New TRANS/CIS tetrahydroisoquinolines. 3. [1,3]‐oxazolo‐[3,2‐B]‐tetrahydroisoquinolinones having an angular aryl substituent

The parent compound 5‐oxo‐10a‐phenyl‐2,3,10,10a‐tetrahydro‐5H‐[1,3]‐oxazolo‐[3,2‐b]‐isoquinoline‐10‐carboxylic acid ( 5 ) was prepared in large scale and a good yield by reaction between homophthalic anhydride ( 3 ) and 4,5‐dihydro‐2‐phenyl‐1,3‐oxazole ( 4 ). Thus, the closure of the isoquinoline ring and fusion of the 1,3‐oxazol ring occur in one step. Trans configuration was assumed for the product. The parent acid 5 was converted in four steps to the target aminomethyl derivatives 9a‐1 . The latter contain four features that make them interesting from pharmaceutical point of view.     

Photochemistry of Spiro[6H‐[1,3]Oxathiin‐2,2′‐tricyclo[3.3.1.13,7]decan]‐ 6‐one

On irradiation (300 nm) in the solid state, the title compound 8 affords tricyclo[3.3.1.1^3,7]decan‐2‐one (=adamantan‐2‐one; 9 ) selectively via [4+2] cycloreversion. A similar result is obtained on photolysis in solution (MeCN or acetone), also in the presence of added alkenes. On irradiation in MeOH, a solvent adduct 11 is isolated in addition to 9 . From experiments in CD₃OD, it can be inferred that 11 is formed via syn‐addition of MeOH to the ground‐state (E)‐heterocycle 16 .     

Convenient Synthesis of Novel Nitrogen Bridgehead Heterocycles Utilizing 3‐Mercapto‐6H‐[1,2,4,5]oxatriazino[3,2‐a]isoindol‐6‐one as a New Synthon

Considering oxatriazino[a]isoindole as a wealthy structure for developing molecules of impressive therapeutic potentials, some new oxatriazino[3,2‐a]isoindoles analogs were synthesized. Thus, 3‐mercapto‐6H‐[1,2,4,5]oxatriazino[3,2‐a]isoindol‐6‐one ( 5 ), was prepared as one‐pot three‐components product and subjected to a series of manipulations including cycloaddition reactions to annulate a series of pharmacophoric motif conjugates. The structures of the newly synthesized compounds were elucidated based on their correct elemental and spectroscopic data.     

Furopyridines. XXVI. Reactions of cyanopyridine derivatives of furo[2,3‐b]‐, ‐[3,2‐b]‐, ‐[2,3‐c]‐ and ‐[3,2‐c]pyridine

Bromination of α‐cyanopyridine derivatives of furopyridines 1a‐d gave the 2,3‐dibromo‐2,3‐dihydro compounds 2a‐d in excellent yields. Treatment of 2a‐d with sodium hydroxide in methanol yielded compounds formed through the dehydrobromination and solvolysis of the nitrile. N‐Oxidation of 1a and 1b gave N‐oxide in much poor yield, while 1c and 1d gave the N‐oxide 13c and 13d in good yields. The nucleophilic reactions (cyanation, chlorination and acetoxylatoin) of 13c through a Reissert‐Henze type reaction gave poor results, which would be caused by the strong electron withdrawing effect of the cyano group.     

Syntheses of 2,3‐dicyano‐5a,8a‐dihydro‐5a‐hydroxycyclopentano[1′,2′:4,5]pyrrolo[2,3‐b]pyrazines and 2,3‐dicyanocyclohexano[1′,2′:4,5]pyrrolo‐[2,3‐b]pyrazines

