Sequential intermolecular Diels-Alder/intermolecular ene reactions of electron-rich vinyl-heteroaromatics have been investigated, as the basis for a new class of three component coupling reactions. This relatively unexplored reaction sequence provides access to the biologically important scaffolds 4,5,6,7-tetrahydro-1H-benzo[d]imidazole and 2,3,4,9-tetrahydro-1H-carbazole, with high atom economy and diastereocontrol of up to 5 new stereocentres, following a two-step reaction process involving three simple molecules (a diene, a dienophile and an enophile). 2-Vinylfuran (1), 2-vinylthiophene (2), N-protected-3-vinylindole (3) and N-protected-4-vinyl-1H-imidazoles (4 and 5) were found to react as dienes in Diels-Alder reactions under thermal conditions, without the need for Lewis acid catalysis. 4 and 5 were then subjected to a program of N-protecting group and dienophile optimisation, and the resulting Diels-Alder adducts were isolated in moderate to high yields (31-79 %) as single diastereoisomers, arising from exclusively endo-cycloaddition (Scheme 1). Scheme 1. Sequential Diels-Alder/Ene reactions. The cycloadducts arising from the Diels-Alder reaction of N-trityl-4-vinylimidazole and N-phenylmaleimide (NPM) were shown to undergo hitherto unreported, facile, sterically driven N→N trityl migrations. These migrations were a key step in several novel, highly diastereoselective domino reaction sequences (Diels−Alder, [1,3]-H shift, [1,3]-trityl migration and Diels−Alder, [1,3]-H shift, [1,3]-trityl migration, Michael reaction), leading to architecturally complex molecules. Heterocycle R 1 Furan CH2OTBS 2 Thiophene CH2OTBS 3 Indole H 4 Imidazole CH2OTBS 5 Imidazole H X: O, NPh Y: CH, N R1: Trt, DMTr, Bn, BnOMe, Ts, Ns, DMAS X1=Y1: C=C, C=O, C=N, N=N, N=O, O=O | Abstract Page | iii The cycloadducts arising from the Diels-Alder reaction of 1-benzyl-4-vinyl-1H-imidazole, (E)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1H-imidazole and N,N-dimethyl-3-vinyl-1H-indole-1-sulfonamide were obtained in high yields, and were then tested in ene reactions with a range of reactive enophiles (Scheme 1). The resulting ene adducts were successfully isolated in moderate to excellent yields (53-95%).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588249 |
| Date | January 2013 |
| Creators | Watson, Lynsey Jayne |
| Publisher | University of Newcastle upon Tyne |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10443/1922 |
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