N-O Bond Activation by Energy Transfer Photocatalysis.

A radical shift toward energy transfer photocatalysis from electron transfer photocatalysis under visible-light photoirradiation is often due to the greener prospects of atom and process economy. Recent advances in energy transfer photocatalysis embrace unique strategies for direct small-molecule activation and sometimes extraordinary chemical bond formation in the absence of additional/sacrificial reagents. Selective energy transfer photocatalysis requires careful selection of substrates and photocatalysts for a perfect match with respect to their triplet energies while having incompatible redox potentials to prevent competitive electron transfer pathways. Substrates containing labile N-O bonds are potential targets for generating reactive key intermediates via photocatalysis to access a variety of functionalized molecules. Typically, the differential electron densities of N and O heteroatoms have been exploited for generation of either N- or O-centered radical intermediates from the functionalized substrates by the electron transfer pathway. However, the latest developments involve direct N-O bond homolysis via energy transfer to generate both N- and O-centered radicals for their subsequent utilization in diverse organic transformations, also in the absence of sacrificial redox reagents. In this Account, we highlight our key contributions in the field of N-O bond activation via energy transfer photocatalysis to generate reactive radical intermediates, with coverage of useful mechanistic insights. More specifically, well-designed N-O bond-containing substrates such as 1,2,4-oxadiazolines, oxime esters, N-indolyl carbonates, and N-enoxybenzotriazoles were successfully utilized in versatile transformations involving selective energy transfer over electron transfer from photocatalysts with high triplet state energy. Direct access to reactive N-, O-, and C-centered (if decarboxylation follows) radical intermediates was achieved for diverse cross-couplings and rearrangement processes. In particular, a variety of open-shell nitrogen reactive intermediates, including N(sp2) and N(sp3) radicals and nitrenes, have been utilized. Notably, diversified transformations of identical substrates have been achieved through careful control of the reaction conditions. 1,2,4-Oxadiazolines were converted into spiro-azolactams through iminyl intermediates in the presence of 1O2, benzimidazoles, or sulfoximines with external sulfoxide reagent through triplet nitrene intermediates under inert conditions. Besides, oxime esters underwent either intramolecular C(sp3)-N radical-radical coupling or intermolecular C(sp3)-N radical-radical coupling by a combined energy transfer-hydrogen atom transfer strategy. Furthermore, a series of electrochemical and photophysical experiments as well as computational studies were performed to substantiate the proposed selective energy-transfer-driven reaction pathways. We hope that this Account will serve as a guide for the rational design of selective energy transfer processes through the activation of further labile chemical bonds.

Photoredox Selective Homocoupling of Propargyl Bromides.

Since the alkynyl moiety is one of the most versatile synthons for many other functional groups, 1,5-diynes (Wurtz-type products of propargyl halides) would be valuable synthetic building blocks for the synthesis of complex functional molecules. However, despite the high and similar reactivity of propargyl radicals compared to allyl and benzyl derivative radicals, a photoredox Wurtz-type reaction of propargyl halides has not yet been developed. In this study, we developed the visible-light-induced selective homocoupling of propargyl bromides to form 1,5-diynes. Electrochemical and photophysical experiments showed that the key propargyl radical generation involves a reductive quenching cycle of the photoexcited [Ir(III)]* photocatalyst in the presence of N,N-dicyclohexylmethylamine. The product 1,5-diyne underwent one-step conversion to the functionalized indole derivative via Rh-catalyzed coupling with N-phenylacetamide. These results indicated the high utility of the developed homocoupling method.

Value-Added Products from Coffee Waste: A Review.

Coffee waste is often viewed as a problem, but it can be converted into value-added products if managed with clean technologies and long-term waste management strategies. Several compounds, including lipids, lignin, cellulose and hemicelluloses, tannins, antioxidants, caffeine, polyphenols, carotenoids, flavonoids, and biofuel can be extracted or produced through recycling, recovery, or energy valorization. In this review, we will discuss the potential uses of by-products generated from the waste derived from coffee production, including coffee leaves and flowers from cultivation; coffee pulps, husks, and silverskin from coffee processing; and spent coffee grounds (SCGs) from post-consumption. The full utilization of these coffee by-products can be achieved by establishing suitable infrastructure and building networks between scientists, business organizations, and policymakers, thus reducing the economic and environmental burdens of coffee processing in a sustainable manner.

