Polar aspects of intramolecular interactions in 2‐amino‐5‐nitro‐4‐methylpyridines and 2‐amino‐3‐nitro‐4‐methylpyridines

The dipole moments of twelve 2‐N‐substituted amino‐5‐nitro‐4‐methylpyridines ( I‐XII ) and three 2‐N‐substituted amino‐3‐nitro‐4‐methylpyridines ( XIII‐XV ) were determined in benzene. The polar aspects of intramolecular charge‐transfer and intramolecular hydrogen bonding were discussed. The interaction dipole moments, μ_int, were calculated for 2‐N‐alkyl(or aryl)amino‐5‐nitro‐4‐methylpyridines. Increased alkylation of amino nitrogen brought about an intensified push‐pull interaction between the amino and nitro groups. The solvent effects on the dipole moments of 2‐N‐methylamino‐5‐nitro‐4‐methyl‐( I ), 2‐N,N‐dimethylamino‐5‐nitro‐4‐methyl‐ ( II ) and 2‐N‐methylamino‐3‐nitro‐4‐methylpyridines ( XIII ) were different. Specific hydrogen bond solute‐solvent interactions increased the charge‐transfer effect in I , but it did not disrupt the intramolecular hydrogen bond in XIII.     

Crystal packing of two 5‐substituted 2‐methyl‐4‐nitro‐1H‐imidazoles

Infinite chains connected by N—H...N hydrogen bonding form the primary packing motif in two closely related 4‐nitroimidazole derivatives, viz. 5‐bromo‐2‐methyl‐4‐nitro‐1H‐imidazole, C₄H₄BrN₃O₂, (I), and 2‐methyl‐4‐nitro‐1H‐imidazole‐5‐carbonitrile, C₅H₄N₄O₂, (II). These chains are almost identical, even though in (II) there are two symmetry‐independent molecules in the asymmetric unit. The differences appear in the interactions between the chains; in (I), there are strong C—Br...O halogen bonds, which connect the chains into a two‐dimensional grid, while in (II), the cyano group does not participate in specific interactions and the chains are only loosely connected into a three‐dimensional structure.     

Contrasting the supramolecular structures in the isomeric pair 5‐bromo‐3‐nitrosalicylaldehyde phenylhydrazone and 3‐bromo‐5‐nitrosalicylaldehyde phenylhydrazone

Isomeric 5‐bromo‐3‐nitrosalicylaldehyde phenylhydrazone and 3‐bromo‐5‐nitrosalicylaldehyde phenylhydrazone, C₁₃H₁₀BrN₃O₃, both crystallize with two molecules in the asymmetric unit. In both isomers, an intramolecular O—H...N hydrogen bond links the hydroxy group and the imine N atom. In the 5‐bromo‐3‐nitro isomer, there are two independent N—H...O hydrogen‐bonded chains, each molecule in the asymmetric unit forming its own chain. These chains are then linked to form a three‐dimensional framework by a combination of weak C—H...O, C—H...Br, C—H...π and π–π stacking interactions. In the 3‐bromo‐5‐nitro isomer, N—H...O hydrogen bonds link the independent molecules alternately into a zigzag chain, which is reinforced by a weak C—H...O interaction. Individual chains are linked by a C—H...Br interaction and a three‐dimensional framework is generated by π–π stacking interactions.     

One‐Pot Synthesis of 1,4‐Oxathiino[2,3‐b]quinoxalines or ‐pyrazines from 2,3‐Dichloroquinoxaline or ‐pyrazine and 1‐Aryl‐2‐bromoalkan‐1‐ones

An efficient one‐pot synthesis of novel heterocyclic derivatives, 2‐aryl‐1,4‐oxathiino[2,3‐b]quinoxalines or ‐pyrazines 5 , via the reaction of 2,3‐dichloroquinoxaline or ‐pyrazine with Na₂S?9 H₂O, and subsequent treatment of the resulting 2‐chloro‐3‐sodiosulfanylquinoxaline or ‐pyrazine 2 with 1‐aryl‐2‐bromo‐1‐alkanones and then NaH under mild conditions is described.     

