Efficient synthesis of tertiary amines from secondary amines Michio Kurosu, * Sevendu Sekhar Dey and Dean C. Crick Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1682 Campus Delivery Fort Collins, CO 80523-1682, USA Received 5 March 2006; accepted 8 May 2006 Available online 26 May 2006 Abstract—Reliable N-alkylations of secondary amines have been developed. By using DIAD and TPP (or PS-TPP) a variety of sec- ondary amines can be converted to the corresponding tertiary amines in good to excellent yields with diverse alkylhalides; no for- mation of quaternary amine salts are observed. These protocols are amenable to combinatorial chemistry libraries, and are also useful for the syntheses of secondary amines by an acid lysis of the cleavable tertiary amino resins. Ó 2006 Elsevier Ltd. All rights reserved. We recently validated that menaquinone A (MenA), 1 the sixth enzyme in menaquinone biosynthesis, is a novel tuberculosis (TB)-drug target. In the discovery of MenA inhibitors, we observed that a tertiary amine in the mole- cule is a critical functional group to exhibit high affinity against MenA enzyme. 2 Although X-ray crystal struc- ture of MenA has not been available, however, analysis of the amino acid sequence of MenA was revealed that MenA is likely to have five transmembrane segments and has highly conserved Asp (D) which would be located in the inner-plasma membrane as being pre- dicted by using a prediction program (Sosui). 3 There- fore, it was speculated that tertiary amine functional group in the inhibitor molecules would increase affinity by forming an ionic interaction with Asp residue(s) in the binding site. 4 In an attempt to deliver target-specific library for the development of MenA inhibitors, we recognized that no reliable method of the synthesis of tertiary amines that can diversify secondary amines both in solution and solid phase has been available in literatures. Espe- cially high-throughput synthesis on polymer-support requires complete conversions (near quantitative yields) with diverse structure of building blocks. Therefore, sec- ondary amines in combinatorial libraries have never been utilized in generating a library of tertiary amine containing small molecules (path a in Scheme 1). On the contrary, successful aminations of alkyl halides with secondary amine to form tertiary amines vary depending on the nucleophilicity of secondary amine and leaving aptitude of R–X (path b in Scheme 1). In addition, the generation of tertiary amine in path b requires diverse structures of low-molecular-weight secondary amine building blocks, which, however, has been limited by the lack of availability from commercial sources. None- theless, two pathways in Scheme 1 would serve as com- plementary manner to generate libraries of tertiary amine molecules. 5 We have encountered difficulty in using direct N-alkyl- ation methods published in literatures for the synthesis of tertiary amines on the polymer-support. An inherent problem of the synthesis of tertiary amine from second- ary amines is an incomplete reaction and/or the forma- tion of a quaternized amine as a by-product. Recently, several useful methods for the syntheses of secondary and tertiary amines from primary alcohols have been re- ported. 6 On the other hand, none of direct N-alkylation methods is sufficient due to the problems described above. 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.05.038 * Corresponding author. Tel.: +1 970 491 7628; fax: +1 970 491 1815; e-mail: michio.kurosu@colostate.edu template template X N R 1 H N-alkylations aminations with secondary-amines high quality tertiary-amine libraries X: leaving group linker or protecting groups in solution PG PG PG: path b path a Scheme 1. Synthesis of tertiary amine libraries in solution or solid phase. Tetrahedron Letters 47 (2006) 4871–4875