Effect of distal metal species on lewis basicity of a µ3-oxo ligand in a doubly oxo-bridged (µ3-O)[Rh(cod)]3(µ4-O)M core.

The Lewis basicity of a µ3-oxo ligand for (µ3-O)[Rh(cod)]3(µ4-O)M (cod = 1,5-cyclooctadiene) complexes was controllable by metal species on the µ4-oxo ligand locating at the opposite site of the µ3-oxo ligand. Coordination of the µ3-oxo ligand of [(µ3-O){Rh(cod)}3(µ4-O){Au(PPh3)}][BF4] (1) to [Au(PPh3)]+ indicated sufficient Lewis basicity of the µ3-oxo ligand in 1 to form [{(Ph3P)Au}(µ3-O){Rh(cod)}3(µ4-O){Au(PPh3)}][BF4] (2). In contrast, the addition of Li+ to 1 induced elimination of the originally coordinated [Au(PPh3)]+ due to the weak Lewis basicity of the µ3-oxo ligand for (µ3-O){Rh(cod)}3(µ4-O)Li(THF)3, in which a pentanuclear species, [{(Ph3P)Au}(µ3-O){Rh(cod)}3(µ4-O){Li(THF)3}][BF4] (3), was assumed to be generated in situ before the dissociation of [Au(PPh3)]+.

Evaluation of Tungsten Catalysis among Early Transition Metals for N-Aryl-2,3,4,5-tetraarylpyrrole Synthesis: Modular Access to N-Doped π-Conjugated Material Precursors.

Low-valent tungsten species generated from WCl6 and N,N'-bis(trimethylsilyl)-2,5-dimethyldihydropyrazine (Si-Me2-DHP) promotes the catalytic formation of N-phenyl-2,3,4,5-tetraarylpyrroles 3aa-ka from diarylacetylenes 1a-k and azobenzene (2a). An initial catalyst activation process is a three-electron reduction of WCl6 with Si-Me2-DHP to afford transient 'WCl3' species. Catalytically active bis(imido)tungsten(VI) species via successive one-electron reduction and N═N bond cleavage of 2a was revealed by isolating W(═NPh)2Cl2(PMe2Ph)2 from imidotungsten(V) trichloride and 2a in the presence of PMe2Ph. The superior catalytic activity of the tungsten catalyst was clarified by a density functional theory study: activation energies for the key three steps, [2 + 2]-cycloaddition of W═NPh and diarylacetylene to form (iminoalkylidene)tungsten species, enyne metathesis with second diarylacetylene, and C-N bond formation, are reasonable values for the catalytic reaction at 180 °C. In addition, this tungsten catalyst overcame two distinct deactivation processes: α-enediamido formation and aggregation of the low-valent species, both of which were observed for previously developed vanadium and titanium catalysts. We also demonstrated the synthetic utility of pentaarylpyrroles 3aa and 3ba as well as N-(2-bromophenyl)-2,3,4,5-tetraarylpyrrole 3ab by derivatizing their π-conjugated compounds 9aa, 10ba, and 11ab.

Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction.

Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and iPrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

Bis(neopentylglycolato)diboron (B2nep2) as a bidentate ligand and a reducing agent for early transition metal chlorides giving MCl4(B2nep2) complexes.

We found that bis(neopentylglycolato)diboron (B2nep2) served as a bidentate ligand and a one-electron reducing agent for early transition metal chlorides to afford MCl4(B2nep2). Treatment of B2nep2 with MCl5 (M = Nb and Mo) produced MCl4(B2nep2) via two successive reactions, coordination of B2nep2 to the metal center and one-electron reduction from M(V) to M(IV), while coordination of B2nep2 to MCl4 (M = Zr, Ti) was observed without reduction of the central metals. DFT studies for the reduction of NbCl5 by B2nep2 clarified the initial formation of seven-coordinated and B2nep2-ligated Nb(V) species, NbCl5(B2nep2), and one chloride on niobium(V) moves to the Lewis acidic boron center to generate NbCl4[(B2nep2)Cl]. The chloride on the boron atom of NbCl4[(B2nep2)Cl] is trapped by the second B2nep2 to give [NbCl4(B2nep2)][ClB2nep2]. After the formation of [ClB2nep2]- as an anionic sp2-sp3 diboron adduct, one-electron reduction of the niobium(V) center produces NbCl4(B2nep2) along with [ClB2nep2]˙ as a plausible diboron species, whose decomposition affords ClBnep and B2nep2. The reduction of metal halides in the presence of B2nep2 was exemplified by green LED irradiation of TiCl4(B2nep2), producing chloride-bridged titanium(III) species, (B2nep2)TiCl2(µ-Cl)2TiCl2(B2nep2).

