Dirhodium Catalysts Research Articles

Facile Recovery and Recycling of a Soluble Dirhodium Catalyst in Asymmetric Cyclopropanation via a Catalyst-in-Bag System

Facile Recovery and Recycling of a Soluble Dirhodium Catalyst in Asymmetric Cyclopropanation via a Catalyst-in-Bag System

Diaryldiazoketones as Effective Carbene Sources for Highly Selective Rh(II)-Catalyzed Intermolecular C-H Functionalization.

A novel donor/acceptor carbene intermediate has been developed using diaryldiazoketones as carbene precursors. In the presence of the chiral dirhodium catalyst, Rh2(S-TPPTTL)4, diaryldiazoketones undergo highly regio-, stereo-, and diastereoselective C-H functionalization of activated and unactivated secondary and tertiary C-H bonds. Computational studies revealed that the arylketo group behaves differently than the carboxylate acceptor group because the orientation of the arylketo group predetermines which face of the carbene will be attacked.

Running Wild through Dirhodium Tetracarboxylate-Catalyzed Combined CH(C)-Functionalization/Cope Rearrangement Landscapes: Does Post-Transition-State Dynamic Mismatching Influence Product Distributions?

A special type of C-H functionalization can be achieved through C-H insertion combined with Cope rearrangement (CHCR) in the presence of dirhodium catalysts. This type of reaction was studied using density functional theory and ab initio molecular dynamics simulations, the results of which pointed to the dynamic origins of low yields observed in some experiments. These studies not only reveal intimate details of the complex reaction network underpinning CHCR reactions but also further cement the generality of the importance of nonstatistical dynamic effects in controlling Rh2L4-promoted reactions.

Self‐Supported Heterogeneous Dirhodium(II) Catalyst for Nitrene and Carbene Transfer Reactions

AbstractThe bimetallic rhodium(II) paddlewheel (Rh2A4) complex is one of the most reactive classes of rhodium catalysts, well‐renowned for the most demanding carbene‐ and nitrene‐transfer reactions. In view of its importance in modern synthetic chemistry, we herein report a facile approach for preparing a self‐supported and reusable dirhodium(II) polymer‐based heterogeneous catalyst through a reductive ligation protocol. The catalyst displays good reactivity for inter‐ and intramolecular nitrene‐ and carbene‐insertions of various olefins, and can also engage in C−H insertion of hydrocarbon derivatives, all under ambient conditions. The catalyst reusability is expected to empower the use of these precious metal catalysts at industrial scales.

Stereoselective Synthesis of Either Exo- or Endo-3-Azabicyclo[3.1.0]hexane-6-carboxylates by Dirhodium(II)-Catalyzed Cyclopropanation with Ethyl Diazoacetate under Low Catalyst Loadings.

Although cyclopropanation with donor/acceptor carbenes can be conducted under low catalyst loadings (<0.001 mol %), such low loading has not been generally effective for other classes of carbenes such as acceptor carbenes. In this current study, we demonstrate that ethyl diazoacetate can be effectively used in the cyclopropanation of N-Boc-2,5-dihydropyrrole with dirhodium(II) catalyst loadings of 0.005 mol %. By appropriate choice of catalyst and hydrolysis conditions, either the exo- or endo-3-azabicyclo[3.1.0]hexanes can be formed cleanly with high levels of diastereoselectivity with no chromatographic purification.

Dirhodium(II) complex catalyzed dehydrosilylation of styrenes: theoretical investigations on the mechanism, selectivity, and ligand effects.

