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.

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 .

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).

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.

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.

Cerium(IV) Carboxylate Photocatalyst for Catalytic Radical Formation from Carboxylic Acids: Decarboxylative Oxygenation of Aliphatic Carboxylic Acids and Lactonization of Aromatic Carboxylic Acids.

We found that in situ generated cerium(IV) carboxylate generated by mixing the precursor Ce(OtBu)4 with the corresponding carboxylic acids served as efficient photocatalysts for the direct formation of carboxyl radicals from carboxylic acids under blue light-emitting diodes (blue LEDs) irradiation and air, resulting in catalytic decarboxylative oxygenation of aliphatic carboxylic acids to give C-O bond-forming products such as aldehydes and ketones. Control experiments revealed that hexanuclear Ce(IV) carboxylate clusters initially formed in the reaction mixture and the ligand-to-metal charge transfer nature of the Ce(IV) carboxylate clusters was responsible for the high catalytic performance to transform the carboxylate ligands to the carboxyl radical. In addition, the Ce(IV) carboxylate cluster catalyzed direct lactonization of 2-isopropylbenzoic acid to produce the corresponding peroxy lactone and γ-lactone via intramolecular 1,5-hydrogen atom transfer (1,5-HAT).

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.

Salt-Free Reduction of Transition Metal Complexes by Bis(trimethylsilyl)cyclohexadiene, -dihydropyrazine, and -4,4'-bipyridinylidene Derivatives.

Chemical reduction of transition metals provides the corresponding low-valent transition metal species as a key step for generating catalytically active species in metal-assisted organic transformations and is a fundamental unit reaction for preparing organometallic complexes. A variety of metal-based reductants, such as metal powders and organometallic reagents of alkali and alkaline-earth metals, have been developed to date to access low-valent metal species. During the reduction, however, reductant-derived metal salts are formed as reaction waste, some of which often interact with the reactive low-valent metal center, thereby disrupting the catalytic performance and hampering the isolation of organometallic complexes as a result of salt coordination to the coordinatively unsaturated vacant and active sites and the formation of thermally unstable ate complexes. In this Account, we emphasize the synthetic utility and versatility of organic reductants containing two trimethylsilyl groups, i.e., 1,4-bis(trimethylsilyl)cyclohexa-2,5-diene (1a) and its methyl derivative (1b), 1,4-bis(trimethylsilyl)dihydropyrazine (2a) and its dimethyl (2b) and tetramethyl (2c) derivatives, and 1,1'-bis(trimethylsilyl)-4,4'-bipyridinylidene (3), leading to the reduction of various kinds of metal compounds in a salt-free fashion by release of two electrons together with the coproduction of easily removable (hetero)aromatics and trimethylsilyl derivatives from these organic reductants 1-3. When homoleptic chlorides of group 5 and 6 metals are treated with 1a and 1b, in situ-generated highly reactive low-valent metal species react with redox-active molecules such as ethylene, α-diimines, and α-diketones to produce metallacyclopentane, (ene-diamido)metal, and (ene-diolato)metal complexes, respectively. The advantage of the salt-free protocol is further exemplified in the low-valent titanocene-catalyzed Reformatsky-type reaction when 2c is used as a reductant: the yield of the product using the organosilicon reductant is higher than that when manganese powder is used as the reductant for the catalytic Reformatsky-type reaction of ethyl 2-bromoisobutyrate and its derivatives with various aldehydes. Moreover, when halides, carboxylates, and acetylacetonate compounds of late transition metals and main-group elements are treated with the organosilicon reductant 2c, metal(0) particles are smoothly precipitated under mild conditions. Among them, metallic nickel(0) nanoparticles are applicable to reductive biaryl formation and reductive cross-coupling of aryl halides/aryl aldehydes. In addition, reduction of the heterogeneous catalysts on a solid supporting matrix was also achieved by this salt-free reduction method; volatile byproducts are easily removed from the catalyst surface without suppressing the catalytic performance. Thus, the salt-free reduction strategy is a very powerful synthetic method that can be extended to various metals throughout the periodic table.

Trivalent Rare-Earth Metal Amide Complexes as Catalysts for the Hydrosilylation of Benzophenone Derivatives with HN(SiHMe2 )2 by Amine-Exchange Reaction.

The rare-earth metal complexes Ln(L1 )[N(SiHMe2 )2 ](thf) (Ln=La, Ce, Y; L1 =N,N''-bis(pentafluorophenyl)diethylenetriamine dianion) were synthesized by treating Ln[N(SiHMe2 )2 ]3 (thf)2 with L1 H2 . The lanthanum and cerium derivatives are active catalysts for the hydrosilylation of benzophenone derivatives with HN(SiHMe2 )2 . An amine-exchange reaction was revealed as a key step of the catalytic cycle, in which Ln-Si-H ß-agostic interactions are proposed to promote insertion of the carbonyl moiety into the Si-H bond.

Monohydride-Dichloro Rhodium(III) Complexes with Chiral Diphosphine Ligands as Catalysts for Asymmetric Hydrogenation of Olefinic Substrates.

