Strategy to Construct Stair‐Shaped Partially Reduced Naphtho[1,2‐b]pyrano[2,3‐d]oxepines and Dinaphtho[1,2‐b,d]oxepines

A concise and efficient base‐induced synthesis of stair‐shaped, 4‐methylthio‐2‐oxo‐5,6‐dihydro‐2H‐naphtho[1,2‐b]pyran[2,3‐d]oxepine‐3‐carbonitriles ( 3 ) has been delineated by the reaction of 3,4‐dihydronaphtho[1,2‐b]oxepin‐5(2H)‐one ( 1 ) and methyl 2‐cyano‐3,3‐dimethylthioacrylate in DMSO using powdered KOH as a base at room temperature. Amination of 3 has been achieved by reaction with secondary amine in ethanol at reflux temperature to yield 4‐sec‐amino‐2‐oxo‐5,6‐dihydro‐2H‐naphtho[1,2‐b]pyran[2,3‐d]oxepine‐3‐carbonitriles ( 4 ). Reaction of 3 with aryl methyl ketone ( 5 ) in DMSO at room temperature using powdered KOH as a base produced stair‐shaped 5‐aryl‐7,8‐dihydro‐1,4‐dioxa‐2,3‐dioxodinaphtho[1,2‐b,d]oxepine ( 6 ) in good yields. However, reaction of 6‐aryl‐2H‐pyran‐2‐one‐3‐carbonitrile ( 8 ) with 3,4‐dihydronaphtho[1,2‐b]oxepin‐5(2H)‐one ( 1 ) did not give similar product, but in lieu 4‐aryl‐5,6‐dihydronaphtho[1,2‐b]oxepino[4,5‐b]pyran‐2‐ylidene)acetonitrile ( 9 ) was isolated and characterized.     

Polycyclic N‐Heterocyclic Compounds. Part 80: Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6‐Dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidine and Related Compounds

Reaction of 3‐(3‐cyanopropylthio)[1]benzothiophene‐2‐carbonitrile with tert‐BuONa gave 5‐amino‐1,2‐dihydro[1]benzothieno[3,2‐d]thieno[2,3‐b]pyridine and 5‐amino‐2,3‐dihydro[1]benzothieno[3,2‐b]thiepin‐4‐carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles, [1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidines. All of our new tetracyclic products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products.     

A new dimerization reaction producing 2‐amino‐9‐oxopyrrolo‐[2,1‐b]quinazoline‐1‐carbonitriles and analogous pyrrolo‐[1,2‐a]thieno[3,2‐d] pyrimidinecar bonitriles

A series of 2‐alkylthio‐4‐oxo‐3‐quinazolineacetonitriles 4 and 2‐alkylthio‐4‐oxothieno[3,2‐d]pyrimidine‐3‐acetonitriles 8 was prepared. Upon treatment with sodium hydride, compounds 4 and 8 react to give 2‐amino‐4,9‐dihydro‐9‐oxopyrrolo[2,1‐b]quinazoline‐1‐carbonitriles 9 and 6‐amino‐4,9‐dihydro‐9‐oxopyrrolo[1,2‐a]thieno[3,2‐d]pyrimidine‐7‐carbonitriles 10 , respectively. The transformation of compounds 4 and 8 to the tricyclic aminonitriles 9 and 10 involves a dimerization step followed by a pyrrole cyclization. The tert‐butyl ester derivatives 4d and 8d upon treatment with sodium hydride underwent a Thorpe‐Ziegler cyclization to provide enaminoesters of fused 1,3‐thiazines ( 16 and 17 , respectively) as major products.     

New Methods for the Synthesis of 3‐Amino‐6,7‐Dihydro‐5H‐Cyclopenta[c]Pyridine‐4‐Carbonitriles and Cyclopenta[d]Pyrazolo[3,4‐b]Pyridines via a Smiles‐type Rearrangement

By reaction with sodium ethoxide and as a function of their structures, 2‐[(1‐alkyl(aryl)‐4‐cyano‐6,7‐dihydro‐5H‐cyclopenta[c ]pyridin‐3‐yl)oxy]acetamides 11 gave 1‐amino‐5‐alkyl(aryl)‐7,8‐dihydro‐6H‐cyclopenta[d ]furo[2,3‐b ]pyridine‐2‐carboxamides 10 and/or 1‐alkyl(aryl)‐3‐amino‐6,7‐dihydro‐5H‐cyclopenta[c ]pyridine‐4‐carbonitriles 12 .     

