In this study, we harness the distinct reactivity of sulfenylnitrenes, which insert a single nitrogen atom to transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, and triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors as a source of a single nitrogen atom. This chemical approach is compatible with free pyrroles, indoles, and imidazoles with diverse functional groups, including oxidation-sensitive functionalities like phenol and thioether. Additionally, this approach facilitates the selective incorporation of a single nitrogen atom into various natural products, amino acids, and pharmaceuticals. Furthermore, we have conducted mechanistic studies and explored regioselectivity outcomes through DFT calculations.

Given the prevalence of nitrogen-containing heterocycles in FDA-approved drugs, selectively incorporating a single nitrogen atom emerges as a promising scaffold-hopping approach to enhance chemical diversity in drug discovery libraries. In this study, we harness the distinct reactivity of sulfenylnitrenes, which insert a single nitrogen atom to transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, and triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors over a broad temperature range (–30 to 150 ºC). This chemical approach is compatible with diverse functional groups, including oxidation-sensitive functionalities like phenols and thioethers, and has been applied to various natural products, amino acids, and pharmaceuticals. Furthermore, we have conducted mechanistic studies and explored regioselectivity outcomes through DFT calculations.

1,2-cis-Furanosides are present in various biomedically relevant glycosides, and their stereoselective synthesis remains a significant challenge. In this vein, we have developed a stereoselective approach to 1,2-cis-furanosylations using earth-abundant copper catalysis. This protocol proceeds under mild conditions at room temperature and employs readily accessible benchtop stable enynal-derived furanose donors. This chemistry accommodates a variety of alcohols, including primary, secondary, and tertiary, as well as mannosyl alcohol acceptors, which have been incompatible with most known methods of furanosylation. The resulting 1,2-cis-furanoside products exhibit high yields and anomeric selectivity with both the ribose and arabinose series. Furthermore, the anomeric selectivity is independent of the C2 oxygen-protecting group and the anomeric configuration of the starting donor. Experimental evidence and computational studies support our hypothesis that copper chelation between the C2 oxygen of the furanose donor and an incoming alcohol nucleophile is responsible for the observed 1,2-cis-stereoselectivity.

Given its earth abundance, cost-effectiveness, and ecofriendly qualities, iron serves as a promising alternative to precious metals in catalysis. This article presents an iron carbene-initiated cascade approach for synthesizing highly substituted tetrahydrofurans at the gram scale. This cascade reaction utilizes readily accessible beta-hydroxyketones and diazo compounds and works with iron catalyst loading as low as 5 mol %. This reaction proceeds through an O-H insertion into diazo-derived iron carbenes, followed by an intramolecular aldol reaction to access functionalized tetrahydrofurans in high yields and diastereoselectivity. The versatile nature of this domino sequence accommodates diverse beta-hydroxyketones and diazo compounds, streamlining access to synthetically challenging spiroethers. Furthermore, this cascade process offers a route to enantiopure tetrahydrofurans by utilizing a diazo ester bearing a chiral auxiliary, 8-phenylmenthol. Postmodifications of the tetrahydrofuran product provide access to various analogues, including a medicinally relevant oxetane motif. Density functional theory (DFT) calculations substantiate a stereospecific mechanism wherein the intramolecular aldol reaction proceeds via a fused six- and five-membered iron-oxygen transition-state complex, yielding the contrathermodynamic cis-aldol product.

