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

Amidines, 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.     

Microwave‐Assisted Synthesis of N,N′‐Disubstituted Acetamidine Ligands

Under microwave activation, triethylorthoacetate reacts with the substituted anilines in the presence of acetic acid as a catalyst, producing acetamidine in moderate to high yields. The X‐ray structures of the new amidines, N,N′‐bis(3,5‐dimethylphenyl)‐acetamidine and N,N′‐bis(p‐tolyl)acetamidine, are also reported, revealing polymeric chains supported by intramolecular H‐bonds.     

Improved hydrogen generation from formic acid

The ruthenium-catalyzed generation of hydrogen from formic acid was investigated in the presence of amines and halide additives. While amidines and halide additives increase the production of hydrogen with [RuCl₂(p-cymene)]₂, >330 mL hydrogen/h is generated in the presence of [RuCl₂(benzene)]₂/dppe and N,N-dimethyl-n-hexylamine.     

Synthesis of N-Sulfonylformamidines by tert-butyl Hydroperoxide–Promoted,metal-free,direct oxidative dehydrogenation of aliphatic amines

A direct and convenient metal-free method to prepare sulfonyl amidines in the presence of aqueous tert-butyl hydroperoxide (T-HYDRO) has been developed. Different tertiary and secondary amines were tested for compatibility with the oxidative conditions and could be coupled with sulfonyl azides to form the corresponding amidines in moderate to good yields.     

General and highly efficient fluorinated-N-heterocyclic carbene–based catalysts for the palladium-catalyzed Suzuki–Miyaura reaction

A general and highly efficient trifluoromethylated-N-heterocyclic carbene (NHC)-based catalyst for the palladium-catalyzed Suzuki–Miyaura reaction was reported. In the presence of the catalyst, reactions of non-activated aryl chlorides and triflates with aryl boronic acids occurred at room temperature with good to excellent yields (63–98%). In addition, catalysts generated from a combination of Pd(OAc)₂/imidazolium salt 6a is not only effective for the coupling of heteroaryl boronic acid with aryl halides and heteroaryl halides, but also efficient for coupling of other heteroaryl halides and heteroaryl boronic acids. Finally, the catalyst is highly effective for Suzuki–Miyaura reaction of aryl bromides and chlorides with 0.01–0.1 mol % loading if the temperature was raised at refluxed THF/H₂O.     

Reaction of N,N-diarylamidines with 3,4,5,6-tetrachloro-1,2-benzoquinone

A synthesis of 5,11b-dihydro-1H-dibenzo[d,f][1,3]diazepin-1-ones was found in the reaction of nitro-substituted N¹,N²-diarylamidines with 3,4,5,6-tetrachloro-1,2-benzoquinone. In contrast, 6,7,8,9-tetrachlorodibenzodioxins were obtained from reaction of N¹,N²-diphenylpropionamidine and N¹,N²-di-(4-tert-butylphenyl)acetamidine with 3,4,5,6-tetrachloro-1,2-benzoquinone.     

Sm°/Cat. I2 and SmI2 induced reductive coupling of nitriles with azides

The intermolecular reductive coupling of nitriles with azides induced by Sm°/Cat. I₂ or SmI₂ was studied. Aromatic and aliphatic amidines were prepared in moderate to good yields under neutral and mild conditions respectively.     

Synthesis of Cyclic N-Acyl Amidines by [3 + 2] Cycloaddition of N-Silyl Enamines and Activated Acyl Azides

In this study, we describe the synthesis of cyclic N-acyl amidines from readily available N-heteroarenes. The synthetic methodology utilized the versatile N-silyl enamine intermediates from the hydrosilylation of N-heteroarenes for the [3 + 2] cycloaddition reaction step. We evaluated various acyl azides and selected an electronically activated acyl azide, thereby achieving a reasonable yield of cyclic N-acyl amidines. We analyzed the relationship between the reactivity of each step and the electronic nature of substrates using in situ nuclear magnetic resonance spectroscopy. In addition, we demonstrated gram-scale synthesis using the proposed methodology.     

Facile N-formylation of amines using Lewis acids as novel catalysts

Alky, aryl, and heteroaryl amines were found to react efficiently with formic acid under Lewis acid catalysis giving N-formyl derivatives in high yields. A study of ZnCl₂-catalyzed N-formylation of a variety of amines using formic acid as formylating agent is described.     

Metal-free and highly regioselective synthesis of N-heteroaryl substituted pyrazoles from α,β-unsaturated N-tosylhydrazones and heteroaryl chlorides

A cascade cyclization/nucleophilic aromatic substitution (S_NAr) reaction of α,β-unsaturated N-tosylhydrazones with N-heteroaryl chlorides was developed for the synthesis of N-heteroaryl pyrazole derivatives. This one-pot reaction provided bi(heteroaryl) derivatives in good to excellent yields and with excellent regioselectivity. The procedure is operationally simple and applicable to large-scale synthesis.     

Synthesis of novel fluorinated 4H-benzo[h]chromen-4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives

New fluorinated 4H-benzo[h]chromen-4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives are obtained in moderate to good yields, through a one-pot aldolization-intramolecular S_NAr process, from the tetrakis(dimethylamino)ethylene (TDAE) mediated reductive cleavage of two N,N-dimethylamino-bis-chlorodifluoroacetyl substrates in the presence of heteroaryl aldehydes.     

