Photoinduced [3+2] Cycloaddition of Carbenes and Nitriles: A Versatile Approach to Oxazole Synthesis.

We have developed a photoinduced protocol for the synthesis of pharmaceutically important oxazole molecules using diazo- and nitrile-containing reactants. The process involves the initial photolysis of the diazo compound to afford singlet carbenes, which are tapped by nitriles in a [3+2] cycloaddition fashion to give substituted oxazoles. With di-nitrile compounds, useful bis-oxazoles were obtained. The applicability of the transformation is showcased through the expedient synthesis of small-molecule drugs and biologically relevant molecules such as felbinac, pimprinine, texamine, ugnenenazole etc. The protocol is also useful for the generation of 2 H and 13 C isotope labelled oxazoles. Merging photolysis with continuous-flow chemistry was demonstrated for scaling up the reaction. The non-requirement of metal catalysis or photosensitizers to harness the light energy with blue light sufficing the execution of the reaction makes it a versatile and general protocol for the synthesis of structurally diverse oxazoles.

Metal-free synthesis and study of glycine betaine derivatives in water for antimicrobial and anticancer applications.

A sustainable synthesis of interesting glycine betaine derivatives from cyclic 3°-amines viz. N-methyl morpholine (NMM), N-methyl piperidine (NMP), and 1,4-diazabicyclo[2.2.2]octane (DABCO) with numerous aryl diazoacetates 1 in water and under blue LED is reported. Generally, 3°-amines and metal carbenoids (from diazoacetates with transition metal catalysts) provide C-H insertion at the α-position of the amines. Computational comparison of the metal carbenoid with the singlet carbene (metal free and generated under blue LED) realized the difference in reactivity. Next, experimental results corroborated the preliminary findings. The products were isolated either by precipitation of the solid or gel-like final products from the aqueous reaction mixture without any chromatographic purification. The reaction mechanism was realized by control experiments. These compounds exhibit selective bactericidal properties against Gram-positive S. aureus, induce lipid droplets (LDs) formation in HePG2 cells and single crystal X-ray diffraction study of their halogenated analogs reveal interesting Hal … Hal contacts.

Unveiling catalyst-free electro-photochemical reactivity of aryl diazoesters and facile synthesis of oxazoles, imide-fused pyrroles and tetrahydro-epoxy-pyridines via carbene radical anions.

Herein, we report a reagent-less (devoid of catalyst, supporting electrolyte, oxidant and reductant) electro-photochemical (EPC) reaction [electricity (50 µA) and blue LED (5 W)] of aryl diazoesters to generate radical anions which are subsequently reacted with acetonitrile or propionitrile and maleimides to generate diversely substituted oxazoles, diastereo-selective imide-fused pyrroles and tetrahydroepoxy-pyridines in good to excellent yield. Thorough mechanistic investigation including a 'biphasic e-cell' experiment supports the reaction mechanism involving a carbene radical anion. The tetrahydroepoxy-pyridines could be fluently converted to fused pyridines resembling vitamin B6 derivatives. The source of the electric current in the EPC reaction could be a simple cell phone charger. The reaction was efficiently scaled up to the gram level. Crystal structure, 1D, 2D NMRs and HRMS data confirmed the product structures. This report demonstrates a unique generation of radical anions via electro-photochemistry and their direct applications in the synthesis of important heterocycles.

Blue LED Induced Three Component Reactions for the Generation of 4,6-Dioxo-hexahydro-1H-furo[3, 4-c] pyrrole: Their Evaluation as Anticancer Agents through PARP-1 Inhibition.

Herein we report a catalyst, metal and additive free generation of carbonyl ylides by blue LED irradiation of aryl diazoacetates in presence of aldehydes. The resulting ylides underwent [3+2] cycloaddition with substituted maleimides present in the reaction mixture to afford 4, 6-dioxo-hexahydro-1H-furo[3, 4-c] pyrrole in excellent yields. Fifty compounds were synthesized based on this scaffold. Molecular docking indicated them to be potential poly ADP ribose polymerase (PARP) inhibitor. Screening a representative member of the library against PARP-1 enzyme revealed a few potential inhibitors with IC50 of 600-700 nM. The phenotypic screening against MCF7, A549 and HepG2 cells furthermore indicated that these compounds selectively inhibit the proliferation of A549, HeLa and HepG2 cells with IC50 of 1-2 µM. The mechanism of action of the most active compound at the cellular level was investigated.

