Current – 2013 ⋅ 2012 – 2008 ⋅ 2007 – 2002
Enantioselective N-heterocyclic carbene-catalyzed nucleophilic dearomatization of alkyl pyridiniums
Darrin M. Flanigan and Prof. Tomislav Rovis
Chemical Science, 2017, Ahead of Print
NHC-catalyzed nucleophilic dearomatization of alkyl pyridiniums has been achieved to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine with high selectivity.
Cluster Preface: Catalytic Aerobic Oxidations
Shannon S. Stahl and Prof. Tomislav Rovis
Synlett, 2017, Ahead of Print
These reports describe a subset of the exciting work going on in this field and highlight both the accomplishments as well as some of the challenges. The field is vibrant as it aims to replace all other oxidants with nature’s simplest one.
A Photochemical Two-Step Formal [5+2] Cycloaddition: A Condensation–Ring-Expansion Approach to Substituted Azepanes
Scott M. Thullen, David M. Rubush, and Prof. Tomislav Rovis
Synlett, 2017, Ahead of Print
Seven-membered nitrogen-containing heterocycles are considerably underrepresented in the literature compared to their five- and six-membered analogues. Herein, we report a relatively understudied photochemical rearrangement of N-vinylpyrrolidinones to azepin-4-ones in good yields. This transformation allows for the conversion of readily available pyrrolidinones and aldehydes to densely functionalized azepane derivatives in a facile two-step procedure.
Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic meso-Anhydrides
Erin E. Stache, Prof. Tomislav Rovis and Prof. Abigail G. Doyle
Angewandte Chemie International Edition, 2017, 56, 3679-3683
Cyclic anhydrides are efficiently desymmetrized through dual nickel- and photoredox-catalyzed alkylation using benzylic trifluoroborates salts as pronucleophiles. A mechanistic nuance illustrates that an intermediate in the catalytic cycle undergoes epimerization leading to trans keto-acid products from cis anhydrides under modified reaction conditions.
Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C–H Activation Reactions: An Experimental and Computational Study
Tiffany Piou, Fedor Romanov-Michailidis, Maria Romanova-Michaelides, Kelvin E. Jackson, Natthawat Semakul, Trevor D. Taggart, Brian S. Newell, Christopher D. Rithner, Robert S. Paton, and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2017, 139, 1296-1310
CpXRh(III)-catalyzed C–H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (CpX) ligand structure on reaction rate and selectivity has been viewed as a black box, and a truly systematic study is lacking. Consequently, predicting the outcomes of these reactions is challenging because subtle variations in ligand structure can cause notable changes in reaction behavior. A predictive tool is, nonetheless, of considerable value to the community as it would greatly accelerate reaction development. Designing a data set in which the steric and electronic properties of the CpXRh(III) catalysts were systematically varied allowed us to apply multivariate linear regression algorithms to establish correlations between these catalyst-based descriptors and the regio-, diastereoselectivity, and rate of model reactions. This, in turn, led to the development of quantitative predictive models that describe catalyst performance. Our newly described cone angles and Sterimol parameters for CpX ligands served as highly correlative steric descriptors in the regression models. Through rational design of training and validation sets, key diastereoselectivity outliers were identified. Computations reveal the origins of the outstanding stereoinduction displayed by these outliers. The results are consistent with partial η5–η3 ligand slippage that occurs in the transition state of the selectivity-determining step. In addition to the instructive value of our study, we believe that the insights gained are transposable to other group 9 transition metals and pave the way toward rational design of C–H functionalization catalysts.
