Gold catalysis in the synthesis of azaindoles: pyrrolo[2,3-b ]pyridines and pyrrolo[2,3-b ]pyrazines

The synthesis of substituted 1-benzyl-1 H -pyrrolo[2,3-b ]pyridines and 5-benzyl-5 H -pyrrolo- [2,3-b ]pyrazines has been performed by cycloisomerization of the corresponding N -benzyl- 3-alkynyl-5-arylpyridin(or pyrazin)-2-yl amines with AuCl 3 . Alkynylamines have been obtained starting from 3-bromo-5-substituted N -(pyridin-or pyrazin-2-yl)pyridinium aminides in a regioselective way.


Introduction
3][4] Nevertheless, this class of heterocycles has attracted considerable interest due to their physicochemical and pharmacological properties.In this way, luminescence properties of 7-azaindole derivatives and complexes have been studied and recently reviewed. 5These compounds have also been examined as models mimicking proton transfer with the assistance of protic solvent molecules in biological processes. 68][9] In most cases the construction of the pyrrolo [2,3-b]pyridine ring is a key step in the synthesis of a more complex molecule.For these and other related reasons, the chemistry of 7-azaindole derivatives has remarkably expanded, allowing the functionalization of almost all the positions of the nucleus. 10Even so, the development of general methods for the regioselective synthesis of these compounds continues to be an active area of research.On the other side, 5H-pyrrolo [2,3-b]pyrazines (or 4,7-diazaindoles) (Figure 1) have recently gained attention since derivatives of the system exhibit diverse biological activities.5][16][17] Abnormalities and deregulations of CDK activities have been associated with many diseases, including cancer, viral infections, diabetes, ischemia and neurodegenerative disorders such as Alzheimer′s and Parkinson′s diseases. 18Compounds that inhibit CDKs, mostly related to 4,7-diazaindoles, were named ′aloisines′ on the basis of the first name (Alois) of Dr. Alzheimer (Figure 1). 15Recently, a family of pyrrolo [2,3-b]pyrazine derivatives was also studied as CFTR (cystic fibrosis transmembrane conductance regulators) activators. 19As a consequence, several approaches for the synthesis of pyrrolo [2,3-b]pyrazines have been developed [20][21][22][23] although more general and selective methods to prepare polysubtituted 4,7-diazaindoles would still be welcome.As a continuation of our studies on the utility of pyridinium N-heteroarylaminides 1 (Scheme 1) as suitable scaffolds [24][25][26][27] to obtain 2-aminoazines, [28][29][30] compounds that, in addition to other uses, have recently been tested in experimental models of human African trypanosomiasis, 31 we became interested in developing a synthetic route to pyrrolo [2,3-b]pyridines and pyrrolo [2,3b]pyrazines starting from the corresponding N-pyridin-2-yl or pyrazin-2-yl pyridinium aminide (1a, 1b, Scheme 1).Pyridinium N-heteroarylaminides 1 are stable heterocyclic betaines in which the negative charge is stabilized by both the pyridinium and the azine moieties.An intramolecular hydrogen bridge prevents alkylation of the heterocyclic aminide nitrogen in aprotic solvents. 24Typical reactions of these aminides are the aromatic electrophilic substitutions that take place in the 3-and 5-positions of the heterocyclic ring. 24,25Halogenated aminides can be converted by means of Pd coupling processes and reduction of the N-N bond into 3,5disubstituted 2-aminopyridines and pyrazines 4 and 5. 28,29 Furthermore, we recently reported the regioselective synthesis of N-alkyl-3-alkynyl-5-arylpyridin-2-yl amines 4 through the 3brominated aminides 2 (Scheme 1). 30Bearing in mind that conjugated alkynes are valuable intermediates in the synthesis of heterocycles, [32][33][34] we describe in this paper the results obtained in the synthesis of the N-alkyl-3alkynyl-5-arylpyrazin-2-yl amines 5, starting from the 3-bromo aminides 3 along with the results of the cyclization of amines 4 and 5 to afford aza-and diazaindoles 6 and 7 (Scheme 1), in an AuCl3-catalyzed processes.
From an environmental point of view, gold catalysts have many valuable features and they have now become a well-established method of choice for many chemical transformations. 48,49hanks to gold-based catalysts, various organic transformations have become accessible under mild conditions and give both high yields and chemoselectivity.In recent years intramolecular carboaminations catalyzed by AuCl3 have been developed [45][46][47] to prepare highly functionalized indole derivatives, 45,47 2-substituted 7-azaindoles, 45 pyrrolocoumarin and pyrroloquinolone derivatives. 46he synthesis of N-benzyl pyrrolo When AuCl3 (3 mol %) was added to a solution of the N-benzyl-3-alkynyl-5-arylpyridin(or pyrazin)-2-yl amines 4, 5 in ethanol and the mixture was stirred at 70 °C, a 5-endo-dig cyclization took place and the corresponding trisubstituted 7-azaindoles 6 or 4,7-diazaindoles 7 were obtained, after purification, in moderate yields (Table 3).Alkynylamines bearing an electron-releasing dimethylamino group, as 5b and 5e, yielded a complex reaction mixture in which the corresponding pyrrolopyrazine was not detected.A tentative mechanism for the cycloisomerization process is given in the Scheme 4.

