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. Applications of Achiral and Chiral Wthanide Shift Reagents to Bupropion

Abstract

The ¹H NMR spectra of racemic samples of the antidepressant drug, bupropion, 1, have been studied in CDCl₃ solution at 60 and 200 MHz 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-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 3. Both LSR produced substantial lanthanide induced shifts consistent with ¹H assignments, but the bound complexes of 1 with 2 versus 3 may not be isostructural. With 3, substantial enantiomeric shift differences were observed for the t-butyl, CH ₃CH, NCH, and the aryl H-2 and H-6 signals, which should permit potential direct determination of enantiomeric excess.     

1H and 13C NMR Spectra of Alditolyl Derivatives of 3-Hydrazino-5-Methyl[1,2,4]triazino[5,6-b]indole and Their Cyclized Products.

The ¹H and ¹³C NMR spectra of sugar (5-methyl [1, 2, 4]-triazino [5, 6-b] indol-3-yl) hydrazones (1), per-0-acetyl aldehydo sugar 1-acetyl-1-(5-methyl [1, 2, 4] triazino [5, 6-b]-indol-3-yl) hydrazones (2), l- (penta-0-acetyl-pentitol-1-yl)-10-methyl [l, 2, 4] triazolo [3′, 4′:3, 4] [l, 2, 4] triazino [5, 6-b]-indoles (3) have been investigated. The 2 D NMR (H, C COSY) spectrum of 2a has been studied.     

1H and 13C Nmr Determination of Polysubstituted Diphenylmethane Dimers Mechanism of Their Formation by Reduction of Polymethoxylated Benzophenones

Reduction of substituted benzophenones 1 with sodium borohydride and trifluoro-acetic acid yields diphenylmethanes 3 as well as dimers 5 and 6. the complete structure of these substituted diphenylmethane dimers 5 may be accurately determined by ¹H, ¹³C, 2D NMR analysis, and a mechanism for their formation is suggested.     

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

The 60 MHz ¹H NMR spectra of mexiletine, 1-(2,6-dimethylphenoxy)-2-propanamine, 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 reagents tris[3-(trifluoromethylhydroxymethylene)-d-camphorato]europium(III), 3, Eu(FACAM)₃, and tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 4, Eu(HFC)₃. Substantial lanthanide-induced shifts were seen for the proton signals of 1 with each reagent. Appreciable enantiomeric shift differences were seen for both methyl signals and for each of the CH₂CH proton signals using 3 and 4 that should permit direct determinations of enantiomeric excess for samples of 1. A predominant conformation for 1 is suggested based on observed splittings of the CH₂ proton signals and their relative lanthanide-induced shifts.     

Structure Elucidation and Assignment of 1H and 13C Spectra of the New Fused Cyclobutane-Naphthofuran Derivative by Two-Dimensional NMR in Different Solvents

One of the major product from the photodimerization of 2-[2-(2-methyl-phenyl)ethenyl)]naphtho[2. 1-b]furan (1) is a new fused cyclobutane-naphthofuran derivative, 6-(2-methylphenyl)-1-[2-(2-methylphenyl)ethenyl]-7-(2-naphtho-[2,1-b]furyl)-3-[2,1]naphtho-2-oxabicyclo[3.2.0]hept-3-ene (2). Its ¹H and ¹³C NMR spectra were fully assigned by the application of COSY, LR COSY, NOESY, APT and HETCOR experiments in deuterated chloroform, acetone and benzene solutions.     

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 Crowded Diels–Alder Adducts of Phencyclone with N‐(2,6‐Dialkylphenyl)maleimides. Hindered Rotations and Magnetic Anisotropy