Nickel-Catalyzed Enantioselective Synthesis of 2,3,4-Trisubstituted 3-Pyrrolines.

The development of synthetic methods to produce highly functionalized chiral 3-pyrrolines is of indisputable importance because of their prevalence in natural and synthetic bioactive molecules. Unfortunately, previous general cycloaddition approaches using allenoates, could not synthesize 3,4-disubstituted 3-pyrrolines. Herein, an original approach to yield 2,3,4-trisubstituted 3-pyrrolines with chirality at the 2-position is presented. A NiII /Fc-i-PrPHOX catalytic system facilitated a redox-neutral highly stereoselective process that exhibited an enantioselectivity of up to 99 %. Enantioenriched 3-pyrrolines can be converted to other valuable classes of N-heterocycles.

Benzothiazole Synthesis: Mechanistic Investigation of an In Situ-Generated Photosensitizing Disulfide.

The use of a visible light absorbing intermediate as a photosensitizer makes a chemical process simple and sustainable, obviating the need for the use of chemical additives. Herein, the formation of a photosensitizing disulfide in benzothiazole synthesis from 2-aminothiophenol and aldehydes was proposed and confirmed through in-depth mechanistic studies. A series of photophysical and electrochemical investigations revealed that an in situ-generated disulfide photosensitizes molecular oxygen to generate the key oxidants, singlet oxygen and superoxide anion, for the dehydrogenation step.

A High-Yield Process for Production of Biosugars and Hesperidin from Mandarin Peel Wastes.

In this research, novel biorefinery processes for obtaining value-added chemicals such as biosugar and hesperidin from mandarin peel waste (MPW) are described. Herein, three different treatment methods were comparatively evaluated to obtain high yields of biosugar and hesperidin from MPW. Each method was determined by changes in the order of three processing steps, i.e., oil removal, hesperidin extraction, and enzymatic hydrolysis. The order of the three steps was found to have a significant influence on the production yields. Biosugar and hesperidin production yields were highest with method II, where the processing steps were performed in the following order: oil removal, enzymatic hydrolysis, and hesperidin extraction. The maximum yields obtained with method II were 34.46 g of biosugar and 6.48 g of hesperidin per initial 100 g of dry MPW. Therefore, the methods shown herein are useful for the production of hesperidin and biosugar from MPW. Furthermore, the utilization of MPWs as sources of valuable materials may be of considerable economic benefits and has become increasingly attractive.

Distinctive reactivity of N-benzylidene-[1,1'-biphenyl]-2-amines under photoredox conditions.

A simple photocatalytic method was developed for the synthesis of unsymmetrical 1,2-diamines by the unprecedented reductive coupling of N-benzylidene-[1,1'-biphenyl]-2-amines with an aliphatic amine. The presence of a phenyl substituent in the aniline moiety of the substrate was critical for the reactivity. The reaction proceeded via radical-radical cross-coupling of α-amino radicals generated by proton-coupled single-electron transfer in the presence of an Ir photocatalyst. On the other hand, symmetrical 1,2-diamines were selectively produced from the same starting materials by the judicious choice of the reaction conditions, showcasing the distinct reactivity of N-benzylidene-[1,1'-biphenyl]-2-amines. The developed method can be employed for the synthesis of various bulky vicinal diamines, which are potential ligands in stereoselective synthesis.

Generation of N-Centered Radicals via a Photocatalytic Energy Transfer: Remote Double Functionalization of Arenes Facilitated by Singlet Oxygen.

An unprecedented approach to the generation of an N-centered radical via a photocatalytic energy-transfer process from readily available heterocyclic precursors is reported, which is distinctive of the previous electron transfer approaches. In combination with singlet oxygen, the in-situ-generated nitrogen radical from the oxadiazoline substrate in the presence of fac-Ir(ppy)3 undergoes a selective ipso addition to arenes to furnish remotely double-functionalized spiro-azalactam products. The mechanistic studies provide compelling evidence that the catalytic cycle selects the energy-transfer pathway. A concurrent activation of molecular oxygen to generate singlet oxygen by energy transfer is also rationalized. Furthermore, the occurrence of the electron transfer phenomenon is excluded on the basis of the negative driving forces for one-electron transfer between oxadiazoline and the excited state of fac-Ir(ppy)3 with a consideration of their redox potentials. The necessity of singlet oxygen as well as the photoactivated oxadiazoline substrate is clearly supported by a series of controlled experiments. Density functional studies have also been carried out to support these observations. The scope of substrates is explored by synthesizing diversely functionalized cyclohexadienone moieties in view of their utility in complex organic syntheses and as potential targets in pharmacology.

