Synthesis Of Amidines Research Articles

Metal‐Free Direct Synthesis of N‐Sulfonyl Amidines from Thioamides and Electron Deficient N‐Sulfonylamides

AbstractA metal‐free, efficient synthesis of N‐sulfonyl amidines has been demonstrated from easily accessible thioamides and electron‐deficient sulfonyl amides. The amidation reaction is facile at room temperature with low sulfonyl amide loading. The reaction with thioamides is illustrated with various thioamides and electron‐deficient sulfonyl amides with broad substrate scope. The utility of N‐sulfonyl amidine synthesis is validated with late‐stage drug functionalization.

Condensation of Amines with S-Methyl Thiouronium Salts: Another Entry for the Synthesis of Amidines

AbstractWe present a condensation of primary aryl or alkyl amines with S-methyl thiouronium salts to obtain N,N,N′-trisubstituted amidines. High yields, short reaction times, and a fair substrate scope are the noteworthy features of this protocol. Surprisingly, the reaction of a thiouronium salt with 4-aminopyridine gave 1-(4-methoxybenzoyl)piperidine.

Convenient access to amidines by mesoionic singlet palladium carbene catalyzed hydrazone-isocyanide-amine (HIA) coupling: Scope and mechanistic insights

Facile synthesis of amidines 5(a-j), 6(a-g) and 7(a-j) by the tandem three-component coupling of N-tosylhydrazones, isocyanides and amines catalysed by the molecular binuclear Pd mesoionic singlet carbene complexes namely, [(R)-1,1′-(C10H6)2–2,2′-(OCH2(1-CH2Ph-3-R-1,2,3-triazol-5-ylidene))2]Pd2I4(NC5H5)2 [R = Me (4a) and Et (4b)] was achieved in good to excellent yields of ca. 51–97% at a low catalyst loading of 0.5 mol% in 6 h of the reaction time. A large opportunity for the utility of this coupling reaction was evident from its broader substrate scope arising from the use of a wide range of N-tosyl hydrazones, amines, and aromatic as well as aliphatic isocyanides. Combined experimental and computational studies performed on the representative substrates namely, PhCHNNHTs, 2,6-Me2C6H3NC, and morpholine indicated that the catalysis proceeded via the formation of palladium (0) active species [(R)-1,1′-(C10H6)2–2,2′-(OCH2(1-CH2Ph-3-R-1,2,3-triazol-5-ylidene))2]Pd2(2,6-Me2C6H3NC)2 [R = Me (B1), Et (B2)] alongside the generation of a ketenimine intermediate 2,6-Me2C6H3NCCHPh in the tricomponent coupling reaction. The dinitrogen elimination from the metal-coordinated diazo intermediate represents the rate-determining step of the reaction. The mechanistic revelations brought forth in this study hold promising potential for enriching our understanding of multi-component reactions leading to amidines enabled by transition metal catalysts.

A modified Beckmann rearrangement for the facile synthesis of amidines and imidates via imidoyl fluoride intermediates.

Herein, we report a modified Beckmann rearrangement using sulfone iminium fluoride (SIF) reagents to rapidly synthesize imidoyl fluoride intermediates. Subsequently, amidine and imidate products can be formed following the introduction of amine and alcohol nucleophiles, respectively. Overall, approximately 50 amidine and imidate products have been isolated in high yields utilizing mild conditions.

Synthesis of amidines via iron-catalyzed dearomative amination of β-naphthols with oxadiazolones

An efficient and convenient method for the synthesis of amidines bearing a β-naphthalenone moiety catalyzed by cheap iron(ii) chloride is presented by employing oxadiazolones as the nitrene precursors.

Experiments and DFT Computations Combine to Decipher Fe-Catalyzed Amidine Synthesis through Nitrene Transfer and Nitrile Insertion

Multicomponent reactions are attracting strong interest as they contribute to the development of more efficient synthetic chemistry. Understanding their mechanism is thus an important issue to opti...

