Janez Košmrlj

Click-Triazole N2 Coordination to Transition-Metal Ions Is Assisted by a Pendant Pyridine Substituent

We report that 1-(2-picolyl)-1,2,3-triazole (click triazole) forms stable complexes with transition-metal ions in which the coordination involves the triazole N2 nitrogen atom and the pendant 2-picolyl group. This is exemplified by model compound 1-(2-picolyl)-4-phenyl-1H-1,2,3-triazole (L(x)) and its complexes with transition-metal ions of Pt(II), Pd(II), Cu(II), Ru(II), and Ag(I). The coordination was investigated experimentally and theoretically. Ligand L(x) easily reacted at room temperature with cis-[PtCl(2)(DMSO)(2)], [Pd(CH(3)CN)(4)](BF(4))(2), CuCl(2), [RuCl(mu-Cl)(eta(6)-p-cymene)](2), and AgNO(3) to give stable chelates [PtCl(2)L(x)] (1), [Pd(L(x))(2)](BF(4))(2) (2), [CuCl(2)(L(x))(2)] (3), [RuCl(eta(6)-p-cymene)L(x)]OTf (4), and [Ag(2)(L(x))(2)(NO(3))(2)] (5), respectively, in 60-98% yield. The structures of 1-5 were unambiguously confirmed by NMR spectroscopy and single-crystal X-ray diffraction analysis. Density functional theory calculations were carried out in order to theoretically investigate the stabilization factors in 1-5. A comparison of the chelating properties of ligand L(x) was made with structurally similar and isomeric 1-(2-aminoethyl)-substituted 1,2,3-triazole (L(y)) and 4-(2-aminoethyl)-substituted 1,2,3-triazole (L(z)). The complexation affinity of L(x) was attributed to pi-back-donation from the metal to the pendant pyridine side arm, whereas the stability of the complexes involving L(y) and L(z) mainly originates from efficient pi-back-donation to the triazole ring.

1-(2-Picolyl)-substituted 1,2,3-triazole as novel chelating ligand for the preparation of ruthenium complexes with potential anticancer activity

The 1,4-disubstituted 1,2,3-triazole ligand prepared by click chemistry 1-(2-picolyl)-4-phenyl-1H-1,2,3-triazole (ppt) was investigated as novel chelating ligand for Ru(II) complexes with potential antitumor activity. The preparation and structural characterization, mainly by NMR spectroscopy in solution and by X-ray crystallography in the solid state, of four new Ru(II) complexes is reported: two isomeric Ru-dmso compounds, trans,cis-[RuCl(2)(dmso-S)(2)(ppt)] (1) and cis,cis-[RuCl(2)(dmso-S)(2)(ppt)] (2), and two half-sandwich Ru-[9]aneS(3) coordination compounds, [Ru([9]aneS(3))(dmso-S)(ppt)][CF(3)SO(3)](2) (3) and [Ru([9]aneS(3))Cl(ppt)][CF(3)SO(3)] (4). In all compounds ppt firmly binds to ruthenium in a bidentate fashion through the pyridyl nitrogen atom and the triazole N2, thus forming a puckered six-membered ring. The chemical behavior in aqueous solution of the water-soluble complexes 3 and 4 was studied by UV-Vis and NMR spectroscopy and compared to that of the previously described organometallic analogue [Ru(η(6)-p-cymene)Cl(ppt)][Cl] (5) in view of their potential antitumor activity. Compounds 3-5 were tested also in vitro for cytotoxic activity against two human cancer cell lines, one sensitive and one resistant to cisplatin, in comparison with cisplatin. Compound 4, the one that aquates faster, was found to be more cytotoxic than cisplatin against human lung squamose carcinoma cell line (A-549).

Suzuki reactions on chloropyridazinones: an easy approach towards arylated 3(2H)-pyridazinones

Abstract The synthesis of 4-aryl-5-methoxy-, 5-aryl-4-methoxy- and 4,5-diaryl-3(2H)-pyridazinones via Suzuki palladium-catalysed cross-coupling reactions with the corresponding chloro-3(2H)-pyridazinones is described.

A selective approach to pyridine appended 1,2,3-triazolium salts.

A selective and highly efficient strategy to obtain a library of pyridine appended 1,4-disubstituted-3-methyl-1,2,3-triazolium salts is described. It features pyridine nitrogen protection at click-derived pyridyl-triazoles through N-oxidation with subsequent N3 alkylation of the triazole ring and deprotection. Triazolium salts are obtained in high yield and purity in either a stepwise or one-pot protocol. Preliminary data indicate their remarkable efficiency in palladium-catalyzed Suzuki-Miyaura catalysis in the environmentally benign solvent water.

Syntheses of 3-Aminoquinoline- 2,4(1H,3H)-diones

Reaction of 3-chloro- (2) and 3-bromoquinoline-2,4(1H,3H)-diones (3) with excess of primary alkyl- or arylamines in dimethylformamide provides the corresponding 3-alkyl- or 3-arylamino derivatives (4). Compounds (4) with the primary amino group at the 3 position were best prepared by reaction of 2 with in situ generated ammonia under anhydrous conditions. An alternative approach to the primary amines (4) via reduction of 3-azidoquinoline-2,4(1H,3H)-diones (5) was investigated. The reduction of 5 with zinc in acetic acid gave moderate to good yields of the desired products, while the reaction with triphenylphosphine afforded exclusively 4-hydroxyquinolin-2(1H)-one (1).

