Pd Catalysis in Cyanide-Free Synthesis of Nitriles from Haloarenes via Isoxazolines.

A method to obtain aryl nitriles from the corresponding halides by Pd catalysis, in the absence of any cyanide source, is reported. The reaction of an aryl halide, ethyl nitroacetate, and an olefin readily delivers an aromatic nitrile. A variety of aryl iodides/bromides have been converted into the corresponding cyanoarenes in fair to excellent yields. The reaction likely involves the following steps: (a) Pd-catalyzed α-arylation of ethyl nitroacetate; (b) nitrile oxide formation;

Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C-H Bond Activation.

Direct C-H bond activation is an important reaction in synthetic organic chemistry. This methodology has the potential to simplify reactions by avoiding the use of prefunctionalized reagents. However, selectivity, especially site selectivity, remains challenging. Sequential reactions, in which different molecules or groups are combined in an ordered sequence, represent a powerful tool for the construction of complex molecules in a single operation. We have discovered and developed a synthetic methodology that combines selective C-H bond activation with sequential reactions. This procedure, which is now known as the "Catellani reaction", enables the selective functionalization of both the ortho and ipso positions of aryl halides. The desired molecules are obtained with high selectivity from a pool of simple precursors. These molecules are assembled under the control of a palladacycle, which is formed through the joint action of a metal (Pd) and an olefin such as norbornene. These two species act cooperatively with an aryl halide to construct the palladacycle, which is formed through ortho-C-H activation of the original aryl halide. The resulting complex acts as a scaffold to direct the reaction (via Pd(IV)) of other species, such as alkyl or aryl halides and amination or acylation agents, toward the sp(2) C-Pd bond. At the end of this process, because of steric hindrance, the scaffold is dismantled by norbornene extrusion. Pd(0) is cleaved from the organic product through C-C, C-H, C-N, C-O, or C-B coupling, in agreement with the well-known reactivity of aryl-Pd complexes. The cycle involves Pd(0), Pd(II), and Pd(IV) species. In particular, our discovery relates to alkylation and arylation reactions. Recently, remarkable progress has been made in the following areas: (a) the installation of an amino or an acyl group at the ortho position of aryl halides, (b) the formation of a C-B bond at the ipso position, (c) the achievement of meta-C-H bond activation of aryl rings bearing a chelating directing group by Pd(II)/Pd(IV)/norbornene catalysis, and (d) the activation of N-H and C-H bonds in sequence for indole 2-alkylation. In this Account, we explain the main features of this methodology, describe its synthetic potential, and illustrate some remarkable progress that has been made, emphasizing the most recent developments and applications in total synthesis.

Correction: A novel enantioselective synthesis of 6H-dibenzopyran derivatives by combined palladium/norbornene and cinchona alkaloid catalysis.

Correction for 'A novel enantioselective synthesis of 6H-dibenzopyran derivatives by combined palladium/norbornene and cinchona alkaloid catalysis' by Di Xu et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c4ob02551b.

A novel enantioselective synthesis of 6H-dibenzopyran derivatives by combined palladium/norbornene and cinchona alkaloid catalysis.

Organometallic and organo-catalysts are cooperatively at work in the enantioselective synthesis of dibenzopyran derivatives; palladium/norbornene and a cinchona alkaloid base guarantee good yields and satisfactory enantioselectivities in a one-pot reaction.

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.

Of the ortho effect in palladium/norbornene-catalyzed reactions: a theoretical investigation.

