LiHMDS-Mediated Deprotonative Coupling of Toluenes with Ketones.

We demonstrate that lithium hexamethyldisilazide (LiHMDS) acts as an effective base for deprotonative coupling reactions of toluenes with ketones to afford stilbenes. Various functionalities (halogen, OCF3 , amide, Me, aryl, alkenyl, alkynyl, SMe, and SPh) are allowed on the toluenes. Notably, this system proved successful with low-reactive toluenes bearing a large pKa value compared to that of the conjugate acid of LiHMDS (hexamethyldisilazane, 25.8, THF), as demonstrated by 4-phenyltoluene (38.57, THF) and toluene itself (∼43, DMSO).

Transition-Metal-Free Intermolecular Hydrocarbonation of Styrenes Mediated by NaH/1,10-Phenanthroline.

A transition-metal-free intermolecular coupling reaction of halocompounds with styrenes in the presence of NaH and 1,10-phenanthroline was developed. This reaction afforded hydrocarbonated products with complete anti-Markovnikov selectivity. The method allows the use of a wide range of halocompounds, including aryl and alkyl halides, and good functional group tolerance. Detailed mechanistic studies indicated that an anilide anion generated in situ by the NaH-mediated reduction of 1,10-phenanthroline works as an electron donor and a hydrogen source.

Defluorinative Transformation of (2,2,2-Trifluoroethyl)arenes Catalyzed by the Phosphazene Base t-Bu-P2.

In this study, we demonstrated that 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ5,4λ5-catenadi(phosphazene) (t-Bu-P2) catalyzes the defluorinative functionalization reactions of (2,2,2-trifluoroethyl)arenes with alkanenitriles to produce monofluoroalkene products. The reaction proceeds through HF elimination from a (2,2,2-trifluoroethyl)arene to form a gem-difluorostyrene intermediate, which is followed by nucleophilic addition of an alkanenitrile and elimination of a fluoride anion. The catalysis is compatible with a variety of functional groups.

Copper-Catalyzed Intramolecular Olefinic C(sp2)-H Amidation for the Synthesis of γ-Alkylidene-γ-lactams.

Herein, we report the copper-catalyzed dehydrogenative C(sp2)-N bond formation of 4-pentenamides via nitrogen-centered radicals. This reaction provides a straightforward and efficient preparation method for γ-alkylidene-γ-lactams. Notably, we could controllably synthesize α,ß-unsaturated- or α,ß-saturated-γ-alkylidene-γ-lactams depending on the reaction conditions.

Copper-catalyzed aerobic benzylic C(sp3)-H lactonization of 2-alkylbenzamides via N-centered radicals.

Herein, we describe the copper-catalyzed aerobic C(sp3)-H functionalization of 2-alkylbenzamides for the synthesis of benzolactones. This reaction proceeds via 1,5-hydrogen atom transfer of N-centered radicals directly generated by N-H bond cleavage and does not require the synthesis of pre-functionalized N-centered radical precursors or the use of strong stoichiometric oxidants.

Loss of p57KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

A complete hydatidiform mole (CHM) is androgenetic in origin and characterized by enhanced trophoblastic proliferation and the absence of fetal tissue. In 15 to 20% of cases, CHMs are followed by malignant gestational trophoblastic neoplasms including choriocarcinoma. Aberrant genomic imprinting may be responsible for trophoblast hypertrophy in CHMs, but the detailed mechanisms are still elusive, partly due to the lack of suitable animal or in vitro models. We recently developed a culture system of human trophoblast stem (TS) cells. In this study, we apply this system to CHMs for a better understanding of their molecular pathology. CHM-derived TS cells, designated as TSmole cells, are morphologically similar to biparental TS (TSbip) cells and express TS-specific markers such as GATA3, KRT7, and TFAP2C. Interestingly, TSmole cells have a growth advantage over TSbip cells only after they reach confluence. We found that p57KIP2, a maternally expressed gene encoding a cyclin-dependent kinase inhibitor, is strongly induced by increased cell density in TSbip cells, but not in TSmole cells. Knockout and overexpression studies suggest that loss of p57KIP2 expression would be the major cause of the reduced sensitivity to contact inhibition in CHMs. Our findings shed light on the molecular mechanism underlying the pathogenesis of CHMs and could have broad implications in tumorigenesis beyond CHMs because silencing of p57KIP2 is frequently observed in a variety of human tumors.

Catalytic amide base system generated in situ for 1,3-diene formation from allylbenzenes and carbonyls.

The amide base generated in situ from tetramethylammonium fluoride and N(TMS)3 catalyzes the synthesis of 1,3-diene from an allylbenzene and carbonyl compound. The system is applicable to the transformations of a variety of allylbenzenes with functional groups (halogen, methyl, phenyl, methoxy, dimethylamino, ester, and amide moieties). Acyclic and cyclic diaryl ketones, pivalophenone, pivalaldehyde, and isobutyrophenone are used as coupling partners. The role of transß-methyl stilbenes in product formation is also elucidated.

Copper-Catalyzed Oxidative Benzylic C(sp3 )-H Cyclization for the Synthesis of ß-Lactams.

