An Efficient and Facile Synthesis of 5‐(Thiophene‐2‐carbonyl)‐6‐(trifluoromethyl)‐tetrahydro‐pyrimidin‐2(1H)‐one and 6‐(Thiophen‐2‐yl)‐4,5‐dihydropyrimidin‐2(1H)‐one from Same Substrates Under Different Conditions

A series of 5‐(thiophene‐2‐carbonyl)‐6‐(trifluoromethyl)‐tetrahydropyrimidin‐2(1H)‐one and 6‐(thiophen‐2‐yl)‐4,5‐dihydropyrimidin‐2(1H)‐one derivatives have been synthesized from the reactions of aromatic aldehydes, 4,4,4‐trifluoro‐1‐(thien‐2‐yl)butane‐1,3‐dione and urea under the different conditions with high yields. In this research, it was found that the p‐toluenesulfonic acid was an efficient catalyst for obtaining 5‐(thiophene‐2‐carbonyl)‐6‐(trifluoromethyl)‐tetrahydropyrimidin‐2(1H)‐one derivative. At the same time, solvent‐free and NaOH were the preferred conditions for the synthesis of 6‐(thiophen‐2‐yl)‐4,5‐dihydropyrimidin‐2(1H)‐one derivative. Moreover, because of short reaction time, excellent yields, simple setup, this research offered an efficient process for preparing these kind compounds.     

Direct Synthesis of Multi‐functional Pyrimidine,Pyrazine, and Pyridine Scaffolds via Inter‐ and Intramolecular Annulations of 3‐Amino‐thieno[2,3‐b]pyridine‐2‐carboxylate

The synthesis of a new series of annulated thieno[2,3‐b]pyridines was performed. Ester compound 1 underwent heterocyclization upon reaction with phenylisothiocyanate and formamide to afford pyrimidines 2 and 3 , respectively. Thienopyrimidine 5 was resulted via reaction of amino derivative 1 with triethyl orthoformate to afford the non‐isolable intermediate 4 , which allowed hydrazinolysis with hydrazine hydrate to afford the target compound. Pyrimidine type 5 was condensed with p‐nitrobenzaldehyde to afford Schiff base 6 . Refluxing of ester 1 with ethyl cyanoacetate and diethyl malonate followed by base‐mediated heterocyclization afforded condensed pyridines 8 and 9 , respectively. The tetracyclic pyrazine derivative 14 was obtained from the reaction of amino compound 1 with 2,5‐dimethoxytetrahydrofuran followed by hydrazinolysis to give carbohydrazide 11 , which undergo diazotization followed by Curtius rearrangement. The antibacterial results illustrated no significant results for the investigated compounds except compound 5 , which has moderate activity against Gram‐positive bacteria.     

2,6‐Diaryl‐4,4‐disubstituted‐4H‐thiopyran: Source for spiro heterocycles

The 1,5‐diaryl‐3,3‐disubstituted‐1,5‐pentanedione on reaction with ammonium acetate, phosphorus pentoxide and phosphorus pentasulfide gave respective 1,4‐dihydropyridine, 4H‐pyran and 4H‐thiopyran. Novel spiro heterocycles have been obtained by the cyclocondensation of 4H‐thiopyran with hydrazine, hydroxylamine, urea and thiourea.     

A simple synthesis of 5‐ethoxycarbonyl‐6‐phenyl‐1,3‐dioxin‐4‐ones and ethyl 3‐benzoyl‐4‐oxo‐2,6‐diphenylpyran‐5‐carboxylate

4‐Ethoxycarbonyl‐5‐phenyl‐2,3‐dihydrofuran‐2,3‐dione 1 reacts with aldehydes via the acylketene intermediate 2 giving the 1,3‐dioxin‐4‐ones 3a‐e and the 1,4‐bis(5‐ethoxycarbonyl‐4‐oxo‐6‐phenyl‐4H‐1,3‐dioxin‐2‐yl)benzene 4 , and a one step reaction between dibenzoylmethane and oxalylchloride gave 3,5‐dibenzoyl‐2,6‐diphenyl‐4‐pyrone 7 . The reaction of 1 with dibenzoylmethane, a dicarbonyl compound, provided ethyl 3‐benzoyl‐4‐oxo‐2,6‐diphenylpyran‐5‐carboxylate derivative 9 . Compound 9 was converted into the corresponding ethyl 3‐benzoyl‐4‐hydroxy‐2,6‐diphenylpyridine‐5‐carboxylate derivative 10 via its reaction with ammonium hydroxyde solution in 1 ‐butanol.     

