Zur Umsetzung des 3,4,5,6-Tetrahydro-6-hydroxy-4,4,6-trimethyl-1,3-thiazin-2-thions mit primären Aminen

Tetrahydro-6-hydroxy-4,4,6-trimethyl-1,3-thiazine-2-thione (1 a) reacts with methyl-, ethyl- and n-butylamine to the corresponding 1-alkyl-6-alkylaminotetrahydro-2(1H)-pyrimidinethione12 but withi-propylamine to tetrahydro-6-isopropylamino-1,3-thiazine-2-thione (6 d). On treatment withDCC,6 d is rearranged to dihydro-4-isopropylamino-2(1H)-pyridinethione (8 d), and 6-amino-tetrahydro-1,3-thiazinethione (6 a) to dihydro-4,4,6-trimethyl-2(1H)-pyrimidinethione (10 a). The reaction of 6-aminothiazinethiones6 a, d and 6-(4-morpholinyl)-thiazinethione13 resp., with methylamine leads to 1-methyl-6-methylamino-pyridinethione12 b. 1-Alkyl-6-alkylamino-tetrahydro-2(1H)-pyrimidinethiones (12) react at reflux temperature to dihydro-1-alkylpyrimidinethiones10. With methylamine only 6-methylamino-3,4,4,6-tetramethyl-1,3-thiazine-2-thione (6 f) is formed from tetrahydro-6-hydroxy-tetramethyl-1,3-thiazine-2-thione (1 b).     

SYNTHESES OF CYCLOHEPTATRIENES WITH SULFUR FUNCTIONAL GROUPS

Abstract

Disodium 1, 6-disulfido-1, 3, 5-cycloheptatriene 3, formed by reduction of 1 with sodium in liq. ammonia, reacts with hydrogen chloride and methyl iodide to give 1, 6-dimercapto-, 4, and 1, 6-bis(methylthio)-1, 3, 5-cycloheptatrienes 5 respectively; however, it is oxidized by bromine to afford cyclic disulfide 6. 1, 6-Diiodo-1, 3, 5-cycloheptatriene 2 is converted to 1, 6-bis(benzylthio)-1, 3, 5-cycloheptatriene 7 by reaction with sodium phenylmethanethiolate, whereas similar reactions with 1-(2-hydroxyethyl)-6-iodo-1, 3, 5-cycloheptatriene 9, obtained from 2 via 1-iodo-6-vinyl-1, 3, 5-cycloheptatriene 8, give 1-benzylthio-6-(2-hydroxyethyl)-1, 3, 5-cycloheptatriene 10. 1-Benzylthio-6-benzylthioethyl-1, 3, 5-cycloheptatriene 11 is synthesized by the reaction from 9 via 1-(2-bromoethyl)-6-iodo-1, 3, 5-cycloheptatriene 10. Attempts to synthesize thiols from 7, 11, and 12 are also described.     

O-Acetyl Protection of 6-Aminoaldopyranosides and 1-Aminoalditols

Abstract

Methyl 6-amino-6-deoxy-α-D-glycopyranosides having the D-gluco, D-manno and D-galacto configurations (1a–3a), 2-aminoethanol (4a), 1-amino-1-deoxy-D-glucitol (5a), and 1-amino-1-deoxy-4-O-β-D-glucopyranosyl-D-glucitol (6a) were transformed into the corresponding per-O-acetyl amine hydrochlorides 1d–6d in excellent yields by using the 2,2-(diethoxycarbonyl)vinyl group for temporary amine protection. Deprotection of the peracetylated enamines 1c–6c was effected with chlorine in chloroform and no O→N acetyl migration occurred when short reaction times were used. Treatment of 1d–6d with thiophosgene resulted in the formation of peracetyl isothiocyanates (1e–6e).     