Heptamethylindenyl (Ind*) enables diastereoselective benzamidation of cyclopropenes via Rh(III)-catalyzed C–H activation
Natthawat Semakul, Kelvin E. Jackson, Robert S. Paton, and Tomislav Rovis
Chemical Science, 2016, 8, 1015-1020
The diastereoselective coupling of O-substituted arylhydroxamates and cyclopropenes mediated by Rh(III) catalysis was successfully developed. Through ligand development, the diastereoselectivity of this reaction was improved using a heptamethylindenyl (Ind*) ligand, which has been rationalized using quantum chemical calculations. In addition, the nature of the O-substituted ester of benzhydroxamic acid proved important for high diastereoselectivity. This transformation tolerates a variety of benzamides and cyclopropenes that furnish cyclopropa[c]dihydroisoquinolones with high diastereocontrol, which could then be easily transformed into synthetically useful building blocks for pharmaceuticals and bio-active molecules.
N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation
Dian-Feng Chen and Tomislav Rovis
Synthesis, 2016, 49, 293-298
A chiral NHC/Brønsted acid cooperative catalysis system has been developed for the asymmetric annulation of functionalized benzaldehydes and activated ketones, through dearomative generation of dienolate, to give 3-aryl-3-(perfluoroalkyl)isochroman-1-ones.
Visible Light-Gated Cobalt Catalysis for a Spatially and Temporally Resolved [2+2+2] Cycloaddition
Kyle E. Ruhl and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 138, 15527-15530
The ability to exert spatial and temporal control over a transition-metal catalyst offers diverse opportunities for the fabrication of functional materials. Using an external stimulus such as visible light to toggle a catalyst between an active and dormant state has proven to be an effective approach for controlled, radical methodologies. Outside of radical bond formation, there is a dearth of evidence that suggests traditional transition metal catalysis can similarly be controlled with visible light energy. Many cobalt complexes that catalyze the [2+2+2] cycloaddition are assisted by UV photolysis, but strict photocontrolled methods are unattainable due to high levels of thermally driven reactivity. Herein, we disclose the first light-controlled, cobalt-catalyzed [2+2+2] cycloaddition via a dual cobalt and photoredox catalyst manifold. We demonstrate the power of this method with a spatially and temporally resolved technique for arene formation using photolithography.
Amide-directed photoredox-catalysed C–C bond formation at unactivated sp3 C–H bonds
John C.K. Chu and Tomislav Rovis
NATURE, 2016, 539, 272-275
Carbon–carbon (C–C) bond formation is paramount in the synthesis of biologically relevant molecules, modern synthetic materials and commodity chemicals such as fuels and lubricants. Traditionally, the presence of a functional group is required at the site of C–C bond formation. Strategies that allow C–C bond formation at inert carbon–hydrogen (C–H) bonds enable access to molecules that would otherwise be inaccessible and the development of more efficient syntheses of complex molecules. Here we report a method for the formation of C–C bonds by directed cleavage of traditionally non-reactive C–H bonds and their subsequent coupling with readily available alkenes. Our methodology allows for amide-directed selective C–C bond formation at unactivated sp3 C–H bonds in molecules that contain many such bonds that are seemingly indistinguishable. Selectivity arises through a relayed photoredox-catalysed oxidation of a nitrogen–hydrogen bond. We anticipate that our findings will serve as a starting point for functionalization at inert C–H bonds through a strategy involving hydrogen-atom transfer.
Rhodium-catalysed syn-carboamination of alkenes via a transient directing group
Tiffany Piou and Tomislav Rovis
NATURE, 2015, 527, 86-90
Alkenes are the most ubiquitous prochiral functional groups—those that can be converted from achiral to chiral in a single step—that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to produce highly complex molecular architectures. Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation, are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon- and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon–hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities.
Rhodium(III)-Catalyzed Allylic C(sp3)–H Activation of Alkenyl Sulfonamides: Unexpected Formation of Azabicycles
Alexis Archambeau, Tomislav Rovis
Angewandte Chemie International Edition, 2015, 54, 13337-13340
Unsaturated N-sulfonamides undergo a RhIII– catalyzed allylic C(sp3)H activation followed by insertion with an exogenous internal alkyne. The reaction generates [3.3.0], [4.3.0], and [5.3.0] azabicyclic structures with excellent diastereoselectivity. Deuterium labeling experiments implicate a 1,3-Rh shift as a key step in the mechanism.
Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes
Darrin M. Flanigan, Fedor Romanov-Michailidis, Nicholas A. White, and Tomislav Rovis
CHEMICAL REVIEWS, 2015, 15, 9307-9387
The field has periodically been reviewed, with the most recent such comprehensive review appearing in this journal in 2007. This review will thus focus on developments since the last review with the caveat that seminal contributions are acknowledged.
Oxidatively Initiated NHC-Catalyzed Enantioselective Synthesis of 3,4-Disubstituted Cyclopentanones from Enals
Nicholas A. White and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 10112-10115
An unprecedented N-heterocyclic carbene (NHC)-catalyzed annulation of enals to form 3,4-disubstituted cyclopentanones has been discovered. Aryl enals undergo dimerization in the presence of a single-electron oxidant to form C2 symmetric cyclopentanones. A cross-reaction has also been developed, allowing for the synthesis of differentially substituted cyclopentanones. Mechanistically, the reaction is thought to proceed through radical intermediates, further establishing the synthetic utility of this class of reactivity.
Organic chemistry: Natural polarity inverted
Fedor Romanov-Michailidis, Tomislav Rovis
NATURE, 2015, 523, 417-418
The concept of umpolung describes the reversal of the naturally occurring electrostatic polarization of chemical groups. It has now been used to make single mirror-image isomers of nitrogen-containing molecules.
Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C–H Activation
Fedor Romanov-Michailidis, Kassandra F. Sedillo, Jamie M. Neely, and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 8892-8895
α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp2)–H insertion with cationic Rh(III) complexes to furnish five-membered metallacycles. In the presence of 1,1-disubstituted olefins, these species participate in irreversible migratory insertion to give, after reductive elimination, 2,3-dihydropyridine products in good yields. Catalytic hydrogenation can then be used to convert these molecules into piperidines, which are important structural components of numerous pharmaceuticals.
Influence of Electronic Effects on the Reactivity of Triazolylidene-Boryl Radicals: Consequences for the use of N-Heterocyclic Carbene Boranes in Organic and Polymer Synthesis
Sofia Telitel, Anne-Laure Vallet, Darrin M. Flanigan, Dr. Bernadette Graff, Dr. Fabrice Morlet-Savary, Prof. Tomislav Rovis, Prof. Jacques Lalevée and Dr. Emmanuel Lacôte
CHEMISTRY – A EUROPEAN JOURNAL, 2015, 21, 13772-13777
A small library of triazolylidene-boranes that differ only in the nature of the aryl group on the external nitrogen atom was prepared. Their reactivity as hydrogen-atom donors, as well as that of the corresponding N-heterocyclic carbene (NHC)-boryl radicals toward methyl acrylate and oxygen, was investigated by laser flash photolysis, molecular orbital calculations, and ESR spin-trapping experiments, and benchmarked relative to the already known dimethyltriazolylidene-borane. The new NHC-boranes were also used as co-initiators for the Type I photopolymerization of acrylates. This allowed a structure–reactivity relationship with regard to the substitution pattern of the NHC to be established and the role of electronic effects in the reactivity of NHC-boryl radicals to be probed. Although their rate of addition to methyl acrylate depends on their electronegativity, the radicals are all nucleophilic and good initiators for photopolymerization reactions.
Rhodium(III)-Catalyzed C–H Activation: An Oxidative Intramolecular Heck-Type Reaction Directed by a Carboxylate
Tyler A. Davis, Chuanqi Wang, Tomislav Rovis
SYNLETT, 2015, 26, 1520-1524
Carboxylates effectively direct C–H activation for rhodium(III)-catalyzed intramolecular Heck-type reactions. A catalytic amount of Cu(OAc)2 is used as the external oxidant with oxygen likely acting as the terminal oxidant. Additionally, a novel electron-deficient rhodium(III) catalyst was found to be more effective than [RhCp*Cl2]2 with some substrates. A wide variety of complex dihydrobenzofurans, dihydrobenzopyrans, and other bicycles that can be easily further functionalized are now accessible through relatively mild reaction conditions.
