Synthesis of Macrocyclic Lactones via Ring Transformation of 4‐(ω‐Hydroxyalkyl)‐1,3‐oxazol‐5(4H)‐ones

The synthesis of α‐benzamido‐α‐benzyl lactones 23 of various ring size was achieved either via ‘direct amide cyclization’ by treatment of 2‐benzamido‐2‐benzyl‐ω‐hydroxy‐N,N‐dimethylalkanamides 21 in toluene at 90 – 110° with HCl gas or by ‘ring transformation’ of 4‐benzyl‐4‐(ω‐hydroxyalkyl)‐2‐phenyl‐1,3‐oxazol‐5(4H)‐ones under the same conditions. The precursors were obtained by C‐alkylations of 4‐benzyl‐2‐phenyl‐1,3‐oxazol‐5(4H)‐one ( 15 ) with THP‐ or TBDMS‐protected ω‐hydroxyalkyl iodides. Ring opening of the THP‐protected oxazolones by treatment with Me₂NH followed by deprotection of the OH group gave the diamides 21 , whereas deprotection of the TBDMS series of oxazolones 25 with TBAF followed by treatment with HCl gas led to the corresponding lactones 23 in a one‐pot reaction.     

(Z)‐5‐[4‐(Dimethylamino)benzylidene]‐2‐(piperidin‐1‐yl)‐1,3‐thiazolidin‐4(5H)‐one

The molecules of the title compound, C₁₇H₂₁N₃OS, are characterized by a wide C—C—C angle at the methine C atom linking the aryl and thiazolidine rings, associated with a short repulsive intramolecular S...H contact between atoms in these two rings. A single piperidine–arene C—H...π hydrogen bond links pairs of molecules into centrosymmetric dimers.     

(5Z)‐4‐Amino‐2‐(4‐hydroxyphenyl)‐1H‐imidazol‐5(2H)‐one oxime 3‐oxide

The title molecule, C₉H₁₀N₄O₃, consists of benzene and imidazole rings which are almost perpendicular to each other. A hydroxyimino group is directly linked to the imidazole ring with a double C=N bond, which is the first example in this type of compound. The double bond may be a good location for the initiation of various reactions with a wide range of potential applications. In the crystal structure, there are π–π interactions between molecules related by a centre of symmetry, with the imidazole and benzene rings almost completely overlapped. The molecules are hydrogen bonded in each direction and form a three‐dimensional hydrogen‐bond network.     

1‐[(1‐Ethoxypropylidene)amino]‐2‐ethyl‐4‐(4‐hydroxybenzyl)imidazol‐5(4H)‐one

The racemic title compound, C₁₇H₂₃N₃O₃, isolated from the reaction of l ‐(−)‐tyrosine hydrazide with triethyl orthopropionate in the presence of a catalytic quantity of p‐toluenesulfonic acid (p‐TsOH), crystallizes with Z′ = 1 in a centrosymmetric monoclinic unit cell. The molecule contains two planar fragments, viz. the benzene and imidazole rings, linked by two C—C single bonds. The dihedral angle between the two planes is 59.54 (5)° and the molecule adopts a synclinal conformation. The HOMA (harmonic oscillator model of aromaticity) index, calculated for the benzene ring, demonstrates no substantial interaction between the two π‐electron delocalization regions in the molecule. In the crystal structure, there is an O—H...N hydrogen bond that links the molecules along the c axis.     

2‐Amino‐5‐(3,4‐dimethoxybenzylidene)‐1‐methylimidazol‐4(5H)‐one N,N‐dimethylformamide monosolvate

The crystal structure of the title compound, C₁₃H₁₅N₃O₃·C₃H₇NO, was determined as part of a larger project focusing on creatinine derivatives as potential pharmaceuticals. The molecule is essentially planar, in part because of intramolecular hydrogen bonding. Inversion‐related pairs of molecules result from intermolecular hydrogen bonding. The π systems of 2‐amino‐5‐(3,4‐dimethoxybenzylidene)‐1‐methylimidazol‐4(5H)‐one and an inversion‐related molecule overlap slightly, indicating a small amount of π–π stacking. Bond lengths, angles and torsion angles are consistent with similar structures, except in the imidazolone ring near the doubly bonded C atom, where significant differences occur.     

