Lewis acid-assisted olefin cross-metathesis reaction: an efficient approach for the synthesis of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin and evaluation of their antitumor activity

A series of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin (2a–g) were synthesized via Lewis acid-assisted olefin cross-metathesis reaction using Ti(OⁱPr)₄ 30 mol % and 10 mol % of Grubb’s second generation catalyst with good to excellent yields. Most of these compounds exhibited significant growth inhibitory effects on all the tested cancer cell lines and three compounds (2c, 2d and 2e) showed potent cytotoxic activity.     

Synthesis and characterization of novel five-membered palladacycles

3-(2-Chloroquinolin-3-yl)-1,5-bis(3,4,5-trimethoxy-phenyl)-pentane-2,4-dione derivatives 3a–b were conveniently synthesized in excellent yields (82% each) by tandem Knoevenagel condensation reactions of 2-chloro-3-carbaldehyde-quinoline 1a–b with 3,4,5-trimethoxy acetophenone, followed by a base catalyzed Michael addition, such as DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) with or without solvent. The reactions of 3a–b with Pd(dba)₂ in the presence of PPh₃ (1:2) in degassed acetone provided the dinuclear palladium complexes {Pd(C,N-2-C₉H₄N–CH–[–CH₂CO(3,4,5-(OMe-)₃–C₆H₂-]₂–3-R-6)Cl(PPh₃)}₂ [(R = H (4a), R = OMe (4b)] in moderate yields (38% and 43%), which in turn reacted with an excess of isonitrile XyNC (Xy = 2,6-Me₂C₆H₃) to give the corresponding palladacycles 5a–b in moderate yields (45% and 43%). The palladacycles 5a–b were also obtained in similar yields (32% and 33%) via a one-pot oxidative addition reaction of 3a-b with isonitrile XyNC:Pd(dba)₂ (4:1). The products were characterized by satisfactory elemental analysis and spectral studies (IR, ¹H, and ³¹P NMR). The crystal structure of 5a was determined by X-ray crystallography diffraction studies.     

Metal or ammonium alginates as Lewis base catalysts for the 1,2-addition of silyl nucleophiles to carbonyl compounds

Several metal (Na⁺, Ca²⁺) or ammonium (n-Bu₄N⁺) derivatives of alginic acid, an abundant bio-polymer obtained from the cell walls of brown algae, were synthesized. Their potential to act as organocatalysts to catalyze the 1,2-addition of various silyl derivatives to carbonyl compounds was evaluated for the first time. Ammonium alginate 1h is able to promote the reaction in modest to good isolated yields (up to 98%) affording access to a large range of substrates (β-cyano alcohols or ester, β-substituted methylacrylate or acrylonitrile, and cyanohydrin) by using only 5 mol % of catalyst.     

Reactivity of chlorodeoxypseudoephedrines with oxo-, thio-, and selenocyanates

Herein, the reactivity of chlorodeoxypseudoephedrine hydrochlorides with oxo-, thio-, and selenocyanate nucleophiles is reported. 1,3-Heterazolidine-2-iminium or ammonium salts were obtained stereoselectively in most cases. The hard–soft nature of the calcogen atom determines the mechanistic pathway via an S_N2 (X = O), aziridine intermediate (X = Se), or both (X = S). A simple method to synthesize stereoselectively the trans-isomer of 3,4-dimethyl-5-phenyl-oxazolidine-2-iminium chloride and the cis-isomer of 4-methyl-5-phenyl-oxazoline-2-ammonium chloride, was also found. In addition, heterazolidine-2-imines or amines were liberated from the corresponding salts [Cl⁻ or XCN⁻ (X = O, S, Se)] with aqueous NaOH. Finally, cis-3,4-dimethyl-5-phenyl-oxazolidine-2-iminium chloride, cis-4-methyl-5-phenyl-oxazoline-2-amine, and trans-4-methyl-5-phenyl-selenazoline-2-amine compounds were studied by X-ray diffraction.     

