Synthesis of 2,6-di(pyrazol-1-yl)-4-bromomethylpyridine, and its conversion to other 2,6-di(pyrazol-1-yl)pyridines substituted at the pyridine ring

Two routes to 2,6-di(pyrazol-1-yl)-4-hydroxymethylpyridine (1) from 2,6-dihydroxy-isonicotinic acid, in four and six steps, are reported. Reaction of 1 with 48% HBr yields 2,6-di(pyrazol-1-yl)-4-bromomethylpyridine (2), which is a powerful precursor to a range of new tridentate ligands for transition metals functionalised at the pyridine ring. As a proof of principle, we describe the further elaboration of 2 to give two 2,6-di(pyrazol-1-yl)pyridines bearing nucleobase substituents, and the back-to-back ligand 1,2-bis[2,6-di(pyrazol-1-yl)pyrid-4-yl]ethane. Crystal structures of two of these new derivatives are presented.     

Regioselective synthesis of optically active (pyrazolyl)pyridines with adjacent quaternary carbon stereocenter: chiral N,N-donating ligands

Novel optically active 2-(pyrazol-1-yl)pyridines have been prepared using resolved the O-methyl ether of atrolactic acid as a source of the adjacent quaternary carbon stereocenter. Different regioisomers were formed selectively in the reaction of 2-hydrazinopyridines with the chiral 1,3-diketone and in the nucleophilic substitution of 2-chloropyridines with the potassium salt of the chiral pyrazole. The second route gave 2-(pyrazol-1-yl)pyridines with the stereogenic center neighboring the coordinating nitrogen in the pyrazole ring. Also, new C₂-symmetric chiral ligands based on 2,6-bis(pyrazolyl)pyridine and 6,6′-bis(pirazolyl)-2,2′-bipyridine structures were obtained.     

Synthesis of 2,2-di(pyrazol-1-yl)enones via the 2:1 coupling of pyrazoles and acylbromoacetylenes in solid alumina

Pyrazoles were reacted with acylbromoacetylenes in solid Al₂O₃ at room temperature to afford 2,2-di(pyrazol-1-yl)enones in 22–69% yield. The reaction proceeds via isolable intermediates, (Z)-2-bromo-2-(pyrazol-1-yl)enones. This unexpected 2:1 coupling is in contrast to similar reactions of pyrroles, furans and thiophenes, which give the corresponding acylethynyl derivatives. This reaction opens a one-pot route to inaccessible gem-dipyrazolylenones, which have potential applications as bidentate chelating ligands and building blocks for drug design.     

A simple one-pot synthesis of functionalised 6-(indol-3-yl)-2,2′-bipyridine derivatives via multi-component reaction under neat condition

A series of 4-aryl-6-(1H-indol-3-yl)-2,2-bipyridine-5-carbonitrile derivatives were synthesized via a one-pot multi-component reaction of aromatic aldehydes, 3-(cyanoacetyl)indole and 2-acetyl pyridine in ammonium acetate by conventional heating and microwave irradiation under solvent-free condition. Also a series of 6,6′-di(1H-indol-3-yl)-4,4′-diaryl-2,2′-bipyridine-5,5′-dicarbonitrile derivatives were synthesized using cinnamils, 3-(cyanoacetyl)indole and ammonium acetate. The methodology affords high yields of product at short reaction time.     

Unexpected product distributions in the synthesis of 2,6-bis-(indazolyl)pyridine and 2-(pyrazol-1-yl)-6-(indazolyl)pyridine

Reaction of 2-bromopyridine with 2 equiv of sodium indazolide in diglyme at 140 °C affords 2,6-bis-(indazol-1-yl)pyridine and 2-(indazol-1-yl)-6-(indazol-2-yl)pyridine in purified yields of 24% and 68% respectively. A similar reaction, using 1 equiv of sodium indazolide at 70 °C, gives a low-yield mixture of 2-(indazol-1-yl)-6-bromopyridine and 2-(indazol-2-yl)-6-bromopyridine. Both these intermediates are transformed into 2-(pyrazol-1-yl)-6-(indazol-1-yl)pyridine and 2,6-di(pyrazol-1-yl)pyridine upon treatment with 1 equiv of sodium pyrazolide in diglyme at 140 °C. These observations imply that the indazolyl group is a leaving group comparable to a bromo substituent under nucleophilic attack by pyrazolide or indazolide ions under these conditions. No reaction was observed between 2-(pyrazol-1-yl)-6-bromopyridine and 1 equiv of sodium indazolide under the same conditions. A single crystal structure of its iron(II) complex confirmed the regiochemistry of 2,6-bis-(indazol-1-yl)pyridine, and revealed significant conformational flexibility in the distal ligand indazolyl groups.     

