Triethyl Orthoformate formylation

Triethyl orthoformate is often used in reactions with enolates and carbanions to form diethyl acetals that on treatment with dilute acid give the corresponding formyl derivatives. However, when indole is heated at 160 C with triethyl orthoformate the locus of reaction is at N-1 rather than at C-3, and 1-(diethoxymethyl)indole is formed (Scheme 7.6). The A -substituent is easily removed by acidic hydrolysis to reform indole. 

The additional carbon atom is believed to arise from dimethoxycarbonium perchlorate. Use of triethyl orthoformate results in a more complex structure. Another example of this formylation-cyclization is the conversion of 3 to 4. 

The isomeric 1-suhstituted imidazole-5-carboxylates are made by cyclization of 3-amino-2-alkylaminopropanoic acids with triethyl orthoformate followed by active manganese dioxide oxidation of the imidazoline product (see Section 3.1.1), or from IV-substituted glycine esters, which are formylated, converted into the enolates and then condensed with potassium thiocyanate... 

The first enantioselective total synthesis of the fungal metabolite (+)-pulvilloric acid was accomplished by H. Gerlach et al. At the final stages of the synthetic effort the carboxylic acid moiety was installed via the Kolbe-Schmitt reaction using CO2 at atmospheric pressure. The final formylation and ring-closure were achieved with triethyl orthoformate. 

Dihydroxycoumarin (55) underwent selective methylation (dimethyl sulfate) to the 7-methoxy derivative (56), which upon benzylation and oxidation (selenium dioxide), afforded the 4-formyl coumarin (74). Conversion to the acetal (75) occured upon treatment with triethyl orthoformate, and subsequent catalytic hydrogenation served the dual purpose of removal of the benzyl group and reduction of the coumarin double bond, to give (76). Hydride reduction of the derived acetate (77), followed by acidic workup, gave directly the furobenzofiiran (75) [presumably through the hydroxy aldehyde (75)]. Comparison of the spectra of racemic (75) with those of the naturally derived material showed the compounds to be identical. 

Triethyl orthoformate has been used for formylation of phenols in methylene chloride in the presence of aluminum chloride."... 

When at least 2 equivalents of an aryl cyanate 9 are treated with one equivalent of ammonia in anhydrous ethereal solution, iminobiscarboximidates 10 can be isolated361,362 (cf. Houben-Weyl, Vol. E4, p 1073). Compounds 10 can be converted to 1,3,5-triazines by reaction with either a further equivalent of aryl cyanate, or with formylating reagents such as triethyl orthoformate.362 A direct synthesis of 1,3,5-triazines 11 from aryl cyanates and ammonium carbonate in aqueous solution has also been described.363... 

Some sulfanyl-substituted derivatives of urea react in a similar manner.465 467 Thus, the synthesis of 4-amino-l,3,5-triazine-2(3i/)-thione (26) is achieved by formylation of thioureacarboximidamide (25) with triethyl orthoformate in refluxing dimethylformamide and subsequent cyclization.466,467... 

Formylation of ferrocene can be accomplished by reaction with triethyl orthoformate in bromobenzene at room temperature (92% yield). Somewhat lower yields are obtained in benzene or dichloromethane. 

B. Reactions with Formylating Reagents 1. With Triethyl Orthoformate... 

The hydrazone and iViV-dimethylformamide dimethyl acetal give the hetero-substituted azine (CFj)]C N N CH-NMe2. Treatment of the hydrazone with triethyl orthoformate-P3O3 followed by aqueous work-up causes hydrolysis of the initial product (CF C N N CH OEt to the formyl draivative (CP3)3C N NH CHO. 

The complete ethanolysis of K CN in the presence of dry HCI gas and cone. H2SO4 furnishes triethyl [ C]orthoformate °. In normal synthetic organic chemistry triethyl orthoformate is used for the conversion of aldehydes and ketones into acetals, enolethers and ketals, respectively, as well as for the formylation of C- and Af-nucleophiles. In carbon-14 labeling the most frequent use has been for the preparation of purines and related compounds labeled at a methine position, through reaction of triethyl [ " C]orthoformate with appropriate substituted pyrimidine such as 131 (Figure 7.32), which reacts with the labeled reagent (in 10-25% excess) in the presence of catalytic amounts of a strong acid (p-TosOH, MsOH) under strictly... 

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

Formylation of dimedone using ethyl orthoformate in the presence of acetic anhydride gave the 2-formyldimedone whose condensation with two moles of dimedone gave the xanthene 472 (57JCS4798), which can also be obtained directly from reaction of dimedone with triethyl... 

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