Improved Synthesis of 1‐Hydroxy‐2,2,5,5‐tetramethyl‐3‐imidazoline 3‐Oxide (HTIO)

A simple, efficient, mild, and reproducible method for the synthesis of 1‐hydroxy‐2,2,5,5‐tetramethyl‐3‐imidazoline 3‐oxide is described. The method is based on the condensation of 2‐hydroxyamino‐2‐methylpropanal oxime with 2,2‐diethoxypropane in the presence of an equimolar quantity of acetic acid. Cost‐effectiveness of the condensation procedure could be also achieved by replacing 2,2‐diethoxypropane with less expensive 2,2‐dimethoxypropane.     

Catalytic Oxidative Cyclocondensation of o‐Aminophenols to 2‐Amino‐3H‐phenoxazin‐3‐ones

The catalytic oxidative cyclocondensation of the o‐aminophenols 1a–f was investigated. The oxidants used were air/laccase, H₂O₂/horseradish peroxidase, H₂O₂/ebselen (3), and TBHP/diphenyl diselenide 4. The products obtained were 2‐amino‐3H‐phenoxazin‐3‐one—questiomycin A, its derivative 2b, and cinnabarinic acid and actinocin (2c,d). Substrates with methyl groups at 4 and 5 positions of benzene ring were converted to different dihydrophenoxazinones 2g,h. Compounds having chlorine atoms at the same positions underwent oxidation to planar phenoxa-zinones 2e,f with elimination of one hydrochloride molecule.     

Synthesis of the Potassium Channel Opener (3S,4R)‐3,4‐Dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐Yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran

The preparation of the potassium channel opener (3S,4R)‐3,4‐dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran (1) as a single enantiomer is reported. Considerable improvements have been implemented with respect to the original synthesis that allow for the preparation of multigram quantities of the final target compound. The optimized synthesis consists of a six‐step linear sequence whose key step is an asymmetric epoxidation protocol through the use of Jacobsen's (S,S)‐(+)‐N,N′‐bis(3,5‐di‐tert‐butylsalicylidene)‐1,2‐cyclohexanediaminomanganese(III) chloride catalyst.     

Structure of 2,4,4,5,5‐pentamethyl‐2‐imidazoline‐1‐oxyl‐3‐oxide

The crystal and molecular structures of the stable nitroxide radical 2,4,4,5,5pentamethyl2imidazoline1oxyl3oxide was determined. The N—O bond lengths are 1.279(2) and 1.280(2), respectively. The O^-—N⁺=C—N— O fragment is nearly planar with carbon atoms of the ethyl fragment that deviated from the O—N⁺=C—N—O plane by –0.204(5) and +0.176(5). The minimum intermolecular distance between the oxygen atoms of NO groups is 4.094.     

Synthesis of cis‐3‐methyl‐4‐aminopiperidine Derivatives

A facile approach for the preparation of cis‐3‐methyl‐4‐aminopiperidine derivatives is described. The synthesis was carried out via regioselective ring opening of N‐benzyl‐3‐methyl‐3,4‐epoxi‐piperidine (8), which can be easily obtained in two steps from the corresponding N‐benzyl‐pyridinium salt (5). Seven new cis‐3‐methyl‐4‐amino and amido piperidines compounds were obtained.     

Solid‐State Synthesis of 4‐[(Indol‐3‐yl)‐arylmethyl]‐1‐phenyl‐3‐methyl‐5‐pyrazolones by Catalysis of Molecular Iodine

4‐[(Indol‐3‐yl)‐arylmethyl]‐1‐phenyl‐3‐methyl‐5‐pyrazolones could be smoothly and effectively obtained in good yields through the iodine‐catalyzed reactions under solid‐state conditions at room tempertaure. The three‐component approach in a one‐pot procedure was reported for the first time. A possible mechanism was suggested to elucidate the remarkable reaction selectivities.     

Regioselective Endocyclic Oxidation of Enantiopure 3‐Alkylpiperidines: Synthesis of (3S,5S)‐(‐)‐3‐Ethyl‐5‐Methylpiperidine

An efficient regioselective endocyclic oxidation of enantiopure 3‐alkylpiperidines 1(a–c) with bromine in acetic acid to generate the corresponding 5‐alkylpiperidin‐2‐ones 3(a–c) as main product is described. In addition, starting from 3a or 3b, the synthesis of (3S,5S)‐(‐)‐3‐ethyl‐5‐methylpiperidine 6 · HCl was achieved. Finally, the X‐ray single‐crystal analysis of compound 4 is reported.     

