Divergent Synthesis Research Articles

Divergent Regioselective Synthesis of Functionalized 1,2,3-1H-Triazoles from Nitriles and Arylazides Under Metal-Free and/or Solvent-Free Conditions.

Highly selective and divergent syntheses, which are crucial in both organic synthesis and medicinal chemistry, involve significant advancements in compound accessibility. By modifying α-cyano esters into α-cyano ketones, the synthesis pathway broadens to include a diverse range of 4-CN, 5-amino, and 5-arylamino derivatives of 1,2,3-triazoles, which are achieved notably through the Dimroth rearrangement. This versatility extends further with the potential for a triple cascade reaction, leading to the production of carboximidamide compounds, which are facilitated by the Cornforth rearrangement. Advancements in compound accessibility not only expand the repertoire of synthesized molecules but also open new avenues for potential pharmacological agents. Building on these findings, we have developed an innovative and efficient method for the divergent synthesis of functionalized 1,2,3-triazoles. This method strategically utilizes α-cyanocarbonyls and arylazides by harnessing their reactivity and compatibility to orchestrate a variety of molecular transformations. By optimizing these substrates, our goal is to simplify synthetic routes, improve product yields, and accelerate the discovery and development of new chemical entities with promising biological activities.

Reductive Amination of Carbonyl C-C Bonds Enables Formal Nitrogen Insertion.

Given its relevance across numerous fields, reductive amination is one of the oldest and most widely used methods for amine synthesis. As a cornerstone of synthetic chemistry, it has largely remained unchanged since its discovery over a century ago. Herein, we report the mechanistically driven development of a complementary reaction, which reductively aminates the C-C σ-bond of carbonyls, not the carbonyl C-O π-bond, generating value-added linear and cyclic 3° amines in a modular fashion. Critical to our success were mechanistic insights that enabled us to modulate the resting state of a borane catalyst, minimize deleterious disproportionation of a hydroxylamine nitrogen source, and control the migratory selectivity of a key nitrenoid reactive intermediate. Experiments support the reaction occurring through a reductive amination/reductive Stieglitz cascade, via a ketonitrone, which can be interrupted under catalyst control to generate valuable N,N-disubstituted hydroxylamines. The method reported herein enables net transformations that would otherwise require lengthy synthetic sequences using pre-existing technologies. This is highlighted by its application to a two-step protocol for the valorization of hydrocarbon feedstocks, the late-stage C-C amination of complex molecules, diversity-oriented synthesis of isomeric amines from a single precursor, and transposition of nitrogen to different positions within a heterocycle.

Copper-Catalyzed Radical Sulfonylation: Divergent Construction of C(sp3)-Sulfonyl Bonds with Sulfonylhydrazones.

Sulfonylhydrazones have been proven to be versatile synthetic intermediates in a panel of transformations. However, radical sulfonylation with sulfonylhydrazone as sulfonyl radical source is relatively rare. Here, we found that sulfonylhydrazone can serve as a new sulfonyl radical precursor to couple various partners such as arylacetic acids, ene-yne-ketones, and para-quinone methides under copper catalysis and microwave irradiation. The reactions of sulfonyl radicals have been successively developed to enable the divergent synthesis of C(sp3)-sulfonyl bonds. In addition, when alkynes and alkenes are used as radical receptors, this method can also promote the formation of C(sp2)-sulfonyl bonds. This finding suggests that sulfonylhydrazone could be regarded as a potentially useful sulfonyl radical in sulfone synthesis.

One-Pot Divergent Synthesis of a 13-Ring Triquinone and its Facile Conversion to a [4.4.4]Tridecastarphene.

Acenes are notable for their optoelectronic properties and applications in organic electronics. Starphenes are structurally related molecules possessing three acene arms that radiate linearly from a central benzene ring (i. e., linearly annellated triphenylenes). Large starphenes have been prepared using convergent syntheses involving transition metal catalyzed cyclotrimerizations of either preformed acenes or arynes. Here, we report a one-pot divergent synthesis of a 13-ring triquinone that is readily converted to a [4.4.4]tridecastarphene derivative. The one-pot procedure involves the sequential reactions of three 1,4-anthraquinones with o-quinodimethane derivatives that are generated sequentially from a stable, trisulfone precursor. The resulting [4.4.4]tridecastarphene derivative bearing p-(t-butyl)phenyl substituents was characterized by 1H NMR, 13C NMR and UV-vis spectroscopies, as well as mass spectrometry, cyclic voltammetry and differential pulse voltammetry. Theoretical and experimental studies reveal a relatively high-lying HOMO orbital (about -4.70 to -4.86 eV) and a relatively small HOMO-LUMO gap (2.1 eV), suggesting utility as a p-type organic semiconductor. Our [4.4.4]tridecastarphene derivative photooxidizes in a CH2Cl2 solution exposed to ambient light and air with a half-life of 150 minutes at room temperature, but shows no sign of degradation after 12 months in the solid-state. Our [4.4.4]tridecastarphene derivative also shows excellent solubility in a number of organic solvents including dichloromethane, chloroform and toluene, potentially enabling printed electronic applications.

