Redox-Paired Alkene Difunctionalization Enables Skeletally Divergent Synthesis.

Multistep organic synthesis enables conversion of simple chemical feedstocks into a more structurally complex product that serves a particular function. The target compound is forged over several steps, with concomitant generation of byproducts in each step to account for underlying mechanistic features of the reactions (e.g., redox processes). To map structure-function relationships, libraries of molecules are often needed, and these are typically prepared by iterating an established multistep synthetic sequence. An underdeveloped approach is designing organic reactions that generate multiple valuable products with different carbogenic skeletons in a single synthetic operation. Taking inspiration from paired electrosynthesis processes that are widely used in commodity chemical production (e.g., conversion of glucose to sorbitol and gluconic acid), we report a palladium-catalyzed reaction that converts a single alkene starting material into two skeletally distinct products in a single operation through a series of carbon-carbon and carbon-heteroatom bond-forming events enabled by mutual oxidation and reduction, a process that we term redox-paired alkene difunctionalization. We demonstrate the scope of the method in enabling simultaneous access to reductively 1,2-diarylated and oxidatively [3 + 2]-annulated products, and we explore the mechanistic details of this unique catalytic system using a combination of experimental techniques and density functional theory (DFT). The results described herein establish a distinct approach to small-molecule library synthesis that can increase the rate of compound production. Furthermore, these findings demonstrate how a single transition-metal catalyst can mediate a sophisticated redox-paired process through multiple pathway-selective events along the catalytic cycle.

Mechanistic Studies of Pd(II)-Catalyzed E/Z Isomerization of Unactivated Alkenes: Evidence for a Monometallic Nucleopalladation Pathway.

Pd(II)-catalyzed E/Z isomerization of alkenes is a common process-yet its mechanism remains largely uncharacterized, particularly with non-conjugated alkenes. In this work, the mechanism of Pd(II)-catalyzed E/Z isomerization of unactivated olefins containing an aminoquinoline-based amide directing group is probed using in situ kinetic analysis, spectroscopic studies, kinetic modeling, and DFT calculations. The directing group allows for stabilization and monitoring of previously undetectable intermediates. Collectively, the data are consistent with isomerization occurring through a monometallic nucleopalladation mechanism.

Ni-Catalyzed 1,2-Diarylation of Alkenyl Ketones: A Comparative Study of Carbonyl-Directed Reaction Systems.

A nickel-catalyzed 1,2-diarylation of alkenyl ketones with aryl iodides and arylboronic esters is reported. Ketones with a variety of substituents serve as effective directing groups, offering high levels of regiocontrol. A representative product is diversified into a wide range of useful products that are not readily accessible via existing 1,2-diarylation reactions. Preliminary mechanistic studies shed light on the binding mode of the substrate, and Hammett analysis reveals the effect of electronic factors on initial rates.

Nickel-Catalyzed 1,2-Diarylation of Alkenyl Carboxylates: A Gateway to 1,2,3-Trifunctionalized Building Blocks.

A nickel-catalyzed conjunctive cross-coupling of alkenyl carboxylic acids, aryl iodides, and aryl/alkenyl boronic esters is reported. The reaction delivers the desired 1,2-diarylated and 1,2-arylalkenylated products with excellent regiocontrol. To demonstrate the synthetic utility of the method, a representative product is prepared on gram scale and then diversified to eight 1,2,3-trifunctionalized building blocks using two-electron and one-electron logic. Using this method, three routes toward bioactive molecules are improved in terms of yield and/or step count. This method represents the first example of catalytic 1,2-diarylation of an alkene directed by a native carboxylate group.

Catalytic, Enantioselective α-Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation.

A palladium(II)-catalyzed enantioselective α-alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL-derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α-disubstituted α-amino-acid derivatives with high yields and high enantioselectivity.

Synthetic and Mechanistic Studies of a Versatile Heteroaryl Thioether Directing Group for Pd(II) Catalysis.

A weakly coordinating monodentate heteroaryl thioether directing group has been developed for use in Pd(II) catalysis to orchestrate key elementary steps in the catalytic cycle that require conformational flexibility in a manner that is difficult to accomplish with traditional strongly coordinating directing groups. This benzothiazole thioether, (BT)S, directing group can be used to promote oxidative Heck reactivity of internal alkenes providing a wide range of products in moderate to high yields. To demonstrate the broad applicability of this directing group, an arene C-H olefination method was also successfully developed. Reaction progress kinetic analysis provides insights into the role of the directing group in each reaction, which is supplemented with computational data for the oxidative Heck reaction. Furthermore, this (BT)S directing group can be transformed into a number of synthetically useful functional groups, including a sulfone for Julia olefination, allowing it to serve as a "masked olefin" directing group in synthetic planning. In order to demonstrate this synthetic utility, natural products (+)-salvianolic acid A and salvianolic acid F are formally synthesized using the (BT)S directed C-H olefination as the key step.

Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides.