Synthesis of novel 3-acyloxy-1,3-dihydro-2H-indol-2-ones and isomeric 4- acyl-1,4-dihydro-3,1-benzoxazin-2-ones: Double rearrangement of 3- hydroxyquinoline-2,4(1H,3H)-diones

Abstract Substituted 3-hydroxyquinoline-2,4(1 H ,3 H )-diones 3 were transformed into 3-acyloxy-1,3-dihydro-2 H -indol-2-ones 4 and isomeric 4-acyl-1,4-dihydro-3,1-benzoxazin-2-ones 5 . The influence of the substituents and the reaction conditions on the course of the reaction was studied. In the proposed mechanism a double rearrangement takes place; α-ketol rearrangement of 3 , leading to α-hydroxy-β-diketone intermediate 8 , is followed by a rearrangement to the isomeric α-ketol-esters 4 and 5 .

RuII, OsII, and IrIII Complexes with Chelating Pyridyl–Mesoionic Carbene Ligands: Structural Characterization and Applications in Transfer Hydrogenation Catalysis

Chelating ligands with one pyridine donor and one mesoionic carbene donor are fast establishing themselves as privileged ligands in homogeneous catalysis. The synthesis of several new Ir(III)-Cp*- and Os(II)-Cym complexes (Cp* = pentamethylcyclopentadienyl, Cym = p-cymene=4-isopropyl-toluene) derived from chelating pyridyltriazolylidenes where the additional pyridine donor was incorporated via the azide part of the triazole is presented. Furthermore, different 4-substituted phenylacetylene building blocks have been used to introduce electronic fine-tuning in the ligands. The ligands thus can be generally described as 4-(4-R-phenyl)-3-methyl-1-(pyridin-2-yl)-1H-1,2,3-triazol-5-ylidene (with R being H (L(1)), Me (L(2)), OMe (L(3)), CN (L(4)), CF3 (L(5)), Br (L(6)) or NO2 (L(7))). The corresponding complexes (Ir-1 to Ir-7 and Os-1 to Os-7) were characterized by standard spectroscopic methods, and the expected three-legged, piano-stool type coordination was unambiguously confirmed by X-ray diffraction analysis of selected compounds. Together with Ru(II) analogues previously reported by us, a total of 21 complexes were tested as (pre)catalysts for the transfer hydrogenation of carbonyl groups, showing a remarkable reactivity even at very low catalyst loadings. The electronic effects of the ligands as well as different substrates were investigated. Some mechanistic elucidations are also presented.

New series of isoniazid hydrazones linked with electron-withdrawing substituents.

A series of new isoniazid hydrazones was synthesized by two procedures. In the first isoniazid was activated with diethoxymethyl acetate and condensed with the appropriate anilines. Alternatively, substituted anilines were activated by diethoxymethyl acetate and subsequently condensed with isoniazid. NMR study confirmed that both synthetic approaches gave the same tautomer. All compounds were screened for in vitro antimycobacterial activity. Most of them exhibited the same activity against Mycobacterium tuberculosis (MIC 1 μmol L(-1)) as isoniazid (INH), better activity against Mycobacterium kansasii 325/80 (MIC 0.125-0.250 μmol L(-1)), high value of selectivity index (SI) and IC(50) between 0.0218 and 0.326 mmol L(-1). Compound 2o with the best SI was used as a model compound for the stability test and was found to be stable at neutral pH, but under acidic conditions it slowly hydrolysed.

Lactone Pathway to Statins Utilizing the Wittig Reaction. The Synthesis of Rosuvastatin

The first entry to statins via lactonized side chain is reported, exemplified by the synthesis of rosuvastatin. The key step is Wittig coupling of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carbaldehyde and phosphonium salt of an appropriately functionalized pyrimidine heterocycle. One-pot deprotection and hydrolysis of the resulting 4-O-TBS rosuvastatin lactone provided rosuvastatin in high yield.

New complexes of lanthanide chlorides.: Reversible isomerization in octahedral [LaCl3(HMPA)3] and the crystal structure of fac-[SmCl3(HMPA)3]

Abstract Complexes of [LnCl3L] (Ln=La, Nd, Sm, Eu, and L=diethylene glycol dimethyl ether, diglyme; Ln=La, Pr, and L=dimethoxyethane, DME) were prepared from the lanthanide oxides and hydrogen chloride, which was formed in situ from chlorotrimethylsilane and water. When hexamethylphosphoramide (HMPA) was added to the suspension of the prepared DME and diglyme complexes in toluene, fac-[LnCl3(HMPA)3] (Ln=La, Pr, Nd, Sm, Eu, Gd) complexes, isomorphous according to the unit cell determination, were formed. The crystal structure of [SmCl3(HMPA)3] was determined. Each samarium atom is octahedrally coordinated by three chlorine atoms and three HMPA molecules, which are distributed in a facial mode. The exchange of coordinated and free HMPA, as well as the reversible fac–mer isomerization of [LaCl3(HMPA)3], was observed by variable temperature 1H NMR spectroscopy. The associative mechanism of the exchange and isomerization was proposed.