An efficient synthesis of 5‐aryl‐4,5‐dihydro‐3‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐1‐(4‐phenylthiazol‐2‐yl)pyrazoles

Some new target products 5‐aryl‐4,5‐dihydro‐3‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐1‐(4‐phenylthiazol‐2‐yl)pyrazoles 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j have been synthesized by reaction of 2‐bromo‐1‐phenylethanone and compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j which were prepared from the combination of thiosemicarbazide and (E)‐3‐aryl‐1‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐prop‐2‐en‐1‐ones 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j . All the structures were established by MS, IR, CHN, and ¹H NMR spectra data. Synthesis of structure diversity is applied. J. Heterocyclic Chem., (2011).     

Synthesis of alkyl 6‐methyl‐4‐(2‐trifluoromethylphenyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates possessing a N‐3 nitro substituent to determine calcium channel modulation structure‐activity relationships

The Bigenelli acid catalyzed condensation of 2‐trifluoromethylbenzaldehyde ( 1 ), urea ( 2 ) and an alkyl acetoacetate ( 3 ) afforded the respective alkyl (Me, Et, i‐Pr, i‐Bu) 6‐methyl‐4‐(2‐trifluoromethylphenyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylate ( 4‐7 ). Subsequent N³‐nitration of the alkyl esters ( 4‐7 ) using Cu(NO₃)₂ 3H₂O and Ac₂O furnished the target alkyl 6‐methyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates ( 8‐11 ). The N³‐nitro compounds ( 8‐11 ) were less potent calcium channel antagonists (IC₅₀ values in the 1.9 × 10^?7 to 3.9 × 10^?6 M range) on guinea pig ileal longitudinal smooth muscle than the reference drug nifedipine (Adalat®, IC₅₀ = 1.4 × 10^?8 M). In vitro calcium channel modulation studies on guinea pig left atrium (GPLA) showed that the methyl and ethyl esters ( 8‐9 ) induced a weak‐to‐modest positive inotropic (agonist) effect, and that the inactive isopropyl ( 10 ) and isobutyl ( 11 ) esters did not alter the cardiac contractile force of GPLA.     

A Facile Synthesis of 1‐Substituted 3‐Alkoxy‐1H‐isoindoles Based on the Reaction of 2‐(Dialkoxymethyl)phenyllithiums with Nitriles,Followed by Acid‐Catalyzed Cyclization

A two‐step synthesis of 1‐substituted 3‐alkoxy‐1H‐isoindoles 4 has been developed. Thus, the reaction of 2‐(dialkoxymethyl)phenyllithium compounds, which are easily generated in situ by Br/Li exchange between 1‐bromo‐2‐(dialkoxymethyl)benzenes 1 and BuLi in THF at ?78°, with nitriles afforded [2‐(dialkoxymethyl)phenyl]methanimines 2 , which were treated with a catalytic amount of TsOH?H₂O in refluxing CHCl₃ to give the desired products in reasonable yields. Similarly, 3‐aryl‐1‐ethoxy‐1‐methyl‐1H‐isoindoles 7 have been prepared starting from 1‐bromo‐2‐(1,1‐diethoxyethyl)benzenes 5 .     

Synthesis and Antifungal Screening of 2‐(2‐Aryl‐4‐methyl‐thiazol‐5‐yl)‐5‐((2‐aryl/benzylthiazol‐4‐yl)methyl)‐1,3,4‐oxadiazole Derivatives

A new series of synthesis and biological screening of 2‐(2‐aryl‐4‐methyl‐thiazol‐5‐yl)‐5‐((2‐aryl/benzylthiazol‐4‐yl)methyl)‐1,3,4‐oxadiazole derivatives 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i was achieved by condensation of 2‐(2‐aryl/benzylthiazol‐4‐yl)acetohydrazide 2a , 2b , 2c with 4‐methyl‐2‐arylthiazole‐5‐carbaldehyde 3a , 3b , 3c followed by oxidative cyclization of N'‐((4‐methyl‐2‐arylthiazol‐5‐yl)methylene)‐2‐(2‐aryl/benzylthiazol‐4‐yl)acetohydrazide 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i using iodobenzene diacetate as oxidizing agent. All the synthesized compounds were screened for their in vitro antifungal activity against Candida albicans, Candida tropicalis, Aspergillus niger, and Aspergillus flavus. Some of the synthesized compounds showed good antifungal activity.     