Zn-Catalyzed Enantio- and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitro-Alkenes
John C. K. Chu, Derek M. Dalton, and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 445-4452
We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.
Cluster Preface: Catalysis Using Sustainable Metals – Part II
SYNLETT, 2015, 26, 306
The discovery of new catalytic reactions involving the use of abundant, inexpensive, and sustainable metal complexes has enjoyed a resurgence of activities in recent years. This Cluster, the second of a two-part series, continues the update of this important field, communicating a variety of approaches that address this important challenge.
Enantioselective Rhodium-Catalyzed Isomerization of 4-Iminocrotonates: Asymmetric Synthesis of a Unique Chiral Synthon
Wen-Zhen Zhang, John C. K. Chu, Kevin M. Oberg, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 553-555
An enantioselective isomerization of 4-iminocrotonates catalyzed by a rhodium(I)/phosphoramidite complex is described. This reaction uses widely available amines to couple with 4-oxocrotonate to provide a convenient access to a central chiral building block in good yield and high enantioselectivity. Although the mechanism of this new transformation remains unclear, both Rh and the phosphoramidite play a central role.
Ligand design for Rh(III)-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones
Todd K. Hyster, Derek M. Dalton, Tomislav Rovis
CHEMICAL SCIENCE, 2015, 6, 254-258
We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(III) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cpt affords product with excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.
Rh(I)–Bisphosphine-Catalyzed Asymmetric, Intermolecular Hydroheteroarylation of α-Substituted Acrylate Derivatives
Claire M. Filloux, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 137, 508-517
Asymmetric hydroheteroarylation of alkenes represents a convenient entry to elaborated heterocyclic motifs. While chiral acids are known to mediate asymmetric addition of electron-rich heteroarenes to Michael acceptors, very few methods exploit transition metals to catalyze alkylation of heterocycles with olefins via a C–H activation, migratory insertion sequence. Herein, we describe the development of an asymmetric, intermolecular hydroheteroarylation reaction of α-substituted acrylates with benzoxazoles. The reaction provides 2-substitued benzoxazoles in moderate to excellent yields and good to excellent enantioselectivities. Notably, a series of mechanistic studies appears to contradict a pathway involving enantioselective protonation of a Rh(I)–enolate, despite the fact that such a mechanism is invoked almost unanimously in the related addition of aryl boronic acids to methacrylate derivatives. Evidence suggests instead that migratory insertion or beta-hydride elimination is enantiodetermining and that isomerization of a Rh(I)–enolate to a Rh(I)–heterobenzyl species insulates the resultant α-stereocenter from epimerization. A bulky ligand, CTH-(R)-Xylyl-P-Phos, is crucial for reactivity and enantioselectivity, as it likely discourages undesired ligation of benzoxazole substrates or intermediates to on- or off-cycle rhodium complexes and attenuates coordination-promoted product epimerization.
Catalysis Using Sustainable Metals – Part I
Matthew Gaunt, Tomislav Rovis, Hak-Fun Chow
SYNLETT, 2014, 25, 2715-2716
The discovery of new catalytic reactions involving the use of abundant, inexpensive and sustainable metal complexes has enjoyed a resurgence of activities in recent years. This Cluster, Part I of a two-part series, focuses on new research findings from several prominent research groups, highlighting the rich diversities of new chemistry that can be originated from the use of sustainable metals in catalytic reactions.
Enantioselective N-Heterocyclic Carbene-Catalyzed β-Hydroxylation of Enals Using Nitroarenes: An Atom Transfer Reaction That Proceeds via Single Electron Transfer
Nicholas A. White, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136, 14674-14677 (2014)
A novel oxidative N-heterocyclic carbene-catalyzed reaction pathway has been discovered. Alkyl and aryl enals undergo β-hydroxylation via oxygen atom transfer from electron-deficient nitrobenzenes, followed by trapping of the resultant acyl azolium by the solvent. The proposed mechanism involves a single electron transfer event to initiate the reaction followed by radical recombination. This represents a profound mechanistic departure from the established two-electron disconnects in NHC catalysis.
