Synthesis and properties of 4-(3-Substituted azulen-1-yl)- 2,6-diphenylpyridines

The syntheses of 4-azulen-1-yl-2,6-diphenylpyridines substituted at the azulene C-3 moiety with electron donating or withdrawing groups, are reported. When electron-donating groups (EDG) are present, the reaction of the corresponding pyranylium perchlorates and ammonium acetate takes place. Because of the difficulties in the generation of pyranylium salts with electron-withdrawing groups (EWG), the corresponding pyridines are obtained by a PdCl 2 -promoted substitution of halogen in 4-chloro-2,6-diphenylpyranylium salt, with an azulene derivative followed by an in situ replacement of oxygen with nitrogen. The physical and chemical properties of the pyridines obtained are discussed.


Introduction
As a part of our interest in the chemistry of azulenes, we have reported recently the synthesis of new 2,6-dimethyl and 2,6-diphenylpyranylium salts substituted at the 4-position with an azulen-1-yl group by the reaction of the corresponding azulenes with 4-chloro-2,6-disubstituted pyranylium salts.Good results are obtained when azulene, alkylated azulenes or azulenes substituted at C-1 with electron donating groups (EDG), such as NHAc, OMe or OOCPh, are used. 1In contrast, the substitution of chlorine by azulenes with electron withdrawing groups (EWG) at the same position occurred in very low yields or even failed.The well known use of pyranylium salts as synthones in the synthesis of pyridines and pyridinium salts suggested the use of such salts for the generation of the corresponding pyridine derivatives.Some (azulen-1yl)pyridines 2 and (azulen-1-yl)pyridinium salts 3 were already synthesized by us and their properties were reported.The investigation of the peculiarities in the synthesis and properties of 4-azulen-1-yl-pyridines, substituted at C-3 in the azulene moiety with various electron demanding groups, constituted the target of this paper.
Pyridine synthesis.The synthetic route to 3 consists of reaction of the 4-(3-substituted azulen-1yl)-2,6-diphenylpyranylium salts with R = EDG (2a-c in Scheme 1 and Table 1) with ammonium acetate in boiling ethanol.However, as shown in Table 1, the good yields in the pyranylium salt preparation step, step (a), are counterbalanced by the moderate efficiency of the subsequent replacement of oxygen by nitrogen, step (b).In contrast, despite the favorable step (b) starting from azulenes with R = EWG, the halogen substitution, step (a), is restrictive.Besides the intrinsic low nucleophilic reactivity of these azulene derivatives, an ipso substitution at C-1 in azulene can be observed in the reaction between the halogenated salt and compounds 1d or 1f, with the elimination of a methoxycarbonyl or nitro group. 1 Therefore, we have considered the utilization of a catalyst based on palladium chloride for enhancing the coupling reactions between these azulene derivatives and the chloropyranylium salt.However, because both azulene and pyranylium salts are sensitive to the palladium salts only a few references about the palladium catalyzed reactions of these substrates are available.For example, Saito et al. 4 have introduced an acetoxy group into azulene using Pd(AcO) 2 and, more recently, Dyker et al. 5 have shown that intermolecular ARKAT arylation of unfunctionalized azulene occurred in the presence of a palladium salt catalyst at high temperatures, however only in low yields. 6e have examined the reaction of 4-chloro-2,6-diphenylpyranylium perchlorate with azulene derivatives, 1, in nitromethane, in the presence of a catalytic amount of PdCl 2 .Under these conditions, 4-azulenylpyranylium salts, 2, were formed and, without their separation, ammonium acetate was added to the reaction mixture.The pyridines, 3, were generated in situ (Scheme 1) and, to the best of our knowledge, this is the first example in which a pyranylium salt is arylated using a palladium salt as catalyst.As shown in Table 2, starting from methyl 1-azulenecarboxylate, 1d, 1-nitroazulene, 1f, or even from 1-(p-tolylsulfonyl)azulene, 1e, and using PdCl 2 as catalyst, acceptable overall yields for steps (a) + (b) were obtained.Under the described reaction conditions, the ipso elimination of a substituent during the coupling process was avoided; thus the nitro group was entirely conserved and only a small amount of the compound without CO 2 Me was formed.Starting from (azulene-1-yl)-phenyl-diazene, 1g, the corresponding pyridine was, unfortunately, not generated, possibly because a stable complex was formed between the metal and the azo group.
It is interesting to observe that the protocol for pyridine generation, which avoided the separation of 4-azulenylpyranylium salts as such, was advantageous even for the azulenes with EDG (e.g.1c→3c); in this instance the catalyst was not necessary.
Scheme 2 Correlation between the pyridine structure and spectra.As expected, the substitution at C-3 in the azulene moiety produces an important effect on the protons belonging to this group by the alteration of electron density.For R = EWG all protons of the seven-membered ring are deshielded (Table 3) due to the charge polarization in azulene, as in contributing structure 3f-B from Scheme 3.This effect is higher for the 8, 6 and, mainly, the 4 positions.The strong deshielding of the latter proton, as well as of the 2-H, contributes also to the magnetic anisotropy generated by the nitro group at C-3.The higher shielding effect of protons 5-H and 7-H and the slight shielding of the 4, 6 and 8 protons for the compounds with EDG at C-3 result from the charge distribution depicted in Scheme 3, structure 3a-B.Regarding the 13 C-NMR spectra, shown in the experimental part, similar behavior can be observed for the values of the carbon chemical shifts at the azulene moiety.The interruption of continuous conjugation between the substituent R and pyridine produces the loss of its influence on this moiety and also on the phenyl groups (Tables 3 and 4).It is interesting to underline that the azulene substitution by either EWG or EDG induces a bathochromic effect in the UV-Vis spectra (Table 4) due to the advanced charge polarization of the azulene system in the ground state.This might be also the explanation for the absence of solvatochromism in the studied compounds.The presented results are in accord with our supposition that the electron demand of the C-3 substituent of azulene in (4-azulen-1-yl)-pyridines induces considerable differences, both for synthesis and for the spectral properties of these compounds.