Synthesis of novel 3‐ and 5‐substituted indole‐2‐carboxamides

The preparation of several novel 3,5‐substituted‐indole‐2‐carboxamides is described. A 5‐nitro‐indole‐2‐carboxylate was elaborated to the 3‐benzhydryl ester, N‐substituted ester, and carboxylic acid intermedi ates, followed by conversion to the amide and then reduction of the 5‐nitro group to the amine. Indole‐2‐carboxamides with 3‐benzyl and 3‐phenyl substituents were prepared in four steps from either a 3‐bromo indole ester using the Suzuki reaction or from a 3‐keto substituted indole ester. N‐Alkylation of ethyl indole‐2‐carboxylate, followed by amidation and catalytic addition of 9‐hydroxyxanthene gave a 3‐xanthyl‐indole‐2‐carboxamide analog and a spiropyrrolo indole as a side product.     

Synthesis of 4‐Arylisocoumarins (=4‐Aryl‐1H‐2‐benzopyran‐1‐ones) through Acidic Hydrolysis of (Z)‐2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehydes,Followed by Oxidation

4‐Arylisocoumarins (=4‐aryl‐1H‐2‐benzopyran‐1‐ones) 6 were prepared from 2‐(1‐aryl‐2‐methoxyethenyl)‐1‐bromobenzenes 1 . Successive treatment of these bromo styrenes with BuLi and 1‐formylpiperidine gave a mixture of (E)‐ and (Z)‐2‐(1‐aryl‐2‐methoxyethenyl)benzaldehydes 2 . Hydrolysis of (Z)‐isomers with conc. HBr, followed by pyridinium chlorochromate (PCC) oxidation of the resulting 1H‐2‐benzopyran‐1‐ol derivatives 4 (and 5 ), afforded the desired products.     

Synthesis and antimicrobial activity of 2‐substituted‐2,3‐dihydro‐5‐propoxy‐1H‐1,3,2‐benzodiazaphosphole 2‐Oxides

Several 2‐alkylcarbamato/thiocarbamato/aryloxy/trichloromethyl‐2,3‐dihydro‐5‐propoxy‐1H‐1,3,2‐benzodiazaphosphole 2‐oxides ( 4 and 6 ) were synthesised by reacting 4‐propoxy‐o‐phenylenediamine ( 1 ) with various N‐dichlorophosphinyl carbamates ( 3 ), aryl phosphorodichloridates ( 5a‐f ) and trichloromethyl phosphonic dichloride ( 5g ) in the presence of triethylamine at 45‐65 °C. Their ir, ¹H, ¹³C, ³¹P nmr and mass spectral data are discussed. The compounds were screened for antifungal activity against Curvularia lunata and Aspergillus niger and for antibacterial activity against Bacillus subtilis and Escherichia coli. Most of these compounds exhibited moderate activity in the assays.     

Synthesis and Elaboration of All‐cis‐1,2,4,5‐Tetrafluoro‐3‐Phenylcyclohexane: A Polar Cyclohexane Motif

A stereocontrolled synthesis of all‐cis‐1,2,4,5‐ tetrafluoro‐3‐phenylcyclohexane is developed as the first functionalised example of this polar cyclohexane motif. The dipolar nature of the ring, arising due to two 1,3‐diaxial C?F bonds, is revealed in the solid‐state (X‐ray) structure. The orthogonal conformation of the aryl and cyclohexyl rings in all‐cis‐1,2,4,5‐tetrafluoro‐3‐phenylcyclohexane, and in an ortho‐nitro derivative, result in intramolecular ^1hJ_HF and ^2hJ_CF NMR couplings relayed through hydrogen bonding. The aryl group of all‐cis‐1,2,4,5‐tetrafluoro‐3‐phenylcyclohexane is elaborated in different ways to demonstrate the versatility of this compound for delivering the motif to a range of molecular building blocks.     

