Imidazolidine Ring Research Articles

NMR and semiempirical conformational analysis of the 2-aryl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidines

2-Aryl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidines (1) were synthesized and their 1H and 13C NMR spectra recorded. Quantum mechanical semiempirical calculations were also performed, for a better understanding of the signals recorded in the NMR spectra of imidazolidines. The conformation of the imidazolidine ring was initially studied for the 2-methyl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidine (2), used as a model molecule. The results of the calculations obtained for structure 2 showed that the methyl groups are located in axial and equatorial positions. At these positions, the methyl groups are affected by the magnetic anisotropic effects of carbon-nitrogen and carbon-carbon bonds of the imidazolinyl ring with different intensities. Semiempirical calculations for structure 2, suggested that the effect of the γ-oxygen on the carbon atoms of methyl groups (γ-effect) might lead to an alteration of the electronic charge density and consequently to a change in the diamagnetic shielding on these groups. These data were used for the analysis of the NMR spectra of compound 1. The diamagnetic shielding effects, estimated from the calculated electronic charge densities on the carbon atoms of methyl groups, are in agreement with the signals observed in the NMR spectra of compound 1. By combining the contribution of the anisotropic and γ-effects, it appears that the axial methyl groups are located relatively closer to the γ-oxygens in compounds 1.

Substituted 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives as novel nonpeptide inhibitors of human heart chymase.

A series of 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives have been synthesized and evaluated for their ability to selectively inhibit human heart chymase. The structure-activity relationship studies on these compounds gave the following results. The 1-phenyl moiety participates in a hydrophobic interaction where an optimum size is required. At this position, 3,4-dimethylphenyl is the best moiety for inhibiting chymase and showed high selectivity compared with chymotrypsin and cathepsin G. A 3-phenylsulfonyl moiety substituted with hydrogen-bond acceptors such as nitrile and methoxycarbonyl enhances its activity. Molecular-modeling studies on the interaction of 3-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-imidazolidine-2,4-dione (29) with the active site of human heart chymase suggested that the 1-phenyl moiety interacts with the hydrophobic P1 pocket, the 3-phenylsulfonyl moiety resides in the S1'-S2' subsites, and the 4-carbonyl of the imidazolidine ring and sulfonyl group interact with the oxyanion hole and the His-45 side chain of chymase, respectively. The complex model is consistent with the structure-activity relationships.

Novel reaction of aminopyridines with glyoxal and formaldehyde; synthesis of 4,8-di (N-aminopyridyl) 2,6-dioxa 4,8-diazabicyclo[3.3.0]octane, 6,8-di(N-aminopyridyl) 2,4-dioxa 6,8-diazabicyclo[3.3.0]octane and X-ray structural study of related 1,3-di(N-aminopyridyl) 4,5-dihydroxy imidazolidine

Condensation of 2-aminopyridine with glyoxal proceeds with high selectivity to a mixture of meso and dl diol 7 to be easily transformed into the corresponding bicyclooctane 2a and 3a with formaldehyde and acetonitrile as solvent. In water, however, the reaction selectively produces imidazolidine 4a. Based on NMR analysis, the major diastereomers were assigned as syn derivatives. X-ray crystal structure of 4a shows a planar configuration for imidazolidine ring, in line with two anomeric effects, first a strong n N → σ C-O ∗ interaction and second a weak n O → σ C-N ∗ one. A network of hydrogen bonding between pyridyl nitrogens and hydroxy hydrogens forms a pattern of twelve atom in a chair-like conformation.

Chloronicotinyl Insecticides. 8. Crystal and Molecular Structures of Imidacloprid and Analogous Compounds

The crystal structures of the chloronicotinyl insecticide imidacloprid and related molecules have been determined by three-dimensional X-ray diffraction analysis. In imidacloprid the nitroimino group is coplanar with the imidazolidine ring plane; shorter ring CN bond lengths and longer exocyclic CN bond length were observed, suggesting a formation of a fully delocalized diene system. Similar molecular frameworks were seen in the nitromethylene and cyanoimine analogues. The interatomic distances between an imidazolidyl nitrogen and a nitro oxygen or a cyano nitrogen were ca. 5.9 Å, a suitable value to bind to the recognition site on nicotinic acetylcholine receptor. Keywords: Chloronicotinyl insecticide; imidacloprid; X-ray structure; nicotinic acetylcholine receptor; nitromethylene insecticide

Entropy in Bi-substrate Enzymes: Proposed Role of an Alternate Site in Chaperoning Substrate into, and Products out of, Thymidylate Synthase

