Synthetic pathways to a family of pyridine-containing azoles-promising ligands for coordination chemistry

A series of pyridine-containing pyrazoles, isoxazoles, imidazoles, oxazoles, thiazoles, oxadiazoles, triazoles, and 1,3,4-triazepines were synthesized and characterized with the aim of their future study as conjugated building blocks for the construction of coordination compounds.


Introduction
The design of coordination polymeric frameworks with unique structures and valuable application properties is a topical area in comprehensive coordination and material chemistry. 1,2any studies are concentrated on metal complexes based on pyridyl-bearing ligands.These ligands are represented by the general formula Py-X-Py, where X is a conjugating unit between two exo-dentate pyridines.The simplest ligand of this type is 4,4′-bipyridyl, which is widely used in constructing coordination polymers. 3Typical X's are C=C and C≡C bonds, azo-and imine-groups, benzene, triazine and tetrazine rings, or a combination of the fragments listed. 4ecently, several research groups published papers on the coordination ability of polydentate ligands based on five-membered azoles as a central linker between two pyridines. 5,6,7,8n this paper we describe our study on the synthesis and characterization of several groups of expanded bipyridines (Py-X-Py type molecules) based on a five-membered heterocyclic central fragment X.We focused our efforts on pyridine-containing pyrazoles, isoxazoles, imidazoles, oxazoles, thiazoles, oxadiazoles, triazoles, and 1,3,4-triazepines.

Results and Discussion
General synthetic routes to 1,2-azoles include the reaction of bis-nucleophiles with β-diketones.Pyridine-containing pyrazoles and isoxazoles are the most investigated class among pyridinecontaining azoles, which is due to the synthetic availability of various β-diketones.Using the known procedures for the synthesis of dipyridinepyrazoles 2a-2c, 9 new aryl and donor-type hetaryl substituted pyrazoles 2d, 2e were synthesized (Scheme 1).The yields of the reactions are in good accordance with the electronic influence of the pyridine moiety, except for product 2c where the stability of the diketone is crucial for the yield.The approach shown is also valuable for the preparation of sym-isoxazole 3a, which could be easily isolated in moderate yield after heating of the appropriate β-diketone with hydroxylamine (see Scheme 1).The presence of hydrogen bond donors (N-H groups in a pyrazole ring) and hydrogen bond acceptors (pyridine nitrogens) might result in intermolecular contact within the crystal structures of the products.Indeed, X-ray structural study of 2c, 10 revealed the existence of hydrogenbonded dimers, which stack along the crystallographic axis, whereas for the compound 2a infinite head-to-tail chains were found. 11zachalcones look like the obvious precursors for the synthesis of unsym-isoxazole.Recently, we found that the synthesis of azachalcones, starting from acetylpyridines and pyridinecarbaldehydes, is more complicated than it was thought before. 12For this reason in the present work, unsym-isoxazoles were not studied.
For the access to 1,3-diazole and triazole subsystems, one can start from cheap and available cyanopyridine using nucleophilic addition reactions.The cyanopyridine could be easily acylated or alkylated by appropriate pyridine derivatives and the intermediates obtained could then be introduced into the next steps of the heterocycle synthesis (Scheme 2).In the synthesis of the isomers of dipyridylimidazole, the key-substance is 2-pyridyl-2aminoethanone 6 -the ambiphilic precursor for cyclocondensation (Scheme 3).In spite of the published results, 13,14,15,16 there were some uncertainties about the influence of the electronic and spatial factors of the substrate on the course of the reaction.We found that the yield of the tosylation step (preparation of compounds 5 -see Scheme 3) is more influenced by the configuration of the oxime than by the electronic factors.The next step -the Neber rearrangement -was found to be dependent neither on the electronic nature of the hetaryl substituent nor on the spatial factor.The isolation of the diketal derivative of the aminoketone might result in an increasing yield. 14The key-step of the reaction, shown in Scheme 3, is based on the reaction of methyl carbimidate 8, generated in situ from the appropriate nitrile 7 and aminoketone 6b. 17The target imidazoles 9a-9d were isolated in moderate to good yields.The main drawback of this method is the formation of the diarylpyrazine, which is the product of autocondensation of 6.

Scheme 3
In order to obtain thiazolylpyridines (Scheme 4), we used the S-alkylation of thioamide 11 by easy-available 18 ω-bromoketone 10.Thioamide is also obtained using a literature procedure, which includes catalytic hydrogen sulfide addition to nitrile 7. 19 We improved the known technique 20 in such a way, that the initially formed insoluble thiouronium salt is separated, and then coverted into the thiazole by quenching with triethylamine.In spite of low and moderate yields of 12, the total outcome for the thiazolylpyridine derivatives was significantly raised as compared to the work cited above.
Our synthetic approach to the oxazole analogue of 12 was based on the preparation of the acyclic intermediate 13.Unfortunately, the latter was unable to form the 5-membered ring under several different dehydrating conditions (Scheme 5).Finally, the oxazole 14 was the minor product along with the starting material.