The dirhodium(II) complexes with bridging phosphine and OAc ligands showed high reactivity and selectivities in olefin dehydrosilylation. In order to determine the structure of the actual catalyst which cannot be determined experimentally, the geometries of the dirhodium catalyst, the detailed catalytic mechanism, and the stereo- and chemo-selectivities of the title reaction were studied using DFT calculations. The results showed that one OAc group is monodentate and the other is bidentate in the dirhodium catalyst C'. The determined catalytic cycle consists of four processes: Rh-H bond activation in C', Si-H bond activation in alkoxysilane, alkylene insertion into the Rh-Si bond, followed by β-H elimination or σ-metathesis reaction. Among them, the alkylene insertion process is the rate-determining step. The stereoselectivity of the title reaction is controlled by the steric effect and orbital interactions between the alkyene and dirhodium catalysts in the β-H elimination process. The chemoselectivity is regulated by the presence of the axial ligand in the dirhodium catalyst, when there is an axial ligand coordinated to the Rh atom, E-alkene is the main product, whereas alkane would be obtained in the absence of an axial ligand. Our work determines the structure of the actual catalyst, and provides explanations and predictions for the activity, and chemo- and stereo-selectivity control of olefin dehydrosilylation.

Dirhodium-Catalyzed Enantioselective Synthesis of Difluoromethylated Cyclopropanes via Enyne Cycloisomerization.

(Difluoromethylated cyclopropane represents an important motif, which is widely found in bioactive and functional molecules. Despite significant progress in modern chemistry, the atom-economic and enantioselective synthesis of difluoromethylated cyclopropanes is still challenging. Herein, an Rh2 (II)-catalyzed asymmetric enyne cycloisomerization is described to construct chiral difluoromethylated cyclopropane derivatives with up to 99% yield and 99% ee in low catalyst loading (0.2 mol%), which can be easily transformed into highly functionalized difluoromethylated cyclopropanes with vicinal all-carbon quaternary stereocenters by ozonolysis. Mechanistic studies and the crystal structures of alkyne-dirhodium complexes reveal that the cooperative weak hydrogen bondings between the substrates and the dirhodium catalyst may play key roles in this reaction.).

Theoretical Analysis of a Three-Component Reaction between Two Diazo Compounds and a Hydroxylamine Derivative: Mechanism, Enantioselectivity, and Effect of Cooperative Catalysis.

The mechanism, enantioselectivity, and effect of chiral phosphoric acid (CPA) cocatalyst were investigated by the density functional theory (DFT) for the three-component asymmetric aminohydroxylation between two diazo compounds and a hydroxylamine derivative. This type of cascade process is cooperatively catalyzed by Rh2(OAc)4 and CPA. The obtained results clearly indicate that the first step of the global reaction involves a nucleophilic attack at the nitrogen center of N-hydroxyaniline by rhodium-carbene intermediates producing imines. Subsequently, an enolate intermediate was recognized as the key species generated from the second diazo compound and the leaving benzyl alcohol (BnOH) fragment of the first step and in the presence of the same dirhodium catalyst. Then, the reaction is terminated by the asymmetric Mannich-type addition, delivering the aminohydroxylation products of an S-R conformation with the assistance of chiral phosphoric acid. The distortion/interaction analysis shows that the relative distortions of CPA and the enol play a vital role in the energy ordering of the stereocontrolling transition states (TSs). Furthermore, the influence of different substituents in CPA was fully rationalized by distortion/interaction analysis. This study opens up novel synthetic possibilities and improves the reaction predictability when exploring the related types of cooperatively catalyzed organic transformations.

Synthesis of 6β-hydroxy androgens from a 3,5-diene steroid precursor to test for cytochrome P450 3A4-catalyzed hydroxylation of androstenedione

6β-Hydroxytestosterone is a biomarker for the activity of human cytochrome P450 3A4 (P450 3A4), the major drug metabolizing cytochrome P450 enzyme. Despite its significance, efficient routes for the chemical synthesis of 6β-hydroxytestosterone are rare. In this study, 6β-hydroxytestosterone was synthesized through the oxidation of a 3,5-diene precursor under the Uemura-Doyle reaction conditions using a dirhodium catalyst in the presence of tert-butylhydroperoxide. Mechanistic studies showed that some oxygen is incorporated from molecular oxygen and CH abstraction is partially rate-limiting. This reaction was used to synthesize 6β-hydroxyandrostenedione, which was used as a standard to test the hypothesis of whether P450 3A4 catalyzes the hydroxylation of androstenedione. Upon incubation of P450 3A4 with androstenedione, a hydroxylated product was formed, which matched the retention time of synthetic 6β-hydroxyandrostenedione. This reaction can be exploited to study other biochemical processes involving compounds with a 6 β -hydroxy-3-keto-Δ4 steroid backbone.

