Polar Effects in Free-Radical Reactions. A Novel Homolytic Acylation of Heteroaromatic Bases by Aerobic Oxidation of Aldehydes, Catalysed by N-Hydroxyphthalimide and Co Salts. Francesco Minisci*, Francesco Recupero, Andrea Cecchetto, Carlo Punta, Cristian Gambarotti Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano Mi, Italy; E-mail francesco.minisci@polimi.it Francesca Fontana Università di Bergamo, Dipartimento di Ingegneria, viale Marconi 5, 24044 Dalmine BG, Italy Gian Franco Pedulli Università di Bologna, Dipartimento di Chimica Organica “A.Mangini”, via S.Donato 15, I-40127 Bologna BO, Italy Received July 12, 2002 A new process for the homolytic acylation of protonated heteroaromatic bases is described; an N-oxyl radical (PINO) generated from N-hydroxyphthalimide by air oxygen and Co(II) abstracts a hydrogen atom from an aldehyde. The resulting nucleophilic acyl radical adds to a heteroaromatic base, which is then rearo- matised in a chain process. Quinazoline has an anomalous behaviour, giving 3H-quinazolin-4-one as the only reaction product. J. Heterocyclic Chem., 40, 325 (2003). The great synthetic interest of the substitution of proto- nated heteroaromatic bases by nucleophilic carbon-centred radicals results from the high regio- and chemoselectivity, due to polar effects, the large variety of inexpensive radical sources and the simple experimental conditions. The over- all polar effect in these reactions is the result of the polarity and the polarisability of both the radicals and the substrates. While carbon-centred radicals usually do not show an extremely marked nucleophilic character, the electrophilic polarity of heteroaromatic bases is greatly increased by pro- tonation. The strongly induced activation of heteroaromatic bases towards nucleophilic species, due to protonation, cannot be exploited with ionic nucleophiles, whose primary effect is deprotonation of the base. This problem is over- come by the use of free-radical nucleophiles, which react with protonated heteroaromatic bases in a large variety of substitutions characterised by high reactivity and selectiv- ity. These reproduce most of the features of the Friedel- Crafts aromatic substitutions, but with opposite reactivity and selectivity, so as to represent one of the main general reactions of this class of aromatic compounds [1]. Because of their high reactivity (absolute rate constants in the range of 10 5 -10 8 M -1 s -1 at r.t.) the most reactive bases are effective traps for revealing the presence of car- bon-centred radicals in a reaction medium. Basically any carbonyl (acyl, carbamoyl, alkoxycarbonyl) or alkyl radi- cal not bearing electron-withdrawing groups directly bonded to the radical centre can be successfully utilised to this purpose [1]. In previous works we have developed two general sources of acyl radicals, useful for the acylation of het- eroaromatic bases: 1. the t-BuOOH/Fe(III) redox system in the presence of aldehydes [2] (eqs. 1, 2) 2. the oxidative decarboxylation of α-ketoacids by the S 2 O 8 = Ag + redox system [3] (eqs.3, 4) In this Note we report a new homolytic acylation of het- eroaromatic bases by aerobic oxidation of aldehydes, catalysed by N-hydroxyphthalimide (NHPI) and Co salts. The overall stoichiometry is given by eq. 5, [HetH 2 ] + being the protonated base. The reaction is carried out by bubbling air in a CH 3 CN or PhCN solution of the heteroaromatic base protonated by CF 3 COOH, the aldehyde, NHPI and the Co(II) salt. In the absence of NHPI no reaction occurs under the same condi- tions. The reactivity of acyl radicals towards protonated heteroaromatic bases is so high that, even in the case of aldehydes R-CHO where R is a tertiary alkyl group, addi- tion of the acyl radical to the heterocyclic ring competes with decarbonylation (eq. 6), which is a fast process [4]. Mar-Apr 2003 325