Molecular Recognition of Aliphatic Alcohols and Carboxylic Acid by Chromophoric Cyclodextrins

Abstract

Molecular recognition behavior of eight cyclodextrin derivatives, i.e. mono(6-pyridinio-6-deoxy)-α-cyclodextrin (1α), mono(6-pyridinio-6-deoxy)-β-cyclodetrin (1β), mono(6-pyridinio-6-deoxy)-γ-cyclodextrin (1γ), mono[6-(p-picolinio)-6-deoxy]-β-cyclodextrin (2β), mono(6-anilino-6-deoxy)-β-cyclodextrin (3β), mono[6-(m-toluidino)-6-deoxy]-β-cyclodextrin (4β), mono[6-O-(8-quinolyl)]-β-cyclodextrin (5β), and novel mono[6-(2-naphthylamino)-6-deoxy]-β-cyclodextrin (6β), with a series of aliphatic alcohols and carboxylic acid has been investigated spectroscopically. Using the appended aromatic group as a spectral probe, spectroflurometric or spectropolarimetric titrations have been performed at 25°C in aqueous phosphate buffer solution (pH 7.20, 0.1 M) to determine the complex stability constants (K_s ) and Gibbs free energy changes (-δG°) for the stoichiometric 1:1 inclusion complexation of cyclodextrin derivatives with the guests. The results obtained demonstrate that the modified cyclodextrins are highly sensitive to the size/shape and hydrophobicity of guest molecules, and particularly 5β gives an excellent molecular selectivity up to 215 for 1-adamantanol/cyclohexanol. The binding ability and selectivity of the modified cyclodextrins (1α, 1β, and 1β-6β) are discussed from the view points of size/shape-fit concept, induced-fit interaction, and the multiple recognition mechanisms.     

Synthesis of N-1-(Indanyloxymethyl) and N-1-(4-Hydroxybut-2-enyloxymethyl) Analogues of the HIV Drugs Emivirine and GCA-186

A series of Emivirine and GCA-186 analogues substituted at N-1 with indan-1-yloxymethyl (6a–6c) and indan-2-yloxymethyl (6d–6f) were synthesized by reaction of the corresponding bis(indanyloxy)methans with uracils having 5-ethyl or 5-isopropyl and 6-benzyl or 6-(3,5-dimethylbenzyl) substituents. A route to the corresponding N-1 substituted 4-hydroxybut-2-enyloxymethyl analogue was also devised. All newly synthesized compounds showed potent activity against wild-type HIV-1, the most active compound being 5-ethyl-1-(indan-1-yloxymethyl)-6-(3,5-dimethylbenzyl)uracil (6b), which was 50-fold more active than Emivirine.     

Synthesis Of 1-Benzazepines as Precursors of 1-Benzazepinediones

The synthesis of 6-hydroxy-7-nitro-1-benzazepine-2-one 7 from 5-hydroxy-1-tetralone 1 and 6-hydroxy-1-benzazepine-2-one 2 is described. Bromination of 6-hydroxy-1-benzazepine-2-one 2 with NBS in ethyl acetate afforded 7-bromo-6-hydroxy-1-benzazepine-2-one 13 and 7,9-dibromo-6-hydroxy-1-benzazepine-2-one 14. Oxidation of benzazepinone 13 with (diacetoxyiodo)benzene provided 7-bromo-1-benzazepine-2,6,9-trione 5.     

The reaction of 4-methoxycoumarins with prenyl bromide: Synthesis of 4′,4′,5′-trimethyl-dihydrofurano-coumarins and 2,2-dimethyl-chromenopyrans

The reaction of 7-hydroxy-4-methoxy- (1a), 7-hydroxy-4,5-dimethoxy-(1b) and 5-hydroxy-4,7-dimethoxy (1c) -2H-1-benzopyran-2-ones with prenyl bromide in acetone in the presence of anhydrous potassium carbonate gave the corresponding prenyloxycoumarins1d,1e, and1f. The prenyloxy coumarins1d,1e,1f onClaisen migration by refluxing inN,N-dimethyl aniline gave the corresponding 4,4,5-trimethyl-dihydrofuranocoumarins2a,2b, and3. However, the reaction of1a,1b, and1c with 3-chloro-3-methyl-but-1-yne in acetone in presence of potassium carbonate and potassium iodide gave the corresponding propargyl ethers1g,1h,1i, which on refluxing inN,N-dimethyl aniline gave the corresponding 2,2-dimethylchromenopyrans4a,4b, and5. These can also be obtained directly if the reaction is carried out in the presence of dioxan.

