Denitrogenative dismantling of heteroaromatics by nucleophilic substitution reactions with diazomethyl compounds.

Nucleophiles from deprotonation of diazomethyl compounds having diverse electron withdrawing groups react with 4-carboxylato-1,2,3-triazines at the 6-position to extrude dinitrogen and produce diazovinylketoesters compounds with five or six linear contiguous sp2-hybridized carbons, whereas these same nucleophiles react with 4-carboxylato-1,2,3-triazine 1-oxides, also at the 6-position, to form pyrazolines with the expulsion of nitrous oxide and cyanocarboxylate. This disparity is due to the significant difference in reactivity of the nucleophilic addition products.

The "cesium effect" magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions.

Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of ß-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.

Site Reversal in Nucleophilic Addition to 1,2,3-Triazine 1-Oxides.

One of the most important reactions of 1,2,3-triazines with a dienophile is inverse electron demand Diels-Alder (IEDDA) cycloaddition, which occurs through nucleophilic addition to the triazine followed by N2 loss and cyclization to generate a heterocycle. The site of addition is either at the 4- or 6-position of the symmetrically substituted triazine core. Although specific examples of the addition of nucleophiles to triazines are known, a comprehensive understanding has not been reported, and the preferred site for nucleophilic addition is unknown and unexplored. With access to unsymmetrical 1,2,3-triazine-1-oxides and their deoxygenated 1,2,3-triazine compounds, we report C-, N-, H-, O-, and S-nucleophilic additions on 1,2,3-triazine and 1,2,3-triazine-1-oxide frameworks where the 4- and 6-positions could be differentiated. In the IEDDA cycloadditions using C- and N-nucleophiles, the site of addition is at C-6 for both heterocyclic systems, but product formation with 1,2,3-triazine-1-oxides is faster. Other N-nucleophile reactions with triazine 1-oxides show addition at either the 4- or 6-position of the triazine 1-oxide ring, but nucleophilic attack only occurs at the 6-position on the triazine. Hydride from NaBH4 undergoes addition at the 6-position on the triazine and the triazine 1-oxide core. Alkoxides show a high nucleophilic selectivity for the 4-position of the triazine 1-oxide. Thiophenoxide, cysteine, and glutathione undergo nucleophilic addition on the triazine core at the 6-position, while addition occurs at the 4-position of the triazine 1-oxide. These nucleophilic additions proceed under mild reaction conditions and show high functional group tolerance. Computational studies clarified the roles of the nucleophilic addition and nitrogen extrusion steps and the influence of steric and electronic factors in determining the outcomes of the reactions with different nucleophiles.

Inverse Electron Demand Diels-Alder-Type Heterocycle Syntheses with 1,2,3-Triazine 1-Oxides: Expanded Versatility.

1,2,3-Triazine 1-oxides are remarkably effective substrates for inverse electron demand Diels-Alder reactions. Formed from vinyldiazoacetates via reaction with tert-butyl nitrite, these stable heterocyclic compounds undergo clean nucleophilic addition with amidines to form pyrimidines, with ß-ketocarbonyl compounds and related nitrile derivatives to form polysubstituted pyridines and with 3/5-aminopyrazoles to form pyrazolo[1,5-a]pyrimidines, in high yield. These practical reactions are rapid at room temperature, are base catalyzed, and offer a diversity of structural modifications.

Synthesis of 1,2,3-Triazine Derivatives by Deoxygenation of 1,2,3-Triazine 1-Oxides.

A convenient, efficient, and inexpensive method has been developed for the synthesis of 1,2,3-triazine derivatives via deoxygenation of 1,2,3-triazine 1-oxide using trialkyl phosphites. Triethyl phosphite is more reactive than trimethyl phosphite, and both phosphites form their corresponding phosphates in these reactions. This procedure provides a range of aromatic and aliphatic substituted 1,2,3-triazine-4-carboxylate derivatives cleanly in high yields. Unexpected 1,2,4-triazine derivatives were also obtained as minor products during deoxygenation of 1,2,3-triazine-4-carboxylate 1-oxides having an aliphatic substituent at the 5-position.

Brain Tumor Classification Using Fine-Tuned GoogLeNet Features and Machine Learning Algorithms: IoMT Enabled CAD System.