Previously synthesized 2‐(3′‐chloro‐5′,6′‐dicyanopyrazin‐2′‐yl)cyclopentan‐1‐one 1 , obtained from the reaction of 2,3‐dichloro‐5,6‐dicyanopyrazine with 1‐pyrrolidino‐1‐cyclopentene, was further reacted with primary alkylamines to give mixtures of diastereomer of 5‐alkyl‐2,3‐dicyano‐5a,8a‐dihy‐dro‐5a‐hydroxycyclopentano[1′,2′:4,5]pyrrolo[2,3‐b]pyrazines 3a‐h in high yield. The reaction of 2‐alkylamino‐3‐chloro‐5,6‐dicyanopyrazine with 1‐pyrrolidino‐1‐cyclohexene gave 5‐alkyl‐2,3‐dicyanocyclopentano[1′,2′:4,5]pyrrolo[2,3‐b]pyrazines 5a‐b together with 5‐alkylamino‐2,3‐dicyano‐6‐pyrrolidinopyrazines 6a‐b . The products prepared are all of interest as potential pesticides and new fluorescent chromophores.     

Synthesis and Evaluation of Bioactivity of Thiazolo[3,2‐b]‐[1,2,4]‐triazoles and Isomeric Thiazolo[2,3‐c]‐[1,2,4]‐triazoles

Synthesis of 2‐(o‐nitrophenyl)‐6‐arylthiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 and its isomer 3‐(o‐nitrophenyl)‐5‐arylthiazolo[2,3‐c]‐[1,2,4]‐triazoles 6 has been achieved starting from the appropriate 1‐(o‐nitrobenzoyl)‐3‐thiosemicarbazide 1 . Compound 1 on condensation with α‐haloketones gives 2‐(o‐nitrobenzoyl)hydrazino‐4‐arylthiazole hydrobromide 5 , which, on cyclization with POCl₃, affords thiazolo[3,2‐b]‐[1,2,4]‐triazoles 6 and not the isomeric thiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 . This has been established by an unequivocal synthesis of 4 through polyphosphoric acid cyclization of 5‐aroylmethylmercapto‐3‐o‐nitrophenyl‐[1,2,4]‐triazole 3 . Compound 3 was synthesized by condensation of α‐haloketones with 5‐mercapto‐3‐(o‐nitrophenyl)‐[1,2,4]‐triazole 2 , obtained cyclization of 2‐(o‐nitrobenzoyl)hydrazinecarbothioamide 1 with NaOH. The antibacterial and antifungal activities of some of the compounds have also been evaluated.     

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.     

Synthesis of benzo[b]thieno‐ and benzo[b]furano‐[2,3‐a]pyrrolo[3,4‐c]carbazole‐5‐, ‐7‐ and ‐5,7‐dione

Benzo[b]thieno[2,3‐a]pyrrolo[3,4‐c]carbazoles and benzo[b]furano[2,3‐a]pyrrolo[3,4‐c]carbazoles were prepared from 2‐(2‐benzo[b]thieno)‐ (8) and 2‐(2‐benzo[b]furano)‐3‐[3‐(2,5‐dioxo‐lH‐pyrrolidinyl)]indole (9) by a palladium(II)acetate/tetrachloro‐1,4‐benzoquinone oxidative A‐E ring closure.     

On triazoles XLVIII. Synthesis of isomeric amino‐thiazolo‐[1,2,4]triazole,amino‐[1,2,4]triazolo‐[1,3]thiazine and ‐[1,3]thiazepine derivatives

Isomeric type 1 and 2 amino‐1,2,4‐triazoles condensed with thiazole, thiazine and thiazepine rings were synthesised from 5‐amino‐2,3‐dihydro‐1H‐1,2,4‐triazol‐3‐thione and α,ω‐dihaloalkanes through the 5‐amino‐3‐(ω‐haloalkylthio)‐1H‐1,2,4‐triazole intermediates. The reaction conditions leading to derivatives 1 and 2 , respectively, were determined. A general and safe method for the unambiguous differentiation between structures 1 and 2 was offered by their cmr spectra.     

