Two different products from the reaction of 1‐aryl‐5‐chloro‐3‐methyl‐1H‐pyrazole‐4‐carbaldehyde with cyclohexylamine when the aryl substituent is phenyl or pyridin‐2‐yl: hydrogen‐bonded sheets versus dimers

Cyclohexylamine reacts with 5‐chloro‐3‐methyl‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carbaldehyde to give 5‐cyclohexylamino‐3‐methyl‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carbaldehyde, C₁₆H₂₀N₄O, (I), formed by nucleophilic substitution, but with 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde the product is (Z)‐4‐[(cyclohexylamino)methylidene]‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one, C₁₇H₂₁N₃O, (II), formed by condensation followed by hydrolysis. Compound (II) crystallizes with Z′ = 2, and in one of the two independent molecular types the cyclohexylamine unit is disordered over two sets of atomic sites having occupancies of 0.65 (3) and 0.35 (3). The vinylogous amide portion in each compound shows evidence of electronic polarization, such that in each the O atom carries a partial negative charge and the N atom of the cyclohexylamine portion carries a partial positive charge. The molecules of (I) contain an intramolecular N—H...N hydrogen bond, and they are linked by C—H...O hydrogen bonds to form sheets. Each of the two independent molecules of (II) contains an intramolecular N—H...O hydrogen bond and each molecular type forms a centrosymmetric dimer containing one R₂²(4) ring and two inversion‐related S(6) rings.     

Reduced 3,4′‐bipyrazoles from a simple pyrazole precursor: synthetic sequence,molecular structures and supramolecular assembly

The reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde and N‐benzylmethylamine under microwave irradiation gives 5‐[benzyl(methyl)amino]‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde, C₁₉H₁₉N₃O, (I). Subsequent reactions under basic conditions, between (I) and a range of acetophenones, yield the corresponding chalcones. These undergo cyclocondensation reactions with hydrazine to produce reduced bipyrazoles which can be N‐formylated with formic acid or N‐acetylated with acetic anhydride. The structures of (I) and of representative examples from this reaction sequence are reported, namely the chalcone (E )‐3‐{5‐[benzyl(methyl)amino]‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl}‐1‐(4‐bromophenyl)prop‐2‐en‐1‐one, C₂₇H₂₄BrN₃O, (II), the N‐formyl derivative (3RS )‐5′‐[benzyl(methyl)amino]‐3′‐methyl‐1′,5‐diphenyl‐3,4‐dihydro‐1′H ,2H‐[3,4′‐bipyrazole]‐2‐carbaldehyde, C₂₈H₂₇N₅O, (III), and the N‐acetyl derivative (3RS )‐2‐acetyl‐5′‐[benzyl(methyl)amino]‐5‐(4‐methoxyphenyl)‐3′‐methyl‐1′‐phenyl‐3,4‐dihydro‐1′H ,2H‐[3,4′‐bipyrazole], which crystallizes as the ethanol 0.945‐solvate, C₃₀H₃₁N₅O₂·0.945C₂H₆O, (IV). There is significant delocalization of charge from the benzyl(methyl)amino substituent onto the carbonyl group in (I), but not in (II). In each of (III) and (IV), the reduced pyrazole ring is modestly puckered into an envelope conformation. The molecules of (I) are linked by a combination of C—H…N and C—H…π(arene) hydrogen bonds to form a simple chain of rings; those of (III) are linked by a combination of C—H…O and C—H…N hydrogen bonds to form sheets of R ²₂(8) and R ⁶₆(42) rings, and those of (IV) are linked by a combination of O—H…N and C—H…O hydrogen bonds to form a ribbon of edge‐fused R ²₄(16) and R ⁴₄(24) rings.     

Cyclic and acyclic products from the reactions between methyl 3‐oxobutanoate and arylhydrazines

The molecules of methyl 3‐(2‐nitrophenylhydrazono)butanoate, C₁₁H₁₃N₃O₄, (I), and methyl 3‐(2,4‐dinitrophenylhydrazono)butanoate, C₁₁H₁₂N₄O₆, (II), both prepared from methyl 3‐oxobutanoate and the corresponding nitrophenylhydrazine, exhibit polarized molecular electronic structures; in each of (I) and (II), the molecules are linked into chains by a single C—H...O hydrogen bond. The molecules of 5‐hydroxy‐3‐methyl‐1‐phenyl‐1H‐pyrazole, C₁₀H₁₀N₂O, (III), prepared by the reaction of methyl 3‐oxobutanoate and phenylhydrazine, are linked into chains by a single O—H...N hydrogen bond. The reaction between methyl 3‐oxobutanoate and 3‐nitrophenylhydrazine yields 5‐hydroxy‐3‐methyl‐1‐(3‐nitrophenyl)‐1H‐pyrazole, (IV), which when crystallized from acetone yields 4‐isopropylidene‐3‐methyl‐1‐(3‐nitrophenyl)‐1H‐pyrazol‐5(4H)‐one, C₁₃H₁₃N₃O₃, (V).     