---

Die Reaktion von 4-Methoxycumarinen mit Prenylbromid: Synthese von 4,4,5-Trimethyl-dihydro-furanocumarinen und 2,2-Dimethylchromenopyranen

Zusammenfassung Die Reaktion von 7-Hydroxy-4-methoxy-(1a), 7-Hydroxy-4,5-dimethoxy-(1b) und 5-Hydroxy-4,7-dimethoxy-2H-1-benzopyran-2-onen (1c) mit Prenylbromid in Aceton in der Gegenwart von wasserfreiem Kaliumcarbonat ergab die entsprechenden Prenylcumarine1d,1e und1f. Diese ergaben durchClaisen-Wanderung bei Rückfluß inN,N-Dimethylanilin die entsprechenden 4,4,5-Trimethyldihydrofuranocumarine2a,2b und3. Die Reaktion von1a,1b und1c mit 3-Chlor-3-methyl-1-butin in Aceton in Gegenwart von wasserfreiem Kaliumcarbonat und Kaliumjodid ergab die entsprechenden Propargylether1g,1h und1i, die ihrerseits bei Rückfluß inN,N-Dimethylanilin die jeweiligen 2,2-Dimethylchromenopyrane4a,4b und5 ergaben. Letztere können auch direkt erhalten werden, wenn die Reaktion in Gegenwart von Dioxan durchgeführt wird.

     

Configurational and Conformational Properties of 1,3,7,9-Tetraphospha-Cyclododeca-1,2,7,8-tetraene: An Ab Initio Study and NBO Analysis

An investigation employing the ab initio molecular orbital (MO) and density functional theory (DFT) methods to calculate structural optimization and conformational interconversion pathways for the two diastereoisomeric forms, (±) and meso configurations of 1,3,7,9-tetraphospha-cyclododeca-1,2,7,8-tetraene (1) was undertaken. Two axial symmetrical conformations are found for (±)-1 configuration. (±)-1-TB axial symmetrical form is found to be about 0.35 and 0.99 kcal mol^?1 more stable than (±)-1-Crown axial symmetrical conformation, as calculated by HF/6-31G*//HF/6-31G* and B3LYP/6-31G*//HF/6-31G* levels of theory, respectively. The unsymmetrical meso-1-TBCC form is found to be the most stable geometry, among the various conformations of meso-1 configuration. HF/6-31G*//HF/6-31G* and B3LYP/6-31G*//HF/6-31G* results showed that between the two most stable conformations of (±) and meso configurations, (±)-1-TB is more stable than meso-1-TBCC by about 3.35 and 2.43 kcal mol^?1, respectively. In addition, MP2/6-31G* and B3LYP/6-311+G** results showed that the (±)-1-TB form is about 1.10 and 2.36 kcal mol^?1 more stable than the meso-1-TBCC form. Further, NBO results revealed that in the most stable form of meso configuration (meso-1-TBCC), the sum of the π* allenic antibonding orbital occupancies (Σ π *_occupancy) is greater than dl configuration ((±)-1-TB). Also, NBO results indicated that in the (±)-1-TB conformer, the sum of σ and π allenic moieties bonding orbital deviations (Σ σ _dev+Σ π _dev) from their normal values, is lower than in the meso-1-TBCC form.     

