NMR experiments on acetals—XXV: Conformational energy for the chair-twist interconversion of the 1,3-dioxane system

Trans-4-t-Bu-6-R-1,3-dioxanes (R = Me, Prⁱ and cyclohexyl) show temperature-dependent values for ²J(H—2) and ³J(H—4(6), H—5) in their PMR spectra. This is the result of the presence of twist-boat conformations. With the aid of typical limit-values of ²J(H—2) for the chair and twist forms, the amount of flexible conformations were determined as a function of temperature (Table 2), allowing the determination of the enthalpy change for chair-twist interconversion in 1,3-dioxane itself (6·2 ± 0·3 kcal/mole). Typical values for ²J(H—2) were obtained from a study of low temperature spectra and from appropriate model compounds of which 4-(1′-adamantyl)-6-t-Bu-1,3-dioxane served as the model for a genuine twist form with a twofold axis through C-2/C-5.     

Relative thermodynamic stabilities of 2-substituted 4-methylene-1,3-dioxolanes and 4-methyl-1,3-dioxoles

The relative thermodynamic stabilities of 24 pairs of carbon-carbon double-bondexo-endo isomeric 2-substituted 4-methylene-1,3-dioxolanes (a) and 4-methyl-1,3-dioxoles (b) have been determined by base-catalyzed chemical equilibration in DMSO solution. In all cases, theendo isomer (b) is the favored species at thermodynamic equilibrium. A single alkyl substitutent on C-2 gives only a negligible contribution to the relative stability of the isomeric forms, but the presence of two alkyl groups on C-2 increases the relative stability of theendo isomer by 2–3 kL mol^–1. A still higher effect in favor of theendo isomer is produced by introduction of a single alkoxy group on C-2; this effect is further slightly accentuated by 2,2-dialkoxy substitution at C-2. The origin of the favorable effect of 2-alkoxy substitution on the relative stability of theendo isomer is not clear, but it seems to arise from an unexpected stability of theendo isomer rather than from an enhanced destabilization of theexo form.     

Conformational analysis. XIII—A 300 MHz 1H NMR study of 2-methyl-, 2-phenyl-, 2-(2-chlorophenyl)-and 2-(4-chlorophenyl)-oxetanes

The 300 MHz spectra of 2-methyl-, 2-phenyl-, 2-(2-chlorophenyl)- and 2-(4-chlorophenyl)-oxetanes were recorded in CCl₄ and C₆D₆. The chemical shifts and the proton-proton coupling constants were solved through iterative calculations. The results were discussed in the light of structural factors and theoretical calculations. The average angle of pucker for the oxetane ring was estimated at c. 5°, in fair agreement with the value of 3·3° derived from a microwave study.     

Carbon-13 NMR spectra of saturated heterocycles: VIII—tetrahydrofurans and 1,3-dioxolanes

The ¹³C NMR spectra of 17 methyl- and ethyl-substituted tetrahydrofurans and 58 alkyl- and aryl- substituted 1,3-dioxolanes are reported. For the cases in which substituents recur, additive substituent parameters are calculated and compared with similar parameters in cyclopentanes and in 6-membered rings. Considering the conformational flexibility of 5-membered ring systems, additivity of the parameters is surprisingly good.     

Conformational analysis: IX–a 300 MHz study of 4-vinylbutyrolactone

The 300 MHz ¹H NMR spectrum of 4-vinylbutyrolactone has been recorded and analysed. The results showed that the compound is a mixture of two rapidly interconverting envelope forms in which (C-3) is the flap atom. The vinyl group favours the pseudo-equatorial orientation by 1·9 ± 0.3 kJ mol^?1, as shown by the dependence of the vicinal coupling constants on temperature.     

NMR experiments on acetals—56 : Conformational study of 1,3-dioxene

From the ¹H-NMR parameters, extracted from the spectra of 1,3-dioxene, 5-Me-1,3-diox-4-ene, 4,5-diMe-1,3-diox-4-ene and of 2,4,5-triMe-1,3-diox-4-ene, it follows that the preferred conformations are the 1,2-diplanar (sofa) C₂ form (Fig. 1B). The barrier to ring reversal in 5-Me-1,3-dioxene was found to be 7·2±0·2 kcal/mole at ?123° (in freon-21).     

