Rhodium Carbenoid Research Articles

Rhodium(I)-Catalyzed Annulation of Bicyclo[1.1.0]butyl-Substituted Dihydroquinolines and Dihydropyridines.

Bicyclo[1.1.0]butane-containing compounds feature a unique chemical reactivity, trigger "strain-release" reaction cascades, and provide novel scaffolds with considerable utility in the drug discovery field. We report the synthesis of new bicyclo[1.1.0]butane-linked heterocycles by a nucleophilic addition of bicyclo[1.1.0]butyl anions to 8-isocyanatoquinoline, or, alternatively, iminium cations derived from quinolines and pyridines. The resulting bicyclo[1.1.0]butanes are converted with high regioselectivity to unprecedented bridged heterocycles in a rhodium(I)-catalyzed annulative rearrangement. The addition/rearrangement process tolerates a surprisingly large range of functional groups. Subsequent chemo- and stereoselective synthetic transformations of urea, alkene, cyclopropane, and aniline moieties of the 1-methylene-5-azacyclopropa[cd]indene scaffolds provide several additional new heterocyclic building blocks. X-ray structure-validated quantum mechanical DFT calculations of the reaction pathway indicate the intermediacy of rhodium carbenoid and metallocyclobutane species.

A Combination of Computational and Experimental Studies to Correlate Electronic Structure and Reactivity of Donor–Acceptor Singlet Carbenes

AbstractMost of the reactivities of donor–acceptor (D–A) singlet carbenes are similar to metal carbenoids. However, the lone pair at the carbenoid carbon, coordinated with metal, is free in D–A carbene thereby making it nucleophilic as well. Herein, DFT-optimized structural features of D–A carbene has been investigated and is compared with rhodium carbenoid. It was observed that, when a D–A carbene reacts with cyclic-1,3-diones in different ethereal solvents, it is the lone pair at the sp2 orbital of the carbene that abstracts the proton from the enol form (of the cyclic-1,3-diones) to form a benzylic carbocation and an enolate. Subsequently, the carbocation undergoes nucleophilic attack by O of the ether solvents and then by the enolate to afford the desired ether-linked products. Accordingly, herein the reaction in THF, which otherwise had failed to work as a substrate in reported amino etherification reactions, worked well. DFT-calculated orbital energy levels and reaction profile support this reverse reactivity of singlet carbenes. Furthermore, HOMO–LUMO calculations indicated that electron-rich arenes in D–A carbene stabilizes the LUMO and destabilizes the HOMO which increases yield. Additionally, a library of 37 enol ether and 39 ether-linked compounds of potential medicinal relevance have been synthesized with good to excellent yields using numerous cyclic-1,3-diones.

A New Method for the Introduction of an Acylsulfonamide Moiety Applied to a 3-Substituted Functionalized Indole Framework ­Related to the Welwitindolinone Alkaloids

AbstractThe one-pot reaction between an α-formylcyclohexanone derivative and tosyl azide in the presence of rhodium trifluoroacetate dimer afforded an acylsulfonamide derivative. This transformation is proposed to arise from a domino mechanism involving the in situ generation, through the Regitz method, of an α-diazoketone, followed by its transformation into a rhodium carbenoid and its combination with N-tosylformamide, generated as a side product of the first step of the mechanism. Overall, this transformation leads to the generation of a C–N bond between the formyl carbon and the azide nitrogen adjacent to the sulfonyl group.

N-Tosyl-1,2,3-triazoles as Scaffolds for Morpholines: The Total Synthesis of (–)-Chelonin A

AbstractSubstituted morpholine derivatives appear frequently in biologically active compounds and thus novel routes towards such structures are of great synthetic interest. Herein, we report the total syntheses of chelonin A, a morpholine-derived marine natural product with reported antibacterial and anti-inflammatory activity. The key step in this process was a rhodium carbenoid 1,3-insertion into a bromohydrin O–H bond, followed by annulation, leading to a 2,6-disubstituted-3,4-dihydro-2H-1,4-oxazine core. This work was then extended to deliver the first asymmetric total synthesis of (–)-chelonin A using an enantioenriched bromohydrin, prepared in turn via asymmetric transfer hydrogenation of an α-bromoketone.

