Gregori Ujaque

Gold-Catalyzed [4C+2C] Cycloadditions of Allenedienes, including an Enantioselective Version with New Phosphoramidite-Based Catalysts: Mechanistic Aspects of the Divergence between [4C+3C] and [4C+2C] Pathways

Gold(I) complexes featuring electron acceptor ligands such as phosphites and phosphoramidites catalyze the [4C+2C] intramolecular cycloaddition of allenedienes. The reaction is chemo- and stereoselective, and provides trans-fused bicyclic cycloadducts in good yields. Moreover, using novel chiral phosphoramidite-based gold catalysts it is possible to perform the reaction with excellent enantioselectivity. Experimental and theoretical data dismiss a cationic mechanism involving intermediate II and suggest that the formation of the [4C+2C] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in a cycloheptenyl Au-carbene intermediate (IV), itself arising from a [4C+3C] concerted cycloaddition of the allenediene. Therefore, these [4C+2C] allenediene cycloadditions and the previously reported [4C+3C] counterparts most likely share such cycloaddition step, differing in the final 1,2-migration step.

The Reaction Mechanism of the Hydroamination of Alkenes Catalyzed by Gold(I)−Phosphine: The Role of the Counterion and the N-Nucleophile Substituents in the Proton-Transfer Step

The reaction mechanism of the gold(I)-phosphine-catalyzed hydroamination of 1,3-dienes was analyzed by means of density functional methods combined with polarizable continuum models. Several mechanistic pathways for the reaction were considered and evaluated. It was found that the most favorable series of reaction steps include the ligand substitution reaction in the catalytically active Ph3PAuOTf species between the triflate and the substrate, subsequent nucleophile attack of the N-nucleophile (benzyl carbamate) on the activated double bond, which is followed by proton transfer from the NH2 group to the unsaturated carbon atom. The latter step, the most striking one, was analyzed in detail, and a novel pathway involving tautomerization of benzyl carbamate nucleophile assisted by triflate anion acting as a proton shuttle was characterized by the lowest barrier, which is consistent with experimental findings.

Computational Perspective on Pd-Catalyzed C–C Cross-Coupling Reaction Mechanisms

Palladium-catalyzed C-C cross-coupling reactions (Suzuki-Miyaura, Negishi, Stille, Sonogashira, etc.) are among the most useful reactions in modern organic synthesis because of their wide scope and selectivity under mild conditions. The many steps involved and the availability of competing pathways with similar energy barriers cause the mechanism to be quite complicated. In addition, the short-lived intermediates are difficult to detect, making it challenging to fully characterize the mechanism of these reactions using purely experimental techniques. Therefore, computational chemistry has proven crucial for elucidating the mechanism and shaping our current understanding of these processes. This mechanistic elucidation provides an opportunity to further expand these reactions to new substrates and to refine the selectivity of these reactions. During the past decade, we have applied computational chemistry, mostly using density functional theory (DFT), to the study of the mechanism of C-C cross-coupling reactions. This Account summarizes the results of our work, as well as significant contributions from others. Apart from a few studies on the general features of the catalytic cycles that have highlighted the existence of manifold competing pathways, most studies have focused on a specific reaction step, leading to the analysis of the oxidative addition, transmetalation, and reductive elimination steps of these processes. In oxidative addition, computational studies have clarified the connection between coordination number and selectivity. For transmetalation, computation has increased the understanding of different issues for the various named reactions: the role of the base in the Suzuki-Miyaura cross-coupling, the factors distinguishing the cyclic and open mechanisms in the Stille reaction, the identity of the active intermediates in the Negishi cross-coupling, and the different mechanistic alternatives in the Sonogashira reaction. We have also studied the closely related direct arylation process and highlighted the role of an external base as proton abstractor. Finally, we have also rationalized the effect of ligand substitution on the reductive elimination process. Computational chemistry has improved our understanding of palladium-catalyzed cross-coupling processes, allowing us to identify the mechanistic complexity of these reactions and, in a few selected cases, to fully clarify their mechanisms. Modern computational tools can deal with systems of the size and complexity involved in cross-coupling and have a continuing role in solving specific problems in this field.

