The synthesis of naphthothiopyranopyranones and naphthothiopyranopyranthiones

The synthesis of fused tetracyclic naphthothiopyranopyranones from dihydronaphthothiopyranones I or II has been studied. Compounds I or II have been cyclised in good yield to the corresponding dioxaborin difluoride complexes III, IV, XIII and XIV by treatment with acetic or propionic anhydride and boron trifluoride etherate. These complexes and the Vilsmeier reagent reacted to produce fused tetracyclic 3-substituted naphthothiopyranopyranones V, VI, XV or XVI . The reaction of dioxaborin difluoride complexes III or IV with dimethylthioformamide (DMTF) afforded dimethylaminovinyldioxaborin difluoride complexes IX or X . Treatment of IX or X with hydrochloric acid solution gave naphthothiopyranopyranones VII or VIII . The reaction of VII, VIII, XV or XVI with DMTF/acetic anhydride yielded new products, which was identified as naphthothiopyranopyranthions XI, XII, XVII or XVIII .     

Altered selectivity of reduction of steroidal carbonyls

The reduction of steroidal ketones in different solvents yielded different products. These conditions which altered the normal path, yielded a selective reduction of the Δ⁴-3 carbonyl without the concomitant reduction of the C-17 or C-20 ketones; this permitted a one step partial synthesis of 3β-hydroxy-Δ⁴-pregnen-20-one (I), 3β-hydroxy-5-pregnan-20-one (II), and of 3β,11β-dihydroxyandrostan-17-one (IV).     

The synthesis of some D-homosteroids

Summary Starting from 3-methoxy-^{1,3,5(11),8,14}-D-homoestrapentaen-17a-one (IV), a four-stage synthesis has yielded (±)-19-nor-D-homotestosterone (IX) and its esters, which possess anabofic activity.     

Crystal and molecular structure of Δ-5,6-diphenyl-5-methoxy-1,2,4-triazacyclohexene-3-thione and Δ-4-methyl-5,6-diphenyl-5-ethoxy-1,2,4-triazacyclohexene-3-thione

Condensation of thiosemicarbazide or N(4)-ethylthiosemicarbazide with 1,2,8,9-tetraphenyl-3,7-diazanona-1,9-dione in the presence of copper(II) acetate in 96% ethanol leads to Δ⁶-5,6-diphenyl-5-methoxy-1,2,4-triazacyclohexene-3-thione, C₁₆H₁₅N₃OS, or Δ⁶-4-methyl-5,6-diphenyl-5-ethoxy-1,2,4-triazacyclohexene-3-thione, C₁₈H₁₉N₃OS. For C₁₆H₁₅N₃OS the crystal data are monoclinic, P2₁/c, a=9.7780(7), b=8.5120(3), c=18.2210(13) Å, β=100.958(3)°, V=1488.89(16) ų, and Z=4 in agreement with an earlier report. For C₁₈H₁₉N₃OS the crystal data are orthorhombic, P2₁2₁2₁, a=8.6940(3), b=12.9946(3), c=15.5139(5) Å, V=1752.68(9) ų, and Z=4.     

Cyclic silylamides of vanadium, niobium, tantalum and hafnium. Crystal and molecular structures of spirocyclic tetraamides of V, CH3Nb and Hf

The spirocyclic silylamides M[(NR)₂SiMe₂]₂ (R = t-Bu: M = Hf (III), V (IV); R = SiMe₃: M = V (V), NbCl (VI), TaCl (VII)) have been prepared by reaction of the HfCl₄, VCl₄, NbCl₅ and TaCl₅, respectively, with Me₂Si[N(Li)R]₂. Methylation of VI and VII with MeLi yields the respective NbCH₃ and TaCH₃ derivatives (VIII and IX). The effective magnetic moments of IV and V are 1.67 and 1.66 μ_B respectively. Infrared and Raman spectra are given, and the ¹H, ¹³C and ²⁹Si chemical shifts for the diamagnetic compounds are reported. Single-crystal X-ray studies have been performed on III, IV and VIII. The structures of III and IV possess distorted tetrahedral symmetry (D_2d), with mean M---N distance of 2.030(4) and 1.853(5) Å, respectively. Distorted trigonal-bipyramidal coordination with an equatorial methyl group is found for each Nb atom of the two crystallographically independent molecules of VIII. Mean Nb---C, Nb---N (equatorial) and Nb---N (axial) bond lengths are 2.218(9), 1.997(4) and 2.026(5) Å, respectively.     

