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A regio- and diastereoselective ring-expansion reaction of N-acylaziridines is described for the synthesis of 4-carboxamide oxazolines using InCl3. A domino Ugi–Joullié/ring-expansion reaction of arylphenylazirines, isocyanides, and carboxylic acids leads to the target products through the N-acylaziridine intermediates in the presence of the indium catalyst. The oxazolines were synthesized in moderate to excellent yields with high atom economy and high bond-forming efficiency under mild reaction conditions.

The multi-component 1,3-dipolar cycloaddition of ninhydrin, α-amino acids (or peptides), and cyclopropenes for the synthesis of spirocyclic heterocycles containing both 3-azabicyclo[3.1.0]hexane and 2H-indene-1,3-dione motifs has been developed. This method provides easy access to 3-azabicyclo[3.1.0]hexane-2,2′-indenes with complete stereoselectivity and a high degree of atom economy under mild reaction conditions. A broad range of cyclopropenes and α-amino acids have been found to be compatible with the present protocol, which offers an opportunity to create a new library of biologically significant scaffold (3-azabicyclo[3.1.0]hexane). In addition, the сomprehensive study of mechanism of azomethine ylide formation from ninhydrin and sarcosine was performed by means of M11 density functional theory (DFT) calculations. It has been revealed that experimentally observed 1-methylspiro[aziridine-2,2′-indene]-1′,3′-dione is a kinetically controlled product of this reaction and appears to act as a 1,3-dipole precursor. This theoretical study also shed light on the main transformations of the azomethine ylide derived from ninhydrin and sarcosine such as a 1,3-dipolar cycloaddition to cyclopropene dipolarophiles, a dimerization reaction and a (1+5) electrocyclization reaction. The antitumor activity of some synthesized compounds against cervical carcinoma (HeLa­) cell line was evaluated in vitro by MTS-assay.

Oxidation of primary alcohols to carboxylic acids is a fundamental transformation in organic chemistry, yet despite its simplicity, extensive use, and relationship to pH, it remains a subject of active research for synthetic organic chemists. Since 2013, a great number of new methods have emerged that utilize transition-metal compounds as catalysts for acceptorless dehydrogenation of alcohols to carboxylates. The interest in this reaction is explained by its atom economy, which is in accord with the principles of sustainability and green chemistry. Therefore, the methods for the direct synthesis of carboxylic acids from alcohols is ripe for a modern survey, which we provide in this review.1 Introduction2 Thermodynamics of Primary Alcohol Oxidation3 Oxometalate Oxidation4 Transfer Dehydrogenation5 Acceptorless Dehydrogenation6 Electrochemical Methods7 Outlook

The metal-free preparation of diazoalkanes through the ring rearrangement of bicyclic triazolines is reported here. Their use in 1,3-dipolar cycloaddition reactions with electron-withdrawing alkenes was investigated. This synthetic procedure allows differently substituted pyrazolines to be obtained in few steps and with high atom economy.

Due to a growing interest in aza-fused polyaromatic systems among various sciences, enormous attention has been continuously paid to design and synthesize novel chemotypes of N-fused hetero­cycles. During the course of continued efforts in this line, it was found that divergent access to new polycyclic N-fused heteroaromatics was enabled by choice of reaction solvent. Described herein are solvent-controlled selective approaches to three novel N-fused azacycles, benzo-[d]imidazole-pyrrolo[1,2-a]pyrazine hybrids, under mild conditions. The plausible reaction mechanism for each class of compound is suggested as well.

Metal-catalyzed reductive coupling processes have emerged as a powerful methodology for the introduction of molecular complexity from simple starting materials. These methods allow for an orthogonal approach to that of redox-neutral strategies for the formation of C–C bonds by enabling cross-coupling of starting materials not applicable to redox-neutral chemistry. This short review summarizes the most recent developments in the area of metal-catalyzed reductive coupling utilizing catalyst turnover by a stoichiometric reductant that becomes incorporated in the final product.1 Introduction2 Ni Catalysis3 Cu Catalysis4 Ru, Rh, and Ir Catalysis4.1 Alkenes4.2 1,3-Dienes4.3 Allenes4.4 Alkynes4.5 Enynes5 Fe, Co, and Mn Catalysis6 Conclusion and Outlook

An efficient stereoselective assembly strategy for the construction of pyrrolidin-2,3′-oxindole cis-fused phosphadihydrocoumarins was established. The process involves the condensation of O-vinylphosphonylated salicylaldehydes and 3-amino oxindoles followed by intermolecular cycloaddition with high diastereoselectivity and atom economy.

