& Alkylation Enolizable Carbonyls and N,O-Acetals: A Rational Approach for Room-Temperature Lewis Superacid-Catalyzed Direct a-Amidoalkylation of Ketones and Aldehydes Bahria Touati, [a, c] Abderrahman El Bouakher, [a] Catherine Taillier, [a] Raja Ben Othman, [b] Malika Trabelsi-Ayadi, [c] Sylvain Antoniotti, [d] Elisabet DuÇach, [d] and Vincent Dalla* [a] Abstract: An efficient catalytic room-temperature direct a- amidoalkylation of carbonyl donors, that is, ketones and al- dehydes with unbiased N,O-acetals, is described. Sn(NTf 2 ) 4 is an optimal catalyst to promote this challenging transforma- tion at low loading and the reaction shows promising scope. A comprehensive and rational evaluation of this reaction has led to the establishment of an empirical scale of nucleophilic reactivity for a broad set of ketones that should be helpful in the synthetic design and development of carbonyl a-func- tionalization methods. Introduction The development of catalytic strategies for the direct a-alkyla- tion of unmodified donor carbonyl components, that is, ke- tones and aldehydes, is a current topic of great interest in or- ganic synthesis. [1–14] The field was pioneered by the develop- ment of purely organocatalytic methods, [2–6] but, despite the unquestionable breakthroughs achieved as a result of these studies, the available methods still suffer from unavoidable lim- itations, and, in most cases, are only suitable for some specific nucleophile/electrophile combinations. As far as S N 1-type alky- lations are concerned, only highly activated and therefore somewhat biased pro-electrophiles were compatible, as a result of the inherent weak acidity associated with the orga- nocatalytic modes of activation used in these strategies. [3–6] The same holds true with the photoredox approaches devel- oped by MacMillan, which are limited to the alkylation of capto-radicals that are generated in situ and that are stabilized by an electron-withdrawing group. [12b,c] The extension to more challenging pro-electrophiles such as the less reactive allylic and propargylic alcohols, that is, precursors of more electro- philic carbenium intermediates, [15] has been made possible only by means of more powerful second-generation strategies merging organocatalysis and metal catalysts. [7–9] Despite these considerable advancements, some limitations persist. By way of example, highly electrophilic carbenium ions, such as regu- lar (electronically unbiased) benzhydrylium and secondary ben- zylic cations generated in situ, have not yet succumbed to the stereoselective alkylation, and their coupling has so far been effected only under the influence of strong (achiral) Lewis acidic catalysts, [14a,b] transition-metal-based catalysts, [14d] or me- diators, [14c] sometimes under drastic conditions. [14b] As these latter contributions show, beside the asymmetric alkylation of well-stabilized carbenium ions, the evaluation of less-biased counterparts, for example, carbocation precursors, which are less prone to ionization [15] and/or which are likely to follow competing pathways such as b-elimination, although of funda- mental importance, is lacking. Heteroatom-stabilized carboca- tions, namely oxonium ions [7c] and N-acyliminium ions, [16] are synthetically very useful transient intermediates. Our interest in developing catalytic methods for their functionalization, [17] mo- tivated us to evaluate their potential as coupling partners for unmodified ketones and aldehydes (Scheme 1). [18] The electro- philicity parameters of N-acyliminium ions are not reported in Mayr’s electrophilicity scale, [15] but these ions are expected to stand as a whole in the top region of this scale, [19] thus sup- porting the view that they constitute stimulating targets in the catalytic alkylation with enolisable carbonyl nucleophiles. How- ever, their clear structural modularity is assumed to translate into variable electrophilicity inside this zone, which should result in subtle differences in their reactivity (strength of the acid catalyst to be used, catalyst loading, reaction kinetics). This predication is illustrated with the approximate empirical [a] B. Touati, Dr. A. El Bouakher, Dr. C. Taillier, Prof. Dr. V. Dalla Normandie Univ., UNIHAVRE, CNRS, URCOM 76600 Le Havre (France) Fax: (+ 33) 2-32-74-43-91 E-mail : vincent.dalla@univ-lehavre.fr [b] Dr. R. B. Othman Ecole supØrieure des sciences et de technologie de Hammam Sousse Rue Lamine Abassi 4011H Sousse (Tunisie) [c] B. Touati, Prof. Dr. M. Trabelsi-Ayadi Laboratoire d’Application de la Chimie aux Ressources et Substances Naturelles et à l’Environnement- LACReSNE-FacultØ des Sciences de Bizerte- 7021 Bizerte UniversitØ de Carthage (Tunisie) [d] Dr. S. Antoniotti, Dr. E. DuÇach Institut de Chimie de Nice, UMR 7272, UniversitØ de Nice Sophia Antipolis C.N.R.S., Parc Valrose, 06108 Nice cedex 2 (France) Supporting information for this article and ORCID for one of the authors are available on the WWW under http://dx.doi.org/10.1002/ chem.201504772. Chem. Eur. J. 2016, 22, 6012 – 6022 # 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 6012 Full Paper DOI: 10.1002/chem.201504772