Elena Motti

Catalytic Sequential Reactions Involving Palladacycle-Directed Aryl Coupling Steps

Catalytic methods are important tools for the synthesis of C-C bonds under mild and ambient conditions. Palladium chemistry predominates in this area because it offers the opportunity to form several different types of bonds in one pot. Palladium can also tolerate a variety of functional groups. Among the many investigations of catalytic aryl-aryl couplings, the most successful technique has been the Suzuki reaction, which uses an arylboronic acid to attack an aryl-Pd bond. This Account reports our methodology, based on the cooperative action of Pd and norbornene, that achieves selective aryl-aryl coupling through C-halide and C-H activation. We are primarily interested in Pd-catalyzed sequential reactions. These reactions combine palladium as an inorganic catalyst and a strained olefin such as norbornene as an organic catalyst and can lead to biphenyl derivatives. While the palladium facilitates C-C bond formation through C-halide and C-H activation, the norbornene contributes to the construction of a palladacycle, an intermediate structure that controls and directs the subsequent reaction steps selectively. To achieve regioselective arylation at the carbon ortho to the original C-halide bond, palladacycles require an additional ortho substituent (R(1)). The palladacycle opens, giving rise to a biphenylylnorbornylpalladium complex. Because of the steric hindrance exerted by the two ortho groups, norbornene deinsertion readily occurs to form a biphenylylpalladium complex. Thus, norbornene acts as a removable scaffold. We used this biphenylylpalladium species to form C-C (with olefins, alkynes, or arylboronic acids) or C-H bonds (by hydrogenolysis). Using nonidentical aryl or heteroaryl halides, we also formed a biaryl-bonded Pd species able to undergo the final termination reaction (C-C, C-N, or C-O bond formation) either inter- or intramolecularly. We used this method to synthesize a variety of aromatic and heteroaromatic compounds. We also obtained the key metallacycle able to selectively direct the reactions by replacing norbornene with an aryl-bonded aminocarbonyl group. This method provided a diverse series of condensed heterocycles.

A Sequential Pd/Norbornene-Catalyzed Process Generates o-Biaryl Carbaldehydes or Ketones via a Redox Reaction or 6H-Dibenzopyrans by C–O Ring Closure

o-Biaryl carbaldeydes and ketones are obtained through the one-pot reaction of o-aryl iodides with o-bromobenzyl alcohols under the catalytic action of Pd and norbornene, in the presence of a base. The same reaction can also give dibenzopyrans by Pd and norbornene catalysis with a different termination, leading to C-O ring closure. In both cases the process first leads to a five-membered palladacycle, which controls C-C coupling, then to a seven-membered oxapalladacycle, which gives aldehydes and ketones or dibenzopyrans.

New catalytic methods for the synthesis of selectively substituted aromatics through palladacycles

Joint palladium and norbornene catalysis for selective aromatic functionalization via palladacycles is reported. Both alkylation and arylation of aromatics are considered after a brief outlook on the mechanism. These are multistep reactions that proceed in ordered sequences and are chemio-, regio-, and stereoselective. The study of the single steps with isolation of the organometallic species involved has allowed us to detect subtle steric and electronic effects which have been exploited to achieve catalytic reactions. Recent developments of aromatic alkylation and arylation are reported, in particular, condensed heterocyclic ring formation involving dialkylated arylpalladium complexes or both symmetrically and unsymmetrically substituted biphenylylpalladium complexes.

Selective aryl coupling via palladacycles: a new route to m-alkylbiphenyls or m-terphenyls

o-Alkyl- or o-aryl-substituted arylnorbornylpalladium chloride complexes react with aromatic iodides in dimethylformamide (DMF) via palladacycles to give after hydrogenolysis m-alkylbiphenyls or m-terphenyls.

A new type of palladium-catalysed aromatic cross-coupling combined with a Suzuki reaction: synthesis of selectively 2,3′-substituted 1,1′;2′,1″-terphenyl derivatives

Abstract A one-pot catalytic synthesis of selectively substituted terphenyl derivatives is reported. The method is based on the combination of a new palladium- and norbornene-mediated aryl–aryl coupling of two molecules of an ortho-substituted aryl iodide with a Suzuki-type arylation. Under the reported conditions, the reaction follows a precisely ordered sequence of steps and the Suzuki coupling only occurs at the end of the sequence. While proposing a new pathway for CC coupling, the process provides a simple and efficient tool for preparing an interesting class of ortho-substituted terphenyls catalytically and with satisfactory yields.

Aromatic arylation via palladacycles: interception of reaction intermediates

Abstract The palladium-catalysed reaction of iodobenzene with norbornene was carried out in the presence of an excess of methyl acrylate in order to intercept palladium-bonded aryl groups. Species of this kind result from a complex sequence of norbornene insertion into arylpalladium bonds, aromatic substitution and arylation of the palladacycle thus formed, followed by a variety of steps including new norbornene insertion and its eventual expulsion when steric hindrance is generated by the process.

Symmetrical and unsymmetrical 2,6-dialkyl-1,1′-biaryls by combined catalysis of aromatic alkylation via palladacycles and Suzuki-type coupling

The title compounds are made readily accessible by a catalytic procedure, occurring under mild conditions, based on palladium-mediated ortho alkylation of aromatic iodides with alkyl bromides followed by reaction with arylboronic acids.

Intramolecular benzylic C–H activation: palladium-catalyzed synthesis of hexahydromethanofluorenes

C–H activation of benzylic methyl groups has been realized catalytically under mild conditions through intramolecular reaction on a palladium complex.

Multiple arylations of aromatics via removable palladacycle scaffolds: polycyclic compounds and their way of formation

Palladium-promoted selective arylation of aromatic substrates can be achieved with aryl iodides or bromides in the presence of bicyclo[2.2.1]hept-2-ene. On the basis of isolation of products corresponding to multiple arylations, evidence is provided that the process occurs according to a complex sequence of steps, involving bicycloheptene insertion into arylpalladium bonds and its expulsion when steric hindrance is generated by the process.

Pd-Catalyzed/Iodide-Promoted α-Arylation of Ketones for the Regioselective Synthesis of Isocoumarins

A variety of isocoumarins have been synthesized directly from 2-halobenzoates and ketones through a palladium-catalyzed α-arylation step followed by an intramolecular cyclization process. The addition of iodide anions to the reaction mixture increased yields and selectivities especially when 2-bromobenzoates were employed. This phosphine-free one-pot synthesis features a high functional group tolerance and gives access to richly decorated isocoumarins. This general methodology was successful in the total synthesis of Xyridin A, an important natural product with antibacterial and antifungal activity.