Asymmetric epoxidation of cinnamic acid derivatives by in situ generated dioxiranes of chloroacetones: scope and limitations

Efficient epoxidation of chiral cinnamic acid derivatives has been achieved by in situ generated dioxiranes of chloroacetones with moderate to good diastereoselectivity (dr up to 90:10) in high yields. Reactivity of cinnamic acid derivatives containing different chiral auxiliaries versus chloroacetones–monochloroacetone 3 (MCA), 1,1-dichloroacetone 4 (DCA) and 1,1,1-trichloroacetone 5 (TCA) and Oxone? loading was studied. Both Oxone? loading and reaction time reduce with an increase of chlorine atoms in the acetone. The use of 1.1 equiv of TCA was found to be effective for the epoxidation of cinnamate substrates and enhances the reaction up to 4–10-fold compared to acetone and that also decreases the Oxone? loading. This method provided methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (?)-2, a key intermediate for the synthesis of diltiazem hydrochloride, with >99% of enantiomeric purity.     

Synthesis,anti-inflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

The title compounds 3a–l have been synthesized by the reaction of thiocarbohydrazide with substituted phenoxy acetic acid to obtained substituted 1,2,4-triazoles (1). Compound 1 was treated with various substituted aromatic aldehydes which results in 4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-2H-1,2,4-triazol-3(4H)-thiones (2a–g), further 2a–g is converted to 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3a–l) derivatives by the reaction with chloroacetic acid. All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 2-[4-(2,4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3d), 2-[4-(4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3e), 2-[4-(2,4-dichlorobenzylideneamino)-5-[(2,4-dichlorophenoxy)methyl]-4H-1,2,4-triazol-3-yl thio] acetic acid (3j) and 2-[5-[(2,4-dichlorophenoxy)methyl)]-4-(4-chlorobenzylideneamino)-4H-1,2,4-triazol-3-yl thio] acetic acid (3k) showed significant anti-inflammatory activity with P < 0.001 (63.4%, 62.0%, 64.1% and 62.5% edema inhibition, respectively), as compared to the standard drug diclofenac (67.0%) after third hour respectively and also compounds 3j, 3k exhibited significant analgesic activity with P < 0.001 (55.9% and 54.9% protection, respectively) and less ulcerogenic activity as compared with standard drug aspirin (57.8%).     

Diazenyl schiff bases: Synthesis,spectral analysis,antimicrobial studies and cytotoxic activity on human colorectal carcinoma cell line (HCT-116)

A series of diazenyl schiff bases have been synthesized by reaction of salicylaldehyde containing azo dyes with various substituted aniline derivatives in the presence of acetic acid as catalyst. The structures of diazenyl derivatives were determined by FTIR, UV–vis, ¹H NMR, ¹³C NMR, CHN analysis, fluorimetric and mass spectroscopic studies. The synthesized derivatives were screened for their in vitro antimicrobial activity against various Gram-positive (S. aureus, B. subtilis, B. cereus), Gram-negative (S. typhi, S. enterica, E. coli, P. aeruginosa) bacterial and fungal (C. albicans, A. niger and A. fumigatus) strains, using cefadroxil (antibacterial) and fluconazole (antifungal) as standard drugs. The diazenyl schiff bases were also screened for their cytotoxicity against human colorectal carcinoma cell line (HCT-116) using 5-fluorouracil as standard drug by Sulforhodamine-B Stain (SRB) assay. The schiff bases exhibited significant activity toward both Gram-positive, Gram-negative bacterial and fungal strains. Most of the synthesized derivatives showed high activity against S. enterica. 4-((2,5-Dichlorophenyl)diazenyl)-2-((3-bromophenylimino)methyl)phenol (SBN-40) was found to be very active against S. aureus, B. cereus and E. coli, with MIC = 0.69 (µM/ml × 10²). The compound 4-((2-bromophenyl)diazenyl)-2-((4-nitrophenylimino)methyl)phenol (SBN-13) possessed comparable activity (IC₅₀ = 7.5 µg/ml) to the standard drug 5-fluorouracil (IC₅₀ = 3.0 µg/ml) against human colorectal carcinoma cell line (HCT-116).     

Preparation of (2,2-difluoroethenylidene)bis(tributylstannane) and arylation reaction: efficient approach to 1,1-diaryl-2,2-difluoroethenes

Reaction of 2,2-difluoro-1-tributylstannylethenyl p-toluenesulfonate (1) with bis(tributyltin) in the presence of 5 mol % Pd(PPh₃)₄ and 30 equiv LiBr in THF at reflux temperature for 7 h afforded (2,2-difluoroethenylidene)bis(tributylstannane) (2) in a 70% yield. Coupling reaction of 2 with aryl iodides in the presence of 5 mol % Pd(PPh₃)₄ and 5 mol % CuI in DMF at 80 °C for 3–4 h provided the coupled products 3 in 59–85% yields.     

