Highly Selective Synthesis of 6-Glyoxylamidoquinoline Derivatives via Palladium-Catalyzed Aminocarbonylation

The aminocarbonylation of 6-iodoquinoline has been investigated in the presence of large series of amine nucleophiles, providing an efficient synthetic route for producing various quinoline-6-carboxamide and quinoline-6-glyoxylamide derivatives. It was shown, after detailed optimization study, that the formation of amides and ketoamides is strongly influenced by the reaction conditions. Performing the reactions at 40 bar of carbon monoxide pressure in the presence of Pd(OAc)₂/2 PPh₃, the corresponding 2-ketocarboxamides were formed as major products (up to 63%). When the monodentate triphenylphosphine was replaced by the bidentate XantPhos, the quinoline-6-carboxamide derivatives were synthesized almost exclusively under atmospheric conditions (up to 98%). The isolation and characterization of the new carbonylated products of various structures were also accomplished. Furthermore, the structure of three new mono- and double-carbonylated compounds were unambiguously established by using a single-crystal XRD study.     

Synthesis of Ortho-alkoxy-aryl Carboxamides via Palladium-Catalyzed Aminocarbonylation

Various aryl carboxamides with alkoxy substituents at the ortho-position, applicable as direct intermediates toward novel ligands, were synthesised via aminocarbonylation of aryl-iodides (2-iodoanisole, 5-chloro-7-iodo-8-methoxy-quinoline, and 5-chloro-7-iodo-8-benzyloxy-quinoline) in the presence of in situ generated palladium(0) catalysts. Simple primary and secondary amines as well as aminoacid esters were used as N-nucleophiles. The optimization of the reaction conditions allowed the preferential formation of carboxamides or ketocarboxamides by simple or double carbon monoxide insertion, respectively. A strong dependence of the chemoselectivity on carbon monoxide pressure was observed.     

Selective Synthesis of N-Acylnortropane Derivatives in Palladium-Catalysed Aminocarbonylation

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)₂/2 PPh₃ catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.     

Synthesis of Amides and Phthalimides via a Palladium Catalyzed Aminocarbonylation of Aryl Halides with Formic Acid and Carbodiimides

A novel method for the preparation of amides and phthalimides has been developed. The process involves a palladium catalyzed aminocarbonylation of an aryl halide, using a carbodiimide and formic acid as the carbonyl source. Experimental data suggest that the mechanistic pathway for this process involves in‐situ generation of carbon monoxide from the reaction of formic acid with a carbodiimide in the presence of a palladium catalyst. The method can be used to produce a variety of amides and N‐substituted phthalimides efficiently.     

Synthesis of Chromeno[3,4-b]piperazines by an Enol-Ugi/Reduction/Cyclization Sequence

Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.     

One-Step Synthesis of 3,4-Disubstituted 2-Oxazolidinones by Base-Catalyzed CO2 Fixation and Aza-Michael Addition

2-Oxazolidinones are saturated heterocyclic compounds, which are highly attractive targets in modern drug design. Herein, we describe a new, single-step approach to 3,4-disubstituted 2-oxazolidinones by aza-Michael addition using CO₂ as a carbonyl source and 1,1,3,3-tetramethylguanidine (TMG) as a catalyst. The modular reaction, which occurs between a γ-brominated Michael acceptor, CO₂ and an arylamine, aliphatic amine or phenylhydrazine, is performed under mild conditions. The regiospecific reaction displays good yields (av. 75 %) and excellent functional-group compatibility. In addition, late-stage functionalization of drug and drug-like molecules is demonstrated. The experimental results suggest a mechanism consisting of several elementary steps: TMG-assisted carboxylation of aniline; generation of an O-alkyl carbamate; and the final ring-forming step through an intramolecular aza-Michael addition.     

Synthesis of Novel [1,2,4]Triazolo[3,4-d][1,5] Benzodiazepinones Derivatives by 1,3-Dipolar Cycloaddition

Cycloaddition of N-aryl-C-ethoxycarbonylnitrilimines and diarylnitrilimines on 1,5-benzodiazepinones was achieved in a one-pot procedure, to give a variety of compounds possessing an additional heterocyclic ring fused to the heterocyclic nucleus. This reaction was revealed to be completely peri and regioselective. The structures were elucidated by spectral methods and X-ray crystallographic analysis.     

Pd-Catalyzed Carbonylative Synthesis of 4H-Benzo[d][1,3]Oxazin-4-Ones Using Benzene-1,3,5-Triyl Triformate as the CO Source

A facile synthesis of 4H-benzo[d][1,3]oxazin-4-one derivatives by Pd-catalyzed carbonylative cross-coupling between N-(ortho-bromoaryl)amides and benzene-1,3,5-triyl triformate (TFBen) was developed. This procedure does not require the toxic and flammable gas CO as the carbonyl source and tolerates a wide scope of functional groups. Remarkably, 4H-benzo[d][1,3]oxazin-4-ones incorporated to natural products and drugs can be constructed by this method.     

Accessing Dihydropyrrolo[3,4-b]indol-1(2H)-ones via Pd-Catalyzed Intramolecular Aminocarbonylative Ring Closure

Present in a number of small molecule derivatives that display a wide range of biological activities, the dihydropyrrolo[3,4-b]indol-(2H)-one (DHPI) core represents an underexplored heterocyclic scaffold. Given the pharmaceutical potential of the DHPI motif, the development of synthetic methodologies that permit their expedient assembly would be highly desirable. Herein, we describe a novel strategy for the construction of the DHPI core from 3-iodo-1H-indolyl substrates, employing an unprecedented Pd-catalyzed intramolecular aminocarbonylative ring closure. The compatibility of our optimized protocol with various functional groups is highlighted through the synthesis of a range of diversely substituted DHPI derivatives in up to 90 % isolated yield.     

