Synthesis and Antibacterial Evaluation of Some Semicarbazides and 1,2,4‐Triazol‐5‐Ones Containing Thiophene Moieties

In this study, some 3‐(thiophen‐2‐ylmethyl)‐4‐substituted‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐one derivatives were synthesized by the cyclization reaction of 1‐(thiophen‐2‐ylacetyl)‐4‐substituted semicarbazide derivatives in alkaline medium or in the immediate reaction of thiophen‐2‐yl‐acetic acid hydrazide with isocyanates. The structures of all new compounds were confirmed by analytical and spectroscopic methods. Selected derivatives were evaluated in vitro against several species of aerobic bacteria. Some of them showed activity against S. pyogenes, P. aeruginosa and S. aureus.     

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.     

Reactivity of Hydroxy and Amino Derivatives of 2‐Phenyl‐1H‐imidazoline and 2‐Phenyl‐1H‐imidazole toward Isocyanates: Synthesis of Appropriate Carbamates and Ureas

Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole toward substituted phenyl isocyanates was studied. When mentioned imidazoline was treated with 2.5 equiv of substituted phenyl isocyanate, three N,O‐dicarboxamides were prepared (substituents are H, 4‐NO₂, and 4‐CH₃). Subsequently, N,O‐diacetylated 2‐(4‐hydroxyphenyl)‐1H‐imidazoline was prepared and selective deprotection method was developed for preparation of 1‐acetyl‐2‐(4‐hydroxyphenyl)‐1H‐imidazoline using diethylamine in acetone. Six carbamates derived from this imidazoline were then prepared using 1.1 equiv of substituted phenyl isocyanates (substituents are H, 4‐CH₃, 4‐OCH₃, 4‐NO₂, 4‐CN, and 3‐CF₃). Finally, two carbamates were prepared from 2‐(4‐hydroxyphenyl)‐1H‐imidazole (substituents are 4‐NO₂ and 4‐CN). No reactivity to imidazole ring was observed in this case. Eight derivatives were subjected to antimycobacterial screening. Concurrently, reactivity of 2‐(2‐aminophenyl)‐ and 2‐(2‐hydroxyphenyl)‐1H‐imidazole toward aliphatic and aromatic isocyanates was studied. Eight ureas were prepared using equivalent mixture of 2‐(2‐aminophenyl)‐1H‐imidazole and isocyanate (Et, Pr, isoPr, terc‐Bu, Cy, Ph, 4‐CH₃C₆H₄, 4‐CNC₆H₄). Similar attempts to obtain related carbamates from 2‐(2‐hydroxyphenyl)‐1H‐imidazole lead only to three substituted phenyl carbamates (substituents are 4‐CH₃, 4‐NO₂, and 4‐CN). In both cases, no reactivity to imidazole ring was observed again.     

Palladium‐Catalyzed Enantioselective Decarboxylative Cycloaddition of Vinylethylene Carbonates with Isocyanates

An efficient method for the enantioselective construction of β‐substituted β‐vinylglycinol derivatives through palladium‐catalyzed decarboxylative cycloaddition of vinylethylene carbonates with isocyanates was developed. By using a palladium complex generated in situ from [Pd₂(dba)₃] ? CHCl₃ (dba=dibenzylideneacetone) and (S)‐Segphos as a catalyst under mild reaction conditions, the process provided 4‐substituted‐4‐vinyloxazolidin‐2‐ones in high yields with a high level of enantioselectivity. The stereochemical outcome of the reaction was explained by DFT calculations and the synthetic utility of the process was demonstrated by the gram‐scale transformation and formal synthesis of MK‐0731 as a kinesin spindle protein inhibitor.     

A Convenient Synthesis of N‐Aryl Benzamides by Rhodium‐Catalyzed ortho‐Amidation and Decarboxylation of Benzoic Acids

The rhodium‐catalyzed amidation of substituted benzoic acids with isocyanates by directed C?H functionalization followed by decarboxylation to afford the corresponding N‐aryl benzamides is demonstrated, in which the carboxylate serves as a unique, removable directing group. Notably, less common meta‐substituted N‐aryl benzamides are generated readily from more accessible para‐ or ortho‐substituted groups by employing this strategy.     

Synthesis of Spiropyrrolidines via Five‐Component 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Olefinic Dipolarophiles Generated In Situ Simultaneously

An efficient and straightforward five‐component cascade protocol has been developed to synthesize the highly substituted dispiroindenoquinoxaline pyrrolidine derivatives from ninhydrin, 1,2‐phenylenediamine, sarcosine, 1,3‐indanedione, and aldehydes via cascade reactions under mild conditions, in which 1,3‐dipole azomethine ylide and the dipolarophile were simultaneously generated in situ. This novel method is complementary to the classical Huisgen cycloaddition in that it is well‐suited to the preparation of dispiroindenoquinoxaline pyrrolidine derivatives.     

Evolution of a Short Route to Strychnine by Using the Samarium‐Diiodide‐Induced Cascade Cyclization as a Key Step

This comprehensive report accounts the development of a highly diastereoselective samarium diiodide‐induced cascade reaction of substituted indolyl ketones. The complexity‐generating transformation with SmI₂ allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra‐ or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI₂‐induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.     

