Green synthesis of new pyrimido[4,5‐d]pyrimidine derivatives using 7‐aminonaphthalene‐1,3‐disulfonic acid‐functionalized magnetic Fe3O4@SiO2 nanoparticles as catalyst

We, herein, describe a novel, simple, efficient and one‐pot multi‐component procedure for the synthesis of substituted pyrimido[4,5‐d]pyrimidines via reaction of N,N‐dimethyl‐6‐amino uracil, isothiocyanate and aromatic aldehydes promoted by 7‐aminonaphthalene‐1,3‐disulfonic acid (ANDSA)‐functionalized magnetic Fe₃O₄@SiO₂ in water as solvent and without using any other harmful organic reagents. Compared with other reactions, using these organic–inorganic hybrid heterogeneous catalysts can help us to achieve a green procedure, high catalytic activity, easy recovery with an external magnetic field, and short reaction times.     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

Reactions in Water – A Greener Approach Using Ruthenium Catalysts

Reactions using transition metals as catalysts have emerged as an efficient method in the recent times. However, the selection of solvent plays a crucial role in this regard. Several solvents used traditionally suffer majorly with problems of toxicity; high boiling point etc. leading to drastic reaction conditions. Water being a non‐toxic, non‐inflammable and environmentally benign can replace the hazardous organic solvents in laboratory as well as industry. Maintaining a minimum catalyst loading percentage we can advantageously avail high levels of selectivity. Water was found to be a good solvent medium for several metal catalysed reactions. An intramolecular deprotonation mechanism is followed by the ruthenium (II) catalysts in water; thereby, facilitating the catalytic action of the metal. These studies can help the industrial chemists to utilize water as a solvent for their reactions towards improvement of their waste management procedure. This review mainly focuses on the several recent developments in the above direction.     

Extraordinary Radical Scavengers: 4‐Mercaptostilbenes

In the past decade, there was a great deal of interest and excitement in developing more active antioxidants and cancer chemoprevention agents than resveratrol, a naturally occurring stilbene. In this work, eight resveratrol‐directed 4‐mercaptostilbenes were constructed based on the inspiration that thiophenol should be a stronger radical scavenger than phenol, and their reaction rates with galvinoxyl (GO^.) and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH^.) radicals in methanol and ethyl acetate were measured by using stopped‐flow UV/Vis spectroscopy at 25 °C. Kinetic analysis demonstrates that 4‐mercaptostilbenes are extraordinary radical scavengers, and the substitution of the 4‐SH group for the 4‐OH group in the stilbene scaffold is an important strategy to improve the radical‐scavenging activity of resveratrol. Surprisingly, in methanol, some of the 4‐mercaptostilbenes are 10⁴‐times more active than resveratrol, dozens of times to hundreds of times more effective than known antioxidants (α‐tocopherol, ascorbic acid, quercetin, and trolox). The detailed radical‐scavenging mechanisms were discussed based on acidified‐kinetic analysis. Addition of acetic acid remarkably reduced the GO^. and DPPH^. radical‐scavenging rates of the 4‐mercaptostilbenes in methanol, a solvent that supports ionization, suggesting that the reactions proceed mainly through a sequential proton loss electron transfer mechanism. In contrast, an interesting acid‐promoted kinetics was observed for the reactions of the 4‐mercaptostilbenes with DPPH^. in ethyl acetate, a solvent that weakly supports ionization. The increased ratio in rates is closely correlated with the electron‐rich environment in the molecules, suggesting that the acceleration could benefit from the contribution of the electron transfer from the 4‐mercaptostilbenes and DPPH^.. However, the addition of acetic acid had no influence on the GO^.‐scavenging rates of the 4‐mercaptostilbenes in ethyl acetate, due to the occurrence of the direct hydrogen atom transfer. Our results show that the radical‐scavenging activity and mechanisms of 4‐mercaptostilbenes depends significantly on the molecular structure and acidity, the nature of the attacking radical, and the ionizing capacity of the solvent.     

CBr4‐Mediated Cross‐Dehydrogenative Coupling Reaction of Amines

A novel CBr₄‐mediated dehydrogenative Povarov/aromatization tandem reaction of glycine derivatives with alkenes, leading to complex quinoline derivatives, and a CBr₄‐mediated dehydrogenative C?H functionalization of N‐aryl tetrahydroisoquinolines with nucleophiles to form C?C and C?P bonds are reported. The reactions were performed under very simple and mild reaction conditions; only CBr₄ was used as a promoter. A plausible mechanism involving a radical process is proposed.     

