Josiphos Ligand Research Articles

Palladium‐Catalyzed Chemoselective Mono‐α‐Arylation of O‐Protected Hydroxyacetone with Ortho‐Substituted (Hetero)aryl Electrophiles

AbstractThe mono‐α‐arylation of 2‐tetrahydropyranyl O‐protection of hydroxyacetone is reported. When using a catalyst system comprised of [Pd(cinnamyl)Cl]2 and the JosiPhos ligands PhPF‐tBu or (4‐CF3Ph)PF‐tBu, such transformations are achieved with ortho‐substituted aryl bromides and triflates in the presence of potentially contending functionalities including chloro groups.

An expedient copper-catalysed asymmetric synthesis of γ-lactones and γ-lactams. Application to the synthesis of lucidulactone A.

The parent Josiphos ligand gave excellent ee values (95-99%) and good yields (60-97%) in the copper-catalysed asymmetric conjugate reduction of β-aryl α,β-unsaturated lactones and lactams with PMHS. The substrates were obtained from stereospecific copper-catalysed addition of arylboronic acids to alkynoates followed by deprotection and cyclisation. The acyclic lactam precursors also underwent reduction with good ee values (83-85%) and yields (79-95%). Application of this asymmetric reduction methodology included the synthesis of natural product lucidulactone A.

Simplified Synthesis of an Air-Stable Copper-Complexed Josiphos Ligand via Ugi's Amine: Complete Preparation and Analysis from Ferrocene.

Ligands containing ferrocene backbones often feature both planar chirality and asymmetric centers, making them attractive options for asymmetric catalysis. Ugi's amine is a ubiquitous ferrocene-based chiral building block that can be functionalized to form a variety of tunable Josiphos ligands; however, few sources lay out the route from start to finish. Starting from ferrocene, we compile a synthetic route to an air- and moisture-stable copper(I)-Josiphos complex via enantiopure Ugi's amine, providing a potential one-stop shop for the synthesis of a wide range of Josiphos ligands.

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

Mechanism of regioselectivity of rhodium-catalyzed hydrothiolation of 1,3-dienes: A computational study

Transition mental-catalyzed hydrothiolation of thiol and alkenes, alkynes or dienes is an important method to construct C-S bonds. To understand the control mechanism of the regioselectivity is of great significance in the hydrothiolation of 1,3-dienes which have two unsaturated C=C double bonds for a specific functionalization. In this paper, we explored the regioselective mechanisms of Rh(I)-catalyzed hydrothiolation of 1,3-dienes with different ligands by using density functional theory (DFT) and EDA analysis. The results reveal that the overall catalytic cycle consists of three elementary steps:(i) oxidant addition (ii) Rh-H insertion (iii) C-S reductive elimination. For the cationic catalysts Rh(cod)2SbF6 with JosiPhos ligand, the rate-determining step is Rh-H insertion, in whcih (S)-1,2-Markovnikov addition forming (S)-3a product, is most feasible among the six regio- and enantioselective pathways. The reasons for this phenomenon are steric repulsions and orbital interactions. While for electrically neutral catalysts the rate-determining step turns to be the C-S reductive elimination. The result uncovers that steric repulsions promots 3,4-anti-Markovnikov addition rather than that of 2,1-anti-Markovnikov.

Catalytic Enantioselective Synthesis of Silicon-Stereogenic Alkoxy­silanes and Siloxanes

AbstractA Rh-catalyzed enantioselective intermolecular dehydrogenative Si–O coupling of dihydrosilanes with alcohols and silanols is demonstrated. Rh(I) catalyst equipped with a Josiphos ligand enables the highly enantioselective alcoholysis process of dihydrosilanes, giving access to a variety of functionalized triorgano-substituted silicon-stereogenic alkoxysilanes and siloxanes in decent yields and ee, which significantly expand the chemical space of the silicon-centered chiral molecules. Utility of this methodology is illustrated by the construction of circularly polarized luminescence (CPL) active chiral alkoxysilane small organic molecules.1 Introduction2 Conditions Optimization3 Substrate Scope4 Application5 Conclusions6 Experimental Procedure

The Mechanism and Origin of Enantioselectivity in the Rhodium-Catalyzed Asymmetric Ring-Opening Reactions of Oxabicyclic Alkenes with Organoboronic Acids: A DFT Investigation

The mechanism and origins of enantio- and stereoselectivity in the asymmetric ring-opening (ARO) reactions of oxabicyclic alkenes with organoboronic acids catalyzed by rhodium/Josiphos has been examined at the B3LYP/defTZVP level of theory. The mechanism consists of four steps including transmetalation, carborhodation, β-oxygen elimination, and hydrolysis. Energetic discrimination in the chirality-imparting step arises from attractive C–H−π interactions between the transmetalated aryl group and the Josiphos ligand, as well as steric clashes between the Josiphos ligand and the oxabicyclic alkene. Computational results indicate that the rate-determining step is involved in the hydrolysis of the rhodium(I) alkoxide from the ring-opened intermediate. In the overall catalytic cycle, the greatest free energy barrier is 23.4 kcal/mol, which supports that the Rh-catalyzed ARO reactions take place at mild reaction conditions, which is consistent with experimental observations.