A transition-metal-free synthesis of pyridine derivatives by 6-endo-dig cyclization of N-propargyl enamines was developed. This method is environmentally friendly and is a high atom economy reaction that is easily accessed to provide pyridine derivatives in moderate to good yield by heating N-propargyl enamines in solvent without additives. The total synthesis of onychine was achieved in 51% yield in only two steps by using this method.

An expeditious, cost-effective synthetic methodology for a wide range of nitrogen-containing unsymmetrical trisubstituted methanes (TRSMs) is reported. The synthesis involves base-mediated 1,6-conjugate addition of heterocyclic amines and amides to substituted para-quinone methides, giving the unsymmetrical TRSMs in moderate to very good yields (up to 83%) in one pot. The low cost, mild temperature, high atom economy and yields, easy scale-up and broad substrate scope are some of the salient features of this protocol. Further, the methodology could be extended for the synthesis of meclizine-, ­hydroxyzine- and cetirizine-like molecules. The structure of one such compound, 2,6-di-tert-butyl-4-((4-chlorophenyl)(4-methylpiperazin-1-yl)methyl)phenol, was determined by single crystal X-ray analysis.

A comparative study of various widely used methods of reductive amination is reported. Specifically, such reducing agents as H2, Pd/C, hydride reagents [NaBH4, NaBH3CN, NaBH(OAc)3], and CO/Rh2(OAc)4 system were considered. For understanding the selectivity and activity of the reducing agents reviewed herein, different classes of starting materials were tested, including aliphatic and aromatic amines, as well as aliphatic and aromatic aldehydes and ketones. Most important advantages and drawbacks of the methods, such as selectivity of the target amine formation and toxicity of the reducing agents were compared. Methods were also considered from the viewpoint of green chemistry.

The iron(II)-catalyzed domino isomerization of 3-alkyl/aryl-4-arylisoxazoles provides a selective access to a wide range of structurally diverse highly substituted indole-3-carboxylates. The operational simplicity, high atom efficiency, and the use of stable starting materials and an inexpensive and low-toxicity catalyst are some of the attractive features of this tandem double ring-opening–ring-closure strategy.

A Brønsted acid catalyzed dehydrative arylation of 4-indolylmethanols with indoles has been established, leading to a series of indolyl-substituted triarylmethanes in good to excellent yields (up to 97% yield). In addition, in this Brønsted acid catalyzed dehydration process, the only byproduct was water. Accordingly, this approach can be considered to have high atom economy and to be environmentally friendly. This approach not only provides a useful strategy for the synthesis of structurally diversified indolyl-substituted triarylmethanes, but also represents the first example of a 4-indolylmethanol-involved reaction, which will advance the chemistry of indolylmethanols.

A concise, atom-economic, and highly regioselective synthetic strategy for the construction of several dinitrogen-fused heterocycles bearing bisphosphonates by 1,3-dipolar cycloaddition reaction of azomethine imines with tetraethyl vinylidene-1,1-bisphosphonate in the presence of CuI in toluene media has been developed. The targeted compounds were obtained in good yields and with excellent regioselectivity. This method for the synthesis of gem-bisphosphonates (BPs) is particularly attractive due to features such as low cost, mild conditions, atom economy, high stereoselectivity, and potential biological activity of the product.

Multiple bond-forming cascade transformations and one-pot procedures are valuable tools in organic synthesis and drug discovery. These atom-economical processes provide rapid access to natural product-like scaffolds from simple precursors. Herein, we report on ruthenium-catalyzed one-pot conversions of simple 1-alkenyl propargyl alcohols with cyclic 3-ketolactones and dienophiles. Thereby, structurally diverse fused polycycles and functionalized bicyclic structures are accessible from a common precursor with high selectivity. Some of the new drug-like molecules exhibit cytotoxic activity against KB cells.

A concise, atom-economic, and highly regio/stereoselective synthetic strategy was developed for the construction of phosphorus- and nitrogen-fused polycyclic skeleton derivatives. The one-pot, two-step, catalyst-free domino condensation/intramolecular cycloaddition reaction of various substituted 2-(vinylphosphoryloxy)benzaldehydes with pyrazolidin-3-one took place at room temperature. Three new bonds (C–C, 2 × C–N) and two new nitrogen and phosphorus heterocycles were simultaneously constructed. The reaction is particularly attractive due to features such as low cost, mild conditions, atom economy, high stereoselectivity, and potential biological activity of the product.

