Selectfluor-Mediated Regioselective C-3 Alkoxylation, Amination, Sulfenylation, and Selenylation of Quinoxalin-2(1H)-ones.

A Selectfluor-promoted oxidative coupling of quinoxalin-2(1H)-ones with alcohols, amines, thiols, and selenols leading to the formation of C-O, C-N, C-S, and C-Se bonds has been developed. The protocol provided good to excellent (53-95%) yields of a wide range of quinoxalin-2(1H)-ones decorated with alkoxy, alkylamino, alkylthio, and arylselenyl groups at the C3-position under metal- and photocatalyst-free conditions. The reaction is believed to proceed through a radical pathway. A broad substrate scope including bioactive molecules, mild reaction conditions, readily available coupling partners, high yields, scalability, step-economy, and metal- and photocatalyst-free conditions are the highlighting features of the method. The synthetic utility of the developed protocol was demonstrated by gram-scale synthesis, C3-alkoxylation of quinoxaline-2(1H)-one with natural alcohols, and synthesis of aldose reductase (ALR2) inhibitor and histamine-4 receptor antagonist in good yields.

Catalyst-Controlled Regiodivergent Oxidative Annulation of 2-Arylimidazo[1,2-a]pyridines with Cinnamaldehyde Derivatives for Construction of Fused N-Heterocyclic Frameworks.

Catalyst-dependent regioselective oxidative annulation of 2-arylimidazo[1,2-a]pyridines with cinnamaldehyde derivatives to construct fused N-heterocyclic frameworks has been described. The annulation reaction afforded 5-arylnaphtho[1',2':4,5]imidazo[1,2-a]pyridine-6-carbaldehydes in the presence of [RhCp*Cl2]2 as catalyst while 1,7-diarylimidazo[5,1,2-cd]indolizine-6-carbaldehydes were obtained using Pd(OAc)2 as catalyst. The reaction produced annulated products in good yields and exhibited broad substrate scope and excellent functional group tolerance. The method provides two different isomeric annulated products bearing an aldehyde functionality which can be elaborated into an array of functionalities leading to valuable compounds.

KPF6-Mediated Esterification and Amidation of Carboxylic Acids.

A novel KPF6-promoted green method has been developed for the synthesis of esters and amides. A wide range of carboxylic acids and alcohols or amines worked well under the developed reaction conditions, thus providing good to excellent (61-98%) yields of the corresponding esters and amides. The method worked well with bioactive substrates such as cholesterol, levulinic acid, and linoleic acid. Wide substrate scope, operational simplicity, scalability, and sustainability make this protocol a practical and economically attractive approach for the preparation of ester and amides.

Mechanochemical Ruthenium-Catalyzed Ortho-Alkenylation of N-Heteroaryl Arenes with Alkynes under Ball-Milling Conditions.

The mechanochemical, solvent-free Ru(II)-catalyzed alkenylation of N-heteroaryl arenes with alkynes has been successfully described. A wide spectrum of arenes bearing N-heteroaryl moieties such as imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine, benzo[d]imidazo[2,1-b]thiazole, imidazo[2,1-b]thiazole, 2H-indazole, 1H-indazole, 1H-pyrazole, and 1,2,4-oxadiazol-5(4H)-one as a directing group reacted with various substituted alkynes under ball milling in the presence of [Ru(p-cymene)Cl2]2, affording dialkenylated products in moderate to good yields. The reaction of 2,3-dihydrophthalazine-1,4-dione with 1-phenyl-1-propyne afforded a monoalkenylated product. Similarly, reaction of 2-phenylimidazo[1,2-a]pyridine with aliphatic terminal alkynes produced a monoalkenylated derivative as the major product along with minor amount of dialkenylated product. The developed method exhibited excellent functional group compatibility, broad substrate scope, shorter reaction times, and no external heating. Moreover, the method can be readily scaled-up as demonstrated by gram-scale synthesis of 2-(2,6-bis((E)1-phenylprop-1-en-2-yl)phenyl)imidazo[1,2-a]pyridine.

Rhodium(III)-Catalyzed Dehydrogenative Annulation and Spirocyclization of 2-Arylindoles and 2-(1H-Pyrazol-1-yl)-1H-indoles with Maleimides: A Facile Access to Isogranulatimide Alkaloid Analogues.

A Rh(III)-catalyzed dehydrogenative annulation and spirocyclization of 2-arylindoles and 2-(1H-pyrazol-1-yl)-1H-indole with maleimides is described. The cascade protocol provided highly functionalized benzo[a]pyrrolo[3,4-c]carbazole-1,3(2H,8H)-diones and spiro[isoindolo[2,1-a]indole-6,3'-pyrrolidine]-2',5'-diones in good to excellent. The developed reaction methodology exhibited broad substrate scope with good functional group tolerance and is operationally simple and scalable. Photophysical properties of the annulated products were investigated. The annulated product of 2-(1H-pyrazol-1-yl)-1H-indole showed high absorption and emission values with a large red-shift as compared to that of 2-phenylindole.