5‐Phenyl‐9H‐1,3‐dioxolo[4,5‐h][2,3]benzodiazepin‐8(7H)‐one

The title compound, C₁₆H₁₂N₂O₃, is a novel potent and selective non‐competitive antagonist at AMPA/kainate receptors [AMPA is 2‐amino‐3‐(3‐hydroxy‐5‐methylisoxazol‐4‐yl)­propionic acid and kainate is 3‐carboxy­methyl‐4‐isopropenyl­pyrrolidine‐2‐carboxylic acid]. The crystal structure has been determined at room temperature by X‐ray diffraction and the seven‐membered ring shows the usual boat conformation. The energy stabilization of the crystal packing of the title compound by significant hydrogen‐bond inter­actions is discussed using theoretical computations.     

5,6‐Di­phenyl­thieno­[2,3‐d][1,3]dithiole‐2‐thione

The title compound, C₁₇H₁₀S₄, has two independent mol­ecules in the asymmetric unit. In both mol­ecules, the fused heterocycle is almost planar and the phenyl groups make dihedral angles of 42.88 (9) and 52.79 (8)° with the fused heterocycle in one mol­ecule, and angles of 40.62 (9) and 52.28 (8)° in the other. The crystal packing is governed by short intermolecular S?S interactions, the shortest contact being 3.333 (1) Å.     

Ring closure reactions of 5‐azidopyrido[2,3‐d]pyrimidinetriones to isoxazolo‐ and oxadiazolopyrido[2,3‐d]pyrimidinetriones

Thermal decomposition of 5‐azidopyrido[2,3‐d]pyrimidines 2 and 7 having reactive ortho‐substituents such as a formyl or a nitro group yielded isoxazolo[3′,4′:4,5]pyrido[2,3‐d]pyrimidines 3 or oxadiazolo‐[3′,4′:4,5]pyrido[2,3‐d]pyrimidines 9. The reaction conditions of the azide decomposition were studied by differential scanning calorimetry (DSC). In addition, desoxygenation of N‐oxides 9 to oxadiazoles 10 and regioselective reduction of azides 7 to amines 8 were studied.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 23 . Naphtho[2′,1′:4,5]thieno‐[2,3‐c]naphtho[2,1‐f]quinoline

A previously unknown heterocyclic ring system, naphtho[2′,1′:4,5]thieno[2,3‐c]naphtho[2,1‐f]quinoline ( 14 ), was synthesized via oxidative photocyclization of 3‐chloro‐N‐(2‐phenanthryl)naphtho[1,2‐b]‐thiophene‐2‐carboxamide ( 9 ). Further elaboration of the lactam 10 yielded the unsubstituted ring system 14 . Structural confirmation of compound 14 was accomplished by a total assignment of its ¹H and ¹³C nmr spectra utilizing the concerted two‐dimensional nmr spectroscopic methods.     

A Novel Diastereoselective Synthesis of 6‐Aryl‐5‐hydroxy‐2,3‐dihydropyrano[2,3‐c]pyrazol‐4(1H)‐ones

A novel one‐pot diastereoselective synthesis of trans‐6‐aryl‐5‐hydroxy‐2,3‐dihydro[2,3‐c]pyrazol‐4(1H)‐ones 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h is described via the Darzens condensation reaction of 2‐chloro‐1‐(5‐hydroxy‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)ethanone ( 2 ) with different aromatic aldehydes in aqueous basic medium. The structures of the compounds prepared were determined by analytical and spectral analyses.     

Fast Efficient and General PASE Approach to Medicinally Relevant 4H,5H‐Pyrano‐[4,3‐b]pyran‐5‐one and 4,6‐Dihydro‐5H‐pyrano‐[3,2‐c]pyridine‐5‐one Scaffolds

The general ‘on‐solvent’ PASE approach was found to be medicinally relevant for 4H,5H‐pyrano[4,3‐b]pyran‐5‐one and 4,6‐dihydro‐5H‐pyrano[3,2‐c]pyridine‐5‐one scaffolds. Ammonium acetate‐catalyzed multicomponent reaction of aldehydes and two different C–H acids in the presence of small amounts of EtOH results in fast (3 – 15 min) and efficient formation of scaffolds, promising for many diverse oriented medical applications.     

