Nitrileketenimine tautomerism in substituted alkylidene malononitriles and alkylidene cyanoacetates: A characteristic UV absorption band

Several alkylidene malononitriles (1b,1d,1e,2b and4b) and alkylidene cyanoacetates (1a,2a and4a) studied exhibit a long wavelength UV absorption band around 355 nm which shows a hyperchromic effect in the presence of ethanolic alkali. This band has been assigned to the ketenimine tautomer (5). Addition of water to1b,1e and2b gives the corresponding pyridine diols (7a,7b and8a) respectively. Similarly, addition of ethanol to1e and2b gave the corresponding ethoxypyridine derivatives (7c and8b). Mechanism of formation of these compounds is discussed. Structures, as well as mechanism of formation of1c,7c and10 obtained from1b,1e and2b respectively on standing at room temperature are also discussed.     

One-pot multicomponent synthesis of some 5,6-dihydro-benzo[h]quinoline derivatives

5,6-Dihydrobenzo[h]quinoline derivatives 4a–f and 5a–c were prepared via condensation of the corresponding arylidenes 2, with 1-tetralone in the presence of ammonium acetate and sodium methoxide, respectively, following thermal, microwave and ultrasound methodologies. The yields of 4a–f were moderate when the latter two methodologies used, but the products were pure. Ultrasound and microwave irradiation methods were also used in the synthesis of 4-aryl-3-cyano-1,2,5,6-tetrahydro-benzo[h]quinoline-2-ones (6a–e) and its analogues 7a,b. The majority of compounds 4–7 were synthesized via one-pot multicomponent reactions of aldehydes, active cyanomethylene compounds, 1-tetralone and ammonium acetate. Attempts to cyclocondensation of the aminocyano derivative 4a,d with acetic anhydride in presence of conc. H₂SO₄ failed; instead the acetylamino derivative 8 was isolated. On the other hand, refluxing of 4d with formamide in DMF led to the formation of dihydrobenzo-pyrimidoquinoline 9 giving good yield. All prepared condensates were structurally elucidated by various spectroscopic methods. Screening of the potential cytotoxicity for compounds 4a–f on five cell lines, namely: colorectal carcinoma (HCT-116), Hepatocellular carcinoma (HEPG2), Human breast adenocarcinoma (MCF7), Cervix adenocarcinoma (HELA) and Glioblastoma (U251), did not show any cytotoxic activity.     

Nucleophilic subsitution at silicon: Synthesis of sterically-hindered bis(2,6-di-t-butylaryloxy)silanes

The reaction of the monomethylsilane (8a) with two equivalents of the 4-(carboalkoxy)-2,6-di-t-butyl-substituted phenol (7b) in toulene using triethylamine as an acid acceptor gave the bis(aryloxy) adduct (9a). The analogus reaction of the dimethylsilane (8b) with sodium 2,6-di-t-butyl-4-(methoxycarboxyl)-phenolate (7a) gave only the monosubstitution product (10a). The reaction of the corresponding phenolate (7e) with 8b gave a mixture of 7a, 10a, and bis-adduct (9b), whereas, in the presence of 15-crown-5, the bis-adduct 9b was obtained. The bis-adducts 9c–e were prepared in an analogous manner. The reaction of n-hexyl 3,5-di-t-butyl-4-hydoxylbenzoate (7h) with the diphenylsilane (8c) gave only the monosubstitution product 12, while forcing conditions gave, unexpectedly, the methyl ether 13. The reaction of 4-(carboalkoxyethyl)-2,6-di-t-butylphenol (16a) with 8a gave the bis adduct. The reaction of 16a with 8b in THF, without a crown ether, gave a low yield of the monosubstitution product. The bis-adducts 17b–c were obtained by the reaction of 8b with the corresponding phenolates (16a–b) in tetraglyme. Compound 17b was also obtained by the reaction of 8b with 16a in THF with a crown ether. These results are discussed in terms of charge dispersal in the phenolate ion and the corresponding effect upon both ion-pairing and aggregation in solution.     

Cleavage and some modifications of the 7-amide group of the cephamycins

The cleavage and some modifications of the 7-amide group of cephamycins are described. Cephamycin derivatives 16b, c which were synthesized from the naturally occurring cephamycin C (16a) were converted to the corresponding oxamic acid derivatives 17a, e respectively by the reaction with oxalyl chloride and successive treatment with water. The reaction of the oxamic acid 17a with diphenylcarbodiimide gave 7-aminocephamycinoic acid (7-ACMA) benzhydryl ester (21a) which was further converted to cefoxitin (21c). These compounds 17a, b, c, d, e, f thus obtained from cephamycin C appear to be favorable intermediates for the syntheses of cephamycin analogues such as cefmetazole (28c).     