Microwave‐Accelerated,Three‐Component,One‐Step Synthesis of 2‐Acylimino‐3‐aryl‐3H‐thiazolines under Solvent‐Free Conditions

2‐Acylimino‐3‐aryl‐3H‐thiazoline derivatives could be generated in excellent yields through three‐component condensations of aroylisothiocyanates, primary amines, and ω‐haloacetophenone under solvent‐free microwave irradiation.     

Efficient Synthesis of Trialkyl (E)‐3‐{3‐Oxo‐2‐3,4‐dihydro‐2‐(1H)‐quinoxalinylidene}‐prop‐1‐ene‐1,2,3‐tricarboxylates

The reaction of dialkyl acetylenedicarboxylates with alkyl 2‐[3‐oxo‐3,4‐dihydro‐2(1H)‐quinoxadinylidene]ethanoates in the presence of triphenylphosphine leads to trialkyl (E)‐3‐{3‐oxo‐2‐3,4‐dihydro‐2‐(1H)‐quinoxalinylidene}‐prop‐1‐ene‐1,2,3‐tricarboxylates in good yields.     

Synthesis of C‐Nucleoside Analogues Starting from 1‐(Methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)‐4‐phenyl‐but‐3‐yn‐2‐one

Abstract

1‐(Methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)‐4‐phenyl‐but‐3‐yn‐2‐one (4) was synthesized by the reaction of (methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)ethanal (2) with lithium phenylethynide and following oxidation. Compound 4 and hydrazine hydrate provided the 3(5)‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl‐methyl)‐5(3)‐phenyl‐1H‐pyrazole (5). The reactions of 4 with amidinium salts and a S‐methyl‐isothiouronium salt, respectively, furnished the pyrimidine C‐nucleoside analogues 6a–6c. Treatment of 4 with 2‐aminobenzimidazole afforded 2‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐ylmethyl)‐4‐phenyl‐benzo [4,5]imidazo[1,2‐a]pyrimidine (7a). Compound 4 and sodium azide yielded 2‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)‐1‐[5(4)‐phenyl‐1H(2H)‐1,2,3‐triazole‐4(5)‐yl]ethanone (8).     

Novel Approach to 3‐Methyl‐1H‐quinoxalin‐2‐ones

A novel approach to the synthesis of 3‐methyl‐1H‐quinoxalin‐2‐ones has been described. These compounds were regioselectively prepared by starting from substituted phenylamines and α‐chloropropionyl chloride through the efficient procedures of acylation, nitration, reduction, intramolecular alkylation, and oxidation.     

Efficient and Simple Synthesis of Substituted 3‐Phenyl‐7‐methoxybenzopyrans as Pseudo‐Vitamin‐D3 Analogs

An efficient and simple synthesis of substituted 3‐phenyl‐7‐methoxybenzopyrans as pseudo‐vitamin‐D₃ analogs in good yields under mild reaction conditions is described.     

Facile Synthesis of 2‐Alkylthio‐3‐alkyl‐5‐phenylmethylidene‐4H‐imidazol‐4‐ones

2‐Alkylthio‐3‐alkyl‐5‐phenylmethylidene‐4H‐imidazol‐4‐ones 6 were synthesized by N‐alkylation and S‐alkylation of 2‐thioxo‐5‐phenylmethylidene‐4‐imidazolidinone 5, which was obtained via cyclization of vinyl isothiocyanate 4 with excess ammonium hydroxide (28% NH₃ in water).     

Efficient Synthesis of Substituted 2‐Amino‐3‐carbethoxythiophenes

A microwave‐assisted method for the synthesis of a variety of thiophene o‐aminoesters (2a–l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur.     

Facile One‐Pot Synthesis of 3‐{2‐[5‐Hydroxy‐4‐(2‐hydroxy‐ethyl)‐3‐methyl‐pyrazol‐1‐yl]‐thiazol‐4‐yl}‐chromen‐2‐ones via a Three‐Component Reaction

Reaction of 3‐(2‐bromo‐acetyl)‐chromen‐2‐one with thiosemicarbazide and 2‐acetylbutyro lactone in anhydrous ethanol gave 3‐{2‐[5‐hydroxy‐4‐(2‐hydroxy‐ethyl)‐3‐methyl‐pyrazol‐1‐yl]‐thiazol‐4‐yl}‐chromen‐2‐one in good yields.     