Three steps along the pathway of binding, orientation of substrates and release of products are revealed by X-ray crystallographic structures of ternary complexes of the wild-type Lactobacillus caseithymidylate synthase enzyme. Each complex was formed by diffusion of either the cofactor 5,10-methylene-5,6,7,8-tetrahydrofolate or the folate analog 10-propargyl- 5,8-dideazafolate into binary co-crystals of thymidylate synthase with 2′-deoxyuridine-5′-monophosphate. A two-substrate/enzyme complex is formed where the substrates remain unaltered. The imidazolidine ring is unopened and the pterin of the 5,10-methylene-5,6,7,8-tetrahydrofolate cofactor binds at an unproductive "alternate" site. We propose that the presence of the pterin at this site may represent an initial interaction with the enzyme that precedes all catalytic events. The structure of the 2′-deoxyuridine-5′-monophosphate and 10-propargyl-5,8-dideazafolate folate analog complex identifies both ligands in orientations favorable for the initiation of catalysis and resembles the productive complex. A product complex where the ligands have been converted into products of the thymidylate synthase reaction within the crystal, 2′-deoxythymidine-5′- monophosphate and 7,8-dihydrofolate, shows how ligands are situated within the enzyme after catalysis and on the way to product release.

Imidacloprid insecticide soil metabolism in sugar beet field crops.

Imidacloprid (1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-N-nitro-1H-imidazol-2-amine, 1) is a new insecticide which is useful for the protection of sugar beet from soil insects (Atomaria, Blaniulus, Agriotes and Pegomya) and leaf insects (aphids). It is applied in pelleted seed dressing. It is a systemic compound which is absorbed by the plant. In the leaves, it gives a long lasting (3 to 4 months) protection against aphids and the virus yellows infections. The metabolism of 14C-imidacloprid was investigated in plant cell suspension cultures (Koester 1992). The main metabolites corresponded to imidacloprid hydroxylation (l-[(6-chloro-3-pyridinyl)methyl]-5-hydroxy-4,5-dihydro-N-nitro-lH-imidazol-2-amine) or dehydrogenation (1-[(6-chloro-3-pyridinyl)methyl] -N-nitro-lH-imidazol-2-amine) of the imidazolidine ring, and to 6-chloronicotinic acid. The nitroso derivative of imidacloprid (1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-N-nitroso-1H-imidazol-2-amine) corresponded to only 0.1% of the total recovered 14C. The imidacloprid soil metabolism has been studied by incubation in laboratory conditions (Scholz and Spiteller 1992). The metabolites observed in plant cell cultures did not accumulate in soil; their total amount was less than 4% of the total recovered radioactivity during 14C-imidacloprid soil biodegradation. 14CO2 was the main product of 14C-imidacloprid soil biodegradation. We previously studied the disappearance of imidacloprid in the soil of a sugar beet, organic fertilizers trial made at Lubbeek in 1992 (Rouchaud et al. 1994). Also, in a sugar beet trial located at Remicourt, one part of the field had not been treated with organic fertilizers for 18 years, but its soil contained a high concentration (4.3%) of soil organic matter. Another part of the field had been treated every 3 years with cow manure for 18 years, but its soil contained a normal concentration (2.4%) of organic matter. In the present work, we studied the imidacloprid soil metabolism in a new organic fertilizers trial made on another field at Lubbeek in 1993. We also searched for the imidacloprid soil metabolites in the trial made in 1992 at Remicourt.

Chiral animals: Powerful auxiliaries in asymmetric synthesis

Abstract

Metabolic Fate of Clonidine. (V): Metabolism of Clonidine after Subcutaneous Administration of Clonidine to Rats, Dogs and Monkeys and Dermal Application of Clonidine Tape, M-5041T, to Rats.

The metabolism of clonidine in rats, dogs and monkeys was investigated after subcutaneous administration of 14C-clonidine or after application of a transdermal delivery system containing 14C-clonidine, 14C-M-5041T. 1. In male rats after subcutaneous dosing, unchanged clonidine was mainly found in the urine, followed by the conjugate of CM-4, a hydroxylated metabolite of the phenyl ring. CM-4 was also found in the feces and bile. 2. The metabolic profile in male rats after 21 times repeated subcutaneous dosing was similar to that after single dosing. Certain metabolites were bound tightly to the constituent proteins of aorta. 3. Unchanged clonidine was mainly found in the skin at the application site of male rats after application of 14C-M-5041T. The metabolic profile was similar to that after subcutaneous dosing. 4. In male dogs after subcutaneous dosing, CM-1, a metabolite formed by cle avage of the imidazolidine ring, was mainly found, whereas the unchanged clonidine was found in minor quantities in the urine and feces. The metabolic profile in a male monkey was similar to that in dogs. 5. From the above results, main metabolic pathways of clonidine were proposed to be the hydroxylation and conjugation of the phenyl ring in rats, and the oxidation and cleavage of the imidazolidine ring in dogs and monkeys.