Synthese und reaktionen von zinn-substituierten pentadienderivaten

(1E, 4E)-1,5-Bis(trimethylstannyl)pentadiene-1,4 (III), 1E-1-trimethylstannyl-pent-1-ene-4-yne (IV) and the 1,1-dialkyl-1-stannacyclohexadienes-2,5 VII and VIII have been synthesized by hydrostannation of pentadiyne-1,4. (1E, 4E)1,5-Dibromapentadiene-1,3 (IX) is formed from III and 1,1,2,4,5,5-hexabromopentane (X) from IX by reaction with bromine. Butyllithium reacts with III to give (1E, 4E)-1,5-dilithium pentadiene-1,4 (XI). The reactions of butyl- and methyllithium with VII and VIII give only the monolithium compounds XIII, XV and XVII. All lithium compounds are characterised in the form of their trimethylsilyl derivatives XII, XIV, XVI and XVIII. ¹H NMR, IR, UV and mass spectral data are described.     

Organotin compounds : X. Organotin hydride addition to methyl cyclohexene-1-carboxylate and methyl indene-3-carboxylate

Free radical hydrostannation of methyl cyclohexene-1-carboxylate (I) and methyl indene-3-carboxylate (III) with trialkyltin hydrides, R₃SnH (R = Me, n-Bu, Ph) gives the energetically unfavourable cis products, 2-trialkylstannyl cyclohexanecarboxylate (II) and 2-trialkylstannyl indane-1-carboxylate (IV) in high yields, via a trans addition of the tin hydrides. The hydride abstractions by the intermediate trialkylstannylcyclohexanyl (VIII) and trialkylstannylindanyl (IX) intermediate radicals take place stereospecifically, and exclusively from the less hindered ring side. The structures of the isomers II and IV were established by (a) their transformation into the corresponding chlorodialkylstannyl derivatives V and VI, which were shown spectroscopically to have cis stereochemistries by intramolecular complexation of the ester group, and (b) their NMR data. Full ¹H, ¹³C, and ¹¹⁹Sn NMR data are given.     

Studies in stereochemistry—I Stereospecific routes to trans- anti- and cis- syn-Δ-dodecahydrophenanthrenes

Reduction of trans-1-oxo-7-methoxy-1,2,3,4,9,10,11,12-octahydrophenanthrene (XI) by lithium tri-t-butoxyaluminohydride gave trans-1β-hydroxy-7-methoxy-1,2,3,4,9,10,11,12-octahydrophenanthrene (XII) which on lithium—liquid ammonia reduction gave trans-anti-1β-hydroxy-7-oxo-Δ⁸⁽¹⁴⁾-dodecahydrophenanthrene (XIII). Reduction of cis-1-oxo-7-methoxy-1,2,3,4,9,10,11,12-octahydrophenanthrene (XV) by sodium borohydride gave cis-1-hydroxy-7-methoxy-1,2,3,4,9,10,11,12-octahydrophenanthrene (XVI) which on lithium—liquid ammonia reduction gave cis-syn-1-hydroxy-7-oxo-Δ⁸⁽¹⁴⁾-dodecahydrophenanthrene (XVII).     

