Application of the acetate of baylis‐hillman adducts in the synthesis of 3‐carbomethoxy‐2H‐thiochromenes

A new route to 2H‐thiochromenes using the tandem S_N2′ and S_NAr reaction of several Baylis‐Hillman acetates having an ortho‐substituent, such as a halogen or nitro group, with sodium sulfide in aqueous dimethyl sulfoxide has been described.     

Application of baylis‐hillman methodology in a new synthesis of 3‐oxo‐2,3‐dihydro‐1H‐isoindoles

The Baylis‐Hillman reaction of 2‐cyanobenzaldehyde with some activated alkenes leading to the formation of 3‐oxo‐2,3‐dihydro‐1H‐isoindoles has been described.     

The dipolar route to naphtho[2,1‐c]isoxazoles from the baylis‐hillman adducts of 2‐alkynylbenzaldehydes

A new synthesis of 4‐carbomethoxynaphtho[2,1‐c]isoxazoles 4a‐d from methyl 3‐(alkynylphenyl)‐2‐nitromethyl‐2‐propenoates 2a‐d by the intramolecular nitrile oxide cycloaddition is described. The latter are readily obtained from 2‐alkynylbenzaldehydes through the Baylis‐Hillman adduct acetates 1a‐d followed by nucleophilic substitution of nitrite anion.     

Synthesis of 4H‐tetrazolo[1,5‐a][1]benzazepines from the baylis‐hillman adducts of 2‐azidobenzaldehyde

Novel heterocycles, 4H‐tetrazolo[1,5‐a][1]benzazepines 6 were prepared by the intramolecular 1,3‐dipolar cycloaddition reaction of azidophenylcyanomethyl compounds 5. The latter were readily obtained from 2‐azidobenzaldehyde through the Baylis‐Hillman adducts 3 followed by acetylation to compounds 4 and nucleophilic substitution by cyanide to compounds 5.     

Synthesis of 5H‐1,2,3‐triazolo[4,3‐a][2]benzazepines from the baylis‐hillman adducts of 2‐alkynylbenzaldehydes

The facile synthesis of 5H‐1,2,3‐triazolo[4,3‐a][2]benzazepines 5a‐d by the intramolecular 1,3‐dipolar cycloaddition reaction of 2‐alkynylphenylallyl azides 4a‐d is described. The latter were readily obtained from 2‐alkynylbenzaldehydes 1a‐d through the Baylis‐Hillman adducts 2a‐d followed by acetylation to compounds 3a‐d and nucleophilic substitution by azide to compounds 4a‐d.     

The [3 + 2] cycloaddition route to 5‐carbomethoxy‐4h‐1,2,3‐triazolo[1,5‐a][1]benzazepines from baylis‐hillman acetates of 2‐azidobenzaldehydes

A new, simple synthesis of 5‐carbomethoxy‐4H‐1,2,3‐triazolo[1,5‐a][1]benzazepines from the reaction of several Baylis‐Hillman acetates of 2‐azidobenzaldehydes with alkynide Grignard reagents such as phenylethynyl‐, 1‐propynyl‐ and ethynylmagnesium bromides followed by cycloaddition reaction has been described.     

A new synthesis of 1,2,3,5‐tetrahydroimidazo[2,3‐b]‐[1,3]benzodiazocines

A new synthesis of 6‐carbomethoxy‐1,2,3,5‐tetrahydroirnidazo[2,3‐b][1,3]benzodiazocines 13 by the intramolecular cycloaddition reaction of methyl 2‐(1‐aziridinylmethyl)‐3‐(2‐ureidophenyl)propenoates 10 under Appel's dehydration conditions is described. The latter were readily obtained from 2‐nitrobenzalde‐hyde with methyl acrylate through the Baylis‐Hillman reaction.     

On the synthesis of 9‐furylnaphtho[2,3‐b]furan derivatives

A simple synthetic pathway to the unknown 9‐furyl‐substituted naphthofuran derivatives has been developed involving intramolecular cyclization of 2‐carboxyaryldifurylmethanes and 2‐formylaryldifuryl‐methanes.     

Alpha vinylation of haloquinoline‐5,8‐diones with methyl acrylate and methyl vinyl ketone under baylis‐hillman reaction conditions

A synthesis of mono‐ and di‐vinylquinolinediones based on substitution of the halogens in 6,7‐dihaloquinoline‐5,8‐diones by DABCO‐assisted enolate ion is described. Divinylquinolines undergo 6π‐electrocyclization by thermally to give the benzo[g]quinoline derivatives.     