NMR studies on 1,2‐dihydro‐2‐(4‐aminophenyl)‐4‐[4‐(4‐aminophenoxy)‐4‐phenyl]‐(2H)phthalazin‐1‐one

An unsymmetrical heterocyclic diamine, 1,2‐dihydro‐2‐(4‐aminophenyl)‐4‐[4‐(4‐aminophenoxy)‐4‐phenyl]‐(2H)phthalazin‐1‐one, was synthesized. Its ¹H and ¹³C NMR spectra were completely assigned by utilizing the two‐dimensional heteronuclear ¹³C–¹H multiple‐bond coherence (HMBC) spectroscopy, and heteronuclear ¹³C–¹H one‐bond correlation spectroscopy, homonuclear shift correlation spectroscopy (H,H‐COSY) and rotating frame Overhauser enhancement spectroscopy (ROESY). The structure of the compound was shown to be the phthalazinone rather than the phthalazine ether from cross peaks and chemical shifts of the protons. Copyright © 2002 John Wiley & Sons, Ltd.     

An Efficient and Facile Synthesis of 5‐(Thiophene‐2‐carbonyl)‐6‐(trifluoromethyl)‐tetrahydro‐pyrimidin‐2(1H)‐one and 6‐(Thiophen‐2‐yl)‐4,5‐dihydropyrimidin‐2(1H)‐one from Same Substrates Under Different Conditions

A series of 5‐(thiophene‐2‐carbonyl)‐6‐(trifluoromethyl)‐tetrahydropyrimidin‐2(1H)‐one and 6‐(thiophen‐2‐yl)‐4,5‐dihydropyrimidin‐2(1H)‐one derivatives have been synthesized from the reactions of aromatic aldehydes, 4,4,4‐trifluoro‐1‐(thien‐2‐yl)butane‐1,3‐dione and urea under the different conditions with high yields. In this research, it was found that the p‐toluenesulfonic acid was an efficient catalyst for obtaining 5‐(thiophene‐2‐carbonyl)‐6‐(trifluoromethyl)‐tetrahydropyrimidin‐2(1H)‐one derivative. At the same time, solvent‐free and NaOH were the preferred conditions for the synthesis of 6‐(thiophen‐2‐yl)‐4,5‐dihydropyrimidin‐2(1H)‐one derivative. Moreover, because of short reaction time, excellent yields, simple setup, this research offered an efficient process for preparing these kind compounds.     

Supramolecular networks of 10‐(2‐hydroxyethyl)acridin‐9(10H)‐one and 10‐(2‐chloroethyl)acridin‐9(10H)‐one

Both 10‐(2‐hydroxyethyl)acridin‐9(10H)‐one, C₁₅H₁₃NO₂, and 10‐(2‐chloroethyl)acridin‐9(10H)‐one, C₁₅H₁₂ClNO, have monoclinic (P2₁/c) symmetry and supramolecular three‐dimensional networks. But the differences in the intermolecular interactions displayed by the hydroxy group and the chlorine substituent lead to stronger intermolecular π‐stacking interactions and hydrogen bonding, and hence a significantly higher melting point for the former.     

Sesquiterpenoids and 2‐(2‐Phenylethyl)‐4H‐chromen‐4‐one (=2‐(2‐Phenylethyl)‐4H‐1‐benzopyran‐4‐one) Derivatives from Aquilaria malaccensis Agarwood

The four new sesquiterpenoids 1 – 4 , and the new 2‐(2‐phenylethyl)‐4H‐chromen‐4‐one (=2‐(2‐phenylethyl)‐4H‐1‐benzopyran‐4‐one) derivative 5 , together with the two known sesquiterpenoids 6 and 7 , the five known chromenones 8 – 12 , and 1‐hydroxy‐1,5‐diphenylpentan‐3‐one ( 13 ), were isolated from a 70% MeOH extract of Aquilaria malaccensis agarwood chips. Their structures were elucidated on the basis of comprehensive spectral analyses and comparison with literature data.     

2‐(4‐Bromophenyl)‐1,2‐dihydropyrimido[1,2‐a]benzimidazol‐4(3H)‐one and 4‐(4‐methylphenyl)‐3,4‐dihydropyrimido[1,2‐a]benzimidazol‐2(1H)‐one form hydrogen‐bonded base‐paired dimers

