Issue in Honor of Prof. Eusebio Juaristi ARKIVOC 2005 (vi) 287-292
Scheme 1. Synthesis of tertiary amines 4a-e.
Based on these less than desirable results, a series of reaction conditions were attempted in order to facilitate the direct alkylation. A variety of bases were screened including potassium carbonate, sodium hydroxide, and potassium hydroxide. Different solvents were also evaluated including methylene chloride, acetonitrile, and biphasic systems that incorporated the use of tetrabutylammonium bromide as a phase transfer catalyst. Unfortunately, all of the reaction conditions examined led to the formation of various byproducts, including the unwanted quaternary ammonium salt, but very little of the desired tertiary amine product.
Eventually, after additional repeated attempts our persistence finally led to success. Unexpectedly we found that in the presence of 1.5 mol equivalents of N,N-diisopropylethylamine (Hunig’s base) the reaction proceeded cleanly to tertiary amine 4a in almost quantitative yield. Following these remarkable results this procedure was repeated using various secondary amines 3 and alkyl halides 1 containing benzophenone and/or highly C-H acidic acetophenone moieties. In all attempted cases the reactions were complete, according to TLC, in approximately 24 hours in acetonitrile at 60 – 70 oC using ratios of secondary amine, alkyl halide, and Hunig’s base at 1.0, 1.1, and 1.5, respectively. According to crude 1H NMR the yield of the desired tertiary amine products was more than 90%. Tertiary amines 4a-e were obtained in analytically pure form via column chromatography on silica gel.
As a result of these findings we also decided to explore the versatility and generality of this method for preparing a variety of unfunctionalized tertiary amines. Since alkyl halides 1 (Scheme 1) are highly complex polyfunctional alkyl halides we envisioned that this method would also be applicable to prepare less functionalized amines and would be superior and more convenient to use than existing literature procedures. For representative examples we chose direct benzylation of symmetrical acyclic (entry 1), cyclic (entry 2), heterocyclic (entry 3), and unsymmetrical substituted derivatives (entry 4) all of which were reacted using our standard conditions at room temperature to give the target tertiary amines in high chemical yields as
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