A waste-free and swift protocol to synthesize symmetrical and unsymmetrical diarylmethyl thioethers from diaryl carbinols and thiols in good to quantitative yields is reported. The thiol scope included alkyl and aryl thiols bearing electron-donating and electron-withdrawing groups. Short reaction time, high atom economy, inexpensive activator, free from workup and aryl halides, and gram-scale synthesis are the significant features of the new protocol.

Carbon–carbon and carbon–heteroatom coupling reactions are among the most important transformations in organic synthesis as they enable complex structures to be formed from readily available compounds under different routes and conditions. Several metal-catalyzed cross-coupling reactions have been developed creating many efficient methods accessible for the direct formation of new bonds between differently hybridized carbon atoms.During the last decade, much effort has been devoted towards improvement of the sustainability of these reactions, such as catalyst recovery and atom efficiency. Polyethylene glycol (PEG) can be used as a medium, as solid-liquid phase transfer catalyst, or even as a polymer support. PEG has been investigated in a wide variety of cross-coupling reactions either as an alternative solvent to the common organic solvents or as a support for catalyst, substrate, and ligand. In this review we will summarize the different roles of PEG in palladium- and copper-catalyzed cross-coupling reactions, with the focus on Heck, Suzuki–Miyaura, Sonogashira, Buchwald–Hartwig, Stille, Fukuyama, and homocoupling reactions. We will highlight the role of PEG, the preparation of PEGylated catalysts and substrates, and the importance for the reaction outcome and applicability.1 Introduction2 PEG in Heck Reactions3 PEG in Homocoupling Reactions4 PEG in Suzuki–Miyaura Reactions5 PEG in Sonogashira Reactions6 PEG in Buchwald–Hartwig Reactions7 PEG in Stille Reactions8 PEG in Fukuyama Reactions9 PEG in Miscellaneous Cross-Coupling Routes10 Conclusions

A regioselective synthesis of N,N′-diphenyl-3-sulfonyl-[1,1′-biphenyl]-4,4′-diamine derivatives is carried out by anodic oxidation of N,N′-diphenylbenzidine in the presence of sulfinic acids as nucleophiles via a convergent paired electrochemical process. The sulfonylated aromatic amine products are obtained under mild reaction conditions with high yields, high current efficiency and atom economy.

A versatile methodology involving the use of substituted racemic lactols as nucleophiles in the enamine-based asymmetric reactions leading to functionalized lactones with multiple stereogenic centers as one single diastereoisomer is reported. Importantly, the desired products could be easily transformed into asymmetric 2,4,5-trisubstituted piperidine derivatives, which are present in numerous alkaloid products but difficult to prepare optically enriched. Moreover, although starting from racemic precursors, the stereoisomeric products were discretely provided by simple column chromatography, which could meet the requirements of atom economy and efficiency.

1 H -Indazoles are important heterocycles as they are a substantial part in many drugs. Here, a DBU-catalyzed aza-Michael reaction of indazole with enones is described. A variety of aromatic and aliphatic enones are well tolerated and afford the corresponding N 1 -substituted 1 H -indazoles in high to excellent yields with exclusive N 1 -regioselectivity. The use of a metal-free catalyst, good substrate tolerance, mild reaction conditions, and high atom economy make this procedure a direct and facile method for the preparation of N 1 -substituted 1 H -indazoles.

A room temperature and silver-free protocol for the formation of quinolines from 2-ethynylanilines through a dimerization event was achieved using a dinuclear gold catalyst, Au2(BIPHEP)(NTf2)2. The reaction is inherently modular, allowing for the incorporation of peripheral substituents at any site of the quinoline product. The reaction is readily applied to other heterocyles also as exemplified by the preparation of naphthyridines. Competition reactions to determine the reactivity of dissimilar alkynes demonstrated that the product ratio of dimerization vs intermolecular addition is rather dependent on the electronic nature of aryl substituent on the alkynes. However, control experiments with substrates possessing internal alkynes resulted in cycloisomerization instead of expected dimerization, which is indicative of possible steric influence of the alkyne terminus in the reaction outcome.