Abstract

Phencyclone, 1, reacted with N‐(2,6‐dimethylphenyl)maleimide, 2a; with N‐(2,6‐diethylphenyl)maleimide, 2b; and with N‐(2,6‐diisopropylphenyl)maleimide, 2c, respectively, to yield the corresponding Diels–Alder adducts, 3a–c. The adducts were extensively characterized by NMR (7 T) at ambient temperatures using one‐ and two‐dimensional (1D and 2D) proton and carbon‐13 techniques for assignments. Slow exchange limit (SEL) spectra were observed, demonstrating slow rotations on the NMR timescales, for the unsubstituted bridgehead phenyl groups [C(sp³)–C(aryl sp²) bond rotations] and for the 2,6‐dialkylphenyl groups [N(sp²)–C(aryl sp²) bond rotations]. Substantial magnetic anisotropic shifts were seen in the adducts. For example, in the N‐(2,6‐dialkylphenyl) moieties of the adducts, one of the alkyl groups is directed “into” the adduct cavity, toward the phenanthrenoid portion, and these “inner” alkyl proton NMR signals were shifted upfield. Thus, in CDCl₃, the “inner” methyl of adduct 3a exhibits a proton resonance at ?0.13 ppm, upfield of tetramethylsilane (TMS); the “inner” ethyl group signals from 3b appear at 0.026 ppm (CH₂, quartet), and ?0.21 ppm (CH₃, triplet); and the “inner” isopropyl group from 3c is seen at ?0.06 ppm (methine, approx. septet) and ?0.39 ppm (CH₃, doublet). Proton NMR of the crude N‐(2,6‐dialkylphenyl)maleamic acids (used as precursors of the maleimides, 2a–c) exhibited two sets of AB quartet signals, suggesting possible conformers from hindered rotation in the amide groups about the HN–C?O bonds.     

1H and 13C NMR Determination of the Enantiomeric Purity of Substituted 4-Amino-3- (thien-2-Yl)-Butyric Acids and 4-Amino-3-(Benzo[b]Furan-2-yl)-Butyric Acids,Ligands of the GabaB Receptor.

The enantiomeric composition and absolute configuration of 4-Amino-3-(benzo[b]furan-2-yl)-Butanoic Acids and of 4-Amino-3-(thien-2-yl)-Butanoic Acids 1 may be accurately determined by ¹H and ¹³C nuclear magnetic resonance analysis of the corresponding derivatives 3 prepared by reaction with chiral reagents. Correlation with HPLC is signaled.     

Interaction between 1-[p-(dimethylamino) benzoyl]-4′-phenyl-semicarbazide and Cu

A new compound, 1-[p-(dimethylamino)benzoyl]-4′-phenyl-semicarbazide (1) was synthesized and showed highly selective response to Cu²⁺ over other metal ions such as Pb²⁺, Mg²⁺, Fe²⁺, Co²⁺, Zn²⁺, Cd²⁺, Hg²⁺, Ni²⁺, Ca²⁺, Ag⁺, Na⁺, K⁺, and Li⁺. The control compound, 1-[p-(dimethylamino)benzoyl]-4-phenyl-thiosemicarbazide (2), showed different fluorescence spectral response to Cu²⁺. A 1:1 complex between Cu²⁺ and 1 was formed while 1:1 and 1:2 complexes between Cu²⁺ and 2 were formed. The binding model between the receptor (1 or 2) and Cu²⁺ was supported by IR spectra, mass spectra, and computation model. 1 possessed higher selectivity towards Cu²⁺ compared with 2 owing to the difference of complexation ability between urea and thiourea groups.     

一个含苯并咪唑环的酰氨基硫脲NMR研究

该文合成了一个新的在医药方面具有潜在应用价值的含苯并咪唑环的酰氨基硫脲化合物,即4-(4-甲氧基苯基)-1-[2-(4-硝基苯氧基甲基)-苯并咪唑-1-基\]甲酰基氨基硫脲,并利用元素分析、IR和NMR对其结构进行了表征. 通过NOESY谱确定了其两种异构体(A和B)的构型,并利用2D NMR技术对它们的¹H NMR 和¹³C NMR谱进行了全归属,给出了相应的偶合常数和两种异构体的含量.     

13C NMR Chemical Shifts of Heterocycles: 3∗. Empirical Substituent Effects in 2-Halomethyl-2-hydroxy-tetrahydrofurans and -5,6-tetrahydro-4H-pyrans

Abstract

Evaluation by empirically derived equations for the Substituent effect (α, β, γ, δ) on the ¹³C NMR chemical shifts for C-2, C-3, C-4, C-5, C-6, the halomethyl-substituted carbon (C-7) and the cyano or oxymic carbon (C-8) in 2-halomethyl-2-hydroxy-tetrahydrofurans 1a-c, 2, 3a, b, 4a and -5,6-tetrahydro-4H-pyrans 5a-c, 6a [with C-2-substituents (R²): CF₃, CCl₃ or CHCl₂, C-3-substituents (R³): CN, C(Me)=NOH, CH=NOMe, C(Me)=NOMe or CH=NOH], taking as reference the 2-trifluoromethyl-2-hydroxy-tetrahydrofuran (la), is reported. From the additivity properties of the α-, β-, γ-, δ-and ?-effects for each Substituent it is possible to predict the chemical shift of each carbon of the compounds 1–6.

