Unusual behaviour of N‐cinnamoyl‐2‐hydroxy‐2‐(trifluoromethyl)‐arylethylamines in pictet‐gams cyclization. Synthesis of 2‐styryl‐5‐aryl‐5‐trifluoromethyl‐2‐oxazolines

Cyclization of N‐acyl‐2‐hydroxy‐2‐(trifluoromethyl)arylethylamines 4 under Pictet‐Gams conditions afforded 2‐oxazolines 5 instead of the expected isoquinolines 6 . The effect of the trifluoromethyl group on the result of the reaction is discussed.     

KHCO3‐ and DBU‐Promoted Cascade Reaction to Synthesize 3‐Benzyl‐2‐phenylquinolin‐4(1 H)‐ones

A novel and convenient one‐pot route for the synthesis of 3‐benzyl‐2‐phenylquinolin‐4(1 H)‐ones has been developed under transition‐metal‐free conditions. This new strategy features high yield and good functional group tolerance. In addition, a proposed mechanism has been confirmed for this reaction.     

Regioselective Synthesis of 3‐(Imidazol‐4‐yl) Indolin‐2‐Ones under Microwave Heating

A formal [3 + 2] cyclization reaction of 3‐(2‐oxo‐2‐arylethylidene)indolin‐2‐ones and amidines has been developed, regioselectively affording a series of new 3‐(imidazol‐4‐yl)indolin‐2‐ones in good to excellent yields. The reaction was easily conducted in ethylene glycol using Cs₂CO₃ as a base promoter under microwave irradiation. Flexible structural modification, and broad functional group compatibility as well as mild reaction conditions make this strategy a useful and attractive process of library generation for drug discovery.     

Facile and Selective Synthesis of 4‐Methyl‐ and 4‐Phenylthiosemicarbazide (=N‐Methyl‐ and N‐Phenylhydrazinecarbothioamide) Derivatives of Benzil (=1,2‐Diphenylethane‐1,2‐dione)

A selective synthesis of 4‐methylthiosemicarbazide (=N‐methylhydrazinecarbothioamide; 4a ) derivatives by reaction with benzil (=1,2‐diphenylethane‐1,2‐dione; 3 ) is described. The reaction conditions determined the condensation product formed. The most important factor was the acid used: in the presence of conc. HCl solution, the open‐chain 2 : 1 compound 1a was exclusively obtained, whereas in the presence of 2M HCl, the cyclic 1 : 1 condensation product 2a was formed. The alcohol used, the presence of H₂O, and the time of heating were additional crucial factors. The new cyclic compound 2a with a MeO group was exclusively formed when working under high‐dilution conditions. The reaction with the 4‐phenyl derivative 4b gave new cyclic compounds as the major products under all conditions used (Scheme).     

Highly efficient AgNO3‐catalyzed approach to 2‐(benzo[d]azol‐2‐yl)phenols from salicylaldehydes with 2‐aminothiophenol, 2‐aminophenol and benzene‐1,2‐diamine

A new, convenient and efficient AgNO₃‐catalyzed strategy for the preparation of 2‐(benzo[d]azol‐2‐yl)phenol derivatives in good to excellent yields (63–98%) is described. The reaction proceeds via condensation/intramolecular nucleophilic addition/oxidation process between substituted salicylaldehydes and 2‐aminothiophenol, 2‐aminophenol or benzene‐1,2‐diamine under mild reaction conditions. Notably, this reaction utilizes cheap AgNO₃ as a readily available and low‐cost benign oxidant at low catalyst loadings with excellent functional group tolerance.     

(±)‐2‐Aryl‐2,3‐dihydro‐4(1H)‐quinolinones by a tandem reduction–Michael addition reaction

An efficient synthesis of (±)‐2‐aryl‐2,3‐dihydro‐4(1H)‐quinolinones has been developed from chalcones prepared from 2′‐nitroacetophenone and a series of substituted benzaldehydes. The cyclization sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron powder in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid–phosphoric acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discussion and reaction optimization studies are presented. J. Heterocyclic Chem., (2011).     

Synthesis of 15‐Cyano‐12‐oxopentadecano‐15‐lactone and 15‐Cyano‐ 12‐oxopentadecano‐15‐lactam

15‐Cyano‐12‐oxopentadecano‐15‐lactone was synthesized in 59% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by reaction with trimethylsilylcyanide, hydrolysis, ring‐expansion, and Nef reaction. A two‐step, one‐pot synthesis of intermediate 2‐hydroxy‐4‐(1‐nitro‐2‐oxycyclododecyl)butanenitrile from 3‐(1‐nitro‐2‐oxocyclododecyl)propanal was developed and the conditions for the Nef reaction were studied. 15‐Cyano‐12‐oxopentadecano‐15‐lactam was synthesized in 40% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by Strecker reaction, ring‐expansion, and Nef reaction. The conditions for the Strecker and Nef reactions were studied. The structures of the target compounds, intermediates, and by‐product were characterized by IR, ¹H‐ and ¹³C‐NMR, and elemental analysis or MS.     

