SHORT COMMUNICATION DOI: 10.1002/ejoc.200600918 Formation of a Tetracyclic Isoquinoline Derivative by Rearrangement of a [(Bromophenyl)butyryl]oxazolidinone Mark D. Roydhouse [a] and John C. Walton* [a] Keywords: Rearrangement / Cyclisation / Heterocycles / Radical ions / EPR spectroscopy Treatment of 3-[4-(2-bromophenyl)-2-phenylbutyryl]-4,4-di- methyloxazolidin-2-one with LDA in THF launched a domino rearrangement sequence ending in the assembly of a tetra- cyclic cyclopentaoxazolo[3,2-b]isoquinolin-6-one derivative. Two mechanisms involving an S RN 1-type process were pro- Introduction Classic radical-mediated ring closures proceed by intra- molecular additions onto alkene acceptors and usually yield five-membered rings. [1] Recently, we have been studying a novel cyclisation strategy that involves fast intramolecular coupling of a radical and an anion (S RN 1 process). This strategy has previously been used by Wolfe and co-workers to prepare, for example, isoquinolines and oxindoles from haloaryl amides. [2] The process works for a different range of functionality and has potential for the formation of qua- ternary centres and larger ring sizes. [3] Rossi et al. have ably reviewed the limited number of such cyclo-couplings in the context of S RN 1 processes in general. [4] We previously re- ported that precursors containing bromoaryl groups at- tached to oxazolines by propyl and butyl linkers yielded indane and tetralin derivatives, respectively, when treated with LDA. [5] We decided to investigate analogous precur- sors containing oxazolidinones in the hope that more ef- ficient and selective methodology could be developed. Ac- cordingly, we carried out exploratory experiments with [(bromophenyl)butyryl]oxazolidinone derivatives 1, but found that, in practice, LDA-promoted reactions of 1 led to the assembly of a new fused tetracyclic cyclopentaoxazolo- isoquinoline system in a remarkable multistage rearrange- ment. Results and Discussion The precursor oxazolidinone was prepared by treatment of 2-(2-bromophenyl)ethyl iodide with the dianion derived from phenylacetic acid. The resulting acid was converted to [a] University of St. Andrews, School of Chemistry, EaStChem, St. Andrews, Fife, KY16 9ST, U.K. Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2007, 1059–1063 © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1059 posed. EPR spectroscopic and 13 C-labelling experiments sug- gested that both were operative. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) its acyl chloride and treated with 4,4-dimethyloxazolidin-2- one to afford [(bromophenyl)butyryl]oxazolidinone (1a). Good conditions for the promotion of ring closure via S RN 1 processes involve the use of 3equiv. of LDA in THF. [2d,5] When the oxazolidinone 1a was treated with LDA in this way at –78°C, and the solution was sub- sequently warmed to room temperature and stirred for 48 h, a waxy-white solid was isolated after column chromatog- raphy (75 %). It was deduced that the structure was cyclopenta-oxazolo-isoquinolin-6-one derivative 2a (Scheme1) from a careful study of the COSY, HSQC and HMBC spectra, and of model systems. [6] Two new ste- reocentres were created during the rearrangement so that four stereoisomers were possible. However, two of these with cis HO and Ph groups were shown by DFT computa- tions to be 46 kJ mol –1 higher in energy. Furthermore, their formation would be strongly sterically disfavoured during the ring-closure steps. Thus 2a was a 50:50 mixture of only Scheme 1.