General Papers
ARKIVOC 2015 (vii) 101-112
A mild alkaline hydrolysis of N- and N,N-substituted amides and nitriles Vassiliki Theodorou,*a Georgios Paraskevopoulos,b and Konstantinos Skobridis*a a
b
Department of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece Department of Inorganic and Organic Chemistry, Charles University, Prague, Hradec Králové 50005, Czech Republic E-mail:
[email protected]
DOI: http://dx.doi.org/10.3998/ark.5550190.p009.205 Abstract A mild protocol for the alkaline hydrolysis of secondary and tertiary amides in non-aqueous conditions, by the use of NaOH in methanol/dichloromethane or methanol/dioxane (1:9) at room temperature or under reflux, has been developed and a plausible reaction mechanism is discussed. Primary amides are hydrolyzed much slower than with the classical procedure, while nitriles are converted selectively to primary amides. Keywords: Alkaline hydrolysis, amides, N-substituted amides, nitriles, imidates, anhydrous conditions, protection
Introduction Amide derivatives constitute important moieties in many pharmaceutical and biologically active molecules. Hydrolysis of an amide, a nitrile or an ester functional group is a very common transformation in organic synthesis with many applications and a common way to prepare carboxylic acids. In general, nitriles and amides are exceptionally stable to acid and basic hydrolysis and classically they are hydrolyzed under vigorous reaction conditions and long reaction times1-3 by heating in the presence of mineral acids or concentrated solutions of alkali hydroxides (10-40%), which can sometimes cause undesirable side reactions and low yield. Tertiary amides are very difficult to be cleaved and in most cases stronger conditions are required than for primary and secondary amides. Nitriles are hydrolyzed first to amides and further to carboxylic acids and ammonia with even more strong reaction conditions. The hydrolysis of amides and nitriles is a well studied reaction and numerous methods have been developed.4-14 Among them, the use of sodium peroxide4 and of phthalic anhydride5 for the amide hydrolysis have been described, while nitriles can also be converted to amides by catalyzed hydration,6-9 enzymatically10 and on unactivated alumina.11 Ames and Islip in their
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