Synthesis and Hypolipidemic Activity of New 6,6‐Disubstituted 3‐R‐6,7‐Dihydro‐2H‐[1,2,4]triazino[2,3‐c]quinazolin‐2‐Ones

Presented article describes the synthesis and hypolipidemic activity of previously unknown 6,6‐disubstituted 3‐R‐6,7‐dihydro‐2H‐[1,2,4]triazino[2,3‐c]quinazolin‐2‐ones. It was shown, that interaction of 6‐R‐3‐(2‐aminophenyl)‐1,2,4‐triazin‐5(2Н)‐оnes with methylalkylketones in acetic acid resulted the single product, namely, the desired tricyclic derivatives. At the same time, after refluxing of 6‐R‐3‐(2‐aminophenyl)‐1,2,4‐triazin‐5(2Н)‐оnes with methylarylketones in acetic acid the mixture of target compound and insignificant amount of corresponding 3‐substituted 6‐methyl‐2H‐[1,2,4]triazino[2,3‐c]quinazolin‐2‐ones were isolated. The mechanism of above‐mentioned mixture formation was discussed. The structures of all synthesized compounds were proven using the appropriate physicochemical methods. The compounds with promising lipid‐lowering activity were identified and the «structure — hypolipidemic activity» correlations were discussed.     

1,2‐Diaza‐3‐silacyclopent‐5‐ene – Synthese und Reaktionen

1,2‐Diaza‐3‐silacyclopent‐5‐ene – Synthesis and Reactions The dilithium salt of bis(tert‐butyl‐trimethylsilylmethylen)ketazine ( 1 ) forms an imine‐enamine salt. 1 reacts with halosilanes in a molar ratio of 1:1 to give 1,2‐diaza‐3‐silacyclopent‐5‐enes. Me₃SiCH=CCMe₃ [N(SiR,R′)‐N=C‐C]HSiMe₃ ( 2 ‐ 7 ). ( 2 : R,R′ = Cl; 3 : R = CH₃, R′ = Ph; 4 : R = F, R′ = CMe₃; 5 : R = F, R′ = Ph; 6 : R = F, R′ = N(SiMe₃)₂; 7 : R = F, R′ = N(CMe₃)SiMe₃). In the reaction of 1 with tetrafluorosilane the spirocyclus 8 is isolated. The five‐membered ring compounds 2 ‐ 7 and compound 9 substituted on the silicon‐fluoro‐ and (tert‐butyltrimethylsilyl) are acid at the C(4)‐atom and therefore can be lithiated. Experiments to prepare lithium salts of 4 with MeLi, n‐BuLi and PhLi gave LiF and the substitution‐products 10 ‐ 12 . 9 forms a lithium salt which reacts with ClSiMe₃ to give LiCl and the SiMe₃ ring system ( 13 ) substituted at the C(4)‐atom. The ring compounds 3 ‐ 7 and 10 ‐ 12 form isomers, the formation is discussed. Results of the crystal structure and analyses of 8 , 10 , 12 , and 13 are presented.     

Supramolecular architectures in two 1:1 cocrystals of 5‐fluorouracil with 5‐bromothiophene‐2‐carboxylic acid and thiophene‐2‐carboxylic acid

In solid‐state engineering, cocrystallization is a strategy actively pursued for pharmaceuticals. Two 1:1 cocrystals of 5‐fluorouracil (5FU; systematic name: 5‐fluoro‐1,3‐dihydropyrimidine‐2,4‐dione), namely 5‐fluorouracil–5‐bromothiophene‐2‐carboxylic acid (1/1), C₅H₃BrO₂S·C₄H₃FN₂O₂, (I), and 5‐fluorouracil–thiophene‐2‐carboxylic acid (1/1), C₄H₃FN₂O₂·C₅H₄O₂S, (II), have been synthesized and characterized by single‐crystal X‐ray diffraction studies. In both cocrystals, carboxylic acid molecules are linked through an acid–acid R ₂²(8) homosynthon (O—H…O) to form a carboxylic acid dimer and 5FU molecules are connected through two types of base pairs [homosynthon, R ₂²(8) motif] via a pair of N—H…O hydrogen bonds. The crystal structures are further stabilized by C—H…O interactions in (II) and C—Br…O interactions in (I). In both crystal structures, π–π stacking and C—F…π interactions are also observed.     

