A Facile Synthesis of Bridged‐tricyclic Skeletons via Intramolecular Diels‐Alder Reaction of Cyclic 1,3‐Dienes Containing an α,β‐Unsaturated Ester

Intramolecular Diels‐Alder reaction (IMDA) precursors are easily available starting from addition of ester functionalized zinc‐copper reagents to cyclohexadienyl‐ and cycloheptadienylirontricarbonyl cation salts. The resulting cyclic 1,3‐dienes containing an α,β‐unsaturated ester functionality underwent smoothly IMDA reaction to afford bridged tricyclic compounds. Bridged heterotricyclic skeletons were also available via IMDA reaction of cyclic 1,3‐dienes bearing an imine or aldehyde functionality.     

One‐pot Two‐Step Cycloaddition Reaction for Convenient Synthesis of Polycyclic Spirooxindole‐fused [1,3]Oxazines

The novel spirooxindoline fused [1,3]oxazines were efficiently synthesized from Diels‐Alder reaction of N‐arylmaleimides with 1,2‐dihydro‐2‐oxospiro[3H‐indole‐3,2′‐[2H,9aH‐pyrido[2,1‐b][1,3]oxazines], which were generated in situ from three‐component reactions of substituted pyridines and isatins with methyl propiolate, or dimethyl acetylenedicarboxylate. The stereochemistry of the products was clearly clarified by the analysis of ¹H NMR data and single crystal structures of the obtained polycyclic compounds.     

Synthesis and Characterization of New 3‐(3‐Hydroxyphenyl)‐4‐ alkyl‐3,4‐dihydrobenzo[e][1,3]oxazepine‐1,5‐dione Compounds

A series of 3‐(3‐hydroxyphenyl)‐4‐alkyl‐3,4‐dihydrobenzo[e][1,3]oxazepine‐1,5‐dione compounds with general formula C_nH_2n+1CNO(CO)₂C₆H₄(C₆H₄OH) in which n are even parity numbers from 2 to 18. The structure determinations on these compounds were performed by FT‐IR spectroscopy which indicated that the terminal alkyl chain attached to the oxazepine ring was fully extended. Conformational analysis in DMSO at ambient temperature was carried out for the first time via high resolution ¹H NMR and ¹³C NMR spectroscopy.     

Synthesis of New Pyrano[2′,3′: 5,6]chromeno[4,3‐b]quinolin‐4‐ones via Aza‐DielsAlder Reaction

New pyrano[2′,3′: 5,6]chromeno[4,3‐b]quinolin‐4‐ones have been synthesized by intramolecular aza‐Diels? Alder reaction of the azadienes generated in situ from aryl amines and 8‐formyl‐7‐(prop‐2‐ynyl)2,3‐disubstituted chromones using CuFe₂O₄ nanoparticles as a catalyst in DMSO at 80–90° in good‐to‐excellent yields. Particularly valuable features of this methodology include simple implementation, inexpensive and reusable catalyst, and good yields. The structures were established by spectroscopic data and further confirmed by X‐ray diffraction analysis of one of the products.     

Synthesis of Some New 6,8‐Disubstituted 7,8‐Dihydropyrimido[2,3:4,3]pyrazolo[1,5‐a]pyrimidines and 6,7,8‐Trisubstituted Pyrimido[2,3:4,3]Pyrazolo[1,5‐a]Pyrimidine Derivatives

Cyclization of 5‐cyano‐1,6‐dihydro‐4‐methyl‐2‐phenyl‐6‐thioxopyrimidine 4 with excess of 85% hydrazine hydrate afforded the 3‐amino‐4‐methyl‐6‐phenylpyrazolo[3,4‐d]pyrimidine 5 , which can react with appropriate Mannich base derivatives 13a‐c and chalcones 27a,b to yield the corresponding 6,8‐disubstituted 7,8‐dihydropyrimido[2,3:4,3]pyrazolo[1,5‐a]pyrimidines 15a‐c and 30a,b , respectively. On the other hand, the 6,7,8‐trisubstituted pyrimido[2,3:4,3]pyrazolo[1,5‐a]pyrimidine derivatives 8a‐g, 20a‐e, 36 and 38 were obtained by treatment of compound 5 with appropriate 1,3‐diketones 6a‐g , 3‐dimethylamino‐1‐(substituted)prop‐2‐enones 18a‐e , 3‐aminocrotononitrile 3 , and ethoxymethylenemalononitrile 37 under acidic condition, respectively.     

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.     