Palladium-Catalyzed Weakly Coordinating Lactone-Directed C-H Bond Functionalization of 3-Arylcoumarins: Synthesis of Bioactive Coumestan Derivatives.

A palladium-catalyzed highly regioselective ortho-selective C-H functionalization of 3-arylcoumarins has been developed. The method utilizes the weakly coordinating lactone as a directing group. The versatility of the strategy is highlighted by developing methodologies for alkenylation, halogenation, fluoroalkoxylation, and hydroxylation. Different functional groups were well tolerated, and functionalized coumarins were obtained in moderate to high yields. The method also showed good selectivity for monofunctionalization versus difunctionalization. The generated ortho-hydroxy derivatives were cyclized in the presence of DDQ, thus developing a simple and fast method for the synthesis of bioactive coumestan from 3-arylcoumarins.

TEMPO-Mediated Synthesis of Indolyl/Imidazo[1,2-a]pyridinyl-Substituted para-Quinone Methides from Butylated Hydroxytoluene.

A series of indolyl or imidazo[1,2-a]pyridinyl-substituted para-quinone methides (p-QMs) is prepared by a metal-free, TEMPO-mediated cross-dehydrogenative coupling of butylated hydroxytoluene (BHT) with indoles or imidazo[1,2-a]pyridines in good to high yields. Broad substrate scope with respect to indoles and imidazo[1,2-a]pyridines, good functional group tolerance, and acid/base-free conditions are advantageous feature of the developed protocol. The method was amenable for scale-up on the gram scale. Based on control experiments, a reaction mechanism is proposed to describe this transformation.

Switchable regioselective hydroalkylation of 2-arylindoles with maleimides.

A condition-based switchable regioselective hydroalkylation of 2-arylindoles with maleimides has been developed. The reaction in the presence of a Ru(ii)-catalyst resulted in hydroalkylation at the ortho-position of the C2-aryl ring via C-H activation whereas the reaction in the absence of the catalyst in TFE resulted in C3-hydroalkylation. Various functional groups both on the indole ring and on the 2-phenyl ring were tolerated and a wide range of hydroalkylated products were obtained in moderate to high (37-88%) yields.

Phenyliodine(III) Diacetate-Mediated 1,2-ipso-Migration in Mannich Bases of Imidazo[1,2-a]pyridines: Preparation of N-Acetoxymethyl/Alkoxymethyl-N-arylimidazo[1,2-a]pyridine-3-amines.

Phenyliodine(III) diacetate -mediated 1,2-ipso-migration of an imidazo[1,2-a]pyridine ring via the formation of an aziridine intermediate in Mannich bases derived from imidazo[1,2-a]pyridines, 2-pyridylamines or arylamines, and formaldehyde is reported. The imidazo[1,2-a]pyridines bearing different substituents showed excellent migratory aptitude and resulted in corresponding N-acetoxymethyl-, N-alkoxymethyl-, and N-hydroxymethyl-N-arylimidazo[1,2-a]pyridine-3-amine derivatives in moderate to excellent (42 examples; 35-93%) yields. Radical trapping experiments confirmed the involvement of a non-radical intermediate. The developed protocol is amenable for a scale-up reaction, and synthetic utility of N-acetoxymethyl products was demonstrated by transforming them to corresponding N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines.

Metal-free benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids.

A simple and straightforward approach has been realized for the direct benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids in the presence of K2S2O8 as an oxidant. Various functional groups were tolerated on both imidazoheterocycles and arylglyoxylic acids and a wide range of C5-benzoyl-imidazoheterocycles were obtained in good to high yields (50-84%). Radical trapping experiments confirmed the involvement of the radical pathway. The developed protocol is amenable for a scale-up reaction.

A straightforward TBHP-mediated synthesis of 2-amidobenzoic acids from 2-arylindoles and their antimicrobial activity.

A simple and highly efficient strategy has been developed for the synthesis of 2-amidobenzoic acids through the tert-butyl hydroperoxide (TBHP)-mediated oxygenation and sequential ring opening of 2-arylindoles in a one-pot fashion under metal-free aerobic conditions. The developed synthetic protocol is operationally simple, tolerates a wide range of functional groups, and is amenable to the gram-scale. Radical trapping experiments revealed that the reaction involves a radical pathway. The synthesized compounds (2a-s) were tested for in vitro antimicrobial activity. Among all screened compounds, 2d showed the maximum antibacterial activity against P. aerugunosa (ZOI = 17 mm, MIC = 32 µg mL-1) and compounds 2d and 2p showed the maximum (32 µg mL-1) antifungal activity against A. flavus and C. albicans.

Synthesis of imidazopyridine-fused indoles via one-pot sequential Knoevenagel condensation and cross dehydrogenative coupling.

