Metal‐Free Route for the Synthesis of 4‐Acyl‐1,2,3‐Triazoles from Readily Available Building Blocks

Functionalized 1,2,3‐triazole heterocycles have been known for a long time and hold an extraordinary potential in diverse research areas ranging from medicinal chemistry to material science. However, the scope of therapeutically important 1‐substituted 4‐acyl‐1H‐1,2,3‐triazoles is much less explored, probably due to the lack of synthetic methodologies of good scope and practicality. Here, we describe a practical and efficient one‐pot multicomponent reaction for the synthesis of α‐ketotriazoles from readily available building blocks such as methyl ketones, N,N‐dimethylformamide dimethyl acetal, and organic azides with 100 % regioselectivity. This reaction is enabled by the in situ formation of an enaminone intermediate followed by its 1,3‐dipolar cycloaddition reaction with an organic azide. We effectively utilized the developed strategy for the derivatization of various heterocycles and natural products, a protocol which is difficult or impossible to realize by other means.     

Design and Synthesis of Urea‐Linked Aromatic Oligomers—A Route Towards Convoluted Foldamers

Herein we report the design and synthesis of crescent‐shaped and helical urea‐based foldamers, the curvature of which is controlled by varying the constituent building blocks and their connectivity. These oligomers are comprised of two, three or five alternating aromatic heterocycles (pyridazine, pyrimidine or pyrazine) and methyl‐substituted aromatic carbocycles (tolyl, o‐xylyl or m‐xylyl) connected together through urea linkages. A crescent‐shaped conformational preference is encoded within these π‐conjugated urea‐linked oligomers based on intramolecular hydrogen bonding and steric interactions; the degree of curvature is tuned by the urea connectivity to the heterocycles and the aryl groups. NMR characterization of these foldamers confirms the intramolecular hydrogen‐bonded conformation expected (Z,E configuration of the urea bond) in both the pyridazyl and pyrimidyl foldamers in solution. An X‐ray crystal structure of the N³,N⁶‐diisobutylpyridazine‐4,6‐diamine–o‐tolyl urea‐linked foldamer ( 4 ) confirms the presence of N? H???N hydrogen bonds between the heterocyclic nitrogen atom and the free hydrogen of the urea linkage. Additionally, the tolyl methyl group interacts unfavourably with the urea carbonyl oxygen, thus destabilising the alternate planar conformation.     

Metal‐Free Oxidative B−N Coupling of nido‐Carborane with N‐Heterocycles

A general method for the oxidative substitution of nido‐carborane (7,8‐C₂B₉H₁₂^?) with N‐heterocycles has been developed by using 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ) as an oxidant. This metal‐free B?N coupling strategy, in both inter‐ and intramolecular fashions, gave rise to a wide array of charge‐compensated, boron‐substituted nido‐carboranes in high yields (up to 97 %) with excellent functional‐group tolerance under mild reaction conditions. The reaction mechanism was investigated by density‐functional theory (DFT) calculations. A successive single‐electron transfer (SET), B?H hydrogen‐atom transfer (HAT), and nucleophilic attack pathway is proposed. This method provides a new approach to nitrogen‐containing carboranes with potential applications in medicine and materials.     

Rhodium‐Catalyzed Cyclization of O,ω‐Unsaturated Alkoxyamines: Formation of Oxygen‐Containing Heterocycles

O,ω‐Unsaturated N‐tosyl alkoxyamines undergo unexpected Rh^III‐catalyzed intramolecular cyclization by oxyamination to produce oxygen‐containing heterocycles. Mechanistic studies show that an aziridine intermediate seems to be responsible for the formation of the heterocycles, possibly via a Rh^V species.     

A novel route to the 5,6‐dihydro‐4‐H‐thieno[3,2‐b]pyrrol‐5‐one ring system involving an intermediate substituted‐thiophene synthesis

A novel route to electron‐deficient thienopyrrolones is disclosed. The target heterocycles are concisely constructed by condensation of activated α‐ or β‐halo‐substituted acrylonitriles, or ortho‐substituted halo, cyano heterocycles with mercaptopyruvate, followed by reduction and subsequent lactamization.     