Divergent Synthesis of (CF3)‐Indazolo[3,2‐a]Isoquinolines with Potent Photophysical Property and Anticancer Activity from 3‐Aryl‐1H‐Indazoles and Sulfoxonium Ylides

AbstractTransition‐metal‐catalyzed inert C−H bond functionalization using sulfoxonium ylides as metal carbene surrogates to replace the explosive and labile diazo compounds is synthetically attractive. Presented herein is a divergent synthesis of (CF3)‐indazolo[3,2‐a]isoquinoline derivatives based on C−H bond activation‐initiated cascade reactions of 3‐aryl‐1H‐indazoles with sulfoxonium ylides. The formation of products involves Rh(III)‐catalyzed C(sp2)−H bond metalation, carbene formation, migratory insertion, proto‐demetalation and intramolecular condensation. In general, this newly developed protocol features simple substrates, structurally diverse products, step‐economy and scalability. In addition, evaluation of the photophysical properties and anti‐proliferative activity against three human cancer cell lines of the products thus obtained showed that some of them possess potent anticancer activity with potential self‐tracking capability through fluorescence detection.

Catalyst-Controlled Switchable Formal Retro-Büchner reaction for the Divergent Synthesis of Benzo[b]azepines and 1, 3-Conjugated Dienes

Catalyst-Controlled Switchable Formal Retro-Büchner reaction for the Divergent Synthesis of Benzo[b]azepines and 1, 3-Conjugated Dienes

Revisiting Pyrimidine-Embedded Molecular Frameworks to Probe the Unexplored Chemical Space for Protein-Protein Interactions.

ConspectusProtein-protein interactions (PPIs) are essential in numerous biological processes and diseases, making them attractive yet challenging drug targets. While many advances have been made in traditional drug discovery, targeting PPIs has been difficult due to a lack of specialized chemical libraries designed to modulate these interactions. Current libraries mainly focus on conventional target proteins like enzymes or receptors as substrate analogs rather than small-molecule modulators targeting PPIs. These traditional drug targets behave differently from PPIs. Conventional druggable targets have relatively small surfaces and binding pockets that have allowed them to be targeted with current libraries, but PPIs behave differently than these traditional drug targets. As a result, there is an urgent need for an innovative approach to expand the druggable space.To address this, we developed a privileged substructure-based diversity-oriented synthesis (pDOS) strategy, aimed at creating maximal skeletal diversity to explore broader biochemical space. Pyrimidine serves as the privileged substructure in our approach, which employs several strategies: (i) silver-catalyzed or iodine-mediated tandem cyclizations to generate pyrimidine-embedded polyheterocycles; (ii) diverse pairing strategies to produce pyrimidodiazepine-containing polyheterocyclic skeletons with enhanced scaffold saturation; (iii) skeletal transformation to develop pyrimidine-fused medium-sized azacycles via chemoselective cleavages or migrations of N-N or C-N bond; (iv) design of small-molecule peptidomimetics that systematically mimic three pivotal protein secondary structures using pyrimidodiazepine-based scaffolds; and (v) identification of pyrimidodiazepine-based small-molecules that allosterically inhibits the interaction between human ACE2 and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to block viral entry into host cells.Through these approaches, we generated 39 distinct pyrimidine-embedded frameworks, demonstrating significant molecular diversity validated by chemoinformatic analyses such as Tanimoto similarity and principal moment of inertia (PMI) analysis. This molecular diversity extends pyrimidine structures beyond traditional linear or bicyclic forms, creating polyheterocycles with enhanced 3D structural diversity. These novel frameworks overcome the limitation of simpler privileged scaffolds, offering promising tools for modulating PPIs.Our pDOS approach highlights how privileged structure-embedded polyheterocycles, particularly those based on pyrimidine, can effectively target previously undruggable PPIs. This strategy provides a new direction for drug discovery, allowing for the development of small molecules that operate beyond traditional drug-like rules. In addition to expanding the chemical space for PPI modulation, our pDOS strategy enables the creation of scaffolds that are particularly suited for targeting complex and dynamic protein interfaces. This innovation could significantly impact therapeutic development, offering solutions for previously intractable drug targets. By expanding the scope of pyrimidine-based scaffolds, we have opened up new possibilities for targeting PPIs and advancing chemical biology.This perspective demonstrates the potential outlines of our pDOS strategy in creating structurally diverse frameworks, offering a platform for the discovery of PPI modulators and facilitating the exploration of untapped biochemical spaces in drug development, potentially transforming the way we approach these complex biological interactions.

