Hydrolysis orthoacetates

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). 

In equation 8.2-6a, the slope of -1 with respect to pH refers to specific hydrogen-ion catalysis (type B, below) and the slope of + 1 refers to specific hydroxyl-ion catalysis (Q if k0 predominates, the slope is 0 (A). Various possible cases are represented schematically in Figure 8.5 (after Wilkinson, 1980, p. 151). In case (a), all three types are evident B at low pH, A at intermediate pH, and C at high pH an example is the mutarotation of glucose. Cases (b), (c), and (d) have corresponding interpretations involving two types in each case examples are, respectively, the hydrolysis of ethyl orthoacetate, of P -lactones, and of y-lactones. Cases (e) and (f) involve only one type each examples are, respectively, the depolymerization of diacetone alcohol, and the inversion of various sugars. 

It seems much more likely that the transfer of the proton is actually involved in the rate-limiting step for the hydrolysis of carboxylic orthoesters. This is consistent with the observed catalytic constants. If Bunton and Dewolfe s estimate of Ka = 107 is accepted for the dissociation constant of the conjugate acid of an orthoester, and if the rate coefficient for the loss of the proton, k2, is of the order of 10" sec-1, then k, will be about 104 l mole-l sec-1, close to the value observed, for example, for the catalytic coefficient for the acid-catalyzed hydrolysis of ethyl orthoacetate at 20°C103. 

The hydrolysis of 4-alkoxybenzopyrylium salts leads to chromones in almost quantitative yields. The route is attractive because of the simple synthesis of the pyrylium salts (81CHE115). This method provides a reliable route to 3-substituted chromones, based on the reaction of 2-hydroxyphenacyl compounds with triethyl orthoformate. Furthermore, the use of triethyl orthoacetate enabled moderate yields of 2-methylchromones to be obtained <78JCR(M)0865). 

N-Bromosuccinimide (NBS) reacted with the free tertiary alcohol group of veracevine D-orthoacetate triacetate 34 to cause a (presumably) free radical insertion into ring F, giving the carbinolamine 35. Cevine D-orthoacetate triacetate similarly gave 36, which on alkaline hydrolysis gave 37 (see Table XVIII) (47,53). Treatment of triacetylcevine with NBS gave 38 (47). 

UV characteristics of the natural product, while further hydrolysis (under acid conditions) yielded asteroidic acid (190)—the chromophoric fragment—together with e-hydroxylysine (191) and acetic acid (97). For the synthesis of asteroidic acid (190), /V-salicyloylglycine (192) was condensed with triethyl orthoacetate to afford 2-(o-hydroxy)phenyl-4-(l -ethoxy)ethylidene-5-oxazolone (193). This product on treatment with base underwent Cornforth rearrangement,... 

The hydrolysis reactions of acetals, ketals, and orthoesters are catalyzed by acids but not by bases. It has been found that these three groups of substrates are hydrolyzed via a common general mechanism — involving similar types of intermediates — though the rate-determining step may vary from case to case. In the hydrolyses of ethyl orthoacetate, orthopropionate, and orthocarbonate, general acid catalysis was unambiguously established for the first time by Bronsted and Wynne-Jones [158]. 

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. 

In Problem 3.14.a, we saw that the reaction of an amine with a carbonyl compound in the presence of an acid catalyst can be driven toward the enamine product by removing water from the reaction mbcture as it is formed. The reverse of this reaction is an example of the acid hydrolysis of an enamine, a mechanism that is very similar to that of the orthoacetate hydrolysis shown in Example 4.18. 

Where the third term is negligible we have curve e, examples being the hydrolysis of orthoacetates and orthocarbonates (Skrabal and Baltadschiewa, 31). 

On removal of the six acetyl groups from hexaacetylturanose methyl 1,2-orthoacetate, either by alcoholic ammonia or by a trace of sodium methoxide according to the method of Zempl n and Pacsu, crystalline turanose methyl 1,2-orthoacetate (Vlllb) was obtained. It crystallized from ethanol in the form of tabular crystals with m. p. 137 and [o]d + 114.6 in aqueous solution. Hydrolysis with alkali did not eliminate the remaining acetyl group until the methyl glycosidic group with which it was linked in the orthoester formation had been removed. The instability of the turanose methyl 1,2-orthoacetate in aqueous solution was illustrated by a gradual decrease in rotation in water from [aln +113.3 to a constant value of [a]n +72.7 in sixty-four hours. 

Miss Frush and IsbelF applied the Konigs-Knorr reaction to their crystalline pentaacetyl-a-D-(a)-guloheptosyl bromide and succeeded in isolating the tetraacetyl-D-(a)-guloheptose methyl 1,2-orthoacetate (XIII) in nearly quantitative yield. The operation was carried out by shaking a mixture of powdered Drierite (anhydrous calcium sulfate), freshly prepared silver carbonate and the crystalline bromide in methanol at 0° for forty-four hours. The reaction was studied by analysis of the final solution. The difference between the results obtained by acid (0.1 N) and by alkaline (0.1 N) hydrolysis determined the amount of orthoacetate. Within experimental error the reaction product consisted exclusively of the orthoacetate. 