Synthesis and conversion of 6‐fluoro derivatives of 1,3,4‐thiadiazolo‐[3,2‐a]pyrimidine

2‐Alkyl‐, 2‐aryl‐, and 2‐halo‐substituted derivatives of 7‐methyl‐6‐fluoro‐1,3,4‐thiadiazolo[3,2‐a]pyrimidin‐6‐one ( 3 ) were prepared by reaction of 2‐substituted 5‐amino‐1,3,4‐thiadiazoles ( 1 ) and ethyl 2‐fluoroacetoacetate ( 2 ) in polyphosphoric acid. A convenient procedure was developed for the synthesis of new 2‐amino derivatives of 2‐R‐7‐methyl‐6‐fluoro‐1,3,4‐thiadiazolo[3,2‐a]pyrimidin‐6‐one ( 5 ). J. Heterocyclic Chem., (2011).     

Synthesis and Functionalization of 8‐Methyl‐2h‐pyrimido [2,1‐c][1,2,4]triazine‐3,6(1h,4h)‐dione

6‐Methyl‐2‐methylthio‐4‐oxopyrimidin‐3(4H)‐yl)acetohydrazide on heating in benzylamine undergo cyclization to 8‐methyl‐2H‐pyrimido[2,1‐c][1,2,4]triazine‐3,6(1H, 4H)‐dione, which under treatment with bromine in glacial acetic acid was converted to 7‐bromo substituted derivative and at reflux with Lawesson's reagent yielded 3‐thioxo compound. The latter reacted with primary and secondary amines to give 3‐amino substituted pyrimidotriazines and on alkylation—the corresponding S‐alkyl derivatives.     

Phosphorylation of 2‐(3‐methyl‐1,3‐diazabuten‐1‐yl)‐3‐ethoxycarbonylthiophenes with phosphorus(III) halides

2‐(3‐Methyl‐1,3‐diazabuten‐1‐yl)‐3‐ethoxycarbonylthiophenes are phosphorylated with phosphorus(III) halides in basic media at position 5 of the thiophene ring. Up to three heteroaromatic substituents can be introduced one by one at the same phosphorus atom. On this basis, mono‐, bis‐, and trishetaryl substituted P(III) and P(V) derivatives have been obtained. Phosphorylated 2‐(N,N‐dimethylformamidino)‐3‐ethoxycarbonylthiophenes provide a synthetic access to phosphorylated thienopyrimidines. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:641–651, 2001     

Diastereo‐ and Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 3‐(ω′‐Alkenyl)‐ and 3‐(ω′‐Alkenyloxy)‐Substituted 5,6‐Dihydro‐1H‐pyridin‐2‐ones

3‐(ω′‐Alkenyl)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 2 – 4 were prepared as photocycloaddition precursors either by cross‐coupling from 3‐iodo‐5,6‐dihydro‐1H‐pyridin‐2‐one ( 8 ) or—more favorably—from the corresponding α‐(ω′‐alkenyl)‐substituted δ‐valerolactams 9 – 11 by a selenylation/elimination sequence (56–62 % overall yield). 3‐(ω′‐Alkenyloxy)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 5 and 6 were accessible in 43 and 37 % overall yield from 3‐diazopiperidin‐2‐one ( 15 ) by an α,α‐chloroselenylation reaction at the 3‐position followed by nucleophilic displacement of a chloride ion with an ω‐alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ=254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5 , tethered by a two‐atom chain, exclusively delivered the respective crossed products 19 and 20 , and substrates 3 , 5 , and 6 , tethered by longer chains, gave the straight products 21 – 23 . The completely regio‐ and diastereoselective photocycloaddition reactions proceeded in 63–83 % yield. Irradiation in the presence of the chiral templates (?)‐ 1 and (+)‐ 31 at ?75 °C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85 % ee. Truncated template rac‐ 31 was prepared as a noranalogue of the well‐established template 1 in eight steps and 56 % yield from the Kemp triacid ( 24 ). Subsequent resolution delivered the enantiomerically pure templates (?)‐ 31 and (+)‐ 31 . The outcome of the reactions is compared to the results achieved with 4‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones and quinolones.     

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.     

Synthesis of 2‐Coumarinyl and Spiroindolyl‐5‐Phenyl‐1,3,4‐Oxadiazoles

The 2H‐1‐benzo/naphthopyran‐2‐one‐4‐yl (un)substituted phenyl‐1,3,4‐oxadiazoles has been synthesized by the oxidative cyclization of benzoic acid hydrazides formed in situ by the condensation of the respective 2H‐1‐benzo/naphthopyran‐2‐one‐4‐carboxaldehyde and (un)substituted monobenzoyl hydrazide in moderate yields. Also, spiro[indoline‐thiozolidine]‐2,4′‐diones has been syhthesized in a similar way from 3‐phenyl‐spiro[3H‐indoline‐3,2′‐thiozolidine]‐2,4′‐(1 H)dione monohydrazide and (un)substituted benzaldehydes.     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.     