Untersuchungen an diazoverbindungen und aziden—XLV: Elektrophile diazoalkansubstitution an phosphoryldiazomethanen mit thiapyryliumsalzen

Electrophilic diazoalkane substitution of the phosphoryl diazomethanes 2a–2e with 2,6-di-tert-butylthiapyrylium-tetrafluoroborate (1) yields the 4-(diazomethyl)-4H-thiapyranes 3a–3e; the olefin 5 is formed as by-product in all cases. The μ-allylpalladium chloride catalyzed decomposition of 3a and c leads via a 1,2-H-shift to the 4-methylen-4H-thiapyranes 6a and b; competing 1,2-C-migration, which should afford the thiepines 7, could not be observed. The 4-methylen-4H-thiapyranes are characterized by addition of perchloric acid (6a→8) and 4-phenyl-1,2,4-triazolin-3,5-dione (6a,b→9a,b). Corresponding substitution reactions with 2,4,6-triphenylthiapyrylium-perchlorate (10) at 3a–3c in so far take an unusual way as the bis(6H-pyrrolino[1,2-b]pyrazoles) 11a–11c are formed instead of (diazomethyl)-4-(or 2)H-thiapyranes. The constitution of the heterobicycles is established by X-ray structure analysis of 11c.     

Synthesis of new chiral keto alcohols by baker’s yeast

Fourteen chiral α- and β-keto alcohols 2a–2r were synthesized by the asymmetric reduction of their corresponding diketones 1a–1r via baker’s yeast. In addition, ten corresponding racemic α-keto alcohols were synthesized by the benzoin condensation of their corresponding aldehydes, which were used for the determination of the ee values through their chiral resolution on chiral HPLC. Amongst the 15 diketones, 1j and chiral α-keto alcohols 2i, 2j and chiral β-keto alcohol 2r are novel compounds. Six keto alcohols 2b, 2c, 2d, 2f, 2h and 2p were synthesized by baker’s yeast for the first time. There are some studies in the literature where baker’s yeast was applied to the diketones 1a, 1g, 1e, 1k and 1n under various conditions different to those reported herein. The yields and the ee values of these studies were not as high as ours. All of the keto alcohols synthesized were characterized by IR, NMR (¹H and ¹³C), and MS. The relationship between the structure of the diketone and the yield, diastereoselectivity and enantiomeric excess is also discussed.     

Novel thiosemicarbazone derivatives containing benzimidazole moiety: Green synthesis and anti-malarial activity

A series of (E)-2-[5-chloro-1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (7a–7t) and (E)-2-[1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (8a–8t) were prepared via the synthesis of 1-(substituted-1H-benzimidazol-2-yl) ethanol (3a–3b) which was synthesized by the condensation of substituted o-phenylenediamine (2a–2b) with dl-lactic acid (1) followed by oxidation with sodium hypochlorite in mild acidic condition to form the corresponding ketones 4a–4b. Final compounds were formed by condensation of 4a–4b with different thiosemicarbazides 6a–6t. A total of 40 compounds were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR, Mass spectral technique and elemental analysis, in addition they were evaluated for anti-malarial properties. Among the compounds tested 7o, 7p, 7q, 7r, 7s, 8e and 8h exhibited good antimalarial activity in vitro.     

The acid-mediated intramolecular 1,3-dipolar cycloaddition of derived 2-nitro-1,1-ethenediamines for the synthesis of novel fused bicyclic isoxazoles

The discovery of a novel synthesis of new fused bicyclic isoxazoles, for example, N-methyl-3-phenyl-5,6-dihydro-4H-isoxazolo[3,4-c]azepin-8-amine (2a), N-methyl-3-phenyl-4,5-dihydroisoxazolo[3,4-c]pyridin-7-amine (2b) and N-methyl-3-phenyl-4H-pyrrolo[3,4-c]isoxazol-6-amine (2d) in high yield is reported. We speculate that the reaction proceeds via acid-mediated intramolecular 1,3-dipolar cycloaddition from 2-nitro-1,1-ethenediamines 1a,b,d.     