Catalysis of O-atom transfer (OAT) reactions is a characteristic of both natural (enzymatic) and synthetic molybdenum-oxo and -peroxo complexes. These reactions can employ a variety of terminal oxidants, e. g. DMSO, N-oxides, and peroxides, etc., but rarely molecular oxygen. Here we demonstrate the ability of a set of Schiff-base-MoO2 complexes (cy-salen)MoO2 (cy-salen=N,N'-cyclohexyl-1,2-bis-salicylimine) to catalyze the aerobic oxidation of PPh3. We also report the results of a DFT computational investigation of the catalytic pathway, including the identification of energetically accessible intermediates and transition states, for the aerobic oxidation of PMe3. Starting from the dioxo species, (cy-salen)Mo(VI)O-2 (1), key reaction steps include: 1) associative addition of PMe3 to an oxo-O to give LMo(IV)(O)(OPMe3) (2); 2) OPMe3 dissociation from 2 to produce mono-oxo complex (cy-salen)Mo(IV)O (3); 3) stepwise O-2 association with 3 via superoxo species (cy-salen)Mo(V)(O)(eta(1)-O-2) (4) to form the oxo-peroxo intermediate (cy-salen)Mo(VI)(O)(eta(2)-O-2) (5); 4) the O-transfer reaction of PMe3 with oxo-peroxo species 5 at the oxo-group, rather than the peroxo unit leading, after OPMe3 dissociation, to a monoperoxo species, (cy-salen)Mo(IV)(eta(2)-O-2) (7); and 5) regeneration of the dioxo complex (cy-salen)Mo(VI)O-2 (1) from the monoperoxo triplet (3)7 or singlet (1)7 by a concerted, asynchronous electronic isomerization. An alternative pathway for recycling of the oxo-peroxo species 5 to the dioxo-Mo 1 via a bimetallic peroxo complex LMo(O)-O-O-Mo(O)L 8 is determined to be energetically viable, but is unlikely to be competitive with the primary pathway for aerobic phosphine oxidation catalyzed by 1.

Thioglycoside activation, crucial for oligosaccharide synthesis, faces challenges with the need for stoichiometric promoters, additives, and cryogenic conditions, particularly in stereoselective 1,2-cis-linkage formation. This study introduces a carbene-based catalytic method using Cu(OTf)2 for thioglycoside activation, enabling efficient 1,2-cis-furanosylation in ribose and arabinose. The method is orthogonal to conventional thioglycoside and alkyne donors, accommodates sterically demanding acceptors, and achieves stereoselectivity independent of the donor anomeric configuration and C2-protecting groups, with copper chelation playing a key role.

Dioxomolybdenum complexes based on salan ligands have been evaluated for their potential in catalyzing the deoxydehydration (DODH) reaction. The DODH reaction is a formal reduction that converts vicinal diols into olefins using an oxometal catalyst and a sacrificial reductant. The reaction holds enormous potential in transforming biomass-derived molecules into platform chemicals. This study evaluated 20 molybdenum complexes supported by salan ligands in the DODH reaction with the goal of establishing structure-activity relationships. Catalyst screenings were performed using styrene glycol as a model substrate and 1-10 mol% loading of the molybdenum complexes at 170 oC producing styrene in up to 54% yield. Aliphatic diols and meso-/R,R-hydrobenzoin were also converted to the corresponding alkenes in moderate to good yields that are comparable to previously reported molybdenum catalysts. A bio-derived glycol, (+)−diethyltartrate, could be converted to the alkene product (diethyl fumarate) in >98% yield using 10 mol% catalyst. A high yield of diethyl fumarate (78%) was also obtained with Na2SO3 (cheap, readily available, and benign) as reductant. Quite significantly, a 42% yield of diethyl fumarate was also obtained at a 1 mol% catalyst loading which represents a turnover number (TON) of 42; this is one of highest activity in a DODH reaction observed with molybdenum catalysts. The catalytic studies along with preliminary kinetic investigations reveal significant ligand effects: sterically bulky ortho-substituents and electron-withdrawing para-substituents on the phenol arms were found to enhance catalytic activity while a rigid phenyl as well as an ethylene backbone featuring a tertiary amine were observed to impede catalysis.

