On the preparation of 1-aryl-2-heteroaryl-and 2-aryl-1-heteroaryl-pyrroles as useful building blocks for biologically interesting heterocycle

A series of 1-aryl-2-pyridinyl/pyrimidinyl-pyrroles and 2-aryl-1-pyridinyl/pyrimidinyl-pyrroles were prepared by using 4+1 ring synthesis. The yields were strongly dependant on the reactivity of the starting amines. Synthetic procedures involving a 3+2 ring formation were discussed . Few 1-heteroaryl derivatives showed weak activity when tested as COX-1 and COX-2 inhibitors


Introduction
2][3][4] In preliminary biological screening tests, several PPHs have shown antiproliferative activity against cell lines derived from human tumors, sensible (FLC) and multidrug resistant (DRTL) with IC 50 in the range 5-50µM. 5More recently they were demonstrated to possess a weak anti-HIV activity, joined to a capability of stimulating the multiplication of MT-4 cells at low concentrations. 6o further explore the biological features of related classes of planar molecules we decided to modify their carbon skeleton introducing the isosteric nitrogen.In particular the introduction of one or two nitrogens in the phenanthridine moiety could lead to several new heterocyclic systems annelated with the pyrrole ring, such as DiAzaPhenanthrenes (DAP) or TriAza-Phenanthrenes (TAP).To extend previously successful synthetic approaches for the preparation of PPHs we needed the access to large quantities of pyrrole derivatives of type 1 and 2, suitably substituted in the aryl/heteroaryl moiety.
These compounds should be useful starting materials for the synthesis of DAP and TAP which incorporate the pyrrole moiety, to be screened for their biological features.Moreover derivatives of type 1 and 2 themselves may be of interest in medicinal chemistry as they are related to 1,2-diaryl substituted pyrroles and pyrazoles that recently have been shown to posses interesting antiviral 7 and anti-inflammatory 8,9 activities.
However despite the apparent simplicity of the preparation of pyrroles of this type, some problems arise for their synthesis on a preparative scale as testified by the large number of papers dealing with pyrrole preparation. 10,11Moreover a literature survey indicated that whereas few 2pyridinyl-pyrroles have been reported, 2-pyrimidinyl-pyrroles of type 2 were unknown.

