Iron-Catalyzed, Light-Driven Decarboxylative Alkoxyamination.

An iron-catalyzed visible-light driven decarboxylative alkoxyamination is disclosed. In the presence of FeBr2 and TEMPO, a large array of carboxylic acids including marketed drugs and biobased molecules is turned into the corresponding alkoxyamine derivatives. The versatility of the latter offers an entry towards molecular diversity generation from abundant starting materials and catalyst. Overall, this method proposes a unified and general approach for LMCT-based iron-catalyzed decarboxylative functionalization.

Cobalt-Catalyzed 1,4-Aryl Migration/Desulfonylation Cascade: Synthesis of α-Aryl Amides.

A cobalt-catalyzed 1,4-aryl migration/disulfonylation cascade applied to α-bromo N-sulfonyl amides was developed. The reaction was highly chemoselective, allowing the preparation of α-aryl amides possessing a variety of functional groups. The method was used as the key step to synthesize an alkaloid, (±)-deoxyeseroline. Mechanistic investigations suggest a radical process.

Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents.

The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.

Cobalt-Catalyzed Cross-Couplings between Alkyl Halides and Grignard Reagents.

Metal-catalyzed cross-couplings have emerged as essential tools for the construction of C-C bonds. The identification of efficient catalytic systems as well as large substrate scope made these cross-couplings key reactions to access valuable molecules ranging from materials, agrochemicals to active pharmaceutical ingredients. They have been increasingly integrated in retrosynthetic plans, allowing shorter and original route development. Palladium-catalyzed cross-couplings still largely rule the field, with the most popular reactions in industrial processes being the Suzuki and Sonogashira couplings. However, the extensive use of palladium complexes raises several problems such as limited resources, high cost, environmental impact, and frequent need for sophisticated ligands. As a consequence, the use of nonprecious and cheap metal catalysts has appeared as a new horizon in cross-coupling development. Over the last three decades, a growing interest has thus been devoted to Fe-, Co-, Cu-, or Ni-catalyzed cross-couplings. Their natural abundance makes them cost-effective, allowing the conception of more sustainable and less expensive chemical processes, especially for large-scale production of active molecules. In addition to these economical and environmental considerations, the 3d metal catalysts also exhibit complementary reactivity with palladium complexes, facilitating the use of alkyl halide partners due to the decrease of ß-elimination side reactions. In particular, by using cobalt catalysts, numerous cross-couplings between alkyl halides and organometallics have been described. However, cobalt catalysis still stays far behind palladium catalysis in terms of popularity and applications, and the expansion of the substrate scope as well as the development of simple and robust catalytic systems remains an important challenge.In 2012, our group entered the cobalt catalysis field by developing a cobalt-catalyzed cross-coupling between C-bromo glycosides and Grignard reagents. The generality of the coupling allowed the preparation of a range of valuable C-aryl and C-vinyl glycoside building blocks. We then focused on the functionalization of saturated N-heterocycles, and a variety of halo-azetidines, -pyrrolidines, and -piperidines were successfully reacted with aryl and alkenyl Grignard reagents under cobalt catalysis. With the objective of preparing valuable α-aryl amides, a cobalt-catalyzed cross-coupling applied to α-bromo amides was studied and then extended to α-bromo lactams. Recently, we also reported an efficient and general cross-coupling involving cyclopropyl- and cyclobutyl-magnesium bromides. This method allows the alkylation of functionalized small strained rings by a range of primary and secondary alkyl halides.

Introduction of Cyclopropyl and Cyclobutyl Ring on Alkyl Iodides through Cobalt-Catalyzed Cross-Coupling.

A cobalt-catalyzed cross-coupling between alkyl iodides and cyclopropyl, cyclobutyl, and alkenyl Grignard reagents is disclosed. The reaction allows the introduction of strained rings on a large panel of primary and secondary alkyl iodides. The catalytic system is simple and nonexpensive, and the reaction is general, chemoselective, and diastereoconvergent. The alkene resulting from the cross-coupling can be transformed to substituted cyclopropanes using a Simmons-Smith reaction. The formation of radical intermediates during the coupling is hypothesized.

Cobalt-Catalyzed (Hetero)arylation of Saturated Cyclic Amines with Grignard Reagents.

(Hetero)aryl substituted saturated cyclic amines are ubiquitous scaffolds in biologically active molecules. Metal-catalyzed cross-couplings between halogeno N-heterocycles and organometallic species are efficient and modular reactions to access these attractive scaffolds. An overview of our work concerning the cobalt-catalyzed arylation of iodo-substituted cyclic amines is presented.