We propose a simple procedure for visualizing the electron density changes (EDC) during a chemical reaction, which is based on a mapping of rectangular grid points for a stationary structure into (distorted) positions around atoms of another stationary structure. Specifically, during a small step along the minimum energy pathway (MEP), the displacement of each grid point is obtained as a linear combination of the motion of all atoms, with the contribution from each atom scaled by the corresponding Hirshfeld weight. For several reactions (identity SN2, Claisen rearrangement, Diels-Alder reaction, [3+2] cycloaddition, and phenylethyl mercaptan attack on pericosine A), our EDC plots showed an expected reduction of electron densities around severed bonds (or those with the bond-order lowered), with the opposite observed for newly-formed or enhanced chemical bonds. The EDC plots were also shown for copper triflate catalyzed N2O fragmentation, where the N–O bond weakening initially occurred on a singlet surface, but continued on a triplet surface after reaching the minimum-energy crossing point (MECP) between the two potential energy surfaces.

Nitrous oxide (N2O) is a potent greenhouse gas (GHG) with limited use as a mild anesthetic and underdeveloped reactivity. Nitrous oxide splitting (decomposition) is critical to its mitigation as a GHG. Although heterogeneous catalysts for N2O decomposition have been developed, highly efficient, long-lived solid catalysts are still needed, and the details of the catalytic pathways are not well understood. Reported herein is a computational evaluation of three potential molecular (homogeneous) catalysts for N2O splitting, which could aid in the development of more active and robust catalysts and provide deeper mechanistic insights: one Cu(I)-based, [(CF3O)4Al]Cu (A-1), and two Ru(III)-based, Cl(POR)Ru (B-1) and (NTA)Ru (C-1) (POR = porphyrin, NTA = nitrilotriacetate). The structures and energetic viability of potential intermediates and key transition states are evaluated according to a two-stage reaction pathway: (A) deoxygenation (DO), during which a metal-N2O complex undergoes N-O bond cleavage to produce N2 and a metal-oxo species and (B) (di)oxygen evolution (OER), in which the metal-oxo species dimerizes to a dimetal-peroxo complex, followed by conversion to a metal-dioxygen species from which dioxygen dissociates. For the (F-L)Cu(I) activator (A-1), deoxygenation of N2O is facilitated by an O-bound (F-L)Cu-O-N2 or better by a bimetallic N,O-bonded, (F-L)Cu-NNO-Cu(F-L) complex; the resulting copper-oxyl (F-L)Cu-O is converted exergonically to (F-L)Cu-(η2,η2-O2)-Cu(F-L), which leads to dioxygen species (F-L)Cu(η2-O2), that favorably dissociates O2. Key features of the DO/OER process for (POR)ClRu (B-1) include endergonic N2O coordination, facile N2 evolution from LR'u-N2O-RuL to Cl(POR)RuO, moderate barrier coupling of Cl(POR)RuO to peroxo Cl(POR)Ru(O2)Ru(POR)Cl, and eventual O2 dissociation from Cl(POR)Ru(η1-O2), which is nearly thermoneutral. N2O decomposition promoted by (NTA)Ru(III) (C-1) can proceed with exergonic N2O coordination, facile N2 dissociation from (NTA)Ru-ON2 or (NTA)Ru-N2O-Ru(NTA) to form (NTA)Ru-O; dimerization of the (NTA)Ru-oxo species is facile to produce (NTA)Ru-O-O-Ru(NTA), and subsequent OE from the peroxo species is moderately endergonic. Considering the overall energetics, (F-L)Cu and Cl(POR)Ru derivatives are deemed the best candidates for promoting facile N2O decomposition.

An uncatalyzed and easily accessible synthetic approach for the preparation of 3-aroylindoles was investigated using nitrosoarenes and aromatic terminal ethynyl ketones. Indole derivatives were produced in good yields and excellent regioselectivity. Functionalizations of the indole products were carried out affording highly valuable and versatile compounds. The indolization protocol was studied as a fundamental step for the preparation of pravadoline and 1-butyl-3-(1-naphthoyl)indole (JWH-073), bioactive molecules showing antinociceptic properties.

