Enantioselective Synthesis of N-Benzylic Heterocycles by Ni/Photoredox Dual Catalysis.

An asymmetric cross-coupling of α-N-heterocyclic trifluoroborates with aryl bromides using Ni/photoredox dual catalysis has been developed. This C(sp2)-C(sp3) cross-coupling provides access to pharmaceutically relevant chiral N-benzylic heterocycles in good to excellent enantioselectivity when bioxazolines (BiOX) are used as the chiral ligand. High-throughput experimentation significantly streamlined reaction development by identifying BiOX ligands for further investigation and by allowing for rapid optimization of conditions for new trifluoroborate salts.

Direct Arylation of Azoles Enabled by Pd/Cu Dual Catalysis.

A practical approach toward the synthesis of 2-arylazoles via direct arylation is described. The transformation relies on a Pd/Cu cocatalyst system that operates with low catalyst loadings. The reaction conditions were found to be tolerant of a wide range of functional groups and nitrogen-containing heterocycles commonly employed in a drug discovery setting.

Rh(III)-Catalyzed Cyclopropanation of Unactivated Olefins Initiated by C-H Activation.

We have developed a Rh(III)-catalyzed cyclopropanation of unactivated olefins initiated by an alkenyl C-H activation. A variety of 1,1-disubstituted olefins undergo efficient cyclopropanation with a slight excess of alkene stoichiometry. A series of mechanistic interrogations implicate a metal-carbene as an intermediate.

Stereodivergent Rhodium(III)-Catalyzed cis-Cyclopropanation Enabled by Multivariate Optimization.

The design of stereodivergent transformations is of great interest to the synthetic community as it allows funneling of a given reaction pathway toward one stereochemical outcome or another by only minor adjustments of the reaction setup. Herein, we present a physical organic approach to invert the sense of induction in diastereoselective cyclopropanation of alkenes with N-enoxyphthalimides through rhodium(III) catalysis. Careful parametrization of catalyst-substrate molecular determinants allowed us to interrogate linear-free energy relationships and establish an intuitive and robust statistical model that correlates an extensive number of data points in high accuracy. Our multivariate correlations-steered mechanistic investigation culminated with a robust and general diastereodivergent cyclopropanation tool where the switch from trans- to cis-diastereoinduction is attributed to a mechanistic dichotomy. Selectivity might be determined by the flexibility of rhodacyclic intermediates derived from ring-opened versus -unopened phthalimides, induced by both their respective ring size and the Sterimol B1 parameter of the CpX ligand on rhodium.

Electronic and Steric Tuning of a Prototypical Piano Stool Complex: Rh(III) Catalysis for C-H Functionalization.

The history of transition metal catalysis is heavily steeped in ligand design, clearly demonstrating the importance of this approach. The intimate relationship between metal and ligand can profoundly affect the outcome of a reaction, often impacting selectivity, physical properties, and the lifetime of a catalyst. Importantly, this metal-ligand relationship can provide near limitless opportunities for reaction discovery. Over the past several years, transition-metal-catalyzed C-H bond functionalization reactions have been established as a critical foundation in organic chemistry that provides new bond forming strategies. Among the d-block elements, palladium is arguably one of the most popular metals to accomplish such transformations. One possible explanation for this achievement could be the broad set of phosphine and amine based ligands available in the chemist's toolbox compatible with palladium. In parallel, other metals have been investigated for C-H bond functionalization. Among them, pentamethylcyclopentadienyl (Cp*) Rh(III) complexes have emerged as a powerful mode of catalysis for such transformations providing a broad spectrum of reactivity. This approach possesses the advantage of often very low catalyst loading, and reactions are typically performed under mild conditions allowing broad functional group tolerance. Cp*Rh(III) is considered as a privileged catalyst and a plethora of reactions involving a C-H bond cleavage event have been developed. The search for alternative cyclopentadienyl based ligands has been eclipsed by the tremendous effort devoted to exploring the considerable scope of reactions catalyzed by Cp*Rh(III) complexes, despite the potential of this strategy for enabling reactivity. Thus, ligand modification efforts in Rh(III) catalysis have been an exception and research directed toward new rhodium catalysts has been sparse. Recently, chiral cyclopentadienyl ligands have appeared allowing enantioselective Rh(III)-catalyzed C-H functionalization reactions to be performed. Alongside chiral ligands, an equally important collection of achiral cyclopentadienyl-derived ligands have also emerged. The design of this new set of ligands for rhodium has already translated to significant success in solving inherent problems of reactivity and selectivity encountered throughout the development of new Rh(III)-catalyzed transformations. This Account describes the evolution of cyclopentadienyl ligand skeletons in Rh(III)-catalysis since the introduction of pentamethylcyclopentadienyl ligands to the present. Specific emphasis is placed on reactivity and synthetic applications achieved with the new ligands with the introduction of achiral mono-, di-, or pentasubstituted cyclopentadienyl ligands exhibiting a stunning effect on reactivity and selectivity. Furthermore, an underlying question when dealing with ligand modification strategies is to explain the reason one ligand outperforms another. Conjecture and speculation abound, but extensive characterization of their steric and electronic properties has been carried out and information about electronic and steric properties of the ligands all contribute to our understanding and give crucial pieces to solve the puzzle.

Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C-H Activation Reactions: An Experimental and Computational Study.

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.

Rhodium-catalysed syn-carboamination of alkenes via a transient directing group.

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. The reaction methodology allows for the intermolecular, stereospecific formation of one carbon-carbon and one carbon-nitrogen bond across an alkene, which is, to our knowledge, unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a new cyclopentadienyl ligand to control the reactivity of rhodium. The results provide a new way of synthesizing functionalized alkenes, and should lead to the convergent and stereoselective assembly of amine-containing acyclic molecules.

Pd-catalyzed dehydrogenative aryl-aryl bond formation via double C(sp(2))-H bond activation: efficient synthesis of [3,4]-fused oxindoles.

A Pd(0)-catalyzed double cyclization of easily available o-bromoanilides leading to strained [3,4]-fused oxindoles was developed. The reaction proceeded through a highly ordered sequence involving key carbopalladation, 1,4-Pd migration, and C(sp(2))-H functionalization steps.

Rh(III)-catalyzed cyclopropanation initiated by C-H activation: ligand development enables a diastereoselective [2 + 1] annulation of N-enoxyphthalimides and alkenes.

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.

Palladium-catalyzed through-space C(sp(3))-H and C(sp(2))-H bond activation by 1,4-palladium migration: efficient synthesis of [3,4]-fused oxindoles.

Palladium two step: Linear anilides were converted into the title compounds in good to excellent yields through a palladium-catalyzed domino carbopalladation/1,4-palladium shift sequence. The C(sp(3) )-H activation involves a seven-membered palladacycle, and is chemoselective in the presence of competitive C(sp(2) )H bonds. DMA=N,N-dimethylacetamide, OPiv=pivalate.

Spirocyclization by palladium-catalyzed domino Heck-direct C-H arylation reactions: synthesis of spirodihydroquinolin-2-ones.

Treatment of a DMA solution of anilide 1 with a catalytic amount of palladium acetate (0.025 equiv) and XPhos (0.05 equiv) in the presence of potassium carbonate (2.0 equiv) at 100 °C afforded dihydroquinolin-2-ones spiro-fused to dihydrofuranyl, indolinyl, and indanyl 2 in good to excellent yields. The reaction went through a domino sequence involving a 5-exo-trig Heck cyclization followed by an intramolecular direct C-H functionalization.

Iodo-carbocyclization of electron-deficient alkenes: synthesis of oxindoles and spirooxindoles.

Cyclisative carbo-iodination of N-alkyl-N-arylacrylamide derivatives (3) in the presence of PhI(OAc)(2)/I(2) afforded functionalized 3-(iodomethyl)-3-substituted-indolin-2-ones (4) in good to excellent yields. With a suitably functionalized linear amide, spirooxindole 8 was prepared in a one-pot fashion via a sequence of iodo-arylation followed by an in situ base-promoted intramolecular S(N)2 reaction.

Palladium-catalyzed carbo-heterofunctionalization of alkenes for the synthesis of oxindoles and spirooxindoles.

A palladium-catalyzed oxidative carbo-heterofunctionalization of aniline derivatives involving concomitant direct C-H functionalization and C-X bond formation was developed. By simply changing the reaction conditions (solvent and catalyst), either 3,3'-disubstituted oxindole or spirooxindole was accessible from the same starting material.