One‐Pot,Three‐Component Synthesis of 1‐(2‐Hydroxyethyl)‐1H‐1,2,3‐triazole Derivatives by Copper‐Catalyzed 1,3‐Dipolar Cycloaddition of 2‐Azido Alcohols and Terminal Alkynes under Mild Conditions in Water

A safe, efficient, and improved procedure for the regioselective synthesis of 1‐(2‐hydroxyethyl)‐1H‐1,2,3‐triazole derivatives under ambient conditions is described. Terminal alkynes reacted with oxiranes and NaN₃ in the presence of a copper(I) catalyst, which is prepared by in situ reduction of the copper(II) complex 4 with ascorbic acid, in H₂O. The regioselective reactions exclusively gave the corresponding 1,4‐disubstituted 1H‐1,2,3‐triazoles in good to excellent yields. This procedure avoids the handling of organic azides as they are generated in situ, making this already powerful click process even more user‐friendly and safe. The remarkable features of this protocol are high yields, very short reaction times, a cleaner reaction profile in an environmentally benign solvent (H₂O), its straightforwardness, and the use of nontoxic catalysts. Furthermore, the catalyst could be recovered and recycled by simple filtration of the reaction mixture and reused for ten consecutive trials without significant loss of catalytic activity. No metal‐complex leaching was observed after the consecutive catalytic reactions.     

β‐Selective Aroylation of Activated Alkenes by Photoredox Catalysis

Late‐stage synthesis of α,β‐unsaturated aryl ketones remains an unmet challenge in organic synthesis. Reported herein is a photocatalytic non‐chain‐radical aroyl chlorination of alkenes by a 1,3‐chlorine atom shift to form β‐chloroketones as masked enones that liberate the desired enones upon workup. This strategy suppresses side reactions of the enone products. The reaction tolerates a wide array of functional groups and complex molecules including derivatives of peptides, sugars, natural products, nucleosides, and marketed drugs. Notably, addition of 2,6‐di‐tert‐butyl‐4‐methyl‐pyridine enhances the quantum yield and efficiency of the cross‐coupling reaction. Experimental and computational studies suggest a mechanism involving PCET, formation and reaction of an α‐chloro‐α‐hydroxy benzyl radical, and 1,3‐chlorine atom shift.     

Synthesis of 4‐Aryl‐1,7‐naphthyridine‐2(1H)‐thiones by the Electrocyclic Reaction of 4‐(1‐Arylalk‐1‐enyl)‐3‐isothiocyanatopyridines Generated in situ from the Corresponding Isocyanides

A convenient synthis for 4‐substituted and 3,4‐disubstituted 1,7‐naphthyridine‐2(1H)‐thiones 7 has been developed. The method is based on the electrocyclic reaction of 4‐(1‐arylalk‐1‐enyl)‐3‐isothiocyanatopyridines 6 , generated in situ by the treatment of the respective isocyanides 5 with S₈ in the presence of a catalytic amount of selenium. The isocyanides 5 can be easily prepared from commercially available pyridin‐3‐amine by conventional organic reactions.     

Metal‐Free Cross‐Dehydrogenative Coupling (CDC): Molecular Iodine as a Versatile Catalyst/Reagent for CDC Reactions

The development of ecofriendly methods for carbon–carbon (C?C) and carbon–heteroatom (C?Het) bond formation is of great significance in modern‐day research. Metal‐free cross‐dehydrogenative coupling (CDC) has emerged as an important tool for organic and medicinal chemists as a means to form C?C and C?Het bonds, as it is atom economical and more efficient and greener than transition‐metal catalyzed CDC reactions. Molecular iodine (I₂) is recognized as an inexpensive, environmentally benign, and easy‐to‐handle catalyst or reagent to pursue CDCs under mild reaction conditions, with good regioselectivities and broad substrate compatibility. This review presents the recent developments of I₂‐catalyzed C?C, C?N, C?O, and C?S/C?Se bond‐forming reactions for the synthesis of various important organic molecules by cross‐dehydrogenative coupling.     

