Triethyl Orthoformate1

(1; R = Et)

[122-51-0]  · C7H16O3  · Triethyl Orthoformate  · (MW 148.23) (2; R = Me)

[149-73-5]  · C4H10O3  · Trimethyl Orthoformate  · (MW 106.14)

(precursor for higher analogs by reaction with alcohols,1c including cyclic orthoesters from polyols;2 for deoxygenation of 1,2-diols, affording alkenes;3 acetalization of carbonyl compounds;4 a dehydrating agent5 for enol ether formation;6 esterification of acids;7 formylation of active methylene compounds,8 heteroatom nucleophiles9 and organometallic reagents;10 formylation of electron-rich species; dialkoxycarbenium ion precursor;11 solvent for thallium trinitrate reactions12)

Alternate Name: triethoxymethane.

Physical Data: (1) bp 146 °C; d = 0.891 g cm-3; (2) bp 102 °C; d = 0.970 g cm-3.

Solubility: sol most organic solvents.

Form Supplied in: clear liquid; widely available.

Purification: distillation.

Handling, Storage, and Precautions: highly moisture sensitive; flammable; irritant with high volatility. Use in a fume hood.

Introduction.

The orthoformates are a remarkably useful group of reagents. They are shelf-stable, yet highly reactive. As alkylating agents, they readily transfer the associated alkyl group, a large variety of which are easily available. As formylation reagents, they are reactive under both acidic and basic conditions. The choice of ester is often arbitrary in this context.

Transesterification.

Higher Orthoformates.

While there are many ways to obtain esters of orthoformic acid,1c an easy method takes advantage of the rapid equilibrium among orthoesters (eq 1). By starting with the lowest analog, trimethyl orthoformate, essentially complete conversion to the higher esters is possible by carrying out the reaction at such a temperature as to distill away the evolving methanol. It is important that reactions be carried out under anhydrous conditions to avoid formation of the formate through hydrolysis.

Cyclic Orthoformates.2

When the above strategy is applied to polyols, cyclic orthoformates can be isolated. Most common are the cyclization of 1,3-diols (eq 2)2,13 and 1,2-diols,14 as well as the formation of caged structures from the use of polyols (eq 3).15,16

Those orthoformates obtained from 1,2-diols (eq 4)3 can undergo cycloelimination upon pyrolysis to afford alkenes in high yield.17 There are a variety of methods for carrying out this overall process,18 but the orthoester route is competitive if the alkene is thermally stable.

Acetals and Enol Ethers.

The conversion of the orthoformate to formate is energetically favored. As a result, the acetalization of ketones by orthoformate is a highly favored process and allows the formation of acetals under exceedingly mild conditions. A wide variety of ketones can be converted into dimethyl acetals by the action of trimethyl orthoformate and p-Toluenesulfonic Acid. The methyl formate thus evolved is distilled away.4

The process is general and allows isolation of quite sensitive acetals (eq 5).19 The technique accommodates protection of a,b-unsaturated carbonyl compounds.20,21,22 While some form of acid catalysis is usually needed, there is great flexibility in the choice of acid, including Amberlyst 1523 and, in particular, Montmorillonite K10.24 Cyclic acetals are also accessible (eq 6).25

Upon distillation of some acetals,26 or upon attempted acetalization of highly conjugated species,26,27 the enol ether can also be observed. The choice of acid often determines whether the acetal or the enol ether is isolated.

Orthoformates are also useful in promoting the formation of other acetals5 by functioning as dehydrating agents. This function is useful for b-lactone formation as well (eq 7).28,29

Esterification.

In a related process, orthoformates are good esterification agents; they operate on carboxylic acids (eq 8),7 sulfonic acids,30 and carboxyboranes,31 often without the need for acid catalysis.

Formylation.

The orthoformate carbon is highly reactive in a number of bond-forming reactions. It is capable of reaction under both electrophilic and nucleophilic conditions and serves as a formylation reagent.

Active Methylene Compounds.

Triethyl orthoformate can formylate diethyl malonate under slightly acidic conditions.8 With less activated compounds it can be induced to undergo a Mannich reaction,32 and can also formylate a cyclohexanone enolate anion (eq 9).33

This reaction is noteworthy in its propensity for C-alkylation and the fact that the protected acetal raises the pKa of the product relative to the unprotected b-dicarbonyl compound.

Heteroatom Nucleophiles.

The formylation of anilines is well known34 and provides entry to a large array of functional groups.35 Of greater interest is the ability of the product to be trapped in a subsequent reaction to afford heterocycles (eq 10).9,36-38 Orthoformates also react readily with phosphorus nucleophiles.39

Organometallic Reactions.

In addition to the enolate reactions described above, orthoformates can also carry out the formal formylation of Grignard reagents.10

Electrophilic Formylation.

It has been shown that the dialkoxycarbenium ion can be readily formed by acid treatment of orthoformates. While the reactive ion can be isolated and used directly,11 the typical practice is to generate it in situ.

While not as universal as the Gatterman-Koch reaction, the cation works well for the formylation of activated aromatic compounds (eq 11).40,41 Of greater synthetic utility is the effective formylation of alkynes (eq 12)42 and alkenes (see below).

Reactions of silyl enol ethers with dialkoxycarbenium ions result in a-formyl ketones (eq 13),43 much like those achieved above through the use of enolate anions. With a dienol silane (eq 14), regioselective g-formylation is achieved.44 In extended alkenic systems, cationic cyclization (eq 15) can be realized.45

Solvent for Thallium Trinitrate Oxidations.

While Thallium(III) Nitrate oxidations of aromatic ketones and chalcones often gives rise to mixtures of products, the use of trimethyl orthoformate as solvent gives substantially cleaner reactions and higher yields (eq 16).12

Related Reagents.

Diethyl Phenyl Orthoformate; Dimethoxycarbenium Tetrafluoroborate; Dimethylchloromethyleneammonium Chloride; N,N-Dimethylformamide; N,N-Dimethylformamide Diethyl Acetal; Methyl Formate.


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Richard T. Taylor

Miami University, Oxford, OH, USA



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