Enantioselective Synthesis of Biscyclopropanes Using Alkynes as Dicarbene Equivalents

AbstractChiral biscyclopropanes are an important skeleton in many bioactive molecules. However, there are few routes to synthesize these molecules with high stereoselectivity due to the nature of multiple stereocenters. Herein, we report the first example of Rh2(II)‐catalyzed enantioselective synthesis of bicyclopropanes with alkynes as dicarbene equivalents. The bicyclopropanes with 4–5 vicinal stereocenters and 2–3 all‐carbon quaternary centers were constructed in excellent stereoselectivity. This protocol features high efficiency and excellent functional group tolerance. Moreover, the protocol was also extended to the cascaded cyclopropanation/cyclopropenation with excellent stereoselectivities. In these processes, both sp‐carbons of alkyne were converted into stereogenic sp3‐carbons. Experimental and density functional theory (DFT) calculations revealed that the cooperative weak hydrogen bonds between the substrates and the dirhodium catalyst may play key roles in this reaction.

Enantioselective Synthesis of Biscyclopropanes Using Alkynes as Dicarbene Equivalents.

Chiral biscyclopropanes are an important skeleton in many bioactive molecules. However, there are few routes to synthesize these molecules with high stereoselectivity due to the nature of multiple stereocenters. Herein, we report the first example of Rh2 (II)-catalyzed enantioselective synthesis of bicyclopropanes with alkynes as dicarbene equivalents. The bicyclopropanes with 4-5 vicinal stereocenters and 2-3 all-carbon quaternary centers were constructed in excellent stereoselectivity. This protocol features high efficiency and excellent functional group tolerance. Moreover, the protocol was also extended to the cascaded cyclopropanation/cyclopropenation with excellent stereoselectivities. In these processes, both sp-carbons of alkyne were converted into stereogenic sp3 -carbons. Experimental and density functional theory (DFT) calculations revealed that the cooperative weak hydrogen bonds between the substrates and the dirhodium catalyst may play key roles in this reaction.

Aspartyl β-Turn-Based Dirhodium(II) Metallopeptides for Benzylic C(sp3)-H Amination: Enantioselectivity and X-ray Structural Analysis.

Amination of C(sp3)-H bonds is a powerful tool to introduce nitrogen into complex organic frameworks in a direct manner. Despite significant advances in catalyst design, full site- and enantiocontrol in complex molecular regimes remain elusive using established catalyst systems. To address these challenges, we herein describe a new class of peptide-based dirhodium(II) complexes derived from aspartic acid-containing β-turn-forming tetramers. This highly modular system can serve as a platform for the rapid generation of new chiral dirhodium(II) catalyst libraries, as illustrated by the facile synthesis of a series of 38 catalysts. Critically, we present the first crystal structure of a dirhodium(II) tetra-aspartate complex, which unveils retention of the β-turn conformation of the peptidyl ligand; a well-defined hydrogen-bonding network is evident, along with a near-C4 symmetry that renders the rhodium centers inequivalent. The utility of this catalyst platform is illustrated by the enantioselective amination of benzylic C(sp3)-H bonds, in which state-of-the-art levels of enantioselectivity up to 95.5:4.5 er are obtained, even for substrates that present challenges with previously reported catalyst systems. Additionally, we found these complexes to be competent catalysts for the intermolecular amination of N-alkylamides via insertion into the C(sp3)-H bond α to the amide nitrogen, yielding differentially protected 1,1-diamines. Of note, this type of insertion was also observed to occur on the amide functionalities of the catalyst itself in the absence of the substrate but did not appear to be detrimental to reaction outcomes when the substrate was present.

In-situ Kinetic Studies of Rh(II)-Catalyzed C-H Functionalization to Achieve High Catalyst Turnover Numbers.

