:44 mixture of threo:erythro isomers in 67% yield.15 An aqueous-mediated condensation of the cyclohexenylstannane (eq 13) furnishes an 85% yield of erythro and threo stereoisomers in a 62:38 ratio.16

Pictet-Spengler condensations of tryptophan derivatives lead to the formation of cis/trans mixtures of tetrahydro-b-carbolines. The ratio of products depends on the nature of the substituent on the nitrogen. N-(Hydroxy)tryptophan ethyl ester on reaction with 1,1-dimethoxyethane (eq 14) and Trifluoroacetic Acid in CH2Cl2 produces a 2:1 (cis/trans) mixture of diastereomers.17 The N-benzyl derivative under the same conditions gives an 84:16 (trans/cis) mixture.18

meso-Tetramethylporphyrinogen is produced in 28% yield by the reaction of pyrrole and the dimethyl acetal of acetaldehyde (eq 15) in CCl4 in the presence of CF3CO2H.19

Miscellaneous.

Calculations20 and NMR investigations21 of the conformations of 1,1-dimethoxyethane have been reported. The acetal can be used to prepare the methoxy(phenylseleno) acetal of acetaldehyde using Diisobutylaluminum Phenyl Selenide,22 and selenoacetaldehyde employing bis(dimethylaluminum) selenide.23

Related Reagents.

Dimethoxymethane; 2,2-Dimethoxypropane; Triethyl Orthoformate.


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Michael J. Taschner

The University of Akron, OH, USA



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