Chemoselective Reaction Research Articles

Brook-Oxidation Reaction of Acylsilanes: General Access to α-Ketoamides and α-Ketothioamides.

A novel chemoselective Brook-oxidation reaction of acylsilanes initiated by the carbamoyl anion has been successfully developed for the first time. This method enables the synthesis of diverse α-ketoamides and α-ketothioamides under transition metal-free and strong oxidant-free conditions with high yields and high chemoselectivity. It also demonstrates tolerance toward a wide range of functional groups. The synthetic utility of this process is underscored by its successful application in the synthesis of an orexin receptor antagonist from acylsilane, highlighting its potential for the development of novel therapeutic agents and further exploration in synthetic chemistry.

Nonaqueous Contact-Electro-Chemistry via Triboelectric Charge.

Mechanochemistry revolutionizes traditional reactions through mechanical stimulation, but its reaction efficiency is limited. Recent advancements in utilizing triboelectric charge from liquid-solid contact electrification (CE) have demonstrated significant potential in improving the reaction efficiency. However, its efficacy remains constrained by interfacial electrical double-layer screening in aqueous solutions. This study pioneered chemistry in nonaqueous systems via CE for catalysis and luminescence. Density functional theory simulations and experiments revealed varying electron transfer capabilities and chemoselectivity of CE across different solvents. Phenol degradation via CE in dimethyl sulfoxide (DMSO) exhibited a rate over 40 times faster than that of traditional mechano-driven chemistry. A more intuitive comparison revealed that CE degradation of phenol in DMSO exhibits a 30-fold rate improvement compared to deionized water, where the degradation remains incomplete. Luminol oxidation by radicals generated solely via CE in DMSO eliminates the dependence on traditional catalysts and side reactions, establishing a pure and simple system for investigating the reaction mechanisms. A high and stable luminescence characteristic was maintained for 3 months, enhancing the imaging accuracy and stability exponentially. This study underscores the impact of triboelectric charge on reaction efficiency and chemoselectivity, establishing a new paradigm in nonmetal catalysis, mechanoluminescence, and providing profound insights into reaction kinetics.

Chemoselective Preparation of Alkynes from Vicinal and Geminal Dibromoalkenes.

The reductive conversion of vicinal and geminal dibromoalkenes into the corresponding alkynes with iPrMgCl-LiCl (Turbo Grignard reagent) is described. This reaction proceeded in the presence of various functional groups such as ethers, esters, or carbamates under mild conditions in high yields. Due to the selective reactivity, the easily prepared vic-dibromoalkene is considered to be a protecting group of alkyne toward an electrophile. Although butyl lithium has been widely used for the conversion of gem-dibromoalkenes into alkynes in the Corey-Fuchs alkyne synthesis, we report here alternative mild and chemoselective reaction conditions for alkyne synthesis.

Catalyst-free and wavelength-tuned glycosylation based on excited-state intramolecular proton transfer

The chemoselectivity of organic reactions is a fundamental topic in organic chemistry. In the long history of chemical synthesis, achieving chemoselectivity is mainly limited to thermodynamic conditions by an exogenous activation strategy. Here, we design an endogenous activation method, which can be used to control the chemoselectivity of phenol and naphthol through the photo-induced excited-state intramolecular proton transfer (ESIPT). A wavelength-tuned glycosylation is developed to showcase the penitential of this new strategy. Traditionally, an exogenous activator (electrophilic promoters) is essential to induce the cleave of a polar single bond, and this strategy has been extensively studied and used in the glycosylation chemistry, for the formation of oxocarbenium cation intermediate. In our systems, the oxocarbenium cation intermediates can be selectively formed from glycosyl donors bearing tunable chromophoric groups under mild conditions of acid-base free and redox neutrality, which enables continuous synthesis of oligosaccharides.

N-Fluorosulfurylamidines Enable Modular Synthesis of 1,5-Disubstituted Tetrazoles.