A simple and efficient strategy for the synthesis of imidazopyridine-fused indoles has been developed that involves one-pot sequential Knoevenagel condensation of readily available active methylene azoles with N-substituted-1H-indole-3-carboxaldehydes or N-substituted-1H-indole-2-carboxaldehydes followed by palladium-catalyzed intramolecular cross dehydrogenative coupling reaction. A series of 36 derivatives was prepared by using this strategy. The products were obtained in moderate to excellent (32-94%) yields and showed broad substrate scope with tolerance of various functional groups and was amiable for gram scale preparation without problems.

Mono and Dinuclear Palladium Pincer Complexes of NNSe Ligand as a Catalyst for Decarboxylative Direct C-H Heteroarylation of (Hetero)arenes.

This report describes the synthesis of a new NNSe pincer ligand and its mono- and dinuclear palladium(II) pincer complexes. In the absence of a base, a dinuclear palladium pincer complex (C1) was isolated, while in the presence of Et3 N base a mononuclear palladium pincer complex (C2) was obtained. The new ligand and complexes were characterized using techniques like 1 H, 13 C{1 H} nuclear magnetic resonance (NMR), fourier transform infrared (FTIR), high-resolution mass spectrometry (HRMS), ultraviolet-visible (UV-Visible), and cyclic voltammetry. Both the complexes showed pincer coordination mode with a distorted square planar geometry. The complex C1 has two pincer ligands attached through a Pd-Pd bond in a dinuclear pincer fashion. The air and moisture-insensitive, thermally robust palladium pincer complexes were used as the catalyst for decarboxylative direct C-H heteroarylation of (hetero)arenes. Among the complexes, dinuclear pincer complex C1 showed better catalytic activity. A variety of (hetero)arenes were successfully activated (43-87 % yield) using only 2.5 mol % of catalyst loading under mild reaction conditions. The PPh3 and Hg poisoning experiments suggested a homogeneous nature of catalysis. A plausible reaction pathway was proposed for the dinuclear palladium pincer complex catalyzed decarboxylative C-H bond activation reaction of (hetero)arenes.

Bulky Selenium Ligand Stabilized Trans-Palladium Dichloride Complexes as Catalyst for Silver-Free Decarboxylative Coupling of Coumarin-3-Carboxylic Acids.

This report describes the syntheses of three new trans-palladium dichloride complexes of bulky selenium ligands. These complexes possess a Cl-Pd-Cl rotor spoke attached to a Se-Pd-Se axle. The new ligands and palladium complexes (C1-C3) were characterized with the help of NMR, HRMS, UV-Vis., IR, and elemental analysis. The single-crystal structure of metal complex C2 confirmed a square planar geometry of complex with trans-orientation. The X-ray structure revealed intramolecular secondary interactions (SeCH-Cl) between chlorine of PdCl2 and CH2 proton of selenium ligand. Variable-temperature NMR data shows coalescence of diastereotopic protons, which indicates pyramidal inversion of selenium atom at elevated temperature. The relaxed potential energy scan of C2 suggests a rotational barrier of ∼12.5 kcal/mol for rotation of chlorine atom through Cl-Pd-Cl rotor. The complex C3 possesses dual intramolecular secondary interactions (OCH2 -Cl and SeCH2 -Cl) with stator ligand. Molecular rotor C2 was found to be a most efficient catalyst for the decarboxylative Heck-coupling under mild reaction conditions. The protocol is applicable to a broad range of substrates with large functional group tolerance and low catalyst loading (2.5 mol %). The mechanism of decarboxylative Heck-coupling reaction was investigated through experimental and computational studies. Importantly the reaction works under silver-free conditions which reduces the cost of overall protocol. Further, the catalyst also worked for decarboxylative arylation and decarboxylative Suzuki-Miyaura coupling reactions with good yields of the coupled products.

TEMPO-Mediated Cross-Dehydrogenative Coupling of Indoles and Imidazo[1,2-a]pyridines with Fluorinated Alcohols.

A simple and highly efficient metal-free method has been developed for hydroxyfluoroalkylation of indoles and imidazo[1,2-a]pyridines via TEMPO-mediated C(sp3)-H and C(sp2)-H bond cross-dehydrogenative coupling of fluorinated alcohols and indoles. The protocol showed broad substrate scope, afforded good yields of hydroxyfluoroalkylated products, and was amenable for scale-up. Mechanistic investigation indicated involvement of the radical pathway.

A selenium-coordinated palladium(ii) trans-dichloride molecular rotor as a catalyst for site-selective annulation of 2-arylimidazo[1,2-a]pyridines.

This report describes the synthesis of a new class of secondary interaction (SeCHCl)-controlled molecular rotor having a Cl-Pd-Cl rotor spoke attached onto a Se-Pd-Se axle. NMR data acquired at various temperatures established ΔG/ΔG values of 15.5 and 17.2 kcal mol-1 for a roughly 4.5 Å-long rotor. The molecular rotor showed excellent catalytic activity with reverse regioselectivity for annulation of 2-arylimidazo[1,2-a]pyridines (yields: ∼53-78%) with only 1.5 mol% catalyst loading.