     

NMR Studies of Hindered Rotation and Magnetic Anisotropy: The Diels–Alder Adducts of Phencyclone with N‐Phenylmaleimide and N‐(2‐Trifluoromethylphenyl)maleimide. Ab Initio Calculations for Optimized Structures

Abstract

N‐Phenylmaleimide, 2, and N‐(2‐trifluoromethylphenyl)maleimide, 3, were separately added to phencyclone, 1, to yield the corresponding phencyclone Diels–Alder adducts, 4 and 5. The resulting adducts (and some precursors) have been characterized by one‐ and two‐dimensional ¹H and ¹³C NMR at 300 and 75 MHz, and by ¹⁹F NMR at 282 MHz, at ambient temperatures. The NMR data are consistent, for both adducts, with: (a) hindered rotation of the bridgehead unsubstituted phenyl groups about the C(sp²)–C(sp³) bonds, based on slow exchange limit (SEL) spectra and (b) endo adduct configuration based on magnetic anisotropic effects in the ¹H NMR. The NMR spectra of the phencyclone adduct, 4, of N‐phenylmaleimide, indicate free rotation on the NMR timescales (fast exchange limit, FEL spectra) about the N‐phenyl bond. The spectra for the adduct, 5, of N‐(2‐trifluoromethylphenyl)maleimide are interpreted as consistent with SEL regimes, for the N‐aryl rotations, with a single rotamer present in which the trifluoromethyl group is directed “out of” the adduct cavity, and away from the phenanthrenoid moiety. This conclusion is based, in part, on NMR data suggesting the apparent slow N‐aryl bond rotation in a pair of atropisomers corresponding to the acetic acid addition products from the N‐(2‐trifluoromethylphenyl)maleimide. Evidence of magnetic anisotropic effects due to the phenanthrenoid moiety and proximal carbonyls is discussed. ¹H, ¹³C, and ¹⁹F assignments are presented and interpreted. Molecular modeling calculations at the Hartree–Fock level, 6‐31G* basis set, were performed to provide geometry optimizations for energy‐minimized structures of selected compounds.     

Structural Assignment of Stilbenethiols and Chalconethiols and Differentiation of Their Isomeric Derivatives by Means of 1H‐ and 13C‐NMR Spectroscopy

Abstract

The ¹H‐ and ¹³C‐NMR spectra of some substituted stilbenes and chalcones were assigned unambiguously on the basis of a combination of homo‐ (COSY) and heteronuclear (HETCOR) two‐dimensional methods, the chemical shifts, as well as spin‐coupling constants. The A_ik empirical parameters of the –O–C(S)–N(CH₃)₂, –S–C(O)–N(CH₃)₂, and –SH group were calculated to help predict the chemical shifts of substituted stilbenes, 4′‐nitrostilbenes, and chalcones. The ¹H‐ and ¹³C‐NMR spectra have been shown to be able to differentiate between the isomers of O‐stilbenyl (4, 5) and S‐stilbenyl N,N‐dimethylthiocarbamates (7, 8) as well as O‐chalconyl (6) and S‐chalconyl N,N‐dimethylthiocarbamates (9).     

Structural Elucidation of Novel Derivatives of Pyranobisquinolines 1H-NMR, 13C-NMR and Mass Spectroscopic Study of (7H)-6,8-Dichloro-7-methyl-pyrano(3,2-c:5,6-c′)bisquinoline and (7H)-6,8-dichloro-7-methyl-pyrano (3,2-c:5,6-b′)bisquinoline

Elucidation of the structure of hitherto unknown novel pyranobisquinoline derivatives, (7H)-6,8-Dichloro-7-methyl -pyrano(3,2-c;5,6-c′)bisquinoline 5 and (7H)-6,8-Dichloro-7-methyl-pyrano(3,2-c:5,6-b′)bisquinoline 4 obtained as unexpected products¹ in the Michael type reaction of vinylacetate on 4-hydroxyquinoline-2(lH)-one 1 by NMR methods is reported.     