Here we report the modular synthesis of 1,5-disubstituted tetrazoles using two highly chemoselective reactions, ligations of N-fluorosulfurylamidines with amines and diazotransfer reactions between FSO2N3 and N-monosubstituted amidines, respectively. Enabled by sulfur(VI) fluoride exchange (SuFEx) click chemistry, we have successfully synthesized a series of N-fluorosulfurylamidines and identified them as stable and scalable organic synthons. We then discover that N-fluorosulfurylamidines react selectively toward a series of aliphatic amines, resulting in the formation of N-monosubstituted amidines that can react further with FSO2N3 to deliver 1,5-disubstituted tetrazoles. Our work provides a new platform for generating a library of 1,5-disubstituted tetrazoles with diverse structures, which is unprecedented.

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.

Direct Synthesis for Benzofuro[3,2-d]pyrimidin-2-Amines via One-Pot Cascade [4+2] Annulation/Aromatization between Benzofuran-Derived Azadienes and Carbodiimide Anions.

The chemoselective [4+2] annulation/aromatization reactions between benzofuran-derived azadienes and N-Ts cyanamides are developed, affording a convenient method for synthesizing benzofuro[3,2-d]pyrimidin-2-amines under mild conditions. Herein, N-Ts cyanamides participated in reactions selectively via carbodiimide anion intermediates and the corresponding cyanamide anion intermediates derived products were not observed. The proposed chemoselective stepwise reaction mechanism was well supported by DFT calculations.

PH-Controlled Chemoselective Rapid Azo-Coupling Reaction (CRACR) Enables Global Profiling of Serotonylation Proteome in Cancer Cells.

Serotonylation has been identified as a novel protein posttranslational modification for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main "writer" enzyme for this PTM, and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibodies for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to specifically label protein serotonylation in a bioorthogonal manner, which depended on a pH-controlled chemoselective rapid azo-coupling reaction. Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 1,000 serotonylated proteins were identified from HCT 116 cells, many of which are highly related to carcinogenesis. Moreover, a number of modification sites of these serotonylated proteins were determined, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics.

Efficient generation of novel phosphorus ylides via chemoselective and chemospecific reactions utilizing 2-(arylamino)-2-thioxoacetamide and methyl benzoylglycinates as precursors with activated acetylenic compounds

A chemospecific and chemoselective procedure has been developed for the efficient synthesis of novel phosphorus compounds, achieving moderate to excellent yields. This method involves the reaction of 2-(arylamino)-2-thioxoacetamide and methyl benzoylglycinate precursors with PPh3 in the presence of activated acetylenic esters. Notably, the reaction exhibits superior selectivity toward the NH2 group in 2-(arylamino)-2-thioxoacetamide, rather than the NH group. Moreover, when methyl benzoylglycinates are employed as a precursor, the reaction yields two distinct families of ylides, each with its own unique percentage yield.

Diversity-oriented synthesis of chromone inden-1-one-fused cyclopentadienylides and C-acylated chromone adducts via allylic phosphorus ylides.

An organophosphine-controlled diversity-oriented synthesis of chromone inden-1-one-fused cyclopentadienylides and C-acylated 2-((chromone-3-yl)methylene)-indandiones is reported. Key attributes of the methodology are the in situ generation of an allylic P-ylide and subsequent regio- and chemoselective intramolecular cyclization reactions that preferentially result in the aforementioned chromone adducts.

Pyridine-Catalyzed Chemoselective Four-Component Cascade Reaction of Aromatic Aldehydes, Malononitrile/Cyanoacetates, MBH Carbonates, and Alcohols.

An efficient pyridine-catalyzed chemoselective four-component cascade reaction of aromatic aldehydes, malononitrile/cyanoacetates, Morita-Baylis-Hillman (MBH) carbonates, and alcohols has been established. This one-pot reaction progressed in an unusual reaction with solvent participation via a Knoevenagel condensation/oxa-Michael addition/SN2' substitution sequence. This method allowed for facile access to an array of functionalized chain alkylbenzenes and dihydroquinolinones bearing one all-carbon quaternary center in moderate to excellent yields. It is worth noting that the configuration of the all-carbon quaternary center could be modulated by changing only the electron-withdrawing groups via a tandem reduction/cyclization reaction.

