Selective C-N Bond Cleavage in Unstrained Pyrrolidines Enabled by Lewis Acid and Photoredox Catalysis.

Cleavage of inert C-N bonds in unstrained azacycles such as pyrrolidine remains a formidable challenge in synthetic chemistry. To address this, we introduce an effective strategy for the reductive cleavage of the C-N bond in N-benzoyl pyrrolidine, leveraging a combination of Lewis acid and photoredox catalysis. This method involves single-electron transfer to the amide, followed by site-selective cleavage at the C2-N bond. Cyclic voltammetry and NMR studies demonstrated that the Lewis acid is crucial for promoting the single-electron transfer from the photoredox catalyst to the amide carbonyl group. This protocol is widely applicable to various pyrrolidine-containing molecules and enables inert C-N bond cleavage including C-C bond formation via intermolecular radical addition. Furthermore, the current protocol successfully converts pyrrolidines to aziridines, γ-lactones, and tetrahydrofurans, showcasing its potential of the inert C-N bond cleavage for expanding synthetic strategies.

2H-Thiazolo[4,5-d][1,2,3]triazole: synthesis, functionalization, and application in scaffold-hopping.

This manuscript unveils the synthesis of 2H-thiazolo[4,5-d][1,2,3]triazole (ThTz), an unprecedented [5-5]-fused heteroaromatic system, and established a scalable synthetic procedure for producing large quantities of the ThTz ring bearing a sulfone group on the thiazole ring. The sulfone moiety proves to be a versatile reactive tag, facilitating diverse transformations such as SNAr reactions, metal-catalyzed couplings, and radical-based alkylations. Furthermore, functionalization of the triazole ring highlights the potential of this newly developed heteroaromatic compound as a valuable heteroaryl building block, promoting scaffold hopping strategies in medicinal chemistry.

Divergent Transformations of Aromatic Esters: Decarbonylative Coupling, Ester Dance, Aryl Exchange, and Deoxygenative Coupling.

ConspectusAromatic esters are cost-effective, versatile, and commonly used scaffolds that are readily synthesized or encountered as synthetic intermediates. While most conventional reactions involving these esters are nucleophilic acyl substitutions or 1,2-nucleophilic additions─where a nucleophile attacks the carbonyl group, decarbonylative transformations offer an alternative pathway by using the carbonyl group as a leaving group. This transition-metal-catalyzed process typically begins with oxidative addition of the C(acyl)-O bond to the metal. Subsequently, the reaction involves the migration of CO to the metal center, the reaction with a nucleophile, and reductive elimination to yield the final product. Pioneering work by Yamamoto on nickel complexes and the development of decarbonylative reactions (such as Mizoroki-Heck-type olefination) using aromatic carboxylic anhydrides catalyzed by palladium were conducted by de Vries and Stephan. Furthermore, reports have surfaced of decarbonylative hydrogenation of pyridyl methyl esters by Murai using ruthenium catalysts as well as Mizoroki-Heck-type reactions of nitro phenyl esters by Gooßen under palladium catalysis. Our group has been at the forefront of developing decarbonylative C-H arylations of phenyl esters with 1,3-azoles and aryl boronic acids using nickel catalysts. The key to this reaction is the use of phenyl esters, which are easy to synthesize, stabilize, and handle, allowing oxidative addition of the C(acyl)-O bond; nickel, which facilitates oxidative addition of the C(acyl)-O bond; and suitable bidentate phosphine ligands that can stabilize the intermediate. By modification of the nucleophiles, esters have been effectively utilized as electrophiles in cross-coupling reactions, encouraging the development of these nucleophiles among researchers. This Account summarizes our advancements in nucleophile development for decarbonylative coupling reactions, particularly highlighting the utilization of aromatic esters in diverse reactions such as alkenylation, intramolecular etherification, α-arylation of ketones, C-H arylation, methylation, and intramolecular C-H arylation for dibenzofuran synthesis, along with cyanation and reductive coupling. We also delve into reaction types that are distinct from typical decarbonylative reactions, including ester dance reactions, aromatic ring exchanges, and deoxygenative transformations, by focusing on the oxidative addition of the C(acyl)-O bond of the aromatic esters to the metal complex. For example, the ester dance reaction is hypothesized to undergo 1,2-translocation starting with oxidative addition to a palladium complex, leading to a sequence of ortho-deprotonation/decarbonylation, followed by protonation, carbonylation, and reductive elimination. The aromatic exchange reaction likely involves oxidative addition of complexes of different aryl electrophiles with a nickel complex. In deoxygenative coupling, an oxidative addition complex with palladium engages with a nucleophile, forming an acyl intermediate that undergoes reductive elimination in the presence of an appropriate reducing agent. These methodologies are poised to captivate the interest of synthetic chemists by offering unconventional and emerging approaches for transforming aromatic esters. Moreover, we demonstrated the potential to transform readily available basic chemicals into new compounds through organic synthesis.