Catalytic synthesis of functionalized amidinesviacobalt-carbene radical coupling with isocyanides and amines

An atom- and step-economic multi-component cobalt-catalyzed synthesis of amidines has been reported by using amines, isocyanides, and diazo compounds as carbene sources.

Utilization of Borane-Catalyzed Hydrosilylation as a Dearomatizing Tool: Six-Membered Cyclic Amidine Synthesis from Isoquinolines and Pyridines

AbstractIn this study, a convenient strategy to synthesize six-membered­ cyclic amidines from isoquinolines and pyridines has been developed. Borane-catalyzed hydrosilylation of each N-heteroarene was utilized as a dearomatizing tool. Substrate scope is broad with respect to both isoquinolines and pyridines, with various reaction pathways depending on the substitution pattern of the N-heteroarenes. The reaction mechanism and reactivity of each class of N-heteroarenes has been discussed. The resulting six-membered (Z)-sulfonyl amidine products are rarely reported and are mostly unprecedented. The scalability of this method and versatility of the cyclic amidine products are also presented.

Sulfuryl Fluoride Mediated Synthesis of Amides and Amidines from Ketoximes via Beckmann Rearrangement.

A metal-free and redox-neutral method for Beckmann rearrangement employing inexpensive and readily available SO2 F2 gas is described. The reported transformation proceeds at ambient temperature and is compatible with a wide range of sterically and electronically diverse aromatic, heteroaromatic, aliphatic and lignin-like oximes providing amides in good to excellent yields. The reaction proceeds through the formation of an imidoyl fluoride intermediate that can also be used for the synthesis of amidines.

A Convenient Synthesis of Amidines via Cycloaddition–Decarboxylation of Isocyanates and Nitrones

A base-promoted reaction between isocyanates and nitrones has been described, allowing an access to a variety of important functionalized amidines under mild reaction conditions. This strategy provides a convenient, effective, and scalable approach for the direct assembly of amidine compounds from simple starting materials in excellent yields.

Facile amidinations of 2-aminophenylboronic acid promoted by boronate ester formation.

Amidine synthesis by amine addition to nitriles normally requires high temperatures or harsh catalysts. Here, we report that boronate esters can facilitate amidination of proximal amines with moderate heating. With amidines present in a number of drugs and the synthetic handle provided by the boron, this chemistry should find useful applications.

Synthesis of Amidines by Palladium-Mediated CO2 Extrusion Followed by Insertion of Carbodiimides: Translating Mechanistic Studies to Develop a One-Pot Method

A palladium-mediated one-pot synthesis of amidines from aromatic carboxylic acids and carbodiimides (RNCNR) is reported as an isoelectronic adaption of CO2ExIn (ExIn = Extrusion–Insertion) reactions developed for the synthesis of thioamides from carboxylic acids and isothiocyanates (RNCS). Multistage mass spectrometry (MSn) experiments for model systems established “proof of concept”, demonstrating decarboxylation of [(L)Pd(O2CAr)]+ (L = 1,10-phenanthroline or py), to give [(L)PdAr]+, followed by reaction with a carbodiimide, RNCNR, to yield [(L)Pd(NRC(NR)Ar)]+ (R = isopropyl). DFT calculations predicted these reactions as highly exothermic and occurring via carbodiimide insertion into the Pd–Ph bond. 2,6-Dimethoxy and 2,4,6-trimethoxy substitution for the Pd–Ar moiety results in slower reactions with minor changes in mechanism. The individual reaction steps associated with the conversion of 2,6-dimethoxybenzoic acid and 2,4,6-trimethoxybenzoic acid into amidines in solution was probed by 1H NMR spectrosc...

Magnesium Ethoxide Mediated Synthesis of Amidines

Magnesium Ethoxide Mediated Synthesis of Amidines

Palladium-catalyzed construction of amidines from arylsilanes in the absence of a ligand under oxidative conditions

An interesting palladium-catalyzed procedure for the synthesis of amidines from arylsilanes, isocyanides and amines has been developed.

Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity

A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2-diaminobenzene. Different amidine synthesis methodologies namely, lithium bis-trimethylsilylamide (LiN[Si(CH3)3]2) and Pinner methods were used to prepare the diamidines. Both types (indole and benzimidazole) derivatives of the new diamidines bind strongly with the DNA minor groove and generally show excellent in vitro antitrypanosomal activity. The diamidino-indole derivatives also showed excellent in vitro antimalarial activity while their benzimidazole counterparts were generally less active. Compound 7c was highly active in vivo and cured all mice infected with Trypanosoma brucei rhodesiense, a model that mimics the acute stage of African sleeping sickness, at a low dose of 4 × 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine.

Synthesis of Amidines from Amides Using a Nickel-Catalyzed Decarbonylative Amination through CO Extrusion Intramolecular Recombination Fragment Coupling.

A catalytic synthesis of amidines from amides has been established for the first time. The newly developed CO extrusion recombination process takes advantage of an inexpensive nickel(II) catalyst and provides the corresponding amidines with high efficiency. The intramolecular fragment coupling shows excellent chemoselectivity, starts from readily available amides, and provides a valuable alternative amidine synthesis protocol.

Revisiting aryl amidine synthesis using metal amide and/or ammonia gas: Novel molecules and their biological evaluation

ABSTRACTAmidines, due to their unique biocompatibility and desirable physical characteristics, have been the functionality of choice as a scaffold for large number of drug synthesis. But still synthesis of amidines in the presence of other active functional groups or pharmacophore, remained a challenge. In this work, a simple and reliable protocol for conversion of nitrile-amide to unsubstituted amidine–amide is developed using metal amide and/or ammonia gas. The scope and efficiency of this synthetic strategy are demonstrated on several substrates which differ in functional groups will be discussed. In this process, 10 novel aryl amidines in good yields (upto 85%) were synthesized. Biological evaluation revealed that compound 4-(aminoiminomethyl)-N-(2-furanyl methyl) benzamide (IC50 = 9 µM) and 4-(aminoiminomethyl)-N-(3-pyridinylmethyl) benzamide (73.36% growth inhibition) showed moderate efficacy for cancer cells.

N-Sulfonyl amidine synthesis via three-component coupling reaction using heterogeneous copper catalyst derived from metal-organic frameworks

Three-component coupling reaction of terminal alkyne, sulfonyl azide, and amine for the synthesis of N-sulfonyl amidine was developed using heterogeneous Cu@C catalyst, which was generated by pyrolysis of HKUST-1 (Cu3(BTC)2, BTC=1,3,5-benzenetricarboxylate). A variety of terminal alkynes, sulfonyl azides, and amines underwent three-component coupling in the presence of 5mol% Cu@C. The used Cu@C catalyst was readily separated by centrifugation and could be reused at least three times with no loss of reactivity. Filtration experiments revealed that the developed Cu@C catalysis is basically heterogeneous.

Sulfated tungstate catalyzed activation of nitriles: addition of amines to nitriles for synthesis of amidines

An efficient and mild method for the synthesis of amidines by direct nucleophilic addition of amines to nitriles using sulfated tungstate as heterogeneous catalyst is described. Highlight of the method is its applicability for the synthesis of amidines using a wide variety of amines including ammonia as ammonium acetate and nitriles. Catalyst is mildly acidic, stable, easy to prepare and separate from the reaction mass.

Palladium‐Catalyzed Construction of Amidines from Arylboronic Acids under Oxidative Conditions

A valuable palladium-catalyzed three-component coupling reaction for the synthesis of amidines has been developed. Using arylboronic acids, isocyanides, and anilines as the reactants under oxidative conditions, various amidines were isolated in good yields with good functional group tolerances.