Polycyclic N‐Heterocyclic Compounds. Part 78: Synthesis of N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclohepten‐1‐yl]formamide Oximes and Their Evaluation as Inhibitors of Platelet Aggregation

N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclohepten‐1‐yl]formamide oximes were synthesized by fusion of (6,7,8,9‐tetrahydro‐5H‐cyclohepta[1,2‐d]pyrimidin‐4‐yl)amidines with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Effects of the products as well as the structurally related N‐[4‐([1,2,4]oxadiazol‐5‐yl)‐2,3‐dihydro[1]benzoxepin‐5‐yl]formamide oximes and N‐[4‐([1,2,4]oxadiazol‐5‐yl)‐2,3‐dihydro[1]benzothiepin‐5‐yl]formamide oximes on platelet aggregation were 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 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 67: Reaction of 6,7‐substituted N‐(quinazolin‐4‐yl)amidine derivatives with hydroxylamine hydrochloride: Formation of in vitro inhibitors of pentosidine

Reactions of N‐(quinazolin‐4‐yl)amidines and their amide oximes with hydroxylamine hydrochloride gave cyclization products that were formed by an initial ring cleavage of the pyrimidine component followed by a ring closure formation of 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)phenyl]formamide oximes. All isolated products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products. Some products exhibited significant inhibitory activity against pentosidine formation. J. Heterocyclic Chem., (2011).     

Synthesis and Fungicidal Activity of (1Z, 3Z)‐4,4‐Dimethyl‐1‐substitutedphenyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pent‐1‐en‐3‐one O‐[2,4‐dimethylthiazole(or 4‐methyl‐1,2,3‐thiadiazole)]‐5‐carbonyl Oximes

A series of novel (Z)‐1‐tert‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐ethanone O‐[2,4‐dimethylthiazole (or 4‐methyl‐1,2,3‐thiadiazole) ?5‐carbonyl] oximes 5a – 5c and (1Z, 3Z)‐4,4‐dimethyl‐1‐substitutedphenyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pent‐1‐en‐3‐one O‐[2,4‐dimethylthiazole (or 4‐methyl‐1,2,3‐thiadiazole)‐5‐carbonyl] oximes 6a – 6e were synthesized by the condensations of (Z)‐1‐tert‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐ethanone oximes 3 or (1Z, 3Z)‐4,4‐dimethyl‐1‐substitutedphenyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pent‐1‐en‐3‐one oximes 4 with 2,4‐dimethylthiazole‐5‐carbonyl chloride or 4‐methyl‐1,2,3‐thiadiazole‐5‐carbonyl chloride in the basic condition. Their structures were confirmed by IR, ¹H NMR, mass spectroscopy, and elemental analyses. The results of preliminary bioassays showed the title compounds 5 and 6 exhibited moderate to good fungicidal activities. For example, compound 6c possessed 86.4% inhibition against Fusarium oxysporum, and compound 6b exhibited 86.4 and 100% inhibition against Fusarium oxysporum and Cercospora arachidicola Hori at the concentration of 50 mg/L, respectively.     

Synthesis of 4‐(1‐phenyl‐1H‐pyrazol‐3‐yl)‐[1,2,4]triazolo[4,3‐a]quinoxalines and their 4‐halogenopyrazolyl analogs

Synthesis of {3‐[1‐(ethoxycarbonyl)‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyrazol‐5‐yl}methyl ethyl oxalate ( 2 ), ethyl 4‐[5‐(acetoxymethyl)‐1‐phenyl‐1H‐pyrazol‐3‐yl]‐[1,2,4]triazolo[4,3‐a]quioxaline‐1‐carboxylate ( 4 ), [4‐halo‐1‐phenyl‐3‐(1‐phenyl‐[1,2,4]triazolo[4,3‐a]quioxalin‐4‐yl)‐1H‐pyrazol‐5‐yl]methyl acetate ( 11 ), {4‐halo‐3‐[1‐methyl‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyraz‐ol‐5‐yl}methyl acetate ( 13 ), and [3‐([1,2,4]triazolo‐[4,3‐a]quinoxalin‐4‐yl)‐4‐halo‐1‐phenyl‐1H‐pyrazol‐5‐yl] methyl formate ( 15 ) was accomplished. The structural investigation of the new compounds is based on chemical and spectroscopic evidences. J. Heterocyclic Chem., (2011)     

Syntheses of Some 3—[1′（1′H）—Substituent—pyrazol—5′—yl] benzo [5,6] coumarins

3-[1′(1′H)-Substituent-pyrazol-5′-yl]benzo[5,6]coumarins and 3-(1′,2′-oxazol-5′-yl)benzo[5,6]coumarin were prepared via condensation of 3-(2′-formyl-1′-chlorovinyl)benzo[5,6] coumarin with hydrazine derivatives or hydroxylamine.Reaction of 3-[1′(1′H)-pyrazol-5′-yl]benzo[5,6]coumarin with alkyl halides,olefinic compunds or acid chlorides are described.     