Synthesis and characterization of 6,6″′-bis(anthracen-9-yl)-2,2′;6′,2″;6″,2″′-quaterpyridine

New bianthracene-quaterpyridine ligand 6,6″′-bis(anthracen-9-yl)-2,2′;6′,2″;6″,2″′-quaterpyridine L has been obtained in a multistep synthesis using Suzuki–Miyaura and Stille-type coupling reactions. The dianthracene ligand L has four nitrogen-donor atoms and can form different supramolecular architectures with transition metal ions. Ligand L and intermediate compounds have been characterized by spectroscopic methods and elemental analyses. 2-(Anthracen-9-yl)-6-bromopyridine and 6-(anthracen-9-yl)-6′-bromo-2,2′-bipyridine have been also characterized by X-ray crystallography.     

Structural diversity in iron(II) complexes of 2,6-di(pyrazol-1-yl)pyridine and 2,6-di(3-methylpyrazol-1-yl)pyridine

The syntheses, magnetochemistry and crystallography of [Fe(L1)2]I0.5[I3]1.5 (1), [Fe(L1)2][Co(C2B9H11)2]2 (2) and [Fe(L2)2][SbF6]2 (3) (L1 = 2,6-di(pyrazol-1-yl)pyridine; L2 = 2,6-di(3-methylpyrazol-1-yl)pyridine) are described. Compounds 1 and 3 are high-spin between 5-300 K. For 1, this reflects a novel variation of an angular Jahn-Teller distortion at the iron centre, which traps the molecule in its high-spin state. No such distortion is present in 3; rather, the high-spin nature of this compound may reflect ligand conformational strain caused by an intermolecular steric contact in the crystal lattice. Compound 2 exhibits a gradual high --> low spin transition upon cooling with T(1/2) = 318 +/- 3 K, that is only 50% complete. This reflects the presence of two distinct, equally populated iron environments in the solid. One of these unique iron centres adopts the same angular structural distortion shown by 1 and so is trapped in its high-spin state, while the other, which undergoes the spin-crossover, has a more regular coordination geometry. In contrast with 3, the solvated salts [Fe(L2)2][BF4]2 x 4 CH3CN and [Fe(L2)2][ClO4]2 x (CH3)2CO both undergo gradual thermal spin-transitions centred at 175 +/- 3 K.     

Synthesis of chelating tertiary phosphine oxides via palladium-catalysed C–P bond formation

Bis(diphenylphosphine oxides) and bis(tert-butyl(phenyl)phosphine oxides) of 1,10-phenanthroline, 2,2′-bipyridine and pyridine were synthesised in good yields via the Pd(OAc)₂/dppf mediated cross-coupling reactions between 6,6′-dichloro-2,2′-bipyridine, 2,9-dichloro-1,10-phenanthroline, or 2,6-dichloropyridine and the corresponding secondary phosphine oxides. These compounds represent potential tetradentate chelating ligands for ions of f-block elements.     

Platinum(IV) complexes with α,ω-bis(pyrazol-1-yl) alkanediyl and diethyl ether/thioether ligands. Crystal structures of dibromodimethyl[1,2-bis(pyrazol-1-yl)ethane]platinum(IV) and trimethyl-bis[2-(pyrazol-1-yl)ethyl]etherplatinum(IV) tetrafluoroborate

Reactions of the flexible α,ω-bis(pyrazol-1-yl) compounds 1,2-bis(pyrazol-1-yl)ethane (L1), 1,8-bis(pyrazol-1-yl)-n-octane (L2), bis[2-(pyrazol-1-yl)ethyl]ether (L3) and bis[2-(pyrazol-1-yl)ethyl]thioether (L4) with precursor organometallic platinum complexes ([(PtBr₂Me₂)_n], [(PtIMe₃)₄] and [(PtMe₂(cod)]/I₂) are described herein. The spectroscopic characterization of the platinum(IV) products of these reactions [PtBr₂Me₂{pz(CH₂)_mpz}], m = 2 (1) or 8 (2), [PtI₂Me₂{pz(CH₂)₂pz}] (3), [PtMe₃(pzCH₂CH₂OCH₂CH₂pz)][BF₄] (4) and [PtMe₃(pzCH₂CH₂SCH₂CH₂pz)][CF₃SO₃] (5), where ‘pz’ is pyrazol-1-yl, is discussed. Furthermore, solid state structures of 1, a complex with a seven-membered chelate ring, and 4, a complex bearing the neutral κ²N,N′,κO ligand bis[2-(pyrazol-1-yl)ethyl]ether (L3) are reported.     