1‐[4‐(Methyl­sulfonyl)­phenyl]‐5‐phenyl‐1H‐pyrazole derivatives

Three related compounds containing a pyrazole moiety with vicinal phenyl rings featuring a methyl­sulfonyl substituent are described, namely 3‐methyl‐1‐[4‐(methyl­sulfonyl)­phenyl]‐5‐phenyl‐1H‐pyrazole, C₁₇H₁₆N₂O₂S, ethyl 1‐[4‐(methyl­sul­fonyl)­phenyl]‐5‐phenyl‐1H‐pyrazole‐3‐carboxyl­ate, C₁₉H₁₈N₂O₄S, and 1‐[4‐(methyl­sulfonyl)­phenyl]‐3‐[3‐(morpholino)­phenoxy­methyl]‐5‐phenyl‐1H‐pyrazole, C₂₇H₂₇N₃O₄S. The design of these compounds was based on celecoxib, a selective cyclo­oxy­genase‐2 (COX‐2) inhibitor, in order to study the influence of various substituents on COX‐2 and 5‐lipoxy­genase (5‐LOX) inhibition.     

Photochemistry of 4‐ and 5‐ phenyl substituted isoxazoles

5‐Phenylisoxazole ( 4 ) and 4‐phenylisoxazole ( 22 ) underwent phototransposition to 5‐phenyloxazole ( 5 ) and 4‐phenyloxazole ( 24 ) respectively. Labeling with deuterium or methyl confirmed that these phototranspositions occurred via the P₄ pathway which involves only interchange of the N2 and C3 ring position. Thus, 4‐deuterio‐5‐phenylisoxazole ( 4‐4d ), 4‐methyl‐5‐phenylisoxazole ( 10 ), and 5‐methyl‐4‐phenylisoxazole ( 23 ) phototransposed to 4‐deuterio‐5‐phenyloxazole ( 5‐4d ), 4‐methyl‐5‐phenyloxazole ( 11 ), and 5‐methyl‐4‐phenyloxazole ( 25 ) respectively. In addition to phototransposition, isoxazoles 4, 10 , and 23 also underwent photo‐ring cleavage to yield benzoylacetonitrile (9), α‐benzoylpropionitrile ( 15 ), and aceto‐α‐phenylacetonitrile ( 26 ) respectively. Irradiation of 5‐phenyl‐3‐(trifluoromethyl)isoxazole ( 16 ) in acetonitrile led to 5‐phenyl‐2‐(trifluoromethyl)oxazole ( 17 ), the P₄ phototransposition product. Irradiation of 16 in methanol led to a substantial decrease in the yield of 17 and to the formation of a mixture of (E) and (Z)‐2‐methoxy‐2‐(trifluoromethyl)‐3‐benzoylaziridines 18a and 18b .     

Conversion of substituted 5‐aryloxypyrazolecarbaldehydes into reduced 3,4′‐bipyrazoles: synthesis and characterization,and the structures of four precursors and two products,and their supramolecular assembly in zero,one and two dimensions

The reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde with phenols under basic conditions yields the corresponding 5‐aryloxy derivatives; the subsequent reaction of these carbaldehydes with substituted acetophenones yields the corresponding chalcones, which in turn undergo cyclocondensation reactions with hydrazine in the presence of acetic acid to form N‐acetylated reduced bipyrazoles. Structures are reported for three 5‐aryloxycarbaldehydes and the 5‐piperidino analogue, and for two reduced bipyrazole products. 5‐(2‐Chlorophenoxy)‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde, C₁₇H₁₃ClN₂O₂, (II), which crystallizes with Z′ = 2 in the space group P, exhibits orientational disorder of the carbaldehyde group in each of the two independent molecules. Each of 3‐methyl‐5‐(4‐nitrophenoxy)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde, C₁₇H₁₃N₃O₄, (IV), 3‐methyl‐5‐(naphthalen‐2‐yloxy)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde, C₂₁H₁₆N₂O₂, (V), and 3‐methyl‐1‐phenyl‐5‐(piperidin‐1‐yl)‐1H‐pyrazole‐4‐carbaldehyde, C₁₆H₁₉N₃O, (VI), (3RS)‐2‐acetyl‐5‐(4‐azidophenyl)‐5′‐(2‐chlorophenoxy)‐3′‐methyl‐1′‐phenyl‐3,4‐dihydro‐1′H,2H‐[3,4′‐bipyrazole] C₂₇H₂₂ClN₇O₂, (IX) and (3RS)‐2‐acetyl‐5‐(4‐azidophenyl)‐3′‐methyl‐5′‐(naphthalen‐2‐yloxy)‐1′‐phenyl‐3,4‐dihydro‐1′H,2H‐[3,4′‐bipyrazole] C₃₁H₂₅N₇O₂, (X), has Z′ = 1, and each is fully ordered. The new compounds have all been fully characterized by analysis, namely IR spectroscopy, ¹H and ¹³C NMR spectroscopy, and mass spectrometry. In each of (II), (V) and (IX), the molecules are linked into ribbons, generated respectively by combinations of C—H…N, C—H…π and C—Cl…π interactions in (II), C—H…O and C—H…π hydrogen bonds in (V), and C—H…N and C—H…O hydrogen bonds in (IX). The molecules of compounds (IV) and (IX) are both linked into sheets, by multiple C—H…O and C—H…π hydrogen bonds in (IV), and by two C—H…π hydrogen bonds in (IX). A single C—H…N hydrogen bond links the molecules of (X) into centrosymmetric dimers. Comparisons are made with the structures of some related compounds.     

Synthesis of 3‐(3,5‐dinitropyrazol‐4‐yl)‐4‐nitrofurazan and its salts

The annulation reaction of vinamidinium salt containing nitrofurazanyl moiety at the β‐position gives access to the corresponding pyrazole. At nitration, two nitro groups were installed to the pyrazole ring. The synthesized 3‐(3,5‐dinitropyrazol‐4‐yl)‐4‐nitrofurazan 13 is strong NH acid and a new family energetic salts was prepared by direct neutralization with high nitrogen bases. Compound 13 crystallizes in the monoclinic space group P2₁/c, and charaterized by high density of 1.979 g/cm³ (at 100 K). J. Heterocyclic Chem., (2012).     

4‐hydroxy‐6‐methyl‐3‐(5‐phenyl‐2E,4E‐pentadien‐1‐oyl)‐2H‐pyran‐2‐one: Synthesis and reactivity with amines

The synthesis and reactivity studies of 4‐hydroxy‐6‐methyl‐3‐(5‐phenyl‐2E,4E‐pentadien‐1‐oyl)‐2H‐pyran‐2‐one 2 with nucleophiles are reported. Reactions of 2 with hydrazine derivatives gave new pyrazole‐type com pounds while the reaction with ortho‐phenylenediamines yielded 1,5‐benzodiazepines. The reaction of 2 with ethylamine implies the 2H‐pyran‐2‐one ring opening and the formation of a strong conjugated compound 3.     

(1H‐Pyrazole‐κN2)(2,2′:6′,2′′‐terpyridine‐κ3N,N′,N′′)platinum(II) bis(perchlorate) nitromethane monosolvate

The reaction between [PtCl(terpy)]·2H₂O (terpy is 2,2′:6′,2′′‐terpyridine) and pyrazole in the presence of two equivalents of AgClO₄ in nitromethane yields the title compound, [Pt(C₃H₄N₂)(C₁₅H₁₁N₃)](ClO₄)₂·CH₃NO₂, as a yellow crystalline solid. Single‐crystal X‐ray diffraction shows that the dicationic platinum(II) chelate is square planar with the terpyridine ligand occupying three sites and the pyrazole ligand occupying the fourth. The torsion angle subtended by the pyrazole ring relative to the terpyridine chelate is 62.4 (6)°. Density functional theory calculations at the LANL2DZ/PBE1PBE level of theory show that in vacuo the lowest‐energy conformation has the pyrazole ligand in an orientation perpendicular to the terpyridine ligand (i.e. 90°). Seemingly, the stability gained by the formation of hydrogen bonds between the pyrazole NH group and the perchlorate anion in the solid‐state structure is sufficient for the chelate to adopt a higher‐energy conformation.     

