Síntesis de indoles y carbazoles funcionalizados: catálisis con complejos de Au(III) y ácidos de Brønsted

Esta Tesis está centrada en el desarrollo de nuevas metodologías en Síntesis Orgánica utilizando ácidos de Brønsted y complejos de oro(III) como catalizadores. El hilo conductor es el núcleo indólico, cuya funcionalización selectiva continúa siendo un objetivo relevante en Química Orgánica. Bajo catálisis con ácidos de Brønsted hemos desarrollado una nueva ruta para acceder a benzo[b]carbazoles por reacción directa de indoles con acetales de o-(hidroxialquil)benzaldehídos. Asimismo, hemos descrito la versión intramolecular de la reacción de indoles con alcoholes -activados, pudiéndose sintetizar derivados de indol fusionados. También hemos demostrado el potencial de las -indolilaciloínas como agentes alquilantes frente a diferentes nucleófilos carbonados y heteroatómicos. Por último, hemos estudiado la reactividad de -bis(indol-3-il)alquilalquinoles, en presencia de complejos de oro(III), los cuales generan 1-(indol-3-il)carbazoles. Los objetivos abordados en esta Tesis han dado lugar a la preparación de una amplia variedad de moléculas que presentan interés por sus potenciales actividades biológicas y/o farmacológicas

Synthesis of α-functionalized α-indol-3-yl carbonyls through direct SN reactions of indol-3-yl α-acyloins

A new and efficient synthesis of α-functionalized α-indol-3-yl ketones from easily available indolyl α-acyloins is reported. This process, catalyzed by Brønsted or Lewis acids, involves an uncommon direct nucleophilic substitution reaction of a secondary α-carbonyl-substituted hydroxyl group. The described methodology allows the introduction of a variety of nucleophiles such as (hetero)arenes, thiophenols, nitroanilines and 1,3-dicarbonyl derivatives. The synthesized α-indol-3-yl carbonyl compounds are important synthetic targets also useful for accessing functionalized tryptophols and furan-3-yl indoles.Ministerio de Economía y Competitividad (MINECO) (CTQ2013-48937-C2-1-P) and Junta de Castilla y León and FEDER (BU237U13 and BU076U16

Gold-Catalyzed Synthesis of 1-(Indol-3-yl)carbazoles: Selective 1,2-Alkyl vs 1,2-Vinyl Migration

Gold(III)-catalyzed cycloisomerization of α-bis(indol-3-yl)methyl alkynols selectively affords 1-(indol-3-yl)carbazoles, in a transformation that takes place through a selective 1,2-alkyl vs 1,2-vinyl migration step in the vinyl-gold intermediate generated from the initial 5-endo-spirocyclization. The reaction proceeds well with either tertiary or secondary starting alkynols as well as with a wide variety of alkyne substituents. The key role of the other indol-3-yl substituent for the unexpected selectivity in the 1,2 rearrangement has also been supported by DFT calculations that reveal a low barrier, two-step mechanism in the alkyl migration path where the second indole significantly stabilizes a carbocationic intermediate.Junta de Castilla y León and FEDER (BU076U16) and Ministerio de Economía y Competitividad (MINECO) (CTQ2016-75023-C2-1-P and CTQ2016-75023- C2-2-P

Synthesis of Fused Polycyclic Indoles by Brønsted Acid-Catalyzed Intramolecular Alkylation of Indoles with Alcohols

An efficient methodology for the synthesis of a series of new fused polyclyclic indoles has been developed by Brønsted acidcatalyzed intramolecular Friedel−Crafts reactions of properly designed indolyl alcohols.Ministerio de Economiá y Competitividad (MINECO) and FEDER (CTQ2013-48937- C2-1-P) and Junta de Castilla y León (BU237U13

Straight access to highly fluorescent angular indolocarbazoles via merging Au- and Mo-catalysis

A straightforward and efficient synthesis of the two less explored types of indolocarbazoles has been developed. Two different processes for the carbazole nucleus preparation, a gold-catalysed regioselective cyclization followed by the dioxomolybdenum-catalysed version of Cadogan reductive cyclization, enables the sequential construction of two carbazole cores. The procedure features total regioselectivity and high overall yields. The required starting α-indol-3-ylalkyl propargylic alcohols are easily and efficiently accessed from commercially available reagents. In addition, the photoluminescent properties of two indolo[2,3-c]carbazoles, with fluorescence quantum yields around 0.7, have been studied.Junta de Castilla y León and FEDER (BU291P18) and Ministerio de Ciencia e Innovación and FEDER (CTQ2016-75023-C2-1-P

From Propargylic Alcohols to Substituted Thiochromenes: gem- Disubstituent Effect in Intramolecular Alkyne Iodo/hydroarylation

This work describes the 6-endo-dig cyclization of Saryl propargyl sulfides to afford 2H-thiochromenes. The substitution at the propargylic position plays a crucial role in allowing intramolecular silver-catalyzed alkyne hydroarylation and Niodosuccinimide-promoted iodoarylation. Additionally, a PTSAcatalyzed thiolation reaction of propargylic alcohols was developed to synthesize the required tertiary S-aryl propargyl ethers. The applicability of merging these two methods is demonstrated by synthesizing the retinoic acid receptor antagonist AGN194310.Junta de Castilla y León and FEDER (BU291P18 and BU049P20) and Ministerio de Ciencia e Innovación and FEDER (CTQ2016-75023-C2-1-P) for financial support. The project leading to these results has received funding from “la Caixa” Foundation, under Agreement LCF/PR/PR18/51130007> (CAIXA-UBU001). N.V., F.M.-L., and S.S.-P. thank Junta de Castilla y León and FSE and FEDER for predoctoral (N.V. and F.M.-L.) and postdoctoral (S.S.-P.) contracts, respectively

Gold-Catalyzed Reactions of 2-Alkynyl-1-indolyl-1,2-diols with Thiols: Stereoselective Synthesis of (Z)-α-Indol-3-yl α-(2-Thioalkenyl) Ketones

Propargylic glycols, 2-alkynyl-1-(indol-3-yl)-1,2-diols, react with thiols undergoing a complex but selective gold-catalyzed transformation that gives rise to α-indol-3-yl α-((Z)-2-thioalkenyl) ketones. The sequence is triggered by the regioselective thiolation of indolyl diols followed by an attack of the sulfur instead of the indole over the activated alkyne. The final compounds are obtained in remarkably high yields and arise from simple starting materials such as indolyl acyloins, ethynyl magnesium bromide and thiols.Ministerio de Ciencia e Innovación and FEDER (CTQ2016-75023-C2-1-P and PID2020- 115789GB-C21), and Junta de Castilla y León and FEDER (BU291P18 and BU049P20) for financial support. The project leading to these results has received funding from “la Caixa” Foundation, under the Agreement LCF/PR/PR18/51130007> (CAIXA-UBU001). F. M.-L., N. V. and S. S.-P. thank Junta de Castilla y León (Consejería de Educación) and Fondo Social Europeo for predoctoral (F. M.-L. and N. V) and postdoctoral (S. S.-P.) contracts, respectively