The first Cu-catalyzed asymmetric allylic C–H amination of alkenes with N-aryl hydroxylamines has been developed. Metal-complexes isolation, ESI-MS analysis and the DFT calculations provided key insights on mechanistic pathway.

Synthetic LMoO2 compounds have long been of keen interest both as structural and functional models for molybdoenzymes and in their own right as catalysts for a variety of oxygen atom-transfer (OAT) reactions. Investigations of their use as catalysts for stereoselective OAT transformations, however, are little known. In this study chiral diimine-salen molybdenum complexes, L*MoO2, are evaluated for their potential to catalyze oxidative kinetic resolution of racemic monophosphines by pyridine N-oxide. A set of six L*MoO2 complexes incorporating chiral salen-type Schiff base ligands derived from 1,2-diaminocyclohexane (7-10) and 1,1'-dia-minobinapthylene (12) has been prepared and characterized. Compounds 7-10 and 12 are active catalysts for the oxidation of racemic (PMePhBu)-Bu-t by pyridine N-oxide, affording low to moderate enantioselectivities (0 35 % ee) of the phosphine oxide (OPMePhBu)-Bu-t. Key structure/reactivity features of the catalysts for these reactions include: the presence of a p-NO2 substituent on the salen-unit increases the catalyst activity; and increasing the steric bulk of the ortho-salen-substituent increases enantioselectivity. DFT computational analysis has identified a viable reaction pathway that features a stereochemically-defining O-transfer transition state involving phosphine attack on the chiral LMoO2 complex, which accounts for the experimental stereoselectivity and catalyst activity.

A series of ruthenium(V)-oxo compounds, LRu(V)O-(n) [L=bipyridinedicarboxylate (BDA), alpha-hydroxycarboxylate (AHA), porphyrin (POR), dimethylglyoximate (DMG), and nitrilotriacetate (NTA); n=+1,0,-1] are evaluated by Density Functional Theory for their ability to produce dioxygen through coupling of Ru(V)-oxo species, bimetallic peroxides (LRu(IV)-O-O-Ru(IV)L), and dioxygen (LRu(IV)-O-2) complexes. Anionic Ru-oxo complexes (AHA)(2)RuO- (2) and (NTA)Ru(O)Cl- (5 e) have prohibitively large free energies of coupling, while neutral and monocationic species (1 b, 3-5 a-d) show small to moderate free energies of coupling. Transition states for O-O coupling were found for (NTA)RuO (5 a), (NTA)RuO(NH3) (5 c), (NTA)RuO(Pyr) (5 d), (DMG)(2)ClRu(O) (8) and (POR)RuO(Cl) (9), yielding moderate activation energies in the range of 18-22 kcal/mol. The overall oxygen evolution reaction (OER) free energies decrease in favourability as the coordination number of LRuO decreases, i. e. 7>6>5. The modest activation energies and free energies along the reaction coordinate for (NTA)(L)RuO and (POR)ClRu(O) suggest that these species would undergo kinetically and thermodynamically favorable oxygen evolution.

Abstract The prospective utilization of abundant, CO2-neutral, renewable feedstocks is driving the discovery and development of new reactions that refunctionalize oxygen-rich substrates such as alcohols and polyols through C–O bond activation. In this review, we highlight the development of transition-metal-promoted reactions of renewable alcohols and epoxides that result in carbon–carbon bond-formation. These include reductive self-coupling reactions and cross-coupling reactions of alcohols with alkenes and arene derivatives. Early approaches to reductive couplings employed stoichiometric amounts of low-valent transition-metal reagents to form the corresponding hydrocarbon dimers. More recently, the use of redox-active transition-metal catalysts together with a reductant has enhanced the practical applications and scope of the reductive coupling of alcohols. Inclusion of other reaction partners with alcohols such as unsaturated hydrocarbons and main-group organometallics has further expanded the diversity of carbon skeletons accessible and the potential for applications in chemical synthesis. Catalytic reductive coupling and cross-coupling reactions of epoxides are also highlighted. Mechanistic insights into the means of C–O activation and C–C bond formation, where available, are also highlighted. 1 Introduction 2 Stoichiometric Reductive Coupling of Alcohols 3 Catalytic Reductive Coupling of Alcohols 3.1 Heterogeneous Catalysis 3.2 Homogeneous Catalysis 4 Reductive Cross-Coupling of Alcohols 4.1 Reductive Alkylation 4.2 Reductive Addition to Olefins 5 Epoxide Reductive Coupling Reactions 6 Conclusions and Future Directions