An efficient catalyst system for diaryl ether synthesis from aryl chlorides

The combination of 2-phosphino-substituted N-arylpyrroles or related indoles (cataCXium^®P) and Pd(OAc)₂ allows for efficient cross-coupling reactions of aryl chlorides and phenols to give diaryl ethers. A variety of aryl and heteroaryl chlorides can be coupled with substituted phenols showing unprecedented catalyst turnover numbers.     

Cu2O/Cs2CO3/DMF: An efficient catalytic system for N-arylation of imidazole with aryl halides under ligand-free conditions

A ligand-free Cu-catalyzed protocol for the Ullmann-type N-arylation of N-containing heterocycles with aryl or heteroaryl iodides and bromides has been established. A broad range of functional groups is well tolerated on both of the cross-coupling partners, producing the desired products in good to excellent yields.     

Amidine als Zwischenprodukte bei Umamidierungsreaktionen. 9. Mitteilung über Umamidierungsreaktionen

Amidines as Intermediates in Transamidation Reactions By loss of water in the presence of p-toluenesulfonic acid/xylole N-aminoalkyllactames form bicyclic amidines. The corresponding N-alkylaminoalkyl-lactames' react to bicyclic amidinium salts or to transamidated products, ring-enlarged by the N-alkylamino residue, respectively (s. Scheme 1). The bicyclic amidines and amidinium salts are partially hydrolyzed by KOH/H₂O to lactames (s. Scheme 2). Which of the two possible isomeric lactames are formed is discussed.     

NBS-mediated practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via oxidative N‒O bond formation

A reaction involving an efficient NBS-mediated oxidative N?O bond formation has been established for the synthesis of 1,2,4-oxadiazoles from readily accessible N-acyl amidines. The features of this synthetic method include simplicity of operation, mild reaction conditions, short reaction times, high yields, and eco-friendliness. The reaction also works well with crude N-acyl amidines obtained by amidation of simple benzoic acids and amidines to produce biologically relevant 1,2,4-oxadiazoles in a scalable fashion.     

1,n-Diamines. Part 2: Synthesis of acyclic and heterocyclic N-arylputrescine derivatives

In the present Letter we report the use of N-arylputrescines as synthetic intermediates for the preparation of N-acyl-N′-aryltetramethylenediamines 3 and related seven-membered heterocyclic amidines 4. Compounds 1 were synthesized by Cs₂CO₃/KI-mediated aminolysis of 4-chlorobutyronitrile and subsequent reduction. N-Acylation of diamines 1 with carboxylic acid anhydrides led selectively to N-acyl-N′-aryl tetramethylenediamines 3. Microwave-assisted ring closure of such precursors promoted by PPE allowed for the synthesis of hitherto unreported 1-aryl-2-alkyl-1H-1,4,5,6-tetrahydro-1,3-diazepines 4.     

CuI catalyzed C-N bond forming reactions between aryl/heteroaryl bromides and imidazoles in [Bmim]BF4

By using CuI as the catalyst and l-Proline as the ligand, the Ullmann-type coupling reactions of aryl/heteroaryl bromides and imidazoles in [Bmim]BF₄ at 105-115 °C gave the corresponding N-arylimidazoles/N-heteroarylimidazoles in good yields. The system offers a convenient, recyclable, and environmentally benign method for these coupling reactions.     

Microwave-assisted synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252): a new potentiator of Nerve Growth Factor (NGF)-induced neurite outgrowth

The synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252) using an MW-assisted nucleophilic aromatic substitution (S_NAr) reaction will be discussed. Utilization of this method allowed for the rapid generation of B-355252 heteroaryl ether core structure in the presence of cesium carbonate in dimethylformamide or tripotassium phosphate in N-methyl-2-pyrrolidone in 94% yield. Evaluation of B-355252 enhancement of nerve growth factor’s ability to stimulate neurite outgrowths was determined using NS-1 cells.     

Reactions of 1,1,1-trihalo-3-nitrobut-2-enes with enamines derived from cycloalkanones. Rearrangement of trifluoromethylated 1,2-oxazine N-oxide into 1-pyrroline N-oxides and stereochemistry of the products

1,2-Oxazine N-oxides derived from (E)-1,1,1-trifluoro-3-nitrobut-2-ene and cyclohexanone enamines underwent spontaneous rearrangement with ring contraction to give 1-pyrroline N-oxides. Reactions of (E)-1,1,1-trifluoro(trichloro)-3-nitrobut-2-enes with N-cyclopent-enylmorpholine resulted in a series of novel CX₃-containing nitroalkyl enamines and g-nitro ketones; the stereochemistry of the synthesized compounds were studied by NMR spectroscopy and X-ray diffraction.     

AcOH-catalyzed aza-Michael addition/N-nitrosation: An efficient approach to CF2HCH2-containing N-nitrosoamines

A simple and highly efficient protocol for the AcOH-catalyzed three-component reaction among nitroalkenes, difluoroethylamine and tert-butyl nitrite through cascade aza-Michael addition/N-nitrosation has been developed. A range of CF₂HCH₂-containing N-nitrosoamines were obtained in good to excellent yields. This approach features easily available cheap materials, without using additional organic solvents, simple operation under room temperature, gram scalable preparation and functionally diverse products.