The acetylated neolactose methyl 1,2-orthoacetate was isolated in crystalline form when the original methanol solution was evaporated in air to a sirup and triturated with ethanol. After several recrystallizations the compound (XIV) had m. p. 121-122 and [a]n -t-25.3 . It showed the reactions and properties which characterize the sugar methyl orthoacetates, including stability of the orthoacetate group toward alkaline hydrolysis. When the new compound was treated with an anhydrous 0.1 V solution of hydrogen chloride in chloroform, it was converted into the crystalline heptaacetyl-a-neolactosyl chloride. Alkaline hydrolysis also indicated the presence of six acetyl groups, whereas dilute acid removed seven. 

Similar results were obtained with 3,4-dimethyl-L-rhamnose methyl 1,2-orthoacetate. Hydrolysis of the glycosidic group took place so quickly in acid solution that the first stage of the reaction could not be followed polarimetrically. The rotation of the substance in pure water, +36°, changed wuthin one minute after addition of the acid... 

Pacsu measured the rate of hydrolysis of the methyl glycosidic group of the hexaacetylturanose methyl 1,2-orthoacetate at 20 in a... 

The problem of the acid-catalyzed hydrolysis of the carbohydrate orthoesters was brought nearer to the final solution by Pacsu s experiments on the hydrolysis of maltose methyl 1,2-orthoacetate. Since two adjacent hydroxyl groups on the same side of the plane are necessary for the formation of orthoester derivatives, the maltose methyl orthoacetate must have an -configuration. Hydrolytic experiments with very dilute hydrochloric acid confirmed this. Two consecutive reactions took place at a pH of 4. In the first reaction, the original specific rotation, Co ]d - -103.7 in pure water, increased to -1-134.6° within two minutes. The latter figure corresponds to the specific rotation of a-maltose 2-acetate. The second reaction k = 0.0095) corresponded to the downward muta-rotation of a-maltose 2-acetate. When the hydrogen-ion concentration,... 

These conclusions do not comply with the explanation given by Haworth, Hirst and Samuels and by Pacsu for the reaction mechanism of the acid-catalyzed hydrolysis of the rhamnose and turanose orthoesters, respectively. It seems, however, that the experimental data of these authors can be re-interpreted without difficulty, to fit into the picture given for the reaction mechanism of the maltose orthoester. The first and very rapid reaction, which Haworth and coworkers associated with the removal of a methoxyl residue, would, as in the maltose orthoester, involve the rupture of the bond between the central carbon atom and that oxygen atom which is linked to carbon atom 1. This process liberates the 3-form of L-rhamnose substituted at position 2 by a methyl hydrogen orthoacetate residue. However, since this intermediate is... 

The first observation of the instability of carbohydrate orthoesters toward alkali came from Haworth, Hirst and Miller in connection with their experiments on the simultaneous deacetylation and methylation of L-rhamnose methyl 1,2-orthoacetate. These authors noticed that methylation by methyl iodide and silver oxide in the presence of solid sodium hydroxide resulted in the formation of crystalline methyl tri-methyl-/3-L-rhamnopyranoside. A similar result was obtained by Bott, Haworth and Hirst on the simultaneous deacetylation and methylation of triacetyl-D-mannose methyl 1,2-orthoacetate by the use of excessive quantities of dimethyl sulfate and alkali. The reaction produced a mixture of a. and /3 forms of methyl tetramethyl-D-mannopyranoside but the yield was only 40%. When the acetylated orthoester was submitted to methylation with silver oxide and methyl iodide in the presence of sodium hydroxide, the product was mainly trimethyl-rhamnose methyl 1,2-orthoacetate. This result indicates that for the alkaline hydrolysis of orthoesters, hydroxyl ions are necessary. Such ions are present in the dimethyl sulfate-alkali process, but are absent in the methyl iodide treatment except when the reaction mixture contains a little water either by accident or from the decomposition of the sugar molecule. Haworth, Hirst and Samuels examined the behavior of dimethyl-L-rhamnose methyl 1,2-orthoacetate in alkaline solution. When the substance was heated under various conditions with 0.1 A alkali at 70 there was no appreciable hydrolysis at the end of ninety minutes, whereas at 80 for... 

All of these experiments strongly indicate that the alkaline hydrolysis of the sugar orthoacetates is a nucleophilic displacement reaction. Any one of the three carbon atoms of the five-membered ring may be attacked. Since the hydroxyl ion must approach the tetrahedron of the attacked carbon atom in the direction of the center of the face opposite the vertex occupied by the group to be displaced, it is evident that the reaction must be accompanied by the inversion of configuration of the attacked carbon atom. It is quite certain that the attack does not take place on carbon atom 2, because in such a case the reaction product would be the epimeric sugar derivative. Therefore, either carbon atom 1 or the central carbon atom of the orthoester group is attacked. In the first case, the reaction is as follows. 

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