Iron-promoted dealkylative carbene aminocyclization of δ-arylamino-α-diazoesters.

Herein, we report a novel methodology to access N-aryl proline derivatives using amino-tethered α-diazoesters and cheap, readily available iron salts. Mechanistically, the aminocyclization reaction involves the initial formation of an iron-carbene complex followed by a nucleophilic attack of the aniline nitrogen atom to give an ammonium ylide intermediate, which finally undergoes the iron-promoted dealkylation.

Site Selectivity in Pd-Catalyzed Reactions of α-Diazo-α-(methoxycarbonyl)acetamides: Effects of Catalysts and Substrate Substitution in the Synthesis of Oxindoles and ß-Lactams.

The Pd-catalyzed intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to prepare oxindoles as well as ß-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to catalyze the carbene CArsp2-H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp3-H insertion leading to ß-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations.

Palladium- and Ruthenium-Catalyzed Intramolecular Carbene CAr -H Functionalization of γ-Amino-α-diazoesters for the Synthesis of Tetrahydroquinolines.

A synthetic method to prepare tetrahydroquinoline-4-carboxylic acid esters has been developed through the transition-metal-catalyzed intramolecular aromatic C-H functionalization of α-diazoesters. Both [{Pd(IMes)(NQ)}2 ] (IMes=1,3-dimesitylimidazol-2-ylidene, NQ=1,4-naphthoquinone) and the first-generation Grubbs catalyst proved effective for this purpose. The ruthenium catalyst was found to be the most versatile, although in a few cases the palladium complex afforded better yields or selectivities. According to DFT calculations, Pd0 - and RuII -catalyzed sp2 -CAr -H functionalization proceeds through different reaction mechanisms. Thus, the Pd0 -catalyzed reaction involves a Pd-mediated 1,6-H migration from the sp2 -CAr -H bond to the carbene carbon atom, followed by a reductive elimination process. In contrast, electrophilic addition of the ruthenacarbene intermediate to the aromatic ring and subsequent 1,2-proton migration are operative in the Grubbs catalyst promoted reaction.

Grubbs catalysts in intramolecular carbene C(sp3)-H insertion reactions from α-diazoesters.

Grubbs catalysts are described as a useful alternative to promote intramolecular carbene C-H insertion from α-diazoesters. Moreover, no competition arises from the possible metathesis reactions on substrates bearing alkene and alkyne moieties. DFT calculations were also carried out to gain insight into the reaction mechanism involved in these transformations.

Palladium-catalysed intramolecular carbenoid insertion of α-diazo-α-(methoxycarbonyl)acetanilides for oxindole synthesis.

A novel, selective palladium-catalysed carbenoid C(aryl)-H insertion of α-diazo-α-(methoxycarbonyl)acetanilides leading to oxindoles is described.

Palladium-Catalyzed Intramolecular Carbene Insertion into C(sp(3) )-H Bonds.

A palladium-catalyzed carbene insertion into C(sp(3) )-H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd(0) and Pd(II) , is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium-catalyzed C(sp(3) )-C(sp(3) ) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp(3) )-H bond functionalization reaction involves an unprecedented concerted metalation-deprotonation step.

Pd(0)-catalyzed intramolecular α-arylation of sulfones: domino reactions in the synthesis of functionalized tetrahydroisoquinolines.

A new strategy for the synthesis of tetrahydroisoquinolines based on the Pd(0)-catalyzed intramolecular α-arylation of sulfones is reported. The combination of this Pd-catalyzed reaction with intermolecular Michael and aza-Michael reactions allows the development of two- and three-step domino processes to synthesize diversely functionalized scaffolds from readily available starting materials.

Controlling the ambiphilic nature of σ-arylpalladium intermediates in intramolecular cyclization reactions.