Enantioselective construction of all-carbon quaternary spirocenters through a Pd-catalyzed asymmetric intramolecular ipso-Friedel–Crafts allylic alkylation of phenols

A novel catalytic asymmetric synthetic method for making spirocyclohexadienones with an all-carbon quaternary spirocenter was developed based on the Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of phenols. When 5 mol % of the Pd catalyst and 12 mol % of (?)-9-NapBN (?)-3e were used, the spirocyclic adduct was obtained with up to 93% ee, albeit with low chemical yield. On the other hand, when using 6 mol% of the Trost ligand (R,R)-3k, the spirocyclic adducts were obtained in good yields with up to 89% ee (diastereoselectivity = 9.2:1).     

New 2-acyl-1,3-dioxane derivatives from (1R)-(−)-myrtenal: stereochemical effect on their relative ability as chiral auxiliaries

Four 3,10-pinanediol derivatives 1a–d, prepared in 50–72% global yields from (1R)-(−)-myrtenal 2, were treated with (RO)₂CHCOR₃ (R₃ = CH₃, Ph) to afford 2-acyl-1,3-dioxanes 3a–f. The latter were submitted to nucleophilic additions using several Grignard reagents to mainly afford carbinols generated by re diastereofacial attack (85–99% yield, ⩾88:12 dr). The lowest diastereoselectivity was observed when PhLi or hydrides were used as nucleophiles. Only an equatorial substituent at C-3 modifies the diastereoselectivity of the nucleophilic additions.     

A green route to enantioenriched (S)-arylalkyl carbinols by deracemization via combined lipase alkaline-hydrolysis/Mitsunobu esterification

Herein we report results of the chemoenzymatic deracemization of a range of secondary benzylic acetates 1a–9a via a sequence of hydrolysis with CAL-B lipase in non-conventional media, combined with esterification of the recovered alcohol according to the Mitsunobu protocol following an enzymatic kinetic resolution (KR). The KR of racemic acetates 1a–9a via an enzymatic hydrolysis, with CAL-B lipase and Na₂CO₃, in non-aqueous media was optimized and gave high selectivities (E ? 200) at good conversions (C >49%) for all of the substrates studied. This method competes well with the traditional one performed in a phosphate buffer solution. The deracemization using Mitsunobu inversion gave the (S)-acetates in moderate to excellent enantiomeric excess 75% < ee < 99%, in acceptable isolated yields 70% < yield < 89%, and with some variations according to the acetate structure.     

General and highly efficient fluorinated-N-heterocyclic carbene–based catalysts for the palladium-catalyzed Suzuki–Miyaura reaction

A general and highly efficient trifluoromethylated-N-heterocyclic carbene (NHC)-based catalyst for the palladium-catalyzed Suzuki–Miyaura reaction was reported. In the presence of the catalyst, reactions of non-activated aryl chlorides and triflates with aryl boronic acids occurred at room temperature with good to excellent yields (63–98%). In addition, catalysts generated from a combination of Pd(OAc)₂/imidazolium salt 6a is not only effective for the coupling of heteroaryl boronic acid with aryl halides and heteroaryl halides, but also efficient for coupling of other heteroaryl halides and heteroaryl boronic acids. Finally, the catalyst is highly effective for Suzuki–Miyaura reaction of aryl bromides and chlorides with 0.01–0.1 mol % loading if the temperature was raised at refluxed THF/H₂O.     

Activation of C–H bonds of hydrocarbons by the ArH–alkali metal systems in THF (ArH – naphthalene,biphenyl, anthracene,phenanthrene, trans-stilbene,pyrene). Alkylation of naphthalene and toluene with ethene