Preparation of 2‐phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline and 2‐methyl‐4‐oxo‐3,4‐dihydroquinazoline derivatives formation

The cyclization of phenacyl anthranilate has been studied with the aim to develop the synthesis of 2‐(2′‐aminophenyl)‐4‐phenyloxazole. However, a different course of the reaction than expected was observed. 2‐Phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 3a ) was formed by the reaction of phenacyl anthranilate ( 2 ) with ammonium acetate under various conditions. 3‐Hydroxy‐2‐phenyl‐4(1H)‐quinolinone ( 4 ) arose by heating compound 3a in acetic acid. The same compound was obtained by melting compound 3a , but the yield was lower. Different types of products resulted in the reaction of compound 3a with acetic anhydride. Under mild conditions acetylated products 2‐acetoxymethyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 7a ) and 2‐acetoxymethyl‐3‐acetyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 8 ) were prepared. If the reaction was carried out under reflux of the reaction mixture, molecular rearrangement took place to give cis and trans 2‐methyl‐4‐oxo‐3‐(1‐phenyl‐2‐acetoxy)vinyl‐3,4‐dihydroquinazolines ( 9a and 9b ). All prepared compounds have been characterised by their ¹H, ¹³C and ¹⁵N NMR spectra, IR spectra and MS.     

New trans/cis tetrahydroisoquinolines. 2. trans‐ and cis‐3‐(1‐methyl‐1h‐pyrrol‐2‐yl)‐1‐(2H)‐oxo‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquino‐lin‐4‐carboxylic acids and subsequent transformations

Stereochemical course of the reaction of homophthalic anhydride and N‐(1‐methyl‐1H‐pyrrol‐2‐yl‐methylidene)‐phenethylamine was studied. Mixtures of the expected trans‐ and cis‐1,2,3,4‐tetrahydroiso‐quinoline‐4‐carboxylic acids trans‐ 4 and cis‐ 4 were obtained along with by‐products 5 and 6 . The ratios of all products and the diastereomers, obtained under different reaction conditions, were established by pmr. THF as a solvent and ultrasonic treatment are applied for the first time in the reaction of this type. The reaction was made diastereoselective towards any isomer. The carboxylic group of trans‐ 4 was transformed in four steps into various cyclic amino‐methyl groups yielding numerous new tetrahydroisoquinolinones trans‐ 10a‐i incorporating a given fragment of pharmacological interest. Reduction of 10a‐i was studied.     

Heterocyclization reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines under appel's conditions

The reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines 12 with triphenylphosphine, carbon tetra‐chloride, and triethylamine (Appel's conditions) led to the corresponding carbodiimides 13 , which underwent intramolecular cycloaddition reaction with aziridine under the reaction conditions to give the pyridine‐fused heterocycles, 2,3‐dihydro‐1H‐imidazo[2′,3′:2,3]imidazo[4,5‐b]pyridines 16 and 12,13‐dihydro‐5H‐1,3 ‐benzodiazepino [2′,3′:2,3] imidazo[4,5‐b]pyridines 17 .     

7‐Halogenated 7‐Deaza‐2′‐deoxyxanthine 2′‐Deoxyribonucleosides

The synthesis of the 7‐halogenated derivatives 1b (7‐bromo) and 1c (7‐iodo) of 7‐deaza‐2′‐deoxyxanthosine ( 1a ) is described. A partial Br→I exchange was observed when the demethylation of 6‐methoxy precursor compound 4b was performed with Me₃SiCl/NaI. This reaction is circumvented by the nucleophilic displacement of the MeO group under strong alkaline conditions. The halogenated 7‐deaza‐2′‐deoxyxanthosine derivatives 1b , c show a decreased S‐conformer population of the sugar moiety compared to the nonhalogenated 1a . They are expected to form stronger triplexes when they replace 1a in the 1 ?dA?dT base triplet.     

An Efficient Synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one Derivatives via Multi‐Component Approach

An easy, highly efficient and a new convenient one‐pot, two‐step approach to the synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one is described. These compounds were synthesized from 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐4‐hydroxy‐6‐methyl‐3,4‐dihydro‐2H‐pyran‐2‐one and α‐bromoketones in good yields. The compounds 4 were synthesized by a multi‐component reaction between 1 , 2 , and 3 and the prominent features of this protocol are mild reaction conditions, operation simplicity, and good to high yields of products.     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.     

