Triethyl Orthoacetate1

(1; R = Et)

[78-39-7]  · C8H18O3  · Triethyl Orthoacetate  · (MW 162.26) (2; R = Me)

[1445-45-0]  · C5H12O3  · Trimethyl Orthoacetate  · (MW 120.17)

(diethyl acetal of ethyl acetate; provides g,d-unsaturated ethyl esters from a,b-unsaturated alcohols through the Claisen rearrangement; converts diols to epoxides of the same relative stereochemistry; gives 2-methyl-1,3-heteroatom ring systems)

Physical Data: (1) bp 144-146 °C; d = 0.8847 g cm-3; (2) bp 107-109 °C; d = 0.9438 g cm-3.

Orthoester Exchange with Alcohols and Water.

Orthoesters (1,1,1-trialkoxyalkanes, ester acetals) are acid labile, base stable, masked forms of carboxylic acid esters. Mild acid-catalyzed hydrolysis of an orthoester produces an ester and an alcohol, in this instance, ethyl acetate and ethanol. Thus ethyl orthoacetate, and orthoesters in general, can serve to drive the equilibrium in Fischer esterifications of carboxylic acids with ethanol by forming low-boiling ethyl acetate and ethanol from the water generated during the esterification.

Higher molecular weight orthoacetates (orthoesters) of nonallylic alcohols are prepared by acid-catalyzed exchange, with removal of the lower boiling alcohol to shift the equilibrium. When this reaction is conducted with a 1,2-diol such as L(+)-diethyl tartrate in the presence of excess ethyl orthoacetate, two of the ethoxy groups are exchanged to form a 2-ethoxy-2-methyl-1,3-dioxolane (eq 1).

Interconversion of Orthoesters and Haloesters.

This exchange is an important element in a reaction sequence designed to convert a diol to the corresponding epoxide without loss of stereochemistry. Thus the dioxolane of D(-)-2,3-butanediol, which is formed from methyl orthoacetate, is cleaved with trityl chloride to produce the b-acetoxy chloride, which, upon treatment with KOH, affords D(+)-2,3-epoxybutane (eq 2). The cleavage procedure, which is also effective with 2-ethoxy-2-methyl-1,3-dioxanes (eq 3), occurs through an SN2 mechanism.2 Because the formation of methyl trityl ether can complicate isolation, Chlorotrimethylsilane, which gives volatile byproducts, is an effective replacement for trityl chloride in the cleavage of dioxolanes.3 Phosphorus(V) Chloride has been found to be effective in the cleavage of a dioxolane derived from ethyl orthoformate (eq 4).4 These reactions proceed through the formation of a cyclic dioxolenium (eqs 2 and 4) or dioxenium (eq 3) ion, an intermediate that can be accessed in the reverse direction to produce an orthoester. This procedure is typified by the transformation of the tetra-O-acetyl glucosyl bromide of eq 5.5 The remaining ethoxy group of the cyclic orthoester can be exchanged intramolecularly by removing ethanol from the equilibrium even if an unfavorable conformation is required (eq 6).6

Orthoester Claisen Rearrangement.

The principal use of triethyl and trimethyl orthoacetate and their more substituted analogs7 is in the orthoester Claisen rearrangement.1c The reagent, which is often used as a solvent, is heated in the presence of an allylic alcohol and a weak acid catalyst with removal of ethanol (or methanol) (eq 7).

The reaction was first applied in the synthesis of the triterpene squalene (1), using a symmetrical bis-allylic alcohol (eq 8).8 The trisubstituted (E)-alkene is formed in >98% purity in excellent yield. The ester group of the product is converted into a secondary isopropenyl carbinol and it is then subjected to a second orthoacetate rearrangement.

The (E)-alkene selectivity is typical of the rearrangement of secondary allylic carbinols. Enantiomerically pure allylic alcohols (2) and (3), both of which are accessible from a common source, undergo rearrangement to give the same enantiomerically pure ester (4) (eq 9).9 The results of eqs 8 and 9 demonstrate that propionic acid is capable of forming the dioxenium carbocation from the orthoacetate without isomerizing or racemizing the allylic alcohol and that the rearrangement is suprafacial.

The Propionic Acid catalyst is often consumed in the form of the propionate ester of the allylic alcohol, thereby stopping the rearrangement process (eq 10).

Esterification can occur in reactions that are slow because of constraints imposed by the transition state. The second step of eq 10 is repressed by using a hindered carboxylic acid, thereby making the rearrangement competitive with esterification. Thus Pivalic Acid (5 mol %) as a catalyst leads to a 74% yield of ester (6); propionic acid affords lower yields and appreciable quantities of the propionate ester of alcohol (5) (eq 11).10a Alternatively, 2,4-dinitrophenol can be employed as a catalyst (eq 12).10b Rearrangement of allylic alcohol (7) at 100 °C is slow because of the low boiling point of methyl orthoacetate (bp 107-9 °C). When propionic acid is employed as the catalyst, the methyl ester is obtained in 50% yield along with esterified allylic alcohol. On occasion, the intermediate ketene acetal can undergo elimination to produce dienes if the rate of rearrangement is slow (eq 13).11

Carbon-Carbon Bond Formation.

Orthoacetates undergo carbon-carbon bond formation with carbon nucleophiles in the presence of acid catalysts to provide acetals (eqs 14 and 15),12a,b enol ethers (eq 16),13 and azulenes (eq 17).14 The azulene formation is believed to be an [8 + 2] electrocyclic reaction wherein the ketene acetal from ethyl orthoacetate is functioning as the two-carbon component.

Exchange with Heteroatoms.

Alkenes are converted into epoxides by 90% Hydrogen Peroxide in the presence of ethyl orthoacetate. Trisubstituted and 1,2-disubstituted alkenes give yields in excess of 80%. The peroxide is thought to exchange with an ethoxy group to give the diethyl acetal of a peroxy acid as the reactive intermediate.15 Orthoacetates exchange with one equivalent of a primary amine to give an acetimidate. A second equivalent produces an acetamidine (eq 18).16

Formation of Heterocycles.

Intramolecular versions of eq 18 lead to heterocyclic systems through the intermediate acetimidate. By this method, imidazoles (eq 19),17 oxazoles,18 benzotriazepinones (eq 20),19 quinazolinones,20 dihydroimidazolium,21 and tetrahydropyrimidinium21 salts are prepared. In eq 19, the C-2 carbon and the C-2 methyl group of the product are derived from the acetic acid portion of methyl orthoacetate; the N-methyl group comes from the methoxy group of the orthoacetate by alkylation of the dioxenium ion. The oxazoline N-oxide (eq 21) is a reactive species that can participate in [3 + 2] cycloadditions.22

Reaction of Acetimidate Intermediates with Carbon Nucleophiles.

Compounds with active methylene groups react with acetimidate-like intermediates to form carbon-carbon bonds in addition to heterocyclic rings. The reaction can be conducted in both the inter-23 (eq 22) and intramolecular sense (eq 23).24

Related Reagents.

Diethyl Phenyl Orthoformate; N,N-Dimethylacetamide Dimethyl Acetal; N,N-Dimethylformamide Diethyl Acetal; Ethoxyacetylene; Ethyl Vinyl Ether; Ketene Bis(trimethylsilyl) Acetal; Ketene t-Butyldimethylsilyl Methyl Acetal; Methylketene Dimethyl Acetal; 1-Methoxy-1-(trimethylsilyloxy)propene; Triethyl Orthoformate.


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Frederick E. Ziegler, Makonen Belema, Patrick G. Harran, & Renata X. Kover

Yale University, New Haven, CT, USA



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