Solvent-Controlled Divergent Cyclization of 3-Ylideneoxindoles with Ethyl 2-Diazoacetate: Access to Spirocyclopropyl and Spiropyrazolines Oxindoles.

Herein a catalyst-free solvent-controlled method for the divergent synthesis of spirocyclopropyl and spiropyrazoline oxindoles from 3-ylideneoxindoles and ethyl diazoacetate was developed. With ClCH2CH2Cl as the solvent, spirocyclopropyl oxindoles were obtained in moderate to excellent yields, whereas the use of MeOH as solvent afforded spiropyrazoline oxindoles in moderate to good yields. The readily available substrates, simple operation and various product transformations further highlighted the utility of this method.

Divergent Total Synthesis of Isoflavone Natural Products and Their Potential as Therapeutic Agents for TTR Amyloidosis.

We have achieved the divergent total synthesis of nine isoflavone natural products 1-9 starting from commercially available 2,4,6-trihydroxyacetophenone as a starting material. The isoflavone skeleton of 1-9 was constructed by the Suzuki-Miyaura coupling reaction as the key reaction. Investigation of the potential of 1-9 as therapeutic agents for transthyretin (TTR) amyloidosis revealed that millexatin F (3) showed the best efficacy in ex vivo competitive binding experiments and thioflavin-T fluorescence studies. Therefore, millexatin F (3) is promising as a seed compound for a novel TTR amyloidosis therapeutic agent.

Divergent Synthesis of Enynals and Dihydrobenzo[f]isoquinolines via Deoxyalkynylation of Enaminones Enabled by the Cooperative Action of Tf2O/Pd/Cu.

A variety of enynals and dihydrobenzo[f]isoquinolines were effectively synthesized with favorable functional group compatibility via deoxyalkynylation of enaminones enabled by the cooperative action of Tf2O/Pd/Cu. The reaction system demonstrated the ability to be expanded to the deoxyarylation/deoxyaryloxylation of enaminones with arylboronic acids or phenols, facilitating the efficient formation of C-C/C-O bonds and showcasing the practicality and versatility of the methodology.

Divergent Synthesis of Benzo[4,5]imidazo[2,1-b][1,3]thiazines and α-Trifluoromethyl-β-arylthio Tertiary Alcohols from 2-Mercaptobenzimidazoles and α-CF3 Alkenes.

An efficient and metal-free approach for the divergent synthesis of 2-fluoro-3-aryl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazines and α-trifluoromethyl-β-arylthio tertiary alcohols from 2-mercaptoimidazoles and α-CF3 alkenes has been developed. The chemoselectivity was well controlled by base or light; a series of 2-fluoro-3-aryl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazines were afforded via base-mediated sequential SN2'- and SNV-type reactions. Meanwhile, α-trifluoromethyl-β-arylthio tertiary alcohols could be selectively achieved through visible-light-driven and electron donor-acceptor (EDA) complex-initiated radical cascade thiolation/hydroxylation in the absence of base, transition metal, and external photocatalyst.

Divergent Synthesis of Trifluoromethyl Ketones via Photoredox Activation of Halotrifluoroacetones

AbstractFluorine's high electronegativity, lipophilicity, and metabolic stability make it a valuable element for drug design and development. Consequently, significant synthetic efforts have focused on introducing fluorine and fluorinated motifs into organic molecules, with the synthesis of trifluoromethyl ketones (TFMKs) recently attracting considerable attention. Building on our ongoing research on radical organofluorine chemistry, we present herein the divergent synthesis of trifluoromethyl ketones directly from olefins using readily available chloro‐ and bromotrifluoroacetone as synthetic precursors of the trifluoroacetonyl radical under photoredox catalysis. Mechanistic studies revealed that the divergence is attained through radical polar crossover (RPC) and hydrogen atom transfer (HAT) mechanisms.

