Asymmetric Catalytic Synthesis of Allylic Sulfenamides from Vinyl α-Diazo Compounds by a Rearrangement Route.

The asymmetric rearrangement of allylic sulfilimines is an effective route to synthetic attractive targets such as allylic sulfenamides and others. The current methods are limited to chirality transfer from chiral allylic sulfilimine precursors. Herein, we report a general and fundamentally new rearrangement route accessing optically enriched allylic sulfenamides and their derivatives. The process involves a S-alkylation and an unusual S-to-N rearrangement step. The chiral nickel complex enables the transformation of a broad scope of sulfenamides and vinyl α-diazo pyrazoleamides under mild conditions. Various allylic sulfenamides have been synthesized with excellent γ-regioselectivity and enantioselectivity, which can be efficiently converted to sulfinamide and 4-aminobutenoic acid derivatives. In addition, DFT calculations demonstrate the connection between the spin state and conformation of nickel vinyl carbenoid, as well as an unknown rearrangement process.

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations.

Hydrazones are important structural motifs in organic synthesis, providing a useful molecular platform for the construction of valuable compounds. Electrooxidative transformations of hydrazones constitute an attractive opportunity to take advantage of the versatility of these reagents. By directly harnessing the electrical current to perform the oxidative process, a large panel of organic molecules can be accessed from readily available hydrazones under mild, safe and oxidant-free reaction conditions. This review presents a comprehensive overview of oxidative electrosynthetic transformations of hydrazones. It includes the construction of azacycles, the C(sp2)-H functionalization of aldehyde-derived hydrazones and the access to diazo compounds as either synthetic intermediates or products. A special attention is paid to the reaction mechanism with the aim to encourage further development in this field.

Photoredox-Enabled Self-(3+2) Cyclization of Vinyldiazo Reagents: Synthesis of Cyclopentenyl α-Diazo Compounds.

A photocatalytic self-(3+2) cycloaddition of vinyldiazo compounds is described, which provides cyclopentene derivatives with conservation of one diazo functional group. Experimental insights and density functional theory indicate that the reaction is triggered by an unusual single electron oxidation of vinyldiazo compounds, while the photolysis for the generation of free carbene species is not involved. The synthetic applications of the resulting cyclopentenyl α-diazo compounds were demonstrated based on the rich chemistry of the diazo functional group.

Head-to-Tail Dimerization of N-Heterocyclic Diazoolefins.

The head-to-tail dimerization of N-heterocyclic diazoolefins is described. The products of these formal (3+3) cycloaddition reactions are strongly reducing quinoidal tetrazines. Oxidation of the tetrazines occurs in a stepwise fashion, and we were able to isolate a stable radical cation and diamagnetic dications. The latter are also accessible by oxidative dimerization of diazoolefins.

Synthesis and Reactivity of an Anionic Diazoolefin.

Bent (hetero)allenes such as carbodicarbenes and carbodiphosphoranes can act as neutral C-donor ligands, and diverse applications in coordination chemistry have been reported. N-Heterocyclic diazoolefins are heterocumulenes, which can function in a similar fashion as L-type ligands. Herein, we describe the synthesis and the reactivity of an anionic diazoolefin. This compound displays distinct reactivity compared to neutral diazoolefins, as evidenced by the preparation of diazo compounds via protonation, alkylation, or silylation. The anionic diazoolefin can be employed as an ambidentate, X-type ligand in salt metathesis reactions with metal halide complexes. Extrusion of dinitrogen was observed in a reaction with PCl(NiPr2 )2 , resulting in a stable phosphinocarbene.

Chemodivergent Staudinger Reactions of Secondary Phosphine Oxides and Application to the Total Synthesis of LL-D05139ß Potassium Salt.

Unprecedented Staudinger reaction modes of secondary phosphine oxides (SPO) and organic azides are herein disclosed. By the application of various additives, selective nitrogen atom exclusion from the azide group has been achieved. Chlorotrimethylsilane mediates a stereoretentive Staudinger reaction with a 2-N exclusion which provides a valuable method for the synthesis of phosphinic amides and can be considered complementary to the stereoinvertive Atherton-Todd reaction. Alternatively, a 1-N exclusion pathway is promoted by acetic acid to provide the corresponding diazo compound. The effectiveness of this protocol has been further demonstrated by the total synthesis of the diazo-containing natural product LL-D05139ß, which was prepared as a potassium salt for the first time in 6 steps and 26.5 % overall yield.