Results and Discussion
In this paper we report our findings on the preparation of the title compounds exploring and comparing the synthetic routes leading to these compounds on a preparative scale on the basis of considerations about (a) low cost and ready availability of starting materials, (b) easy introduction of appropriate substituent in suitable positions of the rings, (c) reasonable yields.The experimental problems related to the synthesis of 1-heteroaryl or 2-heteroaryl-pyrroles are different and will be treated separately.
In the case of derivatives of type 4 and 5, the yields were strongly dependent on the nucleophilicity of the starting amine.In fact, for example, pyrroles 4g and 4h were prepared in good yields whereas 5j and 5l were obtained only in 40-20% yields [together with the corresponding N-acetylated derivatives 5k and 5m (yields 20% -traces) when the reaction was carried out in acetic acid].By using diketone 3a and 2-aminopyridine a furan derivative, arising from intramolecular cyclization of the starting diketone, was always isolated and no traces of 1-(pyridin-2-yl)pyrrole of type 5i could be detected.
In the case of aminopyrimidines it was possible to obtain pyrrole derivatives when the reacting amino group was in the 5 position of the starting pyrimidine (compounds of type 7) in yields ranging from 54 to 95%.When the cyclization reactions were carried out on the less reactive 4-amino derivatives only compound 6n was isolated in 20% yield, whereas compound 6o could not be obtained from the corresponding reactants.From the reaction of 1,4-diketone 3d and 4-amino-6-hydroxy-2-mercaptopyrimidine 8 unexpectedly a pyrido[2,3-d]pyrimidine derivative 9 was formed (Scheme 2).In this case the diketone 3d, being also a 1,3-dicarbonyl compound, preferentially reacted on the unsubstituted 5 position of the pyrimidine ring giving rise to a more stable bicyclic system.In the case of the synthesis of 1-aryl-2-heteroarylpyrroles the main problem is related to the accessibility of suitable 1,4-diketones or their synthetic equivalents.In fact for example the preparation of 2-pyridinyl-1-phenylpyrroles of type 10 was achieved so far according to the procedure outlined in the Scheme 3. Route A 12 involved the condensation of pyridinyl derivatives of type 11 and aniline whereas in the case of route B 13 the key intermediate was the oxazine 12, accessible in turn from 1,3-butadienes 13 and nitrosobenzene 14, which afforded the pyrrole 10 upon treatment with bases or acids.The yields obtained are listed in Since our aim is devoted to the preparation of suitably substituted derivatives of type 10 we synthesized 2-pyridinylpyrroles 10i and 10j, from 1,4-diketones 11 and 3-nitroaniline according to route A. The pyridinylketoaldehydes 11i and 11j (70-60% yields) were prepared from the commercially available heterocyclic aldehydes 15 and acrolein in the presence of KCN.
However it was not possible to find commercially available pyrimidin-aldehydes and the synthetic procedure outlined by route A was not suitable for the preparation of 2pyrimidinylpyrroles. On the other hand attempts to prepare other diketones analogues of 11, by acylation of methylene active compounds with heterocyclic acyl bromides failed since it was impossible to obtain suitably substituted pyridin-or pyrimidin-COCH 2 Br from the corresponding acetyl derivatives.Therefore a different approach was undertaken involving a 3+2 ring formation.In fact Katritzky and coworkers reported 14 a new method for the synthesis of 1,2-diarylpyrroles 18 according to Scheme 4. This route employed as starting compounds the easy synthesizable Schiff bases, accessible in turn from aldehydes and amines.To verify if the reaction could be successful also in the case of heteroarylpyrroles, the imines 17 were prepared, generally in good yields (Table 3), and reacted according to literature procedure with 3-(benzotriazol-1-yl)-1-ethoxyprop-1-ene 16.From these reactions it was possible to isolate the pyrrole derivative 18 only when imine 17a was the starting material; in all the other cases extensive decomposition of the starting material was observed and intractable tars were mainly obtained.Therefore the method fails in the preparation of 2-pyrimidinyl-pyrroles that still remain unknown.
All the new 1-heteroarylpyrrole derivatives were proposed for a preliminary screening as anti-inflammatory agents.In fact it seems that the presence of aryl moieties, substituted with electron-withdrawing groups, in the positions 1 and/or 2 of the five membered ring is necessary for the appearance of the activity, as it was observed in the case of derivatives of type 19. 9 This is even more evident in the case of the isoster pyrazole derivatives (i.e.celecoxib).However, in pyrrole series the structure-activity relationships are less straightforward although recently analogous behaviour was evidenced in the series of 3-aryl-4-aroyl compounds. 8herefore we decided to include in the screening tests also some 1,2-diarylpyrroles, selected from our available database, such as compounds 20, 3 21, 4 and 22. 4 The results of the screening tests for the 1-heteroarylpyrroles and related 1,2-diaryl derivatives 20-22 are reported in Table 4.
The only compounds which showed some activity against COX-1 at concentration 1-10 µM were 22, 4g and 7s, whereas derivative 7s weakly inhibited also COX-2.Therefore also in this case the presence of electron-withdrawing substituents or electron deficient rings seems necessary for the appearance of the activity.a Expression and purification of human COX-1 and COX-2 enzymes and in vitro COX-1 and COX-2 enzyme assays were carried out according to reference 15.The inhibition of LPSinduced PGG 2 production and A23187-induced TBX 2 production in the human whole blood was studied utilizing the literature protocols. 16,17 conclusion from the data reported in this paper the best method for the preparation of heteroarylpyrroles remains the Paal-Knorr synthesis once the suitable 1,4-dicarbonyl compounds are available.1-Heteroarylpyrroles constitute suitable model for the development of interesting biological compounds.

Experimental Section
General Procedures.Melting points (uncorrected) were taken on a Buchi-Tottoli capillary apparatus; IR spectra were determined in bromoform with a Jasco FT/IR 5300 spectrophotometer; 1 H and 13 C NMR spectra were measured at 200 and 50.3 MHz respectively in (CD 3 ) 2 SO solution, unless otherwise specified, using a Bruker AC-E series 200 MHz spectrometer (TMS as internal reference); mass spectra were obtained with a HP 5890 Series II and HP 5989A-GC/MS apparatus.Column chromatography was performed with Merck silica gel 230-400 Mesh ASTM or with a Biotage FLASH40i chromatography module (prepacked cartridge system).For all new compounds analyses indicated by the symbols of the elements or functions were within ±0.4% of theoretical values.