Scheme 5
Concerning the azole systems with three heteroatoms, particular attention was paid to the compounds with an oxadiazole ring.In the case of the 1,2,4-oxadiazole subsystem, no significant complications were found.We were lucky to obtain the target 3,5-dipyridyl-derivatives 18 in two steps with high yields (Scheme 6).Starting from commercially available pyridoyl chlorides 15 and available amidoximes 16, O-pyridoylamidoximes 17 were synthesized. 21,22These intermediates were then converted into oxadiazole by removal of water by heating.i -NH 2 OH, EtOH, reflux; ii -K 2 CO 3 , acetone; iii -toluene, reflux.

Scheme 6
Although pyridine-containing 1,3,4-oxadiazoles were already mentioned in the literature, 23,24 we adopted a novel method 25 for their preparation via a dipolar intermediate (Scheme 7).In this case 5-pyridyl-tetrazole 19 could be regarded as the nucleophilic adduct of the azide-anion and the appropriate nitrile.The nature of the substituent at C 5 influenced the product yield to a negligible extent.We also conducted this reaction under microwave irradiation and found that yields were higher and shorter reaction times were required.
The 4-aryl substituted triazole 23 was obtained in the same manner in three steps, starting from 4-bromoaniline and tetrazole 19b (Scheme 8).In this case, the reaction mixture was contaminated with several side-products that were not identified.It should be emphasized, that in all cases of such rearrangements, no products of further transformation of N 1 -acyl derivatives, such as 1,2,4-oxadiazole or unsym-triazole, were detected (Scheme 9).

Scheme 10
For the synthesis of unsym-triazoles 29, we applied the procedure depicted in Scheme 11.This approach is based on the preparation and isolation of the unsymmetrical amidrazones 28 with their consequent dehydration by heating.i -MeONa, MeOH, rt; ii -MeOH, heat; 180 o C vacuum.

Scheme 11
In summary, by the design of the reaction partners, we have developed a convenient and conceptually simple synthethic pathway to a family of novel azole bearing pyridines which are promising ligands for coordination chemistry.

Experimental Section
General Procedures.All starting materials were obtained commercially, unless otherwise stated, (Aldrich, Lancaster or Acros Organics) and all solvents were dried using literature procedures.TLC was performed using aluminium plates precoated with silica 60 F 254 (Merck) and visualized by iodine or UV light (254 nm).Column chromatography was carried out on silica gel (Fluka, particle size 0.040-0.063nm).The IR-spectra were recorded (nujole) on a Specord 75 IR instrument.NMR spectra were recorded in CDCl 3 , unless otherwise stated, on a Varian VXR 400S NMR spectrometer with tetramethylsilane as an internal standard.Mass spectra were recorded on a Jeol® "MS-D300" Spectrometer (EI, 70 eV), coupled with a Hewlett Packard 5890 series II gas chromatograph using a 25m HP1 (methyl-silicone) column.Elemental analyses data were obtained on a Carlo-Erba® ER-20 elemental analyzer.Melting points and boiling points were recorded at atmospheric pressure, unless otherwise stated, and are uncorrected.

Typical procedure for the preparation of 3,5-diaryl-1H-pyrazoles
Hydrazine hydrate (15 mmol) in MeOH (20 ml) was added to a solution of the appropriate βdiketone 9,27 (10 mmol).The resulting mixture was stirred and refluxed for 2 h, and was then cooled and evaporated.The residue was crystallized from 2-propanol.The yields, melting points and spectral data of 2a-2c are presented in Tables 1,2.

2-Amino-1-(3-pyridyl)ethanone (6a).
The reaction was carried out under an argon atmosphere.Potassium (1.5 g, 38 mmol) was cautiously dissolved in 25 ml of dry ether.(E/Z)-Tosylates of 3acetylpyridine oxime 5a (9.9 g, 34 mmol) was then added to this solution.The resulting mixture was stirred at room temperature for 1 h.The resulting red-colored solution was filtered from sodium tosylate, and quenched by 600 ml of dry ether.The sodium tosylate formed once again was filtered.The product was collected after ethereal phase extraction (3×25 ml 2N HCl), followed by evaporation of the water phase (temperature should not exceed 40 o С).
Under microwave activation, both reagents (2 mmol each) in 5 ml pyridine were used.Irradiation was carried out in domestic MW-oven at 800 W power-level for 30 s period.The yields, melting points and elemental composition data of 20a-20c are presented in Tables 10,11.5 mmol) in 30 ml of DCM, containing 1.2 ml triethylamine and 50 mg TEBAC, was added.The resulting mixture was then intensively stirred for 1 h.The organic layer was separated and the aqueous layer was extracted by 10 ml of DCM.The organic phases were combined and evaporated.The crude oily 2-(N-arylimidoil)tetrazole was placed in 20 ml of dry toluene, and was heated at 90-100 о С for 1 h.in two steps via cyclocondensation of methyl pyridinecarbimidates with the appropriate pyridoylhydrazine.The spectral data of 20a-20c are presented in Table 12.

Supplementary information is Available
Scheme 2 Scheme 7

Table 8 .
Yields and physical data of 3

Table 10 .
Yields, melting points and elemental composition data of 2