Iron-Catalyzed Synthesis of Sulfur-Containing Heterocycles.

An iron-catalyzed synthesis of sulfur- and sulfone-containing heterocycles is reported. The method is based on the cyclization of readily available substrates and proceeded with high efficiency and diastereoselectivity. A variety of sulfur-containing heterocycles bearing moieties suitable for subsequent functionalization are prepared. Illustrative examples of such postcyclization modifications are also presented.

Synthetic Studies toward the C14-C29 Fragment of Mirabalin.

A convergent synthesis of one isomer of the C14-C29 fragment of mirabalin is disclosed. The key steps include a Marshall allenylation, a Mukaiyama aldol reaction and a Crimmins aldolization, which allow the control of 10 out of 25 stereogenic centers present in the molecule.

Iron-Catalyzed C-C Cross-Couplings Using Organometallics.

Over the last decades, iron-catalyzed cross-couplings have emerged as an important tool for the formation of C-C bonds. A wide variety of alkenyl, aryl, and alkyl (pseudo)halides have been coupled to organometallic reagents, the most currently used being Grignard reagents. Particular attention has been devoted to the development of iron catalysts for the functionalization of alkyl halides that are generally challenging substrates in classical cross-couplings. The high functional group tolerance of iron-catalyzed cross-couplings has encouraged organic chemists to use them in the synthesis of bioactive compounds. Even if some points remain obscure, numerous studies have been carried out to investigate the mechanism of iron-catalyzed cross-coupling and several hypotheses have been proposed.

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics.

Alkenes containing N-heteroaromatics are known to be poor partners in cross-metathesis reactions, probably due to catalyst deactivation caused by the presence of a nitrogen atom. However, some examples of ring-closing and cross-metathesis involving alkenes that incorporate N-heteroaromatics can be found in the literature. In addition, recent mechanistic studies have focused on the rationalization of nitrogen-induced catalysts deactivation. The purpose of this mini-review is to give a brief overview of successful metathesis reactions involving olefins containing N-heteroaromatics in order to delineate some guidelines for the use of these challenging substrates in metathesis reactions.

Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans.

An iron-catalyzed cyclization of hydroxy allylic derivatives into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodynamic equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.

Formation of the Main Cores Present in Natural Products by Tandem Additions.

A rapid route to 5,5- and 5,6- bicyclic systems is provided by an 1,3-alkyl-shift process mediated by a hypervalent iodine reagent on aromatics. The structures obtained contain several unsaturations with different behaviors and reactivities. Such diversity allows further elaborations for the rapid formation of compact systems present in a variety of natural products. The potential for further transformations has been demonstrated by performing a double Michael addition. This cyclization process is regio- and stereoselective due to the presence of a former benzylic substituent. Furthermore, an extension of this approach has been accomplished on indole derivatives.

Cobalt-catalyzed cross-coupling of 3- and 4-iodopiperidines with Grignard reagents.

A cobalt-catalyzed cross-coupling between 3- and 4-iodopiperidines and Grignard reagents is disclosed. The reaction is an efficient, cheap, chemoselective, and flexible way to functionalize piperidines. This coupling was used as the key step to realize a short synthesis of (±)-preclamol. Some mechanistic investigations were conducted that highlight the formation of radical intermediates.

Iron- and indium-catalyzed reactions toward nitrogen- and oxygen-containing saturated heterocycles.

