NMR Studies of Hindered Rotation. The Diels-Alder Adduct of Phencyclone with N-n-Propylmaleimide: Restricted Motion of Bridgehead Phenyls

The Diels-Alder adduct of phencyclone and N-n-propylmaleimide has been studied in CDCl₃ solution at ambient temperatures by one-and two-dimensional ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) techniques. Clear evidence is presented from slow exchange limit (SEL) spectra for hindered rotation of the bridgehead phenyls in the adduct. Full ¹H spectral assignments have been made via selective homonuclear decoupling and high resolution COSY experiments. The number of signals in the aryl region of ¹³C NMR spectra also indicated slow rotation about the C(sp²)-C(sp³) bond to the unsubstantiated bridgehead phenyls. Striking evidence of magnetic anisotropic effects, seen from ¹H NMR, permits stereochemical assignment of the adduct as endo.     

NMR Studies of Hindered Rotation. The Diels-Alder Adduct of N-n-Butylmaleimide With Phencyclone: Restricted Motion of Bridgehead Phenyls

The Diels-Alder adduct of phencyclone and N-n-butylmaleimide has been prepared, and NMR studies have been carried out in CDCl₃ solution at ambient temperatures by one-and two-dimensional ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) techniques. The resulting spectra appear to be consistent with slow rotation about the hindered C(sp²)-C(sp³) bonds to the bridgehead unsubstituted phenyls, i.e., slow exchange limit (SEL) spectra. Full rigorous ¹H spectral assignments have been made via high-resolution COSY experiments. The number of signals in the ¹³C NMR aryl region were also consistent with hindered phenyl rotations; preliminary ¹³C assignments are given. Striking evidence for magnetic anisotropic effects due to the phenanthrene moiety, bridging ketone carbonyl, and bridgehead phenyls are discussed, supporting endo stereochemical assignment of the adduct.     

Studies of Hindered Rotation and Magnetic Anisotropy by 1H, 13C and 19F NMR. The Diels-Alder Adduct of N- Pentafluorophenylmaleimide and Phencyclone: A Model for Drugs.

The potent Diels-Alder diene, phencyclone, 1, reacts with N-pentafluorophenylmaleimide, 2, to form an adduct, 3, characterized by ¹H, ¹³C, and ¹⁹F NMR at 300, 75 and 282 MHz, respectively. The one-dimensional (1D) and two-dimensional (2D) ¹H and ¹³C NMR spectra of 3 at ambient temperatures imply a slow exchange limit (SEL) regime with respect to rotation of the unsubstituted bridgehead phenyl groups about severely hindered C(sp²)-C(sp³) bonds. Major non-bonded interactions are expected between the ortho protons of the C₆H₅ groups and H-1, 8 of the phenanthrenoid moiety of 3. ¹⁹F 1D and 2D (COSY) NMR spectra show that the SEL regime also obtains for rotation about the N-C₆F₅ bond of 3, with five separate fluorine signals seen, consistent with a preferred conformation in which the C₆F₅ may lie roughly perpendicular to the plane of the pyrrolidinedione moiety, and may be in the mirror symmetry plane of 3. The results are considered relevant to hindered aryl rotations in numerous Pharmaceuticals. Selected spectral data for 2 and precursors are also presented.     

NMR Studies of Drugs. Methaqualone. Approaches to Rigorous 1H and 13C Assignments with Applications of Achiral and Chiral Shift Reagents

The ¹H and ¹³C NMR spectra of methaqualone, 1, have been extensively studied using one and two-dimensional techniques. These 300 MHz ¹H and 75 MHz ¹³C studies have allowed rigorous assignments to be made for the methyl groups and the quinazolinone nucleus. The 60 MHz ¹H spectra for 1 in CDCl₃ have been examined with     

NMR Studies of Drugs. Applications of Lanthanide Shift Reagents to Afloqualone,an Axially Chiral Quinazolinone.

The skeletal muscle relaxant, aflogualone, 1, has been studied by ¹H NMR in CDC1₃ at 60 and 300 MHz in the presence of added chiral [Eu(HFC)₃] or achiral [Eu(FOD)₃] lanthanide shift reagents (LSR). With Eu(HFC)₃, significant enantiomeric shift differences, ΔΔδ, can be induced for most of the nuclei of 1, with near-baseline resolution obtainable for the H-5 signals of each enantiomer, indicating excellent analytical potential for direct determination of enantiomeric excess of samples of 1. Observation of ΔΔδ directly confirms hindered rotation about the bond between N (3) and the 2-methylphenyl group, i.e., the N (sp²) - C(sp²) bond, leading to axial chirality in 1 with slow rotation on the NMR timescale. Assignments are supported by 2D COSY spectra at 300 MHz. Relative lanthanide-induced shift magnitudes for the protons of 1 are compared.     

