Regio- and Stereoselective Intermolecular 1,2-Difunctionalization of Terminal Alkynes: An Approach to Access (Z)-ß-Amidovinylsulfones.

We have developed the first I2/base-catalyzed regio- and stereoselective intermolecular ß-amidosulfonylation of terminal alkynes using sodium sulfinates and quinoxalinone derivatives. The present methodology is compatible with a broad spectrum of various heterocyclic amides, terminal alkynes, and sodium sulfinates. It provides rapid access to valuable (Z)-ß-amidovinyl sulfones at mild conditions. Moreover, the synthetic application of this methodology was demonstrated by the late-stage functionalization of numerous bioactive molecules.

Copper/Zinc-Catalyzed Stitching of 2-Carbonylanilines with Bis(ynamides): Access to Pyrrolo[2,3-b]quinolines and Its Photophysical Studies.

Herein, a one-pot desulfonylative protocol enabled by copper(II)/zinc(II) salts to access pyrrolo[2,3-b]quinolines in good to excellent yields from 2-carbonylanilines and ynamide-derived buta-1,3-diynes has been reported. Significantly, various 2-carbonylanilines carrying reactive functional groups are well tolerated. Moreover, a gram-scale synthesis and synthetic application highlight the practical utility of the current protocol. Notably, the fluorescence properties of pyrrolo[2,3-b]quinolines have been recorded, and their potential use as a fluorescent probe in the imaging of live cells has been demonstrated.

Chemodivergent phosphonylation of diazocarboxylates: light-on vs. light-off reactions.

By tapping into the divergent reactivity of diazocarboxylates under thermal and photocatalytic conditions, we could develop chemodivergent phosphonylation protocols for α-diazocarboxylates with trialkyl phosphites. While the thermal reaction led to N-P bond formation affording phosphonylated hydrazones, the visible light-mediated reaction furnished phosphonylated aryl carboxylates through C-P bond formation. Both reactions are notable for their operational simplicity and mild conditions affording products in good yields without the requirement of a metal, base or photocatalyst.

Leveraging Zn(II) Catalyst: Synthesis of Amidoquinolines via (3 + 3) Heteroannulation of Aromatic Amines and Ynamides.

Herein, we present a Zn(II)-catalyzed (3 + 3) heteroannulation reaction between aromatic amines and 1,3-diynamides for the synthesis of amidoquinolines. A large number of aromatic amines are well tolerated, furnishing quinoline derivatives in up to excellent yield. Notably, various reactive functional groups have survived under the optimal reaction conditions, highlighting the mildness of the developed protocol. In addition, amines derived from bioactive molecules show modest reactivity.

Regio- and Stereoselective Intermolecular Oxysulfonylation of Alkynes with 1,3-Diketones to Access (Z)-ß-Sulfonated Enethers.

The first multicomponent regio- and stereoselective difunctionalization of alkynes via concomitant C-O and C-S bond formation using 1,3-diketones and sodium sulfinate has been developed for the synthesis of various sulfonated enethers. The viability of this strategy is unveiled by gram-scale, various synthetic modifications and late-stage functionalization. This transformation does not require any prefunctionalization, metal catalysts, and oxidants. The present operationally simple, efficient, and sustainable approach provides various functionalized olefins in a one-pot protocol with high Z-selectivity.

Regioselective Synthesis of Phenanthridines via Pd(II)-Catalyzed Annulative C(sp2)-H Activation.

A robust synthesis of phenanthridines has been described via Pd(II)-catalyzed domino C(sp2)-H activation/N-arylation using oxime esters with aryl acyl peroxides in a highly regioselective manner. This protocol is compatible with acetophenone as well as benzophenone-derived oxime esters and allows modular construction of functionalized phenanthridines with wide tolerance of electronic functionality. Further transformations were conducted to synthesize key building blocks, and control experiments were performed to understand the plausible reaction mechanism.

Palladium-Catalyzed Dearomative [4 + 2]-Cycloaddition toward Hydrocarbazoles.

An efficient method for the construction of hydrocarbazoles bearing three continuous sterically hindered stereocenters, two quaternary and one tertiary, via a highly diastereoselective palladium-catalyzed [4 + 2]-cycloaddition/dearomatization of 3-nitroindoles has been developed. The cycloaddition of 3-nitroindoles occurs at ambient conditions with a 1,4-zwitterionic intermediate, in situ generated from γ-methylidene-δ-valerolactones. The further synthetic utility of this method is demonstrated by the multifaceted transformations possible from the products. The catalytic asymmetric aspect of this transformation has also been explored.