Selective Formal Carbene Insertion into Carbon-Boron Bonds of Diboronates by N-Trisylhydrazones.

Bisborylalkanes play important roles in organic synthesis as versatile bifunctional reagents. The two boron moieties in these compounds can be selectively converted into other functional groups through cross-coupling, oxidation or radical reactions. Thus, the development of efficient methods for synthesizing bisborylalkanes is highly demanded. Herein we report a new strategy to access bisborylalkanes through the reaction of N-trisylhydrazones with diboronate, in which the bis(boryl) methane is transformed into 1,2-bis(boronates) via formal carbene insertion. Since the N-trisylhydrazones can be readily derived from the corresponding aldehydes, this strategy represents a practical synthesis of 1,2-diboronates with broad substrate scope. Mechanistic studies reveal an unusual neighboring group effect of 1,1-bis(boronates), which accounts for the observed regioselectivity when unsymmetric 1,1-diboronates are applied.

Single-Nitrogen Atom Incorporation into B=B Bond via the N=N Bond Splitting of Diazo Compound and Diazirine.

Triboraazabutenyne 3 is synthesized by the reaction of diboraazabutenyne 1 with aryl boron dibromide followed by the reduction. The ligand exchange to replace phosphine on the terminal sp2 B atom with carbene furnishes 4. 11 B NMR, solid-state structures, and computational studies disclose that 3 and 4 feature the extremely polarized B=B bond. 4 readily splits the N=N bond of both diazo compound and diazirine under ambient conditions, whereby one nitrogen atom is incorporated into the B=B moiety leading to a neutral diboraazaallene 6. The mechanism of the reaction between 4 and diazo compound is extensively investigated by density functional theory (DFT) calculations, as well as the isolation of an intermediate.

Asymmetric Catalytic Ring-Expansion of 3-Methyleneazetidines with α-Diazo Pyrazoamides towards Proline-Derivatives.

We realized a highly efficient formal [1,2]-sigmatropic rearrangement of ammonium ylides generated from 3-methylene-azetidines and α-diazo pyrazoamides. The employ of readily available chiral cobalt(II) complex of chiral N,N'-dioxide enabled the ring-expansion of azetidines, affording a variety of quaternary prolineamide derivatives with excellent yield (up to 99 %) and enantioselectivity (up to 99 % ee) under mild reaction condition. For the rearrangement of ammonium ylides, the installation of a pyrazoamide group as a masked brick to build chiral scaffolds proved successful. The enantioselective ring expansion process was elucidated by DFT calculations.

Palladium-Catalyzed Cascade C-H Functionalization/Asymmetric Allylation Reaction of Aryl α-Diazoamides and Allenes: Lewis Acid Makes a Difference.

A Pd-catalyzed cascade C-H functionalization/asymmetric allylation reaction with aryl α-diazoamides and allenes has been developed. The reaction provides an efficient approach to construct chiral 3,3-disubstituted oxindole derivatives in high levels of yield and enantioselectivity (up to 93 % ee). Notably, the chromium complex works as Lewis acid to facilitate the formation of palladium carbene and to enhance acidity of carboxylic acid, allowing for higher stereochemical control and efficiency.

Host-Guest Complexation by ß-Cyclodextrin Enhances the Solubility of an Esterified Protein.

The carboxyl groups of a protein can be esterified by reaction with a diazo compound, 2-diazo-2-(p-methylphenyl)-N,N-dimethylacetamide. This esterification enables the entry of the protein into the cytosol of a mammalian cell, where the nascent ester groups are hydrolyzed by endogenous esterases. The low aqueous solubility of the ensuing esterified protein is, however, a major practical challenge. Solubility screening revealed that ß-cyclodextrin (ß-CD) is an optimal solubilizing agent for esterified green fluorescent protein (est-GFP). Its addition can increase the recovery of est-GFP by 10-fold. α-CD, γ-CD, and cucurbit-7-uril are less effective excipients. 1H NMR titration experiments revealed that ß-CD encapsulates the hydrophobic tolyl group of ester conjugates with Ka = 321 M-1. Combining l-arginine and sucrose with ß-CD enables the nearly quantitative recovery of est-GFP. Thus, the insolubility of esterified proteins can be overcome with excipients.