Arylsilanes are valuable organosilicon compounds and attract significant research interest due to their promising applications in organic synthesis. The development of aromatic C–Si cross-coupling reactions represents a major challenge in both organosilicon chemistry and organic synthesis. A number of investigations are focused on developing transition-metal-catalyzed Si–C coupling reactions due to the associated high atom economy and superior functional group compatibility. This review describes recent advances in transition-metal-catalyzed selective silylations of aryl C–H and C–X (X = halide) bonds with hydrosilanes. 1 Introduction 2 Silylation of Arenes with Hydrosilanes via Aryl C–H Bond Activation 2.1 Rhodium-Catalyzed Dehydrogenative Silylations 2.2 Iridium-Catalyzed Dehydrogenative Silylations 2.3 Ruthenium-Catalyzed Dehydrogenative Silylations 2.4 Platinum-Catalyzed Dehydrogenative Silylations 2.5 Other Transition-Metal-Catalyzed Dehydrogenative Silylations 3 Silylation of Arenes with Hydrosilanes via Aryl C–X Bond Cleavage 3.1 Palladium-Catalyzed Silylations of Aryl Halides 3.2 Rhodium-Catalyzed Silylations of Aryl Halides 3.3 Platinum-Catalyzed Silylations of Aryl Halides 4 Conclusion

A new and operationally and user-simple domino protocol for the efficient synthesis of 2-alkylidene-1,3-dithiolanes has been developed via molecular iodine mediated iodocyclization of S-allylated α-enolic dithioesters at room temperature. The attractive features of this strategy include mild reaction conditions, short reaction time (5 min), high atom economy, high selectivity, easy purification, excellent yields, and wide substrate scope. Notably, many examples gave the exocyclic double bond of the 1,3-dithiolane with Z-configuration, while others gave E/Z mixtures; interconversion of the E- and Z-isomers was observed under acidic and thermal conditions.

The reaction of isocyanides with aliphatic amines in the presence of elemental sulfur was found to proceed efficiently at, or near, room temperature to produce thioureas in excellent yields and with complete atom economy.

Copper(I) oxide nanoparticles (CONPs) catalyze multicomponent coupling/cycloisomerization reactions between various 2-hydroxybenzaldehydes, secondary amines, and nonactivated alkynes to give 2,3-disubstituted 1-benzofurans. All reactions are carried out under solvent- and ligand-free conditions at 100 °C in air. The combination of copper-catalyzed C–H activation and an O-annulation process is essential for this transformation. This methodology provides rapid access to substituted 1-benzofurans in good to excellent yields with high atom economy and high catalytic efficiency. This procedure eliminates the need for propargylamine derivatives, uncyclized intermediates that make purification difficult. The CONPs and tetrabutylammonium bromide were reused successfully for up to five times.

We have developed a convenient and efficient method for the synthesis of dipeptidyl benzoxaboroles and their peptidomimetics. The novel dipeptidyl benzoxaboroles were obtained by the protecting-group-free coupling of 6-amino-1,3-dihydro-2,1-benz­oxaborol-1-ol with various N-(arylcarbonyl)phenylalanines. Bioisosteric replacement of the terminal amide moiety of dipeptidyl benzoxaboroles by 1,3,4-oxadiazoles or 4H-3,1-benzothiazin-4-one provided their peptidomimetics with good molecular diversity. These transformations were based on the pluripotency of methyl (S)-2-isothiocyanato-3-phenylpropanoate and were highlighted by mild reaction conditions, high atom efficiency, and good to excellent isolated yields. This method is a valuable addition to the development of novel drug-like boronic acid molecules.

A practical and convenient solvent-free iridium-catalyzed [2+2+2] cycloaddition of α,ω-diynes and alkynes to prepare fused arenes has been developed. The method has shown high efficiency as isoindolines, dihydroisobenzofurans and indanes have been synthesized in good to excellent yields.

The bifunctional phosphine catalyst 2′-(diphenylphosphino)biphenyl-2-ol was used in an effective synthesis of highly functionalized cyclohexanols through a cascade Michael–Henry reaction of a β-nitroolefin and a 2-(1-substituted 3-oxo-3-phenylpropyl)malononitrile. The method has the advantages of requiring mild conditions and providing a convenient workup, high diastereoselectivity, good atom economy, and a wide substrate scope, rendering it useful for the synthesis of highly functionalized cyclohexanols.