In the healthcare research community, Internet of Medical Things (IoMT) is transforming the healthcare system into the world of the future internet. In IoMT enabled Computer aided diagnosis (CAD) system, the Health-related information is stored via the internet, and supportive data is provided to the patients. The development of various smart devices is interconnected via the internet, which helps the patient to communicate with a medical expert using IoMT based remote healthcare system for various life threatening diseases, e.g., brain tumors. Often, the tumors are predecessors to cancers, and the survival rates are very low. So, early detection and classification of tumors can save a lot of lives. IoMT enabled CAD system plays a vital role in solving these problems. Deep learning, a new domain in Machine Learning, has attracted a lot of attention in the last few years. The concept of Convolutional Neural Networks (CNNs) has been widely used in this field. In this paper, we have classified brain tumors into three classes, namely glioma, meningioma and pituitary, using transfer learning model. The features of the brain MRI images are extracted using a pre-trained CNN, i.e. GoogLeNet. The features are then classified using classifiers such as softmax, Support Vector Machine (SVM), and K-Nearest Neighbor (K-NN). The proposed model is trained and tested on CE-MRI Figshare and Harvard medical repository datasets. The experimental results are superior to the other existing models. Performance measures such as accuracy, specificity, and F1 score are examined to evaluate the performances of the proposed model.

Unveiling the urease like intrinsic catalytic activities of two dinuclear nickel complexes towards the in situ syntheses of aminocyanopyridines.

Designing metal complexes as functional models for metalloenzymes remains one of the main targets in synthetic bioinorganic chemistry. Furthermore, the utilization of the product(s) derived from the catalytic reaction for subsequent organic transformation that occurs in biological systems is an even more difficult challenge for biochemists. Urease, the most efficient enzyme known, catalyzes the hydrolysis of urea and it contains an essential dinuclear NiII cluster in the active site. Inspired by the catalytic properties of urease, two dinickel(ii) complexes viz. Ni2L12(OAc)2(H2O) (1) and Ni2L22(OAc)2(H2O) (2) [HL1 = 2,4-dimethyl-6-{[(2'-dimethyl aminoethyl)methylamino]methyl}-phenol and HL2 = 2,4-dichloro-6-{[(2'-dimethyl aminoethyl)methylamino]methyl}-phenol] have been synthesized and characterized in this report. Both the complexes have shown the urease kind of activity with the liberation of ammonia from urea in aqueous solution. The plausible mechanistic pathway and kinetics of the reactions have been studied. Besides, the liberated ammonia has been utilized in the one-pot synthesis of biologically active products like 2-amino-3-cyanopyridines and their derivatives in aqueous medium with excellent yields.

ß-Oxidation of Ynamides into N,O-Acetals by mCPBA: Application in Enantioselective Intermolecular Transacetalization.

Oxidation of ynamides by mCPBA led to ß-oxygenation and resulted in formation of carbonyl compounds with α-N,O-acetal functionality. These N,O-acetals are formed in high yields and can be stored indefinitely at room temperature. Yet, they can be activated by a chiral Brønsted acid and underwent an enantioselective transacetalization into a α-N,O-acetal. Subsequent diastereoselective transformations occurred with exceptional selectivity according to Felkin-Anh model.

Rationally designed small molecules targeting toxic CAG repeat RNA that causes Huntington's disease (HD) and spinocerebellar ataxia (SCAs).

Huntington's diseases (HD) is a very devastating disease caused by r(CAG) expansion in HTT gene, encoding the huntingtin protein. r(CAG) expansion causes disease via multiple pathways including, 1) loss of normal protein function like sequestration of RNA binding protein such as Muscleblind-like (MBNL) and nucleolin, 2) Gain of function for mutant proteins and 3) repeat-associated non-ATG (RAN) translation; in which expanded r(CAG) translates into toxic poly glu, poly ser, or poly ala without the use of any canonical start codon. Herein, we have rationally designed and synthesized a unique class of pyridocoumarin derivatives that target the r(CAG)exp involved in HD and spinocerebellar ataxia (SCA) pathogenesis. Notably, compounds 3 and 15 showed higher affinity (nanomolar Kd) and selectivity for diseased r(CAG)exp RNA compared to regular duplex AU-paired RNA. Interestingly, both scaffolds are cell permeable, exhibit low toxicity to healthy fibroblast cells and are also capable of reducing the level of poly Q aggregation in cellular models. Indeed, our current study offers promising facet for selectively targeting repeats containing RNAs that cause severe diseases like HD and SCAs.

Metal- and Solvent-Free Approach to Diversely Substituted Picolinates via Domino Reaction of Cyclic Sulfamidate Imines with ß,γ-Unsaturated α-Ketocarbonyls.

An efficient, solvent-free, and eco-friendly domino reaction of 5/6-membered cyclic sulfamidate imines with a variety of ß,γ-unsaturated α-ketocarbonyls in neat conditions under MW irradiation promoted by DABCO as a solid organobase has been developed for the rapid construction of a novel class of densely functionalized picolinates. This interesting metal-solvent-free tactic allows a wide range of useful functionalities on the aryl rings and delivers good to excellent yields of the aforesaid aza-heterocycles within short time spans (20-40 min). A biologically promising imidazo[1,2-a]pyridine was successfully synthesized through our unique procedure.

Domino reaction of cyclic sulfamidate imines with Morita-Baylis-Hillman acetates promoted by DABCO: a metal-free approach to functionalized nicotinic acid derivatives.