How mono- and diphosphine ligands alter regioselectivity of the Rh-catalyzed annulative cleavage of bicyclo[1.1.0]butanes

Rh(I)-catalyzed cycloisomerizations of bicyclo[1.1.0]butanes provide a fruitful approach to cyclopropane-fused heterocycles. Products and stereochemical outcome are highly dependent on catalyst. The triphenylphosphine (PPh3) ligand provides pyrrolidines, placing substituents anti to the cyclopropyl group. The 1,2-bis(diphenylphosphino)ethane (dppe) ligand yields azepanes with substituents syn to the cyclopropyl group. In this work, quantum mechanical DFT calculations pinpoint a reversal of regio- and diastereoselectivity, suggesting a concerted (double) C−C bond cleavage and rhodium carbenoid formation, driven by strain-release. The ligand-influenced cleavage step determines the regioselectivity of carbometalation and product formation, and suggests new applications of bicyclobutanes.

Rhodium-catalyzed aerobic conversion of 2-diazo-1,3-dicarbonyls to vicinal tricarbonyl compounds and their in-situ stability toward oxidative degradation

Several types of 2-diazo-1,3-dicarbonyl compounds (3), including α-diazo-β-ketoesters, 2-diazo-1,3-diketones and diazomalonates, are converted into the corresponding vicinal tricarbonyls (VTCs) (4) upon exposure to Rh2(OAc)4 catalyst and oxygen gas. The transformation is proposed to occur through the aerobic oxygenation of the rhodium carbenoid intermediate, facilitated by the suppression of a Wolff rearrangement via weak interaction with the substrate carbonyl group (ROC=O or RC=O). The reactions of α-diazo-β-ketoesters and 2-diazo-1,3-diketones give the desirable α,β-diketoesters and vic-triketones in 27-78% isolated yields, along with carboxylic acids and/or 2-oxoacids generated by in-situ oxidative C-C single bond cleavage of the former products. Moreover, the bond cleavage process is completely inhibited when the reactions are performed with diazomalonates, leading to the good to excellent formation of oxomalonates (up to 92% yield).

Convergent Synthesis of the C1-C29 Framework of Amphidinolide F.

The complete carbon framework of the macrocyclic marine natural product amphidinolide F has been prepared by a convergent synthetic route in which three fragments of similar size and complexity have been coupled. Key features of the syntheses of the fragments include the stereoselective construction of the tetrahydrofuran in the C1–C9 fragment by oxonium ylide (free or metal-bound) formation and rearrangement triggered by the direct generation of a rhodium carbenoid from 1-sulfonyl-1,2,3-triazole, the highly diastereoselective aldol reaction between a boron enolate and an aldehyde with 1,4-control to prepare the C10–C17 fragment, and the formation of the tetrahydrofuran in the C18–C29 fragment by intramolecular nucleophilic ring opening of an epoxide with a hydroxyl group under acidic conditions.

Effect of Tethered, Axially Coordinated Ligands (TACLs) on Dirhodium(II,II) Catalyzed Cyclopropanation: A Linear Free Energy Relationship Study.

Hammett correlation experiments were used to determine the influence of dirhodium(II,II) paddlewheel complexes with tethered, axially coordinated ligands (TACLs) on the selectivity of rhodium carbenoids in competitive cyclopropanation reactions. The results suggest that dirhodium(II,II) paddlewheel complexes with TACLs are less sensitive to changes in electronics and reduce selectivity in cyclopropanation reactions with acceptor-substituted rhodium carbenoids. Also, Hammett plots with aryl diazoacetates resulted in a nonlinear downward curvature, suggesting a change in the rate-limiting step of the carbene transfer reaction.

Dual Catalysis in Rhodium(II) Carbenoid Chemistry

AbstractDual catalysis represents an alternative archetype in carbene chemistry that surpasses traditional single catalyst systems. By employing dual catalyst systems, one can improve the efficiency of existing reactions and enable new chemical transformations. Reactions involving dual synergistic catalysis are increasingly valuable as they offer convenient strategies for synthesizing challenging quaternary carbon centers and bioactive core structures. This review article focuses on trapping diazo‐derived, rhodium (II) zwitterionic intermediates with varying electrophiles such as Michael acceptors, alkynes, π‐allyl Pd(II) complexes, and the Nicholas intermediate.

1,2-Acyl migration with α-imino rhodium carbenoids leading to substituted 1-naphthols.

A unique method for the synthesis of substituted 1-naphthols by a rhodium(II)-catalysed ring-expansion reaction of 2-triazolyl-1-indanone derivatives is reported. 1,2-Acyl migration occurs with an intermediate α-imino rhodium carbenoid generated from the triazolyl moiety.