Transition‐metal‐free Chemoselective Oxidative C−C Coupling of the sp3 C−H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3‐Aryl Oxindoles,and Benzofuro‐ and Indoloindoles

A transition‐metal (TM)‐free and halogen‐free NaOt Bu‐mediated oxidative cross‐coupling between the sp³ C−H bond of oxindoles and sp² C−H bond of nitroarenes has been developed to access 3‐aryl substituted and 3,3‐aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C−H bond of oxindoles could also react with styrene under TM‐free conditions for the practical synthesis of quaternary 3,3‐disubstituted oxindoles. The synthesized 3‐oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C−H bond of oxindole by tert ‐butoxide base in DMSO. The addition of nitrobenzene to the in‐situ generated carbanion leads to the 3‐(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3‐(nitro‐aryl) oxindole by DMSO.     

Direct N‐Arylation of Azaheterocycles with Aryl Halides under Ligand‐free Condition

A simple and efficient C? N cross‐coupling method of aryl halides with various heterocycles was reported, by using 10 mol% of CuI as catalyst and 1.2 equiv. NaH as base. Aryl iodides, aryl bromides and many substituted aryl chlorides could efficiently react with heterocycles, providing variety of N‐arylated products in good to excellent yields. The ligand‐free catalyst system was stable in air and could be readily reused.     

Synthesis and Antibacterial Activity of New 2,5‐Diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐diones

The synthesis of some biologically interesting pyrrolo‐isoxazolidine derivatives has been accomplished by the 1,3‐dipolar cycloaddition reaction of substituted open chain conjugated azomethine N‐oxides 1 with substituted N‐aryl maleimides 2 leading to the formation of new stereoisomeric 2,5‐diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives 3 in excellent yields. These stereoisomers have been characterized as cis‐ 3A and trans‐ 3B on the basis of their ¹H‐NMR spectral measurements. The synthesized compounds have been screened for their antibacterial activities and have been found to be active against the bacteria Escherichia coli and Pseudomonas aeruginosa up to a significant extent.     

New isomeric N‐substituted hydrazones of 2‐, 3‐ and 4‐pyridinecarboxaldehydes and methyl‐3‐pyridylketone

Twelve compounds unknown in the literature N‐(E)‐2‐stilbenyloxymethylenecarbonyl substituted hydrazones of 2‐, 3‐ and 4‐pyridinecarboxaldehydes, as well as methyl‐3‐pyridylketone have been prepared. The stereochemical behavior of these compounds in dimethyl‐d₆ sulfoxide solution has been studied by ¹H NMR technique. The E geometrical isomers and cis/trans amide conformers have been found for N‐substituted hydrazones 1–12. EI induced mass spectral fragmentation of these compounds were also investigated. The data obtained create the basis for distinguishing isomers.     

Morpholino‐Functionalized and Heteroaryl‐Substituted Titanocene Anti‐Cancer Drugs: Synthesis and Cytotoxicity Studies

From the carbolithiation of 6‐morpholino fulvene ( 3a ) and different ortho‐lithiated heterocycles (furan, thiophene and N‐methylpyrrole), the corresponding lithium cyclopentadienide intermediate ( 4a – c ) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in morpholino‐functionalised titanocenes 5a – c . When these titanocenes were tested against LLC‐PK cells, the IC₅₀ values obtained were of 58, 63 and 115 μM for titanocenes 5a – c respectively. The most cytotoxic titanocene 5a with an IC₅₀ value of 58 μM is found to be approximately 20 times less cytotoxic than cis‐platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC‐PK cell line, and 10 times less cytotoxic than its dimethylamino‐functionalised analogue (Titanocene C , IC₅₀ = 5.5 μM).     

A comparison of 2,7‐di­hydro‐2,2,7,7‐tetra­methyl‐3,6‐di­phenyl‐1,4,5‐thiadiazepine and the corresponding 1,1‐­dioxide

The structures of the highly substituted title heterocycles, C₂₀H₂₂N₂S and C₂₀H₂₂N₂O₂S, have been determined at 123 (1) K. Both mol­ecules possess exact C₂ symmetry and the seven‐membered rings have very similar twist‐boat conformations. The magnitudes of the C—S—C bond angles, 107.13 (6) and 108.27 (7)°, respectively, are influenced significantly by the four substituent methyl groups on the seven‐membered rings.     

