One-pot four-component synthesis of novel isothiourea-ethylene-tethered-piperazine derivatives.

An efficient metal-free four-component approach for the synthesis of piperazine derivatives tethered to an isothiourea group through an ethylene link was developed. 1,4-Diazabicyclo[2.2.2]octane (DABCO) salts, generated in situ through the reactions of DABCO with various alkyl bromides, reacted with phenylisothiocyanate (PITC) and amines in a one-pot manner to give the target products. Initially, through two parallel nucleophilic paths, DABCO and the secondary amine adds to the alkyl bromide and PITC, respectively. The process is followed by the combination of the two respective intermediates to produce the final products by forming a new C-S bond with the expense of a C-N bond cleavage. Consequently, various DABCO salts and secondary amines were tolerated well in this protocol to afford the isothiourea-ethylene-tethered-piperazine compounds in good to high yields.

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer's Disease.

A novel series of coumarin derivatives linked to the N-benzyl triazole group were synthesized and evaluated against 15-lipoxygenase (15-LOX), and acetyl- and butyrylcholinesterase (AChE and BuChE) to find the most potent derivative against Alzheimer's disease (AD). Most of the compounds showed weak to moderate activity against ChEs. Among the most active BuChE and 15-LOX inhibitors, 8l and 8n exhibited an excellent neuroprotective effect, higher than the standard drug (quercetin) on the PC12 cell model injured by H2O2 and significantly reduced aggregation of amyloid Aß1-42, with potencies of 1.44 and 1.79 times higher than donepezil, respectively. Compound 8l also showed more activity than butylated hydroxytoluene (BHT) as the reference antioxidant agent in reducing the levels of H2O2 activated by amyloid ß in BV2 microglial cells. Kinetic and ligand-enzyme docking studies were also performed for better understanding of the mode of interaction between the best BuChE inhibitor and the enzyme. Considering the acceptable BuChE and 15-LOX inhibition activities as well as significant neuroprotection, and anti-amyloid aggregation activities, 8l and 8n could be considered as potential MTDLs for further modification and studies against AD.

Synthesis and structure-activity relationship study of tacrine-based pyrano[2,3-c]pyrazoles targeting AChE/BuChE and 15-LOX.

A series of tacrine-based pyrazolo[4',3':5,6]pyrano[2,3-b]quinolines and related compounds were designed and synthesized for targeting AChE, BuChE and 15-LOX enzymes in the field of Alzheimer's disease therapy. Most of compounds showed potent activity against cholinesterases and mild potency toward 15-LOX enzyme. In particular, compounds 29, 32 and 40 displayed inhibition at nano-molar level against AChE and BuChE (IC50s = 0.005-0.08 µM), being more potent than reference drug tacrine. Moreover, compound 32 with IC50 value of 31 µM was the most potent compound against 15-LOX. The cytotoxicity assay on HepG2 cells revealed that compounds 29 and 32 showed no significant cytotoxic activity even at concentration of 50 µM. The cytotoxicity of compounds 29 and 32 was significantly less than that of tacrine at higher concentrations.

Ultrasound mediation for efficient synthesis of monoarylidene derivatives of homo- and heterocyclic ketones.

Ultrasonic irradiation was efficiently used for high yield synthesis of monoarylidene derivatives of cyclic systems directly from the reaction of ketone with various aldehydes under solvent-free conditions. Reactions took place rapidly in the presence of catalytic amounts of pyrrolidine, while no significant formation of the undesired bis by-products was observed. Moreover, the procedure was applicable to both homo- and heterocyclic ketones.

rac-3-[(3-Chloro-anilino)(4-chloro-phenyl)meth-yl]thian-4-one.

In the title compound, C(18)H(17)Cl(2)NOS, the thio-pyran-one ring adopts a chair conformation, with the substituent in the axial position. The dihedral angle between the two benzene rings is 89.43 (1)°. In the crystal, mol-ecules form inversion dimers through inter-molecular N-H⋯O hydrogen bonds [graph set R(2) (2)(8)].

rac-3-[(Anilino)(naphthalen-2-yl)-methyl]thian-4-one.

In the title compound, C(22)H(21)NOS, the thio-pyran-one ring adopts a chair-like conformation with the substituent in the axial position. The relative configuration of the racemic compound is 3R,7S according to the numbering scheme used in this publication. In the crystal packing, centrosymmetric dimers are built up via N-H⋯O hydrogen bonds, with graph set R(2) (2)(8).

(2E,6E)-2,6-Bis(4-methyl-benzyl-idene)cyclo-hex-3-en-1-one.

