Photocatalytic Multiple Deuteration of Polyethylene Glycol Derivatives Using Deuterium Oxide.

Deuterated molecules are of growing interest because of the specific characteristics of deuterium, such as stronger C-D bonds being stronger than C-H bonds. Polyethylene glycols (PEGs) are widely utilized in scientific fields (e. g.

Raman optical activity study of deuterated sugars: deuterium labelling as a tool for structural analysis.

Structural analyses using Raman optical activity (ROA) spectroscopy conventionally rely on vibrational signals in the fingerprint region ranging from 100 to 1800 cm. Use of deuterium labelling to observe ROA signals in the C-D stretching region provides additional information about a local structure of large molecular systems. So far, the potential of C-D stretching ROA signals for structural analysis has rarely been explored.

Oxidative Coupling of Hydroquinone Derivatives with Olefins to Dihydrobenzofurans.

Dihydrobenzofuran is an important skeleton for bioactive compounds and natural products. Hydroquinones can be easily modified into substituted hydroquinones, which effectively undergo oxidation to produce the corresponding benzoquinone derivatives. Benzoquinones are reactive electrophiles that are frequently utilized in coupling with olefins to dihydrobenzofurans.

Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery.

Deuterated drugs (heavy drugs) have recently been spotlighted as a new modality for small-molecule drugs because the pharmacokinetics of pharmaceutical drugs can be enhanced by replacing C-H bonds with more stable C-D bonds at metabolic positions. Therefore, deuteration methods for drug candidates are a hot topic in medicinal chemistry. Among them, the H/D exchange reaction (direct transformation of C-H bonds to C-D bonds) is a useful and straightforward method for creating novel deuterated target molecules, and over 20 reviews on the synthetic methods related to H/D exchange reactions have been published in recent years.

Furanyl bis(indolyl)methane as a palladium ion-selective chromogenic agent.

The colorless solution of furan-2-yl bis(indolyl)methane (BIM) is newly revealed to work as a palladium (Pd) ion-selective chromogenic agent by turning orange. 5-(-Methyl--phenyl-aminomethyl)-furan-2-yl BIM could be synthesized from 5-chloromethylfurfural as a biorenewable feedstock one-pot and double functionalization, and a mixture of its solution and Pd ions showed the highest absorbance at 465 nm in UV-Vis analysis. On the other hand, other metal ions (Cu, Cr, Cr, Fe, Fe, Ni, Zn, In, Pt, or Ce) exhibited no response.

Impact of multiple H/D replacements on the physicochemical properties of flurbiprofen.

Although deuterium incorporation into pharmaceutical drugs is an attractive way to expand drug modalities, their physicochemical properties have not been sufficiently examined. This study focuses on examining the changes in physicochemical properties between flurbiprofen (FP) and flurbiprofen- (FP-), which was successfully prepared by direct and multiple H/D exchange reactions at the eight aromatic C-H bonds of FP. Although the effect of deuterium incorporation was not observed between the crystal structures of FP and FP-, the melting point and heat of fusion of FP- were lower than those of FP.

Oxidative Functionalization of Catechol Derivatives Substituted with Electron-Withdrawing Groups.

Catechols possessing electron-withdrawing groups at the C3 position effectively underwent oxidative functionalization at the C4 position in the presence of phenyliodine(III) diacetate (PIDA) and heteroarene nucleophiles (e.g., indole, indazole, and benzotriazole) to produce the corresponding biaryl products.

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery.

The pharmacokinetics of pharmaceutical drugs can be improved by replacing C-H bonds with the more stable C-D bonds at the α-position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α-position to heteroatoms.

Multiple deuteration of triphenylphosphine and live-cell Raman imaging of deuterium-incorporated Mito-Q.

All aromatic C-H bonds of triphenylphosphine (PPh) were efficiently replaced by C-D bonds using Ru/C and Ir/C co-catalysts in 2-PrOH and DO, an inexpensive deuterium source. Furthermore, non-radioactive and safe deuterium-incorporated Mito-Q (drug candidate) was prepared from deuterated PPh and used for the live-cell Raman imaging to evaluate the mitochondrial uptake.

Oxidative two-way regiocontrolled coupling of 3-methoxycarbonylcatechol and indoles to arylindoles.

3-Methoxycarbonylcatechol effectively underwent two-way regiocontrolled coupling with indoles an -benzoquinone intermediate, resulting from phenyliodine(III) diacetate oxidation, to generate 4-adducts or 5-adducts with or without BF·EtO in a one-pot manner. DFT calculations confirmed the obtained regioselectivities.