Synthesis of a New,Highly Fluorescent Amino Acid Derivative: N‐[(tert‐Butoxy)carbonyl]‐3‐[2‐(1H‐indol‐3‐yl)benzoxazol‐5‐yl]‐L‐alanine Methyl Ester

A simple method of synthesis of a new, highly fluorescent amino acid derivative from the simple and generally available substrates 3‐nitro‐L ‐tyrosine and 1H‐indole‐3‐carbaldehyde is described. The obtained compound, N‐[(tert‐butoxy)carbonyl]‐3‐[2‐(1H‐indol‐3‐yl)benzoxazol‐5‐yl]‐L ‐alanine methyl ester ( 4 ), possesses a high fluorescence quantum yield. The described method illustrates a new possibility of synthesis of amino acid derivatives possessing desirable photophysical properties.     

Synthesis of Novel 3‐(3‐(5‐Methylisoxazol‐3‐yl)‐7H‐[1,2,4]Triazolo [3,4‐b][1,3,4]Thiadiazin‐6‐yl)‐2H‐Chromen‐2‐Ones

A novel series of coumarin substituted triazolo‐thiadiazine derivatives were designed and synthesized by using 5‐methyl isoxazole‐3‐carboxylic acid ( 1 ), thiocarbohydrazide ( 2 ), and various substituted 3‐(2‐bromo acetyl) coumarins ( 4a , 4b , 4c , 4e , 4d , 4f , 4g , 4h , 4i , 4j ). Fusion of 5‐methyl isoxazole‐3‐carboxylic acid with thiocarbohydrazide resulted in the formation of the intermediate 4‐amino‐5‐(5‐methylisoxazol‐3‐yl)‐4H‐1,2,4‐triazole‐3‐thiol ( 3 ). This intermediate on further reaction with substituted 3‐(2‐bromo acetyl) coumarins under simple reaction conditions formed the title products 3‐(3‐(5‐methylisoxazol‐3‐yl)‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl‐2H‐chromen‐2‐ones ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j ) in good to excellent yields. All the synthesized compounds were well characterized by physical, analytical, and spectroscopic techniques.     

Polycyclic N‐Heterocyclic Compounds. 56 Reaction of N‐(5,6‐Dihydro[1]benzoxepino[5,4‐d]pyrimidin‐4‐yl)amidine or Its Amide Oxime Derivatives with Hydroxylamine Hyrdochloride

The reactions of N‐(5,6‐dihydro[1]benzoxepino[5,4‐ d]pyrimidin‐4‐yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.     

Structural studies of (prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine hetero‐scorpionate copper complexes

The structures of five compounds consisting of (prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine complexed with copper in both the Cu^I and Cu^II oxidation states are presented, namely chlorido{(prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine‐κ³N,N′,N′′}copper(I) 0.18‐hydrate, [CuCl(C₁₅H₁₇N₃)]·0.18H₂O, (1), catena‐poly[[copper(I)‐μ₂‐(prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine‐κ⁵N,N′,N′′:C²,C³] perchlorate acetonitrile monosolvate], {[Cu(C₁₅H₁₇N₃)]ClO₄·CH₃CN}_n, (2), dichlorido{(prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine‐κ³N,N′,N′′}copper(II) dichloromethane monosolvate, [CuCl₂(C₁₅H₁₇N₃)]·CH₂Cl₂, (3), chlorido{(prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine‐κ³N,N′,N′′}copper(II) perchlorate, [CuCl(C₁₅H₁₇N₃)]ClO₄, (4), and di‐μ‐chlorido‐bis({(prop‐2‐en‐1‐yl)bis[(pyridin‐2‐yl)methylidene]amine‐κ³N,N′,N′′}copper(II)) bis(tetraphenylborate), [Cu₂Cl₂(C₁₅H₁₇N₃)₂][(C₆H₅)₄B]₂, (5). Systematic variation of the anion from a coordinating chloride to a noncoordinating perchlorate for two Cu^I complexes results in either a discrete molecular species, as in (1), or a one‐dimensional chain structure, as in (2). In complex (1), there are two crystallographically independent molecules in the asymmetric unit. Complex (2) consists of the Cu^I atom coordinated by the amine and pyridyl N atoms of one ligand and by the vinyl moiety of another unit related by the crystallographic screw axis, yielding a one‐dimensional chain parallel to the crystallographic b axis. Three complexes with Cu^II show that varying the anion composition from two chlorides, to a chloride and a perchlorate to a chloride and a tetraphenylborate results in discrete molecular species, as in (3) and (4), or a bridged bis‐μ‐chlorido complex, as in (5). Complex (3) shows two strongly bound Cl atoms, while complex (4) has one strongly bound Cl atom and a weaker coordination by one perchlorate O atom. The large noncoordinating tetraphenylborate anion in complex (5) results in the core‐bridged Cu₂Cl₂ moiety.     