Die 1,3-dipolare Cycloaddition von Acetylendicarbonsäure-estern an 2-Methyl-4-phenyl-chinazolin-3-oxid

The 1,3-dipolar addition of acetylenedicarboxylic esters (IX and X) to 2-methyl-4-phenyl-quinazoline 3-oxide (VIII) in benzene/methanol and benzene/ethanol, respectively, gives the esters XI and XII of 3-amino-3-phenyl-2-(2-acetamidophenyl)-acrylic acid as main products and the esters XIII and XIV of 2-methyl-4-phenyl-5H-benzo[d][1,3]diazepin-5-carboxylic acid as by-products. The constitutions of XI and XII are elucidated by acid hydrolysis to the 2-phenylindole-3-carboxylic esters VI and VII, respectively, and by ozonolysis of XII to give benzamide and ethyl o-acetamido-mandelate (IV). The alkaline hydrolysis of XI or XII gives the enamine derivative XVIII, which is hydrolysed by acid to oxindole and benzoic acid. The structure elucidation of XIII and XIV is based on spectroscopic data together with thc formation of XV by alkaline hydrolysis. Mechanisms arc proposed for the reaction paths.     

Acyclic diterpene glycosides, capsianosides VIII, IX, X, XIII, XV and XVI from the fruits of Paprika Capsicum annuum L. var. grossum BAILEY and Jalapeño Capsicum annuum L. var. annuum

Paprika and Jalape?o are used as vegetables and spices. We have obtained six new acyclic diterpene glycosides, called capsianosides XIII (2), XV (3), IX (4), XVI (5), X (6) and VIII (7) together with known capsianoside II (1) from the fruits of the Paprika and Jalape?o. The structures of these compounds have been elucidated by the (1)H- and (13)C-NMR spectra and two-dimensional NMR methods.     

Totally synthetic steroid heterocycles. Part 7.. A facile approach to 16-oxa-D-homoestrogens

In search of biologically active modified steroids, novel 16-oxa-D-homoestrone and -D-homoestradiol 3-methyl ethers were synthesized from 16-oxa-3-methoxy- D -homoestra-1,3,5(10),8,14-pentaen-17a-one. The straightforward synthesis involved stereoselective two-step reduction of the 8,14-diene system. The B/C stereoisomers were also derived from the estrapentaene. The stereostructures of these heterocyclic estrogens were determined on the basis of their spectral data.     

Design,synthesis of novel quinazolin-4-one derivatives and biological evaluation against human MCF-7 breast cancer cell line

A new series of 6,8-dibromo-2-(4-chlorophenyl)quinazolin-4(3H)-one derivatives VI–XIII were synthesized. Their chemical structures were confirmed by spectral and elemental analysis. The cytotoxic effect of the newly synthesized compounds was tested in vitro against human breast cancer cell line (MCF-7). Most of the tested compounds have shown promising cytotoxic activity. Compounds X and XIIIb exerted a powerful cytotoxic effect against MCF-7 with a very low IC50 (0.0015 and 0.0047 µmol/ml), while compounds VI, VII, VIII, XIIb, XI, XIIIc and IX exerted a moderate cytotoxic effect (IC50 0.01523, 0.0213, 0.031, 0.0478, 0.049, 0.068 and 0.079 µmol/ml respectively), compared to doxorubicin (0.0025 µmol/ml). Exploring their apoptotic effect; interestingly,all compounds activated apoptotic cascade in MCF-7. Compounds VI, XIIIb, XIIb, XI, XIIa, VII, V and VIII showed potent effect even much more than doxorubicin by 12.87–5.91 folds, while compounds XIIIc, IX, XIIIa, XIIc and X showed moderate increase in CASP3 activity by 4.96–3.22 folds relative to untreated cells more or less similar to doxorubicin (5.57 folds).     

New analogs of D-homoequilenine with substituents in the D ring

Stereoselectivity of reaction with Raney nickel of D-homoestra-1,3,5(10),8,14-pentaenes containing one or two methyl groups in position 16 was investigated. The reaction direction is governed by the orientation of the substituent at C^17a. The signals in the ¹H and ¹³C NMR spectra of four synthesized compounds were completely assigned. Criteria for evaluation of the character of rings junction in analogs of D-homoequilenine were suggested. 16,16-Dimethyl-3-methoxy-D-homo-13α-estra-1,3,5(10),6,8-pentaen-17a-one was subjected to X-ray diffraction analysis.     