Systems based on naphthalene and alkali metals (Li, Na, K) in THF are able to induce the alkylation of naphthalene with ethene at room temperature and atmospheric pressure. The highest activity in this reaction is exhibited by the naphthalene–potassium system which converts naphthalene into 1-ethylnaphthalene (1) and small amounts of two isomeric dihydro derivatives of 1 in a yield of 85% (24 h, K:C₁₀H₈ = 2:1). The same alkylation products are formed when metallic sodium is used instead of potassium. The interaction of ethene with the naphthalene–lithium system (24 h, Li:C₁₀H₈ = 2:1) affords 1 together with 1-n-butylnaphthalene (4), 1-n-hexylnaphthalene (5), 1-n-oktylnaphthalene (6) and dihydro derivatives of 5 and 6 in a total yield of 60%. Alkylation of toluene with ethene in the naphthalene–alkali metal systems leads to the formation of higher monoalkylbenzenes. The greatest toluene conversion (48%, 24 h) is observed on using the lithium-containing system (Li:C₁₀H₈ = 2:1), in the presence of which a mixture of n-propylbenzene (11), n-pentylbenzene (12), 3-phenylpentane (13) and 3-phenylheptane (14) is produced from ethene and toluene. On the replacement of lithium by sodium or potassium, only 11 and 13 are obtained. A treatment of biphenyl, phenanthrene, trans-stilbene, pyrene and anthracene with alkali metals in THF also gives systems capable of catalyzing the alkylation of toluene with ethene at 22 °C. Of particularly active is the stilbene–lithium system (Li:stilbene = 3:1) which converts toluene into a mixture of 11–14, n-heptylbenzene and 5-phenylnonane in a yield of 58%. In all cases, the rate of the alkylation considerably increases in the presence of the solid phase of alkali metal. The mechanism of the reactions found is discussed.     

Enthalpic changes on mixing two couples of S- and R-enantiomers of benzyl-(1-phenyl-ethyl)-amine, 1-phenylethylamine, 1-phenyl-ethanol,butyric acid oxiranylmethyl ester, 4-methyl-[1,3]dioxolan-2-one, 2-chloro-methyloxirane and 3-hydroxyisobutyric acid methyl ester at T = 298.15 K

Enthalpies of mixing of (R)- and (S)-enantomers of liquid chiral compounds such as benzyl-(1-phenyl-ethyl)-amine (1), 1-phenylethylamine (2), 1-phenyl-ethanol (3), butyric acid oxiranylmethyl ester (4), 4-methyl-[1,3]dioxolan-2-one (5), 2-Chloromethyloxirane (6) and 3-hydroxyisobutyric acid methyl ester (7) have been measured over the whole range of mole fractions at 298.15 K, albeit very small values. Mixing of heterochiral liquids of R-1 + S-1, R-5 + S-5, and R-7 + S-7 realized enthalpic stabilization over the whole range of mole fractions, whereas that of R-2 + S-2, R-3 + S-3, R-4 + S-4, and R-6 + S-6 realized enthalpic destabilization over entire compositions. The extreme values of enthalpies of mixing and the intermolecular interaction obtained by the molecular mechanics calculations showed a linear correlation, except few the compounds measured.     

New thioether–dithiolate complexes of Cp1Ir and some reactivity features

The reaction of [Cp1IrCl₂]₂ (Cp* = η⁵ ? C₅Me₅) with the tridentate 3-thiapentane-1,5-dithiolate ligand, S(CH₂CH₂S^?)₂ (tpdt), led to the formation of [Cp1Ir(η³ ? tpdt)] (1) in 81% isolated yield. Subsequent reactions of 1 with [Cp1IrCl₂]₂ in 2:1 and 1:1 molar equiv ratios resulted in the formation of [Cp1Ir(μ ? η²:η³ ? tpdt)Cp1IrCl][PF₆] (2) and [Cp1Irμ ? η²:η³ ? tpdt)Cp1IrCl][Cp1IrCl₃] (3) in 86 and 79% yields, respectively, based on 1, whereas the reactions of 1 with [(COD)IrCl]₂ (COD = 1,5-cyclooctadiene) in 2:1 and 1:1 molar equiv ratios resulted in the formation of the homo-bimetallic derivatives Cp1Ir(μ ? η¹:η³ ? tpdt)(COD)IrCl (4) (92% yield) and [Cp1Ir(μ ? η²:η³ ? tpdt)(COD)Ir] [(COD)IrCl₂] (5) (82% yield). Reactions between 1 and [(COD)RhCl]₂, yielded the hetero-bimetallic derivatives Cp1Ir(μ ? η¹:η³ ? tpdt)(COD)RhCl (6) and [Cp1Ir(μ ? η²:η³ ? tpdt)(COD)Rh][(COD)RhCl₂] (7), in 92 and 93% yields, respectively. The reaction of 1 with methyl iodide gave mono-methylated derivative [Cp1Ir(η³-C₄H₈S₃Me)]I (8) (93% yield). All these compounds have been comprehensively characterized.     

