Jean-Philippe Goddard

Visible-Light-Induced Photoreductive Generation of Radicals from Epoxides and Aziridines†

Epoxides are readily available and highly valuable radical precursors, as demonstrated by their omnipresence in radical transformations. Several methodologies have been reported so far for their radical ring-opening. Epoxides are particularly prone to reductive ring-opening via one-electron transfer. Lithium 4,4′-di-tert-butylbiphenylid (LDBB) has thus been widely used to generate lithiated radical anions such as 99. This latter is immediately reduced to dianion 100 which can add to various electrophiles.

Gold‐ and Platinum‐Catalyzed Cycloisomerization of Enynyl Esters versus Allenenyl Esters: An Experimental and Theoretical Study

Ester-way to heaven: Unexpected formation of bicyclo[3.1.0]hexene 4 was the main focus of combined experimental and theoretical studies on the Au-catalyzed cycloisomerization of branched dienyne 1 (see scheme), which provided better understanding of the mechanistic details governing the cyclization of enynes bearing a propargylic ester group.Experimental and theoretical studies on Au- and Pt-catalyzed cycloisomerization of a branched dienyne with an acetate group at the propargylic position are presented. The peculiar architecture of the dienyne precursor, which has both a 1,6- and a 1,5-enyne skeleton, leads, in the presence of alkynophilic gold catalysts, to mixtures of bicyclic compounds 3, 4, and 5. Formation of unprecedented bicyclo[3.1.0]hexene 5 is the main focus of this study. The effect of the ancillary ligand on the gold center was examined and found to be crucial for formation of 5. Further mechanistic studies, involving cyclization of an enantioenriched dienyne precursor, (18)O-labeling experiments, and DFT calculations, allowed an unprecedented reaction pathway to be proposed. We show that bicyclo[3.1.0]hexene 5 is likely formed by a 1,3-OAc shift/allene-ene cyclization/1,2-OAc shift sequence, as calculated by DFT and supported by Au-catalyzed cyclization of isolated allenenyl acetate 7, which leads to improved selectivity in the formation of 5. Additionally, the possibility of OAc migration from allenyl acetates was supported by a trapping experiment with styrene that afforded the corresponding cyclopropane derivative. This unprecedented generation of a vinyl metal carbene from an allenyl ester supports a facile enynyl ester/allenenyl ester equilibrium. Further examination of the difference in reactivity between enynyl acetates and their corresponding [3,3]-rearranged allenenyl acetates toward Au- and Pt-catalyzed cycloisomerization is also presented.

Oxidation of Alkyl Trifluoroborates: An Opportunity for Tin-Free Radical Chemistry†

