Heterogeneous Fe-N-C Catalyst for Aerobic Dehydrogenation of Hydrazones to Diazo Compounds Used for Carbene Transfer.

Organic diazo compounds are versatile reagents in chemical synthesis and would benefit from improved synthetic accessibility, especially for larger scale applications. Here, we report a mild method for the synthesis of diazo compounds from hydrazones using a heterogeneous Fe-N-C catalyst, which has Fe ions dispersed within a graphitic nitrogen-doped carbon support. The reactions proceed readily at room temperature using O2 (1 atm) as the oxidant. Aryl diazoesters, ketones, and amides are accessible, in addition to less stable diaryl diazo compounds. Initial-rate data show that the Fe-N-C catalyst achieves faster rates than a heterogeneous Pt/C catalyst. The oxidative dehydrogenation of hydrazones may be performed in tandem with Rh-catalyzed enantioselective C-H insertion and cyclopropanation of alkenes, without requiring isolation of the diazo intermediate. This sequence is showcased by using a flow reactor for continuous synthesis of diazo compounds.

Rhodium(II)-Catalyzed Asymmetric Cyclopropanation and Desymmetrization of [2.2]Paracyclophanes.

Chiral [2.2]paracyclophane derivatives are of considerable interest because of their potential in asymmetric catalysis and the development of chiral materials. This study describes the scope of rhodium-catalyzed reactions of aryldiazoacetates with [2.2]paracyclophanes. The reaction with the parent [2.2]paracyclophane resulted in cyclopropanation at two positions, the ratio of which is catalyst-controlled. Because of the strain in the system, one of the cyclopropanes exists primarily as the norcaradiene structure, whereas the other preferentially exists as the cycloheptatriene conformer. In contrast, the reaction with [3.3]paracyclophane results in benzylic C-H functionalization. The reactions with substituted [2.2]paracyclophanes using chiral catalysts can result in either kinetic resolution or desymmetrization. The Rh2(S-p-PhTPCP)]4-catalyzed reaction of monosubstituted paracyclophanes results in kinetic resolution with a selectivity (s) factor of up to 20, whereas reactions on C2v-symmetric disubstituted [2.2]paracyclophanes with Rh2(S-TPPTTL)4 [TPPTTL = 2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] results in effective desymmetrization to form cycloheptatriene-incorporated paracyclophanes in 78-98% ee.

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.

Anhydrous and Stereoretentive Fluoride-Enhanced Suzuki-Miyaura Coupling of Immunomodulatory Imide Drug Derivatives.

Immunomodulatory imide drugs form the core of many pharmaceutically relevant structures, but Csp2-Csp2 bond formation via metal-catalyzed cross coupling is difficult due to the sensitivity of the glutarimide ring ubiquitous in these structures. We report that replacement of the traditional alkali base with a fluoride source enhances a previously challenging Suzuki-Miyaura coupling on glutarimide-containing compounds with trifluoroborates. These enabling conditions are reactive enough to generate these derivatives in high yields but mild enough to preserve both the glutarimide and its sensitive stereocenter. Experimental and computational data suggest a mechanistically distinct process of π-coordination of the trifluoroborate enabled by these conditions.

Enantioselective Intermolecular C-H Functionalization of Primary Benzylic C-H Bonds Using ((Aryl)(diazo)methyl)phosphonates.

Catalyst-controlled C-H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and stereocontrol. This study demonstrated that the scope of the donor/acceptor carbene C-H functionalization can be extended to systems where the acceptor group is a phosphonate. When using the optimized dirhodium catalyst, Rh2(S-di-(4-Br)TPPTTL)4, ((aryl)(diazo)methyl)phosphonates undergo highly enantioselective (84-99% ee) and site-selective (>30:1 r.r.) benzylic C-H functionalization. The phosphonate group is much more sterically demanding than the previously studied carboxylate ester group, leading to much higher selectivity for a primary site versus more sterically crowded positions. The effectiveness of this methodology has been demonstrated by the late-stage primary C-H functionalization of estrone, adapalene, (S)-naproxen, clofibrate, and gemfibrozil derivatives.

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.

A Novel 7H-[1,2,4]Triazolo[3,4-b]thiadiazine-based Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Directed toward Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.