NMR experiments on acetals—57 : Conformational study of 5-alkylidene-1,3-dioxanes

From an extensive ¹H-NMR comparative study (homo-INDOR-, and nmdr-assisted) of a series of 2-, 4- and 2,4-substituted 5-alkylidene-1,3-dioxanes it is concluded that the basic conformation is a flattened chair (Fig. 5c,f). This is substantiated by the low barrier to ring reversal in 5-methylidene- and 5-propylidene-1,3-dioxane of ?G^≠ ～ 5·5 kcal/mole (T_c resp. ?158° and ?161°).     

1 H and 13 C NMR spectra and structure of 2-trichloromethyl-4-methylene-1,3-dioxolanes

The ¹H and ¹³C NMR spectra of a number of 5-substituted 2-trichloromethyl-4-methylene-1,3-dioxolanes were studied. It was observed that the exocyclic double bond is in effective conjugation with the 3–0 ring atom. The configuration of the substituents was established, and a conformational model of these heterocycles of the envelope type with the 1–0 atom deviating from the plane in which the remaining ring atoms are situated is proposed. The applicability of the ¹³C NMR spectra for the determination of the configuration of the compounds is demonstrated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1176–1180, September, 1976.     

Solid-state NMR and computational studies of 4-methyl-2-nitroacetanilide

Studies on the solid-state structure of two polymorphs of 4-methyl-2-nitroacetanilide (MNA) were conducted using magic-angle spinning (13)C, (15)N and (1)H NMR spectroscopy, together with first-principles computations of NMR shielding (including use of a program that takes explicit account of the translational symmetry inherent in crystalline structures). The effects on (13)C chemical shifts of side-chain rotations have been explored. Information derived from these studies was then incorporated within a systematic space-search methodology for elucidation of trial crystallographic structures from powder XRD.     

Preparation of substituted 4-(3-methyl-3-hydroxy-1-butynyl)-2-ethoxy-1,3-dioxolanes

A method has been developed for the preparation of 4-(3-hydroxy-1-alkynyl)-substituted 2-ethoxy-1,3-dioxolanes (which are novel flotation reagents for coal) based on the reaction between acetylene 1,2,5-triols and orthoformic ester in the presence of catalytic quantities of benzoic acid.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 770–771, June, 1987.     

Conformational analysis XX—13C NMR studies of saturated heterocycles 5—substituent effects on the 13C chemical shifts of methyl substituted 1,3-dithiolanes

The ¹³C NMR chemical shifts for 1,3-dithiolane and 13 methyl substituted derivatives are reported. Substituent effects are derived and compared with those for cyclopentanes and 1,3-dioxolanes. The magnitude and variety of the substituent effects are best explained with the aid of a half-chair conformation where the S-1? C-2? S-3 plane passes between C-4 and C-5.     

NMR experiments on acetals—XXXVII: NMR spectral study of cis-, and trans-6-methyl-4-r-1,3-oxaselenans

The NMR spectral parameters are reported for cis-, and trans-6-Me-4-alkyl-1,3-oxaselenans with the aid of the INDOR- technique. Low temperature studies show the conformational equilibrium in the trans series to be pronouncedly one-sided and a value for the inversion barrier has been obtained.     

Preparation and Reactions of Optically Active 4-Hydroxy-1,3-dioxolanes: 2-Hydroxy Aldehyde Equivalents

The preparation and reactions of optically and chemically stable (S)-4-hydroxy-1,3-dioxolane 3 as a 2-hydroxy aldehyde equivalent were explored. Hydroxydioxolane 3 was prepared by reduction of ketodioxolane 2 which was obtained from (S)-2-hydroxycarboxylic acid 1. The reactions of 3 with triethyl phosphonoacetate and organometallic reagents were carried out. These and other conversions gave synthetically and biologically useful products in moderate to good chemical and moderate stereochemical yields.     