A Regioselective Biginelli‐like Reaction Controlled by the Size of Alicyclic Mono‐ketones

A regioselective Biginelli‐like reaction of alicyclic mono‐ketones, aromatic aldehydes, and urea in ionic liquid [BPY]BF₄ has been investigated. The process is controlled by the size of alicyclic mono‐ketones and the steric hindrance of aromatic aldehydes. The reaction of cyclopentanone with urea and aromatic aldehydes afforded 7‐arylidene‐3,4,6,7‐tetrahydro‐4‐aryl‐1H‐cyclopenta[d]pyrimidin‐2(5H)‐ones ( 4 ). When cyclohexanone was used as the source of active methylene to react with urea and aldehydes with slight steric hindrance groups under the same condition, 8‐arylidene‐3,4,5,6,7, 8‐hexahydro‐4‐arylquinazolin‐2(1H)‐ones ( 6 ), a homologue of 4 , were yielded, whereas 4,8‐bisaryloc‐tahydro‐1H‐pyrimido[5,4‐i]‐quinazoline‐2,10(3H,11H)‐diones ( 7 ) were obtained via the simple one‐pot reaction of cyclohexanone, urea, and aromatic aldehydes with high steric hindrance groups. The possible transitional states and mechanism of the regioselective process were discussed.     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).     

溴化镁催化的1,2,3,4-四氢吡啶酮无溶剂合成研究

An efficient and environmentally friendly procedure for the one-pot synthesis of tetrahydropyrimidinones from aldehydes, β-diketones and urea/thiourea by using magnesium bromide as an inexpensive and easily available catalyst under solvent-free conditions was described. Compared with the classical Biginelli reaction conditions, this new method has the advantage of good to excellent yields (74%-94%) and short reaction time (45-90 min). The structure of the Biginelli reaction product from β-diketone, salicylaldehyde and urea has been proposed to possess an oxygen-bridge by cyclization (intramolecular Michael-addition).     

Studies on the reactions of cyclic oxalyl compounds with hydrazines or hydrazones : Synthesis and reactions of 4‐benzoyl‐1‐(3‐nitrophenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylic acid

The 1H‐pyrazole‐3‐carboxylic acid 2 , obtained from the furan‐2,3‐dione 1 and N‐Benzylidene‐N'‐(3‐nitrophenyl) hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N‐nucleo‐philes into the corresponding ester or amide derivatives 4 or 5 , respectively. Nitrile 6 and anilino‐pyrazole acid 7 derivatives of 2 were also obtained by dehydration of 5a in a mixture of SOCl₂ with DMF and reduction of 2 with sodium polysulphide, respectively. While cyclocondensation reactions of 2 or 7 with phenyl hydrazine or hydrazine hydrate and 6 with only anhydrous hydrazine lead to derivatives of pyrazolo[3,4‐d]‐pyridazinone 8 and pyrazolo[3,4‐d]pyridazine amine 9 , respectivel. The reaction of 2 with 2‐hydrazinopyri‐dine provided hydrazono‐pyrazole acid derivative 10 , which was decarboxylated to give hydrazono‐pyra‐zole derivative 11 . Pyrazolo[4,3‐d]oxazinone 12 and 2‐quinolyl pyrazolo[3,4‐d]pyridazine 13 derivatives were also prepared by cyclocondensation reactions of 2 with hydroxylamine hydrochloride and 7 with acetaldehyde, respectively.     

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).     

