TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 1947–1950 Pergamon MCC/S N Ar methodology. Part 2: Novel three-step solution phase access to libraries of benzodiazepines Paul Tempest, b Liping Pettus, a Vijay Gore a and Christopher Hulme a, * a Department of Small Molecule Drug Discovery, AMGEN, One AMGEN Center Drive, Thousand Oaks, CA 91320, USA b Department of Small Molecule Drug Discovery, AMGEN, Cambridge Research Center, Cambridge, MA, USA Received 9 December 2002; revised 23 December 2002; accepted 2 January 2003 Abstract—New developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as sources for new leads for drug discovery. To aid this search a plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. In fact, multi-step solid-phase syntheses of diverse libraries in excess of 10,000 products are now feasible via split and mix techniques. At the same time, a multitude of more efficient, diversity or target oriented solution phase chemical methodologies have appeared in the chemical literature, which have enabled the relatively facile construction of successful lead generation libraries with low FTE input and little capital expenditure. This communication reveals a further application of N-BOC--aminoaldehydes in the Ugi condensation reaction, followed by a secondary S N Ar cyclization, accessing arrays of biologically relevant benzodiazepines in good yield and overall purity. © 2003 Elsevier Science Ltd. All rights reserved. Multi-component reactions (MCR) are widely employed for the rapid assembly of arrays with high molecular diversity. 1 Coupled with a post-condensation modification, their utility is increased even further, giving rise to numerous complex, pharmacologically relevant templates. N -BOC--aminoaldehydes in partic- ular have proven to be valuable reagents for both the Ugi 2,3 and Passerini 4 condensations enabling secondary reactions to ultimately constrain or improve ‘drug-like- ness’ of the initial flexible peptide-like product. Syn- thetic applications include novel routes to norstatines, 5 imidazolines, 6 fused 7,5-azepine-tetrazoles 7 and cyclic ureas. 8 Similarly, S N Ar chemistry of polymer bound 4-fluoro-3-nitrobenzoic acid has seen a resurgence of interest and multiple applications in lead discovery circles have been reported, allowing for example the preparation of arrays of dihydroquinoxalinones, 9 benz- imidazoles, 10 indoles, 11 benzodiazepines, 12 benzo- thiazepines 13 and macrocycles, 14 respectively. Thus, it was envisioned that combining the Ugi condensation of N -BOC--aminoaldehydes with a post-condensation S N Ar cyclization, via use of an internal amino group, would facilitate access to benzodiazepine cores with generic structure 1, Scheme 1. Final target molecules contain three initial points of diversity with room for additional functionalization via modification of the nitro group. 2-Fluoro-5-nitrobenz- oic acid 2 was selected as the electrophilic component of this reaction and its compatibility with Ugi reaction conditions has been previously shown. 15 Simply mixing 2 with N -BOC--aminoaldehydes gives the desired con- densation product 4 in good yield. The use of aldehydes derived from alanine and phenylalanine are exemplified in this article. Purification is possible at this stage by the use of scavenging resins PS-TsNHNH 2 and PS- DIEA which remove excess aldehyde and any unre- acted acid. 16 TFA mediated BOC removal and treatment with the proton scavenger PS-morpholine enables cyclization to the benzodiazepine 1, Scheme 2. In fact, such a route represents a further example of UDC (Ugi/De-BOC/Cyclize) methodology. 17 Three examples of products isolated as diastereomers and associated yields are shown in Figure 1 and these correlate well with A% (Area%) purities. 18 Scheme 1. * Corresponding author. E-mail: chulme@amgen.com 0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0040-4039(03)00084-4