Francisco J. Fañanás

Recent Advances in the Synthesis of Indole and Quinoline Derivatives through Cascade Reactions

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.

A Palladium(II)-Catalyzed Synthesis of Spiroacetals through a One-Pot Multicomponent Cascade Reaction

Functionalized spiroacetals have been easily prepared in a one-pot three-component coupling process that involves the reaction of pentynol derivatives, salicylaldehydes, and amines in the presence of catalytic amounts of a palladium(II) complex (see scheme). Alternatively, oxygen-substituted spiroacetals can be obtained by using orthoesters as the third component.

Gold- or Platinum-Catalyzed Cascade Processes of Alkynol Derivatives Involving Hydroalkoxylation Reactions Followed by Prins-Type Cyclizations

An efficient method for the synthesis of [3.3.1]bicyclic compounds from easily available alkynol derivatives has been developed. The reaction is based on a gold- or platinum-catalyzed tandem process that involves an intramolecular hydroalkoxylation of a triple bond followed by a Prins-type cyclization. The reaction has been carried out with differently substituted alkynol derivatives and oxygen-, nitrogen-, and carbon-centered nucleophiles. The incorporation of halogen atoms as nucleophiles and elimination reactions has also been studied. Enantiomerically pure [3.3.1]bicyclic systems were easily synthesized from the chiral pool.

Synthesis of functionalized indole- and benzo-fused heterocyclic derivatives through anionic benzyne cyclization

The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.

Carbon nucleophile addition to sp2-unsaturated Fischer carbene complexes

Abstract The reactions of group 6 (alkoxy)(aryl)- and (alkoxy)(alkenyl)carbene complexes with organolithium compounds, metal enolates, and enamines are summarized. (Alkoxy)(aryl)carbene complexes underwent mainly nucleophilic addition to the carbene carbon atom, but either 1,4- or 1,6-addition products have been observed with derivatives bearing a bulky alkoxy group and phenyl- or alkyllithiums. The more widely studied (alkoxy)(alkenyl)carbene complexes react with carbon nucleophiles to give 1,2- or 1,4-addition products depending on the steric surroundings of both the metal carbene complex and the nucleophile as well as the nature of the latter. These reactions have been employed for several useful carbon-carbon bond-forming processes taking place with high diastereoselectivity.

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

Tetrahydroquinolines have been found as a key structural unit in many bioactive natural products and pharmaceuticals. In particular, furoquinoline derivatives are alkaloids mainly isolated from Rutaceae and Solanaceae plant species. Owing to the relevant biological properties of both natural and synthetic analogues of these molecules, which include antitumoral, antimicrobial, antibacterial, insecticide, analgesic, antipyretic, antiplatelet, and cytotoxic activities, the isolation and synthesis of new furoquinoline derivatives is an active and rewarding research area. In this connection, the Povarov reaction is a powerful transformation that offers an easy entry to the furoACHTUNGTRENNUNG[3,2-c]quinoline skeleton through a formal [4+ 2] cycloaddition between N-arylaldimines (as diene) and 2,3-dihydrofuran (as dienophile). One of the main limitations of this reaction stems from the enol ether counterpart, since very few functionalized 2,3-dihydrofuran derivatives are available. In fact, the great majority of the furo ACHTUNGTRENNUNG[3,2-c]quinoline derivatives synthesized by this strategy are derived from the commercially available 2,3-dihydrofuran and basically no effort has been directed to the synthesis and study of the biological activity of furo ACHTUNGTRENNUNG[3,2c]quinoline derivatives substituted at the furan ring. In this context, we thought that an easy entry to this kind of compounds could be a Povarov reaction in which a functionalized furan was generated in situ from an alkynol derivative by a cycloisomerization reaction. 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). 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), and details of this process are given herein. As previously reported, 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)PtMe2] (cod= 1,5-cyclooctadiene) by treatment with a protic acid. Another possibility for the in situ generation of the cationic platinum complex is the treatment of [(cod)PtCl2] with a silver salt under nonacidic conditions. Accordingly, in an initial experiment we treated pentynol derivative 1 a with two equivalents of the imine 2 a in the presence of a cationic platinum complex generated in situ by mixing 5 mol % of [(cod)PtCl2] and 10 mol % of AgSbF6. This reaction led to a 3:1 mixture of the spirofuranquinoline derivative 3 a and the furo ACHTUNGTRENNUNG[3,2-c]quinoline 4 a (Table 1, entry 1). Bearing in mind our previous results, 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. The formation of this compound supposes the coupling of three components, a unit of the alkynol 1 a and two units of the imine 2 a, in a process in which a molecule of 4-methoxyaniline is delivered. Moreover, furoquinoline 4 a was formed as [a] Prof. Dr. J. Barluenga, A. Mendoza, Dr. F. Rodr guez, Dr. F. J. FaÇan s Instituto Universitario de Qu mica Organomet lica “Enrique Moles” Unidad Asociada al CSIC, Universidad de Oviedo Juli n Claver a 8, 33006 Oviedo (Spain) Fax: (+34) 985103450 E-mail : barluenga@uniovi.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200802146. Scheme 1. Two different quinoline derivatives obtained from alkynols and N-arylaldimines.