ß-Lactams are important structural motifs because of their ubiquity in natural products and pharmaceuticals. We report herein a Cu-catalyzed intramolecular oxidative C(sp3 )-H amidation for the synthesis of ß-lactams using tBuOOtBu. This method is based on Kharasch-Sosnovsky amidation and does not require prefunctionalization of C(sp3 )-H bonds or the installation of a directing group, thereby allowing for the straightforward synthesis of ß-lactams. Our intramolecular functionalization protocol can be extended to diverse benzylic C(sp3 )-H bonds and shows excellent functional-group tolerance.

Phosphazene Base tBu-P4 Catalyzed Methoxy-Alkoxy Exchange Reaction on (Hetero)Arenes.

The organic superbase tBu-P4 catalyzes methoxy-alkoxy exchange reactions on (hetero)arenes with alcohols. The catalytic reaction proceeded efficiently with electron-deficient methoxy(hetero)arenes as well as with a variety of alcohols, including 3-amino-1-propanol, ß-citronellol, menthol, and cholesterol. An intramolecular version of this reaction furnished six- and seven-membered ring compounds.

Catalytic Alkynylation of Polyfluoroarenes by Amide Base Generated In Situ.

We herein demonstrate that the amide base generated in situ from CsF and N(TMS)3 catalyzes the deprotonative coupling reactions of terminal alkynes with polyfluoroarenes, wherein mono- and dialkynylations occur efficiently for penta- and hexafluorobenzenes, respectively. Tetraalkynylated products could also be synthesized from dialkynylated compounds.

Direct Carboxylation of Electron-Rich Heteroarenes Promoted by LiO-tBu with CsF and [18]Crown-6.

We herein demonstrate that the combination of LiO-tBu, CsF, and [18]crown-6 efficiently promotes the direct C-H carboxylation of electron-rich heteroarenes (benzothiophene, thiophene, benzofuran, and furan derivatives). A variety of functional groups, including methyl, methoxy, halo, cyano, amide, and keto moieties, are compatible with this system. The reaction proceeds via the formation of a tert-butyl carbonate species.

Deprotonative Coupling of Pyridines with Aldehydes Catalyzed by an HMDS-Amide Base Generated in Situ.

Herein, the deprotonative functionalization of pyridine derivatives with aldehydes under ambient conditions has been demonstrated using an amide base generated in situ from a catalytic amount of CsF and a stoichiometric amount of tris(trimethylsilyl)amine (N(TMS)3). Pyridine substrates bearing two electron-withdrawing substituents (i.e., fluoro, chloro, bromo, and trifluoromethyl moieties) at the 3- and 5-positions efficiently react at the 4-position with various aldehydes including arylaldehydes, pivalaldehyde, and cyclohexanecarboxaldehyde.

Tetramethylammonium Fluoride Tetrahydrate-Mediated Transition Metal-Free Coupling of Aryl Iodides with Unactivated Arenes in Air.

Biaryls are important compounds with widespread applications in many fields. Tetramethylammonium fluoride tetrahydrate was found to promote the biaryl coupling of aryl iodides bearing electron-withdrawing substituents with unactivated arenes. The reaction takes place at temperatures between 100 and 150°C and can be applied to a wide range of aromatic and heteroaromatic rings, affording the products in moderate to high yields. The reaction does not require strong bases or expensive additives that are employed in the existing methods and can be conducted in air and moisture without any precautions.

Super electron donor-mediated reductive transformation of nitrobenzenes: a novel strategy to synthesize azobenzenes and phenazines.

The transformation of nitrobenzenes into azobenzenes by pyridine-derived super electron donor 2 is described. This method provides an efficient synthesis of azobenzenes because of not requiring the use of expensive transition-metals, toxic or flammable reagents, or harsh conditions. Moreover, when using 2-fluoronitrobenzenes as substrates, phenazines were found to be obtained. The process affords a novel synthesis of phenazines.

Generation and Characterization of Anti-phenyl Sulfate Monoclonal Antibodies and a Potential Use for Phenyl Sulfate Analysis in Human Blood.

Patients with chronic kidney disease (CKD) have increased blood levels of phenyl sulfate (PS), a circulating uremic toxin. In this study, we produced anti-PS monoclonal antibodies (mAbs) and characterized their cross-reactivity to structural PS analogs. To induce PS-specific mAbs, we synthesized 4-mercaptophenyl sulfate with a sulfhydryl group at the para-position of PS and conjugated it to carrier proteins via bifunctional linkers. Using these PS conjugates as immunogens and as antigens for enzyme-linked immunosorbent assay (ELISA) screening, we produced by a hybridoma method two novel mAbs (YK33.1 and YKS19.2) that react with PS conjugates independent of carrier and linker structures. Although all of the PS analogs tested, with the exception of indoxyl sulfate, were cross-reactive to both mAbs in phosphate buffered saline (PBS), PS specificity for YKS19.2 was enhanced in human plasma and serum. YKS19.2 mAb was cross-reactive only with o-cresyl sulfate, which is absent in human blood. PS sensitivity for YKS19.2 mAb increased to an IC50 of 10.4 µg/mL when 0.1% Tween 20 was added in a primary competitive reaction. To explore potential clinical applications, we determined concentrations of PS in serum samples from 19 CKD patients by inhibition ELISA using YKS19.2 mAb and compared them to those found using an LC-MS/MS method. A good correlation was observed between each value (R2=0.825). Therefore, the unique antigen specificity of YKS19.2 mAb could be useful for prescreening of patients with accumulated PS or for comprehensive analysis of uremic toxins that have a PS-like structure.

