Lihua Yao

Bio: Lihua Yao is an academic researcher from Duquesne University. The author has contributed to research in topics: Allylic rearrangement & Materials science. The author has an hindex of 4, co-authored 7 publications receiving 967 citations.

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Abstract: Fraser F. Fleming,* Lihua Yao, P. C. Ravikumar, Lee Funk, and Brian C. Shook Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, and Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477

Multifunctional Nanocrystalline-Assembled Porous Hierarchical Material and Device for Integrating Microwave Absorption, Electromagnetic Interference Shielding, and Energy Storage.

Abstract: Multifunctional applications including efficient microwave absorption and electromagnetic interference (EMI) shielding as well as excellent Li-ion storage are rarely achieved in a single material. Herein, a multifunctional nanocrystalline-assembled porous hierarchical NiO@NiFe2 O4 /reduced graphene oxide (rGO) heterostructure integrating microwave absorption, EMI shielding, and Li-ion storage functions is fabricated and tailored to develop high-performance energy conversion and storage devices. Owing to its structural and compositional advantages, the optimized NiO@NiFe2 O4 /15rGO achieves a minimum reflection loss of -55 dB with a matching thickness of 2.3 mm, and the effective absorption bandwidth is up to 6.4 GHz. The EMI shielding effectiveness reaches 8.69 dB. NiO@NiFe2 O4 /15rGO exhibits a high initial discharge specific capacity of 1813.92 mAh g-1 , which reaches 1218.6 mAh g-1 after 289 cycles and remains at 784.32 mAh g-1 after 500 cycles at 0.1 A g-1 . In addition, NiO@NiFe2 O4 /15rGO demonstrates a long cycling stability at high current densities. This study provides an insight into the design of advanced multifunctional materials and devices and provides an innovative method of solving current environmental and energy problems.

Allylic and Allenic Halide Synthesis via NbCl5- and NbBr5-Mediated Alkoxide Rearrangements

Abstract: Addition of NbCl5 or NbBr5 to a series of magnesium, lithium, or potassium allylic or propargylic alkoxides directly provides allylic or allenic halides. Halogenation formally occurs through a metalla-halo-[3,3] rearrangement, although concerted, ionic, and direct displacement mechanisms appear to operate competitively. Transposition of the olefin is equally effective for allylic alkoxides prepared by nucleophilic addition, deprotonation, or reduction. Experimentally, the niobium pentahalide halogenations are rapid, afford essentially pure (E)-allylic or -allenic halides after extraction, and are applicable to a range of aliphatic and aromatic alcohols, aldehydes, and ketones.

Direct Conversion of Aldehydes and Ketones to Allylic Halides by a NbX5-[3,3] Rearrangement