Diruthenium Tetracarboxylate-Catalyzed Enantioselective Cyclopropanation with Aryldiazoacetates.

A series of chiral bowl-shaped diruthenium(II,III) tetracarboxylate catalysts were prepared and evaluated in asymmetric cyclopropanations with donor/acceptor carbenes derived from aryldiazoacetates. The diruthenium catalysts self-assembled to generate C4-symmetric bowl-shaped structures in an analogous manner to their dirhodium counterparts. The optimum catalyst was found to be Ru2(S-TPPTTL)4·BArF [S-TPPTTL = (S)-2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate, BArF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate], which resulted in the cyclopropanation of a range of substrates in up to 94% ee. Synthesis and evaluation of first-row transition-metal congeners [Cu(II/II) and Co(II/II)] invariably resulted in catalysts that afforded little to no asymmetric induction. Computational studies indicate that the carbene complexes of these dicopper and dicobalt complexes, unlike the dirhodium and diruthenium systems, are prone to the loss of carboxylate ligands, which would destroy the bowl-shaped structure critical for asymmetric induction.

One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates.

Rapid access to 2,2-difluorobicylco[1.1.1]pentanes is enabled from an α-allyldiazoacetate precursor in a one-pot process through cyclopropanation to afford a 3-aryl bicyclo[1.1.0]butane, followed by reaction with difluorocarbene in the same reaction flask. The modular synthesis of these diazo compounds affords novel 2,2-difluorobicyclo[1.1.1]pentanes that were inaccessible through previously reported methods. The reactions of chiral 2-arylbicyclo[1.1.0]butanes in the same manner generate altogether different products with high asymmetric induction, methylene-difluorocyclobutanes. Larger ring systems including bicyclo[3.1.0]hexanes are also rapidly furnished due to the modular nature of the diazo starting material.

N-Phthalimide as a Site-Protecting and Stereodirecting Group in Rhodium-Catalyzed C-H Functionalization with Donor/Acceptor Carbenes.

The rhodium-catalyzed enantioselective C-H functionalization of unactivated C-H bonds by means of donor/acceptor carbene-induced C-H insertion was extended to substrates containing nitrogen functionality. The rhodium-stabilized donor/acceptor carbenes were generated by rhodium-catalyzed decomposition of aryldiazoacetates. The phthalimido group was the optimum nitrogen protecting group. C-H functionalization at the most sterically accessible methylene site was achieved using Rh2(S-2-Cl-5-BrTPCP)4 as catalyst, whereas Rh2(S-TPPTTL)4 was the most effective catalyst for C-H functionalization at tertiary C-H bonds and for the desymmetrization of N-phthalimidocyclohexane.

Stereoselective Synthesis of Highly Functionalized Cyclohexenes via Strong-Acid-Mediated Endocyclic C-C Bond Cleavage of Monocyclopropanated Cyclopentadienes.

A stereoselective, solvent- and metal-free endocyclic C-C bond cleavage of monocyclopropanated cyclopentadienes mediated by strong acids was developed, leading to highly functionalized six-membered carbocycles with high stereocontrol. The critical step for this ring-expansion is the formation of a cyclopropyl carbocation that undergoes endocyclic ring opening via an SN2'-type attack of various nucleophiles. Subsequent synthetic transformations show the versatility of the resulting cyclohexenes for the synthesis of new compounds with nonconventional substitution patterns.

Enantioselective Synthesis of Triarylmethanes via Intermolecular C-H Functionalization of Cyclohexadienes with Diaryldiazomethanes.

Rhodium-catalyzed C-H functionalization of cyclohexadiene derivatives with diaryldiazomethanes followed by oxidation with DDQ provides ready access to triarylmethanes. Two chiral dirhodium tetracarboxylates, Rh2(S-PTAD)4 and Rh2(S-TPPTTL)4, were found to be the optimum chiral catalysts for these transformations. This method showcases the ability of diaryldiazomethanes to perform intermolecular C-H insertion with high enantioselectivity and good yields. The method has a broad substrate scope, leading to triarylmethane products with a variety of aryl and heteroaryl substituents, including benzofuran and pyridine heterocycles.

Dirhodium C-H Functionalization of Hole-Transport Materials.