Deprotonative Silylation of Aromatic C-H Bonds Mediated by a Combination of Trifluoromethyltrialkylsilane and Fluoride.

A method for the deprotonative silylation of aromatic C-H bonds has been developed using trifluoromethyltrimethylsilane (CF3SiMe3, Ruppert-Prakash reagent) and a catalytic amount of fluoride. In this reaction, CF3SiMe3 is considered to act as a base and a silicon electrophile. This process is highly tolerant to various functional groups on heteroarenes and benzenes. Furthermore, this method can be applied to the synthesis of trimethylsilyl group-containing analogs of TAC-101, which is a bioactive synthetic retinoid with selective affinity for retinoic acid receptor α (RAR-α) binding. We also report further transformations of the silylated products into useful derivatives.

Palladium-Catalyzed Borylative Cyclizations of α-(2-Bromoaryl) Ketones to Form 1,2-Benzoxaborinines.

Herein, we report that palladium catalyzes the borylative cyclization of α-(2-bromoaryl) ketones to afford 1,2-benzoxaborinines. The developed system is compatible with a variety of functionalities (Me, t-Bu, OMe, NMe2, F, Cl, CN, CF3, CO2Me, and heteroaryl groups) and is applicable to the synthesis of B-O-containing tri- and tetracyclic fused-ring compounds.

Combined Brønsted Base-Promoted CO2 Fixation into Benzylic C-H Bonds of Alkylarenes.

Interest in developing methods for direct CO2 fixation into readily available unfunctionalized C-H bonds in organic substances has recently surged. In contrast to the well-studied carboxylations of alkynyl C(sp)-H and aromatic C(sp2)-H bonds, carboxylation of benzylic C(sp3)-H bonds to produce 2-arylacetic acids is limited to photoirradiation reactions and continues to be a challenging issue because of the low chemical reactivity. We herein describe that a combined Brønsted base (i.e., LiO-t-Bu/CsF and LiOCEt3/CsF) achieves benzylic carboxylation of electron-deficient, -neutral, and -rich alkylarenes and enables various functionalities, including fragile ones such as bromide, alkene, alkyne, and carbonyl moieties. Dicarboxylation at the benzylic position is also established. Cs-alkoxide generated in situ acts as a reactive base, as demonstrated in experiments with independently prepared CsO-t-Bu and by 133Cs nuclear magnetic resonance studies.

Direct C-H Carboxylation Forming Polyfunctionalized Aromatic Carboxylic Acids by Combined Brønsted Bases.

CO2 fixation into electron-deficient aromatic C-H bonds proceeds with the combined Brønsted bases LiO-t-Bu and LiO-t-Am/CsF/18-crown-6 (t-Am = CEtMe2) under a CO2 atmosphere to afford a variety of polyfunctionalized aromatic carboxylic acids.

Antioxidant action of persulfides and polysulfides against free radical-mediated lipid peroxidation.

Hydrogen sulfide, hydropersulfides, and hydropolysulfides have been revealed to play important physiological roles such as cell signaling and protection against oxidative stress, but the underlying mechanisms and dynamics of action remain elusive. It is generally accepted that these species act by two-electron redox mechanisms, while the involvement of one-electron redox chemistry has received less attention. In this study, the radical-scavenging activity of hydrogen persulfide, hydrogen polysulfides (HSnH n = 2-4), and diallyl- or dialkyl-sulfides (RSnR, n = 1-4) was measured. Furthermore, their antioxidant effects against free radical-mediated human plasma lipid peroxidation were assessed by measuring lipid hydroperoxides. It was found that disodium disulfide, trisulfide, and tetrasulfide acted as potent peroxyl radical scavengers, the rate constant for scavenging peroxyl radical being 3.5 × 105, 4.0 × 105, and 6.0 × 105 M-1 s-1 in PBS pH 7.4 at 37 °C respectively and that they inhibited plasma lipid peroxidation efficiently, the efficacy is increased with the catenation number. Disodium tetrasulfide was 1.5 times as reactive as Trolox toward peroxyl radical and inhibited plasma lipid peroxidation more efficiently than ascorbate and Trolox. On the other hand, diallyl- and dialkyl-sulfides did not exert significant radical-scavenging activity, nor did they inhibit lipid peroxidation efficiently, except for diallyl tetrasulfide, which suppressed plasma lipid peroxidation, despite less significantly than disodium tetrasulfide. Collectively, this study shows that hydrogen persulfide and hydrogen polysulfides act as potent radical-scavenging antioxidants and that, in addition to two-electron redox mechanisms, one electron redox reaction may also play important role in the in vivo defense against deleterious oxidative stress.