Assessment of Accelerated Aging Effect of Bio-Oil Fractions Utilizing Ultrahigh-Resolution Mass Spectrometry and k-Means Clustering of van Krevelen Compositional Space.

Bio-oils contain a substantial number of highly oxygenated hydrocarbons, which often exhibit low thermal stability during storage, handling, and refining. The primary objectives of this study are to characterize the hydroxyl group in bio-oil fractions and to investigate the relationship between the type of hydroxyl group and accelerated aging behavior. A bio-oil was fractionated into five solubility-based fractions, classified in two main groups: water-soluble and water-insoluble fractions. These fractions were then subjected to chemoselective reactions to tag molecules containing hydroxyl groups and analyzed by negative-ion electrospray ionization 21 T Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). The fractions were also subjected to accelerated aging experiments and characterized by FT-ICR MS and bulk viscosity measurements. Extracting insightful information from ultrahigh-resolution data to aid in predicting upgrading methodologies and instability behaviors of bio-oils is challenging due to the complexity of the data. To address this, an unsupervised learning technique, k-means clustering analysis, was used to semiquantify molecular compositions with a close Euclidean distance within the (O/C, H/C) chemical space. The combination of k-means analysis with findings from chemoselective reactions allowed the distinctive hydroxyl functionalities across the samples to be inferred. Our results indicate that the hexane-soluble fraction contained numerous molecules containing primary and secondary alcohols, while the water-soluble fraction displayed diverse groups of oxygenated compounds, clustered near to carbohydrate-like and pyrolytic humin-like materials. Despite its high oxygen content, the water-soluble fraction showed minimal changes in viscosity during aging. In contrast, a significant increase in viscosity was observed in the water-insoluble materials, specifically, the low- and high-molecular-weight lignin fractions (LMWL and HMWL, respectively). Among these two fractions, the HMWL exhibited the highest increase in viscosity after only 4 h of accelerated aging. Our results indicate that this aging behavior is attributed to an increased number of molecular compositions containing phenolic groups. Thus, the chemical compositions within the HMWL are the major contributors to the viscosity changes in the bio-oil under accelerated aging conditions. This highlights the crucial role of oxygen functionality in bio-oil aging, suggesting that a high oxygen content alone does not necessarily correlate with an increase of viscosity. Unlike other bio-oil categorization methods based on constrained molecule locations within the van Krevelen compositional space, k-means clustering can identify patterns within ultrahigh-resolution data inherent to the unique chemical fingerprint of each sample.

Transforming Waste into Valuable Chemicals: CO2 Conversion Enabled by Porphyrin-Based Catalysts

Carbon dioxide is the primary greenhouse gas responsible for global warming and the resulting climate change, which is provoking a significant increase in extreme weather events that impact our health, environment, and economy. Nowadays the scientific community is focusing many efforts on the use of CO2 as a C1 source in the synthesis of a wide range of useful products, in alignment with circular economy principles [1].Here we report the reaction of CO2 with epoxides and aziridines, forming cyclic carbonates and oxazolidin-2-ones, by a 100% atom-efficient procedure promoted by porphyrin-based catalytic systems [2]. Considering that the contemporary presence of electrophile and nucleophile promoters is usually required for these classes of transformations, several binary and bifunctional porphyrin-based systems will be discussed with the final goal to underline the advantages of employing these systems in terms of broad applicability and eco-tolerance. Porphyrins exhibit remarkable chemical versatility, allowing for precise tuning of catalytic performances and reaction chemo-selectivity. Furthermore, the heterogenization of single-site catalysts onto solid supports enhances practical applicability [3].In addition, synthetic protocols will also be discussed from a mechanistic point of view on the basis of spectroscopic and theoretical studies and taking into account the identification of active intermediates [4].