1H and 13C NMR Studies of Etidocaine Free Base and Hydrochloride Salt. Solvent and Temperature Dependence

The ¹H and ¹³C NMR spectra of etidocaine free base, 1, and its hydrochloride salt, 2, have been examined at 200 MHz in a variety of solvents. Variable temperature ¹H NMR spectra of 2 were measured between 0° and 90°C at 500 MHz. Both ¹H and ¹³C spectra of the salt were strongly dependent on temperature, solvent and spectrometer frequency. Results are interpreted primarily as a consequence of acid-induced chirality at the amine nitrogen, resulting in solvent-dependent diastereoisomerism. Spectral complexity is explained as the result not only of diastereotopic nuclei due to the fixed “natural” chiral center at carbon, but also, in 2, to the presence of diastereomeric racemates resulting from the second chiral center (at nitrogen).     

NMR Studies of Hindered Rotations in Drugs. Use of Achiral and Chiral Lanthanide Shift Reagents with Mecloqualone,an Axially Chiral Drug of Abuse. Rigorous Definition of Spin Systems.

The axially chiral sedative/hypnotic drug of abuse, mecloqualone, 1, has been studied in CDC1₃ by ¹H NMR at 60 and 300 MHz with the added achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5- octanedionato)europium(III), 2, and the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium-(III), 3. Rigorous distinctions between the two (CH)₄ spin systems of 1 with added 2 or 3 were achieved by two-dimensional homonuclear chemical shift correlation spectroscopy, COSY. Substantial up field (“anomalous”) shifts were observed for several nuclei of 1 with each LSR. Use of the chiral 3 elicited enantiomeric shift differences with baseline separations for several nuclei that should permit direct determinations of enantiomeric excess. COSY spectra allow determination of the relative sense of magnetic nonequivalence of selected nuclei of 1 with 3.     

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to a 5-Substituted-4-thiazolidinone

The 60 MHz ¹H NMR spectra of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone, 1, have been studied in CDCl₃ solution at 28° with the achiral lanthanide shift reagent (LSR), tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)- (+)-camphoratojeuropium(III), 3, and tris[3-(trifluoromethylhydroxymethylene-(+) -camphorato]europium (III), 4, Significant enantiomeric shift differences were observed in the presence of added 3, for the aryl protons of 1 that should permit direct determination of enantiomeric excess. Relative magnitudes of lanthanide-induced shift for the different nuclei of 1 with the three LSRs are compared and discussed in terms of preferred LSR binding sites. A favored conformation of 1 with respect to rotation about the C(5)-CH₂ bond is suggested.     

13C NMR and 2D (H,H and H,C COSY) Spectra of Triazolo-triazino-indole Derivatives and the Conformational Analysis of the Respective C-Nucleoside Analogues

¹³C NMR and 2D (H,H and H,C COSY) spectra of selected examples of sugar (5H-1,2,4-triazino[5,6-b]-indol-3-yl) hydrazones, peracetylated sugar-1-acetyl -1- (5-acetyl-1,2,4-triazino[5,6-b]indol-3-yl)hydrazones, and 10-acetyl-3-(per-0-acetylalditol-1-yl)-1,2,4-triazolo[4′, 3′:2,3][1,2,4]triazino[5,6-b]indole have been reported. The conformation of the latter C-nucleoside analogues have been determined by analysis of their ¹H NMR spectra. The D-galacto, D-manno and L-arabino isomers are preponderantly existing in the planar zigzag arrangement of carbon atoms.     

NMR Studies of Drugs. Application of a Chiral Lanthanide Shift Reagent for Potential Direct Determination of Enantiomeric Excess of Methsuximide

The 200 MHz ¹H NMR Spectra of methsuximide, 1,3-dimethy1-3-ogebt1-2,5-otrrikudubeduibem 1, havebeen studied in CDC13 solution with the chiral reagent, tris[3-(heptafluoropropy1-hydroxymethylene)-d-camphorato] europium (III), 2, Eu(HFC)3. Substantial lanthanide-induced shifts are seen. In addition, significant enantiomeric shift differences are observed for several of the nuclei of 1. With a 2:1 molar ratio near 1.0, the CCH3 and NCH3 signals show nearly baseline resolution between the peaks from each enantiomer, providing excellent potential for direct determinations of enantiomeric excess of samples of 1. As little as 2% of a minor enatiomer should be readily detectable.     