The Synthesis of Some New (S)‐1‐Aryl‐N‐(1‐hydroxy‐3‐phenylpropan‐2‐yl)‐5‐methyl‐1H‐1,2,3‐triazole‐4‐carboxamide

Some new (S)‐1‐aryl‐N‐(1‐hydroxy‐3‐phenylpropan‐2‐yl)‐5‐methyl‐1 H‐1,2,3‐triazole‐4‐carboxamides 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j have been synthesized and established by ¹H and ¹³C NMR, IR, MS spectra, CHN analyses, and x‐ray diffraction crystallography. The molecular conformation and packing is stabilized by interactions of intermolecular H‐bond O2’‐H2'···O1, O2‐H2···O1’ and intramolecular H‐bond N4’‐H4'N···N3’, N4’‐H4'N···O2’, N4‐H4N···N3, N4‐H4N···O2. The two rings of five numbers were formed by H‐bond in a molecular.     

Sodium 5‐nitro‐2‐pyridonate trihydrate

The title compound, alternatively sodium pyridin‐2‐olate trihydrate, Na⁺·C₅H₃N₂O₃^?·3H₂O, crystallizes in the P space group. It is made up of edge‐shared chains of NaO₆ octahedra with five water mol­ecules and one 5‐nitro‐2‐pyridonate anion. Four of these water mol­ecules are bicoordinating, involved in connecting the adjacent octahedra, and the fifth is coordinated to only one octahedron. The crystal structure is stabilized by a network of strong O—H?O and O—H?N interactions. The organic moieties occupy the space between the chains with an antiparallel alignment.     

Synthesis of some new 4‐substituted‐3, 5‐bis(2‐pyridyl)‐1h‐pyrazole

Several 4‐substituted‐3, 5‐bis(2‐pyridyl)‐1H‐pyrazoles, where the substituent is chloro, bromo, iodo, nitro, diazo, were synthesized under mild reaction conditions in high yields. The structures of the products were characterized by ¹H NMR, ¹³C NMR, ESI‐MS, IR and elemental analyses.     

Similarities and differences in the structures of 5‐bromo‐6‐hydroxy‐7,8‐dimethylchroman‐2‐one and 6‐hydroxy‐7,8‐dimethyl‐5‐nitrochroman‐2‐one

The title compounds, C₁₁H₁₁BrO₃, (I), and C₁₁H₁₁NO₅, (II), respectively, are derivatives of 6‐hydroxy‐5,7,8‐trimethylchroman‐2‐one substituted at the 5‐position by a Br atom in (I) and by a nitro group in (II). The pyranone rings in both molecules adopt half‐chair conformations, and intramolecular O—H...Br [in (I)] and O—H...O_nitro [in (II)] hydrogen bonds affect the dispositions of the hydroxy groups. Classical intermolecular O—H...O hydrogen bonds are found in both molecules but play quite dissimilar roles in the crystal structures. In (I), O—H...O hydrogen bonds form zigzag C(9) chains of molecules along the a axis. Because of the tetragonal symmetry, similar chains also form along b. In (II), however, similar contacts involving an O atom of the nitro group form inversion dimers and generate R₂²(12) rings. These also result in a close intermolecular O...O contact of 2.686 (4) Å. For (I), four additional C—H...O hydrogen bonds combine with π–π stacking interactions between the benzene rings to build an extensive three‐dimensional network with molecules stacked along the c axis. The packing in (II) is much simpler and centres on the inversion dimers formed through O—H...O contacts. These dimers are stacked through additional C—H...O hydrogen bonds, and further weak C—H...O interactions generate a three‐dimensional network of dimer stacks.     

Synthesis and Antifungal Activities of ω‐[4‐Aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thio]‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenones

New 4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thiones 3 have been synthesized by the intramolecular cyclization of 4‐aryl‐1‐(1‐phenyl‐5‐methyl‐1,2,4‐triazol‐4‐formyl)thiosemicarbazides 2 with an 8% NaOH solution, and then 3 reacted with ω‐bromo‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenone to afford ω‐[4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thio]‐ω‐(1H‐1,2,4‐triazol‐1‐yl)‐acetophenones 4 . The preliminary biological test showed that the representative compounds possess some anti fungal activities.     

