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James M Bailey, Jackie S Scott,
Jonathan B Basilla,
Victoria J Bolton,
Izzy Boyfield,
David G Evans,
Etienne Fleury,
Tom D Heightman,
Emma M Jarvie,
Kirk Lawless, [......],
Hindy Mok,
Alison Muir,
Barry S Orlek,
Gareth J Sanger,
Geoffrey Stemp,
Alexander J Stevens,
Mervyn Thompson,
John Ward,
Kalindi Vaidya,
Susan M Westaway
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ABSTRACT: Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Bioorganic & medicinal chemistry letters 09/2009; 19(22):6452-8. · 2.65 Impact Factor
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ABSTRACT: A wide range of biologically active compounds contain the quinazoline ring system. A new free-radical-based method of making functionalized quinazolines is described, which relies on microwave-promoted reactions of O-phenyl oximes with aldehydes. A small set of 2-aminoaryl alkanone O-phenyl oximes was prepared and shown to produce dihydroquinazolines when mixed with an aldehyde in toluene and subjected to microwave heating. When ZnCl(2) was included in the reaction mixture, fully aromatic quinazolines were produced in high yields by a rapid and convenient process. The method worked well with alkyl, aryl, and heterocyclic aldehydes and for a variety of substituents in the benzenic part of the molecule. Similar reactions employing ketones instead of aldehydes were less efficient. Although some dihydroquinazolines did form, they were accompanied by several byproducts. Surprisingly, in each case, one of the byproducts was a quinoline derivative, and a plausible mechanism to account for this rearrangement is proposed.
The Journal of Organic Chemistry 06/2009; 74(14):4934-42. · 4.45 Impact Factor
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ABSTRACT: Dioxime oxalates are useful precursors for the clean generation of iminyl radicals by sensitised UV photolysis and can be adapted for serviceable preparations of 3,4-dihydro-2H-pyrroles and phenanthridines.
Chemical Communications 10/2008; · 6.17 Impact Factor
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ABSTRACT: Microwave irradiations of 2-(aminoaryl)alkanone O-phenyl oximes and carbonyl compounds generate iminyl radicals in company with imines; iminyl on imine ring closure yields dihydroquinazolines or quinazolines when ZnCl2 is included in the mixture.
Chemical Communications 08/2008; · 6.17 Impact Factor
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ABSTRACT: This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.
The Journal of Organic Chemistry 08/2008; 73(14):5558-65. · 4.45 Impact Factor
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Tom D Heightman, Jackie S Scott,
Mark Longley,
Vincent Bordas,
David K Dean,
Richard Elliott,
Gail Hutley,
Jason Witherington,
Lee Abberley,
Barry Passingham, [......],
Alan Wise,
Ben Powney,
Alison Muir,
Fiona McKay,
Sharon Butler,
Kim Winborn,
Christopher Gardner,
Jill Darton,
Colin Campbell,
Gareth Sanger
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ABSTRACT: High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
Bioorganic & medicinal chemistry letters 01/2008; 17(23):6584-7. · 2.65 Impact Factor
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ABSTRACT: Microwave irradiation of alkenone O-phenyl oximes produces iminyl radicals that ring close to yield dihydropyrrole derivatives; pyrroles and pyridines can be obtained from related precursors.
Chemical Communications 11/2007; · 6.17 Impact Factor
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ABSTRACT: Symmetrical and unsymmetrical dioxime oxalates were prepared by treatment of oximes with oxalyl chloride. UV photolysis of these precursors was found to be an atom-efficient way of generating iminyl radicals. The process was most efficient for dioxime oxalates having aryl substituents attached to their CN bonds. The method was useful for EPR spectroscopic study of iminyl and iminoxyl radicals. Photolyses in toluene solution, of dioxime oxalates containing alkenyl acceptor groups, yielded unsaturated iminyl radicals that ring closed to afford 3,4-dihydro-2H-pyrroles in good yields. Dioxime oxalates with biphenyl substituents also released iminyl radicals that ring closed onto the aromatic acceptor groups and, in acetonitrile solution, this approach provided a useful and atom-efficient method of making substituted phenanthridines.Graphical abstract
Tetrahedron. 64(52):11908-11916.