Synthesis of 5-Methanesulfonamido-6-(2,4-Difluorophenylthio)-1-Indanone

The ethylene ketal of 5-nitro-6-bromo-1-indanone 6 was prepared via oxidation of N-(6-Bromo-5-indanyl)-acetamide 1. A subsequent mild displacement and elaboration to 6-thiosubstituted-5-amino indanone derivative 10 is also described.     

Nukleophile Substitutionen und Eliminierungen von Aminofunktionen via Pyrimidiniumsalze

Reaction of 2,4-diphenyl-1,3-thiazine-6-thione (1) with primary amines leads under ring transformation to 1-organyl-pyrimidine-6-thiones3, which are alkylated to 1-organyl-6-methylthiopyrimidinium salts5. The latter allow a transfer of the 1-organyl group to nucleophilic agents by departure of 2,4-diphenyl-6-methylthio-pyrimidine (8). In special cases an elimination reaction is successful. Preparative advantages and limitations are demonstrated and discussed.

     

Two new benzolactones from the leaves of Nicotiana tabacum and their anti-tobacco mosaic virus activities

Two new benzolactones, 5-methyl-6-prenyl-isobenzofuran-1(3H)-one (1), 5-hydroxymethyl-6-prenyl-isobenzofuran-1(3H)-one (2), together with four known phenolic compounds (3–6), were isolated from the leaves of Nicotiana tabacum. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1–6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compounds 1–6 exhibited high anti-TMV activities with inhibition rates in the range of 16.9–26.2%, respectively.     

Synthesis of <Emphasis Type="Italic">N</Emphasis>-1-(Indanyloxymethyl) and <Emphasis Type="Italic">N</Emphasis>-1-(4-Hydroxybut-2-enyloxymethyl) Analogues of the HIV Drugs Emivirine and GCA-186

Summary. A series of Emivirine and GCA-186 analogues substituted at N-1 with indan-1-yloxymethyl (6a–6c) and indan-2-yloxymethyl (6d–6f) were synthesized by reaction of the corresponding bis(indanyloxy)methans with uracils having 5-ethyl or 5-isopropyl and 6-benzyl or 6-(3,5-dimethylbenzyl) substituents. A route to the corresponding N-1 substituted 4-hydroxybut-2-enyloxymethyl analogue was also devised. All newly synthesized compounds showed potent activity against wild-type HIV-1, the most active compound being 5-ethyl-1-(indan-1-yloxymethyl)-6-(3,5-dimethylbenzyl)uracil (6b), which was 50-fold more active than Emivirine.Present address: Chemistry Department, Faculty of Science, Tanta University, Tanta, EgyptA research center funded by The Danish National Research Foundation for studies on nucleic acid chemical biology     

Conversion of 6-phenylimino-2H-thiopyran-4-amines to 1-phenyl-2,3-dihydro-4(1H)-pyridinones

Summary 6-Phenylimino-3,6-dihydro-2H-thiopyran-4-amines (1) were converted to 1-phenyl-5,6-dihydropyridine-2(1H)-thiones (3). Those were akylated and hydrolyzed, thus yielding 6-methylthio-1-phenyl-2,3-dihydro-4(1H)-pyridinones (5). Finally, the methylthio group was removed withRaney nickel giving the title compounds6. The relative configurations of the formed diastereoisomeric dihydropyridinones have been investigated by NOE measurements.

---

Umwandlung von 6-Phenylimino-2H-thiopyran-4-aminen zu 1-Phenyl-2,3-dihydro-4(1H)-pyridinonen

Zusammenfassung 6-Phenylimino-3,6-dihydro-2H-thiopyran-4-amine (1) wurden in 1-Phenyl-5,6-dihydropyridin-2(1H)-thione (3) umgewandelt. Diese wurden alkyliert und zu 6-Methylthio-1-phenyl-2,3-dihydro-4(1H)-pyridinonen (5) hydrolysiert. Zuletzt gelangte man durch selektives Entfernen der Methylthiogruppe mitRaney-Nickel zu den Titelverbindungen6. Die relativen Konfigurationen der gebildeten diastereomeren Dihydropyridinone wurden durch NOE-Messungen aufgeklärt.

