Leyre Marzo

Visible Light Mediated Photoredox Catalytic Arylation Reactions

Introducing aryl- and heteroaryl moieties into molecular scaffolds are often key steps in the syntheses of natural products, drugs, or functional materials. A variety of cross-coupling methods have been well established, mainly using transition metal mediated reactions between prefunctionalized substrates and arenes or C-H arylations with functionalization in only one coupling partner. Although highly developed, one drawback of the established sp2-sp2 arylations is the required transition metal catalyst, often in combination with specific ligands and additives. Therefore, photoredox mediated arylation methods have been developed as alternative over the past decade. We begin our survey with visible light photo-Meerwein arylation reactions, which allow C-H arylation of heteroarenes, enones, alkenes, and alkynes with organic dyes, such as eosin Y, as the photocatalyst. A good number of examples from different groups illustrate the broad application of the reaction in synthetic transformations. While initially only photo-Meerwein arylation-elimination processes were reported, the reaction was later extended to photo-Meerwein arylation-addition reactions giving access to the photoinduced three component synthesis of amides and esters from alkenes, aryl diazonium salts, nitriles or formamides, respectively. Other substrates with redox-active leaving groups have been explored in photocatalyzed arylation reactions, such as diaryliodonium and triarylsulfonium salts, and arylsulfonyl chlorides. We discus some examples with their scope and limitations. The scope of arylation reagents for photoredox reactions was extended to aryl halides. The challenge here is the extremely negative reduction potential of aryl halides in the initial electron transfer step compared to, e.g., aryl diazonium or diaryliodonium salts. In order to reach reduction potentials over -2.0 V vs SCE two consecutive photoinduced electron transfer steps were used. The intermediary formed colored radical anion of the organic dye perylenediimide is excited by a second photon allowing the one electron reduction of acceptor substituted aryl chlorides. The radical anion of the aryl halide fragments under the loss of a halide ion and the aryl radical undergoes C-H arylation with biologically important pyrrole derivatives or adds to a double bond. Rhodamine 6G as an organic photocatalyst allows an even higher degree of control of the reaction. The dye is photoreduced in the presence of an amine donor under irradiation with green light (e.g., 530 nm), yielding its radical anion, which is a mild reducing reagent. The hypsochromic shift of the absorption of the rhodamine 6G radical anion toward blue region of the visible light spectrum allows its selective excitation using blue light (e.g., 455 nm). The excited radical anion is highly reducing and able to activate even bromoanisole for C-H arylation reactions, although only in moderate yield. Photoredox catalytic C-H arylation reactions are valuable alternatives to metal catalyzed reactions. They have an excellent functional group tolerance, could potentially avoid metal containing catalysts, and use visible light as a traceless reagent for the activation of arylating reagents.

Enantioselective aza-Henry reactions of cyclic α-carbonyl ketimines under bifunctional catalysis

The aza-Henry reaction of nitroalkanes with the C=N group of 2-aryl-3H-indol-3-ones catalyzed by thiourea-chincona derivatives takes place with good yield and high ees.

One-Pot Synthesis of Pentasubstituted Cyclohexanes by a Michael Addition Followed by a Tandem Inter–Intra Double Henry Reaction

Michael, Henry, and Henry: A new one-pot reaction of α,β-unsaturated aldehydes and β-dicarbonyls, which involves a Michael reaction catalyzed by diarylprolinol ethers and an inter–intramolecular Henry tandem reaction catalyzed by TBAF (see scheme), has been developed. The reaction proceeds in high enantio- and diastereoselectivity for a wide range of unsaturated aldehydes and β-dicarbonyl reagents.

Arylsulfonylacetylenes as Alkynylating Reagents of C sp 2H Bonds Activated with Lithium Bases

Chameleon: a new strategy for the synthesis of a wide variety of alkynyl derivatives by the reaction of substituted arylsulfonylacetylenes with organolithium species is described. The high yields, the simplicity of the experimental procedure, the broad scope of this reaction, and the formation of C(sp)-C(sp2) bonds without using transition metals are the main features of this methodology.

Highly Stereoselective Synthesis of Tertiary Propargylic Centers and Their Isomerization to Enantiomerically Enriched Allenes