Gold(I)-catalyzed intermolecular oxyarylation of alkynes: unexpected regiochemistry in the alkylation of arenes.

The reaction between acetylenes and sulfoxides, studied as a test case for gold-catalyzed intermolecular addition, provides the oxyarylation compounds 3 in good yields. Unpredictably, in all cases a single regioisomer arising from the electrophilic aromatic alkylation at the position adjacent to the sulfur atom is obtained instead of the expected Friedel-Crafts regioisomer. A new concerted mechanism based on DFT calculations is proposed to account for the products in this intermolecular gold(I)-catalyzed reaction.

Gold-Catalyzed [4C+3C] Intramolecular Cycloaddition of Allenedienes: Synthetic Potential and Mechanistic Implications

Efficient at room temperature: The Au complex generated in situ from [(IPr)AuCl] and AgSbF(6) promotes the [4C+3C] intramolecular cycloaddition of allenes and dienes at room temperature, and in a particularly efficient and versatile manner. A DFT study on dimethylallenyl precursors agreed with the formation and cycloaddition of a metal-allyl cation intermediate, and points to the 1,2-hydride shift as the key rate-limiting step.

Palladium round trip in the Negishi coupling of trans-[PdMeCl(PMePh2)2] with ZnMeCl: an experimental and DFT study of the transmetalation step.

Compared with the detailed mechanistic knowledge of the Stille reaction, little is known about the Negishi reaction. Recently, we experimentally uncovered the complicated behavior of the transmetalation of transACHTUNGTRENNUNG[PdRfClACHTUNGTRENNUNG(PPh3)2] (Rf= 3,5-dichloro-2,4,6-trifluorophenyl) with ZnMe2 or ZnMeCl, showing that each methylating reagent afforded stereoselectively a different isomer (trans or cis, respectively) of the coupling intermediate [PdRfMe ACHTUNGTRENNUNG(PPh3)2].[4] Moreover, the study revealed the occurrence of undesired transmetalations, such as those shown in Scheme 1, which could eventually produce homocoupling products; the corresponding undesired intermediates were detected and identified by NMR spectroscopy techniques. The formation of undesired intermediates in related reactions with aryl zinc derivatives was later observed by Lei et al. Herein, we report an experimental mechanistic study of the reaction of trans-[PdClMe ACHTUNGTRENNUNG(PMePh2)2] (1) with ZnMeCl, which affords the first experimental determination of thermodynamic parameters of a Negishi transmetalation. This is complemented with a theoretical DFT study, which provides a detailed view of the reaction pathway, consistent with the experimental parameters. The reactions of 1 with ZnMeCl were carried out (with one exception) in 1:20 ratio, simulating catalytic conditions with 5 % Pd, in THF at different temperatures. At room temperature, the only product observed was cis[PdMe2ACHTUNGTRENNUNG(PMePh2)2] (2), in equilibrium with the starting material 1. In these conditions, complex 2 undergoes slow decomposition (reductive elimination) to give ethane. When the reaction was monitored by P NMR spectroscopy at 223 K (Figure 1 a), the coupling rate to give ethane became negligible and the formation of trans-[PdMe2ACHTUNGTRENNUNG(PMePh2)2] (3), as well as cis-[PdMe2ACHTUNGTRENNUNG(PMePh2)2] (2), was observed. The trans isomer 3 seemed to be formed first and then disappeared. The same reaction, carried out at 203 K in 1:1 ratio to get a slower rate of transformation, confirmed that 3 is formed noticeably faster than 2 (Figure 1 b). Thus, the observation of the cis isomer at room temperature is deceptive for the stereoselectivity of the transmetalation. Snapshots of two moments of the transmetalation reaction at 203 K, as seen by P NMR spectroscopy, are shown in Figure 1 c. The behavior of 3 is typical of a kinetic product of noticeably lower stability than the thermodynamic product (2): eventually it disappears from observation as the reaction proceeds and gets closer to the equilibrium concentrations, where the concentration of 3 is very small. In effect, during the progress of the reaction at 223 K (Figure 1 a), the concentration of 2 increases continuously; in contrast, a small accumulation of 3 is produced initially and then its concentration decreases, so that in 300 min 3 has practically disappeared. After about 10 h at 223 K, the system has reached equilibrium between the starting complex 1 and the final thermodynamic product 2 ([1]=5.8 10 3 mol l , [2]=4.4 10 3 mol l , and Keq =2.0 10 ); the concentration of 3 is below the limit of NMR observation. [a] B. Fuentes, Dr. J. A. Casares, Prof. P. Espinet IU CINQUIMA/Qu mica Inorg nica Facultad de CienciasUniversidad de Valladolid 47071 Valladolid (Spain) Fax: (+34) 983423231/ ACHTUNGTRENNUNG(+34) 983186336 E-mail : casares@qi.uva.es espinet@qi.uva.es [b] M. Garc a-Melchor, Prof. A. Lled s, Prof. F. Maseras, Dr. G. Ujaque Qu mica F sica, Edifici C.n, Universitat Aut noma de Barcelona 08193 Bellaterra, Catalonia (Spain) Fax: (+34) 935812920 E-mail : gregori@klingon.uab.es [c] Prof. F. Maseras Institute of Chemical Research of Catalonia (ICIQ) Av. Pa sos Catalans, 16, 43007 Tarragona, Catalonia (Spain) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001332. Scheme 1.