     

Palladium(II) complexes containing cytokinins derived from 6-benzylaminopurine

A series of palladium(II) complexes of general formula [Pd(LH⁺)Cl₃] (1–12) containing 6-benzylaminopurine derivatives has been prepared [L?=?6-(2-methoxybenzylamino)purine (1), 6-(3-methoxybenzylamino)purine (2), 6-(4-methoxybenzylamino)purine (3), 6-(2-hydroxy-benzylamino)purine (4), 6-(3-hydroxybenzylamino)purine (5), 6-(4-hydroxybenzylamino) purine (6), 6-(2-fluorobenzylamino)purine (7), 6-(3-fluorobenzylamino)purine (8), 6-(4-fluorobenzylamino)purine (9), 6-(2-chlorobenzylamino)purine (10), 6-(3-chlorobenzylamino) purine (11) and 6-(4-chlorobenzylamino)purine (12)]. The compounds have been characterized by elemental analysis, IR, ES+ MS and ¹H- and ¹³C-NMR spectroscopy, and two of them, 6 and 12, also by TG/DSC analyses. The complexes have been screened in vitro against the four human tumour cell lines G-361, HOS, K-562 and MCF7.     

Synthese neuartig substituierter Pyridazin-6(1H)-one

Summary Arylhydrazono acetamides1 react with chloroacetic acid chloride to give N-chloroacetyl derivatives2. Subsequent reaction with pyridines followed by ring closure yield 1-(4-amino-6-oxo-pyridazin-5-yl)-pyridinium chlorides3. Analogously, 1-(6-oxo-pyridazin-5-yl)-pyridinium chloride (5) and 6-oxo-5-pyridinio-pyridazin-4-olate (4) are formed from phenylhydrazono derivatives and pyridine. Treatment of3 and4 with hydrazinium hydrate gives 4,5-diamino-6-oxo-pyridazin-3-carbohydrazides6 and 5-amino-4-hydroxy-pyridazin-6(1H)-one (8). An analogous ring cleavage of3e and5 gives rise to 4,5-diamino- and 5-amino-pyridazin-6(1H)-ones7. On treatment of the pyridinium salts3 with caustic soda in water, nucleophilic addition of the amino group to the pyridinium ring takes place and stable dehydrated products9 are isolated.

Herrn Professor Dr. Fritz Sauter zum 65. Geburtstag gewidmet     

Methylpyrimidin—Pyridin-Umlagerung von Dihydro-6-methyl-2 (1H)-pyrimidinthionen bzw.-onen

1-Unsubstituted dihydro-6-methyl-2(1H)-pyrimidinethiones undergo an aminolysis in dialkylformamides or methylformamide resp., at higher temperature, and then are rearranged to 4-dialkylaminodihydro-2(1H)-pyridinethiones6 a, b or the 4-methylamino compound6 c. 1-Alkyl- and 1-aryldihydro-6-methyl-2(1H)-pyrimidinethiones1 b, c and tautom, methylenecompounds2b,c resp., react at the same conditions withDMF not only to 4-alkylamino-or 4-arylaminodihydro-2(1H)-pyridinethiones6 c, d but also to 4-dimethylaminodihydro-2(1H)-pyridinethiones6 a. From 3-substituted dihydro-6-methyl-2(1H)-pyrimidinethiones only the 3-aryl compound12 b is converted byDMF to the corresponding dihydro-4-dimethylamino-1-phenyl-2(1H)-pyridinethione14. Also 4-alkylamino- and 4-arylaminodihydro-2(1H)-pyridones18a, b are formed by heating inDMF at 230°C from 1-alkyl- and 1-aryldihydro-2(1H)-pyrimidinones15b, c and of methylene compounds16b, c resp. 2-Methylimino- and 2-phenyliminodihydro-1,3-thiazinethiones19a, b react inDMF viaDimrothrearrangement to the corresponding 1-alkyl- and 1-phenyl-dihydro-2(1H)-pyrimidinethiones1 b, 2 b, 1 c, 2 c and further to 4-alkylamino-and 4-arylaminodihydro-2(1H)-pyridinethiones6 c, d.     

