SYNTHESIS AND CONFORMATIONAL STUDIES OF A NUMBER OF SATURATED BICYCLIC SIX-MEMBERED RING PHOSPHITES

Abstract

An ¹H NMR study of the conformation of the dioxaphosphorinane ring of a number of diastereoisomeric bicyclic saturated six-membered ring phosphites (3ab-10ab) has been performed. The dioxaphosphorinane ring of these phosphites is transannelated with a tetrahydrofuran, cyclopen-tane, tetrahydropyran or cyclohexane ring. The substituent on the phosphorus atom is a methoxy or phenoxy group. It is shown that the cis isomers 3a-10a prefer a chair conformation of the dioxaphosphorinane ring, independent of the substituent on the phosphorus atom and of the nature of the transannelated ring. In contrast, for the trans isomers 3b-10b a twist rather than a chair conformation of the dioxaphosphorinane ring is preferred. The fraction of the twist conformer in the trans isomers is mainly determined by the substituent on phosphorus. The size and composition of the transannelated ring are relatively unimportant in this respect. For both cis and trans isomers the preferred geometry is solvent-independent. The measured ^3JPOCH couplings of the cis isomers 3a-10a are used to formulate an expression for the dependence of such couplings upon dihedral angles in bicyclic phosphites.     

STUDIES ON ORGANOPHOSPHORUS COMPOUNDS XXX. MASS SPECTROSCOPIC INVESTIGATION OF 2-ALKYL-2-OXO-1,3,2-DIOXA-PHOSPHORINANE AND-PHOSPHEPANE

Abstract

The mass spectra of 2-alkyl-2-oxo-1,3,2-dioxa-phosphorinane and-phosphepane showed that the ring opening was in competition with the cleavage of the P[sbnd]C bond. According to the fragmentation pathway, which was dependent on the structure of exocyclic substituents on phosphorus, the 2-alkyl-2-oxo-1,3,2-di-oxa-phosphorinanes can be classified in two categories. The main process in category A was the ring opening and/or C[sbnd]C bond cleavage. While in category B the cleavage of P[sbnd]C bond was predominant. However, for 2-alkyl-2-oxo-1,3,2-dioxa-phosphepane. no matter how the structure of 2-alkyl group was, the ring opening was a dominant process.     

Novel Synthesis and Structure of Phosphanyl Sugar Derivatives 1

Abstract

Some phosphanyl sugar derivatives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen, were synthesized from 2- and 3-phospholenes as starting materials. Catalytic cis-dihydroxylation of 2-phospholene or 3-phospholene 1-oxide derivatives with osmium(VIII) oxide in the presence of a cooxidant afforded 3-deoxy- or 1-deoxy-tetrofuranose-type phosphanyl sugar derivatives, respectively. cis- Dihydroxylation of 4-acyloxy-2-phospholene 1-oxide derivatives gave tetrofuranose type phosphanyl sugar derivatives. Some of these derivatives of phosphanyl sugars were subjected to structural analyses using ¹H NMR and X-ray crystallography.

     

SYNTHESIS,REACTIVITY AND CONFORMATION OF 10,11-DIHYDRODIBENZO-[b,f]PHOSPHEPIN AND DIBENZO[b,f]PHOSPHEPIN DERIVATIVES. PHOSPHORUS ANALOGUES OF IMINOBIBENZYL ANTIDEPRESSANTS

Abstract

Derivatives of the novel dibenzo[b,f]phosphepin system are prepared from 10,11-dihydro-5-phenyl-5H-bibenzo[b,f]phosphepin 5-oxide (2). New members in the 10,11-dihydro-5H-dibenzo[b,f]phosphepin series, including phosphorus analogues (7, 10) of the andidepressant drug imipramine (30), are also reported. Products of nucleophilic substitution at tetrahedral phosphorus in 2 appear to be determined by the relative apicophilicity of the nucleophile. Conformational analysis based on ¹H NMR data suggests folded (“butterfly”) conformation for the tricyclic compounds. The twisted boat conformation of the central ring in the 10,11-dihydro compounds bears a pseudo-equatorial P[dbnd]O oxygen or a P[dbnd]S sulfur, in solution. Symmetric AA‘BB’ spin systems are found in 4,5 and 7, and their solution conformations appear to be similar to those of analogous 10,11-dihydrodibenzo[b,f]azepine derivatives. The interaction of some compounds with NMR shift reagents and their mass spectral fragmentations are discussed.     

Monosaccharides with Phosphorus in the Sugar Ring

Abstract

In recent years attention has been directed toward the synthesis of modified sugars wherein the oxygen atom in the sugar ring is replaced by sulfur, selenium or phosphorus. Synthesis of sugar analogs with phosphorus as the ring heteroatom is interesting from the point of view of their possible biological activity.     