Methyl 2‐benzamido‐4‐(3,4‐dimethoxyphenyl)‐5‐methylbenzoate and N‐{5‐benzoyl‐2‐[(Z)‐2‐methoxyethenyl]‐4‐methylphenyl}benzamide

Methyl 2‐benzamido‐4‐(3,4‐dimethoxyphenyl)‐5‐methylbenzoate, C₂₄H₂₃NO₅, (Ia), and N‐{5‐benzoyl‐2‐[(Z)‐2‐methoxyethenyl]‐4‐methylphenyl}benzamide, C₂₄H₂₁NO₃, (IIa), were formed via a Diels–Alder reaction of appropriately substituted 2H‐pyran‐2‐ones and methyl propiolate or (Z)‐1‐methoxybut‐1‐en‐3‐yne, respectively. Each of these cycloadditions might yield two different regioisomers, but just one was obtained in each case. In (Ia), an intramolecular N—H...O hydrogen bond closes a six‐membered ring. A chain is formed due to aromatic π–π interactions, and a three‐dimensional framework structure is formed by a combination of C—H...O and C—H...π(arene) hydrogen bonds. Compound (IIa) was formed not only regioselectively but also chemoselectively, with just the triple bond reacting and the double bond remaining unchanged. Compound (IIa) crystallizes as N—H...O hydrogen‐bonded dimers stabilized by aromatic π–π interactions. Dimers of (IIa) are connected into a chain by weak C—H...π(arene) interactions.     

Synthesis,Redox and Optical Properties of Low‐Bandgap Platinum(II) Polyynes with 9‐Dicyanomethylene‐Substituted Fluorene Acceptors

In view of the strong electron‐withdrawing nature of the cyano substituent, a blue donor/acceptor‐type organometallic polymer (trans‐[—Pt(PBu₃)₂—C≡C—R—C≡C—]_n (R = 9‐dicyanomethylenefluorene‐2,7‐diyl)) was prepared in good yield by CuI‐catalyzed polymerization involving the dehydrohalogenating coupling of trans‐[Pt(PBu₃)₂Cl₂] and H—C≡C—R—C≡C—H. The thermal, redox and photoconducting properties of the polymer are reported. Electronic absorption studies indicate that it has a bandgap of 1.58 eV which is the lowest among any of the metal polyyne polymers reported in the literature. The derivatization of the polymer backbone with electron deficient dicyano‐substituted electron acceptor in the side chain is found to be effective to tune the bandgap of this class of materials while maintaining their solubility and processability.     

A series of substituted (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐phenylprop‐2‐en‐1‐ones

In the molecular structures of a series of substituted chalcones, namely (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐phenylprop‐2‐en‐1‐one, C₂₁H₁₅FO₂, (I), (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐(4‐fluorophenyl)prop‐2‐en‐1‐one, C₂₁H₁₄F₂O₂, (II), (2E)‐1‐(4‐chlorophenyl)‐3‐(2‐fluoro‐4‐phenoxyphenyl)prop‐2‐en‐1‐one, C₂₁H₁₄ClFO₂, (III), (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐(4‐methylphenyl)prop‐2‐en‐1‐one, C₂₂H₁₇FO₂, (IV), and (2E)‐3‐(2‐fluoro‐4‐phenoxyphenyl)‐1‐(4‐methoxyphenyl)prop‐2‐en‐1‐one, C₂₂H₁₇FO₃, (V), the configuration of the keto group with respect to the olefinic double bond is s‐cis. The molecules pack utilizing weak C—H...O and C—H...π intermolecular contacts. Identical packing motifs involving C—H...O interactions, forming both chains and dimers, along with C—H...π dimers and π–π aromatic interactions are observed in the fluoro, chloro and methyl derivatives.     

