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 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.     

1 H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Clenbuterol. Method for Direct Optical Purity Determination

The 60 MHz ¹H NMR spectra of clenbuterol, 1, have been studied in CDCl₃ solution with the achiral shift reagent, tris (6,6,7,7,8,8,8-hepta-fluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral reagent tris[3-(heptafluoropropylhydroxyn1ethyl-ene)-(+)-canphorato]europiunr(III), 3. Use of 3 resulted in observable enantiomeric shift differences, ΔΔσ, for the t-butyl, NH₂ benzylic CH and the aryl proton signals. Values of ΔΔσ as high as 135.1 Hz (2.25 ppm) and 86.5 Hz (1.44 ppn) were seen for the methine and aryl protons, respectively, with a solution 0.1035 molal in 1 and a 1:3 molar ratio of 0.551. The aryl resonance is especially well suited for direct optical purity determinations of 1.     

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.     

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.     

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.     

NMR Studies of Hindered Rotation. The Diels-Alder Adduct of 4-Methyl-1, 2, 4-triazoline-3, 5-dione with Phencyclone: Restricted Motion of Unsubstituted Bridgehead Phenyls.

4-Methyl-1, 2, 4-triazoline-3, 5-dione was produced by lead tetraacetate oxidation of 4-methylurazole and allowed to react with phencyclone, 1-The resulting Diels-Alder adduct, 2, has been characterized by one-and two-dimensional ¹H and ¹³C NMR at 300 and 75 MHz, respectively, at ambient temperatures in different solvents. The NMR data are consistent with hindered rotation of the bridgehead unsubstituted phenyl groups about the C(sp²)-C(sp³) bonds, based on numbers of absorption signals in the ¹H and ¹³C NMR aryl region, together with magnetic anisotropic effects in the ¹H spectrum. The spectral simplicity suggests further that stereochemistry at the ring junction nitrogens involves only a single isomer or very rapidly interconverting “exo”/“endo” isomers (if the ring junction nitrogens are pyramidalized).     

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.     

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.     

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.     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. IV. Metaxalone, 5-(3,5-Dimethylphenoxymethyl)-2-oxazolidinone; Evidence for Multidentate Chelation

The 60 MHz ¹H NMR spectra of racemic metaxalone, 1, have been studied in CDC1₃ solution at 28° 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 reagents tris[3-(trifluoromethylhydroxymethylene)-d-cam-phorato]europium(III), 3, and tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 4. Reagent 3 produced modest observable enantiomeric shift differences, ΔΔδ, for the CH₂0, aryl methyl, aryl H₂,6 and the NH siqnals. Although reaquent 4 produced small or no observable ΔΔδ for the CH₂0, aryl methyls or aryl protons. strikingly qreater valuesof lanthanide induced shift, Δδ, as well as ΔΔδ, were found for the NH signal using 4 relative to 3. Analytical feasibility for direct optical purity determinations of 1 with 0 using this NH siqnal sclould allow detection of 74% of the minor enantiomer or less. Results are discussed ir terms of potential bidentate or tridentate chelation of 3 by 1 makinrl a greater contribution than for 4.     

NMR Studies of Hindered Rotation. The Diels-Alder Adduct of Phencyclone with p-Benzoquinone: Restricted Motion of Bridgehead Phenyls

The Diels-Alder adduct of phencyclone with p-benzoquinone has been examined by ¹H NMR at 300 MHz in CDCl₃ at ambient temperatures for evidence of hindered rotation of the unsubstituted bridgehead phenyl groups. The nearly first-order spectrum exhibits four approximate doublets and five approximate triplets in the aromatic region, of roughly equal intensity (ca. 2H). This is consistent with a slow-exchange limit (SEL) spectrum of the hindered phenyls. For rapidly rotating phenyls, the predicted fast-exchange limit (FEL) spectrum would have shown two 2H doublets and one 4H doublet, in addition to three 2H triplets and one 4H triplet, in the aryl region. Full ¹H assignments have been made, based on the two-dimensional ¹H-¹H homonuclear chemical shift correlation spectrum (COSY) and expected magnetic anisotropy effects.     