New Aspects in the Chemistry of Some Cyclic Esters of Alkylphosphonates

Abstract

Several new methods for the synthesis of 2-alkyl-2-oxo-1,3,2-dioxa-phosphorinane (1) and -phosphepane (2) were conducted based on Arbuzov rearrangement, alcoholysis of RP(o)Cl₂ with glycol using dilution method or alkylation of cyclic phosphite under PTC condition. The solvent effect on the ³¹P NMR chemical shift and the characteristic behaviours of the ¹³C NMR spectra of 1 was investigated. It was found that compd 1 with R=CH₃ existed in an equilibrium of e and a forms. The mass spectra of 1 and 2 showed that the ring opening was in competition with the cleavage of P-C bond. According to the fragmentation pathway, 1 can be classified in two categories involving ring opening and cleavage of C-C or P-C bond. For compd 2 the ring opening was a dominant process. Alkaline hydrolysis of 1 and 2 was studied in aqueous dioxane. The hydrolytic process is classified as an AE reaction. Quantitative structure-reactivity relationship was established by multiple regressionanalysis involving the rate constant and the structural parameters of the exocyclic substituents on phosphorus. The difference between the hydrolytic performance of cyclic alkylphosphonates and carboxylates was discussed in terms of various structural changes between ground state and transition state during the hydrolysis.     

Préparation de phosphonates de sucres ramifiés par addition nucléophile conjuguée. Communication préliminaire

Preparation of unsaturated sugars phosphonates using nucleophilic conjugate addition Different types of phosphorus nucleophiles underwent conjugate addition reaction with one of the branched-chain sugars 4, 5 or 11 the addition taking place either on the endo or the exo face of the furanose ring (or on both faces in the case of 11 ). The configuration at C(3) of these new phosphorus-bearing types of sugars as well as the configuration at the phosphorus atom of the cyclic phosphinates 9 and 10 was established by NMR. (³J_P,H–C(2), ³J_P,C(1)). Small amounts (7%) of the spiro enol phosphonate 16 were formed when 11 reacted with trimethyl phosphite.     

The Effect of Trifluoroethoxy Groups on the Structures of Eight-Membered Ring-Containing Cyclic Phosphites 1

New phosphites 1–4 were synthesized from phosphorus trichloride and an appropriate diphenol followed by the addition of trifluoroethanol in the presence of triethylamine. These phosphites are to serve as precursors in the syntheses of biorelated hypervalent phosphoranes. ¹H, ¹⁹F, and ³¹P NMR spectra were recorded. X-ray analysis of 3 and 4 revealed that the sulfur-containing eight-membered ring was in a syn conformation that a allowed a sulfur donor interaction to the phosphorus atom, whereas for phosphite 2, the eight membered sulfonyl containing ring was in an anti conformation that did not allow a donor interaction to phosphorus from the oxygen atom of the sulfonyl group. Structural comparisons are made with related cyclic phosphites and phosphates having donor atoms in eight-membered rings.     

MASS SPECTROMETRIC STUDIES ON SPIROCYCLIC DERIVATIVES OF CYCLODIPHOSPH(V)AZANES

Abstract

The formation and subsequent fragmentation of spirocyclodiphosph(V)azanes (II-III) has been studied by mass spectrometry using the link-field scan technique and structural inferencies are drawn from these data. ³¹P nmr measurements for compound (III) are also described.     

FORMATION AND GC-MS CHARACTERIZATION OF UNUSUAL CYCLIC SULFIDES

Abstract

connection with another project involving the cleavage of the thiirane ring of cyclohexene episulfide in the presence of trifluoromethylthiocopper, the presence of several unusual cyclic sulfides (5–10, Fig. 1) was observed both in the reaction product and the starting material itself. The formation of these compounds has been rationalized on the presence and participation of the thiyl radical species. Details pertaining to their formation and characterization based on their mass spectral fragmentation behavior are presented in this communication.     

INFLUENCE OF ELECTRON-WITHDRAWING SUBSTITUENTS IN THE OXAPHOSPHOLE RING ON THE AXIAL CONFORMATIONAL TRANSMISSION IN Pv COMPOUNDS

