Synthesis of Spiroquinolines through a One‐Pot Multicatalytic and Multicomponent Cascade Reaction

Abstract

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...

Synthesis of Furoquinolines by a One‐Pot Multicomponent Cascade Reaction Catalyzed by Platinum Complexes

“…This reaction led to a 3:1 mixture of the spirofuranquinoline derivative 3 a and the furoA C H T U N G T R E N N U N G [3,2-c]quinoline 4 a ( Table 1, entry 1). Bearing in mind our previous results, [7] the formation of compound 3 a, as a mixture of two diastereoisomers, could be considered as expected. Much more surprising was the isolation of the styryl-substituted furoquinoline 4 a.…”

“…As previously reported, [7] cationic platinum complexes were appropriate catalysts for the in situ formation of enol ethers by intramolecular hydroalkoxylation reactions. In that work the cationic platinum catalyst was formed from [(cod)PtMe 2 ] (cod = 1,5-cyclooctadiene) by treatment with a protic acid.…”

“…[7] In a similar way, under neutral conditions, formation of the spirofuranquinoline 3 a could be explained by intramolecular nucleophilic addition of the aromatic ring to the oxonium ion in 9. When an excess of imine 2 is used, and in particular under the slow addition conditions previously described, the concentration of imine 2 in the reaction media is high and we suppose that the ligand-exchange reaction in 9 to form 8 and the product 10 is favored.…”

“…Thus, we have recently reported a new synthesis of spirofuranquinoline derivatives by reaction of in situ generated N-arylaldimines and exocyclic enol ethers in a process in which a platinum complex and a Brønsted acid are used as catalysts (Scheme 1). [7] Further studies in this field led us to discover an unprecedented platinum-catalyzed three-component coupling reaction that allows the easy and diastereoselective synthesis of functionalized furoquinoline derivatives (Scheme 1), [8] and details of this process are given herein.…”

Multicomponent and Multicatalytic Reactions – A Synthetic Strategy Inspired by Nature

“…[20] In this reaction, the platinum catalyst promotes the formation of an exocyclic enol ether as intermediate and the acid promotes two processes: the condensation of the aldehyde and the amine to form an imine and the subsequent reaction of this imine with the previously formed enol ether through a Povarov reaction.…”