We report full details of the synthesis and characterization of monohydride-dichloro rhodium(III) complexes bearing chiral diphosphine ligands, such as (S)-BINAP, (S)-DM-SEGPHOS, and (S)-DTBM-SEGPHOS, producing cationic triply chloride bridged dinuclear rhodium(III) complexes (1 a: (S)-BINAP; 1 b: (S)-DM-SEGPHOS) and a neutral mononuclear monohydride-dichloro rhodium(III) complex (1 c: (S)-DTBM-SEGPHOS) in high yield and high purity. Their solid state structure and solution behavior were determined by crystallographic studies as well as full spectral data, including DOSY NMR spectroscopy. Among these three complexes, 1 c has a rigid pocket surrounded by two chloride atoms bound to the rhodium atom together with one tBu group of (S)-DTBM-SEGPHOS for fitting to simple olefins without any coordinating functional groups. Complex 1 c exhibited superior catalytic activity and enantioselectivity for asymmetric hydrogenation of exo-olefins and olefinic substrates. The catalytic activity of 1 c was compared with that of well-demonstrated dihydride species derived in situ from rhodium(I) precursors such as [Rh(cod)Cl]2 and [Rh(cod)2 ]+ [BF4 ]- upon mixing with (S)-DTBM-SEGPHOS under dihydrogen.

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.

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

A catalyst system of mononuclear manganese precursor 3 combined with potassium alkoxide served as a superior catalyst compared with our previously reported manganese homodinuclear catalyst 2 a for esterification of not only tertiary aryl amides, but also tertiary aliphatic amides. On the basis of stoichiometric reactions of 3 and potassium alkoxide salt, kinetic studies, and density functional theory (DFT) calculations, we clarified a plausible reaction mechanism in which in situ generated manganese-potassium heterodinuclear species cooperatively activates the carbonyl moiety of the amide and the OH moiety of the alcohols. We also revealed details of the reaction mechanism of our previous manganese homodinuclear system 2 a, and we found that the activation free energy (ΔG≠ ) for the manganese-potassium heterodinuclear complex catalyzed esterification of amides is lower than that for the manganese homodinuclear system, which was consistent with the experimental results. We further applied our catalyst system to deprotect the acetyl moiety of primary and secondary amines.

Catalytic Cleavage of Amide C-N Bond: Scandium, Manganese, and Zinc Catalysts for Esterification of Amides.

Amide C-N bonds are thermodynamically stable and their fission, such as by hydrolysis and alcoholysis, is considered a long-challenging organic reaction. In general, stoichiometric chemical transformations of amides into the corresponding esters and acids require harsh conditions, such as strong acids/bases at a high reaction temperature. Accordingly, the development of catalytic reactions that cleave not only primary and secondary amides, but also tertiary amides in mild conditions, is in high demand. Herein, we surveyed typical stoichiometric transformations of amides, and highlight our recent achievements in the catalytic esterification of amides using scandium, manganese, and zinc catalysts, together with some recent catalyst systems using late-transition metal reported by other groups.

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.

Alternating Copolymerization of CO2 and Cyclohexene Oxide Catalyzed by Cobalt-Lanthanide Mixed Multinuclear Complexes.

Heteromultimetallic complexes consisting of three Co(II) ions and one lanthanide ion were synthesized and applied to the alternating copolymerization of CO2 and cyclohexene oxide. Unlike the conventional cobalt(III) salen complexes, the high thermal stability of the present catalyst allowed us to reach a turnover number of 13000, one of the highest values ever reported for multimetallic systems. The chain propagation was first-order to the catalyst, suggesting a cooperative behavior of the metal centers.

Cobalt-Catalyzed E-Selective Cross-Dimerization of Terminal Alkynes: A Mechanism Involving Cobalt(0/II) Redox Cycles.

A highly E-selective cross-dimerization of terminal alkynes with either terminal silylacetylenes, tert-butylacetylene, or 1-trimethylsilyloxy-1,1-diphenyl-2-propyne in the presence of a dichlorocobalt(II) complex bearing a sterically demanding 2,9-bis(2,4,6-triisopropylphenyl)-1,10-phenanthroline, activated with two equivalents of EtMgBr, gives a variety of (E)-1,3-enynes. A well-characterized diolefin/cobalt(0) complex, with divinyltetramethyldisiloxane, acted as a catalytically active species without any activation, clearly indicating that a cobalt(0) species is involved in the catalytic cycle.

Bis(imido)vanadium(V)-Catalyzed [2+2+1] Coupling of Alkynes and Azobenzenes Giving Multisubstituted Pyrroles.

The combination of VCl3(THF)3 and N, N-bis(trimethylsilyl)aniline (1a) is an efficient catalyst for the [2+2+1] coupling reaction of alkynes and azobenzenes, giving multisubstituted pyrroles. A plausible reaction mechanism involves the generation of a mono(imido)vanadium(III) species as an initiation step, where 1a served as an imido source with concomitant release of 2 equiv of ClSiMe3, followed by a reaction with azobenzene to form a catalytically active bis(imido)vanadium(V) species via N═N bond cleavage.