Copper(I) Complexes of P‐Stereogenic Josiphos and Related Ligands

AbstractStarting from (R)‐Ugi's amine, diastereoselective lithiation followed by Ar'PCl2 and then Ar’’MgBr led to the generation, as single diastereoisomers, of (R,Sp,Sphos) [Ar’=Ph, Ar’’=o‐Tol] and (R,Sp,Rphos) [Ar’=o‐Tol, Ar’’=Ph] PPFA ligand derivatives. Amine substitution of both with HPCy2 gave P‐stereogenic Josiphos ligands, and then addition of CuCl, the corresponding copper(I) complexes. The latter were also generated by using borane P and N protecting groups and in situ Cu(I) complexation, avoiding the isolation of air‐sensitive phosphine intermediates. This protection methodology was also applied to the synthesis of Josiphos/CuCl complexes derived from PCl3. In addition, related bulky cobalt‐sandwich complex‐based derivatives were also obtained. Preliminary investigation revealed isolated CuCl complexes as competent catalyst precursors for enantioselective conjugate addition reactions.

Enantioselective Hydrothiolation: Diverging Cyclopropenes through Ligand Control.

In this article, we advance Rh-catalyzed hydrothiolation through the divergent reactivity of cyclopropenes. Cyclopropenes undergo hydrothiolation to provide cyclopropyl sulfides or allylic sulfides. The choice of bisphosphine ligand dictates whether the pathway involves ring-retention or ring-opening. Mechanistic studies reveal the origin for this switchable selectivity. Our results suggest the two pathways share a common cyclopropyl-Rh(III) intermediate. Electron-rich Josiphos ligands promote direct reductive elimination from this intermediate to afford cyclopropyl sulfides in high enantio- and diastereoselectivities. Alternatively, atropisomeric ligands (such as DTBM-BINAP) enable ring-opening from the cyclopropyl-Rh(III) intermediate to generate allylic sulfides with high enantio- and regiocontrol.

Computational Analysis on the Pd-Catalyzed C-N Coupling of Ammonia with Aryl Bromides Using a Chelate Phosphine Ligand.

The Buchwald-Hartwig amination of arylhalides with the Pd-Josiphos complex is a very useful process for the generation of primary amines using ammonia as a reactant. Density-functional theory (DFT) calculations are carried out to examine the reaction mechanism for this process. Although the general mechanism for the C-N cross-coupling reaction is known, there are still some open questions regarding the effect of a chelate phosphine ligand and the role of the base in the process. Reaction pathways involving the release of one of the arms of the phosphine ligand are compared with those where the chelate phosphine remains fully coordinated. Conformational analysis for the complex with the open chelate phosphine is required to properly evaluate the proposed pathways. The role played by the added base (t-BuO-) as a possible ligand or just as a base was also evaluated. The understanding of all of these aspects allowed us to propose a complete reaction mechanism for the Pd-catalyzed C-N coupling of arylhalides with ammonia using the chelate Josiphos ligand.

Having Fun (and Commercial Success) with Josiphos and Related Chiral Ferrocene Based Ligands.

AbstractThe Josiphos ligand family is arguably one of the most versatile classes of chiral ligands with a wide range of applications, including one of the two largest known enantioselective catalytic hydrogenations. In this personal account, we take a look back at the beginning and describe the role Antonio Togni has played to reach this point and the significance of his contributions for the commercial success, especially concerning today's ligand business of Solvias. This seems a fitting point in time in light of Antonio’s statement on his ETH home page that he ‘is working as a professor at this institution since 1992 (a few more months to go), not looking for a job’ and that the three authors have already retired for some time (H. U. B.) or are about to retire soon (B. P., F. S.).