2,5‐Bis(methylthio)‐1,4‐benzo­quinone and 2‐methyl‐3‐(methylsulfonyl)benzo[b]thiophene

The structure of 2,5‐bis­(methyl­thio)‐1,4‐benzo­quinone, C₈H₈O₂S₂, is composed of an essentially planar centrosymmetric benzo­quinone substituted with two methyl­thio groups. The important bond distances are S—Csp³ 1.788 (2) and S—Csp² 1.724 (2) Å, and the two Csp²—Csp² distances are 1.447 (3) and 1.504 (3) Å, which differ significantly. There are short S?S interactions of 3.430 (1) Å and Csp²—H?O‐type contacts forming a dimeric motif with graph set R₂²(8). The structure of 2‐methyl‐3‐(methyl­sulfonyl)­benzo­[b]­thio­phene, C₁₀H₁₀O₂S₂, is composed of an essentially planar benzo­thio­phene moiety substituted with methyl and methyl­sulfonyl groups. The mean values of the important bond distances are endocyclic S—Csp² 1.734 (3), S=O 1.434 (4) and C—C_aromatic 1.389 (10) Å. The exocyclic S—Csp² and S—Csp³ distances are 1.759 (4) and 1.763 (5) Å, respectively.     

Ferrocene compounds. XXXIV. 1′‐(tert‐Butoxycarbonylamino)ferrocene‐1‐carboxylic acid

Heteroannularly substituted ferrocene derivatives can act as model systems for various hydrogen‐bonded assemblies of biomol­ecules formed, for instance, by means of O—H⋯O and N—H⋯O hydrogen bonding. The crystal structure analysis of 1′‐(tert‐butoxy­carbonyl­amino)­ferrocene‐1‐carbox­ylic acid, [Fe(C₁₀H₁₄NO₂)(C₆H₅O₂)] or (C₅H₄COOH)Fe(C₅­H₄NHCOOC(CH₃)₃, reveals two independent mol­ecules within the asymmetric unit, and these are joined into discrete dimers by two types of intermolecular hydrogen bonds, viz. O—H⋯O and N—H⋯O. The –COOH and –NHCOOR groups are archetypes for dimer formation via two eight‐membered rings. The O—H⋯O hydrogen bonds [2.656 (3) and 2.663 (3) Å] form a cyclic carboxylic acid dimer motif. Another eight‐membered ring is formed by N—H⋯O hydrogen bonds [2.827 (3) and 2.854 (3) Å] between the N—H group and an O atom of another carbamoyl moiety. The dimers are assembled in a herring‐bone fashion in the bc plane.     

4,5‐Di­hydro‐3‐methyl‐5‐(4‐methyl­phenyl)‐1H‐pyrazole‐1‐carboxamidinium acetate acetone hemisolvate

The X‐ray structure analysis of the unexpected product of the reaction between 4‐(4‐methyl­phenyl)­but‐3‐en‐2‐one and amino­guanidine revealed the title compound, C₁₂H₁₇N₄⁺·C₂H₃O₂^?·0.5C₃H₆O, consisting of a protonated amidine moiety joined to a substituted pyrazoline ring at the N1 atom. The amidine group is protonated and the positive charge is delocalized over the three C—N bonds in a similar manner to that found in guanidinium salts. The amidinium moiety of the cation is linked to the acetate anions through four N—H?O hydrogen bonds, with N?O distances of 2.749 (4), 2.848 (4), 2.904 (4) and 2.911 (4) Å. The pyrazoline ring adopts a flattened envelope conformation and the substituted phenyl ring is oriented perpendicular to the attached heterocycle. The acetone solvate molecule lies across a twofold rotation axis.     

Hydrogen‐bonded structures of the isomeric compounds of phthalazine with 3‐chloro‐2‐nitrobenzoic acid, 4‐chloro‐2‐nitrobenzoic acid and 4‐chloro‐3‐nitrobenzoic acid

The structures of three isomeric compounds, C₇H₄ClNO₄·C₈H₆N₂, of phthalazine with chloro‐ and nitro‐substituted benzoic acid, namely, 3‐chloro‐2‐nitrobenzoic acid–phthalazine (1/1), (I), 4‐chloro‐2‐nitrobenzoic acid–phthalazine (1/1), (II), and 4‐chloro‐3‐nitrobenzoic acid–phthalazine (1/1), (III), have been determined at 190 K. In the asymmetric unit of each compound, there are two crystallographically independent chloronitrobenzoic acid–phthalazine units, in each of which the two components are held together by a short hydrogen bond between an N atom of the base and a carboxyl O atom. In one hydrogen‐bonded unit of (I) and in two units of (II), a weak C—H...O interaction is also observed between the two components. The N...O distances are 2.5715 (15) and 2.5397 (17) Å for (I), 2.5655 (13) and 2.6081 (13) Å for (II), and 2.613 (2) and 2.589 (2) Å for (III). In both hydrogen‐bonded units of (I) and (II), the H atoms are each disordered over two positions with (N site):(O site) occupancies of 0.35 (3):0.65 (3) and 0.31 (3):0.69 (3) for (I), and 0.32 (3):0.68 (3) and 0.30 (3):0.70 (3) for (II). The H atoms in the hydrogen‐bonded units of (III) are located at the O‐atom sites.     