Continuous‐Flow Suzuki‐Miyaura and Mizoroki‐Heck Reactions under Microwave Heating Conditions

Microwave‐assisted continuous‐flow reactions have attracted significant interest from synthetic organic chemists, especially process chemists from practical points of view, due to a less complicated shift to large‐scale synthesis based on simple and continuous access to products with low energy requirements. In this personal account, we focused on the Suzuki‐Miyaura and Mizoroki‐Heck reactions, both of which are significantly important cross‐coupling reactions for the synthesis of various functional materials. Microwave power is effective for heating. Typical homogeneous palladium catalysts, such as PdCl₂(PPh₃)₂, Pd(PPh₃)₄, and Pd(OAc)₂, as well as heterogeneous palladium catalysts, such as Pd‐film, Pd/Al₂O₃, Pd/SiO₂, and Pd supported on polymers, can be used for these reactions.     

无溶剂条件下利用微波促进下的多组分反应对2,6-二芳基-4-苯乙烯基吡啶化合物进行非预期的绿色简易合成

在无溶剂条件下,通过微波促进下的3-芳基丙烯醛肟、1-芳基乙酮及醋酸铵的多组分反应,非预期地实现了2,6-二芳基-4-苯乙烯基吡啶化合物的绿色简易合成。该方法具有环境友好、反应时间短、产率高、成本低、操作简便以及适用范围广等优点。     

Ligand‐free,copper‐catalyzed,one‐pot,three‐component synthesis of novel 1,2,3‐triazole‐linked indoles in magnetized water

Magnetized water (MW) is used as a green and new solvent‐promoting medium for the one‐pot, three‐component synthesis of novel 1,2,3‐triazole‐linked indoles catalyzed by copper iodide. A broad range of 2‐aryl‐1‐(prop‐2‐ynyl)‐1H‐indole‐3‐carbaldehydes were reacted with alkyl halides and sodium azide via copper‐catalyzed azide–alkyne cycloaddition reactions in MW in the absence of any ligand. This method offers the advantages of short reaction times, green procedure, low cost, simple work‐up, quantitative reaction yields, and no need for any organic solvent.     

Synthesis of 4‐Vinyl‐1H‐1,2,3‐triazoles on Solid Supports via Polystyrene‐Bound But‐3‐ynyl Selenide

A facile method for solid‐phase organic synthesis of 1‐substituted‐4‐vinyl‐1,2,3‐triazoles from polystyrene‐supported but‐3‐ynyl selenide has been developed. This sequential [3+2] cycloaddition and oxidation–elimination reactions could be carried out under mild reaction conditions with straightforward operation and good yield and purity of the products, and broad scope of substrates, and could be applied in this reaction system in generation of a small library of title compounds.     

Explaining the Size Dependence in Platinum‐Nanoparticle‐Catalyzed Hydrogenation Reactions

Hydrogenation reactions are industrially important reactions that typically require unfavorably high H₂ pressure and temperature for many functional groups. Herein we reveal surprisingly strong size‐dependent activity of Pt nanoparticles (PtNPs) in catalyzing this reaction. Based on unambiguous spectral analyses, the size effect has been rationalized by the size‐dependent d‐band electron structure of the PtNPs. This understanding enables production of a catalyst with size of 1.2 nm, which shows a sixfold increase in turnover frequency and 28‐fold increase in mass activity in the regioselective hydrogenation of quinoline, compared with PtNPs of 5.3 nm, allowing the reaction to proceed under ambient conditions with unprecedentedly high reaction rates. The size effect and the synthesis strategy developed herein may provide a general methodology in the design of metal‐nanoparticle‐based catalysts for a broad range of organic syntheses.     

Non‐Redox‐Metal‐Catalyzed Redox Reactions: Zinc Catalysts

The advantages of zinc catalysts, such as their low toxicity, low cost, and environmentally benignity, are encouraging organic chemists to explore their applications in organic synthesis. As a non‐redox metal, zinc catalysts have been investigated in redox reactions over the past few decades. Because of the importance of redox reactions, the interest in zinc catalysts, and the fact that no review on zinc‐catalyzed redox reactions has been published, herein, I have collected and summarized the main contributions in this area. This review is divided into two parts: reduction reactions and oxidation reactions.     