Ag(I)-Catalyzed Oxidative Cyclization of 1,4-Diynamide-3-ols with N-Oxide for Divergent Synthesis of 2-Substituted Furan-4-carboxamide Derivatives.

This work reports Ag(I)-catalyzed oxidative cyclizations of 1,4-diynamide-3-ols with 8-methylquinoline oxide to form 2-substituted furan-4-carboxamides. The reaction chemoselectivity is distinct from that reported in previous work by Hashmi. We performed density functional theory calculations to elucidate our proposed mechanism after evaluation of the energy profiles of two possible pathways. In this Ag(I) catalysis, the calculations suggest that the amide and alkyne groups of the 3,3-dicarbonyl-2-alkyne intermediates tend to chelate with the Ag(I) catalyst, further inducing a formyl attack at the Ag(I)-π-alkyne moiety to deliver the observed products.

Stable Ditriflates of D‐Glucose in the Synthesis of Iminosugars and Polyhydroxylated Pipecolic Acids

AbstractA synthesis of the five membered iminosugar DAB and a divergent synthesis of the six membered iminosugar 1‐dehydromannojirimycin (DMJ) and the corresponding sugar imino acid are reported. They involve double nucleophilic displacements of a D‐xylose ditriflate by benzyl carbazate and a D‐glucose ditriflate by allyl amine, respectively. They are followed by a similar protocol consisting of hydrolysis and oxidation or reduction of the resulting bicyclic glycosides. This allowed DMJ to be obtained from the cheap sugar D‐glucose.

Diversity Oriented Strategy (DOS) for the Efficient Synthesis of Benzofuro[2,3-b]pyridine Derivatives with Anticancer Activity.

Benzofuropyridines (BFP) are polycyclic compounds with known applications in neuronal diseases. However, its derivatization patterns and anticancer potential remains unexplored. Leveraging the idea of diversity-oriented synthesis (DOS), we developed a highly efficient synthetic route for BFP to increase the library of available analogs producing three compounds in one reaction set up, including the 2O-, 6O-, and the 1N-substituted species, also producing the unusual 2-pyridone derivatives. Key bromination reaction of the BFP moiety was successfully described which can widen the available variation in the compounds' structure. The cytotoxic activity of the compounds was assessed against SH-SY5Y (neuroblastoma), HepG2 (hepatocellular carcinoma), Kb (human oral epidermoid), HeLa (cervical) and MCF-7 (breast) cancer cell lines. In the series, the m-bromobenzyl (5b), methylcyano (5g) and propargyl (5h) 2O-derivatives demonstrated good selectivity against cancer cells with selectivity index (SI) of >71 for 5g against HeLa over the normal cells, as compared to the standard drug, Doxorubicin (SI = 6.7). The quantitative structure-activity relationship (QSAR) analysis revealed an impressive correlation of the defined descriptors with the bioactivity having an R2 value of 0.971 and 0.893 for Kb and HeLa respectively. Altogether, our work highlighted new information on the synthesis of BFP derivatives with potent cytotoxic activity.

Development of a Divergent Synthesis Strategy for 5-Sulfonyl-Substituted Uracil Derivatives.

An efficient, diversity-orientated synthesis of 5-sulfone-substituted uracils was established. The use of protecting groups to synthesize sulfones from N-heterocycles was avoided. Various heterocycles were synthesized for the first time from favorable, easily accessible starting materials. Diversity-orientated syntheses are important for the medicinal chemistry of virostatics and chemotherapeutics. This approach provides a broad substrate tolerance and excellent yields of up to 98%.

Bipolar Membranes Via Divergent Synthesis: On the Interplay between Ion Exchange Capacity and Water Dissociation Catalysis.

