DOI: 10.1002/adsc.201000642 Multicomponent Cascade Reactions: A Novel and Expedient Approach to Functionalized Indoles by an Unprecedented Nucleophilic Addition-Heterocyclization-Oxidative Alkoxycarbonylation Sequence Bartolo Gabriele, a, * Lucia Veltri, b Giuseppe Salerno, b Raffaella Mancuso, b and Mirco Costa c a Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy Fax: (+ 39)-0984-492-044; phone: (+ 39)-0984-492813; e-mail: b.gabriele@unical.it b Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy c Dipartimento di Chimica Organica e Industriale, Università di Parma, 43100 Parma, Italy Received: August 16, 2010; Published online: December 8, 2010 Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/adsc.201000642. Abstract: A novel multicomponent cascade process is reported, based on the sequential combination be- tween an initial nucleophilic attack step to an imine moiety and a palladium-catalyzed oxidative hetero- cyclization-alkoxycarbonylation process. By this new process, five simple molecules [2-alkynylaniline imines, alcohol (ROH), carbon monoxide (CO), al- cohol (ROH), and oxygen (O 2 )] are sequentially acti- vated, selectively leading to high value-added func- tionalized indole derivatives in a single operation. Keywords: carbonylation; cascade reactions; cycliza- tion; indoles; palladium Introduction Cascade reactions have recently acquired an increas- ing importance in synthesis, owing to the possibility to obtain the target molecule through the concatenation of different steps, occurring in situ in ordered se- quence. [1] Of particular interest are multicomponent cascade reactions, in which the final product is ob- tained by the sequential assembly of several simple building blocks. This approach, in fact, permits one to construct multifunctionalized, high value-added com- pounds in a single operation through the concatena- tion of several steps, each one employing readily available starting materials, as shown in Scheme 1 in the case of 2 steps. In this work, we report a novel multicomponent cascade process, which allows a convenient direct syn- thesis of functionalized indoles through an unprece- dented sequence of steps, involving ROH addition to the imino group of 2-alkynylaniline imines to give [(alkoxymethyl)(2-alkynylaryl)]amines as intermedi- ates, followed by the PdI 2 -catalyzed reaction of the latter with CO, ROH, and O 2 to give the final prod- ucts [1-(alkoxyarylmethyl)indole-3-carboxylic esters, Scheme 2]. Thus, five simple molecules (2-alkynylani- line imines, ROH, CO, ROH, and O 2 ) are sequential- ly activated in a 2-step cascade process, selectively leading to highly substituted, functionalized indole de- rivatives in a single operation. Results and Discussion We began our investigations with benzylidene-(2-phe- nylethynyl)phenylamine 3aa (R 1 = R 4 = Ph, R 2 = R 3 = H), obtained from the reaction between 2-(phenyl- ACHTUNGTRENNUNGethynyl)aniline 1a with benzaldehyde 2a in the pres- ence of molecular sieves 4 . Owing to the sensitivity of the imino group to hydrolysis, 3aa was used the Scheme 1. A schematic representation of a 2-step multicom- ponent cascade reaction. A, B,…F are the reactants; I is the intermediate product ensuing from the first step; P is the final product. Adv. Synth. Catal. 2010, 352, 3355 – 3363  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3355 FULL PAPERS