Synthesis of Some New 2‐Oxo‐N‐[(10H‐phenothiazin‐10‐yl)alkyl] Derivatives of Azetidine‐1‐carboxamides

The synthesis of a new series of 4‐aryl‐3‐chloro‐2‐oxo‐N‐[3‐(10H‐phenothiazin‐10‐yl)propyl]azetidine‐1‐carboxamides, 4a – 4m , is described. Phenothiazine on reaction with Cl(CH₂)₃Br at room temperature gave 10‐(3‐chloropropyl)‐10H‐phenothiazine ( 1 ), and the latter reacted with urea to yield 1‐[3‐(10H‐phenothiazin‐10‐yl)propyl]urea ( 2 ). Further reaction of 2 with several substituted aromatic aldehydes led to N‐(arylmethylidene)‐N′‐[3‐(phenothiazin‐10‐yl)propyl]ureas 3a – 3m , which, on treatment with ClCH₂COCl in the presence of Et₃N, furnished the desired racemic trans‐2‐oxoazetidin‐1‐carboxamide derivatives 4a – 4m . The structures of all new compounds were confirmed by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, FAB mass spectrometry, and chemical methods.     

New Synthesis of N‐(1H‐pyrazol‐5‐yl)‐hexahydroquinoline‐3‐carbonitrile and octahydropyrazolo[4′,3′:5,6]pyrimido[1,2‐a]quinoline‐6‐carbonitrile Derivatives from the Cyclic β‐Enaminones

A facile and convenient synthesis of an interesting N‐(1H‐pyrazol‐5‐yl)‐hexahydroquinoline‐3‐carbonitrile and octahydropyrazolo[4′,3′:5,6]pyrimido[1,2‐a ]quinoline‐6‐carbonitrile derivatives via the versatile readily accessible cyclic enaminones incorporating pyrazole moiety was accomplished.     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

Syntheses of N‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzamides and N‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzenesulfonamides

A series of substituted N‐(4‐substituted‐benzoyl)‐N‐[3‐(1‐methyl‐1H‐imidazol‐2‐yl)propyl]amines ( 13 ) and N‐arylsulfonyl‐N‐[3‐(1‐methyl‐1H‐imidazol‐2‐yl)propyl]amines ( 14 ) were prepared from the reaction of 3‐(1‐methyl‐1H‐imidazol‐2‐yl)propan‐1‐amine ( 7 ) with substituted benzoyl chloride or substituted‐benzene sulfonyl chloride respectively. Compound 7 was prepared by two independent methods.     

Synthesis of benzo[c][1,8]phenanthrolin‐6‐one through cyclization of N‐(isoquinol‐5‐yl)‐2‐bromo‐benzamide derivatives

In the course of our search for compounds with potential antitumor properties we have undertaken the synthesis of benzo[c][1,8]phenanthroline derivatives. Our project required the preparation of 8,9‐dimethoxy benzo[c][1,8]phenanthrolin‐6‐ones. This was first attempted by the lithiumdiisopropylamide cyclization of N‐(isoquinol‐5‐yl)‐2‐bromo‐4,5‐dimethoxybenzamide. The reaction led to 40% of the unexpected internal Diels‐Alder adduct 3,4‐dimethoxy‐6H‐pyrido[2,3‐i]6,8a‐ethenoindolo[cd]isoquinoline‐2(1H)‐one, which arose from a benzyne intermediate. In a second and more successful approach, the internal biaryl palladium diacetate‐assisted coupling reaction of properly N‐protected N‐(isoquinol‐5‐yl)‐2‐bromo‐4,5‐dimethoxybenzamide was studied. The optimisation of the protecting group necessary for this procedure led to a 64% yield of the target compound starting from N,N‐(isoquinol‐5‐yl)‐bis‐(2‐bromo‐4,5‐dimethoxybenzamide).     

Utility of 2‐[4‐(3‐oxobenzo[f]‐2H‐chromen‐2‐yl)‐1,3‐thiazol‐2‐yl]ethanenitrile in heterocyclic synthesis

Pyrazolo[4,3‐d]pyrimidines, pyrazolo[4,3‐d]triazolino[4,3‐a]pyrimidines, 3‐(2‐thiazolyl)thiophenes, thiazolo[3,2‐a]pyridine and pyrazolo[1,5‐a]pyrimidines were synthesized from 2‐[4‐(3‐oxobenzo[f]‐2H‐chromen‐2‐yl)‐1,3‐thiazol‐2‐yl]ethanenitrile. The newly synthesized compounds were elucidated by elemental analysis, spectral data, chemical transformation and alternative synthesis route whenever possible.     