1H, 13C and 19F NMR Studies of the Diels-Alder Adduct of p-Fluoranil with Phencyclone. II. Hindered Phenyl Rotations and Anisotropic Effects in a Model Compound for Drugs

Abstract

The Diels-Alder adduct of phencyclone, compound 1, with p-fluoranil, compound 3, has been prepared in refluxing toluene. The adduct, compound 2, has been examined by ¹H, ¹³C and ¹⁹F NMR spectroscopy at 300, 75 and 282 MHz, respectively. At ambient temperature, the unsubstituted bridgehead phenyl groups in adduct 2 are found to exhibit hindered rotation, resulting in slow exchange limit (SEL) ¹H NMR spectra. Full aryl proton assignments are made based on 1D and 2D (COSY45) NMR. The ¹⁹F NMR (proton coupled) reveals one of the two ¹⁹F signals to be a triplet. This resonance collapses to a singlet in the proton decoupled ¹⁹F spectrum, implying an unexpected long range ¹H-¹⁹F coupling. For the ¹³C NMR spectrum, tentative assignments are presented. Data for compound 2 as a model compound for drugs are discussed in terms of the hindered aryl rotation and evidence of magnetic anisotrppic effects.     

On the Twist-Boat Conformation of the Tetrahydropyran Cycle in the Trioxa-Bis-Spiroketal Series

INTRODUCTION

In the solid state the trioxa-bis-spiroketal 2 (fig. 1) has a twist-boat conformation (tetrahydropyran cycle) and its infrared absorption and nuclear magnetic resonance (¹H at 250 MHz, ¹³C at 15,06 MHz) spectra let forsee the same conformation in solution.¹.     

NMR Studies of Agricultural Products. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Fungicide,Triadimefon.

Abstract

The 60 MHz ¹H NMR spectra of the systemic agricultural fungicide, triadimefon, 1, have been studied in CDCl₃ at 28±1° (as the racemic free base) with the added achiral lanthanide shift reagent (LSR), tris(6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium(III), Eu(FOD)₃, 2, for spectral simplification, and with the chiral LSR, tris [3-(heptafluoropropylhydroxymethylene)-(+) -camphorato)europium(III), Eu(HFC)₃, 3, to induce enantiomeric shift differences (ΔΔδ) for several nuclei. Significant ΔΔδ values were seen for the two protons of the heterocyclic ring, the OCH methine, and aryl H-2′, 6′ of the chlorophenoxy ring. For each of these nuclei exhibiting ΔΔδ with added 3, the ΔΔδ magnitudes reached maximum values with 3: 1 molar ratios ca. 0. 18–0. 29, and decreased with higher levels of 3. To confirm analytical utility of 3 for % e. e. determinations of 1, a nonracemic (“spiked”) sample of racemic 1, with added R-(?) triadimefon, was examined with 3. At low 3: 1 ratios, both triazole H-3 and H-5, as well as the OCH and aryl H-2′, 6′ protons of (?)-1 showed a downfield sense of magnetic nonequivalence with (+) -3. With 3: 1 ratios ca. 0. 8, triazole proton H-3 reversed its sense of magnetic noneguivalence. The H-3 and H-5 signals were useful for % e. e determinations at this higher 3: 1 ratio.     

Captopril and Its Disulfide Metabolite: 13C NMR Assignments and Preferred Conformations

The ¹³C nmr assignments for captopril (1) and its disulfide mammalian metabolite (2) were made. Evidence was presented for the preferred conformations of these compounds to be in the trans forms.     

NMR Studies of Drugs: Antipyrine and Analogs. I. Use of Achiral and Chiral Lanthanide Shift Reagents to Examine Hindered Rotation.