The title compounds, 2‐(4‐bromo­phenyl)‐1,2‐di­hydro­pyrimido­[1,2‐a]­benzimidazol‐4‐(3H)‐one, C₁₆H₁₂Br­N₃O, (IVa), and 4‐(4‐methylphenyl)‐3,4‐dihydropyrimido[1,2‐a]benzimidazol‐2‐(1H)‐one, C₁₇H₁₅N₃O, (Vb), both form R(8) centrosymmetric dimers via N—H?N hydrogen bonds. The N?N distance is 2.943 (3) Å for (IVa) and 2.8481 (16) Å for (Vb), with the corresponding N—H?N angles being 129 and 167°, respectively. However, in other respects, the supra­molecular structures of the two compounds differ. Both compounds contain different C—H?π interactions, in which the C—H?π(centroid) distances are 2.59 and 2.47 Å for (IVa) and (Vb), respectively (the latter being a short distance), with C—H?π(centroid) angles of 158 and 159°, respectively. The supramolecular structures also differ, with a short Br?O distance of 3.117 (2) Å in bromo derivative (IVa), and a C—H?O interaction with a C?O distance of 3.2561 (19) Å and a C—H?O angle of 127° in tolyl system (Vb). The di­hydro­pyrimido part of (Vb) is disordered, with a ratio of the major and minor components of 0.9:0.1. The disorder consists of two non‐interchangeable envelope conformers, each with an equatorial tolyl group and an axial methine H atom.     

Synthesis and characterization of poly(arylene ether)s containing 6‐(4‐hydroxyphenyl)pyridazin‐3(2H)‐one or 6‐(4‐hydroxyphenyl)pyridazine moieties

A series of novel soluble pyridazinone‐ or pyridazine‐containing poly(arylene ether)s were prepared by a polycondensation reaction. The pyridazinone monomer, 6‐(4‐hydroxyphenyl)pyridazin‐3(2H)‐one ( 1 ), was synthesized from the corresponding acetophenone and glyoxylic acid in a simple one‐pot reaction. The pyridazinone monomer was successfully copolymerized with bisphenol A (BPA) or 1,2‐dihydro‐4‐(4‐hydroxyphenyl)phthalazin‐1(2H)‐one (DHPZ) and bis(4‐fluorophenyl)sulfone to form high‐molecular‐weight polymers. The copolymers had inherent viscosities of 0.5–0.9 dL/g. The glass‐transition temperatures (T_g's) of the copolymers synthesized with BPA increased with increasing content of the pyridazinone monomer. The T_g's of the copolymers synthesized from DHPZ with different pyridazinone contents were similar to those of the two homopolymers. The homopolymers showed T_g's from 202 to 291 °C by differential scanning calorimetry. The 5% weight loss temperatures in nitrogen measured by thermogravimetric analysis were in the range of 411–500 °C. 4‐(6‐Chloropyridazin‐3‐yl)phenol ( 2 ) was synthesized from 1 via a simple one‐pot reaction. 2 was copolymerized with 4,4′‐isopropylidenediphenol and bis(4‐fluorophenyl)sulfone to form high‐T_g polymers. The copolymers with less than 80 mol % pyridazinone or chloropyridazine monomers were soluble in chlorinated solvents such as chloroform. The copolymers with higher pyridazinone contents and homopolymers were not soluble in chlorinated solvents but were still soluble in dipolar aprotic solvents such as N‐methylpyrrolidinone. The soluble polymers could be cast into flexible films from solution. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 3328–3335, 2006     

A hydrogen‐bonded heterodimer of 1‐(4‐hexyloxyphenyl)pyridin‐4(1H)‐one with 4‐cyano­benzoic acid

The two components of the title heterodimer, C₁₇H₂₁NO₂·C₈H₅NO₂, are linked end‐to‐end via O—H⋯O(=C) and C—H⋯O(=C) hydrogen‐bond inter­actions. Additional lateral C—H⋯O inter­actions link the dimers in a side‐by‐side fashion to produce wide infinite mol­ecular ribbons. Adjacent ribbons are inter­connected viaπ–π stacking and C—H⋯π(arene) inter­actions. This structure represents the first evidence of robust hydrogen‐bond formation between the moieties of pyridin‐4(1H)‐one and benzoic acid.     

6‐(2‐Fluorobenzylidene)‐2‐[1‐(2‐fluoro‐4‐biphenyl)ethyl]thiazolo[3,2‐b][1,2,4]triazol‐5(6H)‐one

The title compound, C₂₅H₁₇F₂N₃OS, was synthesized from 6‐(benzyl­idene)­thia­zolo­[3,2‐b][1,2,4]triazol‐5(6H)‐one. The fused thia­zolo­[3,2‐b][1,2,4]triazole system is essentially planar, and bifurcated C—H⋯O, C—H⋯N and C—H⋯F interactions are present between mol­ecules.     

4‐Amino‐3‐methyl‐6‐phenyl‐1,2,4‐triazin‐5(4H)‐one (metamitron) and 4‐amino‐6‐methyl‐3‐phenyl‐1,2,4‐triazin‐5(4H)‐one (isometamitron)

The title structures, both C₁₀H₁₀N₄O, are substitutional isomers. The N—N bond lengths are longer and the C=N bond lengths are shorter by ca 0.025 Å than the respective average values in the C=N—N=C group of asymmetric triazines; the assessed respective bond orders are 1.3 and 1.7. There are N—H⋯O and N—H⋯N hydrogen bonds in both structures, with 4‐­amino‐3‐methyl‐6‐phenyl‐1,2,4‐triazin‐5(4H)‐one containing a rare bifurcated N—H⋯N,N hydrogen bond. The structures differ in their mol­ecular stacking and the hydrogen‐bonding patterns.     