Abstract: Allylic halides occupy a privaleged position as electrophiles.1 Activation of the carbon-halogen bond by adjacent π electrons dramatically facilitates nucleophilic displacement,2 allowing otherwise difficult bond constructions with a diverse range of carbon, heteroatom, and organometallic nucleophiles.3 Allylic halides prepared as intermediates during total syntheses are typically prepared by halogenation of allylic alcohols. These in turn are often obtained by olefination-reduction sequences4 because the direct “halo-olefination” of carbonyls with Wittig-type procedures is circumvented by elimination in the reagent. A conceptually direct method for converting aldehydes and ketones to allylic halides is through a sequenced vinyl addition-metalla-halo-[3,3]-rearrangement (Scheme 1).5 Addition of vinylmagnesium bromide to an aldehyde or ketone generates the bromomagnesium alkoxide 2,6 potentially allowing transmetallation to a more oxophilic metal capable of weakening the carbon-oxygen bond for a metalla-halo-[3,3]-rearrangement.7 Particularly Lewis acidic halometal alkoxides 3 may cause competitive ionization and halogenation leading to a mixture of allylic halide regioisomers8 whereas metals bearing more nucleophilic halides would favor the rearranged allylic halide 4. Scheme 1 Vinyl Addition-Metalla-Halo-[3,3]-Rearrangement. TiCl4 effectively promotes this sequence with aromatic aldehydes and with magnesium alkoxides derived from deprotonation of allylic alchohols.7 Results presented below show that NbCl5 and NbBr5 expand the scope of this vinyl addition-metalla-halo-[3,3]-rearrangement to include aromatic and aliphatic aldehydes and aromatic and aliphatic ketones. In addition, the [3,3] rearrangement is equally effective for the conversion of a propargylic alcohol to the corresponding bromoallene implying a concerted rearrangement in distinction to the related reactions with TiCl4. Exploring the viability of a sequenced vinyl addition-metalo-halo-[3,3]-rearrangement initially focused on identifying an optimal metal and solvent combination. Using the potassium alkoxide 6 as a prototype, a diverse range of metal chlorides were evaluated for their effectiveness in providing the allylic chloride 4a (Scheme 2). Screening several oxophilic metals9 identified dry10 niobium pentachloride11 in 1,4-dioxane as the optimal combination. After only 10 minutes at room temperature the alcohol 5 was completely converted to the allylic chloride 4a in essentially quantitative yield. 1H and 13C NMR analysis of the crude product indicated the material to be pure.12 Scheme 2 Metalla-Halo-[3,3]-Rearrangement. The use of niobium pentachloride is particularly intriguing because this strong Lewis acid13 is employed under basic conditions. These conditions contrast with many related reactions14 in which transition metal halides exhibit reactivity similar to that of HCl which might be liberated by contact of the reagent with moisture.15 Mechanistically attack of the alkoxide 6 on NbCl5 might trigger rearrangement from the niobiate 3a having an expanded coordination sphere (Scheme 2).16 Sequential ionization and chlorination of 3a is a mechanistic possibility, although the absence of regio- and stereoisomers suggests this to be a minor reaction manifold. Synthetically the NbCl5 rearrangement offers the advantage over related phosphonium-based reagents in facile isolation of (E)-allylic chlorides simply by an aqueous extraction to remove inorganic species. Optimizing the metalo-halo-[3,3]-rearrangement with the allylic alcohol 5 provided a platform for directly converting aldehyde 1a to the allylic chloride 4a (Scheme 3). Partial ring opening of THF17 by NbCl5 led to a procedure in which vinylmagnesium bromide18 was added to a 10 °C, THF solution of aldehyde 1a followed by dilution with four volumes of 1,4-dioxane and addition of solid NbCl5 (1.2 equiv). After 30 minutes the solution was washed with aqueous HCl and concentrated to provide the crude chloride19 4a (99%).20 Scheme 3 Direct Vinyl-Addition NbCl5 Halogenation. The naphthyl-substituted allylic chloride 4a is challenging to purify. Silica-based purification methods resulted in significant mass loss suggesting partial alkylation of the solid-phase.12 Consequently the crude chloride 4a was redissolved in THF and reacted with sodium phenylsulfenylate (Scheme 3). The procedure efficiently provided the sulfide 7a ratifying the efficiency of the niobium rearrangement in generating essentially pure allylic chloride 4a. Performing the vinyl addition-niobium rearrangement-sulfenylate displacement with a series of aldehydes efficiently provides the corresponding sulfides (Table 1). Aromatic aldehydes and ketones smoothly rearrange in the presence of NbCl5 (Table 1, entries 1-5). The nitrile-containing aromatic aldehyde 1e was less reactive toward NbCl5 but was effectively halogenated with NbBr5 (Table 1, entry 5). Aliphatic aldehydes are converted to the corresponding allylic chlorides with NbCl5 but greater efficiency is obtained with NbBr5 (Table 1, entries 6-7). The aliphatic ketone cyclohexanone reacted sluggishly even with NbBr5 (Table 1, entry 8). In each case analysis of the intermediate allylic halide shows complete rearrangement prior to the sulfenylate displacement. Table 1 Sequential Addition-Chlorination-Sulfenylation. The metalo-halo-[3,3]-rearrangement is best suited to hydrocarbons. A conjugated aldehyde (Table 1, entry 4) and a nitrile (Table 1, entry 5) are readily tolerated whereas an acetal is not.21 Effort to further probe the functional group tolerance is in progress. The metalla-halo-[3,3]-rearrangement is not limited to the addition of vinylmagnesium halide to aldehydes and ketones. The strategy was extended to halogenation of the propargylic alcohol 8a with the expectation that a concerted rearrangement would favor a haloallene (Scheme 4). Deprotonating 8a and adding NbCl5 afforded only a trace of the corresponding chloro allene at room temperature with full conversion requiring heating the reaction mixture to reflux. Under these thermal conditions considerable decomposition occurred whereas substituting NbBr5 triggerred a smooth rearrangement at room temperature. After 2 h the bromoallene 10a was obtained in 78% yield. Scheme 4 NbBr5-Rearrangement to an Allenyl Bromide. Direct transformation of aldehydes and ketones to the corresponding allylic halides is readily achieved through a vinyl addition metalo-halo-[3,3]-rearrangement strategy. Sequential addition of vinylmagnesium bromide and NbCl5 or NbBr5 to aromatic and aliphatic aldehydes and ketones provides essentially pure allylic chlorides for use in subsequent displacement reactions. The [3,3] rearrangement is equally effective in the case of a propargyllic alcohol, which provides the corresponding allenyl bromide. Synthetically, the addition-niobium halide rearrangement provides an efficient and direct conversion of aldehydes and ketones to allylic halides in one synthetic operation.

Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed radical relay.

Abstract: Direct methods for stereoselective functionalization of sp3-hybridized carbon–hydrogen [C(sp3)–H] bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C–H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp3)–CN bond formation upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90 to 99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C–H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Abstract: Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads—beyond α,β-unsaturated amides—recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.

When Light Meets Nitrogen-Centered Radicals: From Reagents to Catalysts.

Abstract: Nitrogen-centered radicals (NCRs) are a versatile class of highly reactive species that have a longer history than the classical carbon-based radicals in synthetic chemistry. Depending on the N-hybridization and substitution patterns, NCRs can serve as electrophiles or nucleophiles to undergo various radical transformations. Despite their power, progress in nitrogen-radical chemistry is still slow compared with the popularity of carbon radicals, and their considerable synthetic potential has been largely underexplored, which is, as concluded by Zard, mainly hampered by "a dearth of convenient access to these species and a lack of awareness pertaining to their reactivity".Over the past decade, visible-light photoredox catalysis has been established as a powerful toolbox that synthetic chemists can use to generate a diverse range of radical intermediates from native organic functional groups via a single electron transfer process or energy transfer under mild reaction conditions. This catalytic strategy typically obviates the need for external stoichiometric activation reagents or toxic initiators and often enables traditionally inaccessible ionic chemical reactions. On the basis of our long-standing interest in nitrogen chemistry and catalysis, we have emphasized the use of visible-light photoredox catalysis as a tactic to discover and develop novel methods for generating NCRs in a controlled fashion and synthetic applications. In this Account, we describe our recent advances in the development of visible-light-driven photoredox-catalyzed generation of NCRs and their synthetic applications.Inspired by the natural biological proton-coupled electron transfer (PCET) process, we first developed a strategy of visible-light-driven photoredox-catalyzed oxidative deprotonation electron transfer to activate the N-H bonds of hydrazones, benzamides, and sulfonamides to give the corresponding NCRs under mild reaction conditions. With these reactive species, we then achieved a range of 5-exo and 6-endo radical cyclizations as well as cascade reactions in a highly regioselective manner, providing access to a variety of potentially useful nitrogen heterocycles. To further expand the repertoire of possible reactions of NCRs, we also revealed that iminyl radicals, derived from O-acyl cycloalkanone oxime esters, can undergo facile ring-opening C-C bond cleavage to give cyanoalkyl radicals. These newly formed radical species can further undergo a variety of C-C bond-forming reactions to allow the synthesis of diverse distally functionalized alkyl nitriles. Stimulated by these studies, we further developed a wide variety of visible-light-driven copper-catalyzed radical cross-coupling reactions of cyanoalkyl radicals. Because of their inherent highly reactive and transient properties, the strategy of heteroatom-centered radical catalysis is still largely underexplored in organic synthesis. Building on our understanding of the fundamental chemistry of NCRs, we also developed for the first time the concept of NCR covalent catalysis, which involves the use of in situ-photogenerated NCRs to activate allyl sulfones, vinylcyclopropanes, and N-tosyl vinylaziridines. This catalytic strategy has thus enabled efficient difunctionalization of various alkenes and late-stage modification of complex biologically active molecules.In this Account, we describe a panoramic picture of our recent contributions since 2014 to the development and application of the visible-light-driven photoredox systems in the field of NCR chemistry. These studies provide not only efficient methods for the synthesis of functionally rich molecules but also some insight into the exploration of new reactivity or reaction modes of NCRs.