Gas-liquid chromatographic assay of a new antineoplastic agent, 1,3,3,5,5-pentakis-(azaridino)lambda 6-2,4,6,3 lambda 5, 5 lambda 5-thiatriazadiphosphorine-1-oxide. Application to pharmacokinetic studies

A method for the assay of 1,3,3,5,5-pentakis-(azaridino)-lambda 6,2,4,6,3 lambda 5,5 lambda 5-thiatriazadiphosphorine-1-oxide (SOAz), a new anticancer drug of which the clinical trials are in progress, is described. This method is based on capillary gas chromatography using a thermionic detector. The lower detection limit was 100 pg per injection and a coefficient of variation smaller than 5% could be obtained when parathion was used as external standard. The method is suitable for biological samples and therefore has been proposed for clinical pharmacokinetic studies as well as for the determination of patterns of SOAz distribution in several organs of the mouse. A preliminary clinical study showed that the serum decay curves of SOAz could be fitted to an open two-compartment model for drug disappearance.     

Optically active zwitterionic lambda(5)Si,lambda(5)Si'-disilicates: syntheses, crystal structures, and behavior in aqueous solution

The zwitterionic lambda(5)Si,lambda(5)Si'-disilicates 1-8 were synthesized and characterized by solid-state and solution NMR spectroscopy. In addition, compounds 26 H(2)O, 32 CH(3)CN, 45/2 CH(3)CN, 6CH(3)OH, 7, and 8CH(3)OHCH(3)CN were studied by single-crystal X-ray diffraction. The optically active (Delta,Delta,R,R,R,R)-configured compounds 1-8 contain two pentacoordinate (formally negatively charged) silicon atoms and two tetracoordinate (formally positively charged) nitrogen atoms. One (ammonio)alkyl group is bound to each of the two silicon centers, and two tetradentate (R,R)-tartrato(4-) ligands bridge the silicon atoms. Although these lambda(5)Si,lambda(5)Si'-disilicates contain SiO(4)C skeletons, some of them display a remarkable stability in aqueous solution as shown by NMR spectroscopy and ESI mass spectrometry.     

The first isolable pentacoordinate 1,2 lambda 5-azaphosphetine: synthesis,X-ray crystallographic analysis,and dynamic behaviour

Cycloaddition reaction of an iminophosphorane bearing the Martin ligand with an alkyne gave the first stable 1,2 lambda 5-azaphosphetine, whose structure was determined by X-ray crystallographic analysis, and variable temperature NMR spectroscopy revealed the existence of equilibrium with the corresponding alpha-iminoalkylidenephosphorane.     

Oxidative dearomatization of phenols and anilines via lambda(3)- and lambda(5)-iodane-mediated phenylation and oxygenation

Treatment of 2-methylphenols with chloro(diphenyl)-lambda(3)-iodane led to their regioselective dearomatizing 2-phenylation into cyclohexa-2,4-dienone derivatives via a proposed ligand coupling reaction. In the same vein of investigation, treatment of 2-methylanilines with the lambda(5)-iodane 2-iodoxybenzoic acid IBX reagent led to their regioselective dearomatization into previously undescribed ortho-quinol imines.     

Spirocyclic zwitterionic lambda5Si-silicates with two bidentate ligands derived from alpha-amino acids or alpha-hydroxycarboxylic acids: synthesis, structure, and stereodynamics

A series of zwitterionic lambda(5)Si-silicates with a (2,2,6,6-tetramethylpiperidinio)methyl group and two identical bidentate ligands derived from glycine, (S)-alanine, (S)-phenylalanine, glycolic acid, (S)-lactic acid, (S)-3-phenyllactic acid, or (S)-mandelic acid were synthesized and structurally characterized (solution and solid-state NMR spectroscopy; single-crystal X-ray diffraction). The chiral lambda(5)Si-silicates with ligands derived from optically active alpha-amino acids or alpha-hydroxycarboxylic acids were isolated as enantiomerically and diastereomerically pure compounds that undergo a (Lambda)/(Delta)-epimerization in solution.     

