Approach to 3-Aminoindolin-2-ones via Oxime Ether Functionalized Carbamoylcyclohexadienes A. Franco Bella, Alexandra M. Z. Slawin, and John C. Walton* School of Chemistry, University of St. Andrews, St. Andrews, Fife UK KY16 9ST, Scotland jcw@st-andrews.ac.uk Received March 9, 2004 O-Benzyloxime ether substituted amidocyclohexadienes were prepared in three steps in good yields from 2-aminoacetophenone. EPR spectroscopic observations and product analyses showed that peroxide-induced decompositions of model compounds led to indolin-2-ones with benzyloxyaminyl substitution at their 3-positions. The cyclization steps were very rapid and took place regioselectively at the C-atoms of the CdN bonds, by 5-exo ring closures. An O-trityloxime ether analogue was also prepared. The cyclohexadienyl intermediate smoothly yielded an alkoxylaminyl radical again by rapid 5-exo-cyclization. However, ring closure was quickly followed by another -scission step that released the persistent trityl radical and a 3-nitrosoindolin-2-one derivative. EPR spectroscopic evidence showed that the nitroso compound trapped other transient intermediates to afford a series of nitroxides. GC-MS analyses of products formed in reactions including methyl thioglycolate indicated that 1-benzyl-3-methyl-1,3-dihydro-2H-indol-2-one was derived from the indolinone moiety. Introduction Organotin radical methodology, with its proven reli- ability and flexibility, is an invaluable preparative tool, but its usefulness is somewhat impaired by neurotoxicity problems. Despite determined efforts over the past few years, 1a-c the signs are that a single reagent, capable of comprehensively replacing toxic organotin hydrides in radical-mediated processes, is unlikely to be found. Instead, diverse suites of precursors encompassing metal- based, 2a-f all-organic 1,3a-e and polymer-bound types, 4a,b adapted to fulfill targeted chemical roles, are being developed. Functionalized cyclohexadienes combine within one compound the ability to release a desired radical and hydrogen donor capability. We have successfully used them in radical chain reactions, 5a-e and Studer et al. have introduced silylated 1,4-cyclohexadienes that efficiently release silyl radicals for use in conjunction with an organic halide precursor. 6a,b 1-Carbamoyl-2,5-cyclohexa- dienes release carbamoyl radicals (aminoacyl radicals), suitably unsaturated examples of which ring close to afford - or γ-lactams in moderate yields. 7a-c The oxime ether functional group can exhibit up to 3 orders of magnitude higher radical cyclization rates than analogous alkene acceptors. 8 Moreover, a useful func- tional group remains available for further synthetic elaboration. Other attractive features of oxime ethers are their stability to hydrolysis and the specificity of radical attack at the carbon of the CdN bond. This high regio- selectivity was incisively demonstrated by Warkentin’s competition studies between 5-exo and 6-endo alkyl radical ring closures. It was found that even the normally disfavored 6-endo attack was preferred at the carbon center over 5-exo cyclization at the nitrogen. 9 Currently, radical addition onto oxime ether derivatives is rapidly developing and is becoming a reliable synthetic strategy which can efficiently be applied in syntheses of complex natural products, 10a-c e.g., 1-deoxynorjirimycin, 11 (+)-7- deoxypancratistatin, 12 morphine alkaloids, 13 (-)-balanol fragments, 14 and pyrrolidine nucleoside analogues. 15 * To whom correspondence should be addressed. Phone: 44 (0)1334 463864. Fax: 44 (0)1334 463808. (1) (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072. (b) Sugi, M.; Togo, H. 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J.; Warkentin, J.; Werstiuk, N. H. Aust. J. Chem. 1995, 48, 291. 5926 J. Org. Chem. 2004, 69, 5926-5933 10.1021/jo049617f CCC: $27.50 © 2004 American Chemical Society Published on Web 08/05/2004