Efficient One‐pot Synthesis of Alkyl 3‐(alkyl)‐4‐methyl‐2‐thioxo‐2,3‐dihydrothiazole‐5‐carboxylates in a Multi Component Reaction

A simple and efficient one‐pot synthesis of alkyl 2‐(alkyl)‐4‐methyl‐2‐thioxo‐2,3‐dihydrothiazole‐5‐carboxylates from the reaction of primary alkylamines and carbon disulfide in the presence of 2‐chloro‐1,3‐dicarbonyl compounds is described. This new protocol has several advantages such as lack of necessity of the catalyst, good yields, mild conditions and short times for reaction.     

Synthesis of (−)‐3‐Carene‐2,5‐dione via Allylic Oxidation of (+)‐3‐Carene

Activated carbon‐supported CuCl₂ (CuCl₂/AC) is a heterogeneous catalyst for the liquid‐phase selective allylic oxidation of (+)‐3‐carene with tert‐butyl hydroperoxide (TBHP) and O₂ to produce (?)‐3‐carene‐2,5‐dione. The possible reaction mechanism and the effects of different factors on the allylic oxidation were investigated. The optimal conditions are as follows: reaction temperature, 45 °C; molar ratio of CuCl₂ to (+)‐3‐carene, 1%; volume ratio of (+)‐3‐carene to TBHP, 1:3; and reaction time, 12 h. Under the optimal conditions, the conversion of (+)‐3‐carene reached 100%, whereas the selectivity for (?)‐3‐carene‐2,5‐dione reached 78%. The CuCl₂/AC catalyst was characterized via X‐ray diffraction, and the chemical structure of the target compound was identified via infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectrometry, and optical analysis.     

Reactivity of 2‐Methyl‐4H‐3,1‐benzoxazin‐4‐ones and 2‐Methyl‐4H‐pyrido[2,3‐d][1,3]oxazin‐4‐one under Microwave Irradiation Conditions

The reactivity of variably substituted 2‐methyl‐4H‐3,1‐benzoxazin‐4‐ones and 2‐methyl‐4H‐pyrido[2,3‐d][1,3]oxazin‐4‐one towards carbon and oxygen nucleophiles under microwave irradiation conditions was investigated. Optimization of the reaction conditions of oxazinones with carbon nucleophiles led to the synthesis of a series of 4‐hydroxy‐quinolin‐2‐ones and 4‐hydroxy‐1,8‐naphthyridin‐2‐ones in high yields, whereas reaction with a variety of alcohols proceeded smoothly to the formation of the corresponding N‐acetyl‐anthranilates and nicotinates.     

Synthesis of Dialkyl 2‐(Alkylamino)‐4,9‐dihydro‐9‐oxocyclohepta[b]pyran‐3,4‐dicarboxylates

Dialkyl 2‐(alkylamino)‐4,9‐dihydro‐9‐oxocyclohepta[b]pyran‐3,4‐dicarboxylates are prepared in a one‐pot three‐component reaction of alkyl isocyanide, dialkyl acetylenedicarboxylate, and α‐tropolone (=2‐hydroxycyclohepta‐2,4,6‐trienone). The reaction proceeds smoothly at room temperature and under neutral conditions to afford tropolone derivatives in high yield.     

Reactions of N‐arylmaleimides with 3‐amino‐1,2,4‐triazole and 2‐aminobenzimidazole

The reaction of 3‐amino‐1,2,4‐triazole ( 1 ) with N‐arylmaleimides leads to azolopyrimidines 4 and 5 . The 2‐aminobenzimidazole ( 2 ) in the reaction with 3 gives the pyrimidobenzimidazoles 6 . In similar conditions, the reaction of amine 2 with maleic anhydride ( 7 ) leads to formation of 2‐oxo‐1,2,3,4‐tetrahydropyrimido[1,2‐a]benzimidazole‐4‐carboxylic acid ( 8 ). The structures of 4 , 5 , 6 , and 8 were proved by X‐Ray and NOE NMR measurements. J. Heterocyclic Chem., (2011)     

Platinum‐Catalyzed Cascade Rearrangement Reaction of 1,5‐Diynyl Esters: Unusual Regioselective 1,5‐Hydride Migration

A highly regioselective sequential 1,3‐acyloxy migration/pentannulation/1,5‐hydride migration reaction is disclosed which provides an efficient access to (E)‐2‐vinyl‐3‐oxo‐1‐methyleneindenes under neutral and mild reaction conditions. The migrated hydrogen atom was derived from an unactivated alkyl group, and the long‐range 1,5‐H shift was confirmed through related deuterium experiments.     

Regioselective Synthesis of SCF3‐Substituted 2,4‐Diarylquinazoline Using AgSCF3 as Trifluoromethylthiolation Reagent

A facile and efficient route to 4‐aryl‐2‐[2‐(trifluoromethylthio) aryl]quinazoline derivatives through a tandem directed Rh‐catalyzed C‐H iodination and trifluoromethylthiolation is described. The reaction proceeded under mild reaction conditions, exhibited good functional group tolerance with a broad scope of substrate and excellent regioselectivity in good to excellent yields.