Visible-Light-Induced Trifluoromethylation of Unactivated Alkenes with Tri(9-anthryl)borane as an Organophotocatalyst.

Tri(9-anthryl)borane was successfully applied as an organophotocatalyst for the visible-light-induced trifluoromethylation of unactivated alkenes with CF3I. The mild reaction conditions tolerated a variety of functional groups, and the reaction could be extended to perfluoroalkylations with C3F7I and C4F9I. Mechanistic studies revealed that the photoredox catalysis involves an oxidative quenching pathway.

Fluoroalkenylation of boronic acids via an oxidative Heck reaction.

A fluoroalkenylation of boronic acids with fluoroalkyl alkenes has been developed. The Pd-catalyzed oxidative Heck coupling reaction proceeds under an oxygen atmosphere at room temperature, in the absence of a base and/or a ligand, showing excellent practicality of the process. This simple transformation is highly stereoselective to provide only E-isomers. In addition to the general approach using alkenes with functionalized fluoroalkyl reagents, this method, by transferring an aromatic system to the electron-deficient fluoroalkyl alkene, provides an efficient alternative method to yield valuable organofluorines.

Synthesis of fluoroalkylated alkynes via visible-light photocatalysis.

Fluoroalkylated alkynes, which are versatile building blocks for the synthesis of various biologically active organofluorine compounds, were synthesized from easily available alkynyl halides and fluoroalkyl halides by visible-light photocatalysis. Addition of fluoroalkyl radicals to alkynes and subsequent dehalogenation selectively yielded fluoroalkylated alkynes.

Access to Multifunctionalized Benzofurans by Aryl Nickelation of Alkynes: Efficient Synthesis of the Anti-Arrhythmic Drug Amiodarone.

An unconventional nickel-catalyzed reaction was developed for the synthesis of multifunctionalized benzofurans from alkyne-tethered phenolic esters. The transformation involves the generation of a nucleophilic vinyl NiII species by the regioselective syn-aryl nickelation of an alkyne, which then undergoes an intramolecular cyclization with phenol ester to yield highly functionalized 1,1-disubstituted alkenes with 3-benzofuranyl and (hetero)aryl substituents. The methodology can be used for the late-stage benzofuran incorporation of various drug molecules and natural products, such as 2-propylvaleric acid, gemfibrozil, biotin, and lithocholic acid. Furthermore, this arylative cyclization method was successfully applied for the efficient synthesis of the anti-arrhythmic drug amiodarone.

Visible-Light-Promoted Synthesis of Dibenzofuran Derivatives.

Dibenzofurans are naturally occurring molecules that have received considerable attention for a variety of practical applications, such as in pharmaceuticals and electronic materials. Herein, an efficient and eco-friendly method for the synthesis of dibenzofuran derivatives via intramolecular C-O bond formation, which involves the in situ production of a diazonium salt, is described. The transformation requires a diazotizing agent and is promoted by the use of an organic photosensitizer under visible-light irradiation.

Base-Promoted Synthesis of 2-Aryl Quinazolines from 2-Aminobenzylamines in Water.

A transition-metal-free procedure for the synthesis of a highly valuable class of heteroaromatics, quinazolines, was developed by using easily available 2-aminobenzylamines and α,α,α-trihalotoluenes. The transformation proceeded smoothly in the presence of only sodium hydroxide and molecular oxygen in water at 100 °C, furnishing a variety of 2-aryl quinazolines. The crystallization process of the crude reaction mixture for the purification of the solid products circumvents huge solvent-consuming workup and column chromatographic techniques, which make the overall process more sustainable and economical.

Controlled Fluoroalkylation Reactions by Visible-Light Photoredox Catalysis.