Concise stereoselective and stereodivergent syntheses of (±)-melicolones A and B

The first total syntheses of the epimeric (±)-melicolones A and B, which are bioactive constituents isolated as racemates from the leaves of Melicope ptelefolia, were achieved in 12.3% combined overall yield. The divergent approach to these unusual natural products is remarkably concise and required a longest linear sequence of only nine steps (11 total steps) from commercially available starting materials. The significant synthetic challenge posed by the unique and densely functionalized polycyclic framework characteristic of the melicolones was addressed by a novel and highly regioselective (16:1) and diastereoselective (15:1) dipolar cycloaddition to deliver the oxabicycloheptane core. This pivotal reaction featured an innovative combination of an unsaturated vinylogous ester dipolarophile with a carbonyl ylide that was generated by an unusual cyclization of the carbonyl oxygen atom of an aliphatic aldehyde with a rhodium carbenoid. Stereoselective prenylation of the ketone enolate derived from this bicyclic core gave an intermediate that was processed via a one-pot O-demethylation cycloaldolization sequence to give the penultimate intermediate. The synthesis was completed by a bioinspired tandem epoxidation of the prenyl substituent followed by a regioselective, acid-catalyzed cyclization to deliver (±)-melicolones A and B. This approach may be applicable to the syntheses of other melicolones having a tetracyclic core.

Synergistic Pd(0)/Rh(II) Dual Catalytic [6 + 3] Dipolar Cycloaddition for the Synthesis of Monocyclic Nine-Membered N,O-Heterocycles and Their Alder-ene Rearrangement to Fused Bicyclic Compounds.

The catalytic construction of a monocyclic medium-sized N,O-heterocyclic ring represents a formidable challenge in organic synthesis. Herein we report the synergistic palladium(0)/rhodium(II) dual catalytic cycloaddition of vinylpropylene carbonates with N-sulfonyl-1,2,3-triazoles to afford monocyclic nine-membered N,O-heterocycles. The catalytically generated 1,6-dipole-equivalent zwitterionic π-allyl palladium(II) complex and the 1,3-dipole-equivalent α-imino rhodium(II) carbenoid intermediate react with each other in a formal [6 + 3] dipolar cycloaddition to furnish nine-membered oxazonines, which can be transformed into cis-fused [4.3.0] bicyclic compounds via a transannular Alder-ene rearrangement. The tandem one-pot cycloaddition/Alder-ene rearrangement sequence is also possible.

A One-Pot Reaction of α-Imino Rhodium Carbenoids and Halohydrins: Access to 2,6-Substituted Dihydro-2H-1,4-oxazines.

Herein, we report a Rh(II)-catalyzed reaction between 1-tosyl-1,2,3-triazoles and halohydrins to provide 2,6-substituted 3,4-dihydro-2H-1,4-oxazines under basic conditions. The reaction is proposed to undergo a rhodium carbenoid 1,3-insertion into O-H followed by an annulation. The scope includes phenyl or alkenyl C4-substituted triazoles and a range of halohydrins using catalytic Rh2Oct4 and K2CO3. A synthesis of the antimicrobial natural product (±)-chelonin C is also reported using this novel methodology.

Trapping rhodium vinylcarbenoids with aminochalcones for the synthesis of medium-sized azacycles

A rhodium carbenoid initiated cascade has been developed for the stereoselective synthesis of medium-sized azacycles. The cascade approach utilizes readily accessible N-benzyl protected aminochalcones and vinyldiazo compounds to access 9-membered azacycles through a carbene- nitrogen insertion/aldol/oxy-Cope sequence. The cascade reaction has proven general with a range of N-benzyl protected aminochalcones and vinyldiazos to provide diverse medium-sized azacycles.

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Rhodium catalysis enables the synthesis of a variety of highly useful compounds. The success of catalytic pathways mediated by rhodium depends on the choice of ligand and the nature of the substrate. In this chapter, the application of imides as ligands and substrates is discussed. The thorough description about the homochiral dirhodium catalysts derived from imide-based carboxylate ligands is provided along with many challenging transformations which involve rhodium carbenoids intermediate. A detailed discussion about asymmetric cyclopropanations, C–H activation, and cycloadditions reactions is provided, along with mechanistic insights as well as applications in the synthesis of bioactive compounds and natural products. Illustration about the use of imide as the substrate in rhodium catalysis is also offered for asymmetric hydrogenations, conjugate additions, and C–H activation.

