Acid-Promoted Aza-Cyclization versus π-Cyclization of N-Acyliminium Species into Fused Pyrrolo[1,2-a]imidazolones and Pyrrolo[2,1-a]isoquinolinones

Abstract

A new approach for the synthesis of fused imidazolones and isoquinolinones is presented. The key step of this sequence was the interception of an N-acyliminium species with nitrogen or p-aromatic nucleophiles under kinetic vs. thermodynamic control. In addition, in the presence of two p-aromatic nucleophiles, only the six-membered ring closure into pyrroloisoquinolinones occurred.N-Acyliminium species are intermediates which are widely used in modern organic synthesis. Their importance is underlined by numerous reviews of their generation and use for the elaboration of natural and unnatural aza-heterocyclic systems with therapeutic interest. 1 If the formation of the C-C bonds by this protocol in inter-and intramolecular fashion is widely applied by the scientific community, the one which consists in the formation of the C-X linkage with X as a heteroatom (X = O, S, Se, and N) appears to be a new field of application of this chemistry. 2,3We have described earlier the potential for these species to intercept intramolecularly nitrogen nucleophiles in acidic media. 2 In particular, their presence with both carbon-and nitrogen-tethered nucleophiles showed the reaction operability under kinetic vs. thermodynamic control (Scheme 1). This resulted in the formation of C-N bond (1, reversible) or C-C bond (2, irreversible) depending on the reaction conditions. 3 Similar processes in oxygen series are relatively well documented to provide, in particular, asymmetric macrocyclic N,O-acetals 4 and alkaloids. 5In both cases, Brønsted and Lewis acids were used as promoters.Moreover, cationic cyclization using a nitrogen atom as internal nucleophile was first mentioned during the synthesis of 9a-phenyltetrahydroisoindolo[2,1-a]quinazoline-5,11-dione 6a and ten years later for the production of diethyl tetrahydrodioxolo[4,5-g]pyrrolo[2,1-b]quinazoline-8,8-dicarboxylate. 6b Its power was also illustrated in the total synthesis of (±)-and (-)-physostigmine, 7 (±)-glochidine, and (±)-glochidicine, 8 imidazoloindoline alkaloids, 9a oroidin-derived alkaloids, 9b and more recently, the bioactive enantiopure (-)-decarbamoyloxy-saxitoxin. 10 Reports on this process concern also its use to access aldose reductase inhibitors, 11 in parallel synthesis of Δ 2 -2-oxopiperazines, 12 in asymmetric synthesis of Reissert compounds, 13 in synthesis of lactam-based peptidomimetics, 14 and in sterically hindered N-substituted and fused g-lactams. 15To the best of our knowledge, the use of the present application in both intramolecular and diastereoselective Nacyliminium-mediated cyclization represents a novel illustration of this chemistry (Scheme 2). This can result in the formation of a central five-membered ring of N,N-acetal 3 by nitrogen atom attack of the cation II (path a). However, when the aromatic system at the nitrogen a-position of II is sufficiently activated, a six-membered ring of fused isoquinoline 4 (path b) can be obtained. The cores of these tricyclic systems ars often encountered in natural products and biologically active compo...