Synthesis of Novel Disubstituted Pyrazolo[1,5‐a]pyrimidines,Imidazo[1,2‐a]pyrimidines,and Pyrimido[1,2‐a]benzimidazoles Containing Thioether and Aryl Moieties

A series of novel 6‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]‐7‐phenylpyrazolo[1,5‐a]pyrimidines, 5‐phenyl‐6‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]imidazo[1,2‐a]pyrimidines, and 2‐phenyl‐3‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]pyrimido[1,2‐a]benzimidazoles have been synthesized in four steps starting with 2‐hydroxyacetophenone. The intermediate 3‐[(1,3,4‐thiadiazol‐2‐yl)sulfanyl]‐4H‐1‐benzopyran‐4‐ones reacted with pyrazol‐3‐amines, 5‐methylpyrazol‐3‐amine, and 1H‐imidazol‐2‐amine, 1H‐benzimidazol‐2‐amine via a cyclocondensation to give the title compounds in the presence of MeONa as base, respectively. The approach affords the target compounds in acceptable‐to‐good yields. The new compounds were characterized by their IR, NMR, and HR mass spectra.     

Synthesis of 2‐Azabicyclo[3.2.2]nonane‐Derived Monosaccharide Mimics and Their Evaluation as Glycosidase Inhibitors

The racemic 2‐azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as β‐glycosidase inhibitors. The intramolecular Diels–Alder reaction of the masked o‐benzoquinone generated from 2‐(allyloxy)phenol ( 6 ) gave the α‐keto acetal 7 which was reduced with SmI₂ to the hydroxy ketone 8 . Dihydroxylation, isopropylidenation (→ 12 ), and Beckmann rearrangement provided lactam 15 . N‐Benzylation of this lactam, reduction to the amine 17 , and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5 . Both 5 and 19 proved weak inhibitors of snail β‐mannosidase (IC₅₀ > 10 mM ), Caldocellum saccharolyticum β‐glucosidase (IC₅₀ > 10 mM ), sweet almond β‐glucosidase (IC₅₀ > 10 mM ), yeast α‐glucosidase ( 5 : IC₅₀ > 10 mM ; 19 : IC₅₀ = 1.2 mM ), and Jack bean α‐mannosidase (no inhibition detected).     

Synthesis and Reactions of 3‐Methylthiazolo[3,2‐a]Benzimidazole‐2‐Carboxylic Acid Hydrazide: Synthesis of Some New Pyrazole, 1,3‐Thiazoline, 1,2,4‐Triazole and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐Thiadiazine Derivatives Pendant to Thiazolo[3,2‐a]Benzimidazole Moiety

The reaction of 3‐methylthiazolo[3,2‐a]benzimidazole‐2‐carboxylic acid ethyl ester (1) with hydrazine hydrate gives the hydrazide 2 which reacts with CS₂/KOH to afford the potassium salt 3. Treatment of 3 with l‐aryl‐2‐bromoethanones 4a,b afforded the 1,3‐thiazoline derivatives 6a,b, respectively, while the reaction of 3 with hydrazine hydrate afforded 1,2,4‐triazole‐3‐thione derivative 9. The reaction of 9 with l‐aryl‐2‐bromoethanones 4a,b and with hydrazonyl chlorides 11a,b gave the 1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazine derivatives 10a,b and 12a,b, respectively. Treatment of hydrazide 2 with phenyl isothiocyanate in refluxing benzene gave the thiosemicarbazide derivative 16. The latter reaction gave 1,3,4‐oxadiazole derivative 17 when benzene was replaced by DMF. Cyclization of the thiosemicarbazide derivative 16 with NaOH resulted in the formation of the 1,2,4‐triazole‐3‐thione derivative 18.     

Synthesis of 2,5‐Disubstituted Derivatives of Pyrano[2,3‐d][1,3]thiazines via the Interaction of 2‐Substituted 4‐Hydroxy‐6H‐1,3‐thiazine‐6‐ones with Aldehydes

A new and efficient route for the synthesis of derivatives of the poorly investigated pyrano[2,3‐d][1,3]thiazine heterocyclic system is disclosed. These compounds were prepared via annulation of 2‐aryl‐4‐hydroxy‐6H‐1,3‐thiazine‐6‐ones with aliphatic and aromatic aldehydes in the presence of pyridine. The method is general and versatile, and the interaction is independent on the nature of the aldehyde, the only exceptions being formaldehyde and salicylaldehydes.     