Mechanistic questions concerning palladium and norbornene catalyzed aryl-aryl coupling reactions are treated in this paper: how aryl halides react with the intermediate palladacycles, formed by interaction of the two catalysts with an aryl halide, and what is the rational explanation of the "ortho effect" (caused by an ortho substituent in the starting aryl halide), which leads to aryl-aryl coupling with a second molecule of aryl halide rather than to aryl-norbornyl coupling. Two possible pathways have been proposed, one involving aryl halide oxidative addition to the palladacycle, the other passing through a palladium(II) transmetalation, also involving the palladacycle, as previously proposed by Cardenas and Echavarren. Our DFT calculations using M06 show that, in palladium-catalyzed reaction of aryl halides, not containing ortho substituents, and norbornene, the intermediate palladacycle formed has a good probability to undergo transmetalation, energetically favored over the oxidative addition leading to Pd(IV). The unselective sp(2)-sp(2) and sp(2)-sp(3) coupling, experimentally observed in this case, can be explained in the framework of the transmetalation pathway since the energetic difference between aryl attack onto the aryl or norbornyl carbon of the palladacycle intermediate is quite small. On the other hand, according to the experimentally observed "ortho effect", selective aryl-aryl coupling only occurs in the reactions of ortho-substituted metallacycles. The present work offers the first possible rationalization of this finding. These in situ formed palladacycles containing an ortho substituent could more easily undergo oxidative addition of an aryl halide rather than reductive elimination from the transmetalation intermediate as a result of a steric clash in the transition state of the latter. The now energetically accessible Pd(IV) intermediate, featuring a Y-distorted trigonal bipyramidal structure, can account for the reported selective aryl-aryl coupling through a reductive elimination which is easier than aryl-norbornyl coupling. Thus, the steric effect represents the main factor that dictates the energetic convenience of the system to follow the Pd(IV) or the transmetalation pathway. Ortho substituents cause a higher energy transition state for reductive elimination from the transmetalation intermediate than for oxidative addition to the metallacycle palladium(II) and the pathway based on the latter predominates.

Palladium-catalyzed unsymmetrical aryl couplings in sequence leading to o-teraryls: dramatic olefin effect on selectivity.

Selectively substituted o-teraryls are obtained by palladium/norbornene-catalyzed reaction of aryl iodides, aryl bromides and aryl boronic acids in ordered sequence; high selectivity is attained thanks to the addition of diethyl maleate acting as palladium ligand.

A catalytic synthesis of selectively substituted biaryls through sequential intermolecular coupling involving arene and ketone C-H bond functionalization.

Selectively substituted biaryls containing a ketone unit are obtained under mild conditions in satisfactory yields by a simple reaction of ortho-substituted aryl iodides and ketones in the presence of palladium and norbornene as catalysts.

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.

Sequential unsymmetrical aryl coupling of o-substituted aryl iodides with o-bromophenols and reaction with olefins: palladium-catalyzed synthesis of 6H-dibenzopyran derivatives.

Dibenzopyran derivatives are prepared by palladium- and norbornene-catalyzed reaction of aryl iodides, o-substituted with electron-releasing substituents, o-bromophenols, and activated alkenes.

A simple catalytic synthesis of condensed pyridones from o-bromoarylcarboxamides involving ipso substitution via palladacycles.

A catalytic synthesis of condensed pyridones starting from o-bromoaromatic carboxamides is reported using Pd(OAc)2/TFP as catalyst, K2CO3 as a base in DMF at 105 degrees C. Under these conditions an unprecedented reaction sequence occurs leading to condensed pyridones in 23-86% yield. The proposed pathway proceeds through palladacycle-catalyzed homocoupling of the bromoamide, followed by intramolecular carbon-nitrogen bond-forming reaction with the carbon atom bearing the aminocarbonyl group, which is easily eliminated under palladium catalysis.

Synthesis of 6-phenanthridinones and their heterocyclic analogues through palladium-catalyzed sequential aryl-aryl and N-aryl coupling.

[reaction: see text] 6-Phenanthridinones and their heterocyclic analogues were synthesized through a one-pot procedure based on consecutive Pd-catalyzed aryl-aryl and N-aryl coupling from iodoarenes ortho-substituted by electron-releasing substituents and amides of o-bromoarene- and heteroarenecarboxylic acids.

Iodide effects in transition metal catalyzed reactions.