Bipolar membranes (BPMs) enable the operation of electrochemical reactors with electrode compartments in different chemical environments or pH. The transport properties at the microscopic scale are dictated by the composition and morphology of the interfacial junctions as well as the specific chemistry of the ion-exchange layers that support the current of protons and hydroxide ions. This work elucidates the relation between water-dissociation efficiency and the physicochemical properties of the individual ion-exchange membrane layers in the poly(styrene-b-poly(ethylene-ran-butylene)-b-polystyrene) (SEBS)-based BPM. The optimal water dissociation performance of three previously reported water-dissociation catalysts in the SEBS-based BPM was examined, with junction thickness of graphene oxide > TiO2 > SnO2, resulting in disparate junction morphologies at the BPM's interface. A hybrid junction system, which included both the effective water dissociation catalyst SnO2 and direct contacting of the ion-exchange membrane layer, exhibited high water dissociation efficiency. This was likely due to the immediate ion transport pathway provided by direct membrane contact around the catalyst, which also improved the interfacial adhesion. A higher ion exchange capacity (IEC) in BPMs substantially enhanced the water dissociation performance in BPMs without water-dissociation catalysts. However, the incorporation of the effective SnO2 catalyst into the BPMs with a lower IEC significantly improved performance, an effect attributed to the hybrid junction system. Additionally, the increase in water uptake and ion conductivity of the cation exchange layer with higher IEC suggested that the cation exchange layer and its interface to the water-dissociation catalyst layer may play a key role in water dissociation. This study identifies the key parameters of individual BPM components and their interactions to water dissociation performance, offering new insights to guide in the construction of future BPMs optimized for enhanced water dissociation efficiency at high current densities.

Pd-Catalyzed Dual C-H Activation/Cyclization: Convergent and Divergent Synthesis of 1-Azahelicenes.

Herein, we report a convergent synthesis of 1-azahelicenes using easily available quinoline derivatives and cyclic diaryliodonium salts as starting materials. This reaction undergoes a palladium-catalyzed dual C-H activation/cyclization process to give facile access to a wide range of 1-aza[5]helicenes and 1-aza[6]helicenes with abundant functional groups (including F, Cl, Br, I, CF3, SeR, SR, and heteroaryl) in moderate to excellent yields, thereby providing new opportunities to fine-tune the properties of the helicene backbone. In addition, the obtained products could be further transformed into helicene-based Lewis base catalysts and redox switch materials easily. Notably, one selected 1-azahelicene shined bright yellow light by aggregation. These features enlarge the chemical space of 1-azahelicenes and inspire further utilization in other areas of research.

Divergent Syntheses of Near-Infrared Light-Activated Molecular Jackhammers for Cancer Cell Eradication.

Aminocyanines incorporating Cy7 and Cy7.5 moieties function as molecular jackhammers (MJH) through vibronic-driven action (VDA). This mechanism, which couples molecular vibrational and electronic modes, results in picosecond-scale concerted stretching of the entire molecule. When cell-associated and activated by near-infrared light, MJH mechanically disrupts cell membranes, causing rapid necrotic cell death. Unlike photodynamic and photothermal therapies, the ultrafast vibrational action of MJH is unhindered by high concentrations of reactive oxygen species scavengers and induces only a minimal temperature increase. Here, the efficient synthesis of a library of MJH is described using a practical approach to access a key intermediate and facilitating the preparation of various Cy7 and Cy7.5 MJH with diverse side chains in moderate to high yields. Photophysical characterization reveals that structural modifications significantly affect molar extinction coefficients and quantum yields while maintaining desirable absorption and emission wavelengths. The most promising compounds, featuring dimethylaminoethyl and dimethylcarbamoyl substitutions, demonstrate up to sevenfold improvement in phototherapeutic index compared to Cy7.5 amine across multiple cancer cell lines. This synthetic strategy provides a valuable platform for developing potent, light-activated therapeutic agents for cancer treatment, with potentially broad applicability across various cancer types.

Synergistic Pd/Ni Dual-Catalyzed Cross-Coupling of Azaaryl Acetates with gem-Difluorinated Cyclopropanes.

We herein report the development of a novel Pd/Ni dual-catalyzed ring-opening functionalization of gem-difluorinated cyclopropanes (gem-F2CPs) with azaaryl acetates. This bimetallic catalytic strategy streamlines the diversity-oriented synthesis (DOS) of α-quaternary 2-fluoroallylic azaaryl acetates with features of a broad scope and excellent functional group tolerance, which enables the efficient late-stage transformation of natural product-derived gem-F2CPs. The resulting α-quaternary azaaryl acetates could serve as a valuable platform to prepare other different fluoroallylic azaaryl scaffolds.