[Exhaustive Syntheses of Deuterium-labelled Compounds].

Deuterium (H, D) is a stable isotope of hydrogen (H). Deuterium-incorporated (labelled) compounds are widely utilized in various scientific fields such as mechanistic studies of organic reactions, elucidation of drug metabolism, application as tracers for microanalysis. Recently, development of heavy drugs and molecular imaging using techniques such as neutron scattering and Raman spectroscopy are spotlighted.

Gold-Catalyzed Tandem Oxidative Coupling Reaction between β-Ketoallenes and Electron-Rich Arenes to 2-Furylmethylarenes.

A tandem oxidative coupling reaction of β-ketoallenes and arenes was developed, which leads to the formation of 2-furylmethylarenes using AuCl and phenyliodine diacetate. The Au salt catalyzed the cyclization of β-ketoallenes to form a 2-furylmethyl gold intermediate, and the subsequent C-H functionalization of arenes proceeded smoothly. During the oxidative coupling, nucleophilic additions occurred at the center and terminal carbon atoms of the allene moiety to form C-O and C-C bonds.

Copper-Catalyzed Aqueous N-O Bond Cleavage of 2-Oxa-3-Azabicyclo Compounds to Cyclic cis-1,4-Amino Alcohols.

The N-O bond cleavage of 2-oxa-3-azabicyclo substrates, which are readily prepared by the hetero Diels-Alder reaction between nitroso dienophiles and cyclic 1,3-dienes, was effectively catalyzed by heterogeneous copper-on-carbon (Cu/C) under aqueous conditions to give the corresponding cyclic cis-1,4-amino alcohol derivatives. The present method was applied to the direct incorporation of the hydroxy and amino groups derived from a nitroso substrate into cyclic 1,3-dienes with cis-selectivity by the combination of the in situ formation of 2-oxa-3-azabicyclo compounds and following Cu/C-catalyzed N-O bond cleavage. The obtained cis-4-aminocyclohexenols, derived from cyclohexadiene as a cyclic 1,3-diene, could be selectively oxidized by using the ruthenium-on-carbon (Ru/C) catalyst under oxygen atmosphere to the corresponding 4-aminocyclohexenones at 50-65 °C or para-iminoquinones at 100-110 °C as useful reactive synthetic precursors.

Hydroquinone and benzoquinone-catalyzed aqueous Knoevenagel condensation.

A Knoevenagel condensation of various aldehydes with malononitrile effectively proceeded in the presence of hydroquinone/benzoquinone mixed catalysts at room temperature in HO. Furthermore, γ-deuterium-labeled α,β-unsaturated nitrile derivatives were also constructed via a deuteration of an aliphatic aldehyde in DO using a basic resin and the subsequent Knoevenagel condensation.

Arylation of indoles using cyclohexanones dually-catalyzed by niobic acid and palladium-on-carbons.

3-Arylindoles were easily constructed from indoles and cyclohexanone derivatives using a combination of catalytic niobic acid-on-carbon (NbO/C) and palladium-on-carbon (Pd/C) under heating conditions without any oxidants. The Lewis acidic NbO/C promoted the nucleophilic addition of indoles to the cyclohexanones, and the subsequent dehydration and Pd/C-catalyzed dehydrogenation produced the 3-arylindoles. The additive 2,3-dimethyl-1,3-butadiene worked as a hydrogen acceptor to facilitate the dehydrogenation step.

Facile Hydrogenative Deprotection of -Benzyl Groups Using a Mixed Catalyst of Palladium and Niobic Acid-on-Carbon.

The palladium-on-carbon (Pd/C)-catalyzed hydrogenative deprotection of the -benzyl-protecting group was effectively facilitated by the combined use of niobic acid-on-carbon (NbO/C). NbO/C is an acidic heterogeneous catalyst prepared from NbCl and activated carbon. The catalysts were easily removed from the reaction mixture and reusable.

Preparation of N-Ethyl-2'-deoxyguanosine-d as an Internal Standard for the Electrospray Ionization-Tandem Mass Spectrometric Determination of DNA Damage by Acetaldehyde.

The deuteration of N-ethyl-2'-deoxyguanosine (Et-dG), which is a DNA adduct generated from acetaldehyde, was studied by the addition reaction of acetaldehyde-d to 2'-deoxyguanosine (dG) in deuterium oxide (DO), with the aim to obtain an isotope internal standard for the liquid chromatography/tandem mass spectrometry (LC/MS/MS) quantitation of Et-dG. The replacement of the dG C-8 hydrogen atom by a deuteron atom took place at 50°C in DO and afforded a mixture of Et-dG-d and Et-dG-d. Et-dG-d, which was stable in aqueous solutions, was prepared by incubating the mixture in HO at 60°C for 48 h.