Highly Efficient Redox Isomerisation of Allylic Alcohols Catalysed by Pyrazole‐Based Ruthenium(IV) Complexes in Water: Mechanisms of Bifunctional Catalysis in Water

The catalytic activity of ruthenium(IV) ([Ru(η(3):η(3)-C(10)H(16))Cl(2)L]; C(10)H(16) = 2,7-dimethylocta-2,6-diene-1,8-diyl, L = pyrazole, 3-methylpyrazole, 3,5-dimethylpyrazole, 3-methyl-5-phenylpyrazole, 2-(1H-pyrazol-3-yl)phenol or indazole) and ruthenium(II) complexes ([Ru(η(6)-arene)Cl(2)(3,5-dimethylpyrazole)]; arene = C(6)H(6), p-cymene or C(6)Me(6)) in the redox isomerisation of allylic alcohols into carbonyl compounds in water is reported. The former show much higher catalytic activity than ruthenium(II) complexes. In particular, a variety of allylic alcohols have been quantitatively isomerised by using [Ru(η(3):η(3)-C(10)H(16))Cl(2)(pyrazole)] as a catalyst; the reactions proceeded faster in water than in THF, and in the absence of base. The isomerisations of monosubstituted alcohols take place rapidly (10-60 min, turn-over frequency = 750-3000 h(-1)) and, in some cases, at 35 °C in 60 min. The nature of the aqueous species formed in water by this complex has been analysed by ESI-MS. To analyse how an aqueous medium can influence the mechanism of the bifunctional catalytic process, DFT calculations (B3LYP) including one or two explicit water molecules and using the polarisable continuum model have been carried out and provide a valuable insight into the role of water on the activity of the bifunctional catalyst. Several mechanisms have been considered and imply the formation of aqua complexes and their deprotonated species generated from [Ru(η(3):η(3)-C(10)H(16))Cl(2)(pyrazole)]. Different competitive pathways based on outer-sphere mechanisms, which imply hydrogen-transfer processes, have been analysed. The overall isomerisation implies two hydrogen-transfer steps from the substrate to the catalyst and subsequent transfer back to the substrate. In addition to the conventional Noyori outer-sphere mechanism, which involves the pyrazolide ligand, a new mechanism with a hydroxopyrazole complex as the active species can be at work in water. The possibility of formation of an enol, which isomerises easily to the keto form in water, also contributes to the efficiency in water.