Preparation of 3‐aminoalkylbenzo[b]thiophenes

We report an efficient entry into substituted 3‐(ω‐aminoalkyl)‐benzo[b]thiophenes that allows rapid generation of structural diversity. Alkylation of α,ω‐dihaloketones with thiophenols followed by acid‐catalysed cyclisation led to an efficient synthesis of 3‐(ω‐aminoalkyl)benzo[b]thiophenes. 2‐Carboethoxy derivatives were prepared using a directed ortho‐metallation approach. These derivatives were readily converted into the corresponding amines.     

Revisiting the Hinsberg Reaction: Facile and Expeditious Synthesis of 3‐Substituted Quinoxalin‐2(1H)‐ones under Catalyst‐Free Conditions in Water

Substituted benzene‐1,2‐diamine reacted with various α‐keto esters at 50° under mild conditions for 15 min using H₂O as reaction medium, providing a variety of 3‐substituted quinoxalinone derivatives in excellent yields. The reaction was instantaneous, and products were isolated by simple filtration.     

Visible‐Light‐Induced Trifluoromethylation of Isonitrile‐Substituted Methylenecyclopropanes: Facile Access to 6‐(Trifluoromethyl)‐7,8‐Dihydrobenzo[k]phenanthridine Derivatives

A new visible‐light‐induced trifluoromethylation of isonitrile‐substituted methylenecyclopropanes is developed. A range of substituted 6‐(trifluoromethyl)‐7,8‐dihydrobenzo[k]phenanthridine derivatives are readily furnished by this newly developed tandem reaction with moderate to good yields. This reaction allows the direct formation of two six‐membered rings and three new C?C bonds, including the C?CF₃ bond, under visible light irradiation.     

In Situ Synthesis of Alkenyl Tetrazines for Highly Fluorogenic Bioorthogonal Live‐Cell Imaging Probes

In spite of the wide application potential of 1,2,4,5‐tetrazines, particularly in live‐cell and in vivo imaging, a major limitation has been the lack of practical synthetic methods. Here we report the in situ synthesis of (E)‐3‐substituted 6‐alkenyl‐1,2,4,5‐tetrazine derivatives through an elimination–Heck cascade reaction. By using this strategy, we provide 24 examples of π‐conjugated tetrazine derivatives that can be conveniently prepared from tetrazine building blocks and related halides. These include tetrazine analogs of biological small molecules, highly conjugated buta‐1,3‐diene‐substituted tetrazines, and a diverse array of fluorescent probes suitable for live‐cell imaging. These highly conjugated probes show very strong fluorescence turn‐on (up to 400‐fold) when reacted with dienophiles such as cyclopropenes and trans‐cyclooctenes, and we demonstrate their application for live‐cell imaging. This work provides an efficient and practical synthetic methodology for tetrazine derivatives and will facilitate the application of conjugated tetrazines, particularly as fluorogenic probes for live‐cell imaging.     

Asymmetric Substitutions of 2‐Lithiated N‐Boc‐piperidine and N‐Boc‐azepine by Dynamic Resolution

Proton abstraction of N‐tert‐butoxycarbonyl‐piperidine (N‐Boc‐piperidine) with sBuLi and TMEDA provides a racemic organolithium that can be resolved using a chiral ligand. The enantiomeric organolithiums can interconvert so that a dynamic resolution occurs. Two mechanisms for promoting enantioselectivity in the products are possible. Slow addition of an electrophile such as trimethylsilyl chloride allows dynamic resolution under kinetic control (DKR). This process occurs with high enantioselectivity and is successful by catalysis with substoichiometric chiral ligand (catalytic dynamic kinetic resolution). Alternatively, the two enantiomers of this organolithium can be resolved under thermodynamic control with good enantioselectivity (dynamic thermodynamic resolution, DTR). The best ligands found are based on chiral diamino‐alkoxides. Using DTR, a variety of electrophiles can be used to provide an asymmetric synthesis of enantiomerically enriched 2‐substituted piperidines, including (after Boc deprotection) the alkaloid (+)‐β‐conhydrine. The chemistry was extended, albeit with lower yields, to the corresponding 2‐substituted seven‐membered azepine ring derivatives.     

A Cascade Synthesis of Hetero‐arylated Triarylmethanes Through a Double 5‐endo‐dig Cyclization Sequence

A sequential two‐step method for the synthesis of hetero‐arylated triarylmethanes through a Ag‐catalyzed sequential double cyclization–nucleophilic addition cascade is described. This methodology basically involves an initial 5‐endo‐dig cyclization of o‐alkynyl anilines to provide 2‐substituted indole derivatives, which then react with 2‐(2‐enynyl)‐pyridines to afford indolizine‐containing unsymmetrical triarylmethanes through another 5‐endo‐dig cyclization.     