5,6,7,8-Tetrafluoro-3lambda4delta2,1,2,4-benzothiaselenadiazine, 5,6,7,8-tetrafluoro-1,3lambda4delta2,2,4-benzodithiadiazine, and their hydrocarbon analogues: molecular and crystal structures

5,6,7,8-Tetrafluoro-3lambda4delta2,1,2,4-benzothiaselenadiazine (1) is prepared by the intramolecular nucleophilic cyclization of C6F5SeN=S=NSiMe3 (2) mediated by CsF. According to an X-ray diffraction analysis, the heterocycle of 1 is bent along the Se(1)...N4 line by 6.0(2) degrees in the crystal. Despite the obvious similarities between 1 and its 1,3-dithia analogue (7) with respect to molecular composition and shape, the crystal packing of 1 is substantially different from that of 7. An interesting consequence of this is the inclusion of atmospheric N2 in the crystal lattice of the selenium derivative 1. The molecular structure and bonding of 1 have been investigated using quantum-chemical calculations at the DFT/B3LYP/6-311+G level of theory, and the results have been compared to those of 5,6,7,8-tetrafluoro-1,3lambda4delta2,2,4-benzodithiadiazine (7) and their hydrocarbon analogues (5 and 8).     

X-ray Crystal Structure, ab Initio Calculations, and Reactivity of 1,3,2lambda(5)-Diazaphosphetes: A New Type of 4-pi-Electron 4-Membered Heterocycle

The structure of P,P-bis(diisopropylamino)-4-phenyl-1,3,2lambda(5)-diazaphosphete, 1a, has been determined by a single-crystal X-ray diffraction study (C(19)H(33)N(4)P, monoclinic system, space group P2(1), a = 9.482(1) ?, b = 11.374(3) ?, c = 9.668(2) ?, beta = 97.16(1) degrees, Z = 2). According to quantum chemical calculations at an RHF level of optimization utilizing the 6-31g(d,p) basis set, 1a has a zwitterionic structure with the negative charge delocalized on the NCN allylic fragment and the positive charge localized at the phosphorus. Heterocycle 1a reacts with water and benzaldehyde affording N-phosphoranylbenzamidine 3 (95% yield) and the expected aza-Wittig adduct 4 (85% yield), respectively. Addition of 1 equiv of methyl trifluoromethanesulfonate and of 2 equiv of BH(3).THF to 1a affords cyclic phosphonium salt 5 (94% yield) and the bis(borane) adduct 6a (90% yield), respectively. Dimethyl acetylenedicarboxylate slowly reacts with 1a giving rise to 1,3,4lambda(5)-diazaphosphinine, 9, in 70% yield. The X-ray crystal structures of products 2,3, and 6a are reported (2: C(26)H(38)N(5)P, monoclinic system, space group C2/c, a = 16.337(8) ?, b = 19.810(2) ?, c = 8.800(2) ?, beta = 117.68(2) degrees, Z = 4. 3: C(19)H(35)N(4)OP, orthorhombic system, space group P2(1)2(1)2(1), a = 9.090(1) ?, b = 12.955(2) ?, c = 17.860(3) ?, Z = 4. 6a: C(19)H(39)B(2)N(4)P, orthorhombic system, space group P2(1)2(1)2(1), a = 10.340(1) ?, b = 13.247(1) ?, c = 16.996(1) ?, Z = 4).     

Reaction between naphthols and dimethyl acetylenedicarboxylate in the presence of phosphites. Synthesis of stable oxa-2 lambda 5-phosphaphenanthrenes,and benzochromene derivatives

The reaction of dimethyl acetylenedicarboxylate (DMAD) with 2-naphthol in the presence of trimethyl or triphenyl phosphite leads to stable dimethyl oxa-2 lambda 5-phosphaphenanthrene derivatives in good yields. The reaction of DMAD and trimethyl phosphite in the presence of 1-naphthol or 8-hydroxyquinoline leads to dimethyl 2-(dimethoxyphosphoryl)-3-(1-hydroxy-2-naphthyl)succinate or dimethyl 2-(dimethoxyphosphoryl)-3-(8-hydroxyquinolin-7-yl)-succinate in excellent yields. Using triethyl phosphite and DMAD in the presence of 2-naphthol or 1-naphthol produces methyl 3-oxo-2,3-dihydro-1H-benzo[f]chromene-1-carboxylate or methyl 2-oxo-3,4-dihydro-2H-benzo[h]-chromene-4-carboxylate in excellent yields.     

Oxidative conversion of alpha,alpha-disubstituted acetamides to corresponding one-carbon-shorter ketones using hypervalent iodine (lambda5) reagents in combination with tetraethylammonium bromide

Alpha,alpha-disubstituted acetamides undergo oxidative dehomologation to give one-carbon-shorter ketones when reacted with a hypervalent iodine (lambda(5)) reagent in combination with tetraethylammonium bromide (TEAB) in various solvents. In further studies, one such combination of a hypervalent iodine (lambda(5)) reagent, o-iodoxybenzoic acid, and TEAB has been established as a new, mild, efficient, and general method for the transformation.     

