Palladium(0)-Catalyzed Anti-Selective Addition-Cyclizations of Alkynyl Electrophiles.

Invited for the cover of this issue is the group of Hirokazu Tsukamoto at Tohoku University (current affiliation: Yokohama University of Pharmacy). The image depicts anti-selective arylative cyclization reactions of alkynyl aldehydes with arylboronic acids under palladium catalysis in methanol to afford endo- and exo-cyclic products. Read the full text of the article at 10.1002/chem.202203068.

Palladium(0)-Catalyzed Anti-Selective Addition-Cyclizations of Alkynyl Electrophiles.

Palladium(0)/monophosphine complexes catalyze anti-selective alkylative, arylative, and alkynylative cyclizations of alkynyl electrophiles with organometallic reagents. The remarkable anti-selectivity results from novel oxidative addition, that is, the nucleophilic attack of electron-rich palladium(0) on the electrophile across the alkyne followed by transmetalation and reductive elimination ("anti-Wacker"-type cyclization). With regard to 5-alkynals, triphenylphosphine (PPh3 )-ligated palladium(0) catalyzes the cyclization of terminal alkynes and conjugated alkenyl- or alkynyl-substituted ones to afford 2-cyclohexen-1-ol and 2-alkylidene-cyclopentanol derivatives, respectively. For 6-alkyl- or 6-aryl-5-alkynals, the cyclization does not proceed with the palladium/PPh3 catalyst; however, it does proceed with palladium/tricyclohexylphosphine (PCy3 ), to yield the former products predominantly. Remarkably, the latter catalyst completely switches the regioselectivity in the cyclization of the conjugated diyne-aldehydes. Notably, palladium/PPh3 -catalyzed cyclizations also proceed with other organometallics or even without them.

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.

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).

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.

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.

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.

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.

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.

Structure Determination of an Ag(I) -Mediated Cytosine-Cytosine Base Pair within DNA Duplex in Solution with (1) H/(15) N/(109) Ag NMR Spectroscopy.

The structure of an Ag(I) -mediated cytosine-cytosine base pair, C-Ag(I) -C, was determined with NMR spectroscopy in solution. The observation of 1-bond (15) N-(109) Ag J-coupling ((1) J((15) N,(109) Ag): 83 and 84 Hz) recorded within the C-Ag(I) -C base pair evidenced the N3-Ag(I) -N3 linkage in C-Ag(I) -C. The triplet resonances of the N4 atoms in C-Ag(I) -C demonstrated that each exocyclic N4 atom exists as an amino group (-NH2 ), and any isomerization and/or N4-Ag(I) bonding can be excluded. The 3D structure of Ag(I) -DNA complex determined with NOEs was classified as a B-form conformation with a notable propeller twist of C-Ag(I) -C (-18.3±3.0°). The (109) Ag NMR chemical shift of C-Ag(I) -C was recorded for cytidine/Ag(I) complex (δ((109) Ag): 442 ppm) to completed full NMR characterization of the metal linkage. The structural interpretation of NMR data with quantum mechanical calculations corroborated the structure of the C-Ag(I) -C base pair.

The structure of metallo-DNA with consecutive thymine-HgII-thymine base pairs explains positive entropy for the metallo base pair formation.

We have determined the three-dimensional (3D) structure of DNA duplex that includes tandem Hg(II)-mediated T-T base pairs (thymine-Hg(II)-thymine, T-Hg(II)-T) with NMR spectroscopy in solution. This is the first 3D structure of metallo-DNA (covalently metallated DNA) composed exclusively of 'NATURAL' bases. The T-Hg(II)-T base pairs whose chemical structure was determined with the (15)N NMR spectroscopy were well accommodated in a B-form double helix, mimicking normal Watson-Crick base pairs. The Hg atoms aligned along DNA helical axis were shielded from the bulk water. The complete dehydration of Hg atoms inside DNA explained the positive reaction entropy (ΔS) for the T-Hg(II)-T base pair formation. The positive ΔS value arises owing to the Hg(II) dehydration, which was approved with the 3D structure. The 3D structure explained extraordinary affinity of thymine towards Hg(II) and revealed arrangement of T-Hg(II)-T base pairs in metallo-DNA.

Raman spectroscopic detection of the T-Hg II-T base pair and the ionic characteristics of mercury.

Developing applications for metal-mediated base pairs (metallo-base-pair) has recently become a high-priority area in nucleic acid research, and physicochemical analyses are important for designing and fine-tuning molecular devices using metallo-base-pairs. In this study, we characterized the Hg(II)-mediated T-T (T-Hg(II)-T) base pair by Raman spectroscopy, which revealed the unique physical and chemical properties of Hg(II). A characteristic Raman marker band at 1586 cm(-1) was observed and assigned to the C4=O4 stretching mode. We confirmed the assignment by the isotopic shift ((18)O-labeling at O4) and density functional theory (DFT) calculations. The unusually low wavenumber of the C4=O4 stretching suggested that the bond order of the C4=O4 bond reduced from its canonical value. This reduction of the bond order can be explained if the enolate-like structure (N3=C4-O4(-)) is involved as a resonance contributor in the thymine ring of the T-Hg(II)-T pair. This resonance includes the N-Hg(II)-bonded state (Hg(II)-N3-C4=O4) and the N-Hg(II)-dissociated state (Hg(II+) N3=C4-O4(-)), and the latter contributor reduced the bond order of N-Hg(II). Consequently, the Hg(II) nucleus in the T-Hg(II)-T pair exhibited a cationic character. Natural bond orbital (NBO) analysis supports the interpretations of the Raman experiments.