Allenes are important compounds that exhibit axial chirality and are present in a large number of medicinal and natural products. One of the most frequently used methods for obtaining racemic allenes involves the isomerization of propargylic centers. However, it is surprising that this method has rarely been used for preparing enantiomerically pure compounds, probably due to the rather poor results obtained in its application. Thus, the few examples reported for the synthesis of allenols using chiral auxiliaries are minimally successful, and only moderate enantiomeric excess (ee) has been achieved with organocatalytic methods. Very recently Yoshida et al. reported one of the best procedures for the synthesis of allenols (74 to 92% ee), which is based on the method previously published by Hoppe and co-workers. It consists of the carbolithiation of 2-OCb (OCONiPr2) conjugated enynes in the presence of stoichiometric ( )sparteine, followed by addition of the resulting propargylic anions to electrophiles to give the corresponding allene derivatives (Scheme 1a). The key to the success of this nice transformation seems to be related to the chemical and configurational stability of the propargylic lithium carbanion by association with the OCb group and the ( )-sparteine, which is used in stoichiometric amounts. These results suggest that the main difficulty for obtaining enantiomerically enriched allenes by isomerization of compounds with chiral propargylic centers of a defined configuration is due to the configurational stabilization of the propargylic carbanion intermediates. In recent years, we have reported that an ortho-sulfinyl group is able to provide a high configurational stabilization to differently substituted benzylic anions, allowing them to react with various electrophiles in an almost completely stereoselective manner. From these results we hypothesized that ortho-sulfinyl benzylcarbanions containing acetylenic moieties joined to the benzyl carbon would be able to evolve in a highly stereoselective manner into enantiomerically enriched allenes due to the configurational stabilization provided by the sulfinyl group (Scheme 1b). To confirm this hypothesis, it was necessary to prepare the propargylic precursors shown in Scheme 1. The results obtained in these two fields, synthesis of alkynes and their isomerization into trisubstituted allenes, are presented herein. The preparation of enantiomerically pure tertiary propargylic centers can be achieved by the nucleophilic addition of acetylenic residues to proper electrophiles such as enones, enals, nitroalkenes, Meldrum s acid derivatives, and thioamides. In all these cases, the acetylenic moiety is supported by the reagent acting as nucleophile, and the electrophile contains an electron-withdrawing group (EWG) to allow the conjugate addition (Scheme 2a). As the acidity of the a protons to these groups could interfere with the abstraction of the propargylic protons required for the isomerization to the allene, the resulting compounds from these routes are not appropriated for our study.

Asymmetric synthesis of quaternary α-amino acid derivatives and their fluorinated analogues

In this work, we describe the asymmetric synthesis of a series of fluorinated and non-fluorinated quaternary α-amino acid derivatives. This methodology involves the diastereoselective addition of chiral 2-p-tolylsulfinyl benzylcarbanions to either imines containing a 2-furyl moiety or trifluoromethyl α-imino esters. Synthetic practicality of this method is demonstrated by short (two-steps) and convenient preparation of 2-(trifluoromethyl)indoline-2-carboxylates.

Visible-Light Photocatalysis: Does it make a difference in Organic Synthesis?

Visible-light photocatalysis has evolved over the last decade into a widely used method in organic synthesis. Photocatalytic variants have been reported for many important transformations, such as cross-coupling reactions, α-amino functionalizations, cycloadditions, ATRA reactions, or fluorinations. To help chemists select photocatalytic methods for their synthesis, we compare in this Review classical and photocatalytic procedures for selected classes of reactions and highlight their advantages and limitations. In many cases, the photocatalytic reactions proceed under milder reaction conditions, typically at room temperature, and stoichiometric reagents are replaced by simple oxidants or reductants, such as air, oxygen, or amines. Does visible-light photocatalysis make a difference in organic synthesis? The prospect of shuttling electrons back and forth to substrates and intermediates or to selectively transfer energy through a visible-light-absorbing photocatalyst holds the promise to improve current procedures in radical chemistry and to open up new avenues by accessing reactive species hitherto unknown, especially by merging photocatalysis with organo- or metal catalysis.

Oxidative CH Bond Functionalization and Ring Expansion with TMSCHN2: A Copper(I)-Catalyzed Approach to Dibenzoxepines and Dibenzoazepines†

Tricyclic dibenzoxepines and dibenzazepines are important therapeutic agents for the pharmaceutical industry and academic research. However, their syntheses are generally rather tedious, requiring several steps that involve a Wagner-Meerwein-type rearrangement under harsh conditions. Herein, we present the first copper(I)-catalyzed oxidative CH bond functionalization and ring expansion with TMSCHN2 to yield these important derivatives in a facile and straightforward way.

Visible-Light-Mediated Radical Arylation of Anilines with Acceptor-Substituted (Hetero)aryl Halides

A visible-light-mediated, catalyst-free, direct (hetero)arylation of anilines with mild reaction conditions has been developed. The formation of a donor-acceptor complex between electron-withdrawing substituted (hetero)aryl halides and anilines allows, under blue LED irradiation, the synthesis of ortho and para (hetero)arylated anilines in moderate to good yields. The reaction has a high functional group tolerance. Spectroscopic studies confirmed the donor-acceptor complex formation between aniline and aryl halide.

Mono‐ and Bimetallic Alkynyl Metallocenes and Half‐Sandwich Complexes: A Simple and Versatile Synthetic Approach

A general process for the synthesis of alkynyl mono and dimetallic metallocenes and half-sandwich complexes has been developed. This approach uses the addition of lithium derivatives of sandwich or half-sandwich complexes to arylsulfonylacetylenes. The reaction occurs in two steps (lithiation and anti-Michael addition to alkynylsulfone followed by elimination of the ArSO2 moiety) to form the corresponding mono- or bimetallic alkynes in clearly higher yields, simpler experimental procedures, and more environmentally benign conditions than those of the so far reported for the synthesis of this type of products. The electrochemical properties of the newly obtained complexes have also been studied.