A nickel-catalyzed conjunctive cross-coupling of simple alkenyl amides with aryl iodides and aryl boronic esters is reported. The reaction is enabled by an electron-deficient olefin (EDO) ligand, dimethyl fumarate, and delivers the desired 1,2-diarylated products with excellent regiocontrol. Under optimized conditions, a wide range of amides derived from 3-butenoic acid, 4-pentenoic acid, and allyl amine are compatible substrates. This method represents the first example of regiocontrolled 1,2-diarylation directed by a native amide functional group. Computational analysis sheds light on the potential substrate binding mode and the role of the EDO ligand in the reductive elimination step.

C(alkenyl)-H Activation via Six-Membered Palladacycles: Catalytic 1,3-Diene Synthesis.

A catalytic method to prepare highly substituted 1,3-dienes from two different alkenes is described using a directed, palladium(II)-mediated C(alkenyl)-H activation strategy. The transformation exhibits broad scope across three synthetically useful substrate classes masked with suitable bidentate auxiliaries (4-pentenoic acids, allylic alcohols, and bishomoallylic amines) and tolerates internal nonconjugated alkenes, which have traditionally been a challenging class of substrates in this type of chemistry. Catalytic turnover is enabled by either MnO2 as the stoichiometric oxidant or co-catalytic Co(OAc)2 and O2 (1 atm). Experimental and computational studies were performed to elucidate the preference for C(alkenyl)-H activation over other potential pathways. As part of this effort, a structurally unique alkenylpalladium(II) dimer was isolated and characterized.

Catalytic, Enantioselective Synthesis of Allenyl Boronates.

A method to achieve enantioselective 1,4-hydroboration of terminal enynes to access allenyl boronates under CuH catalysis is described. The reaction typically proceeds in a highly stereoselective manner and tolerates an array of synthetically useful functional groups. The utility of the enantioenriched allenyl boronate products is demonstrated through several representative downstream derivatizations.

E-Selective Semi-Hydrogenation of Alkynes by Heterobimetallic Catalysis.

A unique cooperative H2 activation reaction by heterobimetallic (NHC)M'-MCp(CO)2 complexes (NHC = N-heterocyclic carbene, M' = Cu or Ag, M = Fe or Ru) has been leveraged to develop a catalytic alkyne semi-hydrogenation transformation. The optimal Ag-Ru catalyst gives high selectivity for converting alkynes to E-alkenes, a rare selectivity mode for reduction reactions with H2. The transformation is tolerant of many reducible functional groups. Computational analysis of H2 activation thermodynamics guided rational catalyst development. Bimetallic alkyne hydrogenation and alkene isomerization mechanisms are proposed.

Synthesis and characterization of heterobimetallic complexes with direct Cu-M bonds (M = Cr, Mn, Co, Mo, Ru, W) supported by N-heterocyclic carbene ligands: a toolkit for catalytic reaction discovery.

Building upon the precedent of catalytically active (NHC)Cu-FeCp(CO)2 complexes, a series of (NHC)Cu-[M] complexes were synthesized via the addition of Na(+)[M](-) reagents to (NHC)CuCl synthons. The different [M](-) anions used span a range of 7 × 10(7) relative nucleophilicity units, allowing for controlled variation of nucleophile/electrophile pairing in the heterobimetallic species. Direct Cu-M bonds (M = Cr, Mn, Co, Mo, Ru, W) formed readily when the bulky IPr carbene was used as a support. Crystallographic characterization and computational examination of these complexes was conducted. For the smaller IMes carbene, structural isomerism was observed when using the weakest [M](-) nucleophiles, with (IMes)Cu-[M] and {(IMes)2Cu}{Cu[M]2} isomers being observed in equilibrium. Collectively, the series of complexes provides a toolbox for catalytic reaction discovery with precise control of structure-function relationships.

Experimental determination of redox cooperativity and electronic structures in catalytically active Cu-Fe and Zn-Fe heterobimetallic complexes.

Complexes of the type (NHC)M-Fp (NHC = N-heterocyclic carbene, M = Cu or ZnCl, Fp = FeCp(CO)2) have been used recently as replacements for noble metal C-H functionalization catalysts and for small molecule activation studies. The promising reactivity of these systems has been linked to the use of the late metal electrophiles Cu and Zn in place of early metal electrophiles, and also to the ability of the M-Fe pairs to cooperate during catalytically relevant multielectron redox processes such as bimetallic oxidative addition and bimetallic reductive elimination. Using Mössbauer spectroscopy and metal K-edge XANES analysis, a detailed electronic structure description of these complexes is presented. One unusual feature of the late-metal M-Fp interactions is the presence of significant M → Fe π-backdonation in addition to Fe → M σ-donation; this π-backdonation is absent in early metal analogues and is apparent from analysis of Mössbauer data and Fe K-edge data. Multi-edge XANES analysis of C-I bimetallic oxidative addition at a Cu-Fe reaction center reveals little change in metal effective nuclear charges during the two-electron redox process. IR spectroscopy indicates that the supporting carbonyl ligands participate to a large extent in the redox process.