Design and synthesis of N-acyl and dimeric N-Arylpiperazine derivatives as potential antileishmanial agents.

The current regime for leishmaniasis is associated with several adverse effects, expensive, parenteral treatment for longer periods and the emergence of drug resistance. To develop affordable and potent antileishmanial agents, a series of N-acyl and homodimeric aryl piperazines were synthesized with high purity, predicted druggable properties by in silico methods and investigated their antileishmanial activity. The in vitro biological activity of synthesized compounds against clinically validated intracellular amastigote and extracellular promastigote form of Leishmania donovani parasite showed eight compounds inhibited 50% amastigotes growth below 25 µM. The half maximal inhibitory concentration (IC50) and cytotoxicity assessment of eight active compounds, 4a, 4d and 4e demonstrated activity with an IC50 2.0 - 9.1 µM and selectivity index 10 - 42. Compound 4d (IC50 2.0 µM, SI = 42) found to be the best among them with four-folds more potent and eight-folds less toxic than the control drug miltefosine. Overall, results demonstrated that compound 4d is a promising lead candidate for further development as antileishmanial drug.

Regioselective Synthesis of Functionalized Pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones via Tandem Post-Ugi Cyclization and Gold(I)-Catalyzed Annulation.

A convenient synthesis of less explored pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones is described in two steps from Ugi adducts. The method involves acid-mediated cyclization of Ugi adducts to form dihydropyrazinones followed by gold(I)-catalyzed regioselective annulation. The generality of the transformation was established by reacting a variety of substituted dihydropyrazinones under the optimized reaction conditions to form densely functionalized pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones in good-to-excellent yields. It was also observed some of the acetone-derived Ugi adducts furnish 7-acyl-pyrroloimidazolones as a byproduct during TFA-mediated cyclization via alkyne-carbonyl metathesis and condensation.

Copper-Catalyzed Oxidative [3 + 2]-Annulation of Quinoxalin-2(1H)-one with Oxime Esters toward Functionalized Pyrazolo[1,5-a]quinoxalin-4(5H)-ones as Opioid Receptor Modulators.

Pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives as novel opioid receptor modulators have been synthesized via copper-catalyzed oxidative [3 + 2]-annulation of quinoxalin-2(1H)-one and oxime-O-acetates. This hydrazine-free C-C and N-N bond formation strategy starts with the generation of C2N1 synthon using oxime acetate, which reacts in a [3 + 2] manner with quinoxalin-2(1H)-one, followed by oxidative aromatization. The synthesized compounds were tested against opioid receptors, of which eight compounds exhibited an antagonistic effect with EC50 < 5 µM at various opioid receptors. Molecular docking studies were performed to identify the binding of active pyrazolo[1,5-a]quinoxalin-4(5H)-one ligands with hKOR protein. Docking results indicated that compounds 3d and 3g participate in hydrogen bonding with the hydroxyl group of T111 of the active site pocket residue.

Copper-catalyzed cascade reaction of tryptamines with diazo compounds to access hexahydropyrroloindoline derivatives.

A domino reaction sequence of cyclopropanation/ring-opening/iminium cyclization of tryptamine derivatives with donor-acceptor diazo compounds is developed to furnish pyrroloindolines, creating three consecutive stereogenic centers in a single step. The copper-catalyzed reaction provides pyrroloindolines at room-temperature with good substrate scope.

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates.

A practical enantioselective N-selective nitroso aldol reaction of α-methylmalonamates with a nitrosoarene is reported. The reaction employs the Takemoto thiourea catalyst for the induction of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields.

Base-Mediated Intramolecular Cyclization of α-Nitroethylallenic Esters as a Synthetic Route to 5-Hydroxy-3-pyrrolin-2-ones.

An unprecedented Cs2CO3-mediated intramolecular cyclization/rearrangement cascade that transforms α-nitroethylallenic esters to functionalized pyrrolin-2-ones has been uncovered. This reaction provides a new and practical approach for the synthesis of medicinally privileged 5-hydroxy-3-pyrrolin-2-ones under mild conditions. The broad potential of this new method was demonstrated by an efficient Au/Ag-catalyzed heteroarylation of 5-hydroxy-3-pyrrolin-2-ones employing electron-rich heteroarenes to furnish heteroaryl-lactam derivatives.

Redox-Neutral 1,3-Dipolar Cycloaddition of 2H-Azirines with 2,4,6-Triarylpyrylium Salts under Visible Light Irradiation.