Synthesis of pyrazolo[3,4-c]isoquinoline and pyrazolo[3,4-b]pyridine derivatives from azomethines and CH-acidic compounds

Summary Donor substituted arylidene aminopyrazoles1a–c and CH-acidic 1,3-dicarbonyl compounds2a–e give in ethanol in an addition/cyclization reaction pyrazolo[3,4-c]isoquinolines4a–i and pyrazolo[3,4-b]pyridine derivatives5a,b, respectively. Using ethyl cyanoacetate as CH-acidic component, cinnamate6 and the cyano substituted pyrazolo[3,4-b]pyridine7 are formed.

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Synthese von Pyrazolo[3,4-c]isochinolin- und Pyrazolo[3,4-b]pyridin-Derivaten aus Azomethinen und CH-aciden Verbindungen

Zusammenfassung Die Reaktion der donorsubstituierten Aryliden-aminopyrazole1a–c mit den CH-aciden 1,3-Dicarbonylverbindungen2a–e führt in einer Additions/Cyclisierungsreaktion zu den Pyrazolo[3,4-c]isochinolin-4a–i bzw. Pyrazolo[3,4-b]pyridin-Derivaten5a,b. Verwendet man Cyanessigester als CH-acide Komponente, werden der Zimtsäureester6 und das cyanosubstituierte Pyrazolo[3,4-b]pyridin7 gebildet.

     

新型[1,2,4]三唑[4,3-b]均四嗪类化合物的合成及其抗癌活性

以6-(3,5-二甲基吡唑-1-基)-3-肼基均四嗪和芳醛为原料,经Schiff碱缩合和环合反应合成了6个新型的6-芳基-3-(3,5-二甲基吡唑-1-基)[1,2,4]三唑[4,3-b]均四嗪类化合物(4a～4f),其结构经1HNMR,MS,IR和元素分析表征。以顺铂为对照,采用MTT法测试了体外4a～4f对人白血病细胞株,人肺癌,人乳腺癌和人子宫颈癌细胞株的抗癌活性。结果表明,4a～4f对四种癌细胞均具有较强的抑制活性。     

12H-13-氧(硫)-苯并环庚并[1,2-b]

2-苯氧(硫)甲基-3-喹啉酸(1a-e)可以在Eaton's reagent (P2O5-MeSO3H) 的作用下进行分子内的闭环反应得到12H-13-氧(硫)-苯并环庚并[1,2-b]喹啉-5-酮类衍生物(2a-e).该环化工艺比传统的环化工艺所要求的反应条件更加温和,具有反应温度低和产品易分离等特点.     

Convenient Synthesis of 2,2-Dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines

A convenient general synthesis of 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines using the Wittig reaction is described. The o-nitrobenzaldehydes (1a–d) on reaction with phosphorane 2 provided ( E )-ethyl-α-(2,2-dimethylprop-2-ene)-2-nitrocinnamates (3a–d) in excellent yields, which on cyclization with polyphosphoric acid followed by reductive cyclization using Fe/HCl afforded dihydropyranoquinolines (5a–d). Alternatively, the pyranoquinolines 5a–d were also synthesised from esters 3a–d by employing domino reductive cyclization in a single step.     

2-叔丁基-4-氟-苯并氧杂卓并[3,4-b]喹啉并

以2-溴甲基-6,7-亚甲二氧基-3-喹啉酸乙酯(1) 为原料,经三步合成了2-叔丁基-4-氟-苯并氧杂卓并[3,4-b]喹啉并[9,11]二氧戊环-14(6H)-酮(4).其中,6-(2-氟-4-叔丁基-苯氧甲基)-[1,3]二氧戊环并[4,5-g]喹啉-7-羧酸是经一锅法合成的.它的分子内闭环反应是在Eaton's reagent(P2O5-CH3SO3H)的作用下,在较温和的条件下进行的.所得新化合物3和4的结构经IR、1H NMR和元素分析得以证实.     

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine Derivatives: Synthesis,Anti-Viral In Vitro Study and Target Validation Activity

This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level.     

Multicomponent Synthesis of 2,3-Dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones: A Novel Heterocyclic Scaffold with Antibacterial Activity

A multicomponent reaction of 3-aminopyrazol-5-ones with substituted salicylic aldehydes and acetylacetic ester leading to the formation of novel 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones was discovered. The elucidation of the reaction scope revealed that 5-aminopyrazoles, 3-amino-1,2,4-triazoles and 6-aminouracil could be used as the heterocyclic amine component. Selected heterocyclic products were found to possess notable antibacterial activities.     

Novel Four-Step Synthesis of Thioxo-quinazolino[3,4-a]quinazolinone Derivatives

A novel synthesis of thioxo-quinazolino[3,4-a]quinazolinone framework was developed through a four-step reaction starting from isatoic anhydride. The resulting 2-aminobenzamides from the reaction of isatoic anhydride and different amines underwent coupling–cyclization reaction with 2-nitrobenzaldehydes, reduction of nitro group, and then cyclization reaction with carbon disulfide (CS₂). All steps were carried out under easy and user-friendly conditions in a short time without using expensive catalysts or reagents.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Chemoselective Dehydrogenation of 3-[2-（3,4-Dihydro-1-naphthalenyl）ethyl]imidazolidine-2,4-diones： a New and Convenient Synthesis of 13,16-Diazaequilenin analogs

The synthesis of the title compounds starting with the chemoselective dehydrogenation of 3-[2-(3,4-dihydro-1-naphthalenyl)ethyl]imidazolidine-2,4-diones has been described.