Detailed kinetic studies on the functionalization of unactivated hydrocarbon sp3 C-H bonds by dirhodium-catalyzed reaction of aryldiazoacetates revealed that the C-H functionalization step is rate-determining. The efficiency of this step was increased by using the hydrocarbon as solvent and using donor/acceptor carbenes with an electron-withdrawing substituent on the aryl donor group. The optimum catalyst for these reactions is the tetraphenylphthalimido derivative Rh2(R-TPPTTL)4 and a further beneficial refinement was obtained by using N,N'-dicyclohexylcarbodiimide as an additive. Under the optimum conditions with a catalyst loading of 0.001 mol %, effective enantioselective C-H functionalization (66-97% yield, 83-97% ee) was achieved of cycloalkanes with a range of aryldiazoacetates as long as the aryldiazoacetate was not to sterically demanding. The reaction with cyclohexane using a catalyst loading of 0.0005 mol % could be recharged twice with additional aryldiazoacetate, resulting in an overall dirhodium catalyst turnover number of 580,000.

Dirhodium complex immobilization on modified cellulose for highly selective heterogeneous cyclopropanation reactions

A novel, efficient approach for the functionalization of microcrystalline cellulose (MCC) is presented. The as-obtained material allows the immobilization of chiral dirhodium catalysts preserving their enantioselectivity in asymmetric cyclopropanation reactions. As model, microcrystalline cellulose is modified with a polyethylene glycol derived linker, and Rh2(S-DOSP)4 is grafted on the material to produce a heterogeneous catalyst. SEM images at different stages of the immobilization show an unchanging uniform morphology, providing constantly good separation characteristics. The modification of the cellulose material with the polyethylene derived linker and the immobilization process are monitored using DNP enhanced 1H → 13C CP MAS NMR, quantitative 19F MAS NMR, TGA and ICP-OES analysis, confirming the success of the immobilization as well as the stability of bonds between the used linker molecule and the cellulose material. Finally, the evaluation of the produced catalyst is demonstrated in the asymmetric cyclopropanation reaction between styrene and methyl(E)-2-diazo-4-phenylbut-3-enoate showing excellent enantioselectivity with an ee of nearly 90% over a wide temperature range as well as good recyclability characteristics in four consecutive catalysis cycles.

Front Cover: Rh(II)‐catalyzed Intermolecular Benzylic C(sp3)−H Alkylation of Methyl‐substituted Arenes by N‐Aryl‐α‐diazo‐β‐amidoesters (ChemCatChem 11/2022)

The Front Cover depicts the ability of N-aryl-α-diazo-β-amidoesters to bypass a maze representing the circuitous route to the functionalization of C(sp3)−H bonds. In their Research Article, S. Yuan et al. showcase N-aryl-α-diazo-β-amidoesters as competent carbene precursors for rhodium-catalyzed benzylic C(sp3)−H alkylations of methyl-substituted arenes that provide products exhibiting exceptional orthogonality about the carbonyl groups. Selectivity for benzylic vs aromatic C−H bonds was influenced by both the steric environment about the site of reaction and about the dirhodium catalyst. The combination of a highly electrophilic carbene and transition state stabilization provided by an intramolecular hydrogen bond resulted in a broad substrate scope with good functional group tolerance. More information can be found in the Research Article by S. Yuan et al.

Rh(II)‐catalyzed Intermolecular Benzylic C(sp3)−H Alkylation of Methyl‐substituted Arenes by N‐Aryl‐α‐diazo‐β‐amidoesters

AbstractHerein, a general approach to intermolecular benzylic C(sp3)−H alkylation of methyl‐substituted arenes is reported using metal carbenes derived from N‐aryl‐α‐diazo‐β‐amidoesters and dirhodium catalysts. Alkylated products were formed in up to 81 % yield with demonstrated functional group tolerance, outpacing previous literature. The unique amide‐ester scaffolding can be exploited through various derivatizations for broad synthetic utility and provides a starting point for the development of selectivity rules and reactivity profiles for these intermolecular C(sp3)−H functionalizations.