A novel visible light mediated redox-neutral 1,3-dipolar cycloaddition of 2H-azirines with 2,4,6-triarylpyrylium tetrafluoroborate salts providing tetrasubstituted pyrroles has been developed. The 2,4,6-triarylpyrylium salt acts as dipolarophile as well as photosensitizer in the reaction, under blue light irradiation. The control experiments indicated single electron oxidation of 2H-azirines by photoexcited pyrylium salts, followed by coupling between an azaallenyl radical cation and triarylpyranyl radical as the key mechanistic feature. The mild conditions, wide substrate scope, and complete regioselectivity are the noticeable attributes of the reaction.

Cu(II)-Catalyzed C-N, C-O, C-Cl, C-S, and C-Se Bond Formation via C(sp2)-H Activation Using 7-Azaindole as an Intrinsic Directing Group.

A general protocol has been developed for the construction of carbon-heteroatom (C-N, C-Cl, C-O, C-S, and C-Se) bonds using the bench stable, earth-abundant, and environmentally benign copper catalyst. Only oxygen is sufficient to regenerate the copper catalyst. Control experiments suggested that the proto-demetalation step is reversible. Depending on the coupling partner, the reaction follows either disproportionation or radical pathways to complete the catalytic cycle. The synthetic utility of the developed protocol has been demonstrated via various functional group transformations.

Microwave-assisted efficient synthesis of pyrazole-fibrate derivatives as stimulators of glucose uptake in skeletal muscle cells.

The design and synthesis of a series of pyrazolo[3,4-d]pyrimidinones containing fibrate side chains have been accomplished by utilizing the concept of molecular hybridization. All the synthesized compounds were evaluated for the glucose uptake stimulatory effect in L6 rat skeletal muscle cells. Four compounds (3f, 3g, 3j and 3q) were found to show significant stimulation of glucose uptake. Further these four compounds have been examined for their Glut4 translocation stimulatory effect in L6-Glut4myc myotubes. Compound 3q was found to exert maximum increase in GLUT4myc translocation.

Regioselective synthesis of functionalized pyrazole-chalcones via a base mediated reaction of diazo compounds with pyrylium salts.

A base-mediated reaction of triaryl/alkyl pyrylium tetrafluoroborate salts with α-diazo-phosphonates, sulfones and trifluoromethyl compounds affords the corresponding functionalized pyrazole-chalcones as 5-P-5 and 3-P-3 tautomeric mixture. The reaction proceeds through an initial nucleophilic addition of diazo substrates to pyrylium salts followed by a base-mediated pyrylium ring-opening and intramolecular 1,5-cyclization to afford formal 1,3-dipolar cycloaddition products. The products underwent a Nazarov-type cyclization upon hydride reduction followed by acidic-workup, furnishing the corresponding indenyl-pyrazoles in high yields.

Lewis Base/Brønsted Acid Cocatalysis for Thiocyanation of Amides and Thioamides.

Lewis base/Brønsted acid cocatalysis for electrophilic thiocyanation of olefins is reported. Using a combination of triphenylphosphine selenide and diphenyl phosphate as a catalyst, a wide range of unsaturated amides and thioamides underwent thiocyanation to furnish thiocyanated thiazoline and oxazoline derivatives in high yields (up to 97%).

Cu(II)-Mediated Cross-Dehydrogenative Coupling of Indolines with Sulfonamides, Carboxamides, and Amines.

A facile and efficient Cu-mediated protocol for the cross-dehydrogenative coupling of indoline with sulfonamides, carboxamides, and anilines is reported. The reaction takes place through Cu-mediated C7-H activation via a 6-membered metallacycle to afford the amide and amine derivatives in good yields with a wide range of functional group tolerance. The importance of the protocol has been demonstrated by synthesizing the antiproliferative agent, ER-67836.

Fluoride-Mediated α-Selective 1,6-Conjugate Addition of Allenic Esters to p-Quinone Methides.

An efficient and expedient fluoride-mediated α-selective 1,6-conjugate addition of allenic esters to para-quinone methides has been developed. The reaction exhibited an excellent substrate scope, and a wide range of α-diarylmethylated allenic esters were obtained in good to excellent yields. It was further shown that the strategy could be extended to isatin-derived quinone methides yielding allenic esters containing 3,3-disubstituted oxindoles. The tert-butyl ester of α-diarylmethylated allenoate was effectively converted into γ-butenolide through a Au/Ag catalyzed cyclization strategy.