Synthesis of Functionalized Thietanes via Electrophilic Carbenoid-Induced Ring Expansion of Thiiranes with Sulfonium Acylmethylides as Carbene Precursors.

Various functionalized thietanes were prepared from thiiranes via an electrophilic ring expansion with rhodium carbenoids as electrophiles generated from safe and readily accessible dimethylsulfonium acylmethylides. The reaction appears to proceed through electrophilic metallocarbenoid-induced activation of thiiranes, nucleophilic ring-opening of the activated thiiranes with dimethyl sulfide as a transient nucleophile, and nucleophilically intramolecular cyclization. The Umpolung from the nucleophilic ylides to the electrophilic carbenoids plays an important role in both the activation and ring opening of thiiranes and subsequent cyclization. The current method provides a new strategy for the efficient preparation of functionalized thietanes from readily available thiiranes.

Asymmetric N-H Insertion Reaction with Chiral Aminoalcohol as Catalytic Core of Cinchona Alkaloids.

In order to develop an efficient organocatalyst for the enantioselective N-H insertion reaction via carbene/carbenoid, the catalytic core of the cinchona alkaloids was investigated. According to our working hypothesis of an eight-membered ring transition state in the N-H insertion reaction, two pairs of enantiomers related to 2-amino-1-phenylethanol were investigated for their chiral inducing potential. Since both (1R,2S)-isomers gave the N-phenyl-1-phenylglycine derivative enriched in the R-form, while their enantiomers gave the S-form, the 2-amino-1-phenylethanol structure is concluded to be the catalytic core of the cinchona alkaloid in the enantioselective N-H insertion reaction via rhodium(II) carbenoid.

Synthesis of Isoindoles from Intramolecular Condensation of Benzyl Azides with α-Aryldiazoesters.

Rh-catalyzed intramolecular condensation of the benzyl azides with α-aryldiazoesters was explored. The reaction proceeded through the nucleophilic attack of the organic azide onto a rhodium carbenoid, while releasing nitrogen gas, affording the α-imino esters as the primary product. Tautomerization of the imino esters efficiently gave 13 desired isoindoles with good to excellent yields.

2 + 1 + 1] Assembly of spiro β-lactams by Rh(ii)-catalyzed reaction of diazocarbonyl compounds with azirines/isoxazoles.

A domino synthesis of dispiro-fused N-vinyl β-lactams from diazo-Meldrum's acid and 2H-azirines or 5-alkoxyisoxazoles via the "2-azabuta-1,3-diene formation/Staudinger ketene-imine cycloaddition" sequence is described. The Rh2(Piv)4-catalyzed formation of the 2-azabuta-1,3-diene intermediates in the first stage of the reaction sequence proceeds via addition of the rhodium carbenoid to the azirines/isoxazoles and provides the first example of the generation of iminium-type ylides from diazo-Meldrum's acid. This methodology was extended to monospiro-β-lactams, which were synthesized in two steps using acyclic α-diazocarbonyl compounds in the stage of the formation of 2-azabuta-1,3-dienes. The method allows for the rapid assemblage of the carbon part of the azetidin-2-one system from diazo compounds only and affords spiro- and dispiro-β-lactams in moderate yields. A bromine atom in the 2-bromoalkenyl moiety of the synthesized β-lactams can be easily substituted by hydrogen under catalytic hydrogenation conditions or by 2-pyridyl-substituent via the Stille cross-coupling reaction.

Stereoselective Synthesis of Diverse Lactones through a Cascade Reaction of Rhodium Carbenoids with Ketoacids.

A convergent cascade approach for the stereoselective synthesis of diverse lactones is described. The Rh2(TFA)4-catalyzed cascade reaction proceeds via a carboxylic acid O-H insertion/aldol cyclization with high chemo-, regio-, and diastereoselectivity. The cascade reaction provides quick access to highly functionalized γ-butyro- and δ-valerolactones from readily accessible ketoacid and diazo synthons. To demonstrate the utility of this approach, a thermally induced oxy-Cope ring-expansion strategy has been incorporated in the cascade sequence to access medium-sized lactones, which can undergo a serendipitous rearrangement to form spiro-lactones through an intramolecular aldol/trans-lactonization sequence. The reaction has proven to be general, with a range of ketoacids and diazo carbonyls to provide functionalized lactones of varying ring sizes.