Synthesis of O6‐Corona[3]arene[3]pyridazines and Their Molecular Recognition Property in Organic and Aqueous Media

O₆‐Corona[3]arene[3]pyridazines were synthesized from the one‐pot macrocyclic condensation reaction of 3,6‐dichlorotetrazine with 1,4‐dihydroquinone derivatives followed by the inverse electron demand Diels‐Alder reaction of the tetrazine rings with a cyclopentanone‐derived enamine. Conversion of six ester groups within macrocycle into all sodium acetate moieties afforded a water soluble O₆‐corona[3]arene[3]pyridazine. The coronary macrocycle host formed complexes selectively with organic ammoniums and dinitrile guests in a 1: 1 stoichiometric ratio in organic solvents with association constants ranging from (2.96 ± 0.10) × 10¹ to (2.53 ± 0.33) × 10⁵ L·mol⁻¹. Water soluble O₆‐corona[3]arene[3]pyridazine was also able to complex strongly with organic ammoniums in water to give an association constant up to (2.67 ± 0.21) × 10⁴ L·mol⁻¹. The pseudo‐rotaxane and inclusion structures of the host‐guest complexes were revealed by the X‐ray crystallography.     

Formation and Molecular Structure of an Ion Pair Iron (II) Compound Derived from 2,6‐Bis‐ [1‐(2,6‐dibromophenylimino) ‐ethyl] pyridine and 2‐Acetyl‐6‐[1‐(2, 6‐dibromophenylimino)‐ethyl] pyridine

Two novel tridentate ligands of 2,6‐bis‐[l‐(2,6‐dibromophenylimino) ethyl] pyridine (L₁) and2‐acetyl‐6‐[1‐(2,6‐dibromophenylimino) ethyl] pyridine (L2) have been synthesized. The iron(II) complex of L₁ and L₂ has been characterized with the crystal structure of [Fe(L₁)(L₂)]²⁺ [FeCl₄]² CH₂Cl₂ [monoclinic, P2₁ (#11), a = 1.0562(4), b = 2.0928(4), c = 1.2914(2) nm, β = 100.12°, V = 2.810(1) nm³ D_c = 1.879 g/cm³ and Z = 2].     

1,3‐Dipolar Cycloadditions of Ethyl 2‐Diazo‐3,3,3‐trifluoropropanoate to Alkynes and [1,5] Sigmatropic Rearrangements of the Resulting 3H‐Pyrazoles: Synthesis of Mono‐, Bis‐ and Tris(trifluoromethyl)‐Substituted Pyrazoles

The 1,3‐dipolar cycloadditions of ethyl 2‐diazo‐3,3,3‐trifluoropropanoate with electron‐rich and electron‐deficient alkynes, as well as the van Alphen? Hüttel rearrangements of the resulting 3H‐pyrazoles were investigated. These reactions led to a series of CF₃‐substituted pyrazoles in good overall yields. Phenyl‐ and diphenylacetylene proved to be unreactive, but, at high temperature, the diazoalkane and phenylacetylene furnished a cyclopropene derivative. As expected, the 1,3‐dipolar cycloaddition to the ynamine occurred much faster than those to electron‐deficient alkynes. With one exception, all cycloadditions proceeded with excellent regioselectivities. The [1,5] sigmatropic rearrangement of the primary 3H‐pyrazoles provided products with shifted acyl groups; products resulting from the migration of a CF₃ group were not detected. In agreement with literature reports, this rearrangement occurs faster with 3H‐pyrazoles bearing electron‐withdrawing substituents.     

Regioselective Synthesis of 6‐[Chloro(difluoro)methyl]salicylates by [3+3] Cyclocondensations of 1,3‐Bis(trimethylsilyloxy)buta‐1,3‐dienes with 1‐Chloro‐1,1‐difluoro‐4‐(trimethylsilyloxy)pent‐3‐en‐2‐one

The TiCl₄‐mediated [3+3] cyclocondensation of various 1,3‐bis(trimethylsilyloxy)buta‐1,3‐dienes with 1‐chloro‐1,1‐difluoro‐4‐(trimethylsilyloxy)pent‐3‐en‐2‐one provides a regioselective access to novel 6‐(chlorodifluoromethyl)salicylates (=6‐(chlorodifluoromethyl)‐2‐hydroxybenzoates) with very good regioselectivity. For selected products, it was demonstrated that the CF₂Cl group can be transformed to CF₂H and CF₂(Allyl) by free‐radical reactions.     