The diastereoisomers methyl 5‐(S)‐[2‐(R)/(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate

The title diastereoisomers, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate and methyl 5‐(S)‐[2‐(R)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxylate, both C₁₉H₂₃N₃O₅, have been studied in two crystalline forms. The first form, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate–methyl 5‐(S)‐[2‐(R)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate (1/1), 2(S),5(S)‐C₁₉H₂₃N₃O₅·2(R),5(S)‐C₁₉H₂₃N₃O₅, contains both S,S and S,R isomers, while the second, methyl 5‐(S)‐[2‐(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydro­pyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate, 2(S),5(S)‐C₁₉H₂₃N₃O₅, is the pure S,S isomer. The S,S isomers in the two structures show very similar geometries, the maximum difference being about 15° on one torsion angle. The differences between the S,S and S,R isomers, apart from those due to the inversion of one chiral centre, are more remarkable, and are partially due to a possible rotational disorder of the 2‐­(methoxycarbonyl)tetrahydropyrrole group.     

N‐N migration of a carbamoyl group in a pyrazole derivative revealed by NMR

During a synthesis of 5‐amino‐4‐(6‐methoxy‐2‐methylpyridin‐3‐yl)‐3‐methyl‐1H‐pyrazole‐1‐carboxamide (see Scheme 1), a side‐reaction produced 3‐amino‐4‐(6‐methoxy‐2‐methylpyridin‐3‐yl)‐5‐methyl‐1H‐pyrazole‐1‐carboxamide as a by‐product that forms an equilibrium with the target‐compound. The structure of the by‐product was elucidated by the interpretation of 1D and 2D (HMQC, HMBC) NMR data where ¹H‐¹⁵ N HMBC correlations revealed the position of carbamoyl group attachment on the pyrazole. Comparison of structures of the target‐compound and the by‐product showed that the latter resulted from N‐N migration of the carbamoyl group in the target‐compound. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of N1‐substituted coumarino[4,3‐c] pyrazoles

3‐Acyl‐4‐hydroxy‐2‐oxo‐2H‐chromen derivatives 1a‐d were condensed with (7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl)‐acetic acid hydrazide 2 , (4‐methyl‐2‐oxo‐2H‐chromen‐7‐yloxy)‐acetic acid hydrazide 3 , and (7‐hydrazinocarbonylmethoxy‐2‐oxo‐2H‐chromen‐4‐yl)‐acetic acid hydrazide 4 , to give corresponding 3‐alkyl‐1‐[2‐(7‐hydroxy‐2‐oxo‐2H‐chromeno‐4‐yl)‐acetyl]‐1H‐chromeno[4,3‐c]pyrazole‐4‐one 5a‐d , 3‐alkyl‐1‐[2‐(4‐methyl‐2‐oxo‐2H‐chromeno‐7‐yloxy)‐acetyl]‐1H‐chromeno[4,3‐c]pyrazole‐4‐one 6a‐d , and 1‐{4‐[(3‐alkyl‐1H‐chromeno[4,3‐c]pyrazole‐4‐one‐1‐yl)‐carbonylmethyl]‐2‐oxo‐2H‐chromen‐7‐yloxy‐acetyl}‐3‐alkyl‐1H‐chromeno[4,3‐c]pyrazole‐4‐one 7a‐d.     

Structure elucidation of a novel ring‐constrained biaryl pyrazole CB1 cannabinoid receptor antagonist

Upon irradiation with a 450 W high‐pressure mercury lamp, the CB₁ cannabinoid antagonist N‐(piperidinyl)‐5‐(4‐chlorophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (SR14‐1716; 1 ) undergoes a photocyclization reaction to yield a single reaction product. This product, 2 , the structure of which is based on a pyrazolo[1,5‐f]phenanthridine ring system, was established by two‐dimensional NMR techniques (COSY, HSQC, HMBC and ROESY), and was later confirmed by single‐crystal x‐ray diffraction analysis. The crystal structure shows two independent molecules of 3 and a half molecule of the 1,2‐dichloroethane solvate. Compound 2 has reasonably high affinity for the CB₁ receptor (K_i = 48.0 ± 2.7 nM ). Copyright © 2003 John Wiley & Sons, Ltd.     