N^N^C platinum(II) and palladium(II) cyclometallates of 6,6′-diphenyl-2,2′-bipyridine, L: Crystal and molecular structure of [Pd(L-H)Cl]

Reaction of K₂[PtCl₄] or Na₂[PdCl₄] with 6,6′-diphenyl-2,2′-bipyridine, L, gives the cyclometallated species [Pt(L-H)Cl], 1, and [Pd(L-H)Cl], 2, respectively, where L-H is a terdentate N^N^C anionic ligand originated by direct activation of a C(sp²)-H bond. The crystal structure of 2 has been solved by X-ray diffraction and compared to that of the analogous complex [Pd(L′-H)Cl] L′ = 6-phenyl-2,2′-bipyridine. The second phenyl ring in 2 entails a considerable distortion of the coordination around the metal. A similar distortion is also to be expected in the analogous compound 1, due to the almost equal covalent radii of palladium(II) and platinum(II).From the complexes 1 and 2 the chloride can be displaced with AgBF₄ and substituted by CO or PPh₃ to give the corresponding cationic species. By reaction of 1 with Na[BH₄] substitution of H⁻ for Cl⁻ can be achieved: the rare hydrido complex [Pt(L-H)H], stabilized only by nitrogen ligands, was isolated in the solid state and fully characterized in solution. It is noteworthy that in the case of the 6-phenyl-2,2′-bipyridine the analogous terminal hydride [Pd(L′-H)H] is unstable. In platinum chemistry the reaction of 6-substituted 2,2′-bipyridines is known to give either N^N^C or N′^C(3) rollover cyclometallation, depending on the nature of the metal precursor. In the case of 6,6′-Ph₂-2,2′-bipy cyclometallation was also shown to undergo multiple C-H activation giving the C^N^C pincer complex [Pt(L-2H)(DMSO)]. The latter species can be related to complex 1: indeed its reaction with HCl produces complex 1 and [Pt(L-H)(DMSO)Cl], a rollover species with a pendant phenyl substituent.     

Synthesis of 1,8-di(pyrazol-1-yl)-3,6-dioxaoctane and its derivatives

From pyrazole, 3,5-dimethylpyrazole, and 1,8-dibromo-3,6-dioxaoctane in a superbasic medium KOH-DMSO the corresponding 1,8-di(pyrazol-1-yl)-3,6-dioxaoctanes were synthesized and converted into iodo-, nitro-, amino-, and formylderivatives.     

Synthesis and structure of novel 6-(pyrazol-1-yl)-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-ol derivatives

New 6-(pyrazol-1-yl)pyrazolo[3,4-b]pyridin-3-ol compounds were synthesized by cyclization reaction from 2,6-dichloro-4-methylnicotinonitrile. Their derivatives exist as the 3-hydroxy tautomer. The structure of the compound 1a of one of the resulting compounds was studied in detail by X-ray diffraction.     

New multidentate heteroscorpionate ligands: N-Phenyl-2,2-bis(pyrazol-1-yl)thioacetamide and ethyl 2,2-bis(pyrazol-1-yl)dithioacetate as well as their derivatives

