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Tandem Sonogashira coupling/5-endo-dig cyclization reactions on 2,3-dihalophenols suppose a straightforward entry to 4-halobenzo[b]furans, which can be easily transformed into 4-functionalized benzo[b]furans, that are difficult to synthesize by other procedures. On the other hand, the starting 2,3-dihalophenols are efficiently prepared from commercially available 3-halophenols, via their N,N-diethyl carbamates by selective lithiation at the 2-positions by treatment with s-BuLi/TMEDA or LDA at low temperature and reaction with halogen electrophilic reagents.

Indoles and quinolines are ubiquitous structural motifs in many natural products and biologically active pharmaceuticals. The pursuit of synthetic efficiency has stimulated the design and development of new synthetic strategies to construct these heterocycles. One of the most effective ways of achieving efficiency is to implement reaction cascades, enabling multiple bond-forming and bond-cleaving events to occur in a single synthetic operation, thus circumventing the waste associated with traditional stepwise synthesis. In general, cascade reactions offer the opportunity to access highly functionalized final products from simple starting materials. For all these reasons, it is not a surprise that most of the recently reported methods for the synthesis of indoles and quinolines are based on the use of cascade reactions. In this Focus Review we discuss some of the most representative and interesting recent reports on the synthesis of indoles and quinolines through cascade reactions.

Dedicated to Professor Josep Font on the occasion of his 70th birthdayThe role played by organic chemistry in the pharmaceutical industry continues to be one of the main drives in the drug discovery process. More than ever, the industry demands from organic chemists the development of new strategies and technologies to obtain novel compounds in a fast, clean, and efficient way. Among these procedures are multicomponent reactions (MCRs) which offer the opportunity of building up complex molecules with exceptional synthetic efficiency, frequently with high stereoselectivity, from simple and easily available substrates.[1] Among MCRs, the Povarov reaction (the reaction of an aromatic imine and an activated olefin) provides a powerful method giving access to quinoline derivatives.[2] As a consequence of their relevant pharmacological profile, [3] the search for new methodologies to synthesize this kind of compounds is a research field of undoubted current attention.Following our interest in the development of new catalytic cascade reactions, [4] we considered the possibility of synthesizing functionalized quinolines in a single synthetic operation from alkynol, aldehyde, and aniline substrates (Scheme 1). Thus, we hypothesized that an intramolecular hydroalkoxylation reaction of alkynols 1, which is catalyzed by an appropriate metal complex, would provide exocyclic enol ethers 5. Subsequently, 5 and aromatic imines 6, which are formed in situ by condensation of aldehydes 2 and anilines 3, would react to form spirofuranquinoline derivatives 4 in a very simple way. Interestingly, this proposed reaction would circumvent one of the main limitations of the Povarov reaction-it is difficult to access functionalized starting enol ether reagents.[5] As far as we know, the Povarov reaction performed with exocyclic enol ethers has never been reported.Our initial efforts were directed at finding the appropriate catalyst and reaction conditions to perform the proposed sequence. Regarding the catalyst for the intramolecular hydroalkoxylation of alkynols 1, we considered platinum or gold complexes because of their ability to activate the alkyne functionality under mild conditions.[6] We also hypothesized that the required in situ formation of imines 6, from aldehydes 2 and amines 3, would be favored by the presence of a Brønsted acid. At the same time, this acid could also facilitate the addition of enol ether 5 to the imine 6 by coordination of the proton to the nitrogen atom of the imine. The cooperative action of both catalysts-the platinum complex and the Brønsted acid-in one pot would provide a new example of concurrent tandem catalysis. [7] Taking into consideration all the above-mentioned points we thought that the combination of [PtMe 2 (cod)] (cod = 1,5-cyclooctadiene) and HBF 4 would be ideal.[8] On the one hand, under the protic conditions the [PtMe 2 (cod)] complex would be transformed into a highly reactive cationic platinum complex. On the other hand, the presence of the Brønsted acid would favor the formation of the...