2‐Ethyl‐1‐[5‐(4‐methylphenyl)pyrazol‐3‐yl]‐3‐(thiophene‐2‐carbonyl)isothiourea: molecular ribbons containing three types of hydrogen‐bonded ring

The title compound, C₁₈H₁₈N₄OS₂, was prepared by reaction of S,S‐diethyl 2‐thenoylimidodithiocarbonate with 5‐amino‐3‐(4‐methylphenyl)‐1H‐pyrazole using microwave irradiation under solvent‐free conditions. In the molecule, the thiophene unit is disordered over two sets of atomic sites, with occupancies of 0.814 (4) and 0.186 (4), and the bonded distances provide evidence for polarization in the acylthiourea fragment and for aromatic type delocalization in the pyrazole ring. An intramolecular N—H...O hydrogen bond is present, forming an S(6) motif, and molecules are linked by N—H...O and N—H...N hydrogen bonds to form a ribbon in which centrosymmetric R₂²(4) rings, built from N—H...O hydrogen bonds and flanked by inversion‐related pairs of S(6) rings, alternate with centrosymmetric R₂²(6) rings built from N—H...N hydrogen bonds.     

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.     

Synthesis,crystal structure and cytotoxic activity of novel 5‐methyl‐4‐thiopyrimidine derivatives

This article presents the synthesis of three new 4‐thiopyrimidine derivatives obtained from ethyl 4‐methyl‐2‐phenyl‐6‐sulfanylpyrimidine‐5‐carboxylate as the starting material, namely, ethyl 4‐[(4‐chlorobenzyl)sulfanyl]‐6‐methyl‐2‐phenylpyrimidine‐5‐carboxylate, C₂₁H₁₉ClN₂O₂S, ( 2 ), {4‐[(4‐chlorobenzyl)sulfanyl]‐6‐methyl‐2‐phenylpyrimidin‐5‐yl}methanol, C₁₉H₁₇ClN₂OS, ( 3 ), and 4‐[(4‐chlorobenzyl)sulfanyl]‐5,6‐dimethyl‐2‐phenylpyrimidine, C₁₉H₁₇ClN₂S, ( 4 ), which vary in the substituent at the 5‐position of the pyrimidine ring. The compounds were characterized by ¹H NMR, ¹³C NMR, IR and mass spectroscopies, and also elemental analysis. The molecular structures were further studied by single‐crystal X‐ray diffraction. Compound ( 2 ) crystallizes in the space group P with one molecule in the asymmetric unit, whereas compounds ( 3 ) and ( 4 ) crystallize in the space group P2₁/c with two and one molecule, respectively, in their asymmetric units. The conformation of each molecule is best defined by the dihedral angles formed between the pyrimidine ring and the planes of the two aryl substituents attached at the 2‐ and 4‐positions. The only structural difference between the three compounds is the substituent at the 5‐position of the pyrimidine ring, but they present significantly different features in the hydrogen‐bond interactions. Compound ( 2 ) displays a one‐dimensional chain formed by hydrogen bonds and the chains are further extended into a two‐dimensional network. Molecules of ( 3 ) and ( 4 ) generate one‐dimensional chains formed through intermolecular interactions. The study examines the cytotoxicity of compounds ( 3 ) and ( 4 ) against Human umbilical vein endothelial cells (HUVEC) and HeLa, K562 and CFPAC cancer cell lines. The presence of the hydroxymethyl and methyl groups in ( 3 ) and ( 4 ), respectively, offers an interesting new insight into the structures and behaviour of these derivatives. Compound ( 4 ) was found to be nontoxic against CFPAC and HUVEC; however, it shows weak activity against the HeLa and K563 cell lines. The presence of a hydroxy group in ( 3 ) significantly increases its cytotoxicity towards both, i.e. the cancer (HeLa, K562 and CFPAC) and normal (HUVEC) cell lines.     

A Divergent Synthesis of Spiropyrazole Derivatives Containing Iminolactone and/or Cyclic Imide Moiety

An approach to spiropyrazole derivatives containing iminolactone and/or cyclic imide moiety starting from 1H‐pyrazole‐4‐acetic acid derivative is described. Hydrolysis of C‐cyanomethylated 1H‐pyrazole‐4‐acetic acid methyl ester ( 1 ), which was easily prepared from 1H‐pyrazole‐4‐acetic acid derivative by a C‐cyanomethylation, led to the C‐cyanomethylated 1H‐pyrazole‐4‐acetic acid ( 2 ). Compound 2 was reacted with ethanol in the presence of tin(IV) chloride in refluxing chloroform to give the key intermediate ethyl imidate ( 3 ). Sodium hydride‐assisted lactonization of 3 in N,N‐dimethylformamide afforded the spiropyrazole derivative containing iminolactone moiety ( 4 ). On the other hand, thermal treatment of 3 with sodium acetate in the absence of solvent caused another intramolecular cyclization to yield the spiropyrazole derivative containing cyclic imide moiety ( 6 ).     