Synthesis and in vitro cytotoxic evaluation of some novel hexahydroquinoline derivatives containing benzofuran moiety

A series of new ethyl 4-(2-(benzofuran-2-yl)-4-substituted-1,4,5,6,7,8-hexahydroquinolin-1-yl)-benzoate 3a–c was synthesized by Michael condensation of benzofuran chalcones 1a–c and cyclohexanone to give 2-(2-benzofuranyl)-4-substituted-5,6,7,8-tetrahydro-4-H -chromene 2a–c, followed by reaction of the latter with ethyl 4-aminobenzoate. Condensation of 3a–c with different amines afforded the corresponding amides 4a–e. On the other hand, upon treatment compounds 3a–c with hydrazine hydrate gave the benzohydrazide derivatives 5a–c. The reaction of compounds 5a–c with different thio/isocyanate gave the corresponding thiosemicarbazide and semicarbazide derivatives 6a–c. Meanwhile compounds 5a–c were reacted with ethyl cyanoacetate and different β-dicarbonyl compounds such as acetyl acetone, ethyl acetoacetate, and diethyl malonate to afford pyrazolyl derivatives 7a, b; 8a, b; 9a, b; and 10a–c, respectively. Moreover, 5a–c were reacted with carbon disulfide to synthesize the corresponding oxadiazolyl derivatives 11a–c, while their condensation with different aromatic aldehydes gave the corresponding Schiff bases 12a–d. Cytotoxic evaluation of some of the newly synthesized compounds against human hepatocellular carcinoma cell lines (HepG-2) revealed that the tested compounds produce promising inhibitory effect against the growth of HepG-2 cells with IC₅₀ values ranged from 11.9 to 19.3 µg/mL.     

Unconventional nucleotide analogues—XVIII: Ring expansion of uridine halocarbene adducts. Synthesis of diazepine nucleosides

The diastereomeric adducts of dichlorocarbene and dibromocarbene with (protected) uridine react with alcohols to give diazepine nucleosides (4a–c). The endo-chloro-exo-fluorocarbene adducts (1d and 2d) also react analogously to yield diazepine nucleoside 4d. On the other hand, the corresponding exo-chloro-endo-fluoro isomers (1e and 2e) are totally inert under the same reaction conditions. The adducts 1b and 2b yield, besides the ring-expanded product (4b), uridine-5-aldehyde (6a) in varying amounts which depend upon the conformation of the diastereomer. These results are explained on the basis of a possible role of the ring-oxygen of the ribose moiety.     

Stereoselective synthesis of uncommon α,α′-dialkyl-α-aminoacids. Part 1

The alkylation of the diastereomeric mixture of chiral morpholinone derivatives 4 and 5 occurs with good yield and trans induction. Cleavage of the alkylated products 6a,b,c,e gives enantiomerically pure uncommon (and sterically constrained) α,α′-dialkyl-α-aminoacids. The absolute configuration of the new stereocentres of 4, 5, 6 and 7 has been assigned on the basis of the ¹H-NMR spectra and NOE measurements.     

Furanyl spiroketals: thermodynamic control of remote asymmetry

(E,E)-2-Alkyl-8-furanyl-1,7-dioxa-spiro[5.5]undecanes (1a-i) have been prepared in good yield and with very high diastereoselectivity from lactones (2a-e) and alkynes (3a,b) using lithium acetylide coupling, hydrogenation, desilylation and acid catalysed cyclisation/equilibration.     

Generation and fate of free radicals of Δ2-oxazolin-5-ones

The reaction of Δ² -oxazolin-5-ones 1a and 1b with nickel peroxide in benzene produces the corresponding 4,4-dehydrodimers 5a and 5b as the main products in yields over 75%. Under the same conditions, the 2-aryl -4-methyl - Δ²-oxazolin-5-ones 1c, 1d and 1e yield five products. In the case of 1c, the constituents of the product mixture were separated and identified as two 4,4-dehydrodimers ( meso and d] pair isomers) 5c and 5c', (40.7%), 2,4-dehydrodimer 6c (34.9%), acetylanisoylimide 8c (8.5%) and anisamide (15.9%). Adequate mechanistic schemes are discussed to account for the products formed.     

Improved approaches and structures of new ferrocenyl carbene complexes of chromium, tungsten, and molybdenum

Ferrocenyllithium reacts with M(CO)₆ (M = Cr, W, Mo) in THF to give, after alkylation at oxygen, the corresponding carbene complexes 3a-c in good yield. Complexes 3a,b were characterized by X-ray analysis. These complexes react with pentylamine to give the corresponding aminocarbene complexes 7a-c and with allylamine to give, in the case of chromium and tungsten, the corresponding and expected aminonocarbene complexes 8a,b, and for molybdenum, complex 9c in which the double bond is already coordinated to the metal. 8a,b could be converted in 9a,b in excellent yield. The structure of 9a could be confirmed by an X-ray analysis. Alkylations at nitrogen could be carried on complex 9c as well as on complexes 9a,b.     