The title compound, C(22)H(20)O, shows an approximately planar cyclo-hexenone ring [maximum deviation = 0.069 (4) Å], with a disordered position of the C=C bond [ratio = 0.71 (2)/0.29 (2)]. The benzene rings of the 4-methyl-benzyl-idene units, attached in the 2- and 6-positions to the cyclo-hexenone ring, are rotated in the same direction by 28.6 (4) and 22.4 (4)°, with respect to the mean plane of the cyclo-hexenone ring [fraction 0.71 (2); maximum deviation = 0.06 (3) Å]. In the crystal, mol-ecules are packed in the manner of a distorted hexa-gonal rod packing with their long axes all aligned along [201]. A number of C-H⋯π inter-actions stablize the crystal structure.

(4Z,6Z)-4,6-Bis(4-meth-oxy-benzyl-idene)-2,2-dimethyl-1,3-dioxan-5-one.

The title compound, C(22)H(22)O(5), crystallizes with two independent mol-ecules in the asymmetric unit, both of which possess pseudo-C(s) symmetry. The central 1,3-dioxanone rings have envelope conformations, with the C atom bearing the two methyl groups at the flap. The benzene rings of the meth-oxy-benzyl-idene units, attached in the 4- and 6-positions on the central 1,3-dioxanone rings, are tilted in the same direction with dihedral angles varying between 8.2 (1) and 18.1 (1)°. The crystal packing is influenced by π-stacking inter-actions of the parallel displaced type [centroid-centroid distance of 3.723 (1) Šfor mol-ecule 1 and 3.884 (1) Šfor mol-ecule 2, with ring slippages of 1.432 and 1.613 Å, respectively] and the T-shaped type, with the long mol-ecular axes all aligned along [010].

Switching the reactivity of dihydrothiopyran-4-one with aldehydes by aqueous organocatalysis: Baylis-Hillman, aldol, or aldol condensation reactions.

An aqueous medium containing catalytic amounts of a tertiary amine was employed to direct the chemoselectivity of the reaction of aldehydes with 1a. With DBU, 2 was formed at room temperature as a rare exemplary of Baylis-Hillman reactions in heterocyclic enones. DABCO alternated the pathway toward an aldol reaction to form syn/anti mixtures of 3 with the syn isomers being the major products. With Et(3)N, aldol condensation dominated.

Diels-alder reactions of styrylcyclohexenones: an efficient procedure for the synthesis of substituted dehydrodecaline derivatives.

The Diels-Alder reaction of styrylcyclohex-2-enone derivatives 1 with N-phenylmaleimide was shown to be an efficient pathway for the synthesis of substituted dehydrodecaline derivatives. At elevated temperatures, mixtures of endo/exo adducts were formed, while in the presence of TiCl4 exclusive formation of the endo stereoisomer was observed. Spectroscopic analysis and X-ray crystallography confirmed the formation of the endo adducts.

Convenient ultrasound mediated synthesis of substituted pyrazolones under solvent-free conditions.

Smooth condensation of hydrazine derivatives with various beta-keto esters was performed under solvent-free conditions by using ultrasound irradiation to facilitate the formation of pyrazolone derivatives in good to excellent amounts within very short time periods.

Ultrasound promoted aminolysis of epoxides in aqueous media: a rapid procedure with no pH adjustment for additive-free synthesis of beta-aminoalcohols.

An efficient and environmentally friendly procedure promoted by ultrasound irradiation is developed for stereoselective ring opening of various epoxides with aromatic and aliphatic amines under aqueous conditions in the presence of no catalyst or additive. Chemoselectivity of the protocol is shown by competition of piperidine and aniline to react with different epoxides resulting in exclusive formation of the respective products of piperidine.

Lithium bromide as a flexible, mild, and recyclable reagent for solvent-free Cannizzaro, Tishchenko, and Meerwein-Ponndorf-Verley reactions.

A room temperature convenient disproportionation or reduction of aldehydes prompted by lithium bromide and triethylamine is described in a solvent-free environment. Distribution of the products to selectively direct the process toward Cannizzaro or Tishchenko reactions is controlled by the type of workup selection. The presence of hydrogen donor alcohols in the mixture completely diverts the process toward the Meerwein-Ponndorf-Verley reaction.

Ultrasound promoted protection of alcohols: an efficient solvent-free pathway for the preparation of silyl ethers in the presence of no additive.

Various types of alcohols and phenols were rapidly protected by hexamethyldisilazane in good to excellent yields at room temperature using high-intensity ultrasound irradiation in the presence of no solvent or any additive. Good to excellent chemoselectivity was observed for competitive protection of hydroxyl groups in favor of sterically less hindered alcohols. Exclusive protection of phenols in the presence of aromatic amines was also demonstrated successfully.

Room-temperature Cannizzaro reaction under mild conditions facilitated by magnesium bromide ethyl etherate and triethylamine.

[reaction: see text] A room-temperature convenient Cannizzaro reaction prompted by magnesium bromide ethyl etherate and triethylamine is described for smooth conversion of aromatic aldehydes into their respective alcohols and carboxylic acids. The methodology is applicable to both inter- and intramolecular reactions and could be directed to obtain the carboxylic moiety in the form of an acid, an amide, or an ester compound depending on the selected reaction conditions or workup procedure.