New domino‐reaction for the synthesis of N4‐(5‐aryl‐1,3‐oxathiol‐2‐yliden)‐2‐phenylquinazolin‐4‐amines and 4‐[4‐aryl‐5‐(2‐phenylquinazolin‐4‐yl)‐1,3‐thiazol‐2‐yl]morpholine

The model morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide (1) reacts with phenacyl bromides to afford N⁴‐(5‐aryl‐1,3‐oxathiol‐2‐yliden)‐2‐phenylquinazolin‐4‐amines (4) or N⁴‐(4,5‐diphenyl‐1,3‐oxathiol‐2‐yliden)‐2‐phenyl‐4‐aminoquinazoline ( 5 ) by a thermodynamically controlled reversible reaction favoring the enolate intermediate, while the 4‐[4‐aryl‐5‐(2‐phenylquinazolin‐4‐yl)‐1,3‐thiazol‐2‐yl]morpholine ( 8 ) was produced by a kinetically controlled reaction favoring the C‐anion intermediate. ¹H nmr, ¹³C nmr, ir, mass spectroscopy and x‐ray identified compounds ( 4 ), ( 5 ) and ( 8 ).     

Synthesis of chloro,fluoro, and nitro derivatives of 7‐amino‐5‐aryl‐6‐cyano‐5H‐pyrano pyrimidin‐2,4‐diones using organic catalysts and their antimicrobial and anticancer activities

Chloro, fluoro, and nitro derivatives of 7‐amino‐5‐aryl‐6‐cyano‐5H‐pyrano pyrimidin‐2,4‐diones were produced by reacting malononitrile, barbituric acid, and aromatic aldehydes together with a DABCO catalyst in an aqueous one‐pot reaction. This is the first report of these compounds being synthesized with DABCO as a catalyst, which produced the compounds in yields in excess of 90%. The 2,4‐difluoro derivative ( 11 ) was novel. The structures of the synthesized compounds were elucidated by means of ¹H, ¹³C, and 2D NMR spectroscopy. Compound 2 (2‐Cl derivative) had MBC values of <200μM against both Staphylococcus aureus and MRSA, and the 2‐nitro derivative 5 had an MBC of 191μM against the Gram–ve Escherichia coli. The synthesized compounds were also tested for their anticancer activity against a HeLa cell line, where all the compounds showed better activity (IC₅₀ values between 129μM and 340μM) than 5‐fluorouracil, a commonly known anticancer drug.     

Supramolecular architectures in cytosinium 6‐chloronicotinate monohydrate and 5‐bromo‐6‐methylisocytosinium hydrogen sulfate

Aminopyrimidine derivatives are biologically important as they are components of nucleic acids and drugs. The crystals of two new salts, namely cytosinium 6‐chloronicotinate monohydrate, C₄H₆N₃O⁺·C₆H₃ClNO₂⁻·H₂O, ( I ), and 5‐bromo‐6‐methylisocytosinium hydrogen sulfate (or 2‐amino‐5‐bromo‐4‐oxo‐6‐methylpyrimidinium hydrogen sulfate), C₅H₇BrN₃O⁺·HSO₄⁻, ( II ), have been prepared and characterized by single‐crystal X‐ray diffraction. The pyrimidine ring of both compounds is protonated at the imine N atom. In hydrated salt ( I ), the primary R₂²(8) ring motif (supramolecular heterosynthon) is formed via a pair of N—H…O(carboxylate) hydrogen bonds. The cations, anions and water molecule are hydrogen bonded through N—H…O, N—H…N, O—H…O and C—H…O hydrogen bonds, forming R₂²(8), R₃²(7) and R₅⁵(21) motifs, leading to a hydrogen‐bonded supramolecular sheet structure. The supramolecular double sheet structure is formed via water–carboxylate O—H…O hydrogen bonds and π–π interactions between the anions and the cations. In salt ( II ), the hydrogen sulfate ions are linked via O—H…O hydrogen bonds to generate zigzag chains. The aminopyrimidinium cations are embedded between these zigzag chains. Each hydrogen sulfate ion bridges two cations via pairs of N—H…O hydrogen bonds and vice versa, generating two R₂²(8) ring motifs (supramolecular heterosynthon). The cations also interact with one another via halogen–halogen (Br…Br) and halogen–oxygen (Br…O) interactions.