Propargyl-dicobalt carbonyl complexes ((RC2CRR3)-C-1-R-2)Co-2(CO)(6)(+)Z(-) (2), first discovered nearly fifty years ago, have been extensively investigated and developed as useful reagents for propargyl-nucleophile coupling reactions. However, aside from early spectroscopic and semi-empirical theoretical studies, the structures, electronic properties and reactivity of these compounds have received scant attention using more rigorous computational methods. In this report a DFT analysis is presented of the structures, electronic character, stability, fluxionality and reactivity of two sets of propargyl complexes, the -Co-2(CO)(6) derivatives 2 and ((RC2CRR3)-C-1-R-2)Co-2(CO)(5)(PZ(3))(+)Z(-) (3), focusing on the effects of substituents and auxiliary ligands. The key findings include: 1) confirmation of their eta(2),eta(3)-low temperature-limiting unsymmetrical structures; 2) that most substituents on the propargyl unit have relatively small effects on their stability, while auxiliary ligands of 3 can have substantial stabilizing effects; 3) calculated atomic charges, frontier MO analysis, IR and NMR spectra together indicate extensive electronic delocalization in 2 and 3, with a majority of positive charge dispersed onto the -Co-2(CO)(5,6)(L) unit and a greater residual charge and LUMO character on C1 of the propargyl unit; 4) the latter factors account for the regioselective C-1 attack of nucleophiles on 2 and 3; 5) that two isomerization processes, enantiomerization and syn/anti diastereomerization, are viable via corresponding parallel and perpendicular transition states, the former generally being the lower in energy by ca. 2-3 kcal/mol); 6) that C-3 substituents on the propargyl unit, with one exception (R-1=OR), have small effects on these isomerization barriers, as is case for electron-poor phosphines, e.g. L=PF3; 7) that stronger donor phosphines increase rigidity, stability and isomerization barriers, but non-linearly; and 8) that an alternative dynamic isomerization process, involving tetrahedral-to-planar squashing of the Co2C2 cluster, could be energetically accessible. Insights into the underlying factors causing these effects are presented along with some prospects for new reactivity and selectivity possibilities. (C) 2020 Elsevier B.V. All rights reserved.

Although carbon radicals generated from a variety of alcohol derivatives have proven valuable in coupling and addition reactions, the direct use of alcohols as synthetically useful radical sources is less known. In this report, benzylic alcohols are shown to be effective radical precursors for addition reactions to alkenes when treated with triphenylphosphine or piperidine with the catalyst ReIO2(PPh3)2 (I).

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.

The hexacarbonyldicobalt complexes of propargylic cations are generated readily, predominantly from alkynedicobalt complexes bearing propargylic leaving groups. These cations have both good stability and reactivity, and enter into reaction with a wide range of carbon‐ and heteroatom‐based nucleophiles in a reliable manner; these are widely known as Nicholas reactions. In conjunction with the ready incorporation and removal of the dicobalt unit, these reactions have been employed extensively in total synthesis.