Deoxygenative Hetero- and Carbofunctionalizations of Diarylketones.

Direct transformations of diarylketones to hetero- and carbofunctionalized diarylmethanes have been developed. The reactions involve a phospha-Brook rearrangement of diphenylphosphine oxide with diarylketones, followed by substitutions with various nucleophiles such as amides, amines, phenols, thiols, and diborylmethane under palladium catalysis to afford the corresponding functionalized diarylmethanes in a reductive manner.

Palladium-Catalyzed Denitrative Synthesis of Aryl Nitriles from Nitroarenes and Organocyanides.

A denitrative cyanation of nitroarenes using organocyanides and a palladium catalyst was developed. The key for this reaction was the utilization of an aminoacetonitrile as a cyano source to avoid the generation of stoichiometric metal- and halogen-containing chemical waste. A wide range of nitroarenes, including heteroarenes and pharmaceutical molecules, can be converted into aryl nitriles.

A Small-Molecule Modulator Affecting the Clock-Associated PSEUDO-RESPONSE REGULATOR 7 Amount.

Circadian clocks are biological timekeeping systems that coordinate genetic, metabolic and physiological behaviors with the external day-night cycle. The clock in plants relies on the transcriptional-translational feedback loops transcription-translation feedback loop (TTFL), consisting of transcription factors including PSUEDO-RESPONSE REGULATOR (PRR) proteins, plant lineage-specific transcriptional repressors. Here, we report that a novel synthetic small-molecule modulator, 5-(3,4-dichlorophenyl)-1-phenyl-1,7-dihydro-4H-pyrazolo[3,4-d] pyrimidine-4,6(5H)-dione (TU-892), affects the PRR7 protein amount. A clock reporter line of Arabidopsis was screened against the 10,000 small molecules in the Maybridge Hitfinder 10K chemical library. This screening identified TU-892 as a period-lengthening molecule. Gene expression analyses showed that TU-892 treatment upregulates CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) mRNA expression. TU-892 treatment reduced the amount of PRR7 protein, a transcriptional repressor of CCA1. Other PRR proteins including TIMING OF CAB EXPRESSION 1 were altered less by TU-892 treatment. TU-892-dependent CCA1 upregulation was attenuated in mutants impaired in PRR7. Collectively, TU-892 is a novel type of clock modulator that reduces the levels of PRR7 protein.

Concise Synthesis of (±)-Fortuneicyclidins and (±)-Cephalotine B Enabled by Pd-Catalyzed Dearomative Spirocyclization.

Total syntheses of C11-oxygenated Cephalotaxus alkaloids, fortuneicyclidins A and B, and cephalotine B, were achieved. The key for the synthesis is a Pd-catalyzed dearomative spirocyclization of bromofurans with N-tosylhydrazones, followed by acid-mediated tandem transformation to construct the tetracyclic skeleton with the C11-oxygen functional group. Chemo-selective and catalytic functional group conversions of the tetracyclic intermediate completed the synthesis of fortuneicyclidins and cephalotine B in 8 and 9 steps, respectively.