Rh(III)-Catalyzed Cyclopropanation Initiated by C–H Activation: Ligand Development Enables a Diastereoselective [2 + 1] Annulation of N-Enoxyphthalimides and Alkenes
Tiffany Piou, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136, 11292-11295
N-Enoxyphthalimides undergo a Rh(III)-catalyzed C–H activation initiated cyclopropanation of electron deficient alkenes. The reaction is proposed to proceed via a directed activation of the olefinic C–H bond followed by two migratory insertions, first across the electron-deficient alkene and then by cyclization back onto the enol moiety. A newly designed isopropylcyclopentadienyl ligand drastically improves yield and diastereoselectivity.
Stereoelectronic Basis for the Kinetic Resolution of N-Heterocycles with Chiral Acylating Reagents
Sheng-Ying Hsieh, Benedikt Wanner, Philip Wheeler, André M. Beauchemin, Tomislav Rovis, Jeffrey W. Bode
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 20, 7228-7231
The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.
Cobaltate Anion Couples Terminal Dienes with Trifluoroacetic Anhydride: A Direct Fluoroacylation of 1,3-Diene
Benjamin L. Kohn, Tomislav Rovis
CHEMICAL SCIENCE, 2014, 5, 2889-2892
Perfluoroketones are useful products and intermediates in medicinal chemistry. Herein, cobalt-mediated fluoroacylation of 1,3-dienes is described using perfluorinated anhydrides such as TFAA. The reaction is thought to proceed through a fluoroacylcobalt reagent formed in situ. Perfluoroacylation of 1,3-dienes can also be performed to attain longer chain perfluorinated ketones.
A Late-Stage Strategy for the Functionalization of Triazolium-Based NHC Catalysts
Kerem E. Ozboya, Tomislav Rovis
SYNLETT, 2014, 25, 2665-2668
A strategy for the diversification of triazolium-based catalysts is presented. This method is based on the reduction to the triazoline, which serves as a suitable and stable substrate for palladium-mediated cross-coupling, followed by trityl cation mediated reoxidation to the triazolium.
Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via an N-Heterocylic Carbene Catalyzed Homoenolate Addition to Nitroalkanes
Nicholas A. White, Kerem E. Ozboya, Darrin M. Flanigan, Tomislav Rovis
ASIAN JOURNAL OF ORGANIC CHEMISTRY, 2014, 3, 442-444 (2014)
A concise enantionselective synthesis of (-)-paroxetine (Paxil) and (-)-femoxetine has been achieved. Key to these syntheses is an N-heterocyclic carbene catalyzed homoenolate addition to a nitroalkene followed by in situ reduction of the nitro group to rapidly access δ-lactams.
Stereoselective Synthesis of Dioxolanes and Oxazolidines via a Desymmetrization Acetalization/Michael Cascade
David M. Rubush, Tomislav Rovis
SYNLETT, 2014, 25, 713-717
The desymmetrization of p-quinols using a Brønsted acid catalyzed acetalization/Michael cascade was achieved in high yields and diastereoselectivities for aldehydes and imines. Use of a chiral Brønsted acid allowed for the synthesis of 1,3-dioxolane and 1,3-oxazolidine products in modest enantioselectivity.
Rh(III)-Catalyzed Decarboxylative Coupling of Acrylic Acids with Unsaturated Oxime Esters: Carboxylic Acids Serve as Traceless Activators
Jamie M. Neely, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136, 2735-2738
α,β-Unsaturated carboxylic acids undergo Rh(III)-catalyzed decarboxylative coupling with α,β-unsaturated O-pivaloyl oximes to provide substituted pyridines in good yield. The carboxylic acid, which is removed by decarboxylation, serves as a traceless activating group, giving 5-substituted pyridines with very high levels of regioselectivity. Mechanistic studies rule out a picolinic acid intermediate, and an isolable rhodium complex sheds further light on the reaction mechanism.