Practical and reliable synthesis of 2',3',5',5″-tetradeuterated uridine derivatives.

Deuterated drugs are valuable in the fields of drug discovery and medicinal chemistry. 2',3',5',5″-tetradeuterated uridine derivatives were synthesised from 2,3,5,5'-selectively tetradeuterated ribose using Sajiki's H-D exchanged Ru/C-H2-D2O-NaOH system and silyl-Hilbert-Johnson methods. The total deuterium content of the tetradeuterated uridines was over 92% using either basic or acidic reaction conditions.

Birch-Type Reduction of Arenes in 2-Propanol Catalyzed by Zero-Valent Iron and Platinum on Carbon.

Catalytic arene reduction was effectively realized by heating in 2-propanol/water in the presence of Pt on carbon (Pt/C) and metallic Fe. 2-Propanol acted as a hydrogen source, obviating the need for flammable (and hence, dangerous and hard-to-handle) hydrogen gas, while metallic Fe acted as an essential co-catalyst to promote reduction. The chemical states of Pt and Fe in the reaction mixture were determined by X-ray absorption near-edge structure analysis, and the obtained results were used to suggest a plausible reaction mechanism, implying that catalytic reduction involved Pt- and Fe-mediated single-electron transfer and the dehydrogenation of 2-propanol.

Polyethyleneimine-Modified Polymer as an Efficient Palladium Scavenger and Effective Catalyst Support for a Functional Heterogeneous Palladium Catalyst.

The polyethyleneimine-modified polymers, polystyrene-divinylbenzene-based (TAs) and polymethacrylate-based polymers (TAm), were used as palladium scavengers to eliminate residual palladium species after palladium on carbon-catalyzed Sonogashira-type coupling reaction. Since both TAs and TAm indicated relatively favorable elimination abilities toward residual palladium species in the reaction mixture, the affinities of TAs and TAm for palladium species were used as supports for palladium catalysts. The TAm-supported palladium catalyst (Pd/TAm) indicated better catalyst properties for the chemoselective hydrogenation compared to those of the corresponding TAs-supported palladium catalyst (Pd/TAs).

Chemoselective Nucleophilic Functionalizations of Aromatic Aldehydes and Acetals via Pyridinium Salt Intermediates.

The development of a novel chemoselective functionalization can diversify the strategy for synthesizing the target molecules. The perfect chemoselectivity between aromatic and aliphatic aldehydes is difficult to achieve by the previous methods. The aromatic aldehyde-selective nucleophilic addition in the presence of aliphatic aldehydes was newly accomplished.

Continuous-Flow Suzuki-Miyaura and Mizoroki-Heck Reactions under Microwave Heating Conditions.

Microwave-assisted continuous-flow reactions have attracted significant interest from synthetic organic chemists, especially process chemists from practical points of view, due to a less complicated shift to large-scale synthesis based on simple and continuous access to products with low energy requirements. In this personal account, we focused on the Suzuki-Miyaura and Mizoroki-Heck reactions, both of which are significantly important cross-coupling reactions for the synthesis of various functional materials. Microwave power is effective for heating.

Stainless Steel-Mediated Hydrogen Generation from Alkanes and Diethyl Ether and Its Application for Arene Reduction.

Hydrogen gas can be generated from simple alkanes (e.g., n-pentane, n-hexane, etc.

New Gateways to the Platinum Group Metal-Catalyzed Direct Deuterium-Labeling Method Utilizing Hydrogen as a Catalyst Activator.

Deuterium-labeled compounds are widely utilized in various scientific fields. We summarize the recent advances in the direct deuteration of sugar, saturated fatty acid, and arene derivatives using heterogeneous platinum group metal on carbon catalysts by our research group. Hydrogen gas is a key catalyst-activator to facilitate the present H-D exchange reactions.

Aromatic aldehyde-selective aldol addition with aldehyde-derived silyl enol ethers.

The aldol reaction using aldehyde-derived silyl enolates as nucleophiles with aromatic aldehydes chemoselectively proceeded in the presence of silyl triflate and 2,2'-bipyridyl to produce β-siloxy aldehydes, while the aliphatic aldehydes were completely recovered. The unprecedented chemoselectivities depend on the reactivities of the pyridinium-type intermediates derived from the aromatic and aliphatic aldehydes.