DOI: 10.1002/adsc.200600343 Lewis Acid-Catalyzed Sequential Transformations: Straightfor- ward Preparation of Functional Dihydropyridines Ramandeep Kaur Vohra, a Christian Bruneau, a and Jean-Luc Renaud a, * a SciencesChimiquesdeRennes,CatalyseetOrganomØtalliques,UMR6226,CNRS,UniversitØdeRennes1,Campusde Beaulieu,35042RennesCedex,France Fax:(+ 33)-2–2323–6939; e-mail: jean-luc.renaud@univ-rennes1.fr Received:July11,2006;Accepted:October18,2006 Abstract: Lewis acids catalyze the addition of b-en- aminoacrylates or b-enaminones to a,b-unsaturated aldehydes leading to substituted dihydropyridines inhighyieldsundermildreactionconditions. Keywords: domino reactions; homogeneous cataly- sis;iron;Lewisacids;nitrogenheterocycles;scandi- um 4-Substituted Hantzsch-type 1,4-dihydropyridines are analogues of NADH coenzymes and represent an im- portantclassofdrugs. [1] Current literature reveals that 1,4-dihydropyridines exhibit neuroprotectant and pla- teletanti-aggregratoryactivity,andshowefficientbio- logical properties as cerebral anti-ischemic agents in the treatment of Alzheimer)s disease and as chemo- sensitizers in tumour therapy. [2–5] Dihydropyridines are usually subsequently oxidized to pyridines. [6] Many classical methods for the synthesis of symmetri- cal 1,4-dihydropyridines have been reported [7–11] based onconventionalheatingofa b-ketoester,anammoni- um salt and an aldehyde in organic solvents, but most of these methods involve long reaction times, harsh reaction conditions and generally lead to low yields. Therefore, it is necessary to develop more efficient and versatile methods for the preparation of 1,4-dihy- dropyridines and the progress in this field has been recently achieved by the use of promoters such as mi- crowaves, [6b,12] TMSCl, [5] ionic liquids, [13,14] poly- mers [15,16] and YbACHTUNGTRENNUNG(OTf) 3 . [17] A synthesis of N-benzyl- 1,4-dihydropyridines was also disclosed from 1-aza- 1,3-butadiene via a Diels–Alder reaction. [18] However, to the best of our knowledge, few reports have been madesofaraboutanefficient,versatileandmildpro- cedure for the synthesis of unsymmetrical 1,4-dihy- dropyridines. b-Enamino ketones and esters are useful precursors in synthesis as they combine nucleo- philicity of the enamine [19,20] and electrophilicity [20] of the enone moieties. They are subsequently potential intermediates in a domino-cascade 1,4-Michael addi- tion/enamine formation to lead to substituted and non-symmetrical 1,4-dihydropyridines (Scheme1). [21] Wereporthereourpreliminaryresultsontheprep- aration of this type of compound by a cascade reac- tion involving b-enaminocarbonyl derivatives and conjugated enals in the presence of a catalytic amountofaLewisacidundermildconditions. In our continuing work on Lewis acid-catalyzed synthesisoffunctionalized b-enaminoestersand b-en- aminones, [22] we anticipated that a Lewis acid could activate the unsaturated aldehyde, then favour the conjugated addition and the final amine condensa- tion/isomerization(Scheme1). A blank reaction carried out at room temperature in dichloromethane overnight from ethyl N-benzyl- aminobut-2-enoate (2a) and 3-methylbut-2-enal (3a), withoutanyLewisacid,didnotleadtothedesireddi- hydropyridine and only the starting substrates were isolated. Zinc(II) acetate, which was shown to be active in the synthesis of compound 2a from ethyl 3- oxobutanoate and benzylamine, [22] was first tested as Lewis acid but no catalytic activity was found. By contrast, ceriumACHTUNGTRENNUNG(III) chloride promoted the formation of 1a at room temperature in a moderate 15% yield. The structure of 1a was assigned on the basis of 1 HNMR, 13 CNMR, and mass spectra. NMR analysis ( 1 H, 13 C, HMBC and HMQC) revealed that the prod- uct formed during this catalysis is the 4,4-dimethyldi- hydropyridine. By comparison with the thermal reac- tioninvolvingacyclicenaminoesterandan a,b-unsa- Scheme 1. Adv. Synth. Catal. 2006, 348,2571–2574 #2006Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim 2571 COMMUNICATIONS