Three‐Step Synthesis of 3‐Aryl‐2‐sulfanylthieno[2,3‐b]‐, ‐[2,3‐c]‐, or ‐[3,2‐c]pyridines from the Corresponding Aryl(halopyridinyl)methanones

A convenient three‐step procedure for the synthesis of three types of 3‐aryl‐2‐sulfanylthienopyridines 4, 8 , and 12 has been developed. The first step of the synthesis of thieno[2,3‐b]pyridine derivatives 4 is the replacement of the halo with a (sulfanylmethyl)sulfanyl group in aryl(2‐halopyridin‐3‐yl)methanones 1 by successive treatment with Na₂S?9 H₂O and chloromethyl sulfides to give aryl{2‐[(sulfanylmethyl)sulfanyl]pyridin‐3‐yl}methanones 2 . In the second step, these were treated with LDA (LiNⁱPr₂) to give 3‐aryl‐2,3‐dihydro‐2‐sulfanylthieno[2,3‐b]pyridin‐3‐ols 3 , which were dehydrated in the last step with SOCl₂ in the presence of pyridine to give the desired products. Similarly, thieno[2,3‐c]pyridine and thieno[3,2‐c]pyridine derivatives, 8 and 12 , respectively, can be prepared from aryl(3‐chloropyridin‐4‐yl)methanones 5 and aryl(4‐chloropyridin‐3‐yl)methanones 9 , respectively.     

On triazoles XLIX. Synthesis of 5,6‐dihydrothiazolo[3,2‐b]‐[1,2,4]triazol‐2‐yl‐, 6,7‐dihydro‐5H‐[1,2,4]triazolo[5,1‐b][1,3]thiazin‐2‐yl‐, and 5,6,7,8‐tetrahydro[1,2,4]triazolo[5,1‐b] [1,3]thiazepin‐2‐yl‐isoquinolinium salts

5′‐Mercapto‐1′H‐1,2,4‐triazol‐3′‐yl‐isoquinolinium salts (6) were synthesised by the reaction of ortho‐acyl phenylacetones (2) or the corresponding pyrylium salts (3) and 5‐amino‐2,3‐dihydro‐1H‐1,2,4‐triazole‐3‐thione (5) . Treatment of thioles 6 withα,ω‐dibromoalkanes led to type 15, 16 and 17 isoquinolinium salts condensed with thiazole, thiazine and thiazepine rings. When 6 are reacted with dibromomethane (10) 11 type dimeric structures are obtained.     

Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

On the chemistry of 5‐aryl‐2‐hydrazino‐benzo[6,7]cyclohepta[1,2‐b]pyrido[2,3‐e] pyrimidin‐4‐one

Several pyrido[2,3‐e]pyrimidine fused with other rings have been prepared by intramolecular cyclization of 5‐(4‐chlorophenyl)‐2‐hydrazino‐benzo [6,7]cyclohepta‐[1,2‐b]pyrido[2,3‐e]pyrimidine‐4‐one ( 1 ) with acids, carbon disulfide to form triazole derivatives ( 2,4 ), halo‐ketones to give triazine derivative ( 5 ), β‐ketoesters, β‐cyanoesters, and β‐diketones to yield 2‐(1‐pyrazolyl) derivatives ( 7,9,10 ), and aldehydes to form arylhydrazone derivatives ( 11a,b ) which cyclized to form triazoles ( 12a,b ). Also, acyclic N‐nucleosides are prepared by heating under reflux 2‐hydrazino‐benzo[6,7]cyclohepta[1,2‐b]pyrido[2,3‐e] pyrimidin‐4‐one ( 1 ) with xylose and glucose to give the corresponding acyclic N‐nucleosides ( 13a,b ) which are cyclized to afford the corresponding protected tetra and penta–O‐acetate C‐nucleosides ( 14a,b ). Deacetylating of the latter nucleosides afforded the free acyclic C‐nucleosides ( 15a,b ). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:34–43, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20248