Cationic Intermediates in the Pd-Catalyzed Negishi Coupling. Kinetic and Density Functional Theory Study of Alternative Transmetalation Pathways in the Me–Me Coupling of ZnMe2 and trans-[PdMeCl(PMePh2)2]

The complexity of the transmetalation step in a Pd-catalyzed Negishi reaction has been investigated by combining experiment and theoretical calculations. The reaction between trans-[PdMeCl(PMePh(2))(2)] and ZnMe(2) in THF as solvent was analyzed. The results reveal some unexpected and relevant mechanistic aspects not observed for ZnMeCl as nucleophile. The operative reaction mechanism is not the same when the reaction is carried out in the presence or in the absence of an excess of phosphine in the medium. In the absence of added phosphine an ionic intermediate with THF as ligand ([PdMe(PMePh(2))(2)(THF)](+)) opens ionic transmetalation pathways. In contrast, an excess of phosphine retards the reaction because of the formation of a very stable cationic complex with three phosphines ([PdMe(PMePh(2))(3)](+)) that sequesters the catalyst. These ionic intermediates had never been observed or proposed in palladium Negishi systems and warn on the possible detrimental effect of an excess of good ligand (as PMePh(2)) for the process. In contrast, the ionic pathways via cationic complexes with one solvent (or a weak ligand) can be noticeably faster and provide a more rapid reaction than the concerted pathways via neutral intermediates. Theoretical calculations on the real molecules reproduce well the experimental rate trends observed for the different mechanistic pathways.

Why Is the Suzuki−Miyaura Cross-Coupling of sp3 Carbons in α-Bromo Sulfoxide Systems Fast and Stereoselective? A DFT Study on the Mechanism

The stereoselectivity-determining oxidative addition step in the Suzuki-Miyaura cross-coupling of alpha-bromo sulfoxides is analyzed computationally through DFT calculations on a model system defined by Pd(PMe(3))(2) and CH(3)SOCH(2)Br. Both monophospine and bisphosphine complexes have been considered, different reaction pathways being characterized through location of the corresponding transition states. The lowest energy transition states correspond to nucleophilic substitution mechanisms, which imply inversion of configuration at the carbon, in good agreement with experimental data on the process. The energy-lowering and stereodirecting role of the sulfinyl substituent is explained through its attractive interactions with the palladium center, which are only possible in the most favored mechanisms.

Hydroamination of Alkynes with Ammonia: Unforeseen Role of the Gold(I) Catalyst

The formation of nitrogen–carbon bonds represents a highly valuable synthetic method to prepare products ranging from chemical feedstocks to pharmaceutical materials. It is therefore not surprising that such reactions have been the focus of catalysis research. The use of ammonia as a reactant is highly desired as the addition of NH3 to C C multiple bonds represents a highly attractive process for C N bond formation, and complete atom economy is achieved. Nevertheless, atom-efficient processes for combining NH3 with simple organic molecules are rather scarce. It is known that transition-metal complexes can make N H bonds reactive for additional functionalization, however in most cases when metals react with ammonia (there are some exceptions) the supposedly inert Werner complex is formed. Hence, functionalization of NH3 was difficult to obtain until the groups of Hartwig and Buchwald described the palladium-catalyzed coupling of ammonia with aryl halides. Hydroamination is the addition reaction of the N H bond of an amine moiety to an unsaturated carbon–carbon double bond. Earlier, several metal complexes involving palladium, rhodium, ruthenium, and platinum centers were found to be active catalysts for this process, and gold has been recently identified as an efficient hydroamination catalyst. Bertrand and co-workers recently reported a seminal work describing the hydroamination of a variety of unactivated alkynes and allenes catalyzed by gold complexes prepared with a cyclic (alkyl)(amino)carbene (CAAC; Scheme 1). The authors also carried out mechanistic investigations, in which several gold complexes formed in the presence of ammonia and 3-hexyne were detected. The precursor complex reacted with ammonia to form the cationic complex A, and with 3-hexyne to form complex B (Scheme 2). The addition of NH3 to complex B instantaneously forms complex A. However, A in the excess of the