ZnII and CuII complexes generated from 5‐(pyridin‐4‐yl)‐3‐[2‐(pyridin‐4‐yl)ethyl]‐1,3,4‐oxadiazole‐2(3H)‐thione

A new 1,3,4‐oxadiazole‐containing bispyridyl ligand, namely 5‐(pyridin‐4‐yl)‐3‐[2‐(pyridin‐4‐yl)ethyl]‐1,3,4‐oxadiazole‐2(3H)‐thione (L), has been used to create the novel complexes tetranitratobis{μ‐5‐(pyridin‐4‐yl)‐3‐[2‐(pyridin‐4‐yl)ethyl]‐1,3,4‐oxadiazole‐2(3H)‐thione}zinc(II), [Zn₂(NO₃)₄(C₁₄H₁₂N₄OS)₂], (I), and catena‐poly[[[dinitratocopper(II)]‐bis{μ‐5‐(pyridin‐4‐yl)‐3‐[2‐(pyridin‐4‐yl)ethyl]‐1,3,4‐oxadiazole‐2(3H)‐thione}] nitrate acetonitrile sesquisolvate dichloromethane sesquisolvate], {[Cu(NO₃)(C₁₄H₁₂N₄OS)₂]NO₃·1.5CH₃CN·1.5CH₂Cl₂}_n, (II). Compound (I) presents a distorted rectangular centrosymmetric Zn₂L₂ ring (dimensions 9.56 × 7.06 Å), where each Zn^II centre lies in a {ZnN₂O₄} coordination environment. These binuclear zinc metallocycles are linked into a two‐dimensional network through nonclassical C—H...O hydrogen bonds. The resulting sheets lie parallel to the ac plane. Compound (II), which crystallizes as a nonmerohedral twin, is a coordination polymer with double chains of Cu^II centres linked by bridging L ligands, propagating parallel to the crystallographic a axis. The Cu^II centres adopt a distorted square‐pyramidal CuN₄O coordination environment with apical O atoms. The chains in (II) are interlinked via two kinds of π–π stacking interactions along [01]. In addition, the structure of (II) contains channels parallel to the crystallographic a direction. The guest components in these channels consist of dichloromethane and acetonitrile solvent molecules and uncoordinated nitrate anions.     

Study on the reaction of methyl N‐Methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates with sodium alkoxides

Methyl N‐methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates ( 4a‐n ), obtained from 6‐substituted‐4‐chloro‐5‐nitropyrimidines and sarcosine methyl ester (methyl 2‐(methylamino)acetate), in the reaction with sodium alkoxides underwent transformations to give different products. N‐methyl‐N‐(5‐nitropyrimidin‐4‐yl)glycinates ( 4a,i,j ) bearing amino and arylamino groups in the position 6 of the pyrimidine ring gave corresponding 6‐substituted‐4‐methylamino‐5‐nitrosopyrimidines ( 5a,i,j ). In the reaction of N‐(6‐alkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4b,f‐h ) with sodium alkoxides the corresponding 6‐alkylamino‐4‐methylamino‐5‐nitrosopyrimidines ( 5b,f‐h ) and 5‐hydroxy‐8‐methyl‐5,8‐dihydropteridine‐6,7‐diones ( 6b,f‐h ) were formed. The main products of the reaction of N‐(6‐dialkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4c‐e,k,l ), after work‐up, were the corresponding 6‐dialkylamino‐9‐methylpurin‐8‐ones ( 7c‐e,k,l ) and 8‐alkoxy‐6‐dialkylamino‐9‐methylpurines ( 9c,1,10c,l ). Methyl N‐methyl‐N‐{[6‐(2‐methoxy‐oxoethyl)thio]‐5‐nitropyrimidin‐4‐yl}glycinate ( 4n ) under the same conditions gave methyl 7‐methylaminothiazolo[5,4‐d]pyrimidine‐2‐carboxylate ( 13 ). Mechanisms of the observed transformations are discussed.     

Heterospirocyclic N‐(2H‐Azirin‐3‐yl)‐L‐prolinates: New Dipeptide Synthons

The synthesis of methyl N‐(1‐aza‐6‐oxaspiro[2.5]oct‐1‐en‐2‐yl)‐L ‐prolinate ( 1e ) has been performed by consecutive treatment of methyl N‐[(tetrahydro‐2H‐pyran‐4‐yl)thiocarbonyl]‐L ‐prolinate ( 5 ) with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16 , which is an analogue of the C‐terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X‐ray crystal‐structure analysis (Figs. 1 and 2).