One‐pot synthesis of tetrahydroindeno[1,2‐b]pyrrolo‐3‐carboxylates derivatives

Tetrahydroindeno [1,2‐b]pyrrole‐3‐carboxylate were synthesized in a one‐pot procedure by the reaction of 1,3‐dicarbonyl and activated carbonyl compounds such as benzyl or ninhydrin in ethanol/water in the presence of ammonium acetate. J. Heterocyclic Chem., (2011).     

Synthesis of Ethyl 2‐Arylaminoimidazo[2,1‐b]benzothiazole‐3‐carboxylates

3‐Arylamino‐4‐ethoxycarbonylisoxazol‐5(2H)‐ones, substituted on nitrogen with a benzothiazole group, reacts with triethylamine in ethanol under reflux conditions to provide a convenient synthesis of ethyl 2‐aryl‐aminoimidazo[2,1‐b]benzothiazole‐3‐carboxylates.     

Syntheses of substituted pyrrolo[2,3‐d]imidazole‐5‐carboxylates and substitued pyrrolo[3,2‐d]imidazole‐5‐carboxylates

Starting from readily available p‐substituted‐benzylamines a series of ethyl 2‐alkylthio‐1‐substituted‐ben‐zylpyrrolo[2,3‐d]imidazole‐5‐carboxylates was prepared. In addition, starting from 2‐alkyl‐4(or 5)‐formylimidazoles and methyl 4′‐bromomethylbiphenyl‐2‐carboxylate a series of methyl substituted‐pyrrolo[2,3‐d]imidazole‐5‐carboxylates and methyl substituted‐pyrrolo[3,2‐d]imidazole‐5‐carboxylates was prepared.     

2,5‐Dimethyl‐6,7‐dihydrobenzo[h]pyrazolo[1,5‐a]quinazoline and 2‐tert‐butyl‐5‐methyl‐6,7‐dihydrobenzo[h]pyrazolo[1,5‐a]quinazoline

In both 2,5‐dimethyl‐6,7‐dihydrobenzo[h]pyrazolo[1,5‐a]quinazoline, C₁₆H₁₅N₃, (I), and 2‐tert‐butyl‐5‐methyl‐6,7‐dihydrobenzo[h]pyrazolo[1,5‐a]quinazoline, C₁₉H₂₁N₃, (II), which crystallizes with Z′ = 2 in the space group P, the non‐aromatic carbocyclic rings adopt screw‐boat conformations. The molecules of (I) are linked into chains of rings by a combination of C—H...N and C—H...π(arene) hydrogen bonds, while in (II) there are no hydrogen bonds of any kind.     

Synthesis and antimalarial activity of ethyl 3‐amino‐4‐oxo‐9‐(phenylsubstituted)thieno[2,3‐b]quinoline‐2‐carboxylate derivatives

A series of thieno[ 2 ,3‐b]quinolone derivatives were synthesized and investigated for their abilities to inhibit β‐hematin formation, hemoglobin hydrolysis and in vivo for their efficacy in rodent Plasmodium berghei. Compound 3b was the most promising as inhibitor of hemoglobin hydrolysis, and its effects as inhibitor of β‐hematin formation was promising. When the aromatic ring was substituted in 2 (Me), in 3 (CF₃) or in 2,4 (Cl) the inhibition of hemoglobin proteolysis was maximal (88%), the rest of compounds maintained a low inhibition. The most active compound to emerge in vitro and in murine studies, was 3b suggesting an antimalarial activity via multiple mechanisms.     

Quinolone analogues 2. A facile synthesis of novel 3‐substituted 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalines

The reaction of the 2‐(1‐alkylhydrazino)‐6‐chloroquinoxaline 4‐oxides 1a,b with diethyl acetone‐dicarboxylate or 1,3‐cyclohexanedione gave ethyl 1‐alkyl‐7‐chloro‐3‐ethoxycarbonylmethylene‐1,5‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylates 5a,b or 6‐alkyl‐10‐chloro‐1‐oxo‐1,2,3,4,6,12‐hexahydroquinoxalino[2,3‐c]cinnolines 7a,b , respectively. Oxidation of compounds 5a,b with nitrous acid afforded the ethyl 1‐alkyl‐7‐chloro‐3‐ethoxycarbonylmethylene‐4‐hydroxy‐1,4‐dihydropyridazino‐[3,4‐b]quinoxaline‐4‐carboxylates 9a,b , whose reaction with base provided the ethyl 2‐(1‐alkyl‐7‐chloro‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)acetates 6a,b , respectively. On the other hand, oxidation of compounds 7a,b with N‐bromosuccinimide/water furnished the 4‐(1‐alkyl‐7‐chloro‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)butyric acids 8a,b , respectively. The reaction of compound 8a with hydroxylamine gave 4‐(7‐chloro‐4‐hydroxyimino‐1‐methyl‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)‐butyric acid 12 .     