Chemoenzymatic synthesis of piperoxan,prosympal, dibozane,and doxazosin

The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (±)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee ～99%, E = 535) at 258 mmol (50 g/L) substrate concentration.     

Triplet-sensitized photolysis of alkoxycarbonyl azides in solution and matrices

Photolysis of azides 1–4 in methanol, which have a built-in intramolecular triplet sensitizer, yields mainly carbamates 5–8. Laser flash photolysis of 1–4 shows formation of their triplet-excited ketone, which decays by intramolecular energy transfer to form triplet nitrenes 1n–4n. Irradiating 1–3 in matrices yields isocyanic acid, whereas photolysis of 4 forms isocyanate 4i. The depletion rate of the azide bands between 2100 and 2200 cm^?1 is different than the rate of formation for the isocyanic acid bands at ～2265 cm^?1; thus, the formation of isocyanic acid is a stepwise process. Irradiating 1 in matrices produces an absorption band due to nitrene 1n (λ_max ～ 343 nm), which is depleted upon further irradiation, whereas the absorption due to 4-acetyl benzaldehyde (λ_max ～ 280 nm) increases with prolonged irradiation. We propose that formation of isocyanic acid in matrices must come from secondary photolysis of nitrenes 1n–3n. This mechanism is further supported by calculation, which show that the estimated transition state for 1n–4n to fall apart to yield alkoxy and cyanato radicals is only ～34 kcal/mol above the ground state of the triplet nitrenes and thus the cleavage can take place photochemically. Thus, nitrenes 1n–4n can be formed selectively, but these intermediates are highly photosensitive and undergo secondary photolysis in matrices.     

New thioether–dithiolate complexes of Cp1Ir and some reactivity features

The reaction of [Cp1IrCl₂]₂ (Cp* = η⁵ − C₅Me₅) with the tridentate 3-thiapentane-1,5-dithiolate ligand, S(CH₂CH₂S⁻)₂ (tpdt), led to the formation of [Cp1Ir(η³ − tpdt)] (1) in 81% isolated yield. Subsequent reactions of 1 with [Cp1IrCl₂]₂ in 2:1 and 1:1 molar equiv ratios resulted in the formation of [Cp1Ir(μ − η²:η³ − tpdt)Cp1IrCl][PF₆] (2) and [Cp1Irμ − η²:η³ − tpdt)Cp1IrCl][Cp1IrCl₃] (3) in 86 and 79% yields, respectively, based on 1, whereas the reactions of 1 with [(COD)IrCl]₂ (COD = 1,5-cyclooctadiene) in 2:1 and 1:1 molar equiv ratios resulted in the formation of the homo-bimetallic derivatives Cp1Ir(μ − η¹:η³ − tpdt)(COD)IrCl (4) (92% yield) and [Cp1Ir(μ − η²:η³ − tpdt)(COD)Ir] [(COD)IrCl₂] (5) (82% yield). Reactions between 1 and [(COD)RhCl]₂, yielded the hetero-bimetallic derivatives Cp1Ir(μ − η¹:η³ − tpdt)(COD)RhCl (6) and [Cp1Ir(μ − η²:η³ − tpdt)(COD)Rh][(COD)RhCl₂] (7), in 92 and 93% yields, respectively. The reaction of 1 with methyl iodide gave mono-methylated derivative [Cp1Ir(η³-C₄H₈S₃Me)]I (8) (93% yield). All these compounds have been comprehensively characterized.     

An efficient and solvent-free one-pot synthesis of dihydropyrimidinones under microwave irradiation

An efficient synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives using formic acid as catalyst, from aldehydes,β-ketoester and urea(thiourea) without solvent under the irradiation of microwave is described. Compared with the classical Biginelli reaction, this new method has the advantage of good yields (77-94% for aromatic aldehydes) and short reaction time (3-8 min).     

Enantioselective intramolecular Morita–Baylis–Hillman reaction using chiral bifunctional phosphinothiourea as an organocatalyst

Chiral cyclohexane-based phosphinothioureas were found to be efficient organocatalysts for the enantioselective intramolecular Morita–Baylis–Hillman reaction of ω-formyl-enone. Among the solvents screened, t-BuOH was the best one which provided good yield and enantioselectivity. Moreover in the presence of 3 mol % of phosphinothiourea 2b, the desired products were obtained in good-to-excellent yields with up to 98% ee under mild reaction conditions.