A facile, green, metal-free new one-pot synthetic strategy has been developed for easy access to a wide array of medicinally promising functionalized pyridines having an ester, a nitrile or an acetyl group at the C-3 position in good to excellent yields via a domino SN2/elimination/6π-aza-electrocyclization/aromatization reaction of several 4-aryl/hetero-aryl-substituted 5-membered cyclic sulfamidate imines with a broad range of MBH acetates of acrylate/acrylonitrile/MVK in 2-MeTHF promoted by DABCO as an organobase under an O2 atmosphere. Moreover, a biologically interesting triazolopyridine derivative was achieved through a unique procedure.

Access to 4,6-Diarylpicolinates via a Domino Reaction of Cyclic Sulfamidate Imines with Morita-Baylis-Hillman Acetates of Nitroolefins/Nitrodienes.

An interesting domino reaction of 5-membered cyclic sulfamidate imines with a variety of Morita-Baylis-Hillman acetates of nitroolefins/nitrodienes in the presence of DABCO as an organic base at 55 °C is reported for the first time. This new synthetic strategy provides a series of pharmacologically interesting 4,6-diarylpicolinates in high to excellent yields and allows several compatible functionalities on aryl rings. Moreover, the biologically interesting imidazo[1,2-a]pyridine (alpidem derivative) has been prepared in high chemical yield through a unique procedure.

DABCO catalyzed domino Michael/hydroalkoxylation reaction involving α-alkynyl-ß-aryl nitroolefins: excellent stereoselective access to dihydropyrano[3,2-c]chromenes, pyranonaphthoquinones and related heterocycles.

Excellent stereoselective (up to ≤96 : 4 Z/E ratio) construction of pharmaceutically interesting functionalized pyrano[3,2-c]chromenes, pyranonaphthoquinones and related pyrano-fused heterocycles has been achieved in good to high yields (72-89%) through a domino Michael/hydroalkoxylation reaction involving several enolizable cyclic ß-keto esters/1,3-dicarbonyls and α-arylacetylenyl-ß-nitrostyrenes as binucleophiles in EtOH at room temperature using DABCO as an organocatalyst. Moreover, syn-2-benzyl-4-aryl-3,4-dihydropyrano[3,2-c]chromenes were obtained in high yields (81-86%) via a stereoselective denitrohydrogenation of the corresponding 2-benzylidene-3,4-dihydropyrano[3,2-c]chromenes using a catalytic amount of 10% Pd/C.

An organocatalytic highly efficient approach to the direct synthesis of substituted carbazoles in water.

A simple, mild, green, catalytic and general procedure for the direct synthesis of highly functionalized 1-methoxycarbonyl-2-aryl/alkyl-3-nitro-9H-carbazoles has been achieved in water medium via a one-pot domino Michael-Henry/aromatization reaction of methyl 2-(3-formyl-1H-indol-2-yl)acetates with aryl/alky-substituted ß-nitroolefins under air using DABCO (30 mol%) as an organocatalyst. In addition, the bench scale synthesis can be performed without using toxic organic solvents and a biologically important new fused carbazole has been prepared.

L-proline catalyzed stereoselective synthesis of (E)-methyl-α-indol-2-yl-ß-aryl/alkyl acrylates: easy access to substituted carbazoles, γ-carbolines and prenostodione.

A simple, mild and robust method for the stereoselective synthesis of (E)-methyl α-(3-formyl-1H-indol-2-yl)-ß-aryl/alkyl-substituted acrylates via a condensation reaction of methyl 2-(3-formyl-1H-indol-2-yl)acetate with several alkyl or aryl aldehydes using L-proline (25 mol%) as a catalyst is presented for the first time. In addition, completely metal free based high yielding methods for the syntheses of highly substituted biologically important carbazoles, γ-carbolines and the marine alkaloid prenostodione have been developed through our methodology.

Microwave assisted synthesis and characterization of acrylamide grafted gellan, application in drug delivery.

The synthesis of acrylamide-grafted-gellan gum was carried out by microwave-assisted free radical polymerization using cerric ammonium nitrate (CAN) as redox initiator. A series of graft copolymers, varying in amount of acrylamide, CAN and microwave irradiation time was prepared. The modified gum was extracted with 20% (v/v) methanol to remove the homopolymer formed during polymerization reaction. These graft copolymers were characterized by FTIR, (13)C NMR, CHN, SEM, rheological studies and DSC studies. Comparison of grafting parameters such as grafting efficiency, percentage grafting and percentage conversion were carried out among various series of graft copolymers and then correlating it with elemental analysis, DSC, viscosity results. The acute oral toxicity study of grated gum was evaluated as per OECD guideline. Tablets were prepared by incorporating antidiabetic drug metformin hydrochloride (MTF) in grafted gum along with excipients. In vitro studies were performed on prepared tablet formulations showing release up to 8 h.