Chloroacetyl boronate N-tosylhydrazone as a versatile synthetic building block.

Chloroacetyl boronate N-tosylhydrazone (CABT) has been synthesized as a reagent to generate a diverse range of molecular skeletons. CABT can undergo a series of transformations involving nucleophilic substitution of the chloride and coupling of the N-tosylhydrazones, followed by boryl group functionalization. We further demonstrated that this CABT reagent could enable a diversity-oriented synthesis.

Ring-Opening Fluorination of Carbo/Heterocycles and Aromatics: Construction of Complex and Diverse Fluorine-Containing Molecules.

Fluorine-containing molecules have attracted much attention in medicinal, agrochemical, and materials sciences because they offer unique physical and biological properties. Therefore, many efficient fluorination reactions have been developed over the years. Recent advancements in fluorination chemistry have expanded the range of substrates, and regioselectivity/stereoselectivity control has also been achieved. Ring-opening fluorination is an efficient method to construct complex fluorine-containing molecules with diversity, starting from simple cyclic compounds. This review aims to summarize developments in ring-opening fluorination, particularly with larger-sized cyclic compounds. Fluorine introduction and bond cleavage of cyclic compounds such as carbocycles, heterocycles, and aromatics provide efficient access to fluorine-containing compounds that are difficult to be synthesized by conventional methods.

Unified synthesis of multiply arylated alkanes by catalytic deoxygenative transformation of diarylketones.

A deoxygenative transformation of diarylketones leading to multiply arylated alkanes was developed. Diarylketones were reacted with diphenylphosphine oxide resulting in a phospha-Brook rearrangement, followed by palladium-catalyzed cross-couplings or a Friedel-Crafts type alkylation to afford the corresponding multiply arylated alkanes. A variety of diarylketones can be converted to multiply arylated alkanes such as diarylmethanes, tetraarylethanes, and triarylmethanes by reduction, dimerization, and arylation in one pot. Furthermore, a one-pot conversion from arylcarboxylic acids to diarylmethanes and tetraarylethanes, and a synthesis of tetraarylmethane and triphenylethane using sequential coupling reactions are also presented.

Aryl Dance Reaction of Arylbenzoheteroles.

We report a 1,2-migration (aryl dance reaction) of the aryl group on heteroles. AlCl3 can efficiently convert C3-arylheteroles to C2-arylheteroles. Depending on the electron density of the substrate, conversion from C2- to C3-arylheteroles was also possible with catalytic Zn(OTf)2. A one-pot aryl dance/acylation or bromination and arylation/aryl dance cascade was also demonstrated.

Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease.

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases.

Structure-Function Study of a Novel Inhibitor of Cyclin-Dependent Kinase C in Arabidopsis.

The circadian clock, an internal time-keeping system with a period of about 24 h, coordinates many physiological processes with the day-night cycle. We previously demonstrated that BML-259 [N-(5-isopropyl-2-thiazolyl) phenylacetamide], a small molecule with mammal CYCLIN DEPENDENT KINASE 5 (CDK5)/CDK2 inhibition activity, lengthens Arabidopsis thaliana (Arabidopsis) circadian clock periods. BML-259 inhibits Arabidopsis CDKC kinase, which phosphorylates RNA polymerase II in the general transcriptional machinery. To accelerate our understanding of the inhibitory mechanism of BML-259 on CDKC, we performed structure-function studies of BML-259 using circadian period-lengthening activity as an estimation of CDKC inhibitor activity in vivo. The presence of a thiazole ring is essential for period-lengthening activity, whereas acetamide, isopropyl and phenyl groups can be modified without effect. BML-259 analog TT-539, a known mammal CDK5 inhibitor, did not lengthen the period nor did it inhibit Pol II phosphorylation. TT-361, an analog having a thiophenyl ring instead of a phenyl ring, possesses stronger period-lengthening activity and CDKC;2 inhibitory activity than BML-259. In silico ensemble docking calculations using Arabidopsis CDKC;2 obtained by a homology modeling indicated that the different binding conformations between these molecules and CDKC;2 explain the divergent activities of TT539 and TT361.