Reaction of 2‐acyl‐6‐methylbenzo[b]furan‐3‐acetic acids derivatives with hydrazine

Reaction of 2‐acyl‐6‐methylbenzo[b]furan‐3‐acetic acids and their derivatives such as amides and esters with hydrazine does not give expected 1‐alkyl‐5H‐benzofuro[2,3‐e]diazepin‐4‐ones ones but results in 2‐amino‐7‐methyl‐2H‐benzo[4,5]furo[2,3‐c]pyridin‐3‐ones or (3‐R‐6‐methylbenzo[b]furan‐2‐yl)alkyl ketone azines.     

Synthesis of New Pyrimido[4′,5′:3,4]pyrazolo[1,2‐b]phthalazine‐4,7,12‐triones: Derivatives of a New Heterocyclic Ring System

Several derivatives of the new pyrimido[4′,5′:3,4]pyrazolo[1,2‐b]phthalazine‐4,7,12‐trione ring system have been prepared by the reaction of 3‐amino‐1‐aryl‐5,10‐dioxo‐5,10‐dihydro‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles with aliphatic carboxylic acids in the presence of phosphoryl chloride (POCl₃). The synthesized compounds were characterized on the basis of IR, ¹H NMR, and ¹³C NMR spectral and microanalytical data.     

Polycyclic N‐Heterocyclic Compounds. Part 84: Reaction of N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines or N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines with Hydroxylamine Hydrochloride

The reactions of nine N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines ( 3 ) with hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4‐oxadiazole‐forming ring closure to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)thieno[2,3‐b]pyridin‐3‐yl]formamide oximes ( 11 ). Reaction of six N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines ( 12 ) with hydroxylamine hydrochloride gave similar results. Effects of the newly synthesized compounds on pentosidine formation were also evaluated.     

Polycyclic N‐Heterocyclic Compounds,Part 72: Reaction of N‐([1]Benzofuro (or Benzothieno)[3,2‐d]pyrimidin‐4‐yl)formamidine and N‐(Pyrido[2,3‐d]pyrimidin‐4‐yl)formamidine Derivatives with Hydroxylamine Hydrochloride

The reactions of N‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring closure of the 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide oximes. N‐([1]Benzothieno[3,2‐d]pyrimidin‐4‐yl)formamidines and N‐(pyrido[2,3‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave similar results.     

Polycyclic N‐Heterocyclic Compounds. Part 81: Synthesis and Evaluation of Pentacyclic 1,2,4,5‐Tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine and Related Compounds as Potential Antiplatelet Aggregators

Dehydrative ring closure reactions were carried out on fused 4‐(2‐hydroxyethylamino) (or 2‐hydroxyethoxy or 2‐hydroxyethylthio)pyrimidines ( 2a , 2b , 2c ) to give fused 2,3‐dihydroimidazo[1,2‐c] (or 2,3‐dihydrooxazolo[3,2‐c] or 2,3‐dihydrothiazolo[3,2‐c])pyrimidines. This reaction produced the pentacyclic 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine ( 3a ) and 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]thiazolo[3,2‐c]pyrimidinium chloride ( 3c ) from the 2‐hydroxyethylamino‐derivative and 2‐hydroxyethylthio‐derivative, respectively. In contrast, 2‐hydroxyethoxy‐derivative ( 2b ) gave the rearrangement product, 3‐(2‐chloroethyl)‐5,6‐dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidin‐4(3H)‐one ( 4 ). Effects of the synthesized compounds on collagen‐induced platelet aggregation were also evaluated.     

Synthesis of 1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine

The synthesis of 7,8‐dihydro‐5(6H)‐quinolinone ( 3 ) from commercially available 3‐amino‐2‐cyclohexen‐1‐one ( 1 ) and 3‐(dimethylamino)acrolein ( 4 ) in 23% yield avoids the preparation of propynal ( 2 ). Conversion of 5‐(4‐methylphenylsulfonyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]azepine ( 12 ) to 6‐(4‐methylphenylsulfonyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 24 ) is described. Removal of the N‐(4‐methylphenylsulfonyl) group with 40% sulfuric acid in acetic acid gave the tricyclic azepine 26. Application of a similar series of reactions to 5‐(4‐nitrobenzoyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]‐azepine ( 13 ) afforded 6‐(4‐nitrobenzoyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 25 ).     