Unexpected ring contraction in the barium-assisted cyclocondensation of 2,6-diformylpyridine and N,N-bis(2-aminoethyl)-2-phenylethylamine

The cyclocondensation reaction between N,N-bis(2-aminoethyl)-2-phenylethylamine and 2,6-diformylpyridine in the presence of a barium template gave an unexpected 18-membered macrocyclic product in which a ring contraction at one side-arm has occurred to produce an imidazolidine ring.

Effects of multidrug resistance (MDR1) P-glycoprotein expression levels and coordination metal on the cytotoxic potency of multidentate (N4O2) (ethylenediamine)bis[propyl(R-benzylimino)]metal(III) cations.

Enhanced mitochondrial transmembrane potentials in tumor cells have been proposed to confer tumor-selective-targeting properties to modestly lipophilic monocationic compounds. To explore the potential cytotoxic activity of lipophilic cationic metallopharmaceuticals containing a highly flexible hexadentate N4O2 Schiff-base phenolic ligand, we first synthesized precursors H3Mabi (1) and H3DMabi (2) by condensation of an appropriate linear tetraamine with substituted salicylaldehydes. The desired N4O2 ligands, (ethylenediamine)-N,N'-bis[propyl[(2-hydroxy-3-methoxybenzyl)imino]] and (ethylenediamine)-N,N'-bis[propyl[2-hydroxy-4,6-dimethoxybenzyl)-imino]] (R-ENBPI), were obtained by cleavage of the imidazolidine ring, and their corresponding monocationic complexes were produced by reaction with appropriate hydrated salts or acetylacetonates of Al(III), Fe(III), Ga(III), and In(III). All complexes were stable to neutral hydrolysis. In human epidermal carcinoma KB-3-1 cells, cytotoxic potencies of racemic mixtures of these complexes were in the low micromolar range and, for a given ligand, depended on the identity of the coordinating central metal. The active 4,6-dimethoxy-ENBPI complexes were more potent than their 3-methoxy analogs, while the free ligands and metal(III) ions showed little or no cytotoxic activity. Furthermore, in colchicine-selected KB-8-5 multidrug resistant (MDR) cells, modest cellular expression of human MDR1 P-glycoprotein conferred protection from the cytotoxic activities of Al(III), Fe(III), and Ga(III) R-ENBPI complexes indicating that these complexes were recognized as transport substrates by the P-glycoprotein efflux transporter. However, the cytotoxic activities of the corresponding In(III) complexes, while among the lowest in potencies, were also not altered by expression of MDR1 P-glycoprotein. Thus, for the Group III elements, human cells were capable of distinguishing R-ENBPI complexes formed of the same ligands with different metals. Furthermore, selected R-ENBPI metal(III) complexes may be useful as novel anticancer metallopharmaceuticals.

5-Imino-1,4,4-triphenylimidazolidin-2-one: an Imidazolidine with an Exocyclic Imino Group

The conformation of the imidazolidine ring in the title compound, C 21 H 17 N 3 O, is almost flat with a maximum deviation of ±0.031(8)A from the least-squares plane through the ring. The structure is stabilized by an intermolecular hydrogen bond. This type of compound can be used in addition reactions with isocyanates.

Actions of nitromethylenes on an α-Bungarotoxin-sensitive neuronal nicotinic acetylcholine receptor

Nine nitromethylene analogues were tested for their actions on insect neuronal nicotinic acetylcholine receptors (nAChRs). Microelectrode recordings were used to study the actions of nitromethylenes on the cell body of an identified cockroach ( Periplaneta americana) motor neurone, the fast coxal depressor ( D f ) in the metathoracic ganglion. Six nitromethylenes showed potent nAChR agonist actions; others were without nAChR agonist actions. Five nitromethylenes competitively displaced bound [ 125I]-α-bungarotoxin from cockroach nervous system membranes. The rank orders of potency for the compounds determined by their depolarizing actions and their ability to displace [ 125I]-α-bungarotoxin binding were similar. These findings, together with toxicity data obtained on the insects, Nephotettix cinciteps and Nilaparvata lugens, support the hypothesis that insect nAChRs are molecular targets of nitromethylene insecticides. Structure-activity relationships of the nitromethylenes suggest that optimal activity at neuronal nAChRs requires the presence of an electron-withdrawing component in the region of the aryl substituent and an electron-donating component at the 3′ position of the imidazolidine ring.

