Amines, solution-phase combinatorial

The earliest report of a solution-phase combinatorial library of small drug-like molecules was by Smith et al. [2], The reaction of 40 individual acid chlorides with an equimolar mixture of 40 nucleophiles (alcohols or amines) and of the individual nucleophiles with an equimolar mixture of the acid chlorides produced a library of 1600 amides and esters as pools of 40 compounds. The orthogonal design strategy determined that each possible product should appear in a unique pair of samples to allow the rapid identification of lead compounds after screening. 

An alternative synthetic approach to amine alkylation, reductive amination, has also been used in solution-phase combinatorial chemistry (Table 3.4). Parallel syntheses implying alkylation of amines via acylation and subsequent reduction with diborane has also been reported [29,86]. 

The piperazine-2-carboxylic acid scaffold 4 is well suited for a combinatorial approach as it is a small, constrained structure with three functional groups (one carboxylic acid and two amines) that may be conveniently substituted by solid-phase chemistry. Orthogonal protection of the two amino groups could easily be carried out on a large scale by solution-phase chemistry18 (Scheme 1). 

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

The reaction of an a-haloketone with thiourea gives rise to the 2-aminothiazole. This reaction has been used in a combinatorial approach for the synthesis of libraries of 2-aminothiazoles in excellent yields and purities first in the solution phase <1996BML1409> and then on a solid support using Rink amide MBHA, glycyl-Rink amide MBHA, and reductively aminated ArgoGel MB-CHO resins (Scheme 55) <1998JOG196>. 

The high level of diversity possible in each of the three conqmnents coiq>led with our desire to rapidly develop a structure activity relationship and identify potential field candidates led us to choose a positional scanning approach to nanow each reactant set We would fiien do combinatorial crosses of the best amines wifii the best carbonyl conqmnents with the best olefins to identify the optimally active analogs. The synthesis was carried out in parallel using solution phase liquid handling methods and filtration blocks to collect die precipitated products. 

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