Abstract

A MNDO and 300-MHz ¹H NMR study of some trigonal-bipyramidal (TBP) five-coördinated phosphorus (P^v) compounds is reported. It is shown by the MNDO calculations that, in the oxaphosphole P^v TBP compounds 5a-c, the electron distribution in the axial bonds of the TBP is affected by the electronegativity of the substituent at C₄ of the oxaphosphole ring. With increasing electronegativity of the substituent at C₄, the electron density on the axial exocyclic oxygen atom O₁ decreases whereas the electron density on the axial endocyclic atom O₁ increases. This is supported by a ¹H NMR conformational analysis of the C₁[sbnd]C₂ bond of the oxaphosphole P^v TBP compounds 6–11. The gauche(-) rotamer fraction (O¹ and O¹ trans situated) of these compounds, which is correlated to the electron density on O₁, is reduced to 30% as compared to the absolute axial g^?rotamer fraction (59%) of the dioxaphosphole P^v TBP compound 13, most likely because of the presence of the carbonyl group at C₄ of the oxaphosphole ring. So, both the ¹H NMR and MNDO study show that electron withdrawing substituents on the oxaphosphole ring of P^v TBP compounds reverse the electron transfer in the axial P[sbnd]O bonds of the TBP (as compared to dioxaphosphole compounds), from exocyclic O₁ towards endocyclic O₁.     

CYCLIC ORGANOPHOSPHORUS COMPOUNDS. PART XVI1. MASS SPECTROMETRIC FRAGMENTATION OF SOME 5,5-DIMETHYL-1,3,2-DIOXAPHOSPHORINAN 2-OXIDES AND 2-SULPHIDES

Abstract

The mass spectra of seventeen 5,5-dimethyl-1,3,2-dioxaphosphorinan 2-oxides and nineteen 5,5-dimethyl-1,3,2-dioxa-phosphorinan 2-sulphides, mostly with amino substituents on phosphorus, have been determined. In some cases, interpretation of the spectra was aided by accurate mass measurements and by the examination of deuterated compounds. For the 2-sulphides, sulphur is lost either as such or as the thiol radical, both processes often being of weak intensity, and the thiol hydrogen appears to be derivable from either a ring methylene group or a C-5 methyl group. Loss of S or HS occurs more strongly for the phosphoramidothionates which, together with the phosphoramidates, also fragment to an important extent in the amido substituent with retention of the dioxaphosphorinan ring; P[sbnd]N bond cleavage is also observed. For the 2-thiones, the ions at m/e 165 (14; R[dbnd]H) and 133 (15; R[dbnd]H) are characteristic.     

Characterisation of selected hypnotic drugs and their metabolites using electrospray ionisation with ion trap mass spectrometry and with quadrupole time-of-flight mass spectrometry and their determination by liquid chromatography-electrospray ionisation-ion trap mass spectrometry

The electrospray ionisation-ion trap mass spectrometry (ESI-MSⁿ) of selected hypnotic drugs, i.e. zopiclone, zolpidem, flunitrazepam and their metabolites have been investigated. Sequential product ion fragmentation experiments (MSⁿ) have been performed in order to elucidate the degradation pathways for the [M+H]⁺ ions and their predominant fragment ions. These MSⁿ experiments show certain characteristic fragmentations in that functional groups are generally cleaved from the ring systems as neutral molecules such as H₂O, CO, CO₂, NO₂, amines and HF. When an aromatic entity is present in a drug molecule together with a nitrogen-containing saturated ring structure as with zopiclone and its N-desmethyl metabolite fragmentation initially occurs at the latter ring with the former being resistant to fragmentation. The structures of fragment ions proposed for ESI-MSⁿ can be supported by electrospray ionisation-quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS).These molecules can be identified and determined in mixtures at low ng/ml concentrations by the application of liquid chromatography (LC)-ESI-MSⁿ which can be used for their analysis in saliva samples.This paper includes a tabulation of mass losses/signals at low m/z values for these hypnotic drugs and many others in recent publications which will be of value in the characterisation of drug metabolites of unknown structure and also natural product pharmaceuticals isolated from plants, etc.     

REACTIVITY OF SULFUR HETEROCYCLES

Abstract

The relationship between ring strain and the reactivity of alicyclic compounds has been of fundamental importance in the development of modern organic chemistry. Because of their biological interest, the reactivity and stereochemistry of cyclic phosphorus compounds have been extensively studied.^1,2 In recent years the reactivity of cyclic sulfur compounds has also begun to attract considerable interest. In 1966 it was pointed out that the common feature of sulfur-containing heterocycles is that nucleophilic attack at sulfur, be it di-, tri-, or tetra-coordinated, is always faster than the corresponding open-chain analogues.³ The present review attempts to discuss some fo the factors which affect the reactivity of cyclic sulfur compounds towards nucleophilic attack and to draw attention to some of the recently observed exceptions to this generalization.     

