Rhodium Carbenoid Research Articles

Thermal Cyclization of Copper Carbenoid of α‐Dizao α‐Phosphorylacetate: Unexpected and Novel Access to Oxaphosphirane

AbstractUnder the catalysis of Cu(OTf)2 in refluxing CH2Cl2, ethyl α‐dizao α‐(diethylphosphoryl)acetate was shown to undergo a new cyclization reaction to afford a pentacovalent oxaphosphirane product. The reaction is proposed to occur through the addition of the P=O double bond to the copper carbenoid, followed by the hydrolysis of the ylide intermediate. Our finding represents the first example on producing oxaphosphiranes from dizao phosphoryl compounds. On the other hand, the corresponding rhodium carbenoid displayed the different reactivity under the same thermal conditions, to produce the β‐propiolactone through the well‐recognized C‐H insertion pathway.

Intramolecular cyclopropanation and C-H insertion reactions with metal carbenoids generated from cyclopropenes.

Activation of unsaturated carbon-carbon bonds by means of transition metal catalysts is an exceptionally active research field in organic synthesis. In this context, due to their high ring strain, cyclopropenes constitute an interesting class of substrates that displays a versatile reactivity in the presence of transition metal catalysts. Metal complexes of vinyl carbenes are involved as key intermediates in a wide variety of transition metal-catalyzed ring-opening reactions of cyclopropenes. Most of the reported transformations rely on intermolecular or intramolecular addition of nucleophiles to these latter reactive species. This Account focuses specifically on the reactivity of carbenoids resulting from the ring-opening of cyclopropenes in cyclopropanation and C-H insertion reactions, which are arguably two of the most representative transformations of metal complexes of carbenes. Compared with the more conventional α-diazo carbonyl compounds, the use of cyclopropenes as precursors of metal carbenoids in intramolecular cyclopropanation or C-H insertion reactions has been largely underexploited. One of the challenges is to devise appropriately substituted and readily available cyclopropenes that would not only undergo regioselective ring-opening under mild conditions but also trigger the subsequent desired transformations with a high level of chemoselectivity and stereoselectivity. These goals were met by considering several substrates derived from the readily available 3,3-dimethylcyclopropenylcarbinols or 3,3-dimethylcyclopropenylcarbinyl amines. In the case of 1,6-cyclopropene-enes, highly efficient and diastereoselective gold(I)-catalyzed ring-opening/intramolecular cyclopropanations were developed as a route to diversely substituted heterocycles and carbocycles possessing a bicyclo[4.1.0]heptane framework. The use of rhodium(II) catalysts enabled us to widen the scope of this transformation for the synthesis of medium-sized heterocyclic scaffolds incorporating an eight-membered ring. The reactivity of rhodium(II) carbenoids generated from 3,3-dimethylcyclopropenylcarbinols was also investigated in intramolecular C(sp(3))-H insertions. Despite their low electrophilic character, these purely donor rhodium(II) carbenoids underwent remarkably efficient diastereoselective 1,5- or 1,6-C-H insertions allowing access to a wide variety of substituted cyclopentanols, cyclohexanols, bicycloalkanols, and tetrahydropyrans with high level of diastereoselectivity and with complete tolerance of a free hydroxyl group. The products arising from the gold(I)- or rhodium(II)-catalyzed ring-opening/intramolecular cyclopropanation or C-H insertion of 3,3-dimethylcyclopropenylcarbinols or 3,3-dimethylcyclopropenylcarbinyl amines always incorporate an isopropylidene moiety, which can potentially undergo subsequent oxidative cleavage into a carbonyl group without epimerization. By virtue of this operation, the 3,3-dimethylcyclopropenyl group formally behaves as a valuable surrogate for an α-diazoketone, with obvious advantages considering the ease of access to the corresponding substrates and that no hazardous reagents are involved in their preparation. These studies have set a useful basis for the development of other reaction pathways involving metal carbenoids generated from these readily available families of substituted cyclopropenes, including the investigation of the yet underexploited synthetic potential of purely donor rhodium(II) carbenoids.

Solvent and ligand effects associated with the Rh(II)-catalyzed reactions of α-diazo-substituted amido esters.