A kinetic study of the high temperature rearrangement of 4‐ethyl‐3,5‐diphenyl‐4H‐1,2,4‐triazole

The kinetics of the thermal rearrangement 4‐ethyl‐3,5‐diphenyl‐4H‐1,2,4‐triazoles, 1 , to the corresponding 1‐ethyl‐3,5‐diphenyl‐1‐alkyl‐1H‐1,2,4‐triazoles, 2 , was studied in 15‐Crown‐5 and octadecane at 330 °C. The reaction was very slow in octadecane but proceed well in 15‐Crown‐5. The reaction order for the reaction was not constant but changed from an initial second order rate law towards a first order rate law as the reaction progressed. This was confirmed by the concentration dependent reaction order, n_c, which was larger than the time dependent rate law, n_t. The rationale for the observation was, that at high substrate concentrations the reaction order was second order while at lower concentrations a competing solvent assisted reaction plays an increasing important role. The data were in agreement with a mechanism in which the neutral 4‐alkyl‐triazoles in an intermolecular nucleophilic displacement reaction form a triazolium triazolate, which in a subsequent nucleophilic reaction gives the observed product.     

Photoredox Catalysis of Aromatic β‐Ketoesters for in Situ Production of Transient and Persistent Radicals for Organic Transformation

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic β‐ketoesters by using a photocatalyst. Under visible‐light irradiation, a small amount of photocatalyst fac‐Ir(ppy)₃ generates a transient α‐carbonyl radical and persistent ketyl radical in situ. In contrast to the well‐established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α‐carbonyl radicals with alkynes to give a series of highly substituted 1‐naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional‐group tolerance make this reaction a useful synthetic tool.     

Novel Nucleophilic Substitution Reactions of 5‐Halo‐4‐Sulfur‐Substituted 5,6‐Dihydro‐2‐Pyridones

The title compounds ( 3 , 8 , 9 and 10 ) were efficiently synthesized, and their substitution reactions with various nucleophiles were carried out. The effects of leaving group, sulfur‐substituent, solvent, reaction temperature, and the nature of the nucleophiles on the reactivity and S_N2/S_N2′ regioselectivity were studied and rationalized with semi‐empirical calculations.     

Phosphosulfonic acid‐catalyzed green synthesis and bioassay of α‐aryl‐α′‐1,3,4‐thiadiazolyl aminophosphonates

A series of new α‐aminophosphonates containing 1,3,4‐thiadiazole moiety (4a–l) were synthesized via a simple, efficient, and one‐pot three‐component Kabachnik–Fields reaction of 2‐amino‐5‐ethyl‐1,3,4‐thiadiazole with various aryl/heteroaryl aldehydes and diethylphosphite under solvent‐free microwave irradiation conditions using phosphosulfonic acid, as a reusable and heterogeneous solid acid catalyst. All the title compounds were screened for radical scavenging activity by DPPH and H₂O₂ methods, and antimicrobial activity against bacteria (Gram‐positive and Gram‐negative) and fungi using the disc diffusion technique. They exhibited potent in vitro antioxidant and moderate antimicrobial activity.     

Free‐radical 4‐nitrophenylation of thieno[2,3‐b]pyridine. Part 3: Consideration of mechanistic and selectivity factors involved in the substitution process

A 1:1 geometrically oriented encounter complex between thieno[2,3‐b]pyridine (1) and 4‐nitrophenyldia‐zoacetate (2) is proposed to account for the dominant formation (ca. 64%) of the 2‐isomer in the mixture of 4‐nitrophenyl‐l isomers obtained previously. A mechanism involving one‐electron transfer from 1 to 2 plus fragmentation of 2· into 4‐nitrophenyl free radical, N₂, and acetate ion is invoked. Formation of other isomers is discussed. It is noted that there is a close correlation between orientational rules plus mechanisms of reaction for numerous free‐radical substitutions (S_R) with S_N reactions of alkyllithiums on furan, thiophene, N‐alkylpyrroles, pyridine, and their condensed aromatic molecules, including 1, as substrates. Also isomeric selectivities for S_E, S_N, and S_R substitutions into 1 were shown to be qualitatively consistent with one another. While S_E reactions occur largely at position 3 and then at 2, S_N and S_R reactions occur either at 2 or 6. Selectivity for positions 4 or 5 is small or zero.