Efficient synthesis of ethyl 2-(oxazolin-2-yl)alkanoates via ethoxycarbonylketene-induced electrophilic ring expansion of aziridines.

Alkyl 2-diazo-3-oxoalkanoates generate alkoxycarbonylketenes, which undergo an electrophilic ring expansion with aziridines to afford alkyl 2-(oxazolin-2-yl)alkanoates in good to excellent yields under microwave heating. The method is a convenient and clean reaction without any activators and catalysts and can be also applied in the synthesis of 2-(oxazolin-2-yl)alkanamides and 1-(oxazolin-2-yl)alkylphosphonates.

Enantioselective Protonation of Cyclic Carbonyl Ylides by Chiral Lewis Acid Assisted Alcohols.

Chiral Lewis acid-catalyzed asymmetric alcohol addition reactions to cyclic carbonyl ylides generated from N-(α-diazocarbonyl)-2-oxazolidinones featuring a dual catalytic system are reported. Construction of a chiral quaternary heteroatom-substituted carbon center was accomplished in which the unique heterobicycles were obtained in good yields with high stereoselection. The alcohol adducts were successfully converted to optically active oxazolidine-2,4-diones by hydrolysis. Mechanistic studies by DFT calculations revealed that alcohols could be activated by Lewis acids, enabling enantioselective protonation of the carbonyl ylides.

Development of Novel Methodology Using Diazo Compounds and Metal Catalysts.

The ability to control the reactions of highly active chemical species to enable straightforward synthesis of valuable compounds such as bioactive natural products and pharmaceuticals is a continuing challenge in synthetic organic chemistry. This review describes the development of a methodology using reactive metal-carbene species and its synthetic application in our laboratory. First, regioselective synthesis of γ-amino acid equivalents to take advantage of their metal-dependent reactivities and the mechanistic rationale are presented. Chemoselective and enantioselective dearomatization reactions of several arenes with silver-carbene are also discussed. In the second half of the review, we discuss a carbene-insertion reaction into an amide and urea C-N bond for the assembly of nitrogen-bridged cyclic molecules.

Intramolecular Carbene C-H Insertion Reactions of 2-Diazo-2-sulfamoylacetamides.

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The chemoselectivity is controlled by electronic effect of the aryl group.

Light-Induced Mechanistic Divergence in Gold(I) Catalysis: Revisiting the Reactivity of Diazonium Salts.

In a systematic study of the Au-catalyzed reaction of o-alkynylphenols with aryldiazonium salts, we find that essentially the same reaction conditions lead to a change in mechanism when a light source is applied. If the reaction is carried out at room temperature using a AuI catalyst, the diazonium salt undergoes electrophilic deauration of a vinyl AuI intermediate and provides access to substituted azobenzofurans. If the reaction mixture is irradiated with blue LED light, C-C bond formation due to N2 -extrusion from the diazonium salt is realized selectively, using the same starting materials without the need for an additional photo(redox) catalyst under aerobic conditions. We report a series of experiments demonstrating that the same vinyl AuI intermediate is capable of producing the observed products under photolytic and thermal conditions. The finding that a vinyl AuI complex can directly, without the need for an additional photo(redox) catalyst, result in C-C bond formation under photolytic conditions is contrary to the proposed mechanistic pathways suggested in the literature till date and highlights that the role of oxidation state changes in photoredox catalysis involving Au is thus far only poorly understood and may hold surprises for the future. Computational results indicate that photochemical activation can occur directly from a donor-acceptor complex formed between the vinyl AuI intermediate and the diazonium salt.

Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles.

A one-pot iodine-catalyzed multicomponent reaction has been developed for the selective preparation of 5-amino-4-(arylselanyl)-1H-pyrazoles from a diverse array of benzoylacetonitriles, arylhydrazines and diaryl diselenides. The reactions were conducted in MeCN as solvent at reflux temperature under air. The methodology presents a large functional group tolerance to electron-deficient, electron-rich, and bulky substituents and gave the expected products in good to excellent yields. The synthesized 1,3-diphenyl-4-(phenylselanyl)-1H-pyrazol-5-amine was submitted to an oxidative dehydrogenative coupling to produce a diazo compound confirmed by X-ray analysis.