Synthesis,Characterization, and Screening for Anti‐inflammatory and Antimicrobial Activity of Novel Indolyl Chalcone Derivatives

Because of the great biological importance of substituted indole derivatives, in the present study, a series of pyrazolylindole, thiazolylindole, and pyrimidinylindole derivatives have been synthesized with good yield. The precursor indolyl chalcone 2a – d was prepared by reaction of 3‐chloro‐1H‐indole‐2‐carbaldehyde 1 with different ketones. Then, compounds 3b – d , 4 , and 5a – d have been synthesized by the reaction of chalcones 2a – d with hydrazine, phenylhydrazine, and thiosemicarbazide. When the chalcone derivative 2b subjected to react with hydroxylamine hydrochloride gave isoxazolylindole derivative 6b . N‐thiazolidine pyrazolyl indole 7 was obtained by reacting compound 5a with ethyl chloroacetate. On the other hand, when chalcone derivative 2b allowed to react with urea and thiourea gave the corresponding pyrimidinylindole derivatives 8 and 9 . Finally, when chalcone derivative 2b reacted with ethyl cyanoacetate or malononitrile gave pyridinylindole derivatives 10 and 11 . The structures of the all synthesized compounds were elucidated on the basis of spectral analysis infrared, NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their antimicrobial and anti‐inflammatory activity. Compound 4b was the highest antibacterial activity against all strains of bacteria with values higher than those of the corresponding reference antibiotics (ciprofloxacin and levofoxacin, respectively) and almost the same as (gemifloxacin, moxifloxacin, clindamycin, gentamycin, and streptomycin). Compounds 4 , 5 , 6 , and 7 showed high anti‐inflammatory activity compared with the standard drug indomethacin.     

Conventional and Microwave‐Activated the Synthesis of a Novel Series of Imidazoles,Pyrimidines, and Thiazoles Candidates

A novel series of imidazoles, pyrimidines, and thiazoles were synthesized using microwave irradiation and conventional method from commercial available p‐aminobenzoic acid. Thus, one‐pot condensation of p‐aminobenzoic acid, urea, and chloroacetic acid have been provided two types of imidazole derivatives as separated mixture 2a and 2b . [3 + 2 + 1] Cyclocondensation of 2a , benzaldehyde, and urea/thiourea in acidic medium afforded imidazolo oxazine derivative 3 and Imidazolothiazine 4 . Coupling of 2a with benzene diazonium salt gave the phenyldiazenyl imidazolidine 5 . While the reaction of 2a , thiourea, and benzaldehyde in sodium ethoxide afforded imidazolothiazine 6 . Oxidative cyclization of thiourea derivative 7 resulted a mixture of benzithiazole derivative 7a and oxathiazole derivative 7b . Cyclocondensation of 7a with phenylenediamine and 4‐methyl phenylenediamine furnished imidazole 8 and 9 , respectively. Reaction of P‐aminobenzioc acid with potassium cyanate followed by Biginelli reaction with (acetyl acetone, ethyl acetoacetate, and diethyl malonate) and salicyladehyde in HCl tolerated pyrimidine derivatives 10a–c , respectively. In the same manner, the reactions and short reaction time make microwave technique one of the greenest methodology for synthesis of this class of heterocyclic system.     

Synthesis and some reactions of 4‐(ethoxycarbonyl)‐1,5‐diphenyl‐1H‐pyrazole‐3‐carboxylic acid

1,5‐Diphenyl‐1H‐pyrazole‐3,4‐dicarboxylic acid‐4‐ethyl ester 2 , obtained from the 4‐ethoxycarbonyl‐5‐phenyl‐2,3‐furandione 1 and N‐benzylidene‐N′‐phenyl hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N‐nucleophiles into the corresponding ester 5 or amide derivatives 6 , respectively. In addition, 2 was decarboxylated to give ethyl 1,5‐diphenylpyrazole‐4‐carboxylate 4 . Nitrile 7 derivative of 2 was also obtained by dehydration of 6a in a mixture of SOCl₂ and DMF. While cyclocondensation reaction of 2 with hydrazine hydrate leads to the formation of pyrazolo[3,4‐d]pyridazine‐4,7‐dione 8 , the reaction of 3 with anhydrous hydrazine provided a new bis pyrazole derivative 9 .     