Cationic tetranuclear macrocyclic CaCo3 complexes as highly active catalysts for alternating copolymerization of propylene oxide and carbon dioxide.

We found that a cationic hetero tetranuclear complex including a calcium and three cobalts exhibited high catalytic activity toward alternating copolymerization of propylene oxide (PO) and carbon dioxide (CO2). The tertiary anilinium salt [PhNMe2H][B(C6F5)4] was the best additive to generate the cationic species while maintaining polymer selectivity and carbonate linkage, even under 1.0 MPa CO2. Density functional theory calculations clarified that the reaction pathway mediated by the cationic complex is more favorable than that mediated by the neutral complex by 1.0 kcal mol-1. We further found that the flexible ligand exchange between Ca and Co ions is important for the alternating copolymerization to proceed smoothly.

New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors.

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel-Crafts acylation with TiCl4, followed by reduction with TiCl4/NaBH4. The new protocol proceeded more cleanly than the previous methods employing AlCl3 and BF3·OEt2/Et3SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl3/Al/BF3·OEt2.

Chromium-catalyzed olefination of arylaldehydes with haloforms assisted by 2,3,5,6-tetramethyl-N,N'-bis(trimethylsilyl)-1,4-dihydropyrazine.

Chromium-catalyzed olefination of arylaldehydes with haloforms was achieved using 2,3,5,6-tetramethyl-N,N'-bis(trimethylsilyl)-1,4-dihydropyrazine (1a) as an organic reducing agent, giving ß-halostyrene derivatives in a trans-selective manner. The reaction required no metal powders, such as zinc and manganese, as reductants, thereby minimizing metal-based reaction waste.

Syntheses and Redox Properties of Carboxylate-Ligated Hexanuclear Ce(IV) Clusters and Their Photoinduced Homolysis of the Ce(IV)-Ligand Covalent Bond.

Oxo- and hydroxo-bridged hexanuclear Ce(IV) clusters surrounded by 12 carboxylate ligands, Ce6O4(OH)4(O2CR)12(L)n (R = 2,6-Me2-4-MeOC6H2 (1a), 2,6-Me2-4-tBuC6H2 (1b), 2,4,6-Me3C6H2 (1c), 2,6-Me2C6H3 (1d), 2,6-Me2-4-FC6H2 (1e), 2,6-Me2-4-ClC6H2 (1f), 9-anthracenyl (1g), and CH2tBu (1h), L = H2O or RCO2H), were synthesized by treating Ce(OtBu)4 with the corresponding carboxylic acids (2-3 equiv.) in acetone or toluene, and the molecular structures of 1d and 1g were clarified by X-ray diffraction studies. UV-vis analyses of the clusters showed broad absorption corresponding to the ligand-to-metal charge transfer (LMCT) in the ultraviolet A (315-400 nm) to blue light region; density functional theory (DFT) studies of the simplified Ce(IV) and related Zr(IV) clusters, M6O4(OH)4(O2CR)12 (M = Ce, Zr, R = Ph, Me), revealed that the low-lying vacant 4f-orbitals of the Ce(IV) were responsible for absorption in the ultraviolet A to blue light region. Irradiation of blue LED light to 1a-f under an argon atmosphere resulted in the formation of 7-methylisobenzofuran-1(3H)-one (2a-f), which involved the following four steps: photoinduced homolysis of the Ce(IV)-OCOR bond, intramolecular hydrogen atom transfer to generate the corresponding benzyl radical, oxidation to the benzyl cation, and intramolecular cyclization. Cyclic voltammetry of cerium clusters 1a-f having 2,6-dimethyl-4-substituted arylcarboxylate ligands showed electrochemically irreversible redox waves in the range of -0.79 to -0.38 V (vs [Cp2Fe]+/Cp2Fe for E1/2). The one-electron-reduced Ce(III)Ce(IV)5 clusters 3a-h were isolated by reducing 1a-h with Cp*2Co to give [Cp*2Co][Ce6O4(OH)4(O2CR)12(thf)n] (3a-h); cluster 3d was the first structurally determined hexanuclear cerium cluster containing a [Ce6O4(OH)4]11+ core.

Preparation of Functionalized Amides Using Dicarbamoylzincs.

