N-Acyl-2-phenyliminooxazolidines as Chemoselective Monoacylating Agents

Abstract

The selective monoacylation of amino groups in the presence of other functional groups has great practical utility. N-Acylation is sometimes carried out using acyl transfer reagents developed by devising an appropriate leaving group. Several reagents have been developed for the above purpose, however, some of the reagents available are unsatisfactory in terms of their usefulnesses and selectivities. Thus, satisfactory alternatives are required. Recently we reported on the preparation of 2-phenylamino-2-oxazoline 2 based on the cyclization of N-(2hydroxyethyl)-N'-phenylthiourea. The 2-phenylamino-2oxazoline heterocyclic system is believed to be a good leaving group for a chemoselective acylating reagent of amines. Moreover, it is generally believed that reagents containing a bulky, electron accepting leaving group satisfy this requirement. Here we report that N-acyl-2-phenyliminooxazolidine 3 may be used as a neutral reagent for the chemoselective acylation of primary amine in the presence of secondary amine or alcohol, and for the acylation of the less sterically hindered amine rather than other hindered primary amines. 2-Phenylamino-2-oxazoline was readily synthesized by reacting 1,2-aminoalcohol with phenyl isothiocyanate to give the corresponding N-(2-hydroxyethyl)-N'-methylthiourea. This process was followed by the cyclo-desulfurization of the thiourea to 2-phenylamino-2-oxazoline in good yield using p-toluenesulfonyl chloride and NaOH in a onepot reaction, as described previously. Acylation of the 2phenylamino-2-oxazoline can conceivably proceed through an attack upon acyl halide either by the exo-nitrogen (to provide N-acylated-2-phenylamino-2-oxazolines) or by the endo-nitrogen (to give N-acylated 2-phenyliminooxazolidine). Acylation of 2-phenylamino-2-oxazolines 2 with acetic anhydride or benzoyl chloride in presence of tertBuOK provided the acylated endo-nitrogen product. Column chromatography yielded 3a and 3b in good yields (70% and 77%, respectively), which are stable in air and easily handled. We then evaluated the N-acyl transfer abilities of 3a-b. The acylations of several amines, i.e., benzylamine, αmethylbenzylamine, α,α-dimethylbenzylamine, and Nmethylbenzylamine were examined at room temperature in CCl4. Results were summarized in Table 1. Reaction times depended on amine bulkiness for 3a and 3b. The steric influences of substituents on the amino group were clearly demonstrated by reactions using various amines, in particular, primary amines were more reactive than secondary amines. These observed reactivity differences were attributed to differences in the steric demands of primary and secondary amines in accordance with aminolysis of esters. The hindered primary amine, α-methylbenzylamine required more time than the less hindered primary amine. Sterically hindered α,α-dimethylbenzylamine with 3a was not acylated at room temperature after 48 h (entry 4). Thus, reaction rates were greatly affected by steric bulkiness (in the environs) of the amine starting material and by that of the acylating reagent 3. The leaving group, 2-phenylamino-2oxazoline 2a-b was almost quantitatively recovered for recycling by extracting the organic layer with acidified aqueous solution. Concentration of the organic layer provided the amide product, which was then purified by column chromatography or recrystallization. The substantial observed difference between the reaction rates of hindered and less hindered amines encouraged us to examine the chemoselective acylation of amines. Thus the competitive acylations of mixtures (1 : 1 equiv) of benzylTable 1. N-Acylation of various amines using 3a-b