We report a detailed investigation into the Rh(II)-catalyzed reactions of 2-alkynyl 2-diazo amido-substituted esters. The distribution of products was found to be dependent on the substituent group on the nitrogen atom, the ligand on the Rh(II) center, and the solvent used. The dominant product obtained from the reaction of 3-(trimethylsilyl)prop-2-ynyl-2-(dibenzylcarbamoyl)-2-diazoacetate (34) with Rh2(OAc)4 in hexane corresponds to an azetidinone derived by CH-insertion of the carbenoid into the neighboring benzyl group. In contrast, the Rh2(esp)2-catalyzed reaction of 34 in CH2Cl2 afforded a 3-oxocyclohepta[c]pyrrole formed by cyclopropanation of the rhodium carbenoid across the aromatic π-bond. Related systems were studied, and CH-insertion into an adjacent alkyl group was found to be the dominant or exclusive pathway. In none of the cases studied was it possible to detect products derived from a carbenoid/alkyne cascade sequence as had previously been found with a series of 2-alkynyl-2-diazo-3-oxobutanoates.

ChemInform Abstract: Synthesis of 3‐Pyrrolin‐2‐ones by Rhodium‐Catalyzed Transannulation of 1‐Sulfonyl‐1,2,3‐triazole with Ketene Silyl Acetal.

α-Imino rhodium carbenoids generated from 1-sulfonyl 1,2,3-triazole were applied to the 3 + 2 cycloaddition with ketene silyl acetal, offering a novel and straightforward synthesis of biologically interesting compound 3-pyrrolin-2-one with broad substrate scope.

Expedient Synthesis of Fused Azepine Derivatives Using a Sequential Rhodium(II)‐Catalyzed Cyclopropanation/1‐Aza‐Cope Rearrangement of Dienyltriazoles

AbstractA general method for the formation of fused dihydroazepine derivatives from 1‐sulfonyl‐1,2,3‐triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α‐imino rhodium(II) carbenoid, leading to a transient 1‐imino‐2‐vinylcyclopropane intermediate which rapidly undergoes a 1‐aza‐Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst‐free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.

Expedient synthesis of fused azepine derivatives using a sequential rhodium(II)-catalyzed cyclopropanation/1-aza-Cope rearrangement of dienyltriazoles.

A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino rhodium(II) carbenoid, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst-free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.

Synthesis of 3-pyrrolin-2-ones by rhodium-catalyzed transannulation of 1-sulfonyl-1,2,3-triazole with ketene silyl acetal.

α-Imino rhodium carbenoids generated from 1-sulfonyl 1,2,3-triazole were applied to the 3 + 2 cycloaddition with ketene silyl acetal, offering a novel and straightforward synthesis of biologically interesting compound 3-pyrrolin-2-one with broad substrate scope.

ChemInform Abstract: Synthesis of Conformationally Restricted C2 Symmetric Macrodiolides via Head to Tail Dimerization of Carbonyl Ylides.

AbstractA simple procedure is developed for the synthesis of the title species via rhodium(II) carbenoid induced head to tail dimerization of carbonyl ylides having unactivated alkyne or alkene functionalities.

Unexpected rearrangements of rhodium carbenoids containing a pyrrolidin-1-yl group

Ketone- and ester-substituted diazo compounds, which contain a pyrrolidine moiety were treated with dirhodium tetraacetate generating the corresponding rhodium carbenoids. They were expected to insert into a CH bond of the pyrrolidine moiety but reacted differently. The ketone-substituted rhodium carbenoid underwent a Wolff rearrangement. The resulting ketene continued to react by lactamization and electrocyclic ring-opening and gave an acrylamide. The ester-substituted rhodium carbenoid underwent a [1.2]-shift of the (pyrrolidin-1-yl)methyl moiety, which resulted in a methacrylic ester. For each rearrangement a mechanism is suggested.

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.

The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. High-content screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.

6th Heron Island Conference on Reactive Intermediates and Unusual Molecules

The 6th Heron Island Conference on Reactive Intermediates and Unusual Molecules - Synthesis and Mechanism was held at the Heron Island Resort on the Great Barrier Reef, 7- 13 July 2013, with some 80 scientists in attendance from all over the world, presenting highlights of their work in lecture and poster format ( Fig. 1). These meetings, which enjoy an excellent international reputation, present unique opportunities for interaction between Australian and overseas chemists in subject areas varying from organic synthesis to reaction mechanism, computational and theoretical chemistry, physical/ materials chemistry, inorganic chemistry, biological/ medicinal chemistry, and spectroscopy. This issue of Aust. J. Chem. presents a collection of papers authored by delegates at the meeting and comprise a wide range of topics, including amine boranes ( S.- Y. Liu et al.),[ 1] rhodium carbenoids ( A. Padwa et al.),[ 2] singlet oxygen ( T. Linker et al.),[ 3] hydrogen peroxide fuel cells ( S. Fukuzumi et al.),[ 4]

