Xu, Z., Martinez-Ariza, G., Cappelli, A. P., Roberts, S. A., & Hulme, C. (2015). (Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction. The Journal of organic chemistry, 80(18), 9007-15.
Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.
Magnus, P., Hulme, C., & Weber, W. (1994). α-Azidonation of amides, carbamates, and ureas with the iodosylbenzene/trimethylsilyl azide reagent combination: N-acyliminium ion precursors. Journal of the American Chemical Society, 116(10), 4501-4502.
Hulme, C., Chappeta, S., Griffith, C., Lee, Y., & Dietrich, J. (2009). An efficient solution phase synthesis of triazadibenzoazulenones: 'designer isonitrile free' methodology enabled by microwaves. Tetrahedron Letters, 50(17), 1939-1942.
Abstract:
A novel two-step solution phase protocol for the synthesis of arrays of triazadibenzoazulenones is reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables two tandem ring closing transformations. The order of ring closure is shown to be key for optimal conversion to the desired tetra-cyclic product and initially proceeds through a benzimidazole intermediate, followed by second ring closure to give the desired fused benzodiazepine. The two-step protocol is further facilitated by microwave irradiation. Prudent selection of the isonitrile reagent enables the correct order of ring forming events. As such the methodology represents the first example of a post-condensation Ugi modification that employs two internal amino nucleophiles. © 2009 Elsevier Ltd. All rights reserved.
Nixey, T., Kelly, M., & Hulme, C. (2000). The one-pot solution phase preparation of fused tetrazole-ketopiperazines. Tetrahedron Letters, 41(45), 8729-8733.
Abstract:
A novel application of the TMSN3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused tetrazole-ketopiperazine libraries. The reaction of an aldehyde, primary amine, methyl isocyanoacetate and trimethylsilylazide in methanol at reflux affords bicyclic tetrazole-ketopiperazines in good yield. This efficient one step protocol, producing products with three potential diversity points, may be used to generate arrays of biologically relevant small molecules for general and targeted screening. (C) 2000 Elsevier Science Ltd.
Gunawan, S., Petit, J., & Hulme, C. (2012). Concise one-pot preparation of unique bis-pyrrolidinone tetrazoles. ACS Combinatorial Science, 14(3), 160-163.
PMID: 22330239;PMCID: PMC3299871;Abstract:
A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates. © 2012 American Chemical Society.