Facile Access to Optically Active 2,6‐Dialkyl‐1,5‐Diazacyclooctanes

The chiral substituted 1,5‐diazacyclooctane (1,5‐DACO) is of considerable importance and has attracted attention from a wide range of fields due to their unique chemical and biological properties. Despite the application potential, further study has not been optimized due to difficulties in their synthetic accessibility. Here, we report that the 1,5‐DACO bearing a chiral auxiliary obtained from the formal [4+4] cycloaddition of N‐alkyl‐α,β‐unsaturated imines can be further derivatized by nucleophilic alkylation to give various chiral substituted 1,5‐DACO derivatives. The removal of the chiral auxiliary was effectively carried out using hydrogenation over Pearlman's catalyst. This methodology allows the production of a broad range of unprecedented optically active 2,6‐dialkyl‐1,5‐DACO, which could not be accessed by other methods.     

L‐Lysine/imidazole‐catalyzed Multicomponent Cascade Reaction: Facile Synthesis of C5‐substituted 3‐Methylcyclohex‐2‐enones

A facile and simple route for the direct preparation of substituted 3‐methylcyclohex‐2‐enone via Aldol‐Robinson cascade reaction of aldehydes and acetones catalyzed by the new catalytic system of L‐lysine/imidazole in n‐heptane with 0.5% water was reported. A variety of substrates can participate in the process efficiently. The merits of this method included inexpensive and easily available starting materials and catalyst, the good yield of products and the straightforward work‐up.     

4‐Phenyl‐1H‐imidazole (a low‐temperature redetermination), 1‐benzyl‐1H‐imidazole and 1‐mesityl‐1H‐imidazole

Low‐temperature studies of the simple variously substituted imidazole types 4‐phenyl‐1H‐imidazole, C₉H₈N₂, 1‐benzyl‐1H‐imidazole, C₁₀H₁₀N₂, and 1‐mesityl‐1H‐imidazole, C₁₂H₁₄N₂, extend comparisons between parent imidazole species and their derivatives, the pronounced double‐bond localization opposite the substituted N atom common to simple neutral species being redistributed aromatically on protonation.     

金催化的炔烃羟基化反应: 合成2取代苯并呋喃化合物

本文报道了一种以邻炔基苯酚为原料,通过金催化的炔烃羟基化反应合成2取代苯并呋喃的方法. 该方法可以在温和的条件下快速以高产率得到各种2取代苯并呋喃. 关键前体邻炔基苯酚可以很容易由Sonogashira 反应制备.     

Synthesis of 4‐hydroxyquinolin‐2(1H)‐one analogues and 2‐substituted quinolone derivatives

A versatile synthetic method for preparing 4‐hydroxyquinolone and 2‐substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates were keto esters 4a‐e , which could be transformed to 4‐hydroxyquinolones 5a,b or 2‐substituted quinolone ethyl esters 6a‐c depending on the reaction conditions. 4‐Hydroxyquinolone analogues were prepared and investigated for N‐methyl‐D‐aspartate (NMDA) activity in vitro. Among these derivatives, 6,7‐difluoro‐3‐nitro‐4‐hydroxyquinolin‐2(1H)‐one ( 9 ) exhibited moderate activity.     

A Visible Light Photocatalytic Cross‐Dehydrogenative Coupling/Dehydrogenation/6π‐Cyclization/Oxidation Cascade: Synthesis of 12‐Nitroindoloisoquinolines from 2‐Aryltetrahydroisoquinolines

A visible light‐induced photocatalytic dehydrogenation/6π‐cyclization/oxidation cascade converts 1‐(nitromethyl)‐2‐aryl‐1,2,3,4‐tetrahydroisoquinolines into novel 12‐nitro‐substituted tetracyclic indolo[2,1‐a]isoquinoline derivatives. Various photocatalysts promote the reaction in the presence of air and a base, the most efficient being 1‐aminoanthraquinone in combination with K₃PO₄. Further, the 12‐nitroindoloisoquinoline products can be accessed directly from C1‐unfunctionalized 2‐aryl‐1,2,3,4‐tetrahydroisoquinolines by extending the one‐pot protocol with a foregoing photocatalytic cross‐dehydrogenative coupling reaction, resulting in a quadruple cascade transformation.     

Efficient One‐Pot Access to 2,9‐Dihydrothiopyrano[2,3‐b]indole Scaffolds Showing Large Stokes Shifts

A simple, mild and efficient one‐pot approach for the construction of 2‐aryl‐3‐nitro‐2,9‐dihydrothiopyrano[2,3‐b]indole derivatives has been realized in CH₂Cl₂ medium at ambient temperature via three‐component tandem reaction of N‐protected‐2‐chloro‐3‐formylindoles, sodium hydrosulfide and β‐substituted nitroolefins/δ‐substituted nitrodienes using DABCO (10 mol%) as an organocatalyst, followed by dehydration in the presence of activated molecular sieves (4 Å). The significant advantages of this protocol are simple operation, shorter reaction time, high atom economy, good to high yields (73% –89%) and wider substrate scope. In addition, all the synthesized compounds have shown the large positive Stokes shift values (5632–6081 cm^?1).