As a result of its unique attributes, radical chemistry offers intriguing synthetic opportunities which are now fully recognized and belong to mainstream chemistry. Nowadays the challenge is to develop more scalable and ecocompatible reactions and to notably circumvent the use of tin reagents, which has remained so far the traditional option. 3] In that context, redox processes have held great promise as recently illustrated by several research groups through asymmetric transformations and their applications to the synthesis of natural products. While oxidation of classical organometallic compounds such as Grignard or lithium reagents is well-known, this approach suffers from the drawbacks associated with organometallic chemistry—stringent reaction conditions and poor tolerance of a variety of function groups. Inspired by the seminal work of Kumada and co-workers on organopentafluorosilicate compounds, we reasoned that the oxidation of softer organometallic derivatives was possible and we focused our attention on the now well-developed organotrifluoroborate compounds as precursors to radical species. Moreover, their oxidation chemistry has remained largely unexplored. 10] To initially probe our design, we examined the behavior of benzyl trifluoroborate 1a, bearing in mind that the benzyl radical should be an easy one to generate and that trapping with TEMPO would give strong evidence for the radical intermediate formation (adduct 2a ; Table 1). A preliminary screening of the reaction conditions provided valuable information. We initially ran reactions with Cu(OAc)2 as the oxidant and a default of 0.5 equivalents of TEMPO to easily monitor the reactions by TLC. While the reaction did not proceed in hydrocarbon solvents and was rather sluggish in alcohols (34 % of 2a in tBuOH; Table 1, entry 1), the use of DMSO provided better results (Table 1, entry 2). Remarkably, a good yield of 2a was also observed in a H2O/DMSO (9:1) mixture (Table 1, entry 3). In DMSO, copper salts proved to be superior to ferrocenium salts or CAN. Interestingly, CuCl2 was successful in Et2O at room temperature (Table 1, entry 8). Having defined an appropriate set of reaction conditions, we then studied the reactivity of other substrates (Table 2). As expected, allyl substrate 1b provided good yields of TEMPO adduct 2b in conditions similar to the oxidation of 1a (Table 2, entries 1 and 2). We then looked at the alkyl series. Hexenyl substrate 1c was oxidized under the same type of conditions and gave, as the major product, linear adduct 2cL accompanied by about 10 % of cyclized product 2 cC. Substrate 1c was also oxidized by Dess–Martin periodinane in Et2O at room temperature and delivered only 2cL. These findings are consistent with a very rapid TEMPO trapping of the hexenyl radical intermediate, which has little time to cyclize, especially at room temperature because of a lower cyclization rate constant. Secondary and tertiary substrates proved to be easy to oxidize under mild conditions using CuCl2 at room temperature or DMP (Table 2, entries 5–10). Gratifyingly, other functionalized organotrifluoroborate compounds 1 h–j were amenable to this oxidation process, as illustrated in Scheme 1 by the formation of TEMPO adducts such as 2h bearing a benzyl ether group, the fragile ketone 2 i, and the very intriguing allylsilane 2j. Thus, this process is compatible with function groups that are susceptible to nucleophilic attack and oxidation. Table 1: Oxidation of benzyl substrate 1a.

Tracking gold acetylides in gold(I)-catalyzed cycloisomerization reactions of enynes

The intermediacy of gold acetylides in the gold(I)-catalyzed cycloisomerization of enynes was questioned. While dinuclear gold complexes are observed under electrospray ionization conditions, the solution reactivity of gold acetylides also leads to the conclusion of their high affinity for the second coordination of a gold moiety, leading to dinuclear gold complexes. However, the involvement of gold acetylides and the corresponding diaurated species in the elementary steps of cycloisomerization mechanisms of enynes appears unlikely.

Photoredox Catalysis for the Generation of Carbon Centered Radicals

Radical chemistry has witnessed over the last decades important advances that have positioned it as a methodology of choice in synthetic chemistry. A number of great attributes such as specific reactivities, the knowledge of the kinetics of most elementary processes, the functional group tolerance, and the possibility to operate cascade sequences are clearly responsible for this craze. Nevertheless, at the end of the last century, radical chemistry appeared plagued by several hurdles to overcome such as the use of environmentally problematic mediators or the impossibility of scale up. While the concept of photocatalysis was firmly established in the coordination chemistry community, its diffusion in organic synthetic chemistry remained sporadic for decades until the end of the 2000s with the breakthrough merging of organocatalysis and photocatalysis by the MacMillan group and contemporary reports by the groups of Yoon and Stephenson. Since then, photoredox catalysis has enjoyed particularly active and intense developments. It is now the topic of a still increasing number of publications featuring various applications from asymmetric synthesis, total synthesis of natural products, and polymerization to process (flow) chemistry. In this Account, we survey our own efforts in this domain, focusing on the elaboration of new photocatalytic pathways that could lead to the efficient generation of C-centered functionalized alkyl and aryl radicals. Both reductive and oxidative manifolds are accessible through photoredox catalysis, which has guided us along these lines in our projects. Thus, we studied the photocatalytic reduction of onium salts such as sulfoniums and iodoniums for the production of the elusive aryl radical intermediates. Progressing to more relevant chemistry for synthesis, we examined the cleavage of C-O and the C-Br bonds for the generation of alkyl C-centered radicals. Activated epoxides could serve as valuable substrates of a photocatalyzed variant of the Nugent-RajanBabu-Gansäuer homolytic cleavage of epoxides. Using imidazole based carbamates, we could also devise the first photocatalyzed Barton-McCombie deoxygenation reaction. Finally, bromophenylacetate can be reduced using the [Au2(μ-dppm)2]Cl2 photocatalyst under UVA or visible-light. This was used for the initiation of the controlled atom transfer radical polymerization of methacrylates and acrylates in solution or laminate. Our next endeavors concerned the photocatalyzed oxidation of stabilized carbanions such as enolates of 1,3-dicarbonyl substrates, trifluoroborates, and more extensively bis-catecholato silicates. Because of their low oxidation potentials, the later have proved to be exquisite sources of radical entities, which can be engaged in diverse intermolecular reactions such as vinylation, alkynylation, and conjugate additions. The bis-catecholato silicates were also shown to behave as excellent partners of dual photoredox-nickel catalysis leading in an expeditious manner to libraries of cross coupling products.

