Emma Drinkel

Unprecedented Selectivity via Electronic Substrate Recognition in the 1,4‐Addition to Cyclic Olefins Using a Chiral Disulfoxide Rhodium Catalyst

From zero to hero? Sulfoxides are generally not considered useful ligand entities in asymmetric metal catalysis. However, a chiral disulfoxide as a chelating ligand in the rhodium-catalyzed 1,4-addition of aryl boronic acids to cyclic, alpha,beta-unsaturated ketones and esters gives impressive catalytic results, thus opening the door to future applications of this new chiral ligand class.

Room-temperature synthesis of tetra-ortho-substituted biaryls by NHC-catalyzed Suzuki-Miyaura couplings

Transition-metal-catalyzed cross couplings have become some of the most powerful and widely used methods to construct C C bonds. Among them, the Suzuki–Miyaura coupling, has emerged as a particularly attractive and practical tool for synthetic organic chemistry. Indeed, over the last decade, several limitations of this methodology have been successfully addressed by using bulky, electron-rich monodentate phosphines or sterically demanding NHC ligands (NHC= N-heterocyclic carbene). One of the few challenges remaining in the Suzuki–Miyaura coupling reaction involves transformations with sterically demanding substrates that lead to tetra-ortho-substituted products. Especially in cases where aryl chlorides are used, the relatively poor nucleophilicity of the arylboron reagents results in diminished catalytic activities. In 2004, Glorius and co-workers showed for the first time that aryl chlorides can indeed be coupled to aryl boronic acids to generate such tetra-orthosubstituted biaryls at elevated temperature (110 8C) by employing a very bulky, yet flexible derivative of their bioxazoline-derived NHC ligands in combination with a Pd metal salt. More recently in 2009 and following the same concept of flexible steric bulk of the NHC ligand, Organ and coworkers used the complex Pd-PEPPSI-IPent as the catalyst for the Suzuki–Miyaura couplings to form bulky tetra-orthosubstituted biaryls at milder conditions (65 8C). Since then, various other ligand systems have been shown to effect similar couplings involving aryl chlorides when appropriate heating is employed. To date, systems that work at room temperature have not been reported for the construction of these important tetra-ortho-substituted biaryl structures by way of the Suzuki–Miyaura coupling. Recently, we have presented a new class of saturated NHC ligands with naphthyl-derived side chains that showed excellent reactivities in a variety of catalytic applications. In related studies, we noticed that a ligand with a cyclooctyl group in position 2 of the naphthalene moieties led to significantly increased reactivity. On the basis of these observations, we now report the application of such NHC ligand systems in the palladium-catalyzed Suzuki–Miyaura couplings to give tetra-ortho substituted biaryls and present conclusive evidence concerning the reasons leading to their superior behavior in these reactions. Reaction of NHC ligands with saturated and unsaturated N-heterocycles incorporating 2or 2,7-cyclooctyl groups on the naphthalene side chains with a Pd ACHTUNGTRENNUNG(cin)Cl dimer (cin =cinnamyl) and appropriate workup gave the four complexes depicted in Table 1 in good yield as single isomers (anti-configured). To explore the effect of these new NHC ligands on biaryl formation in difficult Suzuki–Miyaura couplings, we chose the reaction between 2,4,6-trimethylphenyl chloride and 2,6dimethylphenyl boronic acid (Table 1). Under optimized reaction conditions, the four new catalyst systems were benchmarked against the commercially available, SIPr/IPrmodified congeners (Nolan s catalysts) as well as Organ s Pd-PEPPSI-IPent system, currently the most powerful precatalyst for such transformations. At room temperature, these reference systems resulted in low product yields (Table 1, entries 1–5, GC yields). In entries 4 and 5 in Table 1, we used Organ s previously reported reaction conditions, which deteriorated the reaction outcome. Gratifyingly, all catalysts incorporating the new NHC structures showed higher conversions and yields than the benchmark systems. Among the four substructures tested, anti-C clearly stands out as being particularly effective as it shows both high conversions and yields at room temperature. We then proceeded in evaluating the coupling of a variety of hindered aryl bromides (Table 2) and aryl chlorides (Table 3) employing precatalyst anti-C. As can be seen from the data reported in Table 2, high isolated product yields were normally obtained at room temperature within short reaction times when employing aryl bromides. In entry 2 in Table 2, where the coupling proceeded very slowly at room temperature, slight heating (65 8C) was applied, leading to a [a] L. Wu, E. Drinkel, F. Gaggia, S. Capolicchio, Priv.-Doz. Dr. A. Linden, Prof. Dr. R. Dorta Organisch-chemisches Institut, Universit t Z rich Winterthurerstrasse 190, 8057 Z rich (Switzerland) E-mail : dorta@oci.uzh.ch [b] L. Falivene, Prof. Dr. L. Cavallo Dipartimento di Chimica Universit di Salerno Via Ponte don Melillo, 84084 Fisciano (Italy) [] New Address: School of Biomedical, Biochemical and Chemical Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009 (Australia) [**] NHC=N-heterocyclic carbene. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201102442.

Highly Chemo- and Enantioselective Synthesis of 3-Allyl-3-aryl Oxindoles via the Direct Palladium-Catalyzed α-Arylation of Amides

A new NHC x Pd-catalyzed asymmetric alpha-arylation of amides is reported that gives direct access to synthetically valuable, allylated oxindoles with quaternary carbon centers. The reaction is made possible by the introduction of a new chiral NHC ligand. The palladium complexes derived therefrom combine excellent reactivity with high chemo- and enantioselectivity for the title transformation.

Impact of NHC ligand conformation and solvent concentration on the ruthenium-catalyzed ring-closing metathesis reaction

Two saturated N-heterocyclic carbene ligands with substituted naphthyl side chains were used for the preparation of Blechert-type ruthenium metathesis precatalysts. The resulting conformers of the complexes were separated and unambiguously assigned by X-ray diffraction studies. All new complexes were compared in terms of activity to the original, SIMes-derived Blechert catalyst and were shown to be superior. A study on the impact of solvent concentration in RCM reactions using the most active of these new catalysts ultimately led to the ring closing of a variety of substrates at very low catalyst loadings.

C2-Symmetric Chiral Disulfoxide Ligands in Rhodium-Catalyzed 1,4-Addition: From Ligand Synthesis to the Enantioselection Pathway

A family of chiral C(2)-symmetric disulfoxide ligands possessing biaryl atropisomeric backbones has been synthesized by using the Andersen methodology. Complete characterization includes X-ray crystallographic studies of all ligands and some of their rhodium complexes. Their synthesis, optical purity, electronic properties, and catalytic behavior in the prototypical rhodium-catalyzed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one are presented through an in depth study of this ligand class. Density functional theory calculations on the step of the catalytic cycle that determines the enantioselectivity are presented and reinforce the first hypothetical explanations for the high levels of asymmetric induction observed.

Efficient Ring-Closing Metathesis of Alkenyl Bromides: The Importance of Protecting the Catalyst during the Olefin Approach

We present the first productive ring-closing metathesis reaction that leads to the construction of cyclic alkenyl bromides. Efficient catalysis employing commercially available Grubbs II catalyst is possible through appropriate modification of the starting bromoalkene moiety.