Etude des petits cycles—XXXVI. Photo-oxygenation d'alkylidenecyclopropanes. Syntheses specifiques d'alkenylcyclopropanols,de β′-hydroxy α-enones et d'α,α′-dienones

The dye-sensitized photo-oxygenation of alkylidenecyclopropanes 1a–4a at –50°C gives the hydroperoxydes 1b–4b, which were reduced in situ by PPh₃ into 1-alkenylcyclopropanols 1c–4c in high yield. At higher temperatures, 1b–4b rearranged exclusively into β′-hydroxy α-enones 1d–4d if pyridine was added (α,α′-dienones 1e–4e are also formed competitively in absence of pyridine). At 3°C the photosensitised oxygenation of alkylidenecyclopropanes 1a–4a gives ketones 1k–4k, cyclobutanones 1i–4i and β′-hydroxy α-enones 1d–4d. The origin of products is discussed.     

Solvent-dependent reactivities of acyclic nitrones with β-diketones: catalyst-free syntheses of endiones and enones

Reactions of the nitrones ^?O⁺N(Me)C(H)Ar 1 (Ar=phenyl 1a, 4-methylphenyl 1b, 2,4,6-trimethylphenyl 1c, and anthracen-9-yl 1d) with the cyclic β-diketones 1,3-indandione 2 or barbituric acid 3 in CH₂Cl₂, afford the corresponding endiones 2′a–2′d or 3′a–3′d. In contrast, dimedone 4 reacts with 1a or 1b to give the endione 4′a or 4′b and the bis-adduct 4″a or 4″b. Nevertheless, reaction of 4 with 1c or 1d in CH₂Cl₂ furnishes only the endione adducts 4′c or 4′d. However, the reaction of 4 with 1a or 1b in methanol gives only 4″a or 4″b, respectively. Among acyclic β-diketones only malonic acid 7 reacts with 1a–1c. Reaction of 7 with 1a in CH₂Cl₂ forms cinnamic acid 7″a, whereas in the case of 1b, the endione 7′b and (E)-3-p-tolylacrylic acid 7″b are obtained. The nitrone 1c reacts with 7 in CH₂Cl₂ to afford the endione 7′c or with acetone yielding (E)-4-mesitylbut-3-en-2-one 8. X-ray analyses are reported for 4′c, 5, and 7″b. In addition, the calculated acidity of the hydrogen at the α-C atom is shown to correlate with the reactivity of the β-diketones with nitrones.     

Synthesis of silicon-functionalized 7-silanorbornadienes and their thermolysis and photolysis

A series of 7-silanorbornadienes were prepared and characterized by X-ray crystallographic analysis. 2,3-Benzo-7-mesityl-1,4,5,6-tetraphenyl-7-silanorbornadiene (1a) was prepared by the [4+2] cycloaddition reaction of 1-mesityl-2,3,4,5-tetraphenyl-1-sila-2,4-cyclopentadiene (4) with benzyne. 7-Hydro 1a was converted into 7-chloro-substituted silanorbornadiene 1b. Treatment of 1b with lithium phenylamide and lithium phenylthiolate gave 7-phenylamino-substituted silanorbornadiene 1c and 7-phenylthio-substituted silanorbornadiene 1d, respectively. Reductive lithiation of 1b with lithium naphthalenide afforded 7-lithiated silanorbornadiene 1f, which reacted with chlorotrimethylsilane to give 7-trimethylsilyl-substituted silanorbornadiene 1e. Stereochemistry at the bridging silicon during these transformations was determined by X-ray crystallographic analysis. Thermolysis of 1 produced corresponding silylenes 5, which were trapped with triethylsilane to give disilanes 6. Photolysis of 1 except 1c also afforded corresponding silylenes 5. Theoretical calculation of the models of silanorbornadienes was performed at the MP2/6-31+G(d, p) level.     

(1-Benzylpiperazin-2-yl)methanols: novel EPC synthesis from (S)-serine and transformation into ligands for central nervous system receptors

A novel three-step synthesis of 4-substituted-(1-benzylpiperazin-2-yl)methanols 5a–5c is described starting from the methyl ester of the proteinogenic amino acid (S)-serine, which involves the diastereomeric oxazolidine derivatives 11a–11c as key intermediates. 5b and 5c were transformed into the chiral, non-racemic bicyclic lactams 14b and 14c via Swern oxidation followed by Wittig reaction and subsequent hydrogenation. In the screening for central nervous system receptor affinity the butyl derivative 14b was found to have promising interaction with σ₁-receptors (K_i=345 nM).     

Zur reaktionsweise von triafulvenen mit azomethinyliden

The reaction of the azomethine ylides 2a–c with cyclopropenones 3 and of 2a with methylene cyclopropenes 7 leads via (3+3)-cycloaddition to pyridones-4 5 and 1,4 - dihydro - N - methyl - 4 - methylene - pyridines 8, respectively. The merocyanine systems 8 exhibit marked solvatochromic and thermochromic properties.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.