Owing to their unique biological, physical, and chemical properties, fluoroalkylated organic substances have attracted significant attention from researchers in a variety of disciplines. Fluoroalkylated compounds are considered particularly important in pharmaceutical chemistry because of their superior lipophilicity, binding selectivity, metabolic stability, and bioavailability to those of their nonfluoroalkylated analogues. We have developed various methods for the synthesis of fluoroalkylated substances that rely on the use of visible-light photoredox catalysis, a powerful preparative tool owing to its environmental benignity and mechanistic versatility in promoting a large number of synthetically important reactions with high levels of selectivity. In this Account, we describe the results of our efforts, which have led to the development of visible-light photocatalytic methods for the introduction of a variety of fluoroalkyl groups (such as, -CF3, -CF2R, -CH2CF3, -C3F7, and -C4F9) and arylthiofluoroalkyl groups (such as, -CF2SPh, -C2F4SAr, and -C4F8SAr) to organic substances. In these studies, electron-deficient carbon-centered fluoroalkyl radicals were successfully generated by the appropriate choice of fluoroalkyl source, photocatalyst, additives, and solvent. The redox potentials of the photocatalysts and the fluoroalkyl sources and the choice of sacrificial electron donor or acceptor as the additive affected the photocatalytic pathway, determining whether an oxidative or reductive quenching pathway was operative for the generation of key fluoroalkyl radicals. Notably, we have observed that additives significantly affect the efficiencies and selectivities of these reactions and can even change the outcome of the reaction by playing additional roles during its course. For instance, a tertiary amine as an additive in the reaction medium can act not only as a sacrificial electron donor in photoredox catalysis but also as a hydrogen atom source, an elimination base for dehydrohalogenation of the intermediate, and also a Brønsted base for deprotonation. In the same context, the selection of solvent is also critical since it affects the rate and selectivity of reactions depending upon its polarity and reagent solubilizing ability and plays additional roles in the process, for example, as a hydrogen atom source. By clearly understanding the roles of additives and solvent, we designed several controlled fluoroalkylation reactions where different products were formed selectively from the same starting substrates. In addition, we could exploit one of the most important advantages of radical reactions, that is, the use of unactivated π-systems such as alkenes, alkynes, arenes, and heteroarenes as radical acceptors without prefunctionalization. Furthermore, fluoroalkylation processes under mild room-temperature reaction conditions tolerate various functional groups and are therefore easily applicable to late-stage modifications of highly functionalized advanced intermediates.

Chemoselective Hydrodehalogenation of Organic Halides Utilizing Two-Dimensional Anionic Electrons of Inorganic Electride [Ca2N]+·e.

Halogenated organic compounds are important anthropogenic chemicals widely used in chemical industry, biology, and pharmacology; however, the persistence and inertness of organic halides cause human health problems and considerable environmental pollution. Thus, the elimination or replacement of halogen atoms with organic halides has been considered a central task in synthetic chemistry. In dehalogenation reactions, the consecutive single-electron transfer from reducing agents generates the radical and corresponding carbanion and thus removes the halogen atom as the leaving group. Herein, we report a new strategy for an efficient chemoselective hydrodehalogenation through the formation of stable carbanion intermediates, which are simply achieved by using highly mobile two-dimensional electrons of inorganic electride [Ca2N]+·e- with effective electron transfer ability. The consecutive single-electron transfer from inorganic electride [Ca2N]+·e- stabilized free carbanions, which is a key step in achieving the selective reaction. Furthermore, a determinant more important than leaving group ability is the stability control of free carbanions according to the s character determined by the backbone structure. We anticipate that this approach may provide new insight into selective chemical formation, including hydrodehalogenation.

Extended Study of Visible-Light-Induced Photocatalytic [4 + 2] Benzannulation: Synthesis of Polycyclic (Hetero)Aromatics.

Herein we report an extended study of [4 + 2] benzannulation reactions of 2-(hetero)aryl-substituted anilines with alkynes by visible light photocatalysis. The method requires the use of tBuONO as a diazotizing agent and 0.3 mol % of fac-Ir(ppy)3 as a photocatalyst at room temperature. The reaction proceeded in a chemo- and regioselective manner with high functional group tolerance under mild conditions allowing the preparation of a wide variety of polycyclic (hetero)aromatic compounds, including phenanthrenes, in moderate to high yields. This procedure is amenable to gram-scale synthesis of 9-phenylphenanthrene.