Complexes of Trivalent Metal Ions with Potentially Heptadentate N4O3 Schiff Base and Amine Phenol Ligands of Varying Rigidity

The synthesis and characterization of several potentially heptadentate N{sub 4}O{sub 3} Schiff bases and amine phenols, as well as a series of their mononuclear and dinuclear complexes with indium and the lanthanides are reported. Schiff bases containing imidazolidine rings were the products of the known condensation reaction of triethylenetetramine with 3 equiv of 5-substituted salicylaldehydes to form H{sub 3}api (5-H-substituent), H{sub 3}Clapi (5-Cl-substituent), or H{sub 3}Brapi (5-Br-substituent); KBH{sub 4} reduction of these Schiff bases gave the appropriate isomeric N{sub 4}O{sub 3} amine phenols H{sub 3}(1,2,4-btt) and H{sub 3}(1,1,4-btt), as well as an acetone adduct, H{sub 3}(1,2,4-ahi). The Schiff bases reacted with 1 equiv of a lanthanide (Ln{sup 3+}) nitrate to produce mononuclear nine-coordinated [Ln(H{sub 3}Xapi)-(NO{sub 3}){sub 3}] complex wherein the ligand adopts a tridentate capping coordination mode, whereas the amine phenols formed mononuclear seven-coordinate complexes with the lanthanides and indium; homodinuclear complexes [LnL]{sub 2} were also obtained with the Schiff bases. The X-ray structures of the Schiff bases H{sub 3}api and H{sub 3}Clapi, the mononuclear amine phenol complexes Yb(1,2,4-btt){center_dot}0.5CH{sub 3}OH and In(1,1,4-btt), and the homodinuclear Schiff base complex [La(Brapi)]{sub 2}{center_dot}2CHCl{sub 3} have been determined.

Copper-63 nuclear quadrupole resonance frequencies and molecular geometries of three-co-ordinate complexes of copper(I) halides with N-alkylimidazolidinethione and thiazolidinethione ligands

The crystal structures of seven three-co-ordinated complexes of copper(I) halides with thione ligands, [CuXL2], where L = 1,3-thiazolidine-2-thione and X = Cl or Br, L =N-ethylimidazolidine-2-thione and X = Br, L =N-isopropylimidazolidine-2-thione and X = Cl or Br, and L =N-propylimidazolidine-2-thione and X = Cl or I have been determined. In all complexes, the copper lies in a trigonal-planar environment and the thiazolidine or imidazolidine rings show no major distortion from planarity. Owing to the presence of hydrogen bonding involving H[N(2)], or H[N(02)], and the halogen atom all complexes adopt a W-shaped conformation. The 63Cu NQR frequencies of these complexes, together with those of two other similar complexes whose structures were already available, depend, for a given halide, on the S–Cu–S bond angle, a decrease in angle producing an increase in resonance frequency: νCl= 28.7 – 0.544Δθ and νBr= 26.9 – 0.229Δθ MHz, where Δθ is the difference between the S–Cu–S bond angle and 120°. This behaviour has been rationalized in terms of a partial field-gradient model of the resonance frequencies.

Structure of 1-carbamoyl-3-phenyl-(1,2-dideoxy-α-D-glucofurano) [1,2-d]imidazolidin-2-one

Abstract The compound (C14H17N3O6) crystallizes in the monoclinic space group P21 with a = 13.640(3) Å, b = 4.692(1) Å, c = 11.299(3) Å, β = 93.09(1)°, (V = 722.1(3) Å3; Z = 2; Dc = 1.487 Mgm−3, λ(MoKα ) = 0.7107 Å, μ = 0.11 mm−1, F(000) = 340, T = 293 K). The structure was solved by direct methods and refined by full matrix least squares method to a final R = 0.039 (Rw = 0.040). The furano ring adopts a perfect envelope E4 conformation with the substituent C71 in equatorial and O6 in axial position. The imidazolidine ring is planar and the substituents O2,O31 and C11 are at 0.028, −0.041 and −0.200 Å from this plane. The mean planes of furano and imidazolidine rings make an angle of 108.6(1)°. The pertinent dihedral angles are 7.5(1)° (phenyl-imidazoline); 115.9(1)° (phenyl-furane), and 7.1(3)° (imidazoline-amide). The molecules are stakked along the b axis forming two infinite chains through an intermolecular H-bond O71 … O6.