Mechanistically Guided Workflow for Relating Complex Reactive Site Topologies to Catalyst Performance in C-H Functionalization Reactions.

Leveraging congested catalyst scaffolds has emerged as a key strategy for altering innate substrate site-selectivity profiles in C-H functionalization reactions. Similar to enzyme active sites, optimal small molecule catalysts often feature reactive cavities tailored for controlling substrate approach trajectories. However, relating three-dimensional catalyst shape to reaction output remains a formidable challenge, in part due to the lack of molecular features capable of succinctly describing complex reactive site topologies in terms of numerical inputs for machine learning applications. Herein, we present a new set of descriptors, "Spatial Molding for Approachable Rigid Targets" (SMART), which we have applied to quantify reactive site spatial constraints for an expansive library of dirhodium catalysts and to predict site-selectivity for C-H functionalization of 1-bromo-4-pentylbenzene via donor/acceptor carbene intermediates. Optimal site-selectivity for the terminal methylene position was obtained with Rh2(S-2-Cl-5-MesTPCP)4 (30.9:1 rr, 14:1 dr, 87% ee), while C-H functionalization at the electronically activated benzylic site was increasingly favored for Rh2(TPCP)4 catalysts lacking an ortho-Cl, Rh2(S-PTAD)4, and Rh2(S-TCPTAD)4, respectively. Intuitive global site-selectivity models for 25 disparate dirhodium catalysts were developed via multivariate linear regression to explicitly assess the contributing roles of steric congestion and dirhodium-carbene electrophilicity in controlling the site of C-H functionalization. The workflow utilizes spatial classification to extract descriptors only for reactive catalyst conformers, a nuance that may be widely applicable for establishing close correspondence between ground-state model systems and transition states. Broader still, SMART descriptors are amenable for delineating salient reactive site features to predict reactivity in other chemical and biological contexts.

C(sp3)–H 1,3-diamination of cumene derivatives catalyzed by a dirhodium(ii) catalyst

Using the single-electron oxidation cycle of a dirhodium catalyst, amination can form two primary C–N bonds in a one-step process.

Immobilization of a chiral dirhodium catalyst on SBA-15 via click-chemistry: Application in the asymmetric cyclopropanation of 3-diazooxindole with aryl alkenes

A novel immobilized chiral dirhodium catalyst, Rh2(S-PTTL)3(S-PTTL-linker)∼SBA-15 (8), has been prepared via click reaction of azide-groups on functionalized SBA-15 with the dirhodium complex Rh2(S-PTTL)3(S-PTTL-alkyne) (6) containing an alkyne moiety. During the synthesis of this complex, one chiral ligand of the parent Rh2(S-PTTL)4 catalyst is exchanged with an analogous chiral ligand system containing an alkyne moiety, which to a great extent maintains the intrinsic catalytic performance of the catalyst. The heterogeneous dirhodium catalyst is characterized by FT-IR and 13C solid-state NMR to validate the successful immobilization. The catalytic performance of the heterogeneous catalyst 8 is investigated in the asymmetric cyclopropanation of 3-diazooxindole with different aryl alkenes that form spiro-cyclopropyloxindoles which serve as precursors for pharmaceuticals. The resulting heterogeneous catalyst shows high catalytic activity and significant enantioselectivity. Importantly, it can be readily recovered and reused at least four times without significant loss of its catalytic performance.

Chiral Dirhodium Tetraphosphate-Catalyzed Enantioselective Si-H Bond Insertion of α-Aryldiazoacetates.

A highly enantioselective Si-H bond insertion reaction of α-aryldiazoacetates catalyzed by chiral spiro dirhodium tetraphosphate was developed. Various chiral α-silyl esters were prepared with high yield (up to 92%) and excellent enantioselectivity (up to >99% ee) through this protocol. It is noteworthy that the 2-substituted aryl diazoacetates, which are challenging substrates for other chiral dirhodium catalysts, also exhibited good results in this reaction. This work represents one of the few successful applications of chiral dirhodium phosphates in asymmetric catalysis.