Conformational analysis—VIII : 1H NMR conformational study of 5-methyl-, 2,5-dimethyl- and 2,2,5-trimethyl-4-oxo-1,3-dioxans

Substituent effects on ¹H chemical shifts of a large number of methyl-substituted 4-oxo-1,3-dioxans have been estimated and shown to be additive for compounds with a uniform half-chair conformation. The additivity rule fails, however, if the substitution pattern forces the ring into a non half-chair conformation. The ring conformations of 5-methyl-, cis- and trans-2,5-dimethyl- and 2,2,5- trimethyl-4-oxo-1,3-dioxans have been clarified by NMR and through acid-catalyzed equilibration of the epimeric 2,5-dimethyl derivatives.     

Cyclodimerisation reactions of conjugated dienes with aldehydes—I: Formation of tetrahydropyrans and their 300 MHz 1H NMR spectra

The palladium catalysed reaction of butadiene with aldehydes yields 2-substituted 3,6-divinyl-tetrahydropyrans.^1–4 The reaction has been extended to isoprene and myrcene. With formaldehyde only 2,5-substituted pyrans have been isolated. The isomeric tetrahydropyrans obtained were fully characterised by ¹H NMR, and representative 300 MHz spectra are given. Attempts to react aldehydes with 2-methoxybutadiene were unsuccessful.     

Conformational analysis: XXI—1H NMR study of 4,5-dimethyl-, 2,4,5-trimethyl- and 2,2,4,5-tetramethyl-1,3-dithiolanes

The 60 MHz ¹H NMR spectra of seven differently substituted 4,5-dimethyl-1,3-dithiolanes have been recorded and analysed. Configurational assignments are made and conformational aspects are discussed in the light of the spectral parameters.     

Nitrogen-15 NMR studies of 1,4-benzodiazepines: 2—The triazolobenzodiazepines

Nitrogen-15 NMR data for a series of 21 triazolobenzodiazepines are presented, including ¹⁵N chemical shifts and substituent effects. The line assignments made by correlation to other model compounds were confirmed by a shift reagent and protonation study. A Yb(dpm)₃ study on alprazolam showed that the molar shifts of the four nitrogens ranged from 35 to 150 ppm.     

NMR experiments on acetals. 300 MHz spectrum and conformational aspects of the 1-aza-4,6-dioxabicyclo[3.3.0]octane system

Complete analyses of the 300 MHz ¹H NMR spectra of 1-aza-4,6-dioxabicyclo[3.3.0]octane ( 1a ), the 5-Me- ( 1b ), and both the cis- and trans-3,5-diMe- derivatives ( 1c and 1t ), as well as most of the corresponding methiodides are reported. Spectral data suggest probable conformations to be 11 ( 1a , 1b and 1c ) and 13 ( 1t ), respectively. The corresponding methiodides adopt slightly different forms, having flattened N? C-2? C-3 moieties ( 12 for 2a , 2b and 2c ).     

Aspirin prodrugs: synthesis and hydrolysis of 2-benzyloxy-2-methyl-4H-1,3-benzodioxin-4-ones

Aspirin is widely used for its analgesic, antiinflammatory and antipyretic properties. Among its disadvantages are the relatively narrow therapeutic margin, its irritancy towards the gastric mucosa, and occasionally patient hypersensitivity towards aspirin. As part of our effort to develop prodrugs without these liabilities eleven new title compounds have been isolated and characterized. These 'superaspirin' candidates were subjected to non-enzymatic hydrolysis for a first rapid screening in vitro. Only 2-(2,6-dimethoxybenzyloxy)-2-methyl-4H-1,3-benzodioxin-4-one (4c) was observed to act as an exclusive aspirin prodrug, while 2-(2-methoxybenzyloxy)-2-methyl-4H-1,3-benzodioxin-4-one (4b) and 2-(2-ethoxybenzyloxy)-2-methyl-4H-1,3- benzodioxin-4-one (4d) were shown to release both aspirin 6 and salicylic acid 7. Subsequently, these three candidates were further characterized by investigation of the pH profile of their hydrolysis rates.