General Papers
ARKIVOC 2015 (vii) 101-112
work,12 described the use of N,N-dimethylamide as a protecting group for long-chain ωacetylenic acids. The amide achieved by the reaction of the appropriate acid chloride and dimethylamine, was hydrolyzed under vigorous alkaline conditions, with KOH/H2O in refluxing 2-methoxyethanol. Confalone et al., during the total synthesis of biotin13 in the presence of more active sites, protected the carboxylic group as its piperidide, for the removal of which vigorous hydrolysis conditions were required. Gassman et al. succeeded to hydrolyze tertiary amides using two equivalents of the strong base t-BuOK14 in diethyl ether and one equivalent of water at room temperature, while primary and secondary amides were extremely resistant under the same conditions. The mechanism of the alkaline amide hydrolysis has been intensively investigated.14-21 It is similar to that of the esters, with the exception that the tetrahedral intermediate, formed after the addition of the hydroxide, could regenerate the amide than give the hydrolysis products. The loss of the hydroxide anion is the thermodynamically preferred route and the accompanying oxygen exchange is generally faster than hydrolysis (Scheme 1).15-19
HN'2R + OOCR '2RN R C + OH + O2H O
N'2R+ HOOCR 2'RN R C O-H HO
OH
2'RN R C OH O H O H 2'RN R C OH O
'2RN R C
O
OH
'2RN R C OH H O O H
Scheme 1. Alkaline hydrolysis reaction and oxygen exchange (where R' = H, alkyl, aryl). We previously developed a very mild and rapid procedure for an efficient alkaline hydrolysis of esters in non aqueous conditions22 by the use of NaOH in dichloromethane /methanol (9:1) as the solvent. That “anhydrous” hydroxide in aprotic solvent proved to be an excellent reagent for ester hydrolysis. The facility of this process suggested to us that similar reaction conditions might operate also for the basic hydrolysis of similar substrates. Changing the traditional protic solvents, used in hydrolysis reactions, to less polar aprotic solvents, that do not stabilize the reactants, seemed to be a good modification, since the relatively unsolvated hydroxide acts as a stronger nucleophile. Procedures allowing simple and mild reactions, without large excess or high concentrations of the reagents, avoiding undesirable side reactions, are very helpful in organic synthesis. On the basis of these data, we considered to use the same protocol as an efficient and mild hydrolysis process of amides and nitriles in non aqueous conditions.
Results and Discussion In order to establish our methodology, we performed the alkaline hydrolysis of a range of amides
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