Aside from alkene cross metathesis, involving two different alkene units, cross metathesis reactions of two functionally different unsaturated units - heterofunctional cross metathesis - are virtually unknown. We report here on our efforts to realize alkene-diazene cross metathesis to produce imines. The proven alkene-metathesis catalyst (Cy3P)(2)Cl2Ru = CHPh (1) reacts with aryl diazenes at room temperature to produce imines derived from coupling of the alkylidene unit of 1 with the nitrene fragment of the diazene. Attempts to induce catalytic alkene-diazene cross metathesis by 1 or (NHC)(PCy3)Cl2Ru = CHR (NHC = N-heterocyclic carbene, 2) result only in the transfer of the alkylidene unit from 1 without reaction of the alkene. H-1- and P-31 NMR monitoring and other characterizational probes are consistent with the formation of an unreactive imido- or aza-metallacycle intermediate. DFT computational modeling of a potential catalytic pathway for diazene-alkene metathesis with (PMe3)(2)Cl2Ru=CH2 (4) has revealed viable intermediates and transition states, involving metal-carbene, metal-nitrene (imido) and derived azametallacyclobutanes. The turnover-limiting steps are calculated to occur during combination of the intermediate imido-complex (PMe3)(2)Cl2Ru = NMe (4) with alkene via a transition state for retrocyclization of an aza-ruthenacyclobutane (J) with a large energetic span of 47.8 kcal/mol. Modeling of the same reaction step with the experimental complex 1 reacting with PhN = NPh and PhCH = CHPh finds an even larger energetic span, accounting for the experimentally observed stoichiometric production of imine PhCH = NPh. In contrast, the corresponding energy profile for alkene-diazene metathesis promoted by phosphite-carbene complex [(MeO)(3)P](2)Cl2Ru=CH2 (5) finds a much lower energetic span of 26.4 kcal/mol for conversion of imido complex G' to imine via the aza-ruthenacyclobutane (J') and that the turnover-limiting step would involve retrocyclization of the first stage diaza-metallacyclobutane C' with an energetic span of 29.7 kcal/mol. (C) 2019 Elsevier B.V. All rights reserved.

A mechanistic investigation of the reductive coupling of benzylic and allylic alcohols by triphenylphosphine catalyzed by ReIO2(PPh3)(2) (1) is disclosed utilizing (1) stoichiometric reaction studies of 1 with alcohols, with PPh3 and with OPPh3; (2) rate law determination of the reaction of benzhydrol with PPh3 catalyzed by 1; (3) substrate structure dependent reactivity/selectivity studies; and (4) DFT computational analysis of various potential reaction pathways in the benzyl alcohol/PPh3 reaction. In situ NMR monitoring of reactions of 1 with PPh3 and various alcohols demonstrate (a) facile, reversible PPh3 dissociation from 1; (b) association of various alcohols to form Re-alcohol/alkoxide complexes, (Ph3P)IReO2(ROH) and (Ph3P)IReO(OH)(OR); and (c) thermal conversion of these alcohol(ate)-rhenium complexes to Ph2CH CHPh2 and OPPh3 at >50 degrees C. Under pseudo-first-order conditions, the initial rate kinetics of reductive coupling of Ph2CHOH/PPh3 catalyzed by 1 shows (a) a reaction rate that is first-order each in ROH, catalyst and first-order (or higher) in PPh3 and (b) the reaction is inhibited by OPPh3. Alcohol structure effects show (a) relative reactivity of sec-, tert-benzylic = allylic > prim-benzylic/allylic >> sec-, prim-alkyl and (b) low regioselectivity of the dimers from unsymmetrical allylic alcohols. A DFT computational study of the reaction of benzyl alcohol/PPh3 with 1 reveals a preferred pathway involving: (a) formation of rhenium-alcohol and alkoxide intermediates, (Ph3P)IReO2(ROH) and (Ph3P)IReO(OH)(OR); (b) reduction of the latter by PPh3 to form (OPPh3)(Ph3P)IRe(OH)(OBn) (E); (c) association of a second BnOH with E to give (Ph3P)IRe(OBn)(2) (K); (d) facile dissociation of a benzyl radical from K by C-O homolysis; and (e) a second rhenium-O-Bn homolysis from (PPh3)IRe(H2O)(OBn) (O), giving bibenzyl via benzyl radical recombination and regenerating (PPh3)ReIO2.