Metal-Free Switchable Chemo- and Regioselective Alkylation of Oxindoles Using Secondary Alcohols.

In this study, we have disclosed N-alkylation and C-alkylation reactions of 2-oxindoles with secondary alcohols. Interestingly, these chemoselective reactions are tunable by changing the reaction conditions. Utilization of protic solvent and Brønsted acid catalyst afforded C-alkylation, whereas, aprotic solvent and Lewis acid catalyst afforded N-alkylation of 2-oxindoles in good to excellent yields. Regioselectivity is achieved by protecting the N-center of the oxindole and C5 alkylated product is furnished exclusively. This protocol is notable because it demonstrates functionalization at the C7 position of oxindole without the need for any directing group at the N-center. Further, a new protocol has been reported for C-H oxygenation at the benzylic position of one of the C5 alkylated derivative.

PH-Controlled chemoselective rapid azo-coupling reaction (CRACR) enables global profiling of serotonylation proteome in cancer cells.

Serotonylation has been identified as a novel protein post-translational modification for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main writer enzyme for this PTM and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibodies for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to specifically label protein serotonylation in a bioorthogonal manner, which depended on a pH-controlled chemoselective rapid azo-coupling reaction (CRACR). Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 1,000 serotonylated proteins were identified from HCT 116 cells, many of which are highly related to carcinogenesis. Moreover, a number of modification sites of these serotonylated proteins were determined, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics.

Organocatalytic Asymmetric Construction of Spirooxazines via Chemoselective Cascade Addition of N-Substituted Hydroxylamine with Keto-bis-enone.

Spirooxazines represent a privileged heterocyclic scaffold having pronounced biological importance. Herein, we introduce a chiral bifunctional squaramide catalyzed highly chemoselective cascade reaction involving aza-Michael/1,2-addition/oxa-Michael addition of N-substituted hydroxylamine with keto-bis-enones. This strategy enables the synthesis of highly enantioenriched oxa-spirooxazines with a broad substrate tolerance. Scalability and synthetic transformation have demonstrated the feasibility of the protocol. Furthermore, control experiments provided insights into the reaction mechanism.

Catalyst-free selective oxidation of C(sp3)-H bonds in toluene on water

The anisotropic water interfaces provide an environment to drive various chemical reactions not seen in bulk solutions. However, catalytic reactions by the aqueous interfaces are still in their infancy, with the emphasis being on the reaction rate acceleration on water. Here, we report that the oil-water interface activates and oxidizes C(sp3)-H bonds in toluene, yielding benzaldehyde with high selectivity (>99%) and conversion (>99%) under mild, catalyst-free conditions. Collision at the interface between oil-dissolved toluene and hydroxyl radicals spontaneously generated near the water-side interfaces is responsible for the unexpectedly high selectivity. Protrusion of free OH groups from interfacial water destabilizes the transition state of the OH-addition by forming π-hydrogen bonds with toluene, while the H-abstraction remains unchanged to effectively activate C(sp3)-H bonds. Moreover, the exposed free OH groups form hydrogen bonds with the produced benzaldehyde, suppressing it from being overoxidized. Our investigation shows that the oil-water interface has considerable promise for chemoselective redox reactions on water without any catalysts.

Synthesis of N-Alkyl-3-[2-oxoquinolin-1(2H)-yl]propanoic Acid Derivatives and Related Compounds: Cytotoxicity and EGFR Inhibition of Some Propanamide Derivatives.