The 200 MHz ¹H NMR spectra of the analgesic, antipyrine, 1, have been studied in CDC1₃ solution at ambient temperatures with the achiral lanthanide shift reagent (LSR) tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), Eu(FOD)₃, 2, and with the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)₃, 3., Lanthanide-induced shift (LIS) magnitudes and broadening of selected signals are consistent with predominant LSR binding at the carbonyl oxygen with either 2 or 3. Of the different possible conformational regimes for the N-phenyl group of 1, our results appear to rule out a slow exchange limit (SEL) system with the N-phenyl coplanar with the heterocyclic ring. Perpendicular rings in an SEL regime can not be ruled out. A rapidly-rotating N-phenyl (fast exchange limit, FEL system) would also be consistent with observed results. Accurate chemical shifts for the aryl protons (overlapped in the 200 MHz spectrum of unshifted 1) are determined from spectra with added LSR by extrapolation to zero molar ratios of [LSR]:[1]. Relative slopes in the plots of chemical shift versus [LSR]:[1] molar ratios are calculated for each proton signal of 1.     

1 H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Tocainide. Method for Direct Optical Purity Determination and Observation of an “Anomalous” Shift

The 60 MHz ¹H NMR spectra of racemic tocainide, 1, have been studied in CDCL₃ solution at 28° with the achiral shift reagent, tris(6,6,7,7,8,8,8-heptafluor-2,2-dimethyl-3,5-octanedionato)europiumIII), 2, and the chiral reagent, tris[3- (heptafluoropropylhydroxymethylene)-d-canphorato]- europium(III), 3. Substantial lanthanide induced shifts, Δδ, were served with both 2 and 3, A significant “anomalous” upfield shift for the CH signal of 1 was seen with added 2. The chiral reagent 3 led to appreciable emtiomeric shift differences for the CH₃CH and amide NH signals. The potential for direct optical purity determinations of 1 using 3 was demonstrated for a non-racemic (“spiked”) sample of 1, based on the CH₃ resonance. The sense of magnetic non-equivalence for these resonances was also determined.     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Methastyridone, 2,2-Dimethyl-5-(2-Phenylethenyl)-4-Oxazolidinone

Abstract

The 60 MHz ¹H NMR spectra of methastyridone, 2,2-dimethyl-5-(2-phenylethenyl)-4-oxazolidinone, 1, have been studied at 28° in CDCl₃ solution with the achiral reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, Eu(FOD)₃, and the chiral reagent tris[3-(heptafluoropropylhydroxy-methylene)-d?camphorato]europium(III), 3, Eu(HFC)₃.     

NMR Studies in the Heterocyclic Series. XXIII. - 13C Spectra of Indazole and 3-Azido-Indazole in Acidified Dimethylsulfoxid Solutions

We reported previously the ¹³C NMR spectra of indazole 1 ² and 3-azido-indazole 2 ³.     

NMR Studies of Drugs. Sulindac Methyl Ester. Applications of Achiral and Chiral Lanthanide Shift Reagents

The potent nonsteroidal anti-inflammatory agent, sulindac, (Z) -5-fluoro-2-methyl-1-{[4-(methylsulfinyl) - phenyl]methylene} -1H-indene-3-acetic acid, has been examined by ¹H NMR as its methyl ester in CDCl₃ solution with the added achiral lanthanide shift reagent (LSR) tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III), Eu (FOD)₃, 2, for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene) - (+) - camphorato] europium (III), 3, and tris[3-(trifluoromethyl-hydroxymethylene) - (+) -camphorato] europium (III), 4, to induce enantiomeric shift differences (ΔΔδ) for several nuclei. Studies employed 60 and 300 MHz spectrometers. At the higher frequency, analytically useful ΔΔδ values were observed with added 3 for the aryl protons ortho to the methylsulfinyl group that should permit direct determinations of enantiomeric excess (% ee). By conversion of sulindac samples to the methyl ester, use of 3 would then formally constitute an ee determination of sulindac.     

NMR Studies of Drugs. 5-Methyl-5-phenylhydantoin. Applications of Lanthanide Shift Reagents in Polar Solvents to a Non-Chelating Substrate

The 200.1 MHz ¹H NMR spectra of 5-methyl-5-phenylhydantoin, 1, have been studied in CD₃CN solution at ambient temperatures with the achiral shift reagent, tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III), 3. Although 1 cannot chelate the LSRs, use of sufficiently high LSR:1 molar ratios served to compensate for competitive binding of LSR by the polar solvent, and permitted substantial lanthanide-induced shifts to be observed with 2 or 3. With 3, significant enantiomeric shift differences were produced for the ortho aryl protons and for the CH₃ signals. The ortho proton signal appears to offer excellent potential for direct determination of enantiomeric excess of 1. These results demonstrate the utility of LSRs 2 or 3 even in a polar solvent with a nonchelating substrate.