Structural Assignment of Isomeric S‐ and S,N‐1‐Alkoxycarbonylalkylated 6‐Amino‐2‐thiouracil Derivatives by Means of 1H and 13C NMR Spectroscopy

Abstract

The structures of new isomeric 2‐alkoxycarbonylalkylthio‐ and 2‐alkoxy‐ carbonylalkylthio‐1‐alkoxycarbonylalkyl‐6‐aminouracils (1–21) have been established on the basis of the ¹H NMR and ¹³C NMR spectroscopic data. The ¹H NMR and ¹³C NMR spectra of 1–21 have been fully assigned by a combination of two‐dimensional experiments [heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond correlation (HMBC)]. The ¹³C NMR spectra have been shown to be able to differentiate between isomers.     

1H NMR Study of Hydrogen Bonding and Hydrogen to Deuterium Isotope Exchange in Ureido Sugars

Abstract

The acidic properties of ureido NH protons in two new derivatives of methyl 3,4,6-triacetyl-2-deoxy-β-D-glucopyranoside and i-butylamine (1) and L-leucine (2) were studied by ¹H NMR. Stronger influence of polar aprotic solvents, more effective interaction with nitroxyl radical and faster H/D exchange indicate that N1'-H proton which is proximate to the glucopyranose ring is more acidic than N3'-H one in both ureido sugars, this conclusion was supported by semi-empirical AM1 calculation. Hydrogen to deuterium exchange rates are 1.2 x 10^?2 to 5.5x 10^?3 M^?1 min^?l. Significantly slower exchange of N3'-H proton standing by Leu residue in 2 can be explained by the existence of internal H-bonds.     

Complete Analysis of the 1H and 13C NMR Spectra of 5-Isopropylsulfonyl-2-Norbornenes Through the Application of Two-Dimensional NMR Techniques

Total assignment of ¹³C and ¹H NMR spectra of the 5-isopropylsulfonyl-2-norbornenes 2 was achieved using the concerted application of two-dimensional homonuclear and heteronuclear chemical shift correlations. The stereochemistry of both the diastereoisomers endo 2a and exo 2b have been established using the magnitude of the proton coupling constants.     

1H and 13C NMR Spectral Study of Some 2r-Aryl-6c-phenylthian-4-ones,Their 1-Oxides and 1,1-Dioxides

ABSTRACT

Four 2r-aryl-6c-phenylthian-4-ones 1b?1e and their 1-oxides 2b?2e and 1,1-dioxides 3b?3e have been newly synthesized. ¹H and ¹³C NMR spectra have been recorded for all these compounds and 2r,6c-diphenylthian-4-one 1-oxide 2a. ¹³C NMR spectrum has been recorded for the sulfone 3a of 1a. For selected compounds ¹H-¹H COSY, HSQC, HMBC, and NOESY spectra have been recorded. The vicinal proton–proton coupling constants suggest that in all these compounds, the heterocyclic ring adopts chair conformation with equatorial orientations of the aryl and phenyl groups. Proton and carbon chemical shifts suggest that in the sulfoxides, the S=O bond is axial and enhances the J _aa value by some special effect. The S = O bond causes a significant upfield shift even on carbons without hydrogens. Significant solvent shifts also were observed.     

1H NMR Studies on the Methylation,Protonation, and Hydration Sites in Some Benzo[b]Naphthyridines (Azaacridines)

Abstract

The 300.13 MHz ¹H NMR spectra of the methylated and protonated 6(9)-methylbenzo[b][1,x] naphthyridines (x=5, 6, 7, 8) (5-methylazaacridines) were collected at 298 K in deuterated dimethyl sulfoxide and chloroform, respectively. The methylation and protonation sites were assigned by comparisons of these data with those of the free bases. The results were compared with similar data for related heterocycles and showed that both methylation and protonation occur at the nitrogen in the outer pyrido ring in all four series.

The hydration site in some 2-and 3-azaacridines was determined by specific line broadening in their ¹H NMR spectra to be the same nitrogen as that involved in methylation and protonation. Variable temperature ¹H NMR demonstrated that the specific line broadening results from some changes of ¹⁴N quadrupolar relaxation produced by the slow chemical exchange between unhydrated and hydrated species. Deuterium exchange experiments indicated that the direct spin-spin interaction of a water proton and the protons alpha to the hydrated nitrogen may also have some contribution.