Conversion of Cyclic Phosphorothioates into Halophosphates and Neutral Phosphorus Esters and Amides

Abstract

Cyclic phosphorus esters and amides in the 1,3,2-dioxaphosphorinane-2-one series are usually obtained by the condensation of a diol with a suitable phosphorus oxyhalide. In the case of dissymetric diols the formation of two diastereoisomeric products, epimeric at phosphorus, can be expected. This procedure failed or proceeded with low yields when applied to the preparation of cyclic phosphates which would lead to the formation of sterically strained dioxaphosphorinane ring.¹     

2-phosphaindolizines

Eight new 2-phosphaindolizines 2 have been obtained by [4 + 1] cyclocondensation of 1,2-dialkylpyridinium halides 1 with PCl₃. The X-ray structure analysis of 2a is consistent with the integration of the 1,3-azaphosphole ring in the 10π-aromatic system. The charge densities on phosphorus of various representatives as obtained by PM3 calculations correlate approximately with the ³¹P-NMR shifts. The mass spectral fragmentation of 2a resembles that of its nonphosphorus analog. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:333–339, 1998     

STUDIES OF HETEROCYCLIC COMPOUNDS: VI1 THE MASS SPECTRA OF SOME 2-THIOPHENEMERCURIC DERIVATIVES

Abstract

The mass spectra of some 2-thiophenemercuric derivatives are determined and the fragmentation interpretations are based on mechanistic analogy and supported in some cases by metastable peaks and low energy mass spectra. They all fragment ultimately to the 2-thienyl cation formed either through a two-step process, by cleavage of Hg[sbnd]X bond to give the 2-thienylmercuric cation, followed by extrusion of mercury, or by a one-step process through cleavage of carbon-mercury bond. Their base peaks being the C₃H₃ ⁺ion (m/e 39).     

STUDIES ON THE FRAGMENTATION OF DIALKYL DISULFIDES UPON ELECTRON IMPACT

Abstract

Recent studies on the fragmentation of some organic disulfides upon electron impact in a mass spectrometer have shown two main decomposition routes besides simple bond disconnection: skeletal rearrangements^1–3 and proton transfer⁴. Transposition of the molecular components takes place via loss of one or two sulfur atoms while the carbon skeleton is preserved. Such molecular rearrangements are particularly noticeable in small molecules like dimethyl disulfide. Larger systems show a different fragmentation pattern in which proton transfer to give alkyl hydro-disulfides becomes predominant. The transfer of protons has been shown to proceed by way of intramolecular 1,2 and 1,3 hydrogen shifts from α and β carbons respectively by means of selective deuterium labbeling of diethyl disulfide.⁴     

PHOSPHORYL TO CARBONYL MIGRATION OF AMINO GROUPS IN MIXED ANHYDRIDES. REACTIVITY AND CRYSTAL STRUCTURE OF N-METHYL-2-BENZOYLOXY-2-OXO-1,3,2-OXAZAPHOSPHORINANE

Abstract

Cyclic mixed anhydride, N-methyl-2-benzoyloxy-2-oxo-1,3,2-oxazaphosphorinane (1a) has been synthesised and the rate of its fragmentation involving nitrogen migration from phosphorus to carbonyl carbon has been measured. (1a) was found to be ca. 60 times less reactive than the non-cyclic, O-methyl-N,N-dimethyl analogue. The crystal and molecular structure of (1a) has been determined using x-ray diffraction. Pna2₁, a=22.229(6), b=7.597(2), c=7.210(2) Å; V=1217.6(6) ų. Final R=3.08% for 1037 reflections with I(rel) > 2[sgrave]I(rel) and 157 parameters. The observed conformation of the molecule of (1a) is very different from that required for the fragmentation to occur; in order to achieve the geometry postulated for the transition state significant rotations about the P[sbnd]O and O[sbnd]C bonds would be necessary and steric hindrance by the 4,6-axial hydrogens would be expected.     

CONFORMATION OF EIGHT-MEMBERED DIOXATHIASILOCIN HETEROCYCLES IN SOLUTION

Abstract

The dibenzo[d,g][1,3,6,2]dioxathiasilocin derivatives 3a-f were prepared by the reaction of the thiobisphenols 1a-b with the corresponding dichlorosilanes 2a-e using triethylamine as an acid acceptor. The free energy of activation for ring inversion of the 2,4,8,10-tetra-tert-butyl-substituted 3a was determined by variable temperature ¹H NMR to be 13.9 kcal/mol. The ¹H NMR spectral data of 3a requires that the ring conformer possess a σ plane of symmetry passing through the silicon and bridging sulfur atoms. In the variable temperature ¹H NMR spectra of the 2,4,8,10-tetramethyl-substituted 3b no evidence was observed for the slowing of ring inversion at-55^oC, suggesting that the energy of activation for ring inversion is less than 10.9 kcal/mol. The ¹H NMR spectral data of 3e-f indicates the presence of equilibrating conformational isomers. The results of this study supports the suggestion that steric factors are a major contributor to the barrier of ring inversion for the dibenzo-[d, g][1,3,6,2]dioxathiasilocin ring system.