The reactivity of main group organometallics, such as organolithium compounds (RLi) and Grignard reagents (RMgX), is quite straightforward. In these species the R group usually exhibits nucleophilic reactivity without any possibility of inducing electrophilic character. In contrast, in organopalladium complexes, researchers can switch the reactivity from electrophilic to nucleophilic relatively simply. Although σ-aryl and σ-vinylpalladium complexes are commonly used as electrophiles in C-C bond-forming reactions, recent research has demonstrated that they can also react with carbon-heteroatom multiple bonds in a nucleophilic manner. Nevertheless, researchers have completely ignored the issue of controlling the ambiphilic nature of such species. This Account describes our efforts toward selectively promoting the same starting materials toward either electrophilic α-arylation or nucleophilic addition reactions to different carbonyl groups. We could tune the properties of the σ-arylpalladium intermediates derived from amino-tethered aryl halides and carbonyl compounds to achieve chemoselective transformations. Therefore, chemists can control the ambiphilic nature of such intermediates and, consequently, the competition between the alternative reaction pathways by the adequate selection of the reaction conditions and additives (base, presence/absence of phenol, bidentate phosphines). The nature of the carbonyl group (aldehydes, ketones, esters, and amides) and the length of the tether connecting it to the aniline moiety also play an important role in the outcome of these processes. Our joint computational and experimental efforts to elucidate the reaction mechanism of these palladium-catalyzed transformations suggest that beyond the formation of the four-membered azapalladacycle, two major factors help to control the dual character of the palladium(II) intermediates derived from 2-haloanilines. First, their high nucleophilicity strongly modifies the interaction of the metal center with the carbonyl group. Second, the additive phenol exchanges the iodide ligand to give an arylpalladium(II) phenoxide complex, which has a beneficial effect on the arylation. The formation of this transient intermediate not only stabilizes the arylpalladium moiety, thus preventing the nucleophilic attack at the carbonyl group, but also assists the enolization reaction, which takes place in a more favorable intramolecular manner. The azapalladacycle intermediate is, in the words of J. R. R. Tolkien, "the one ring to bring them all and in the darkness to bind them." With this intermediate, we can easily achieve the synthesis of a variety of heterocyclic systems by selectively promoting electrophilic α-arylation or nucleophilic addition reactions from the same precursors.

Synthesis of dibenzo[b,e]azepin-11-ones by intramolecular palladium-catalyzed acylation of aryliodides with aldehydes.

The paper describes an efficient methodology for the synthesis of diversely functionalized dihydrodibenzo[b,e]azepin-11-ones based on the Pd(0)-catalyzed intramolecular acylation of aryl iodides with aldehydes.

Intramolecular Pd(0)-catalyzed reactions of (2-iodoanilino)-aldehydes: a joint experimental-computational study.

An extensive joint experimental-computational density functional theory (DFT) study has been carried out to gain insight into the factors that control the chemoselectivity (i.e., acylation vs α-arylation reaction) of palladium-catalyzed cyclizations of (2-iodoanilino)-aldehydes. To this end, the nature of the tethers joining the aniline nitrogen and the aldehyde moiety, different palladium precatalysts and reaction conditions (base and temperature), as well as different additives (mono- and bidendate ligands) has been explored. The adequate selection of these variables allows for the control of the selectivity of the process. Thus, (2-iodoanilino)-aldehydes generally lead to the formation of nucleophilic addition derived products when Cs(2)CO(3)/Et(3)N is used as base. In contrast, the use of stronger bases like K(t)OBu (in the presence of PhOH) mainly forms α-arylation reaction products. The different reaction pathways leading to the experimentally observed reaction products have been studied by means of computational tools.

Control over the chemoselectivity of Pd-catalyzed cyclization reactions of (2-iodoanilino)carbonyl compounds.

The factors that control the chemoselectivity of palladium-catalyzed cyclization reactions of (2-iodoanilino)carbonyl compounds have been explored by an extensive experimental computational (DFT) study. It was found that the selectivity of the process, that is, the formation of fused six- versus five-membered rings, can be controlled by the proper selection of the initial reactant, reaction conditions, and additives. Thus, esters or amides produce ketones by a nucleophilic addition process, whereas the addition of PhO(-) ions leads to the formation of indolines by an α-arylation reaction. In contrast, the corresponding ketone reactants yield a mixture of both reaction products, the ratio of which depends on the base used, in the presence of phenol. The outcome of the processes can be explained by the formation of a common four-membered palladacycle intermediate from which the competitive nucleophilic addition and α-arylation reactions occur. The remarkable effect of phenol in the process, which makes the α-arylation reaction easier, favored the formation of enol complexes, which are stabilized by an intramolecular hydrogen bond between the hydroxy group of the enol moiety and the oxygen atom of the phenoxy ligand. Moreover, the chemoselectivy of the process can be also controlled by the addition of bidendate ligands that lead to the almost exclusive formation of indoles at expenses of the corresponding alcohols.

Intramolecular palladium-catalysed enolate arylation of 2- and 3-iodoindole derivatives for the synthesis of ß-carbolines, γ-carbolines, and pyrrolo[3,4-b]indoles.