New multidentate heteroscorpionate ligands, N-phenyl-2,2-bis(3,5-dimethylpyrazol-1-yl)thioacetamide PhHNCSCH(3,5-Me₂Pz)₂ (1), N-phenyl-2,2-bis(3,4,5-trimethylpyrazol-1-yl)thioacetamide PhHNCSCH(3,4,5-Me₃Pz)₂ (2), and ethyl 2,2-bis(3,5-dimethylpyrazol-1-yl)dithioacetate EtSCSCH(3,5-Me₂Pz)₂ (8), have been synthesized and their coordination chemistry studied. These heteroscorpionate ligands can act as monodentate, bidentate, or tridentate ligands, depending on the coordinate properties of different metals. Reaction of W(CO)₆ with 1 or 2 under UV irradiation yields monosubstituted carbonyl tungsten complexes W(CO)₅L (L = 1 or 2), in which N-phenyl-2,2-bis(pyrazol-1-yl)thioacetamide acts as a monodentate ligand by the s-coordination to the tungsten atom. In addition, these monosubstituted tungsten complexes have also been obtained by heating ligand 1 or 2 with W(CO)₅THF in THF. While similar reaction of Fe(CO)₅ with 1, 2, or 8 under UV irradiation results in tricarbonyl iron complexes PhHNCSCH(3,5-Me₂Pz)₂Fe(CO)₃ (5), PhHNCSCH(3,4,5-Me₃Pz)₂Fe(CO)₃ (6), and EtSCSCH(3,5-Me₂Pz)₂Fe(CO)₃ (9), respectively, in which N-phenyl-2,2-bis(pyrazol-1-yl)thioacetamide or ethyl 2,2-bis(pyrazol-1-yl)dithioacetate acts as a bidentate ligand through one pyrazolyl nitrogen atom and the CS π-bond in an η²-C,S fashion side-on bonded to the iron atom to adopt a neutral bidentate κ²-(π,N) coordination mode. Treatment of the lithium salt of 1 with Co(ClO₄)₂ · 6H₂O gives complex [PhNCSCH(3,5-Me₂Pz)₂]₂Co(ClO₄) with the oxidation of cobalt(II) to cobalt(III), in which N-phenyl-2,2-bis(3,5-dimethylpyrazol-1-yl)thioacetamide acts as a tridentate monoanionic κ³-(N,N,S) chelating ligand by two pyrazolyl nitrogen atoms and the sulfur atom of the enolized thiolate anion.     

Lanthanide Complexes of Polyacid Ligands derived from 2, 6-bis(pyrazol-1-yl)pyridine,pyrazine, and 6, 6′-bis(pyrazol-1-yl)-2, 2′-bipyridine: Synthesis and luminescence properties

The synthesis of three novel pyrazole-containing complexing acids, N,N,N′,N′-{2, 6-bis[3-(aminomethyl)pyrazol-1-yl]-4-methoxypyridine}tetrakis(acetic acid)( 1 ), N,N,N′,N′-{2, 6-bis[3-(aminomethyl)pyrazol-1-yl]pyrazine}-tetrakis(acetic acid) ( 2 ), and N,N,N′,N′-{6, 6′-bis[3-(aminomethyl)pyrazol-1-yl]-2, 2′-bipyridine}tetrakis(acetic acid) ( 3 ) is described. Ligands 1–3 formed stable complexes with Eu^III, Tb^III, Sm^III, and Dy^III in H₂O whose relative luminescence yields, triplet-state energies, and emission decay lifetimes were measured. The number of H₂O molecules in the first coordination sphere of the lanthanide ion were also determined. Comparison of data from the Eu^III and Tb^III complexes of 1–3 and those of the parent trisheterocycle N,N,N′,N′-{2, 6-bis[3-(aminomethyl)pyrazol-l-yl]pyridine}tetrakis(acetic acid) showed that the modification of the pyridine ring for pyrazine or 2, 2′-bipyridine strongly modify the luminescence properties of the complexes. MeO Substitution at C(4) of 1 maintain the excellent properties described for the parent compound and give an additional functional group that will serve for attaching the label to biomolecules in bioaffinity applications.     

An efficient route to 5,5″-diaryl-2,2′:6′,2″-terpyridines through 2,6-bis(1,2,4-triazin-3-yl)pyridines

A new route to substituted 2,2′:6′,2″-terpyridines based on a new method for the synthesis of substituted 2,6-bis(1,2,4-triazin-3-yl)pyridines and their inverse electron demand Diels-Alder reaction is shown to be an efficient strategy for the synthesis of structurally diverse terpyridine ligands.     

Synthesis and characterizations of 3,3′-bis(diphenylphosphinoamine)-2,2′-bipyridine and 3,3′-bis(diphenylphosphinite)-2,2′-bipyridine and their chalcogenides

New bis(phosphinoamine) and bis(phosphinite) derivatives of 2,2′-bipyridine were prepared through a single step reaction of 3,3′-diamino-2,2′-bipyridine or 3,3′-dihydroxy-2,2′-bipyridine with diphenylchlorophosphine, respectively. Their P = E chalcogenides (E = O, S, Se) were also prepared. All the new compounds were characterized by elemental analysis, IR and NMR spectroscopies. The molecular structure of 3,3′-bis(diphenylthiophosphinite)-2,2′-bipyridine was elucidated by single-crystal X-ray crystallography.     