We report a new convenient preparation of dicarbamoylzincs of type (R1 R2 NCO)2 Zn by the treatment of ZnCl2 and formamides R1 R2 NCHO with LiTMP in THF (15 °C, 15 min) or by the reaction of formamides R1 R2 NCHO with TMP2 Zn (25 °C, 16 h). This second method tolerates sensitive groups such as an ester, ketone or nitro function. Reaction of these dicarbamoylzincs with allylic, benzylic, aryl, alkenyl bromides, acid chlorides, aldehydes or enones provided various polyfunctional amides in 47-97 % yields. 13 C NMR characterization of these new carbamoylzinc derivatives is reported.

Diarylcuprates for Selective Syntheses of Multifunctionalized Ketones from Thioesters under Mild Conditions.

Ketones were selectively synthesized from thioesters by using diarylcuprates(I) generated in situ from copper(I) salts and aryl Grignard reagents in a 1 : 1.3-1.5 ratio under ambient temperature. During the ketone synthesis, various functional groups, such as carbonyl (ketones, esters, and amides), O-protecting groups, halogens, and heteroarenes, were tolerated to afford multifunctionalized ketones in excellent yields. This copper-mediated ketone synthesis could be applied to the synthesis of not only gluconolactone-derived ketone 6, a synthetic intermediate in the transformation to the SGLT2 inhibitor canagliflozin, but also thiolactol 8, a valuable synthetic intermediate for (+)-biotin. Control experiments on an isolated diphenylcuprate(I), [CuPh2 ]- (12), and DFT calculations revealed that this ketone synthesis proceeded by oxidative addition of the C-S bond of thioesters to [CuPh2 ]- , while reductive elimination from the CuIII intermediate produced the corresponding ketone and an inactive species [(RS)CuPh]- , the latter reacted with [CuPh]4 (11) to regenerate the reactive diphenylcuprate(I).

Olefin Metathesis Catalysts Generated In Situ from Molybdenum(VI)-Oxo Complexes by Tuning Pendant Ligands.

Tailored molybdenum(VI)-oxo complexes of the form MoOCl2 (OR)2 (OEt2 ) catalyse olefin metathesis upon reaction with an organosilicon reducing agent at 70 °C, in the presence of olefins. While this reactivity parallels what has recently been observed for the corresponding classical heterogeneous catalysts based on supported metal oxide under similar conditions, the well-defined nature of our starting molecular systems allows us to understand the influence of structural, spectroscopic and electronic characteristics of the catalytic precursor on the initiation and catalytic proficiency of the final species. The catalytic performances of the pre-catalysts are determined by the highly electron withdrawing (σ-donation) character of alkoxide ligands, Ot BuF9 being the best. This activity correlates with both the 95 Mo chemical shift and the reduction potential that follows the same trend: Ot BuF9 >Ot BuF6 >Ot BuF3 .

Aerobic oxygenation of α-methylene ketones under visible-light catalysed by a CeNi3 complex with a macrocyclic tris(salen)-ligand.

A hetero-tetranuclear CeNi3 complex with a macrocyclic ligand catalysed the aerobic oxygenation of a methylene group adjacent to a carbonyl group under visible-light radiation to produce the corresponding α-diketones. The visible-light induced homolysis of the Ce-O bond of a bis(enolate) intermediate is proposed prior to aerobic oxygenation.

Effects of Silver Carbonate and p-Nitrobenzoic Acid for Accelerating Palladium-Catalyzed Allylic C-H Acyloxylation.

An allylic C-H acyloxylation of terminal alkenes with 4-nitrobenzoic acid was assisted by a bidentate-sulfoxide-ligated palladium catalyst combined with 1,4-benzoquinone and Ag2CO3 under mild reaction conditions. The catalytic activity was remarkably enhanced by Ag2CO3 as an additive and 4-nitrobenzoic acid as a carboxylate source; both components were essential to exhibiting high catalytic activity, high branch selectivity, and a wide substrate scope with low loading of the palladium catalyst. Branch-selective allylic acyloxylation of ethyl 7-octenoate (1a) gave the product which was led to ethyl 6,8-dihydroxyoctanoate (5), a useful synthetic intermediate of (R)-α-lipoic acid.

Renaissance of Homogeneous Cerium Catalysts with Unique     Ce(IV/III) Couple: Redox-Mediated Organic Transformations Involving Homolysis of Ce(IV)-Ligand Covalent Bonds.