Addition of 1,2-dibromo-1-chlorotrifluoroethane to chlorotrifluoroethylene induced by uv-radiation. Synthesis of perfluoro-1,3-butadiene and perfluoro-1,3,5-hexatriene

Photochemically initiated reaction of 1,2-dibromo-1-chlorotrifluoroethane (II) with chlorotrifluoroethylene (I) gave 38% 1,4-dibromo-2,3-dichlorohexafluorobutane (III) and 19% 1,6-dibromo-2,3,5-trichlorononafluorohexane (IV) in addition to the higher telomers. Dehalogenations of III and IV yielded perfluoro-1,3-butadiene (VI) and perfluoro-1,3,5-hexatriene (VIII) with 3-chlorononafluoro-1,5-hexadiene (VII), respectively. Photochemical reduction of butane III with 2-propanol resulted in a preferential reduction of CBr bonds, and from 2,3-dichloro-1,1,2,3,4,4-hexafluorobutane (IX) thus formed, esters of difluoroacetic acid were prepared by dehalogenation of IX and subsequent oxidation and esterification of the product. The photochemical reduction of hexane IV gave a mixture of 79% trichlorononafluorohexane XII and 21% dichlorononafluorohexane XIII. The mechanism of formation of the unusual products of the title addition reaction is discussed.     

Studies on the syntheses of heterocyclic compounds. Part CCLXXIII. Synthesis of C-nordihydrocorynantheol and its related compounds

Mannich reaction of tryptamine with 3,3,4-triethoxycarbonylhexaldehyde (IV) gave the cyclized product (VIII), whose hydrolysis, followed by decarboxylation, afforded the acid (IX). After esterification of IX, reduction of ester (X) with lithium aluminum hydride gave the C-nordihydrocorynantheol (II). The syntheses of IV and XV were also described. Furthermore, the Mannich reaction of L-N-benzyl-1-methyltryptophan methyl ester (XV) with IV was also examined. This reaction gave the ester (XVII), which was hydrolyzed and decarboxylated to give the acid (XVIII). Esterification of XVIII, followed by catalytic hydrogenation, gave the lactam (III).     

Synthesis and some reactions of sulfides of the thiophene series

By the action of four equivalents of sodium in liquid ammonia on the bis(alkylmercapto)thiophenes I, II, and IX we have obtained the corresponding dimercaptothiophenes VII, IX, and VIII, which were characterizied in the form of their dibenzoyl derivatives XI–XIII. The dimercaptothiophenes VII and VIII and the o-alkylthiothiophenethiols III and IV form the internally complex compounds XIV–XVII with metal acetates.     

C---H bond activation by rhodium(I) and the mechanism of the olefin isomerization: new synthesis of β,γ-unsaturated ketones via η- or η-alkylallylrhodium(III) complexes by reductive elimination

Acylrhodium(III)-η³-1-ethylallyl complex (7) was prepared by the reaction of 8-quinolinecarboxaldehyde (3) and 1,4-pentadienerhodium(I) chloride (2) by C---H bond activation, followed by hydrometallation, and double bond migration. Higher concentrations of pyridine as coordinating ligand transforms η³-1-ethylallylrhodium(III) complexes (8a,8b) into η¹-pent-2-enylrhodium(III) complex (11a). Acylrhodium(III)-η³-syn,anti-1,3-dimethylallyl complex (14) was also prepared from 1,3-pentadienerhodium(I) chloride (16) and 3. The reductive elimination of acylrhodium(III)-η¹- and -η³-1-alkylallyl complexes by trimethylphosphite gives various β,γ-unsaturated ketones.     

Some novel cyclizations of propiophenones with chlorosulfonic acid

The reaction of chlorosulfonie acid with propiophenones was found to give the 3-chloro-2-methylbenzothiophene-1, 1-dioxides (I) and (VIII); reaction of Mannich bases of aceto-phenone, with chlorosulfonie acid, gave the corresponding 3-chloro-2-substituted amino-methylbenzothiophene-1,1-dioxides (IX) and (X). The above structures were established by reaction with various nucleophiles and by hydrogenation. o-Hydroxypropiophenones, under the above conditions, are cyclized to the cyclic sulfones (XII) and (XIII). Ring opening with pyrrolidine gave the corresponding phenolic sulfonamides (XIV) and (XV).     