A series of 20 new structure-modified quinolin-2-one derivatives were prepared for biological evaluation. This was successfully achieved based on chemoselective reactions of heterocyclic amides with acrylic acid derivatives, which gave 3-[2-oxoquinolin-1-(2H)-yl] propanoic acid derivatives (N-substitution via a unique behavior). The ester was reacted with hydrazine to afford the corresponding hydrazide. Both the corresponding ester and hydrazide were used as building blocks to modify the quinolone structure and give N-hydroxyl propanamides, oxadiazoles, and thiosemicarbazides. The corresponding carboxylic acid and hydrazide were used to prepare several amides: N-alkyl-3-[2-oxoquinolin-1(2H)-yl]propanamides via azide and dicyclohexyl carbodiimide coupling methods. Among derivatives, compound 9e exhibited potent cytotoxicity against MCF-7 cells with an IC50 value of 1.32 μM compared to doxorubicin with an IC50 value of 1.21 μM. Additionally, it caused potent EGFR inhibition by 97% with an IC50 value of 16.89 nM compared to Erlotinib with an IC50 value of 29.8 nM. Finally, the binding mode of compound interactions toward EGFR was highlighted using a molecular docking study; compound 9e exhibited good binding affinity with a binding energy of -17.89 kcal/mol, and it formed H-bond interactions with Met 769 as the key amino acid of interaction. Accordingly, compound 9e may be developed as an EGFR-oriented chemotherapeutic antibreast cancer agent.

Sabatier phenomenon in chemoselective gas-sensing reactions induced by Ag cluster coordination

The Sabatier principle in heterogeneous catalysis provides guidance for designing optimal catalysts with the highest activity. We report a new Sabatier phenomenon induced by nanoclusters on different atomic scales in gas-sensitive reactions. We prepared a series of Ag nanocluster catalysts with coordination structures ranging from Ag0 to Ag13 through a surface coordination strategy. When used as catalysts for gas-sensitive reactions, a volcano-type relationship between the coordination number of Ag nanoclusters and gas-sensitive activity emerges, with a summit at a moderate coordination of Ag5. Mechanistic studies show that the efficient adsorption of activated *C2H6O on electron-rich Ag5 clusters is a key factor for the Sabatier phenomenon (adsorption energy from −0.322 eV to −0.663 eV), which leads to highly selective sensing. We found that the catalyst electron-rich surface layer induced by Ag5 clusters serves as a descriptor to explain the structure–activity relationship. Furthermore, due to the well-defined geometric and electronic structures in the Ag5 clusters, the optimized catalyst achieves both maximum activity and selectivity in chemoselective sensing reactions. This study reveals the Sabatier principle and provides insightful guidance for the rational design of more efficient and practical nanocluster catalysts for heterogeneous catalysis.

Chemoselective synthesis, X-ray structure study, Hirshfeld surface analysis, antitumor, and antimicrobial activities of new Thiophene and Thiazole derivatives

A base-controlled chemoselective reaction of 1-phenylbutane-1,3‑dione with PhNCS and 1-chloropropan-2-one is described. Thiophene derivative 5 is obtained from the reaction in NaOEt solution, whereas thiazole 11 was isolated using potassium carbonate/DMF mixture. Spectral and X-ray structure analyses were used to characterize the synthesized compounds. Possible intermolecular interactions that control the molecular packing of the studied crystalline compounds were elucidated using Hirshfeld topology analysis. For thiophene 5, the O…H contacts are the most important and contribute to 17.7 % of the whole predicted interactions. In the case of thiazole 11, the CH…π and O…H non-covalent interactions are the most important contacts whereas the%C…H and%O…H contacts are 16.7 and 22.8 %, respectively. Additionally, there are some short H…H (47.0 %) interactions were detected where the H16A…H10A (2.165 Å) is the most important. The H…H interaction is the most dominant interaction which contributed by 47.0 and 47.0 % in 5, and 11, respectively.When compounds 5 and 11 were tested for their antimicrobial activity, the results revealed that thiophene derivative 5 has promising activity against both Salmonella SP. and Escherichia coli when compared to the standard medication gentamicin. Moreover, they were tested using the MTT assay for their antitumor activities against the colon carcinoma cell line (HCT-116) and the human hepatocellular carcinoma cell line (HepG-2). The results showed a lower cytotoxic effect against various cell lines in comparison to doxorubicin.