Synthesis of Some New [1,8]Naphthyridine,Pyrido[2,3‐d]‐Pyrimidine,and Other Annulated Pyridine Derivatives

2‐Aminopyridine‐3‐carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3 , 5 , 8 , 11 , and 14 , respectively. Further annulations of 3 , 5 , and 8 gave the corresponding pyrido[2,3‐b][1,8]naphthyridine‐3‐carbonitrile derivative 17 , pyrido[2,3‐h][1,6]naphthyridine‐3‐carbonitrile derivatives 18 and 19 , respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4‐isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a , b , 21 , 22a , b , and 26 , respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27 . Compound 27 reacted with 4‐chlorobenzaldehyde and 1H‐indene‐1,3(2H)‐dione to give the pyridopyrimidine derivative 28 and spiro derivative 30 , respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34 . Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35 . The structures of the newly synthesized compounds were established by elemental and spectral data.     

Hydrogen‐transfer polymerization of vinyl monomers derived from 4‐methylbenzoyl isocyanate and acrylamide derivatives

The anionic polymerization of N‐acryloyl‐N′‐(4‐methylbenzoyl)urea (1) was carried out at 80°C for 24 h in DMF, DMSO, acetonitrile, or toluene by t‐BuOK or DBU (3 mol %) as an initiator to obtain polymer 3 in a good yield. The structure of 3 was dependent upon the initiator used, in which t‐BuOK selectively conducted the hydrogen‐transfer polymerization, while DBU partially induced the vinyl polymerization (16–20%). Likewise, N‐acryloyl‐N‐methyl‐N′‐(4‐methylbenzoyl)urea (2, i.e., an N‐methylated derivative of 1) was subjected to the hydrogen‐transfer polymerization. Although the yield of the polymer was lower in comparison with 1, the structure of the obtained polymer 4 was similarly governed by the initiator. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 465–472, 1999     

Heterocycles Derived from 5‐(2‐Aminothiazol‐4‐yl)‐8‐hydroxyquinoline: Synthesis and Antimicrobial Activity

5‐(2‐Aminothiazol‐4‐yl)‐8‐hydroxyquinoline 2 has been synthesized by treating thiourea with 5‐chloroacetyl‐8‐hydroxyquinoline 1 . The amine 2 was treated with aromatic aldehydes to furnish schiff bases 6a‐c which on treatment with phenyl isothiocyanate gave the corresponding thiazolo‐s‐triazines 7a‐c . Reaction of 2 with phenyl isothiocyanate gave the corresponding aminocarbothiamide derivative 8 which on reaction with malonic acid in acetyl chloride afforded thiobarbituric acid derivative 9 . Coupling of 9 with diazonium salt gave the phenyl hydrazono derivative 10 . However, reaction of 2 with carbon disulphide and methyl iodide afforded dithiocarbamidate 12 which on treatment with ethylenediamine, o‐aminophenol and/or phenylenediamine gave the aminoazolo derivatives 13–15 , respectively. Other substituted fused thiazolopyrimidines 16–20 have been also prepared by the reaction of 2 with some selected dicarbonyl reagents. The characterisation of synthesized compounds has been done on the basis of elemental analysis, IR, ¹H‐NMR and mass spectral data. All the newly synthesized compounds have been screened for their antimicrobial activities.     

Chlorobis[N′‐ethoxycarbonyl‐N‐(4‐methylphenyl)thiourea‐κS]copper(I)

The title complex, chloro­bis{ethyl N‐[(4‐methyl­anilino)­thio­carbonyl]­carbamate‐κS}copper(I), [CuCl(C₁₁H₁₄N₂O₂S)₂], was synthesized by the reaction of cupric chloride with the corresponding thio­urea derivative. The complex has imposed crystallographic m symmetry and the Cu^I coordination environment is trigonal planar, formed by two S atoms and one Cl atom. The formation of intramolecular hydrogen bonds promotes the stability of the complex.     