3‐[4‐(4‐Fluoro­phenyl)­piperazin‐1‐yl­methyl]‐5‐methyl‐1,3‐benzoxazol‐2(3H)‐one and 3‐[4‐(2‐fluoro­phenyl)­piperazin‐1‐yl­methyl]‐5‐methyl‐1,3‐benzoxazol‐2(3H)‐one

The title compounds, both C₁₉H₂₀FN₃O₂, contain essentially planar benzoxazolinone ring systems, within which the C—N bond distances and angles do not differ significantly between the two compounds. In both cases, the piperazine ring adopts an almost perfect chair conformation and the benzoxazo­l­inone ring system lies nearly perpendicular to it. The structures contain intermolecular C—H⋯O contacts, and the interactions between the benzoxazolinone and fluoro­phenyl­piperazine portions of the mol­ecules are segregated.     

Conformational study of (Z)‐5‐(4‐chlorobenzylidene)‐2‐[4‐(2‐hydroxyethyl)piperazin‐1‐yl]‐3H‐imidazol‐4(5H)‐one in different environments: insight into the structural properties of bacterial efflux pump inhibitors

The 2‐amine derivatives of 5‐arylidene‐3H‐imidazol‐4(5H )‐one are a new class of bacterial efflux pump inhibitors, the chemical compounds that are able to restore antibiotic efficacy against multidrug resistant bacteria. 5‐Arylidene‐3H‐imidazol‐4(5H )‐ones with a piperazine ring at position 2 reverse the mechanisms of multidrug resistance (MDR) of the particularly dangerous Gram‐negative bacteria E. coli by inhibition of the efflux pump AcrA/AcrB/TolC (a main multidrug resistance mechanism in Gram‐negative bacteria, consisting of a membrane fusion protein, AcrA, a Resistant‐Nodulation‐Division protein, AcrB, and an outer membrane factor, TolC). In order to study the influence of the environment on the conformation of (Z )‐5‐(4‐chlorobenzylidene)‐2‐[4‐(2‐hydroxyethyl)piperazin‐1‐yl]‐3H‐imidazol‐4(5H )‐one, ( 3 ), two different salts were prepared, namely with picolinic acid {systematic name: 4‐[(Z )‐4‐(4‐chlorobenzylidene)‐5‐oxo‐3,4‐dihydro‐1H‐imidazol‐2‐yl]‐1‐(2‐hydroxyethyl)piperazin‐1‐ium pyridine‐2‐carboxylate, C₁₆H₂₀ClN₄O₂⁺·C₆H₄NO₂⁻, ( 3 a )} and 4‐nitrophenylacetic acid {systematic name: 4‐[(Z )‐4‐(4‐chlorobenzylidene)‐5‐oxo‐3,4‐dihydro‐1H‐imidazol‐2‐yl]‐1‐(2‐hydroxyethyl)piperazin‐1‐ium 2‐(4‐nitrophenyl)acetate, C₁₆H₂₀ClN₄O₂⁺·C₈H₆NO₄⁻, ( 3 b )}. The crystal structures of the new salts were determined by X‐ray diffraction. In both crystal structures, the molecule of ( 3 ) is protonated at an N atom of the piperazine ring by proton transfer from the corresponding acid. The carboxylate group of picolinate engages in hydrogen bonds with three molecules of the cation of ( 3 ), whereas the carboxylate group of 4‐nitrophenylacetate engages in hydrogen bonds with only two molecules of ( 3 ). As a consequence of these interactions, different orientations of the hydroxyethyl group of ( 3 ) are observed. The crystal structures are additionally stabilized by both C—H…N [in ( 3 a )] and C—H…O [in ( 3 a ) and ( 3 b )] intermolecular interactions. The geometry of the imidazolone fragment was compared with other crystal structures possessing this moiety. The tautomer observed in the crystal structures presented here, namely 3H‐imidazol‐4(5H )‐one [systematic name: 1H‐imidazol‐5(4H )‐one], is also that most frequently observed in other structures containing this heterocycle.     