1-Aryl-6-azauracile, 10. Mitt.: Herstellung einiger p-Nitro-und p-Aminophenylderivate

Zusammenfassung In der vorliegenden Arbeit wird die Darstellung des p-Nitrophenylhydrazono-cyanacetylcarbamidsäureäthylesters (1a), eines analogen p-Acetylaminoderivates (1b) sowie die Cyclisierung dieser Substanzen zu den entsprechenden 1-Aryl-5-cyan-6-azauracilen (2a und2b) beschrieben. Diese Nitrile wurden zu den Säuren (3a–3c) verseift und daraus die 1-Aryl-6-azauracile der 1-Phenyl-6-azauracil-5-carbonsäure, die Säure3c durch Reduktion der Säure3a gewonnen. Auf eine leicht verlaufende Ringspaltung des Nitrils2a zum p-Nitrophenylhydrazonocyanacetamid (5a) wird hingewiesen.5a wurde auch durch Kupplung von p-Nitrobenzoldiazoniumacetat mit Cyanacetamid hergestellt.

---

1-Aryl-6-azauracils, X: Synthesis of some p-nitro-and p-aminophenyl derivatives

The preparation of ethyl p-nitrophenylhydrazonocyanoacetyl carbamidate1a, its p-acetylamino analogue and the cyclization of both substances to the corresponding 1-aryl-5-cyano-6-azauracils is described. From the latter, the acids3a–3c and the 1-aryl-6-azauracils4a and4b were prepared in the usual way. Acid3a was also obtained by nitration of1-phenyl-6-azauracil-5-carboxylic acid, and acid3c by subsequent reduction. p-Nitrophenylhydrazonocyanacetamide (5a) may be prepared conveniently by cleavage of the nitrile2a or coupling of p-nitrodiazonium acetate with cyanoacetamide.

     

A new diketopiperazine derivative from a deep sea-derived Streptomyces sp. SCSIO 04496

A new diketopiperazine (DKP) derivative, (6R,3Z)-3-benzylidene-6-isobutyl-1-methyl piperazine-2,5-dione (1), as well as five known DKPs 2–6 was isolated from a deep sea-derived Streptomyces sp. SCSIO 04496. The structure of 1 was elucidated using a combination of 1D and 2D NMR, HR-ESI-MS and chiral-phase HPLC techniques. Compounds 1–6 did not show cytotoxic activity at a concentration of 100 μM in bioactivity assay.     

Conformational Energies in Organic Six-Membered Cyclic Sulfoxides

Ab initio Hartree–Fock calculations at the HF/6?31 G* level of theory for geometry optimization and the MP2/6?31 G*//HF/6?31 G* and B3LYP/6-311G(2df,p)//HF/6?31 G* levels for a single point total energy calculation are reported for the important energy-minimum conformations of 1-oxo-thiane (1), 1-oxo-1,2-dithiane (2), 1-oxo-1,3-dithiane (3), 1-oxo-1,4-dithiane (4), 1,2-dioxo-1,2-dithiane (5), 1,3-dioxo-1,3-dithiane (6), and 1,4-dioxo-1,4-dithiane (7). According to the MP2/6-31G*//HF/6-31G* calculations, while the axial conformations of compounds 1, 2, and 4 are more stable than the equatorial forms by 6.0, 20.0, and 9.9 kJ mol^?1, respectively, the equatorial geometry of 3 is 3.0 kJ mol^?1 more stable than the axial form. The diaxial conformations of 5 and 7 are calculated to have similar energies, but the diaxial form of 6 is about 43 kJ mol^?1 less stable than that of 5 or 7.