Preparation of Alkyl Carbamate of 1‐Protected Indole‐3‐methylamine as a Precursor of Indole‐3‐methylamine

A series of alkyl carbamates 3 of 1‐protected indole‐3‐methylamines, alkyl carbamates 6 of thiophenylmethylamines, and pyrrolylmethylamines were prepared from the corresponding acetamides 2 and 5 in good to excellent yields via diacetoxyiodobenzene‐promoted Hofmann rearrangement. For a successful Hofmann rearrangement, an electron‐withdrawing group on position 1 of indolylacetamide and pyrrolylacetamide was required. The alkyl carbamate 3g was demonstrated to serve well as a stable precursor of 1‐protected indole‐3‐methylamine 1.     

Synthesis of New N‐(5‐Oxo‐2,5‐dihydro)pyrrol‐3‐yl Glycines and N‐(5‐Oxo‐2,5‐dihydro)pyrrol‐3‐yl Glycines Esters

Following our efforts towards the synthesis of new potential inhibitors of Xanthine Dehydrogenase (XDH), we describe here a general method for the preparation of N-(5-oxo-2,5-dihydro)pyrrol-3-yl glycines and N-(5-oxo-2,5-dihydro)pyrrol-3-yl glycine esters from glycine ethyl ester hydrochloride and various 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid esters and carbonitriles.     

Two‐Step Novel Synthesis of 2‐Amino‐6‐(1,3‐dioxo‐2,3‐dihydro‐1H‐inden‐2‐yl)‐4,7‐diphenyloxepine‐3‐carbonitrile and 5‐(1,3‐Dioxo‐2,3‐dihydro‐1H‐inden‐2‐yl)‐2‐imino‐6‐phenyl‐2H‐pyran‐3‐carbonitrile

Starting from indan‐1,3‐dione, a novel two‐step synthesis of the oxepine derivatives 5a,b and the pyran derivatives 7 and 8 under very simple reaction conditions is described.     

Microwave‐Assisted Synthesis of cAMP Phosphodiesterase Inhibitor 8‐Hydroxy‐6,7‐dimethoxy‐3‐hydroxymethylisocoumarin

An efficient microwave‐assisted synthesis of 8‐hydroxy‐6,7‐dimethoxy‐3‐hydroxymethyl isocoumarin (1), a metabolite of Streptomyces mobaraensis and structural relative of reticulol and cytogenin that possesses potent cyclic nucleotide phosphodiesterase inhibitor activity, is described. 3,4,5‐Trimethoxyhomophthalic acid (2) was condensed with acetoxyacetyl chloride under microwave irradiation and the acid hydrolysis of resulting 6,7,8‐trimethoxy‐3‐acetoxymethylisocoumarin (3) afforded the 6,7,8‐trimethoxy‐3‐hydroxymethylisocoumarin (4). Regioselective demethylation of the latter using magnesium iodide in THF yielded the title compound (1).     

Novel Synthesis of 5‐Substituted‐3‐phenylindole‐2‐(1,2,4‐triazole) Derivatives

Various substituted 3‐phenylindole 2‐carboxylates (1a–c) were prepared according to the literature methods. These carboxylates (1a–c) on reaction with thiosemicarbazide yielded 5‐substituted‐3‐phenylindol‐2‐(1,2,4‐triazole‐3‐thione) (2a–c) on refluxing in pyridine for 8 h. The 5‐substituted‐3‐phenylindole‐2‐[1,2,4‐triazolo‐3‐thioacetic acid] (3a–c) were prepared from 5‐substituted‐3‐phenyl indole‐2‐[1,2,4‐triazole‐3‐thione] (2a–c) on reaction with an appropriate alkylating agent and sodium acetate in acetic acid. Further, (3a–c) were reacted with acetic anhydride to bring about a cyclocondensation reaction to yield 5‐substituted‐3‐phenylindol‐2‐thiazolo(2,3‐b)‐triazole (4a–c). The 5‐substituted‐3‐phenylindole‐2‐[1,2,4‐triazolo‐3‐acetic acid] (3a–c) were reacted with o‐phenylenediamino dihydrochloride in ethylene glycol to yield 5‐substituted‐3‐phenylindole‐1,2,4‐triazolo‐3′‐yl‐thiomethyl)benzimidazoles (5a–c).