Dichloro(diisopropylamino)phosphonio[5(4H)oxopyrazol‐4‐ylide‐5‐one]: Synthesis and properties

Chlorination of the 4‐[chloro(diisopropylamino)phosphino]pyrazole 1 leads to the dichlorophosphonium chloride 2 , which immediately after its formation transforms into the dichloro(diisopropylamino)phosphonio[5(4)oxopyrazol‐4‐ylide‐5‐one] 3 , as a result of dealkylation through loss of ethyl chloride. Reactions of 3 with various nucleophilic reagents were studied. The partial hydrolysis of 3 in the presence of nitriles, resulting in new phosphorus‐containing cyclic systems, is of particular interest. It was demonstrated that chlorination of the P‐dichloropyrazolylphosphine A leads to the stable tetrachlorophosphorane 12 . The C P bond of 12 is broken upon heating. An X‐ray structure determination of compound 11b revealed a planar central heterocycle (mean deviation 0.029 Å). © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:452–458, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10177     

Synthesis and analgesic‐antiinflammatory activities of ethyl 2‐[3‐(1‐phenoxy(methoxy)carbonyl‐4‐aryl‐(alkyl)‐1,4‐dihydropyridyl)]acetates

Reaction of ethyl 2‐(3‐pyridyl)acetate 4a or ethyl 2‐methyl‐2‐(3‐pyridyl)acetate 4b , with phenyl chloroformate or methyl chloroform ate, afforded the intermediate pyridinium salt 5 which undergoes regioselective nucleophilic attack at C‐4 upon reaction with a Grignard reagent in the presence of a cuprous iodide catalyst at ?23° to yield the corresponding ethyl 2‐[3‐(1‐phenoxy(methoxy)carbonyl‐4‐aryl(alkyl)‐1,4‐dihydropyridyl)]acetates 6a‐f in 64–96% chemical yield. No product arising from reaction of the ester substituent of the pyridinium salt 5 with the Grignard reagent was observed. The ¹H nmr spectra of 6a‐f exhibited dual resonances for the 1,4‐dihydropyridyl H‐2, H‐5 and H‐6 protons at 25° in deuteriochloroform. These dual resonaces were attributed to two different rotameric configurations resulting from restricted rotation about the nitrogen‐to‐carbonyl carbamate bond due to its double bond character. Compound 6 generally exhibited superior analgesic and antiinflammatory activities, compared to the reference drugs aspirin and ibuprofen, respectively. These structure‐activity correlations indicate the 1,4‐dihydropyridyl ring system present in 6 is a suitable bioisostere for the aryl (heteroaryl) ring present in aryl(heteroaryl)acetic acid non‐steroidal antiinflammatory drugs.     

Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HCl) via 3‐(2‐Chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione (2) or Dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one (1)

The synthesis of ketanserin ( 5 ) and its hydrochloride salt ( 5.HCl ) using respectively equimolar amounts of 3‐(2‐chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione ( 2 ) with 4‐(parafluorobenzoyl)piperidine ( 3 ) and dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one ( 1 ) with hydrochloride salt of 4‐(parafluorobenzoyl)piperidine ( 3.HCl ) is reinvestigated. The one‐pot reaction of ethyl‐2‐aminobenzoate with ethyl chloroformate and ethanol amine has afforded 3‐(2‐chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione ( 2 ) (86%) that was then refluxed with 4‐(parafluorobenzoyl)piperidine ( 3 ) in ethyl methyl ketone in the presence of sodium carbonate to obtain free base of ketanserin (87%). In another attempt, a very pure hydrochloride salt of ketanserin ( 5.HCl ) was synthesized using equimolar amounts of dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one ( 1 ) and hydrochloride salt of 4‐(parafluorobenzoyl)piperidine ( 3.HCl ) by a solvent‐less fusion method. Thus, under optimized conditions, 180°C and a reaction time of 30 min, the powder mixture was transformed into glassy crystals that were initially readily soluble in chloroform but were transformed afterwards over time (2 h) to white precipitates ( 5.HCl ) suspended in chloroform with a yield of 72%.     

An X‐ray crystallographic and density functional theory study of (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one

The Schiff base enaminones (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₃H₁₇NO₄S, (I), and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₅H₂₁NO₂, (II), were studied by X‐ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C—C=C—N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino–phenol group canted relative to the rest of the molecule; the twist about the N(enamine)—C(aryl) bond leads to dihedral angles of 40.5 (2) and −116.7 (1)° for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N—H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one‐dimensional hydrogen‐bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H—O hydrogen bond, and consequently also forms a one‐dimensional hydrogen‐bonded chain. The DFT‐calculated structures [in vacuo, B3LYP/6‐311G(d,p) level] for the keto tautomers compare favourably with the X‐ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol⁻¹ lower in energy than the enol tautomers for (I) and (II), respectively.