The unique properties of I(-) allow it to be involved in several different ways in reactions catalyzed by the late transition metals: in the oxidative addition, the migration, and the coupling/reductive elimination steps, as well as in substrate activation. Most steps are accelerated by I(-)(for example through an increased nucleophilicity of the metal center), but some are retarded, because a coordination site is blocked. The "soft" iodide ligand binds more strongly to soft metals (low oxidation state, electron rich, and polarizable) such as the later and heavier transition metals, than do the other halides, or N- and O-centered ligands. Hence in a catalytic cycle that includes the metal in a formally low oxidation state there will be less tendency for the metal to precipitate (and be removed from the cycle) in the presence of I(-) than most other ligands. Iodide is a good nucleophile and is also easily and reversibly oxidized to I(2). In addition, I(-) can play key roles in purely organic reactions that occur as part of a catalytic cycle. Thus to understand the function of iodide requires careful analysis, since two or sometimes more effects occur in different steps of one single cycle. Each of these topics is illustrated with examples of the influence of iodide from homogeneous catalytic reactions in the literature: methanol carbonylation to acetic acid and related reactions; CO hydrogenation; imine hydrogenation; and C-C and C-N coupling reactions. General features are summarised in the Conclusions.

A new reaction sequence involving palladium-catalyzed unsymmetrical aryl coupling.

Biphenylylalkenes containing an ortho substituent in one ring and a different ortho-, meta-, or para-substituent in the other are prepared in satisfactory yield from an ortho-substituted aryl iodide, an ortho-, meta-, or para-substituted aryl bromide, a terminal olefin, and a base in DMF under the joint catalytic action of palladium(0) and norbornene.

Palladium-arene interactions in catalytic intermediates: an experimental and theoretical investigation of the soft rearrangement between eta1 and eta2 coordination modes.

A series of dichloro-bridged arylbicycloheptylpalladium complexes have been synthesized and characterized by means of NMR spectroscopy. The compound [(C16H19)PdCl]2*CH2Cl2 with ortho and para methyl substituents at the arene has been characterized by means of X-ray diffraction techniques. The C(ipso) atom of the arene lies almost at the fourth planar coordination site of the metal [Pd-C(ipso) = 2.22(1) A (average)], and due to the arene's tilting, the substituted C(ortho) atom is relatively close to the metal atom [2.54(1) A (average)]. The coordinated C(ipso)-C(ortho) linkage, in a seemingly dihapto coordination, is anti with respect to the CH2 bridge of the bicycloheptyl unit. Variable-temperature NMR experiments for the para-substituted dimer 9 reveal restricted rotation of the two aryl groups about the corresponding C-C(ipso) bonds (DeltaE < or =17 kcal x mol(-1)). DFT-B3LYP calculations have been carried out on the known and similar monomer (phenylbicycloheptenyl)Pd(PPh3)I (4) and its related substituted derivatives. The essential results are as follows: (i) The potential energy surface for twisting the phenyl ring away from the symmetric eta(1) coordination in 4 is very flat (DeltaE < or = 1 kcal x mol(-1)) whereas an Atoms in Molecules analysis excludes the existence of an actual Pd-C(ortho) bond in the seemingly eta2-type conformer. (ii) Complete rotation of the unsubstituted phenyl ring is not facile but feasible. A significant strain affects the transition-state structure featuring a Pd-HC(aryl) agostic-type bond. The calculated destabilization of 10.3 kcal x mol(-1), with respect to the ground state, can be compared to the experimental barrier of the dimer 9. (iii) Various methyl-substituted derivatives of 4 have been optimized, and their structural and energetic trends are discussed. An almost ideal eta1 coordination is shown by the anti conformer of the C(ortho)-substituted complex due steric effects. For all of the other cases, a slipped eta2 coordination may be described. As a general conclusion, the unsaturated metal center receives pi electron density of the arene mainly through its C(ipso) atom. The effect may be slightly improved if the C(ortho) atom also gets closer to the metal, but in no case, does the slipped eta2 coordination seem to be crucial for the stability of the system.