Monocyclic biradicals in the imidazolidine series

The reaction of 1-hydroxy-3-imidazoline 3-oxides with alkyl- or phenyliithium followed by oxidation gives stable biradicals with two nitroxyl groups in the imidazolidine ring. Anisotropic ESR spectra of these biradicals are discussed.

New degradation product of spiradoline mesylate in aqueous solution: Formation of an imidazolidine ring

AbstractA new degradation product of spiradoline mesylate was recognized in aqueous solution stored at 80°C for 10 days. The structure of the degradation product was elucidated with spectroscopic data and a synthetic method as (1 RS, 3RS, 8RS, 10RS)-2-methyl-2, 7-diazatricyclo-[6.4.0.03, 7]dodecane-10-spiro-2′-tetrahydrofurane by several two-dimensional NMR spectra. The fused imidazolidine ring system was synthesized from (5RS, 7RS, 8RS)-N-methyl-8-(7-pyrrolidino-1-oxaspiro-[4.5]decane)amine reacted with mercuric acetate. Because the degradation was promoted by bubbling air or oxygen gas into the solution or by adding α, α′-azobisisobutylonitrile for radical initiation, and the reaction was suppressed by bubbling nitrogen gas or deaerating, the reaction mechanism of the degradation was considered to be oxidation caused by an oxygen radical.

On the nature of the anhydride of the lactam of guanidinoglutaric acid

When glutamic acid is amidinated, guanidinoglutaric acid is formed. This is readily converted by boiling in water to its lactam [2-imino-4-oxo-5-(3′-propane acid) imidazolidine; GGAL]. In the present study GGAL is dehydrated to form a second lactam, anhydro-GGAL (AGGAL), with trifluoroacetic anhydride. The molecular weight of this compound was ascertained gravimetrically by precipitation with flavianic acid and by mass spectrography to be 153.14. UV and infrared spectra and hydrogen and 13C NMR studies determined its structure as an imidazolidine ring fused to a pyrrol ring, 2-imino-4-oxo-imidazolidine-1,5-pyrrolidone-8. On paper electrophoresis, GGAL traveled to the anode, while AGGAL traveled to the cathode. On TLC plates (butanol 60, H 2O 25, acetic 15), the R f value of GGAL was 0.42 and that of AGGAL was 0.38, confirming that AGGAL was more basic than GGAL. The preparation of 1,3-di-(phenylcarbamoyl)-GGAL is also described.

Synthesis and ocular antihypertensive activity of new imidazolidine derivatives containing a .beta.-blocking side chain

The syntheses of new phenylimidazolidine derivatives (3-6)1 containing a propanolamine oxime or an oxypropanolamine moiety attached either to the aromatic or to the imidazolidine ring are described. These compounds were evaluated for potential ocular antihypertensive activity in alpha-chymotrypsin-induced ocular hypertension in rabbits. These compounds represent a unique series of effective ocular antihypertensive agents that despite possessing structural characteristics of beta-blockers and of imidazolidine derivatives, exhibit weak alpha- and beta-adrenergic agonist and antagonist activities. These findings may be of significant therapeutic importance in the medical management of glaucoma.

Addition of twisted 1,1-bis(thioacyl)-2,2-diaminoethylenes to dimethyl acetylenedicarboxylate. 2. Structure determination of two isomeric spiro adducts by x-ray crystallography and of a rearrangement product by the 2D INADEQUATE technique

Chromatography of the complex reaction mixture gave two isomeric 1:2 adducts, shown by X-ray crystallography to be (E)- and (Z)-[1,2-bis(methoxycarbonyl) vinyl] thio-substituted thiopyran-4-spiro-2'-imidazolidines. Treatment of the spiro compounds with dilute nonaqueous acid led to isomers in which the imidazolidine ring had opened, and acid hydrolysis gave a thiopyrone and its enol tautomer. Continued chromatography of the original reaction mixture gave three new compounds, a thiopyran-4-thione, a tetrakis-(methoxycarbonyl)-1,4-dithiaphenalene, and a precursor to this with the same ring system. The formation of these compounds requires migration of a sulfur atom from the cyclohexene ring to the annelated thiopyran ring, and a possible mechanism is discussed. The dithiaphenalene structure was firmly established by the 2D IN-ADEQUATE technique