The influence of sulfur substituents on the molecular geometry and packing of thio derivatives of N‐methylphenobarbital

The room‐temperature crystal structures of four new thio derivatives of N‐methylphenobarbital [systematic name: 5‐ethyl‐1‐methyl‐5‐phenylpyrimidine‐2,4,6(1H,3H,5H)‐trione], C₁₃H₁₄N₂O₃, are compared with the structure of the parent compound. The sulfur substituents in N‐methyl‐2‐thiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenyl‐2‐thioxo‐1,2‐dihydropyrimidine‐4,6(3H,5H)‐dione], C₁₃H₁₄N₂O₂S, N‐methyl‐4‐thiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenyl‐4‐thioxo‐3,4‐dihydropyrimidine‐2,6(1H,5H)‐dione], C₁₃H₁₄N₂O₂S, and N‐methyl‐2,4,6‐trithiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenylpyrimidine‐2,4,6(1H,3H,5H)‐trithione], C₁₃H₁₄N₂S₃, preserve the heterocyclic ring puckering observed for N‐methylphenobarbital (a half‐chair conformation), whereas in N‐methyl‐2,4‐dithiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidine‐6(5H)‐one], C₁₃H₁₄N₂OS₂, significant flattening of the ring was detected. The number and positions of the sulfur substituents influence the packing and hydrogen‐bonding patterns of the derivatives. In the cases of the 2‐thio, 4‐thio and 2,4,6‐trithio derivatives, there is a preference for the formation of a ring motif of the R₂²(8) type, which is also a characteristic of N‐methylphenobarbital, whereas a C(6) chain forms in the 2,4‐dithio derivative. The preferences for hydrogen‐bond formation, which follow the sequence of acceptor position 4 > 2 > 6, confirm the differences in the nucleophilic properties of the C atoms of the heterocyclic ring and are consistent with the course of N‐methylphenobarbital thionation reactions.     

A Versatile Synthesis,PM3‐Semiempirical,Antibacterial, and Antitumor Evaluation of Some Bioactive Pyrazoles

This research work describes the synthesis and biological properties of some novel isolated or fused heterocyclic ring systems with pyrazole, for example; enaminones containing pyrazolone ring photochromic functional unit, 4‐[(4‐chlorophenylamino)methylene]‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one (3) and some analogous derivatives 4, 9, and 10, also as pyrazolo[3,4‐b]pyridine, pyrazolo[3,4‐b]quinoline, pyrazolo[3′,4′:4,5]thieno[2,3‐c]pyrazoline and pyrazolo[3,4‐c]pyrazole were synthesized and characterized. Newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, mass spectral data and quantum mechanical calculations. Selected products were tested for their antibacterial and antitumor agents.     

Three sterically hindered 6‐amino‐5‐cyano‐2‐methyl‐4‐(1‐naphthyl)‐4H‐pyran‐3‐carboxylate derivatives

In the title compounds, 2‐methoxyethyl 6‐amino‐5‐cyano‐2‐methyl‐4‐(1‐naphthyl)‐4H‐pyran‐3‐carboxylate, C₂₁H₂₀N₂O₄, (II), isopropyl 6‐amino‐5‐cyano‐2‐methyl‐4‐(1‐naphthyl)‐4H‐pyran‐3‐carboxylate, C₂₁H₂₀N₂O₃, (III), and ethyl 6‐amino‐5‐cyano‐2‐methyl‐4‐(1‐naphthyl)‐4H‐pyran‐3‐carboxylate, C₂₀H₁₈N₂O₃, (IV), the heterocyclic pyran ring adopts a flattened boat conformation. In (II) and (III), the carbonyl group and a double bond of the heterocyclic ring are mutually anti, but in (IV) they are mutually syn. The ester O atoms in (II) and (III) and the carbonyl O atom in (IV) participate in intramolecular C—H...O contacts to form six‐membered rings. The dihedral angles between the naphthalene substituent and the closest four atoms of the heterocyclic ring are 73.3 (1), 71.0 (1) and 74.3 (1)° for (II)–(IV), respectively. In all three structures, only one H atom of the NH₂ group takes part in N—H...O [in (II) and (III)] or N—H...N [in (IV)] intermolecular hydrogen bonds, and chains [in (II) and (III)] or dimers [in (IV)] are formed. In (II), weak intermolecular C—H...O and C—H...N hydrogen bonds, and in (III) intermolecular C—H...O hydrogen bonds link the chains into ladders along the a axis.