The palladium-catalysed intramolecular α-arylation of carbonyl compounds with amino-tethered 2- and 3-iodoindoles provides a useful methodology for the synthesis of indolo-b-fused nitrogen heterocycles. A variety of substituted tetrahydro ß- and γ-carbolines, and pyrrolo[3,4-b]indoles, have been prepared by means of this palladium-catalysed annulation process.

A straightforward synthetic entry to cleavamine-type indole alkaloids by a ring-closing metathesis-vinyl halide Heck cyclization strategy.

An indole-templated ring-closing metathesis has been used to create the central nine-membered ring of the cleavamine-type alkaloids. A subsequent intramolecular vinyl halide Heck reaction upon the resulting azacyclononene ring completes the assembly of the strained 1-azabicyclo[6.3.1]dodecane framework of the alkaloids. The usefulness of the approach is illustrated with the synthesis of (±)-cleavamine and (±)-dihydrocleavamine.

A DFT study of the ambiphilic nature of arylpalladium species in intramolecular cyclization reactions.

The remarkable structure-dependent reactivity observed in the cyclization of (2-haloanilino)-ketones with Pd-catalysts has been studied computationally within the density functional theory framework. The experimental reaction products ratio may be explained through the formation of a common palladaaminocyclobutane intermediate which can undergo a nucleophilic addition reaction and/or an enolate α-arilation process. The evolution of this metallacycle to the final products depends on two factors, the length of the tether joining the amino and the carbonyl groups, and the electronic nature of the substituent directly attached to the nitrogen atom. Thus, shorter chains (2 CH(2)) facilitate the nucleophic addition reaction by approximating the reactive aryl and Pd-coordinated carbonyl groups whereas longer chains (3 CH(2)) favor the enolate α-arylation proccess. For electron-withdrawing groups attached to the aniline nitrogen atom, the nucleophilic addition pathway becomes slightly disfavored, mainly due to the electron-withdrawing effect of the CO(2)Me group which avoids the delocation of the LP in the π-system, thus decreasing the nucleophilicity of the reactive arylic carbon atom. In contrast, the enolate α-arylation reaction is facilitated by the CO(2)Me group. This is translated into a small computed barrier energy difference of these competitive reaction pathways which should lead to a mixture of reaction products as experimentally found.

Selective synthesis of either isoindole- or isoindoline-1-carboxylic acid esters by Pd(0)-catalyzed enolate arylation.

Two efficient palladium-catalyzed intramolecular α-arylation reactions of α-amino acid esters have been developed that allow either 1-isoindolecarboxylic acid esters or the corresponding isoindolines to be selectively synthesized simply by a slight change of reaction conditions.

Total synthesis of the bridged indole alkaloid apparicine.

An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of the indole alkaloid apparicine. From this key intermediate, an intramolecular vinyl halide Heck reaction accomplished the closure of the strained 1-azabicyclo[4.2.2]decane framework of the alkaloid with concomitant incorporation of the exocyclic alkylidene substituents.

Palladium-catalysed synthesis of 1-isoindolecarboxylic acid esters and sequential Diels-Alder reactions: access to bridged- and fused-ring heterocycles.

The Pd-catalysed intramolecular alpha-arylation of alpha-amino acid esters provides a useful methodology for the synthesis of substituted isoindole derivatives, which have been used in Diels-Alder reactions to access diverse skeletal frameworks.

The first total synthesis of (+/-)-apparicine.

The first total synthesis of the indole alkaloid apparicine has been developed through a sequence that includes an indole-templated ring-closing metathesis and a vinyl halide Heck cyclization.

Intramolecular Pd(0)-catalyzed reactions of beta-(2-iodoanilino) carboxamides: enolate arylation and nucleophilic substitution at the carboxamide group.

Two different reaction pathways, the enolate arylation and the acylation of the aryl halide, can be promoted by a Pd(0) catalyst starting from beta-(2-iodoanilino) carboxamides. The intramolecular acylation of beta-(2-iodoanilino) carboxamides reported here is the first example of a nucleophilic attack of a sigma-arylpalladium species at the carboxamide group, a framework that is usually inert toward organopalladium reagents.

Synthesis of indole-3-carboxylic acid derivatives by Pd(0)-catalyzed intramolecular alpha-arylation of beta-(2-iodoanilino) esters.

beta-(2-Iodoanilino) esters undergo intramolecular alpha-arylation in the presence of Pd(PPh(3))(4) and potassium phenoxide. The reaction is a useful methodology for the preparation of indole-3-carboxylic acid ester derivatives.