Enantioselective synthesis of hexahydrofuro[3,2-c] quinolines through a multicatalytic and multicomponent process. A new “aromatic sandwich” model for BINOL-phosphoric acid catalyzed reactions

A new and straightforward metal–organo orthogonal-relay catalytic asymmetric reaction for the enantioselective synthesis of hexahydrofuro[3,2-c]quinolines is reported. The process involves a three-component coupling reaction between an alkynol, an aldehyde and an arylamine catalyzed by a gold complex and a chiral BINOL-derived phosphoric acid. Quantum chemical calculations of the reaction mechanism suggest that the involved acid-catalyzed Povarov reaction is better described as a sequential Mannich/intramolecular Friedel–Crafts process between the 5-phenyl-2,3-dihydrofuran and protonated N-phenylaldimine reactants generated in situ. Moreover, computations of the reaction mechanisms for the formation of the four stereoisomers of the hexahydrofuro[3,2-c]quinoline adduct using (R)-TRIP-suggested a rationale for the face selectivity of the asymmetric Povarov cycloaddition. With a single coordination mode by ion pairing of the chiral phosphoric acid and the imine, the preferred approach of 5-phenyl-2,3-dihydrofuran to the iminium ion results from a combination of more favourable π-stacking and reduced steric interactions in the Re-exo transition state relative to the alternative diastereoisomeric orientations.

Scalable Total Synthesis of (−)-Berkelic Acid by Using a Protecting-Group-Free Strategy†

Supply chain: the polycyclic core of (-)-berkelic acid (1) was constructed in just one step from very simple starting materials. The total synthesis of 1 involves a seven-step linear sequence. Protection/deprotection steps were avoided and all but the last step were performed on a gram scale. This synthesis could solve the supply problem associated with the exhaustion of the natural source.

Synthesis of Polycyclic Compounds by a Cascade Cycloisomerisation/Diels–Alder Reaction

Cascade (domino) reactions provide an efficient way to construct complex molecular structures from readily available organic compounds. Particularly interesting is the synthesis of heterocycles through cascade reactions, involving the intramolecular addition of a heteroatomic nucleophile to an alkyne that is activated by a p-acid (as defined by F rstner and Davies). The increasing interest in this field of research is probably due to the ability of gold complexes to promote unusual processes. For example, some elegant new gold-catalysed reactions involving atypical intramolecular redox processes have recently been published. In this context, we have developed several transition-metal-catalysed reactions of w-alkynols based on the initial formation of enol ethers, through an intramolecular hydroalkoxylation process, which react in situ with nucleophiles and/or electrophiles. Following on with our interest in this field, we thought that the cycloisomerisation of functionalised enynes 1 would afford 1,3-butadiene derivatives 2 (or 2’), which might then react in situ with appropriate dienophiles 3 to afford interesting fused bicyclic compounds 4 or spirocycles 5, depending upon the initial mode of cyclisation (endo or exo) of enyne derivative, 1 (Scheme 1). The preliminary results of this reaction are given here. First, we evaluated the reactivity of a series of functionalised enynes 1 (n= 1), derived from 3-butyn-1-ol or 3-butyn1-amine, in the presence of dienophiles, such as N-phenylmaleimide (3 a) and tetracyanoethylene (3 b). After screening catalysts we discovered that gold ACHTUNGTRENNUNG(III) chloride (AuCl3) was the most suitable to perform the desired cascade 5-endo cycloisomerisation/Diels–Alder cycloaddition reaction. When the reaction was carried out in dichloromethane, at room temperature, we obtained compounds 4 in high yields (Scheme 2). Structural assignments of these new compounds were based on a series of H NMR studies. Additionally, the structures of compounds 4 d and k were confirmed by single-crystal X-ray diffraction analyses. Compounds 4 are the result of an initial intramolecular hydroalkoxylation (products 4 a–l) or hydroamination (products 4 m–o) of the triple bond in 1, followed by cycloaddition of the formed diene 2 with the corresponding di ACHTUNGTRENNUNGenoACHTUNGTRENNUNGphile 3. In those cases in which N-phenylmaleimide 3 a was used, the corresponding products 4 were obtained as single diastereoisomers, because of an endo-cycloaddition of the corresponding intermediate 2 with N-phenylmaleimide (3 a). It should be noted that in compounds 4 a and o isomerisation of the double bond into an endocyclic position occurs [a] Prof. Dr. J. Barluenga, J. Calleja, Dr. A. Mendoza, Dr. F. Rodr guez, Dr. F. J. FaÇan s Instituto Universitario de Qu mica Organomet lica “Enrique Moles”, Unidad Asociada al CSIC Universidad de Oviedo, Juli n Claver a 8 33006 Oviedo (Spain) Fax: (+34) 985103450 E-mail : barluenga@uniovi.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000515. Scheme 1. Concept of the cascade cycloisomerisation/Diels–Alder cycloaddition reaction.

Synthesis of 2,5-Dihydropyridine Derivatives by Gold-Catalyzed Reactions of β-Ketoesters and Propargylamines

The reaction of simple β-ketoesters and propargylamines under gold(III) catalysis leads to the formation of the elusive 2,5-dihydropyridine system. This new reaction provides the synthesis of potentially bioactive compounds in moderate to high yields.