Light induced diversity-oriented synthesis (DOS) library of annulated indolizine fluorophores for imaging non-lysosomal lipid droplets (LDs).

We report the design, synthesis, and biological evaluation of a novel class of annulated indolizines as fluorescent probes. The compounds were generated through an eco-friendly, blue LED-induced domino reaction in ethyl acetate. A library of 24 coloured compounds exhibited tuneable emissions. One of the compounds (which we call DASS-fluor) proved to be an excellent polarity sensing probe. It is biocompatible, photostable, and detects specific types of lipid droplets (LDs in response to oleic acid, stress, and drug-induced autophagy in lungs and hepatic carcinoma cells). In comparison to Nile Red (a commercial probe), DASS-fluor can differentiate non-lysosomal LDs from lysosomal LDs and offers an advantage in precisely mapping drug-induced lipidosis caused by increased non-lysosomal LDs in cancerous cells. This unique probe could be a potential fluorescent marker for specific types of lipidosis induced by drugs.

Cu(II)-Catalyzed Multicomponent Reaction of Pyridine Derivatives/Isoquinolines with Iodonium Ylide and 1,4-Quinones Using Mechanochemistry.

An efficient copper-catalyzed solvent-free multicomponent reaction for pyridine derivatives, iodonium ylides, and 1,4-quinones is developed via a room-temperature ball milling technique. The reported protocol provides a sustainable synthesis of isoindolo[2,1-a]pyridine/isoquinoline class of molecules in good to excellent yield in a mixer mill (RETSCH MM400) engaging the commercially available copper acetate (Cu(OAc)2) as a catalyst without the use of organic solvents. It tolerates a myriad of electron-rich and electron-deficient functionalities on the pyridine moiety. The scalability of the protocol was illustrated by successfully performing the reaction in the gram scale. The photoluminescence and related cellular study revealed that these can be used as a fluorescent chromophore-based cellular probe. A clean reaction profile and a facile experimental setup that is devoid of anhydrous reaction conditions and toxic organic solvents have established the advantages of this strategy over the reported process.

Blue Light-Emitting Diode-Mediated In Situ Generation of Pyridinium and Isoquinolinium Ylides from Aryl Diazoesters: Their Application in the Synthesis of Diverse Dihydroindolizine.

Blue light-emitting diode-mediated environmentally sustainable three component reactions among pyridine/isoquinoline 1/2, aryl diazoesters 3, and acrylic ester/3-alkenyl oxindoles 5/6 provide various dihydroindolizines 7 to 9 in excellent yield. The principle of the strategy is photolytic generation of nitrogen ylides from N-heteroarenes and aryl diazoesters and their subsequent [3 + 2] cycloaddition reaction with dipolarophiles. Detailed mechanistic analysis of the transformation through control experiments establishes this strategy as the foundation for the photolytic multicomponent reaction.

Blue LED-Mediated N-H Insertion of Indoles into Aryldiazoesters at Room Temperature in Batch and Flow: Reaction Kinetics, Density Functional Theory, and Mechanistic Study.

Mild blue light-mediated N-H insertion of indole and its derivatives into aryldiazoesters has been reported in a batch and flow strategy to afford the corresponding N-alkylated product in moderate-to-excellent yield. Detailed high-performance liquid chromatography-based reaction kinetics measurements, control experiments, and kinetic isotope effect reveal that 3-substituted indoles with electron-withdrawing groups such as -CN and -CHO facilitated the product formation, whereas the electron-donating group retarded the process. The neutral indole performed in between them. Furthermore, Hammett plot and density functional theory-based transition-state optimization studies showed substantial correlation of the electronic nature of the substituents at the C3 position of indoles with the rate of the N-H insertion reaction. The strategy was utilized to synthesize a key intermediate for the natural product (-)-psychotrimine.