Recent advances in the catalytic application of cerium complexes were achieved through controlling the Ce(IV/III) redox couple. Although Ce(IV) complexes have been extensively investigated as stoichiometric oxidants in organic synthesis on the basis of their highly positive redox potentials, these complexes can be used as catalysts, not only by introducing supporting ligands around the coordination sphere of cerium, but also by taking advantage of the photoresponsive properties of Ce(IV) and Ce(III) species. Cerium is highly abundant, comparable to that of some first-row transition metals such as copper, nickel, and zinc. Cerium complexes are new and promising homogeneous catalyst candidates for a variety of organic transformations under mild reaction conditions. They are typically used to activate dioxygen to oxidize organic compounds and applied for organic radical generation using the photoresponsive character of Ce(IV) carboxylates and alkoxides as well as electronic transition of Ce(III), in which homolysis of Ce(IV)-ligand covalent bonds is an important step for the overall catalytic cycle. In this Perspective, we first review the early discovery of Ce(OAc)4-mediated oxidative transformations to emphasize the importance of Ce(IV)-OAc bond homolysis in various C-C bond-forming reactions and its relation to recent developments. We then focus on the fundamental importance of Ce(IV) reactivity involving thermal and photoassisted homolysis of the Ce(IV)-ligand covalent bond and the developments regarding Ce(IV/III) redox changes in catalytic reactions together with our recent findings on cerium-based catalysis.

Direct Synthesis of Indoles from Azoarenes and Ketones with Bis(neopentylglycolato)diboron Using 4,4'-Bipyridyl as an Organocatalyst.

Multifunctionalized indole derivatives were prepared by reducing azoarenes in the presence of ketones and bis(neopentylglycolato)diboron (B2nep2) with a catalytic amount of 4,4'-bipyridyl under neutral reaction conditions, where 4,4'-bipyridyl acted as an organocatalyst to activate the B-B bond of B2nep2 and form N,N'-diboryl-1,2-diarylhydrazines as key intermediates. Further reaction of N,N'-diboryl-1,2-diarylhydrazines with ketones afforded N-vinyl-1,2-diarylhydrazines, which rearranged to the corresponding indoles via the Fischer indole mechanism. This organocatalytic system was applied to diverse alkyl cyclic ketones, dialkyl, and alkyl/aryl ketones, including heteroatoms. Methyl alkyl ketones gave the corresponding 2-methyl-3-substituted indoles in a regioselective manner. This protocol allowed us to expand the preparation of indoles having high compatibility with not only electron-donating and electron-withdrawing groups but also N- and O-protecting functional groups.

Self-Assembled Multilayer Iron(0) Nanoparticle Catalyst for Ligand-Free Carbon-Carbon/Carbon-Nitrogen Bond-Forming Reactions.

Self-assembled multilayer iron(0) nanoparticles (NPs, 6-10 nm), namely, sulfur-modified Au-supported Fe(0) [SAFe(0)], were developed for ligand-free one-pot carbon-carbon/carbon-nitrogen bond-forming reactions. SAFe(0) was successfully prepared using a well-established metal-nanoparticle catalyst preparative protocol by simultaneous in situ metal NP and nanospace organization (PSSO) with 1,4-bis(trimethylsilyl)-1,4-dihydropyrazine (Si-DHP) as a strong reducing agent. SAFe(0) was easy to handle in air and could be recycled with a low iron-leaching rate in reaction cycles.

Syntheses of SGLT2 Inhibitors by Ni- and Pd-Catalyzed Fukuyama Coupling Reactions.

Nickel- and palladium-catalyzed Fukuyama coupling reactions of a d-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2-bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.

Reactivity of terminal imido complexes of group 4-6 metals: stoichiometric and catalytic reactions involving cycloaddition with unsaturated organic molecules.

Imido complexes of early transition metals are key intermediates in the synthesis of many nitrogen-containing organic compounds. The metal-nitrogen double bond of the imido moiety undergoes [2+2] cycloaddition reactions with various unsaturated organic molecules to form new nitrogen-carbon and nitrogen-heteroatom bonds. This review article focuses on reactivity of the terminal imido complexes of Group 4-6 metals, summarizing their stoichiometric reactions and catalytic applications for a variety of reactions including alkyne hydroamination, alkyne carboamination, pyrrole formation, imine metathesis, and condensation reactions of carbonyl compounds with isocyanates.

Esterification of Tertiary Amides: Remarkable Additive Effects of Potassium Alkoxides for Generating Hetero Manganese-Potassium Dinuclear Active Species.

Invited for the cover of this issue are the groups of Fahmi Himo and Kazushi Mashima at Stockholm University and Osaka University. The image depicts a Mn-K scissor, which is able to break a C-N bond, represented by a tree branch. Read the full text of the article at 10.1002/chem.202001447.