Hydrogen‐bonded dimers in 3‐amino‐4‐anilino‐1H‐isochromen‐1‐one and a hydrogen‐bonded sheet in 3‐amino‐4‐[methyl(phenyl)amino]‐1H‐isochromen‐1‐one

The molecules of 3‐amino‐4‐anilino‐1H‐isochromen‐1‐one, C₁₅H₁₂N₂O₂, (I), and 3‐amino‐4‐[methyl(phenyl)amino]‐1H‐isochromen‐1‐one, C₁₆H₁₄N₂O₂, (II), adopt very similar conformations, with the substituted amino group PhNR, where R = H in (I) and R = Me in (II), almost orthogonal to the adjacent heterocyclic ring. The molecules of (I) are linked into cyclic centrosymmetric dimers by pairs of N—H...O hydrogen bonds, while those of (II) are linked into complex sheets by a combination of one three‐centre N—H...(O)₂ hydrogen bond, one two‐centre C—H...O hydrogen bond and two C—H...π(arene) hydrogen bonds.     

Exo conformers of N‐(pyridin‐2‐yl)‐ and N‐(pyridin‐3‐yl)norbornene‐5,6‐dicarboximide crystals

Two isomeric pyridine‐substituted norbornenedicarboximide derivatives, namely N‐(pyridin‐2‐yl)‐exo‐norbornene‐5,6‐dicarboximide, (I), and N‐(pyridin‐3‐yl)‐exo‐norbornene‐5,6‐dicarboximide, (II), both C₁₄H₁₂N₂O₄, have been crystallized and their structures unequivocally determined by single‐crystal X‐ray diffraction. The molecules consist of norbornene moieties fused to a dicarboximide ring substituted at the N atom by either pyridin‐2‐yl or pyridin‐3‐yl in an anti configuration with respect to the double bond, thus affording exo isomers. In both compounds, the asymmetric unit consists of two independent molecules (Z′ = 2). In compound (I), the pyridine rings of the two independent molecules adopt different conformations, i.e. syn and anti, with respect to the methylene bridge. The intermolecular contacts of (I) are dominated by C—H...O interactions. In contrast, in compound (II), the pyridine rings of both molecules have an anti conformation and the two independent molecules are linked by carbonyl–carbonyl interactions, as well as by C—H...O and C—H...N contacts.     

Substituted 2,2′‐Bis(2‐oxidobenzylideneamino)‐4,4′‐dimethyl‐1,1′‐biphenyl Complexes of Zinc

The condensation reaction of 2,2′‐diamino‐4,4′‐dimethyl‐6,6'‐dibromo‐1,1′‐biphenyl with 2‐hydroxybenzaldehyde as well as 5‐methoxy‐, 4‐methoxy‐, and 3‐methoxy‐2‐hydroxybenzaldehyde yields 2,2′‐bis(salicylideneamino)‐4,4′‐dimethyl‐6,6′‐dibromo‐1,1′‐biphenyl ( 1a ) as well as the 5‐, 4‐, and 3‐methoxy‐substituted derivatives 1b , 1c , and 1d , respectively. Deprotonation of substituted 2,2′‐bis(salicylideneamino)‐4,4′‐dimethyl‐1,1′‐biphenyls with diethylzinc yields the corresponding substituted zinc 2,2′‐bis(2‐oxidobenzylideneamino)‐4,4′‐dimethyl‐1,1′‐biphenyls ( 2 ) or zinc 2,2′‐bis(2‐oxidobenzylideneamino)‐4,4′‐dimethyl‐6,6′‐dibromo‐1,1′‐biphenyls ( 3 ). Recrystallization from a mixture of CH₂Cl₂ and methanol can lead to the formation of methanol adducts. The methanol ligands can either bind as Lewis base to the central zinc atom or as Lewis acid via a weak O–H ··· O hydrogen bridge to a phenoxide moiety. Methanol‐free complexes precipitate as dimers with central Zn₂O₂ rings.