General Papers
ARKIVOC 2015 (vii) 101-112
Conclusions Amides and nitriles are very stable to basic hydrolysis in aqueous solutions and forcing reaction conditions are often needed. Primary amides are hydrolyzed more easily than secondary, tertiary amides are very difficult to be cleaved, while nitriles are hydrolyzed first to amides and further to carboxylates and amines with even more strong reaction conditions. With our methodology, in non aqueous conditions, the rank is reversed. As the lipophilicity of the amide increases, going from the primary to the tertiary amides, the rate of the alkaline hydrolysis increases, depending also on the acyl group and the amide leaving anion. This simple methodology offers an attractive alternative, available for the alkaline hydrolysis of sec- and tert-amides and for the selective hydrolysis of nitriles to primary amides. Furthermore, it may allow the protection of both, secondary amines and carboxylic acids, via their conversion to tert-amides.
Experimental Section General. 1H NMR spectra were recorded on a 250 MHz spectrometer (Bruker AMX 250) at ambient temperature using tetramethylsilane (TMS) as an internal standard. The high resolution ESI mass spectra were obtained using a Thermo Fischer Scientific Orbitrap XL spectrometer. Column chromatography was performed either on silica gel (230–400 mesh, Fluka). Melting points were measured on an Büchi 510 apparatus. IR spectra were obtained in KBr discs on a Shimadzu FTIR-84005 spectrophotometer. Elemental analyses were performed on a Heraeus CHN-Rapid Analyzer. All chemicals were used as purchased from commercial sources without further purification. Most of the hydrolysis products are known compounds and were identified by comparison with authentic samples, derived from the pure products suppliers. Amide synthesis. The amides 11-13 had been prepared by reaction of the sec-amine (2 mmol) in dry THF (10 mL) with the appropriate acid chloride, CH3COCl or PhCOCl, (1 mmol) in dry THF or dry CH2Cl2 at 0 °C under argon26. After addition was complete, the mixture was stirred for a further 1-2 h at room temperature, then refluxed for about 1 h until completion. At the end of the reaction, as inspected by TLC, the reaction mixture was cooled, evaporated to dryness and the residue was diluted with CH2Cl2 and extracted with H2O, 5% NaHCO3 and 5% solution of KHSO4. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel (CH2Cl2-MeOH, 9:1) to afford the desired products (overall yield 60-70%). Their identity was confirmed by NMR spectroscopy. Amide and nitrile hydrolysis. In a typical procedure, a solution of 4N NaOH in methanol (1 mL, 4 mmol) was mixed with a solution of the amide or the nitrile (1 mmol) in dioxane or dichloromethane (9 mL) and the mixture ([NaOH]= 0.4 N) was stirred at the indicated temperature. The course of the reaction was followed by TLC analysis (SiO2, EtOAc/hexane,
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