Experimental Section
General Procedures.Melting points: Kofler apparatus (Reichert Austria).Elemental analyses: Perkin Elmer CHN 240B. 1 H-and 13 C-NMR: Bruker Avance DRX4 ( 1 H: 400 MHz, 13 C: 100.62 MHz), J values are given in Hz, TMS was used as internal standard in CDCl 3 or DMSO-d 6 as solvent; COSY and HETCOR correlation experiments were used for the structure assignment.UV-Vis spectra in methanol: Specord UV-Vis spectrometer (C.Zeiss Jena).Mass spectra: JEOL JMS-DX303 spectrometer coupled to analytical gas-chromatograph Shimadzu GC-14B with a DB-1 capillary column and C-R6A integrator and Finnigan MAT 311-A/100 MS; for the spectral recording in the solid state a Carlo Erba QMD 1000 (EI+, 70 eV) device was used.Column chromatography: silica gel [70-230 mesh (ASTM)].The pyranylium salts 4-substituted with azulene or chlorine were obtained as described in our previous paper. 1The numbering for the positions in the pyridines characterized below were presented in Scheme 1.The nomenclature was obtained by use of the ACD/I-Lab web service (ACD/IUPAC Name Free 7.06).Experimental procedures Preparation of pyridines.(a) From pyranylium salts.To a solution of 2,6-diphenyl-4-(3substituted-azulen-1-yl)-pyranylium perchlorate 2R (1 mmol) in ethanol, ammonium acetate (10 eq) was added and the solution was magnetically stirred and refluxed for 1 hour.The alcohol was evaporated in vacuo and the residue was separated by column chromatography on silica gel using chloroform as eluent.The pyridine was collected as the first colored fraction due to the lower polarity of pyridines as compared with the other products (with unknown structure) in the reaction mixture.The pyridine migrated as a brown band on the column, however the solution was generally green.ARKAT (b) From 4-chloro-2,6-diphenyl-pyranylium perchlorate.A magnetically stirred mixture containing azulenic compound 1R (1 mmol) and 2,6-diphenyl-4-chloropyranylium perchlorate (1 mmol) in nitromethane (10 ml) was heated at 100 °C for one hour and cooled to room temperature.When PdCl 2 (1% molar) was used as catalyst (starting from 2d, 2e and 2f) the reaction time was prolonged to 4 hours.Ammonium acetate (10 eq) was then added and the reflux was continued for one hour.The nitromethane was evaporated in vacuum and the resulting mixture was worked-up as above.

Table 1 .
Synthesis of pyranylium perchlorates, 2, and subsequent reaction with ammonium acetate (yield of pyridines 3 without starting salt recovery)