N,N′‐Dicyclohexyl‐N‐[4‐(1H‐indol‐3‐yl)butanoyl]urea

The title compound, C₂₅H₃₅N₃O₂, is a novel urea derivative. Pairs of intermolecular N—H...O hydrogen bonds join the molecules into centrosymmetric R₂²(12) and R₂²(18) dimeric rings, which are alternately linked into one‐dimensional polymeric chains along the [010] direction. The parallel chains are connected via C—H...O hydrogen bonds to generate a two‐dimensional framework structure parallel to the (001) plane. The title compound was also modelled by solid‐state density functional theory (DFT) calculations. A comparison of the molecular conformation and hydrogen‐bond geometry obtained from the X‐ray structure analysis and the theoretical study clearly indicates that the DFT calculation agrees closely with the X‐ray structure.     

The Synthesis of New Heterocycles Using 2‐(4‐Chloro‐1,3‐dihydro‐3,3,7‐trimethyl‐2H‐indol‐2‐ylidene) Propanedial

4‐Chloro‐2,3,3,7‐tetramethyl‐3H‐indole (an indolenine) was produced by the reaction of 5‐chloro‐2‐methylphenylhydrazine hydrochloride with 3‐methylbutan‐2‐one via Fischer reaction. Exposure of the indolenine to the Vilsmeier reagent at 50°C produced a β‐diformyl compound, 2‐(4‐chloro‐1,3‐dihydro‐3,3,7‐trimethyl‐2H‐indol‐2‐ylidene)propanedial. This dialdehyde was reacted with arylhydrazines, acetamidinium chloride, urea, thiourea, guanidinium chloride, and cyanoacetamide to give various 5‐membered and 6‐membered heterocyclic products, each carrying a 4‐chloro‐3,3,7‐trimethyl‐3H‐indol‐2‐yl unit as a substituent, in excellent yields.     

Chemoselective Switch in the Asymmetric Organocatalysis of 5H‐Oxazol‐4‐ones and N‐Itaconimides: Addition–Protonation or [4+2] Cycloaddition

We report a synthetic strategy for a chemoselective switch and a diastereo‐divergent approach for the asymmetric reaction of 5H‐oxazol‐4‐ones and N‐itaconimides catalyzed by l ‐tert‐leucine‐derived tertiary amine–urea compounds. The reaction was modulated to harness either tandem conjugate addition–protonation or [4+2] cycloaddition as major product with excellent enantio‐ and diastereoselectivities. Subjecting the enantio‐enriched cycloaddition products to a basic silica gel reagent yields the diastereomer vis‐à‐vis the product directly obtained under conditions for addition–protonation, thus opening a diastereo‐divergent route for creating 1,3‐tertiary‐hetero‐quaternary stereocenters. Quantum chemical studies further provide stereochemical analysis for the [4+2] process and a plausible mechanism for this chemoselective switch is proposed.     

Synthesis of new 2,2′‐disubstituted 5,5′‐dimethyl‐4,4′‐bitriazoles and 2‐(4‐Triazolyl)quinoxalines

Thermal rearrangement of 3‐acylisoxazole arylhydrazones allowed facile preparation of 2H‐1,2,3‐triazoles which were firstly reacted with isoamyl nitrite and then with an opportune arylhydrazine to produce the corresponding α‐hydroxyiminohydrazones 8a‐h . The reaction of compounds 8a‐h with phosphorus pentachloride afforded the desired 4,4′‐bitriazoles 1a‐h . The α‐hydroxyiminoketone derivative 7 or the α‐diketone 14 reacted easily with 1,2‐phenylenediamine to afford 1,2,3‐triazoles 2a‐c bearing the quinoxaline moiety at position 4. Improved yields of the quinoxalines 2a‐c were obtained when 1,2‐phenylenediamine was reacted with the dioxime 15.