2‐amino‐4‐oxo‐6‐substituted‐pyrrolo[2,3‐d]pynmidines as potential inhibitors of thymidylate synthase

Classical, antifolate inhibitors of thymidylate synthase often suffer from a number of potential disadvantages when used as antitumor agents. These include impaired uptake due to an alteration of the active transport system required for cellular uptake, as well as the formation of long acting, non‐effluxing polygluta‐mates via folypolyglutamate synthetase, which are responsible for toxicity to normal cells. To overcome some of the disadvantages of classical thymidylate synthase inhibitors, there has been considerable interest in the synthesis and evaluation of nonclassical inhibitors, which could enter cells via passive diffusion and are not substrates for folypolyglutamate synthetase. A series of eight nonclassical 6‐substituted 2‐amino‐4‐oxo‐pyrrolo[2,3‐d]pyrimidines 2a‐2h were designed as potential inhibitors of thymidylate synthase. The synthesis of the target compounds 2a‐2h was achieved via regioselective iodination at the 6‐position of 5 , palladium‐catalyzed coupling with the appropriate phenylacetylenes, reduction of the C8‐C9 triple bond followed by saponification. Preliminary biological results indicated that none of the target compounds showed inhibitory activities against thymidylate synthase from Escherichia coli, Lactobacillus casei, rat or human thymidylate synthase at the concentrations tested. None of the target compounds showed inhibitory activity against dihydrofolate reductase from Escherichia coli, Lactobacillus casei, rat or human at 3.0 × 10^?5 M. However, 50% inhibition of dihydrofolate reductase from Pneumocystis carinii and from Toxoplasma gondii was achieved with compound 2d and with compound 2g at 3.0 × 10^?5 M.     

An efficient synthesis of pyrazolo[3,4‐b]pyrrolo[2,3‐d]pyridines from 5‐aminopyrazoles and cyclic β‐keto ester

5‐Chloroethylpyrazolo[3,4‐b]pyridines were synthesized by condensation of 5‐aminopyrazoles with α‐acetyl γ‐butyrolactone followed by cyclization treating with phosphorous oxychloride. 5‐Chloroethyl‐pyrazolo[3,4‐b]pyridines, thus obtained, were then converted to the corresponded tricyclic pyrazolo[3,4‐b]‐pyrrolo[2,3‐d]pyridines by treating with some primary amines.     

Regio‐ and stereoselective synthesis of 1‐benzopyrano[2,3‐b]pyrrolo[2,3‐d]pyridines: A microwave‐accelerated intramolecular [3+2] cycloaddition reaction of azomethine ylide

Regio‐ and stereoselective syntheses of tetracyclic compounds having chromone, pyrrolidine, and piperidine rings have been accomplished by an intramolecular [3+2] cycloaddition reaction involving azomethine ylide. The reactions were carried out thermally as well as by irradiation with microwave. The latter process accelerates the reaction. The selectivities were investigated by density functional theory computation. J. Heterocyclic Chem., (2011).     

Exploration of the Photodegradation of Naphtho[2,3‐g] quinoxalines and Pyrazino[2,3‐b]phenazines

Nitrogen‐containing polycyclic aromatic hydrocarbons are very attractive compounds for organic electronics applications. Their low‐lying LUMO energies points towards a potential use as n‐type semiconductors. Furthermore, they are expected to be more stable under ambient conditions, which is very important for the formation of semiconducting films, where materials with high purity are needed. In this study, the syntheses of naphtho[2,3‐g]quinoxalines and pyrazino[2,3‐b]phenazines is presented by using reaction conditions, that provide the desired products in high yields, high purity and without time‐consuming purification steps. The HOMO and LUMO energies of the compounds are investigated by cyclic voltammetry and UV/Vis spectroscopy and their dependency on the nitrogen content and the terminal substituents are examined. The photostability and the degradation pathways of the naphtho[2,3‐g]quinoxalines and pyrazino[2,3‐b]phenazines are explored by NMR spectroscopy of irradiated samples affirming the large influence of the nitrogen atoms in the acene core on the degradation process during the irradiation. Finally, by identifying the degradations products of 2,3‐dimethylnaphtho[2,3‐g]quinoxaline it is possible to track down the most reactive position in the compound and, by blocking this position with nitrogen, to strongly increase the photostability.