Gold(I)-Catalyzed Cyclization of β-Allenylhydrazones: An Efficient Synthesis of Multisubstituted N-Aminopyrroles

The gold(I)-catalyzed cycloisomerization of β-allenylhydrazones provides an efficient access to multisubstituted N-aminopyrroles, which are obtained in good to excellent yields. This new intramolecular cyclization method can be applied either to alkyl- or aryl-substituted allenes. The reaction proceeds under mild conditions with short reaction times through a selective intramolecular 1,2-alkyl or -aryl migration extending the general scope of the reaction.

The Role of Water in Platinum‐Catalyzed Cycloisomerization of 1,6‐Enynes: A Combined Experimental and Theoretical Gas Phase Study

PtII‐catalyzed cycloisomerization of a 1,6‐enyne proceeds quickly in CHCl3 at room temperature, and also in the gas phase. However, calculations predict a slow reaction, because of the formation of a very stable chelate that undergoes oxidative cyclization at a high energy cost. The electrophilic activation of the alkyne followed by nucleophilic attack of the double bond to generate a cyclopropyl carbene would lead to a faster reaction, but the decomplexation of the double bond to generate an unsaturated platinum species is also energetically disfavored. However, decomplexation can be envisaged if an adventitious molecule of water enters the coordination sphere of the metal. This crucial role of water in PtII‐catalyzed cycloisomerization of enynes, initially sensed some years ago (Echavarren et al., J. Am. Chem. Soc. 2001, 123, 10511) is now supported by mass spectrometry studies.

Combination of gold catalysis and Selectfluor for the synthesis of fluorinated nitrogen heterocycles

Summary We herein report the synthesis of 3-fluoro-2-methylene-pyrrolidine (3a) and -piperidine (3b) from 1,5- and 1,6-aminoalkynes, respectively, using a combination of a gold-catalyzed hydroamination reaction followed by electrophilic trapping of an intermediate cyclic enamine by Selectfluor. Careful attention was paid to the elucidation of the mechanism and Selectfluor was suggested to play the double role of promoting the oxidation of gold(I) to a gold(III) active species and also the electrophilic fluorination of the enamine intermediates.

Spirosilane derivatives as fluoride sensors.

Spirosilane derivatives have been investigated as fluoride sensors. The reactions between these compounds and different fluoride sources, which resulted in structural alterations, have been monitored and quantified by UV and fluorescence spectroscopy. The high selectivity of these probes for fluoride ions has been demonstrated in either organic or aqueous media.

Highly diastereoselective ionic/radical domino reactions: single electron transfer induced cyclization of bis-sulfoxides.

SET oxidation of bis-sulfinyl anions has enabled the uses of bis-sulfinyl radical as a synthetic equivalent of chiral acyl and methylene radicals involved in tandem reactions leading to the enantioselective construction of various carbo- and heterocyclic derivatives.