Selective Ring-Opening of N-Alkyl Pyrrolidines with Chloroformates to 4-Chlorobutyl Carbamates.

Our study shows that among aza-heterocycles of various ring sizes, including aziridines, azetidines, pyrrolidines, and piperidines, only N-alkyl pyrrolidines undergo competitive reaction pathways with chloroformates to yield N-dealkylated pyrrolidines and 4-chlorobutyl carbamates. The pathway taken depends on the substituent on the nitrogen, i.e., ring-opening with methyl and ethyl substituents and dealkylation with a benzyl substituent. Computational calculations support the substituent-dependent product formation by showing the energy difference between the transition states of both reaction pathways. Selective ring-opening reactions of N-methyl and N-ethyl pyrrolidine derivatives with chloroformates were utilized to prepare various 4-chlorobutyl carbamate derivatives as valuable 1,4-bifunctional compounds.

Total kidney and liver volume is a major risk factor for malnutrition in ambulatory patients with autosomal dominant polycystic kidney disease.

BACKGROUND: In patients with autosomal dominant polycystic kidney disease (ADPKD), malnutrition may develop as renal function declines and the abdominal organs become enlarged. We investigated the relationship of intra-abdominal mass with nutritional status. METHODS: This cross-sectional study was performed at a tertiary hospital outpatient clinic. Anthropometric and laboratory data including serum creatinine, albumin, and cholesterol were collected, and kidney and liver volumes were measured. Total kidney and liver volume was defined as the sum of the kidney and liver volumes and adjusted by height (htTKLV). Nutritional status was evaluated by using modified subjective global assessment (SGA). RESULTS: In a total of 288 patients (47.9% female), the mean age was 48.3 ± 12.2 years and the mean estimated glomerular filtration rate (eGFR) was 65.3 ± 25.3 mL/min/1.73 m2. Of these patients, 21 (7.3%) were mildly to moderately malnourished (SGA score of 4 and 5) and 63 (21.7%) were at risk of malnutrition (SGA score of 6). Overall, patients with or at risk of malnutrition were older, had a lower body mass index, lower hemoglobin levels, and poorer renal function compared to the well-nourished group. However, statistically significant differences in these parameters were not observed in female patients, except for eGFR. In contrast, a higher htTKLV correlated with a lower SGA score, even in subjects with an eGFR ≥45 mL/min/1.73 m2. Subjects with an htTKLV ≥2340 mL/m showed an 8.7-fold higher risk of malnutrition, after adjusting for age, hemoglobin, and eGFR. CONCLUSIONS: Nutritional risk was detected in 30% of ambulatory ADPKD patients with relatively good renal function. Intra-abdominal organomegaly was related to nutritional status independently from renal function deterioration.

HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis.

HL156A is a novel AMP-activated protein kinase (AMPK) activator. We aimed to investigate the protective mechanism of HL156A against peritoneal fibrosis (PF) in in vivo and in vitro models. The rat PF model was induced by daily intraperitoneally injection of chlorhexidine (CHX) solution containing 0.1% CHX gluconate and 15% ethanol for 4 wk. The rats in the treatment group were treated with HL156A (1 mg·kg(-1)·day(-1)). Control rats were injected with vehicle alone. In vitro, cultured rat peritoneal mesothelial cells (RPMCs) were treated with either high glucose (HG; 50 mM), normal glucose (NG; 5 mM), NG+HL156A, or HG+HL156A. HL156A in supplemented rats ameliorated peritoneal calcification, cocoon formation, bowel obstruction, and PF. Immunohistochemistry showed reduced fibronectin accumulation in the peritoneum of HL156A-treated rats compared with those injected with CHX alone. HL156A treatment of RPMCs inhibited HG-induced myofibroblast transdifferentiation and markers of epithelial-mesenchymal transition (EMT). Moreover, HL156A ameliorated HG-induced transforming growth factor-ß1, Smad3, Snail, and fibronectin expression in the RPMCs via AMPK upregulation. These results suggest that HL156A exhibits a protective effect in PF progression. Further research is warranted to seek the therapeutic potential of HL156A as an antifibrotic agent in peritoneal dialysis patients.