Synthesis and reactions of 11H‐benzo[b]pyrano[3,2‐f]indolizines an pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolines

2‐Methyl‐3H‐indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4‐hydroxy‐11H‐benzo[b]pyrano[3,2‐f]indolizin‐2,5‐diones 3, whereas 2‐mefhyl‐2,3‐dihydro‐1H‐indoles 9 give under similar conditions regioisomer 8‐hydroxy‐5‐methyl‐4,5‐dihydro‐pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolin‐7,10‐diones 10 . The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 or 5‐acetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo‐[3,2,1‐ij]quinolin‐4‐ones 11 , respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subsequent ring opening 7‐dichloroacetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 5 or 5‐dichloracetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 12 . The dichloroacetyl group of 5 can be reduced with zinc to 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 7. Treatment of the acetyl compounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8‐hydroxy‐10H‐pyrido[1,2‐a]‐indol‐6‐ones 6 and 8 , and 6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 13 . Reaction of dichloroacetyl compounds 12 with sodium azide yields 6‐hydroxy‐2‐methyl‐5‐(1H‐tetrazol‐5‐ylcarbonyl)‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 14 via intermediate geminal diazides.     

Synthesis of novel pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidines,pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[l,6‐a]benzimidazoles and related fused systems

3‐Amino‐4‐aryl‐5‐ethoxycarbonyl‐6‐methylthieno[2,3‐b]pyridine‐2‐carboxamides 3a‐c were prepared from ethyl 4‐aryl‐3‐cyano‐6‐methyl‐2‐thioxo‐1,2‐dihydropyridine‐5‐carbonylates 1a‐c and reacted with some carbonyl compounds to give tetrahydropyridothienopyrimidine derivatives 6a‐c, 7a‐c and 8a‐c , respectively. Treatment of compound 3c with chloroacetyl chloride led to the formation of a next key compound, ethyl 2‐chloromethyl‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 9 . Also, 3‐amino‐2‐benzimidazolylthieno[2,3‐b]pyridine‐5‐carboxylate 5 and 2‐(3′‐aminothieno [2,3‐b]pyridin‐2′‐yl)‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 17 were prepared from 1c. The compounds 5, 9 and 17 were used as good synthons for other pyridothienopyrimidines and pyridothienopyrimidobenzimidazoles as well as for related fused polyheterocyclic systems.     

Preparation of a series of benzothieno[3,2‐b]pyridine‐3‐carbonitriles and benzofuro[3,2‐b]pyridine‐3‐carbonitriles

New and shorter routes to the benzothieno[3,2‐b]pyridine‐3‐carbonitrile and benzofuro[3,2‐b]pyridine‐3‐carbonitrile ring systems are reported. These heterocycles may function as new templates for kinase inhibitors.     

Regioselective Synthesis of Amino Substituted Indazolo[2,1‐b]phthalazine‐triones and Pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles Catalyzed by 2‐1′‐Methylimidazolium‐3‐yl‐1‐ethyl Sulfate

The regioselective reactions of luminol with 1,3‐cyclohexanedione (or malononitrile) and aromatic aldehydes catalyzed by 2‐1′‐methylimidazolium‐3‐yl‐1‐ethyl sulfate were developed to synthesize 7‐amino‐3,4‐dihydro‐2H‐indazolo[2,1‐b]phthalazine‐1,6,11(13H)‐triones and 3,9‐diamino‐5,10‐dihydro‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles in good to excellent yields in short times.     

Synthesis of Novel Pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine Derivatives and Their Cytotoxic Activity

The 3‐amino‐6‐(trifluoromethyl)furo[2,3‐b]pyridine‐2‐carbohydrazide ( 5 ) was prepared from 3‐cyano‐6‐trifluoromethyl‐2(1H)pyridone ( 2 ) in series of steps via selective O‐alkylation, Thorpe–Ziegler cyclization followed by reaction with hydrazine hydrate. The 2‐carbohydrazide ( 5 ) was further reacted with aliphatic acids under different reaction temperatures to form a series of novel N‐acylfuro[2,3‐b]pyridine‐2‐carbohydrazide ( 6 ) and pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine derivatives ( 7 ). All the compounds 6 and 7 were screened for cytotoxic activity against breast carcinoma MD Anderson‐Metastatic Breast (MDA‐MB) 231 (aggressive) cell lines at 10 µM concentration. Compounds 6a , 6b , and 6c showed promising activity.     

Synthesis of Fluoroalkylated Heterocycles via the Reaction of 3-（1-Hydropolyfluoroalkenyl）-l-oxo-2,4,1-benzoxazines with Dinucleophilic Reagents

The reaction of 3-（1-hydropolyfluoroalkenyl）-1-oxo-2,4,1-benzoxazines 1 with some dinucleophiles was investigated. 7-Fluoroalkyl-2,3-dihydro- 1,4-diazepine[ 1,2-d]quinazolin- 11-ones 2, 2-fluoroalkylisoxazolo[3,2-b]quinazolin-9-ones 3 and 2-fluoroalkylbenzoimidazoles 4 were obtained from the reaction of 1 with 1,2-diaminoethane, hydroxylamine hydrochloride and 1,2-diaminobenzene respectively.     