Rh(II)-carbenoid mediated 2H-azirine ring-expansion as a convenient route to non-fused photo- and thermochromic 2H-1,4-oxazines

The Rh2(OAc)4-catalyzed domino reaction of 2H-azirines with 2-acyl-2-diazoacetates provides a unique synthetic approach to non-fused 2H-1,4-oxazines. The reaction proceeds via sequential formation of a rhodium carbenoid, an azirinium ylide, and a 1-acyl-1-(alkoxycarbonyl)-2-azabuta-1,3-diene to give, after 1,6-π-electrocyclization, a 2H-1,4-oxazine derivative in good yield. The observed stereoselectivity of 2-azadiene formation is consistent with DFT calculations of the azirinium ylide–2-azadiene isomerization, providing evidence for the ylide mechanism of the reaction. The substitution pattern and configuration of the carbon–carbon double bond in 2-azadienes has a dramatic influence on their cyclization to oxazines: the CO2R group on C4 stabilizes an open-chain form and, as the result of this, a new class of stable 2-azadienes, 1-acyl-2-azadiene-1,4-dicarboxylates, could be isolated. The 1,4-oxazines obtained by this method are the first representatives of monocyclic 2H-1,4-oxazine derivatives, which exhibit photo- and thermochromic activity.

ChemInform Abstract: Highly Efficient Stereoselective Catalytic C(sp3)—H Insertions with Donor Rhodium Carbenoids Generated from Cyclopropenes.

AbstractThe tetrahydropyrans (II) arise as single anti diastereomers by 1,6‐C—H insertions.

ChemInform Abstract: Alkynoate Synthesis Through the Vinylogous Reactivity of Rhodium(II) Carbenoids.

Siloxy group migration: A rhodium(II) carbenoid approach has been developed for the synthesis of alkynoates. This transformation combines the addition of enol ethers at the vinylogous position of β-siloxy-substituted vinyldiazo derivatives with a siloxy group migration to give the products as single diastereomers.

Rhodium(II) Carbenoids for Alkynoate Synthesis

Rhodium(II) Carbenoids for Alkynoate Synthesis

Synthesis of Enaminones by Rhodium-Catalyzed Denitrogenative Rearrangement of 1-(N-Sulfonyl-1,2,3-triazol-4-yl)alkanols

Enaminones are synthesized by the rhodium(II)-catalyzed denitrogenative rearrangement reaction of 1-(N-sulfonyl-1,2,3-triazol-4-yl)alkanols, which are readily prepared from propargylic alcohols and N-sulfonyl azides. Intramolecular 1,2-hydride (or -alkyl) migration occurs with an intermediary α-imino rhodium(II) carbenoid species generated through denitrogenation of the 1,2,3-triazol-4-yl moiety. The resulting enaminones is converted into various heterocycles with replacement of the N-sulfonyl group.

Highly Efficient Stereoselective Catalytic C(sp3)H Insertions with Donor Rhodium Carbenoids Generated from Cyclopropenes

5-und 6-Ringe: Donor-Alkenyl-Rhodiumcarbenoide, die aus 3,3-Dimethylcyclopropenylcarbinolen hergestellt werden, sind hochreaktiv in intramolekularen C-H-Insertionen. Die Reaktionen verlaufen unter bemerkenswert milden Bedingungen, tolerieren eine freie Hydroxygruppe und liefern einen effizienten und stereoselektiven Weg zu verschiedenen funktionalisierten Carbocyclen und Sauerstoff-Heterocyclen.

Highly Efficient Stereoselective Catalytic C(sp3)H Insertions with Donor Rhodium Carbenoids Generated from Cyclopropenes

Highly Efficient Stereoselective Catalytic C(sp³)H Insertions with Donor Rhodium Carbenoids Generated from Cyclopropenes

Alkynoate Synthesis through the Vinylogous Reactivity of Rhodium(II) Carbenoids

Siloxygruppen-Wanderung: Ein Rhodium(II)-Carbenoid-Ansatz wurde für die Synthese von Alkinoaten entwickelt (siehe Schema). Diese Umwandlung kombiniert die Addition von Enolethern an die vinyloge Position von β-siloxysubstituierten Vinyldiazo-Derivaten mit einer Siloxygruppen-Wanderung und gibt die Produkte als einzelne Diastereomere.

Alkynoate synthesis through the vinylogous reactivity of rhodium(II) carbenoids.

Siloxy group migration: A rhodium(II) carbenoid approach has been developed for the synthesis of alkynoates. This transformation combines the addition of enol ethers at the vinylogous position of β-siloxy-substituted vinyldiazo derivatives with a siloxy group migration to give the products as single diastereomers.