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

A series of N‐substituted 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylate esters has been prepared in two steps from ethyl 2‐(2‐chloronicotinoyl)acetate. Treatment of the β‐ketoester with N,N‐dimethylformamide dimethyl acetal in N,N‐dimethylformamide (DMF) gave a 95% yield of the 2‐dimethylaminomethylene derivative. Subsequent reaction of this β‐enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr‐addition‐elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.     

NH‐Heterocyclic Aryliodonium Salts and their Selective Conversion into N1‐Aryl‐5‐iodoimidazoles

The synthesis of N‐arylimidazoles substituted at the sterically encumbered 5‐position is a challenge for modern synthetic approaches. A new family of imidazolyl aryliodonium salts is reported, which serve as a stepping stone on the way to selective formation of N1‐aryl‐5‐iodoimidazoles. Iodine acts as a “universal” placeholder poised for replacement by aryl substituents. These new λ³‐iodanes are produced by treating the NH‐imidazole with ArI(OAc)₂, and are converted to N1‐aryl‐5‐iodoimidazoles by a selective copper‐catalyzed aryl migration. The method tolerates a variety of aryl fragments and is also applicable to substituted imidazoles.     

Efficient Synthesis of 2,3‐Disubstituted‐1,3‐benzoxazines by Chlorotrimethylsilane‐Mediated Aza‐Acetalizations of Aromatic Aldehydes

A series of novel substituted 3,4‐dihydro‐2H‐1,3‐benzoxazines were prepared in moderate to good yields by aza‐acetalizations of aromatic aldehydes with 2‐(N‐substituted aminomethyl)phenols in the presence of chlorotrimethylsilane or SnCl₄. It was found that chlorotrimethylsilane was more effective for the reaction, especially for the reaction of fluorobenzaldehyde, and thereby, an efficient method for the preparation of 3,4‐dihydro‐2H‐1,3‐benzoxazines was developed. The structures of the compounds were determined by FT‐IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis.     

Theoretical Study on Gas—phase Pyrolytic Reactions of N—Ethyl,Isopropyl and N—t—Butyl Substituted 2—Aminopyrazine

Density functional theory (DFT) and ab initio methods were used to study gas‐phase pyrolytic reaction mechanisms of iV‐ethyl, N‐isopropyl and N‐t‐butyl substituted 2‐aminopyrazine at B3LYP/6–31G* and MP2/6–31G*, respectively. Single‐point energies of all optimized molecular geometries were calculated at B3LYP/6–311 + G(2d,p) level. Results show that the pyrolytic reactions were carried out through a unimolecular first‐order mechanism which were caused by the migration of atom H(17) via a six‐member ring transition state. The activation energies which were verified by vibrational analysis and correlated with zero‐point energies along the reaction channel at B3LYP/6–311 + G(2d,p) level were 252.02 kJ. mo^?1 (N‐ethyl substituted), 235.92 kJ‐mol^?1 (N‐t‐isopropyl substituted) and 234.27 kJ‐mol^?1 (N‐t‐butyl substituted), respectively. The results were in good agreement with available experimental data.     

Azo‐Coupling Reactions of Para‐X‐Benzenediazonium Cations with 3‐Ethoxythiophene in Acetonitrile

Kinetic studies for the azo‐coupling reactions of 3‐ethoxythiophene 1 with a series of 4‐X‐substituted diazonium cations 2a‐e (X = OCH₃, CH₃, H, Cl, and NO₂) have been investigated in acetonitrile at 20°C. The second‐order rate constants have been employed to determine the nucleophilicity parameters N and s of the thiophene 1 according the Mayr equation. Thus, the nucleophile‐specific parameters N and s of thiophene 1 have been derived and compared with the reactivities of other C‐nucleophiles in acetonitrile (pyrroles, furan, indoles, etc.). The Yukawa–Tsuno plot resulted in an excellent correlation (R² = 0.9980) with an r value of 0.89, suggesting that the nonlinear Hammett plot observed in the present work is due to resonance demand of the π–electron donor substituent of on the –N₂⁺ moiety. Importantly, using the concept of global electrophilicity (ω) proposed by Parr, we successfully predict the electrophilicity parameters E of seven substituted diazonium cations whose experimental data are available.     