Synthesis of New Furo[3,4‐b]quinolin‐1(3H)‐one Scaffolds Derived from γ‐Lactone‐Fused Quinolin‐4(1H)‐ones

In the context of our aim of discovering new antitumor drugs among synthetic γ‐lactone‐ and γ‐lactam‐fused 1‐methylquinolin‐4(1H)‐ones, we developed a rapid access to 5‐methyl‐1,3‐dioxolo[4,5‐g]furo[3,4‐b]quinoline‐8,9(5H,6H)‐dione ( 9 ) exploiting the γ‐lactone‐fused chloroquinoline 10 previously synthesized in our laboratory (Scheme 1). We also elaborated efficient synthetic methods allowing for a rapid access to two nonclassical bioisosteres of 9 , i.e., a deoxy and a carba analogue. The deoxy analogue 11 was prepared in two steps from the γ‐lactone‐fused quinoline 13 which was also the synthetic precursor of 10 (Scheme 1). The carba analogue 6,9‐dihydro‐5‐methyl‐9‐methylene‐1,3‐dioxolo[4,5‐g]furo[3,4‐b]quinolin‐8(5H)‐one ( 12 ) was easily prepared by HCl elimination from the 9‐(chloromethyl)dioxolofuroquinoline 15 , which was obtained via a three‐component one‐pot reaction from N‐methyl‐3,4‐(methylenedioxy)aniline (=N‐methyl‐1,3‐benzodioxol‐5‐amine; 16 ), commercially available chloroacetaldehyde, and tetronic acid ( 17 ) (Scheme 2).     

1,4‐Dipolar Cycloaddition Reactions in Ionic Liquids: A Facile Synthesis of 9aH,15H‐[1]Benzopyrano[3′,2′: 3,4]pyrido[2,1‐a]isoquinolines (=9aH,15H‐Benzo[a][1]benzopyrano[2,3‐h]quinolizines)

Ionic liquids were found to be a suitable reaction medium for 1,4‐dipolar cycloaddition reactions of an isoquinoline, an activated alkyne, and a 4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehyde at room temperature to afford [1]benzopyrano‐pyrido‐isoquinoline (=9aH,15H‐benzo[a][1]benzopyrano[2,3‐h]quinolizine) derivatives selectively in good yields. The ionic liquid can be recovered and recycled in further runs without loss of activity.     

ZrOCl2·8H2O as an efficient and recyclable catalyst for the one‐pot multicomponent synthesis of novel [1,3]oxazino[5,6‐c]quinolin‐5‐one derivatives

A simple, efficient and eco‐friendly procedure has been developed using ZrOCl₂·8H₂O as catalyst for the synthesis of novel [1,3]oxazino[5,6‐c]quinolin‐5‐one derivatives in aqueous ethanol at room temperature. The present methodology offers several advantages such as operational simplicity, use of ZrOCl₂·8H₂O as a green, non‐toxic, inexpensive and reusable catalyst, reusability of reaction media, high yields, mild and environmentally benign reaction conditions.     

Efficient Synthesis of [1,3]Oxazino[3,2‐f]phenanthridine Derivatives by a Novel 1,4‐Dipolar Cycloaddition Involving a Phenanthridine–Dimethyl Acetylenedicarboxylate Zwitterion and Aromatic Aldehydes

An efficient synthesis of [1,3]oxazino[3,2‐f]phenanthridine derivatives via a three‐component reaction of phenanthridine, dimethyl acetylenedicarboxylate (DMAD), and aromatic aldehydes is described. This novel method is complementary to the classical Huisgen 1,4‐dipolar cycloaddition in that it is well‐suited to the preparation of [1,3]oxazino[3,2‐f]phenanthridines.     

The Synthesis of 2,11‐Diamino‐4,9‐diphenyl‐4,9‐dihydrobenzo [f] pyrano[3,2‐h]chromene‐3,10‐dicarbonitrile Derivatives using Triethanolammonium Acetate as a Green Ionic Liquid

Triethanolammonium acetate [TEA ][HOAc ] was used as a green ionic liquid and successfully utilized for the multi‐component synthesis of 2,11‐diamino‐4,9‐diphenyl‐4,9‐dihydrobenzo[f]pyrano[3,2‐h]chromene‐3,10‐dicarbonitrile derivatives as new compounds by the reaction of 2,3‐naphthalenediol with malononitrile and various aldehydes. Mild reaction conditions and high yields are some of the advantages of this method. These compounds were identified by IR , NMR spectroscopy and mass analysis.