Nixey, T., Kelly, M., Semin, D., & Hulme, C. (2002). Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 43(20), 3681-3684.
Abstract:
A novel application of the TMSN3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused azepine-tetrazole libraries. The reaction of a N-Boc-α-amino aldehyde, secondary amine, methyl isocyanoacetate and trimethylsilylazide in methanol, followed by acid treatment, proton scavenging and reflux affords bicyclic azepine-tetrazoles. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for general and targeted screening. © 2002 Elsevier Science Ltd. All rights reserved.
Nichol, G. S., Gunawan, S., Dietrich, J., & Hulme, C. (2010). 2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1, 3(2H)-dione. Acta Crystallographica Section E: Structure Reports Online, 66(3), o625.
PMID: 21580382;PMCID: PMC2983587;Abstract:
The title compound, C21H21N3O2, was obtained following a five-step synthetic procedure yielding weakly diffracting rod and needle-shaped crystals which crystallized concomitantly. Structural analysis of a rod-shaped crystal showed that the central seven-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat, with the H-bearing (CH2 and NH) atoms lying well out of the least-squares mean plane fitted through the other five atoms in the ring (r.m.s. deviation 0.075 Å). In the crystal, the compound packs as a twisted chain, which propagates along the b axis by means of an R 12(6) motif formed by one of the carbonyl O atoms acting as a bifurcated acceptor in an N - H⋯O and C - H⋯O inter-action. No diffraction was observed from the needle-shaped crystals.
Nichol, G. S., Zhigang, X. u., Kaiser, C. E., & Hulme, C. (2011). 4-(piperidin-1-yl)-4H-benzo[b]tetrazolo-[1,5-d][1,4]diazepin-5(6H)-one. Acta Crystallographica Section E: Structure Reports Online, 67(1), o23-o24.
PMID: 21522729;PMCID: PMC3050344;Abstract:
There are two crystallographically unique molecules present in the asymmetric unit of the title compound, C14H16N 6O; in both molecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related n-h ⋯ o interactions and the second formed by c-h ⋯ o and c-h⋯n interactions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. hydrogen bonding between molecule B and symmetry equivalents forms one ring motif by inversion-related n-h ⋯ o interactions and a second ring motif by c-h ⋯ o interactions, which propagate as a single tape parallel with the c axis.
Hulme, C. (2005). Applications of Multicomponent Reactions in Drug Discovery - Lead Generation to Process Development. Multicomponent Reactions, 311-341.
Hulme, C., Gunawan, S., Ayaz, M., De Moliner, F., Frett, B., Kaiser, C., Patrick, N., Xu, Z., & Hulme, C. -. (2012). Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation. Tetrahedron, 68(27-28).
A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the 4-component Ugi-Azide reaction to afford MCR (Multi Component Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products.