5-Methylthio-, 5-Methylsulfinyl- und 5-Methylsulfonyluracil

Zusammenfassung 5-Methylthiouracil wird auf verschiedenen Wegen durch Ringschlußreaktionen von Formylmethylthioessigester bzw. Derivaten mit S-Methylisothioharnstoff oder Thioharnstoff und Hydrolyse des primär gebildeten 2,5-Di-(methylthio)-4-oxypyrimidins bzw. 5-Methylthio-thiouracils dargestellt.Oxydation mit Peressigsäure führt zu 5-Methylsulfinyl- und 5-Methylsulfonyluracil. 5-Methylsulfonyluracil kann auch durch Oxydation von 2,5-Di-(methylthio)-4-oxypyrimidin und 5-Methylthio-thiouracil gewonnen werden.Herrn Prof. Dr.F. Wessely in freundschaftlicher Verehrung zu seinem 70. Geburtstag gewidmet.     

Synthesis of 2, 2, 5, 5-tetramethyltetrahydrothiophene

Under the conditions of the Grignard reaction, 2, 5-dimethyl-2, 5-hexanediol has been obtained from diethyl succinate. Under the action of sulfuric acid, the latter has been cyclized to 2, 2, 5, 5-tetramethyl-tetrahydrofuran which, in its turn, by treatment with phosphorus pentasulfide, has given 2, 2, 5, 5-tetramethyltetrahydrothiophene. Its reaction with methyl iodide has given 2, 2, 5, 5-tetramethyltetrahydrothiophene methiodide.     

A sigma 4, lambda 5-phosphinine palladium complex: a new type of phosphorus ligand and catalyst. Application to the Pd-catalyzed formation of arylboronic esters

A palladium(II) complex of a S-P-S pincer ligand featuring a metallated ylidic P-atom efficiently catalyzes the coupling between pinacolborane and various iodoaryls to yield the corresponding arylboronic esters (TON between 5100 and 76,500).     

Conversions of 5-hydroxy-5, 6-dihydro-4H-1, 2, 5-oxadiazines

Oxidation of 5-hydroxy-5, 6-dihydro-4H-1, 2, 5-oxadiazines leads to the formation of 6H-1,2, 5-oxadiazine-5-oxides. Acid treatment of 5, 6-dihydro-4H-1, 2, 5-oxadiazines and 6H-1, 2, 5-oxadiazine-5-oxides results in heterocyclic-ring contraction with the formation of imidazole 3-oxides and 1-hydroxyimidazole 3-oxides. The structures of the products are established by their spectral properties and confirmed by independent synthesis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1264–1266, September, 1970.     

Oxetane from A-nor-steroides: 2-alpha, 5-oxido-A-nor-5-alpha-cholestane, 2-beta, 5-oxido-A-nor-5-beta-cholestane and 2-alpha-ethyl-2-beta,2'-oxido-A-nor-5-alpha-cholestane

Treatment of 2β-tosyloxy-A-nor-5α-cholestane-5-ol ( 2 ) with t-butoxide in t-butanol gave 2α, 5-epoxy-A-nor-5α-cholestane ( 3 ) in quantitative yield. When A-nor-5β-cholestane-2α, 5-diol ( 4 ) was treated with tosyl chloride in pyridine 2β-chloro-A-nor-5β-cholestane-5-ol ( 7 ) and 2α-tosyloxy-A-nor-5β-cholestane-5-ol ( 8 ) were obtained. Whereas the chloride 7 was resistant to t-butoxide the tosylate 8 was transformed into an 1 : 1 mixture of 2α, 5-epoxy-5β-cholestane ( 10 ) and 2ξ-t-butoxy-A-nor-5β-cholestane-5-ol ( 11 ). In 2α-tosyloxy-A-nor-5α-cholestane-5-ol ( 12 ) substitution occurred as the only reaction. Both oxetanes 3 and 10 isomerize after heating above 50° and in polar or protic solvents to form A-nor-Δ³⁽⁵⁾-cholestene-2α-ol ( 6 ) and -2β-ol ( 14 ) respectively. Also, 2, 5-diols are encountered. 2α-Ethyl-2β, 2′-epoxy-A-nor-5α-cholestane ( 23 ) was synthesized starting from A-nor-5α-cholestane-2-one ( 17 ). The intermediates were the ester 16 , the diol 18 , the hydroxy-tosylate 19 and the chlorhydrin 20 . The spirocyclic oxetane 23 was reduced by LiAlH₄ in dioxane (not in ether). By chromatography on silica gel 23 was isomerized to the homoallylic alcohol 21 and transformed into 2-methylene-A-nor-5α-cholestane ( 24 ) by fragmentation. The IR. and NMR. spectra of the new oxetanes were compared with those of a series of known oxetanes.