Hole-transport materials (HTMs) based on triarylamine derivatives play important roles in organic electronics applications including organic light-emitting diodes and perovskite solar cells. For some applications, triarylamine derivatives bearing appropriate binding groups have been used to functionalize surfaces, while others have been incorporated as side chains into polymers to manipulate the processibility of HTMs for device applications. However, only a few approaches have been used to incorporate a single surface-binding group or polymerizable group into triarylamine materials. Here, we report that Rh-carbenoid chemistry can be used to insert carboxylic esters and norbornene functional groups into sp2 C-H bonds of a simple triarylamine and a 4,4'-bis(diarylamino)biphenyl, respectively. The norbenene-functionalized monomer was polymerized by ring-opening metathesis; the electrochemical, optical, and charge-transport properties of these materials were similar to those of related materials synthesized by conventional means. This method potentially offers straightforward access to a diverse range of HTMs with different functional groups.

Catalyst Controlled Site- and Stereoselective Rhodium(II) Carbene C(sp3)-H Functionalization of Allyl Boronates.

Rhodium(II) catalyst-controlled site- and stereoselective carbene insertion into the distal allylic C(sp3)-H bond of allyl boronates is reported. The optimum chiral catalyst for this reaction is Rh2(S-TPPTTL)4. The fidelity and asymmetric induction of this catalytic transformation allows for a highly diastereoselective and enantioselective C-C bond formation without interference from the allyl boronate functionality. The resulting functionalized allyl boronates are susceptible to stereoselective allylations, generating products with control of stereochemistry at four contiguous stereogenic centers.

Unearthing the Subtleties of Rhodium(II)-Catalyzed Carbenoid Cycloadditions to Furans with an N-Sulfonyl-1,2,3-triazole Probe.

The rhodium(II)-catalyzed reaction of a model alkenyl donor/acceptor N-sulfonyltriazole with a wide selection of furans is reported. This investigation unearthed a range of structurally diverse carbocyclic and ring-opened products, in good to excellent yields. The products obtained are proposed to arise selectively via cyclopropanation or zwitterionic rearrangement pathways, which are highly dependent on both the structural and electronic features of the furan substrate.

Asymmetric Cyclopropanation with 4-Aryloxy-1-sulfonyl-1,2,3-triazoles: Expanding the Range of Rhodium-Stabilized Donor/Acceptor Carbenes to Systems with an Oxygen Donor Group.

Rhodium-catalyzed enantioselective synthesis of 1-phenoxycyclopropane-1-carbaldehydes by intermolecular cyclopropanation of terminal alkenes followed by imine hydrolysis is described. This methodology utilizes 4-aryloxy-1-sulfonyl-1,2,3-triazoles as the carbene precursors and the chiral dirhodium(II) tetracarboxylates Rh2(S-NTTL)4 or Rh2(S-DPCP)4 as the catalysts. These reactions are considered to proceed via rhodium-stabilized donor/acceptor carbene intermediates, and these studies demonstrate that a heteroatom donor group is compatible with an enantioselective transformation.

Leveraging Regio- and Stereoselective C(sp3)-H Functionalization of Silyl Ethers to Train a Logistic Regression Classification Model for Predicting Site-Selectivity Bias.

The C-H functionalization of silyl ethers via carbene-induced C-H insertion represents an efficient synthetic disconnection strategy. In this work, site- and stereoselective C(sp3)-H functionalization at α, γ, δ, and even more distal positions to the siloxy group has been achieved using donor/acceptor carbene intermediates. By exploiting the predilections of Rh2(R-TCPTAD)4 and Rh2(S-2-Cl-5-BrTPCP)4 catalysts to target either more electronically activated or more spatially accessible C-H sites, respectively, divergent desired products can be formed with good diastereocontrol and enantiocontrol. Notably, the reaction can also be extended to enable desymmetrization of meso silyl ethers. Leveraging the broad substrate scope examined in this study, we have trained a machine learning classification model using logistic regression to predict the major C-H functionalization site based on intrinsic substrate reactivity and catalyst propensity for overriding it. This model enables prediction of the major product when applying these C-H functionalization methods to a new substrate of interest. Applying this model broadly, we have demonstrated its utility for guiding late-stage functionalization in complex settings and developed an intuitive visualization tool to assist synthetic chemists in such endeavors.

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.