A myriad of natural and/or biologically active products include nitrogen- and oxygen-containing saturated heterocycles, which are thus considered as attractive scaffolds in the drug discovery process. As a consequence, a wide range of reactions has been developed for the construction of these frameworks, much effort being specially devoted to the formation of substituted tetrahydropyrans and piperidines. Among the existing methods to form these heterocycles, the metal-catalyzed heterocyclization of amino- or hydroxy-allylic alcohol derivatives has emerged as a powerful and stereoselective strategy that is particularly interesting in terms of both atom-economy and ecocompatibility. For a long time, palladium catalysts have widely dominated this area either in Tsuji-Trost reactions [Pd(0)] or in an electrophilic activation process [Pd(II)]. More recently, gold-catalyzed formation of saturated N- and O-heterocycles has received growing attention because it generally exhibits high efficiency and diastereoselectivity. Despite their demonstrated utility, Pd- and Au-complexes suffer from high costs, toxicity, and limited natural abundance, which can be barriers to their widespread use in industrial processes. Thus, the replacement of precious metals with less expensive and more environmentally benign catalysts has become a challenging issue for organic chemists. In 2010, our group took advantage of the ability of the low-toxicity and inexpensive FeCl3 in activating allylic or benzylic alcohols to develop iron-catalyzed N- and O-heterocylizations. We first focused on N-heterocycles, and a variety of 2,6-disubstituted piperidines as well as pyrrolidines were synthesized in a highly diastereoselective fashion in favor of the cis-compounds. The reaction was further extended to the construction of substituted tetrahydropyrans. Besides triggering the formation of heterocycles, the iron salts were shown to induce a thermodynamic epimerization, which is the key to reach the high diastereoselectivities observed in favor of the most stable cis-isomers. It is worth noting that spiroketals could be prepared by using this method, which was successfully applied to a synthetic approach toward natural products belonging to the bistramide family. We then turned our attention to heterocycles incorporating two heteroatoms such as isoxazolidines. These frameworks can be found in biologically active natural products, and in addition, they can be transformed into 1,3-amino alcohols, which are of importance in organic chemistry. The use of FeCl3·6H2O allowed the access to a large variety of 3,5-disubstituted isoxazolidines from δ-hydroxylamino allylic alcohol derivatives with good yields and diastereoselectivities in favor of the cis-isomer. Recently, a Lewis acid-catalyzed synthesis of six- and five-membered ring carbonates starting from linear tert-butyl carbonates was reported. In some cases, the mild and chemoselective InCl3 was preferred over FeCl3·6H2O to avoid side-product formation. The resulting cyclic carbonates were easily transformed into 1,3- or 1,2-diols, and a total synthesis of (3S,5S)-alpinikatin was achieved.

Heck coupling using a vinyliodo-MIDA boronate: an efficient and modular access to polyene frameworks.

A simple Heck coupling between an alkenyl iodo-boronate and a variety of terminal olefins is disclosed. This method gives access to a wide range of dienic moieties including valuable bis-functionalized dienes. The synthetic potential of the coupling reaction is demonstrated by a short and modular preparation of several tetraenic compounds.

Iron- and cobalt-catalyzed arylation of azetidines, pyrrolidines, and piperidines with Grignard reagents.

Iron- and cobalt-catalyzed cross-couplings between iodo-azetidines, -pyrrolidines, -piperidines, and Grignard reagents are disclosed. The reaction is efficient, cheap, chemoselective and tolerates a large variety of (hetero)aryl Grignard reagents.

Lewis basicity modulation of N-heterocycles: a key for successful cross-metathesis.

Cross-metathesis involving N-heteroaromatic olefinic derivatives is disclosed. The introduction of an appropriate substituent on the heteroaromatic ring decreases the Lewis basicity of the nitrogen atom, thus preventing the deactivation of the ruthenium-centered catalyst. The reaction is quite general in terms of both N-heterocycles and olefinic partners.

Synthetic strategy toward the C44-C65 fragment of mirabalin.

A convergent and flexible stereoselective synthesis of one isomer of the C44-C65 fragment of mirabalin is described. The key steps include organocatalytic aldolization, ruthenium-catalyzed asymmetric hydrogenation, amide formation, Marshall stereoselective allenylation, and the Nozaki-Hiyama-Kishi reaction.

Silver-free two-component approach in gold catalysis: activation of [LAuCl] complexes with derivatives of copper, zinc, indium, bismuth, and other Lewis acids.

Complexes of type [LAuCl] (L = phosphine, phosphite, NHC and others) are widely employed in homogeneous catalysis, however, they are usually inactive as such and must be used jointly with a halide scavenger. To date, this role has mostly been entrusted to silver salts (AgSbF6 , AgPF6, AgBF4, AgOTf, etc.). However, silver salts can be the source of deactivation processes or side reactions, so it is sometimes advisable to use silver-free cationic gold complexes, which can be difficult to synthesize and to handle compared with the more robust chloride. We show in this study that various Lewis acids of the transition and main group metal families are expedient substitutes to silver salts. We have tested Cu(I), Cu(II), Zn(II), In(III), Si(IV), Bi(III), and other salts in a variety of typical Au(I)-catalyzed transformations, and the results have revealed that [LAuCl] can form active species in their presence.

FeCl3·6H2O, a catalyst for the diastereoselective synthesis of cis-isoxazolidines from N-protected δ-hydroxylamino allylic acetates.

An ecofriendly and diastereoselective synthesis of cis-3,5-disubstituted isoxazolidines through the FeCl3·6H2O-catalyzed cyclization of δ-hydroxylamino allylic acetates is described. The synthetic potential of these products is highlighted by the preparation of several functionalized 1,3-amino alcohol precursors.