New Approach to N‐substituted‐1,2,3,6‐tetrahydro‐pyridine‐4‐carbaldehyde,a Precursor for Synthesizing Aricept®, Isoguvacine,and Deethylibophyllidine

A new route towards the synthesis of N‐substituted‐4‐formylpiperidine using N‐benzyl or tryptaminyl‐sulfonylacetamide and α,β‐unsaturated ester as starting materials is described. Formal synthesis of Aricept^®, deethylibophyllidine, and isoguvacine, which have potential biological activities, were synthesized via this strategy.     

Intramolecular Alkene Aminocarbonylation Using Concerted Cycloadditions of Amino‐Isocyanates

The ubiquity of nitrogen heterocycles in biologically active molecules challenges synthetic chemists to develop a variety of tools for their construction. While developing metal‐free hydroamination reactions of hydrazine derivatives, it was discovered that carbazates and semicarbazides can also lead to alkene aminocarbonylation products if nitrogen‐substituted isocyanates (N‐isocyanates) are formed in situ as reactive intermediates. At first this reaction required high temperatures (150–200 °C), and issues included competing hydroamination and N‐isocyanate dimerization pathways. Herein, improved conditions for concerted intramolecular alkene aminocarbonylation with N‐isocyanates are reported. The use of βN‐benzyl carbazate precursors allows the effective minimization of N‐isocyanate dimerization. Diminished dimerization leads to higher yields of alkene aminocarbonylation products, to reactivity at lower temperatures, and to an improved scope for a reaction sequence involving alkene aminocarbonylation followed by 1,2‐migration of the benzyl group. Furthermore, fine‐tuning of the blocking (masking) group on the N‐isocyanate precursor, and reaction conditions relying on base catalysis for N‐isocyanate formation from simpler precursors resulted in room temperature reactivity, consequently minimizing the competing hydroamination pathway. Collectively, this work highlights that controlled reactivity of aminoisocyanates is possible, and provides a broadly applicable alkene aminocarbonylation approach to heterocycles possessing the β‐aminocarbonyl motif.     

Exo conformers of N‐(pyridin‐2‐yl)‐ and N‐(pyridin‐3‐yl)norbornene‐5,6‐dicarboximide crystals

Two isomeric pyridine‐substituted norbornenedicarboximide derivatives, namely N‐(pyridin‐2‐yl)‐exo‐norbornene‐5,6‐dicarboximide, (I), and N‐(pyridin‐3‐yl)‐exo‐norbornene‐5,6‐dicarboximide, (II), both C₁₄H₁₂N₂O₄, have been crystallized and their structures unequivocally determined by single‐crystal X‐ray diffraction. The molecules consist of norbornene moieties fused to a dicarboximide ring substituted at the N atom by either pyridin‐2‐yl or pyridin‐3‐yl in an anti configuration with respect to the double bond, thus affording exo isomers. In both compounds, the asymmetric unit consists of two independent molecules (Z′ = 2). In compound (I), the pyridine rings of the two independent molecules adopt different conformations, i.e. syn and anti, with respect to the methylene bridge. The intermolecular contacts of (I) are dominated by C—H...O interactions. In contrast, in compound (II), the pyridine rings of both molecules have an anti conformation and the two independent molecules are linked by carbonyl–carbonyl interactions, as well as by C—H...O and C—H...N contacts.     

Transformation of schiff bases derived from alpha‐naphthaldehyde. Synthesis,spectral data and biological activity of new‐3‐aryl‐2‐(α‐naphtyl)‐4‐thiazolidinones and N‐aryl‐N‐[1‐(α‐naphthyl)but‐3‐enyl]amines

New N‐aryl substituted 2‐(α‐naphthyl)‐4‐thiazolidinones were prepared by the cyclocondensation of α‐mercaptoacetic acid and corresponding N‐(α‐naphthyliden)anilines. The same starting materials were utilized to obtain a new series of N‐aryl‐N‐[1‐(α‐naphthyl)but‐3‐enyl]amines, which was synthesized through an addition of the Grignard reagent (allylmagnesium bromide) to the double bond C?N of the aldimines. The antichagasic and trichomonacidal in vitro activity, as well as, the antifungal and cytotoxic properties of some of these compounds were evaluated.