Ethyl orthoformate, hydrolysis

Compounds i, ii, and iii can be prepared by an acid-catalyzed reaction of a diol and the cycloalkanone in the presence of ethyl orthoformate and mesitylenesul-fonic acid. The relative ease of acid-catalyzed hydrolysis [0.53 M H2SO4, H2O, PrOH (65 35), 20°] for compounds i, iii, acetonide, and ii is C5 C7 > ace-... 

This approach has been extended by Tieckelmann, Mulvey, and Gottis to 2-amino-5-cyanonicotinamides (16 and 18), whiob were prepared directly by partial hydrolysis of the corresponding dir itriles. Diethyl carbonate, ethyl orthoacetate, and ethyl orthoformate all underwent reaction to yield the corresponding pyrido[2,3-( ]pyri-midines (17 and 19). 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

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. 

A small amount (5-10 ml.) of lower-boiling material usually comes over before the ethanol this is probably ethyl formate, produced by hydrolysis of the ethyl orthoformate. 

Ethyl orthoformate hydrolyzes easily in dilute acid to give formic acid and three equivalents of ethanol. Propose a mechanism for the hydrolysis of ethyl orthoformate. 

Ethyl orthoformate resembles an acetal with an extra alkoxy group, so this mechanism should resemble the hydrolysis of an acetal (Section 18-17). There are three equivalent basic sites the three oxygen atoms. Protonation of one of these sites allows ethanol to leave, giving a resonance-stabilized cation. Attack by water gives an intermediate that resembles a hemiacetal with an extra alkoxy group. 

The A2 mechanism can be excluded with certainty for the hydrolyses of all orthoesters discussed. This is done on the basis of the determined volume of activation, AF = +2.4 cm3 (Table 1) for ethyl orthoformate [32], on the basis of the strongly increased rate in comparison to orthoformate (no steric hindrance) for orthoacetate and orthopropionate, and on the basis of the results of experiments with added nucleophiles for orthobenzoate [183] and orthocarbonate [192]. The observed AS values (Table 12) are in agreement with these conclusions. Consequently, the mechanism of orthoester hydrolysis must be either A1 or A-SE2, or possibly a concerted process with proton transfer and carbonium ion formation in the same step. 

Example 4.18. Hydrolysis of ethyl orthoformate to ethyl formate. 

Thiophenealdehyde has been prepared by the decarboxylation of 2-thienylglyoxalic acid, by the action of 2-thienylmagne-sium iodide on ethyl orthoformate followed by hydrolysis of tbe acetal, in small yields by the Rosenmund reduction of 2-thio-phenecarboxylic acid chloride, in small yields by the action of hydrogen cyanide, hydrogen chloride, and aluminum chloride on thiophene using benzene as a solvent, by a series of reactions from l-chloro-2,3-diketocyclopentane, by the hydrolysis of 2-thienylmethylhexamethylenetetrammonium chloride in neutral solution, and by the action of N-mcthylformanilidc on thiophene in the presence of phosphorus oxychloride. ... 

Other ketals which are frequently used if a modified acid stability is wanted are the cyclopentylidene, the cyclohexylidene and the cycloheptylidene ketals. They are readily prepared by the reaction of a diol and the cycloalkanone in toe presence of ethyl orthoformate and mesitylenesulfonic acid. The relative rates of their acid-catalyzed hydrolysis are given in Scheme 50. 

Hydrolysis of pyranosides follows the trend observed for other compounds where the hydrolysis proceeds through an A-1 mechanism having positive AS values. Overend and coworkers calculated AS values at 60° for the hydrolysis of 24 pyranosides. All are positive, ranging from -f 4.1 to -1-23.0 cal. mole deg. all but two are greater than -f 10.0 cal. mole deg., and the mean is - - 13.7 cal. mole deg. h They compared their values with those reported for the acid-catalyzed hydrolysis at 25° of sucrose (- -7.9), ethyl orthoformate (-f5.8), and ethylal (diethoxy-methane) (-f-7.3), aU of which are known to proceed by the A-1 mechanism, and with the values calculated by Capon and Overend from the results of Heidt and Purves for the hydrolysis of methyl, benzyl, and phenyl a- and /3-n-glucopyranosides (mean, - -13.6). Many other values in the same range have been reported and are listed in Section VI (see pp. 91-100). 

Apart from the technical route described to p-apo-8 -carotenal, readily available vitamin A alcohol (Cjo) has served as an intermediate in the form of the phosphonium salt by reaction with the monodiethyl acetal of a Cio dial (ref. 54). The required Cjo monodiethylacetal was obtained (ref.5, p409) by the reaction of the mono aldehyde-protected derivative, the enol ether of methylmalonaldehyde, (C4) with the acetylenic Grignard reagent from trans 3-methyl-2-penten-4-yn-l-ol (C ) followed by acidic dehydration and partial reduction with Lindlar catalyst to give firstly 8-hydroxy-2,6-dimethylocta-2, 4,6-triene-l-al (Cio). Protection of the hydroxyl group by acetylation in pyridine solution with acetyl chloride and formation of the diethyl acetal with ethyl orthoformate followed by hydrolysis of the acetyl group and oxidation afforded the final CIO aldehyde component (D)shown in Scheme 15a. 

LXIVc) followed by condensation of the product with ethyl orthoformate furnished the orthoformate (LXIVd). Hydrolysis of (LXIVd) with sodium hydroxide and sulphuric acid gave adriamycin. 

Saloutin et al. reported [138] that the self-condensation of ethyl pentafluorobenzo-ylacetate (271) on refluxing without any catalyst leads to the formation of compound 272 in 37 % yield, acid hydrolysis of which gave 2-pentafluorobenzoyhnethyl-5,6,7,8-tetrafluorochromone (273). Other routes for preparing some new ring-fluorinated chromones have been performed from the 2-ethoxymethylene pentafluorobenzo-ylacetic ester (274) and also via intramolecular cyclization of ethyl pentafluoroben-zoylpyravate (275). The reaction of ester 271 with ethyl orthoformate results in the... 

---