Nickel‐Catalyzed Mono‐Selective α‐Arylation of Acetone with Aryl Chlorides and Phenol Derivatives

The challenging nickel-catalyzed mono-α-arylation of acetone with aryl chlorides, pivalates, and carbamates has been achieved for the first time. A nickel/Josiphos-based catalytic system is shown to feature unique catalytic behavior, allowing the highly selective formation of the desired mono-α-arylated acetone. The developed methodology was applied to a variety of (hetero)aryl chlorides including biologically relevant derivatives. The methodology has been extended to the unprecedented coupling of acetone with phenol derivatives. Mechanistic studies allowed the isolation and characterization of key Ni0 and NiII catalytic intermediates. The Josiphos ligand is shown to play a key role in the stabilization of NiII intermediates to allow a Ni0 /NiII catalytic pathway. Mechanistic understanding was then leveraged to improve the protocol using an air-stable NiII pre-catalyst.

Synthesis of Enantioenriched β-Aryl-β-aryloxy Esters via Sequential Photoisomerization and Enantioselective Hydrogenation.

A general method to prepare valuable chiral synthon β-aryl-β-aryloxy esters from enantioselective hydrogenation of (E)-β-aryl-β-aryloxy-α,β-unsaturated esters is described. The E-isomer was prepared via isomerization of the mixture of E- and Z-isomers using photocatalyst [Ir(ppy)2(dtbbpy)]PF6. A laser as the light source facilitated isomerization with only 0.05 mol % catalyst. The enantioselective hydrogenation was conducted with (NBD)2Rh(BF4) and a commercially available Josiphos ligand to provide the synthons in up to 95% yield with 97% ee.

Copper-Catalyzed Asymmetric Reduction of β,β-Disubstituted Alkenylboramides.

A highly enantioselective copper-catalyzed reduction of β,β-disubstituted alkenylboron compounds was developed using hydrosilane. The copper hydride catalyst coordinated with chiral Josiphos ligand efficiently discriminated β-geminal substituents to generate corresponding β-chiral alkylboramides with excellent enantioselectivities up to 99% ee. The enantioselective reduction protocol provides a facile approach to β-chiral alkylboron compounds with less sterically discriminating substituents and spans a wide substrate range including aryl-substituted borylalkenes with effective functional group tolerance.

Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands.

The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2 , Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.

Buckminsterfullerene (Fullerene), bullvalene, dickite and josiphos ligands nano molecules incorporation into the nano polymeric matrix (NPM) by immersion of the nano polymeric modified electrode (NPME) as molecular enzymes and drug targets for human hematology and thromboembolic diseases prevention, diagnosis and treatment under synchrotron and synchrocyclotron radiations

Buckminsterfullerene (Fullerene), bullvalene, dickite and josiphos ligands nano molecules incorporation into the nano polymeric matrix (NPM) by immersion of the nano polymeric modified electrode (NPME) as molecular enzymes and drug targets for human hematology and thromboembolic diseases prevention, diagnosis and treatment under synchrotron and synchrocyclotron radiations

Enantioselective semireduction of allenes

Rh-hydride catalysis solves a synthetic challenge by affording the enantioselective reduction of allenes, thereby yielding access to motifs commonly used in medicinal chemistry. A designer Josiphos ligand promotes the generation of chiral benzylic isomers, when combined with a Hantzsch ester as the reductant. This semireduction proceeds chemoselectively in the presence of other functional groups, which are typically reduced using conventional hydrogenations. Isotopic labelling studies support a mechanism where the hydride is delivered to the branched position of a Rh-allyl intermediate.

Nickel‐Catalyzed Amination of Aryl Carbamates with Ammonia

Aryl carbamates were employed in the nickel‐catalyzed monoarylation of ammonia. The applied, well‐defined single‐component nickel(II) precatalyst contains a Josiphos ligand, is air‐stable, and operates without any ancillary reductant. This catalyst system also promotes the amination of aryl carbamates with ammonium sulfate as well as with hydrochloride salts of primary alkylamines. Their easy preparation, robustness, and directing group ability makes aryl carbamates particularly attractive synthetic intermediates.

ChemInform Abstract: Selective Palladium‐Catalyzed Amination of 4‐Chloropyridines with Benzylamines Using the Josiphos Ligand.

ChemInform Abstract: Selective Palladium‐Catalyzed Amination of 4‐Chloropyridines with Benzylamines Using the Josiphos Ligand.

Enantioselective ruthenium-catalyzed carbonyl allylation via alkyne-alcohol C-C bond-forming transfer hydrogenation: allene hydrometalation vs oxidative coupling.

Chiral ruthenium(II) complexes modified by Josiphos ligands catalyze the reaction of alkynes with primary alcohols to form homoallylic alcohols with excellent control of regio-, diastereo-, and enantioselectivity. These processes represent the first examples of enantioselective carbonyl allylation using alkynes as allylmetal equivalents.