Orthoformic acid derivatives acetals

Acetalization with Trialkyl Orthoformates. In an acetal exchange reaction, trialkyl orthoformates will convert carbonyl groups to their corresponding acetal derivatives without concomitant formation of water. Weak acids such as NH4NO3 or amberlyst-15 (a sulfonic acid resin) catalyze the acetalization. ... 

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. 

Although esters of (oxomethyl)phosphonic acid have proved to be so elusive, derived acetals (495 R = H, X = O) have been prepared with relatively little difficulty from the acid-catalysed interaction of dialkyl hydrogenphosphonates and orthoformic esters ", and from mixtures of phosphorus(III) chlorides and orthoformic esters when heated in sealed tubes the reaction is included here since the ultimate stage is presumably of the Michaelis-Arbuzov type. The current view (Scheme 48) appears to be that the phos-phorus(III) chloride reacts with triethyl orthoformate in a stepwise fashion where appropriate, and with the formation, in the penultimate step, of a phosphorus(III) triester and ClCH(OEt)2. Such reactions were observed in a highly detailed study, by P NMR spectroscopy, of the very slow reaction, even at 150 °C, between triethyl orthoformate and the chloride 496, from which the phosphinic ester 497 was isolated the reaction between the chloride 498 and triethyl orthoformate was much faster, but even so, took place over an... 

The formamides 16 are intermediates. Formamide (Bredereck variant of the Traube synthesis [149]), formamidine, orthoformic ester, diethoxymethyl acetate, Vilsmeier reagent (fi om DMF and POCI3) and dithioformic acid are used as formic acid derivatives. 4,5-Diaminopyrimidines can be obtained from 4-aminopyrimidines 17 by nitrosation with HNO2 followed by reduction of the nitroso compounds 18 ... 

The formation of porphyrins from 1,19-dideoxybi)enes-/r can be achieved starting either from the 1-methyl derivatives or from l,19-dideoxybilene-Z>-l,19-dicarboxylic acid esters. In the first case the desired methine bridge of the porphyrin stems from the 1-methyl group whereas in the latter case orthoformates have to be added in the condensation step as a precursor for the methine unit. The 1-methyl- and also 1,19-dimethyl-l,19-dideoxybilene- > salts can be cy-clized to the corresponding porphyrins with copper(II) acetate in methanol.56 However, when the bilenes contain /i-acceptor substituents, the yields of porphyrins obtained by this method are very low.57... 

The hydrazine 70 reacts with triethyl orthoformate, sodium nitrite in acetic acid, or pyruvic acid, to yield l,2,4-triazolo[4,3-c]-, tetrazolo[l,5-c]- and l,2,4-triazino[5,6-c]pyrano [4 ,3 4,5]pyrrolo[3,2-e]pyrimidine derivatives 71(X= CH), 71(X= N) and 72 respectively <95KGS700 96CA(124)176023>. 

Alkyl and aryl thiohydrazide derivatives react with orthoesters and trihalomethyls to afford 1,3,4-thiadiazoles. The reactions proceed via a thiosemicarbazone intermediate which cyclizes to eliminate either alcohol or hydrogen chloride. Treatment of the iV-thiohydrazide pyrazole 143 with triethyl orthoformate in acetic acid at reflux gave the 5-acetamido-l,3,4-thiadiazol-2-ylpyrazole 144 (Equation 51), and in the absence of acetic acid the 5-amino-l,3,4-thiadiazol-2-ylpyrazole 145 in 76% yield <2000JCM544>. 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

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 pyrido[l,2-a]pyrimidine (63 R = H) gave the 3-anilinomethylene derivative of type 224299 with ethyl iV-phenylformimidate, and it gave the bis compound (225) with triethyl orthoformate in a dimethylformamide-acetic acid mixture.300 The exact structure of 225 has not been elucidated. 

Methoxythiocarbonylamino-4//-pyridopyrimidin-4-one 704 (R = H) was obtained in 23% yield when A-methoxythiocarbonylglycine and triethyl orthoformate were reacted in acetic acid. The reaction mixture was evaporated in vacuo to dryness, the residue was dissolved in ethanol, and triethylamine and 2-aminopyridine were added. Then the reaction mixture was left to stand at room temperature for l week (94JHC125). The treatment of 3-methoxythiocarbonyl-8-methyl-4//-pyrido[l, 2-a]pyrimidin-4-one 704 (R = Me) with methyl iodide in methanolic sodium methylate at ambient temperature for 3 hours afforded 3-(l-methylthio-l-methoxymeth-yleneamino) (705) and 3-dimethoxymethyleneamino derivatives (706) in 23% and 3% yields, respectively. 

Methyl-8-azapurin-6-one was finally obtained from 76a by a most unusual combination of reagents, namely, triethyl orthoformate and 10 N hydrochloric acid, with which it was refluxed for 1 h (yield, 86%) 76b similarly gave the 9-benzyl derivative (80% yield). The stability of the orthoester in 10 Wacid was attributed to formation of the diethoxycarbe-nium ion (78), which apparently synthesized the acetal 79 from 76a the desired product was formed from this by loss of two molecules of ethanol. 

Extension to aliphatic aldehydes leads to the 2,4,6-trialkyl-5-phenyl derivatives (342). When H3PO2 is refluxed in toluene with benzaldehyde or isobutyraldehyde the phosphinic acids (343 R = Ph, Pr ) are formed <68IZV397, 92EUP463994>. Di(hydroxymethyl)phosphines (344) react with aldehydes, ketones and acetals to form the 2-mono- or 2,2-disubstituted 1,3,5-dioxaphosphinanes (345) <86IZV2506,86ZOB2256>. With triethyl orthoformate the 2-ethoxy derivatives (346) are obtained (Scheme 70) <86IZV418, 86IZV640>. 

---