Enantioselective alkynylation to aldimines catalyzed by chiral 2,2′-di(2-aminoaryloxy)-1,1′-binaphthyl-copper(I) complexes

The enantioselective alkynylation of aldimines with terminal acetylenes catalyzed by chiral Cu(I) complexes with (R)-2,2′-di(2-aminoaryloxy)-1,1′-binaphthyl ligands (7) was examined. Chiral C₂-symmetric N,N-ligands 7, which have primary aniline moieties, were readily prepared from inexpensive (R)-1,1′-binaphthol (BINOL) as a chiral source. In particular, the reaction of N-benzylidenebenzeneamine 1a with phenylacetylene 2a proceeded smoothly in the presence of 5 mol % of (CuOTf)₂·C₆H₅CH₃ and 10 mol % of (R)-7d at room temperature for 24 h, and the corresponding propargylamine 3a was obtained with up to 82% ee.     

6,6′-Dimethyl-2,2′-bipyridine-4-ester: A pivotal synthon for building tethered bipyridine ligands

We describe an efficient and scalable synthesis of 4-carbomethoxy-6,6′-dimethyl-2,2′-bipyridine starting from easily available substituted 2-halopyridines and based on the application of modified Negishi cross-coupling conditions. This compound is a versatile starting material for the synthesis of 4-functionalized 2,2′-bipyridines bearing halide, alcohol, amine, and other functionalities, suitable for conjugation to biological material (2a-c, 3a-g). The utility of this compound in the construction of more complex architectures was further demonstrated by the synthesis of two bifunctional lanthanide chelators; an open chain ligand based on one 2,2′-bipyridine unit and a cryptand based on three 2,2′-bipyridine units [N₂(bpy)₃COOMe]. In the field of luminophoric biolabels, the photophysical properties of the corresponding Eu(III) cryptate are reported.     

InCl3 mediated one-pot synthesis of indol-3-yl pyridine and 2,2′-bipyridine derivatives through multi-component reaction

A simple protocol for the efficient preparation of 2-(1H-Indol-3-yl)-6-methoxy-4-aryl pyridine-3,5-dicarbonitrile and 6-methoxy-4-aryl-2,2′-bipyridine-5-carbonitrile derivatives has been achieved through one-pot multi-component reaction under reflux condition. Particularly valuable features of this method include high yields of products in short reaction time and broad substrate scope. It is an efficient and promising synthetic strategy to build indol-3-yl pyridine and 2,2′-bipyridine skeletons.     

Reactivity of bis(pyrazol-1-yl)methanes functionalized by 2-hydroxyphenyl and 2-methoxyphenyl on the methine carbon atom with W(CO)5THF

Reactions of 2-hydroxyphenyl and 2-methoxyphenylbis(pyrazol-1-yl)methanes as well as 2-hydroxyphenyl and 2-methoxyphenylbis(3,5-dimethylpyrazol-1-yl)methanes with W(CO)₅THF have been carried out. Heating 2-hydroxyphenylbis(pyrazol-1-yl)methane (L¹) with W(CO)₅THF in THF at reflux yielded complex (L¹)W(CO)₄.L¹, while similar reaction of 2-hydroxyphenylbis(3,5-dimethylpyrazol-1-yl)methane (L²) with W(CO)₅THF resulted in the cleavage of a C_sp3-N bond to generate 1,2-bis(2-hydroxyphenyl)-1,2-bis(3,5-dimethylpyrazol-1-yl)ethane (L) and pyrazole derivative W(CO)₅(3,5-Me₂PzH) (Pz = pyrazol-1-yl). These two fragments were connected together through strong O…H-N and O-H…N hydrogen bonds to form complex L.[W(CO)₅(3,5-Me₂PzH)]₂. The analogous results were observed in the treatment of 2-methoxyphenylbis(pyrazol-1-yl)methane (L³) with W(CO)₅THF, which gave product L′.[W(CO)₅(PzH)]₂ (L′ = 1,2-bis(2-methoxyphenyl)-1,2-bis(pyrazol-1-yl)ethane) as well as certain amount of complex (L³)W(CO)₄. In addition, during the reaction of 2-methoxyphenylbis(3,5-dimethylpyrazol-1-yl)methane (L⁴) with W(CO)₅THF, partial decomposition reactions took place to yield complexes (L⁴)W(CO)₄ and W(CO)₅(3,5-Me₂PzH), but no hydrogen bond was found between these two moieties.