Synthesis and Properties of Pyridine-Fused Triazolylidene-Palladium: Catalyst for Cross-Coupling Using Chloroarenes and Nitroarenes.

The synthesis and catalytic activity of pyridine-fused triazolylidene as a novel abnormal N-heterocyclic carbene (aNHC) ligand is described. The evaluation of physical properties using X-ray crystallographic analysis and infrared spectroscopy revealed that these triazolylidenes have a high electron-donating ability toward the metal center. The application of this triazolylidene to the palladium-catalyzed cross-coupling of chloroarenes and nitroarenes with arylboronic acids showcased its ability to activate C-Cl and C-NO2 bonds.

Chemical biology to dissect molecular mechanisms underlying plant circadian clocks.

Circadian clocks regulate the diel rhythmic physiological activities of plants, enabling them to anticipate and adapt to day-night and seasonal changes. Genetic and biochemical approaches have suggested that transcription-translation feedback loops (TTFL) are crucial for Arabidopsis clock function. Recently, the study of chemical chronobiology has emerged as a discipline within the circadian clock field, with important and complementary discoveries from both plant and animal research. In this review, we introduce recent advances in chemical biology using small molecules to perturb plant circadian clock function through TTFL components. Studies using small molecule clock modulators have been instrumental for revealing the role of post-translational modification in the clock, or the metabolite-dependent clock input pathway, as well as for controlling clock-dependent flowering time.

Pd-Catalyzed 1,4-Carboamination of Bicyclic Bromoarenes with Diazo Compounds and Amines.

A palladium-catalyzed 1,4-carboamination of bromoarenes with diazo compounds and amines was developed. This reaction proceeds through a palladium-carbene that then generates a π-benzylpalladium intermediate, forming ipso C-C and para C-N bonds on bromoarenes in a regioselective manner. The successful application of this transformation to the rapid synthesis of an antitumor agent demonstrates its synthetic utility.

Palladium-Catalyzed Tandem Ester Dance/Decarbonylative Coupling Reactions.

"Dance reaction" on the aromatic ring is a powerful method in organic chemistry to translocate functional groups on arene scaffolds. Notably, dance reactions of halides and pseudohalides offer a unique platform for the divergent synthesis of substituted (hetero)aromatic compounds when combined with transition-metal-catalyzed coupling reactions. Herein, we report a tandem reaction of ester dance and decarbonylative coupling enabled by palladium catalysis. In this reaction, 1,2-translocation of the ester moiety on the aromatic ring is followed by decarbonylative coupling with nucleophiles to enable the installation of a variety of nucleophiles at the position adjacent to the ester in the starting material.

Ring-Opening Fluorination of Isoxazoles.

A ring-opening fluorination of isoxazoles has been developed. Upon treatment of isoxazoles with an electrophilic fluorinating agent (Selectfluor), fluorination followed by deprotonation leads to tertiary fluorinated carbonyl compounds. This method features mild reaction conditions, good functional group tolerance, and a simple experimental procedure. Diverse transformations of the resulting α-fluorocyanoketones were also demonstrated, furnishing a variety of fluorinated compounds.

Pd-Catalyzed Asymmetric Dearomative Arylation of Indoles via a Desymmetrization Strategy.

Pd-catalyzed asymmetric dearomative arylation of C3-substituted indoles is realized via a desymmetrization strategy. A BINOL-derived chiral phosphoramidite ligand is found to be highly efficient for the stereoselective control in this reaction. This method provides a convenient synthesis of spiroindolenines bearing two stereogenic centers in good yields (up to 98%) with excellent diastereo- and enantioselectivities (up to >20:1 dr and 97% ee), which could also be applied in asymmetric dearomative arylation of the simple C3-tethered indoles.

Ring-opening fluorination of bicyclic azaarenes.

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon-fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.