1H NMR Spectral Simplification with Chiral Solvating Agents and with Achiral and Chiral Lanthanide Shift Reagents. Cis-4,5-Dihydro-4-Methyl-5-Phenyl-2-Oxazolamine, “Cis-4-Methylaminorex,” a Potent Stimulant and Anorectic

Abstract

The 60 MHz ¹H NMR spectra of racemic (+)-cis-4,5-dihydro-4-methyl-5-phenyl-2-oxazolamine, 1, have been studied at 28° in CDC1₃, solution 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 reagent tris[3?(heptafluoropropylhydroxymethy1ene)-d-camphor-ato]europium(III), 3. Additional NMR studies were performed at 400 MHz in CDC1, solution at 24° using the chiral solvating agents (CSA), (E)-(-)-2,2,2-trifluoro-1- (9-anthryl) ethanol, 4, and (R) - (+) -α-methoxy- α-(trifluoromethy1)phenylacetic acid, 5. Substantial enantiomeric shift differences, for the CH₃, signal of 1 using 3 or 5, and for the ortho aryl protons using4, which should make possible direct optical purity determinations of 1. Accurate 400 MHz data f o r chemical shifts and vicinal coupling constants of, of racemic cis-1 are presented, and compared with values for (optically active) (-)-trans-1; some dfferences are seen compared to previously reported data. solution. The LSR and CSA results are compared and Some additional data were obtained in C₆D₆ discussed.     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Lofexidine

The ¹H NMR spectra of the potent anti-hypertensive drug, lofexidine, 1, have been studied in CDCl₃ at 60 and 300 MHz. Both the achiral shift reagentr tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionatol-europium(III), 2 and the chiral reagents1 tris[3-(heptafluoropropylhydroxymethylenel-d-camphoratoleuropium(III), 3 and tris[3-(trifluoromethylhydroxymethylenel-d-camphoratoleuropium(III), 4, were employed. Substantial lanthanide induced shifts were observed with 2, 3 or 4, with the largest shifts seen for the methine at the chiral centerr followed by the signal of the NH. Enantiomeric shift differences for the CH₃ signal of 1 were seen with 3 OK 4, with 4 inducing larger values of potential analytical utility. Using a non-racemic sample of 1, the (-) enantiomer was shown to have a downfield sense of magnetic nonequivalence for the methyl resonance in the presence of added 4.     

Binuclear NMR Shift Reagents. An Apparent Anomalous Effect with Vinclozolin

The 60 MHz ¹H NMR spectra of racemic vinclozolin, 1, have been studied at 28° in CDC1₃ solution with the chiral reagent tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 2, by incremental additions of (6,6,7,7,8,8,8-heptafluoro-2,2-di-methyl-3,5-octanedionato)silver(I), 3. Although the solution of 1 with 2 displayed substantial downfield lanthanide-induced shifts, Δδ, and enantiomeric shift differences, ΔΔδ, for selected nuclei, relative to the spectrum of unshifted 1, additions of 3 to the solution of 1 and 2 were unexpectedly found to dramatically reduce the magnitudes of both Δδ and ΔΔδ.     

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     

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Meparfynol, 3-Methyl-L-Pentyn-3-Ol. Apparent Anomalous Results with a Binuclear Shift Reagent

The 60 MHz ¹H NMR spectra of racemic meparfynol, 1, have been studied in CDCl₃ solution at 28° with the achiral shift reagentt tris(6,6,7,7,8,8,8-hepta-fluoro-2,2-dimethyl-3,5-octanedionato) europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropyl-hydroxymethylene)-d-camphorat01 europium(III), 3. With 3, observable enantiomeric shift differences for the 3-methyl should make possible direct optical purity determinations. Additions of increments of (6,6,7,7,8,8,8-heptafluoro-2,2-dimenthyl-3,5-octane-dionato)silver(I) 4, to a CDCl₃ solution of 1 and 3 resulted in changes in Δδ magnitudes and in some line intensities that are discussed in terms of interactions with the ethynyl and hydroxyl groups.     

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.     

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.