Ringschlussreaktionen von 1-(2-Aminophenyl)-1-phenyl-äthylenen durch Kondensation mit Phosgen

Cyclization of 1-(2-aminophenyl)-1-phenyl-ethylenes or 1-(2-aminophenyl)-1-phenyl-propenes (II) by condensation with phosgene led to 4-phenyl-carbostyrils (III) or 2-chloro-4-phenyl-quinolines (IV). Similarly, thiophosgene afforded 4-phenyl-thiocarbostyril. Treatment of 1-(2-aminophenyl)-2-methyl-1-p-tolyl-propene (VII) with phosgene led to the corresponding isocyanate IX, which cyclized in the presence of aluminum chloride with loss of a methyl group to 3-methyl-4-p-tolyl-carbostyril (III-6). However, 1-(2-aminophenyl)-2-methyl-1-phenyl-propene (VIII) treated with phosgene gave the isocyanate XI and 3-phenyl-3-isopropenyloxindole (X). Cyclization of the isocyanate XI with aluminium chloride led simultaneously to 3-methyl-4-phenyl-carbostyril (XIV), and with migration of a methyl group to 3-methylene-4-methyl-4-phenyl-3. 4-dihydro-carbostyril (XV).     

The mechamism of action of vitamin B12

A novel rearrangement reaction is introduced as a model for the rearrangement of methylitaconic acid (III) to α-methyleneglutaric acid (IV), one of three enzyme catalyzed, coenzyme B₁₂-dependent, carbonskeleton rearrangements whose mechanism has been a source of puzzlement for many years. The key feature of the new model is the direct attachment of the substrate, methylitaconic acid, to the cobalt atom of vitamin B₁₂ This was accomplished by reacting butadiene-2,3-decarboxylic acid with hydrobromic acid generating bromomethylitaconic acid (VIII). Use of two moles of hydrobromic acid yielded bis-2,3-(bromomethyl)succinic acid (IX). Reaction of the monobromide VIII with vitamin B_12s did not yield the desired carbon-cobalt bonded adduct. Instead, the lactone ηa- methylene-γbutyrolactone-β-carboxylic acid (X) was formed. Accordingly, the ester, dimethyl bromomethylitaconate (XIa), was reacted with vitamin B_12s and yielded the carbon-cobalt bonded adduct XIIa. Bis-trimethylsilyl bromomethylitaconate did not yield an adduct when reacted with vitamin B_12s, but bis-tetrahydropyranyl bromomethylitaconate (XIb) did yield the adduct XIIb. The ester cobalamin XIIb undergoes spontaneous decomposition at room temperature, in aqueous solution, at pH 8 and in the dark - biochemically ideal circumstances - yielding a mixture of butadiene-2,3-decarboxylic acid (VII), methylitaconic acid (III) and α- methyleneglutaric acid (IV). The presence of the latter indicates that a skeletal change has taken place in a way which mimics the enzymatic reaction. This is the first non-enzymic model in this carbon-skeleton rearrangement series. The methyl ester cobalamin XIIa was stable in the dark but did decompose on irradiation with a sunlamp to butadiene-2,3decarboxylic acid (VII) and methylitaconic acid (III). No α-methyleneglutaric acid IV was observed in the latter reaction.Authentic methylitaconic acid (III) was prepared by alkylation of triethyl prop-2-ene-l,l,2-tricarboxylate (XIII) with methyl iodide followed by hydrolysis and decarboxylation. The lactone X and lactone α-methyl-γ-butyrolactone-β-carboxylic acid (XVI) were prepared by condensing the triester XIII with formaldehyde, hydrolyzing the lactone diester XV to the lactone X and hydrogenating to the saturated lactone XVI.