Transition-metal-catalyzed [2+2+2] cyclo(co)trimerization reactions are a powerful methodology to synthesize various complex multi-substituted (poly)cyclic molecules in a single step with optimal atom efficiency. Ever since the discovery, the reaction has been plagued by issues concerning regio- and chemoselectivity. Over the last decades many advances have been made to overcome these issues by, for example, employing regio-directing groups or tethering the reaction partners together in an intramolecular approach. These solutions, however, have certain limitations. Nowadays, it is also possible to synthesize chiral molecules by performing an asymmetric transition-metal-catalyzed [2+2+2]-cyclo(co)trimerization reaction. This review focuses on the recent advances in mechanistic insight, solving the regioselectivity issue, synthesis of chiral molecules and alternative approaches for the synthesis of substituted benzenes, pyridines and 2-pyridones. In addition, recent applications in areas such as total synthesis of natural products are also described, demonstrating that the transition-metal-catalyzed [2+2+2]-cyclo(co)trimerization reaction is a powerful tool and a welcome addition to the chemist’s ‘synthetic toolbox’. 1 Introduction 2 Synthesis of Benzene Derivatives 2.1 Mechanistic Insight 2.2 Regioselectivity 2.3 Synthesis of Chiral Systems 2.4 Other [2+2+2] Approaches 2.5 Synthesis of (Iso)quinolines 3 Synthesis of Pyridine Derivatives 3.1 Mechanistic Insight 3.2 Regioselectivity 3.3 Synthesis of Chiral Systems 4 Synthesis of Pyridone Derivatives 4.1 Mechanistic Insight 4.2 Regioselectivity 4.3 Synthesis of Chiral Systems 5 Applications 6 Future Directions 7 Conclusion

A concise synthesis of AMN107, a compound currently undergoing several phase II/III clinical trials for chronic myeloge-nous leukemia is described. The new procedure reduces the number of synthetic steps from eight to four, with an overall yield of 65%.

Highly regioselective nuclear bromination of activated aromatic and heteroaromatic compounds has been accomplished us- ing N-bromosuccinimide in tetrabutylammonium bromide. Pre- dominant para-selective monobromination of activated aromatics such as phenols and anilines, rate acceleration of bromination for moderately activated and less reactive substrates on addition of acidic montmorillonite K-10 clay, with or without microwave assis- tance, are the notable features of this protocol. Bromination of aromatics and heteroaromatics is an elec- trophilic substitution reaction of immense synthetic and industrial importance. Brominated arenes and hetero- arenes are useful as pharmaceuticals, flame retardants, agrochemicals, specialty chemicals 1 and synthetic inter- mediates capable of undergoing carbon-carbon bond for- mation via transmetalation reactions such as Heck, Stille, Suzuki, Sonogashira and Tamao-Kumada reactions. 2 In general, ring brominated aromatics and heteroaromatics exhibit interesting biological activities. 3 Halogen substi- tuted pyrimidines and purines are particularly important for their chemotherapeutic, biochemical and biophysical properties. 4 Apart from their usefulness as fluorophores and potential intermediates for photophysical probes, 5a bromocoumarins are also important as synthetic precur- sors of furocoumarins and dihydrofurocoumarins that are widely used as photosensitizers and chemotherapeutic agents to combat skin diseases, 5b-d and naturally abundant linear coumarins. 5e Despite their usefulness, scanty work is documented for regiospecific monobromination of cou- marins. 5f,g Bromination of activated arenes and hetero- arenes is often an unselective reaction resulting in a mixture of mono- and polybrominated derivatives with consequent tedious separation problems and poor atom economy. Therefore, the search for new regioselective methods of bromination has evoked great contemporary interest. Use of NBS for nuclear bromination in polar me- dia such as DMF, 6a MeCN, 6b,c aqueous NaOH, 6d in the presence of acids, 6e,f,g silica gel, 6h zeolite, 6i HZSM-5 6j and isopropylamine 7a is well-documented. These protocols of- fer different levels of selectivity depending primarily on

Microwave-assisted rapid organic reactions constitute an emerging technology that could make industrially important organic syntheses more eco-friendly than conventional reactions. In our laboratory Microwave-Induced Organic Reaction Enhancement (MORE) chemistry techniques have been developed that are safe since all reactions are conducted in open systems to avoid any chance of explosions that have been observed in sealed systems. MORE chemistry can be conducted without an added solvent if one or more of the reactants is a liquid that absorbs microwaves efficiently. When it is necessary to add a dipolar solvent for transferring microwave energy to the reactants, it is adequate to add just enough solvent to form a slurry at room temperature. The growing concern about the effect of organic solvents and chemical wastes on the environment is attracting attention to non-traditional synthetic approaches that might 'reduce pollution at the source'. In this context MORE chemistry techniques are potentially valuable as they reduce the need for organic solvents and also increase 'atom economy' by improving product selectivity and chemical yield.