Imidazo[2,1‐b]thiazoles,imidazo[2,1‐b]imidazoles and Pyrrolo[1,2‐c]imidazoles. synthesis,structure and evaluation of benzodiazepine receptor binding

As a continuation of our studies on bicyclic heterocycles with benzodiazepine receptor affinity, derivatives with a 5:5 bicyclic skeleton, namely imidazo[2,1‐b]thiazoles, imidazo[2,1‐b]imidazoles and pyrrolo[1,2‐c]imidazoles were prepared. The compounds possessed an aromatic substituent with different spatial arrangement and distance to the bicyclic skeleton. X‐ray structure analysis was performed for Z‐2‐(4‐chlorobenzylidene)‐5,5‐diphenyl‐2,3,5,6‐tetrahydroimidazo[2,1‐b]imidazoline‐3,6‐dione ( 6a ) and 5‐amino‐6‐cyano‐7‐phenyl‐1‐oxo‐3‐thioxo‐2,3‐dihydro‐1H‐pyrrolo[1,2‐c]imidazole ( 20a ). In contrast to the previously described arylideneimidazo[2,1‐b]thiazepinones the smaller heterocyclic ring systems investigated in this study were devoid of meaningful benzodiazepine receptor affinity as well as anti‐convulsant activity.     

Synthesis of novel pyrido[3′,2′:5,6]thiopyrano[3,2‐b]indol‐5(6H)‐ones and 6H‐pyrido[3′,2′:5,6]thiopyrano[4,3‐b]quinolines,two new heterocyclic ring systems

The synthesis of new pyrido[3′,2′:5,6]thiopyrano[3,2‐b]indol‐5(6H)‐ones was accomplished by the Fischer‐indole cyclization of some 2,3‐dihydro‐3‐phenylhydrazonothiopyrano[2,3‐b]pyridin‐4(4H)‐ones, obtained from the 2,3‐dihydro‐3‐hydroxymethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐one, by the Japp‐Klingemann reaction. 6H‐Pyrido[3′,2′:5,6]thiopyrano[4,3‐b]quinolines were obtained by reaction of 2,3‐dihydrothiopyrano‐[2,3‐b]pyridin‐4(4H)‐ones with o‐aminobenzaldehyde or 5‐substituted isatins. The preparation of some derivatives, functionalized with an alkylamino‐substituted side chain, is also described.     

Synthesis of dihydrofuro[2,3‐b]pyridines by the reaction of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles with α,β‐unsaturated carbonyl compounds

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles 1a‐d with α,β‐unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a‐d , 3a‐d and 4a‐d. Compounds 2a‐d and 3a‐c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a‐alkoxyhexahydrofuro[2,3‐b]pyridines 5a‐d, 6a‐d, 7a‐c and 8a‐c . Treatment of 5a‐d, 6a‐d, 7a‐c and 8a‐c with potassium tert‐butoxide produced the corresponding dihydrofuro[2,3‐b]pyridines 9a‐d and 10a‐c . The reaction of 4a‐c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro‐furo[2,3‐b]pyridines 11a‐c .     

Synthesis of new hetero[1,2,4]thiadiazin‐3‐one S,S‐dioxides and oxazolo[3,2‐b]hetero[1,2,4]thiadiazine S,S‐dioxides as potential psychotropic drugs

A series of 2‐substituted 2H‐thieno[3,4‐e][1,2,4]thiadiazin‐3(4H)‐one 1,1‐dioxides ( 2 ), 2‐substituted 2H‐thieno[2,3‐e][1,2,4]thiadiazin‐3(4H)‐one 1,1‐dioxides ( 3 ), 2‐substituted 4,6‐dihydropyrazolo[4,3‐e]‐[1,2,4]thiadiazin‐3(2H)‐one 1,1‐dioxides ( 4 ), 2‐substituted 2,3‐dihydrooxazolo[3,2‐b]thieno[3,4‐e]‐[1,2,4]thiadiazine 5,5‐dioxides, ( 5 ), 6‐substituted 6,7‐dihydro‐2H‐oxazolo[3,2‐b]pyrazolo[4,3‐e][1,2,4]thia‐diazine 9,9‐dioxides ( 6 ) and 7‐substituted 6,7‐dihydro‐2H‐oxazolo[3,2‐b]pyrazolo[4,3‐e][1,2,4]thiadiazine 9,9‐dioxides ( 7 ) were synthesized as potential psychotropic agents.