Diphenylcarbene Protected by Four ortho-Iodine Groups: An Unusually Persistent Triplet Carbene.

Diphenyldiazomethane with four iodine groups at the ortho positions and two tert-butyl groups at the para positions, i.e., bis(4-tert-butyl-2,6-diiodophenyl)diazomethane (1a-N2), was synthesized as a sterically hindered triplet carbene precursor. Irradiation of 1a-N2 in solution effectively generated the corresponding triplet diphenylcarbene ³1a, which was characterized by UV-vis spectroscopy at low temperature, along with laser flash photolysis techniques at room temperature. The UV-vis spectrum of ³1a was obtained by irradiating 1a-N2 in a 2-methyltetrahydrofuran matrix at 77 K. The ESR spectrum showed no triplet carbene signals, while a radical species was observed at the anticipated temperature of the decomposition of triplet carbene ³1a. Transient absorption bands ascribable to ³1a were observed by laser flash photolysis of 1a-N2 in a degassed benzene solution and decayed very slowly with a second-order rate constant (2k/εl) of 5.5 × 10-³·s-¹. Steady-state irradiation of 1a-N2 in degassed benzene afforded 9,10-diarylphenanthrene derivative 2a in a 31% yield. Triplet carbene ³1a was also trapped by either oxygen (kO2 = 6.5 × 105 M-¹·s-¹) or 1,4-cyclohexadiene (kCHD = 1.5 M-¹·s-¹) to afford the corresponding ketone 1a-O or the diarylmethane 1a-H2. The carbene was shown to be much less reactive than the triplet diphenylcarbene that is protected by two ortho-iodo and two ortho-bromo groups, ³1b.

Molecular Design of Diazo Compound for Carbene-Mediated Cross-Linking of Hole-Transport Polymer in QLED with Reduced Energy Barrier and Improved Charge Balance.

Polymeric hole-transport materials (HTMs) have been widely used in quantum-dot light-emitting diodes (QLEDs). However, their solution processability normally causes interlayer erosion and unstable film state, leading to undesired device performance. Besides, the imbalance of hole and electron transport in QLEDs also damages the device interfaces. In this study, we designed a bis-diazo compound, X1, as carbene cross-linker for polymeric HTM. Irradiated by ultraviolet and heating, a poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt(4,4'-(N-(4-butylphenyl))] (TFB)/X1 blend can achieve fast "electronically clean" cross-linking with ∼100% solvent resistance. The cross-linking reduced the stacking behaviors of TFB and thus led to a lower hole-transport mobility, whereas it was a good match of electron mobility. The carbene-mediated TFB cross-linking also downshifted the HOMO level from -5.3 to -5.5 eV, delivering a smaller hole-transport energy barrier. Benefiting from these, the cross-linked QLED showed enhanced device performances over the pristine device, with EQE, power efficiency, and current efficiency being elevated by nearly 20, 15, and 83%, respectively. To the best of our knowledge, this is the first report about a bis-diazo compound based carbene cross-linker built into a polymeric HTM for a QLED with enhanced device performance.

Regio- and Stereoselective Rhodium(II)-Catalyzed C-H Functionalization of Cyclobutanes.

Recent developments in controlled C-H functionalization transformations continue to inspire new retrosynthetic disconnections. One tactic in C-H functionalization is the intermolecular C-H insertion reaction of rhodium bound carbenes. These intermediates can undergo highly selective transformations through the modulation of the ligand framework of the rhodium catalyst. This work describes our continued efforts towards differentiating C-H bonds in the same molecule by judicious catalyst choice. Substituted cyclobutanes which exist as a mixture of interconverting conformers and possess neighboring C-H bonds within a highly strained framework are the targets herein for challenging the current suite of catalysts. While most C-H functionalization tactics focus on generating 1,2-disubstituted cyclobutanes via substrate-controlled directing group methods, the regiodivergent methods in this paper provide access to chiral 1,1-disubstituted and cis-1,3-disubstituted cyclobutanes simply by changing the catalyst identity, thus permitting entry to novel chemical space.