Compound
Ar a Ar′ a Yield (%) b O C H

Experimental Section
General Microwave experiments were performed using a Biotage Initiator and a Biotage 5 mL vial.This is a single mode operating system, working at 2.45 GHz, with a programmable power level from 0 to 400 W. Stirring was performed at 400 rpm with the magnetic stirrer included in the apparatus.(8).General procedure.N-(5-Bromopyrazin-2yl)pyridinium aminide (1 mmol), 25 the corresponding boronic acid (1.5 mmol) and K2CO3 (10 mmol) were dissolved in a toluene/ethanol mixture (4:1, 10 mL).Pd(PPh3)4 (5 mmol %) was added and the mixture was stirred under argon and heated under reflux.The course of the reaction was followed by TLC.Once the starting material had been consumed, the system was allowed to reach room temperature; the mixture was filtered through Celite and washed with acetonitrile until colour was no longer observed in the filtrate.The combined filtrates were evaporated to dryness.The crude product was purified by flash chromatography on a silica gel column, with ethanol as the eluent.

N-(5-Aryl-3-bromopyrazin-2-yl)pyridinium aminides (3). General procedure.
To a stirred solution of N-(5-arylpyrazin-2-yl)pyridinium aminide 8 (1 mmol) in dichloromethane (8 mL) at room temperature (-50 °C in the case of compound 8d), a solution of NBS (1.1 mmol) in the same solvent (15 mL) was added dropwise.The reaction mixture was stirred at the same temperature until the starting material had been consumed (TLC analysis).The solvent was evaporated and the residue was purified by flash chromatography on silica gel using ethanol as eluent and then crystallized from a suitable solvent and identified.

N-(3-Bromo-5-phenylpyrazin-2-yl)pyridinium aminide (3a)
. 26   Reaction of 3-bromo-5-substituted pyridinium aminides 3 with benzyl bromide.General procedure.The appropriate aminide 3 (1 mmol) was dissolved in anhydrous acetone (11 mL) in a dry round-bottomed flask.The corresponding benzyl bromide (3.5 mmol) was added and the mixture was stirred at room temperature under argon until the starting aminide was no longer detected by TLC.Once the reaction was complete, the solid was filtered off and washed well with cold ethyl acetate.The salt 9a is soluble in acetone and, in this case, once the solvent had been eliminated in vacuo, the residue was dissolved in a small amount of DMF and poured over ethyl acetate.The resulting suspension was filtered and the solid was washed with ethyl acetate (3 × 5 mL) to remove excess benzyl bromide.Alkylation of aminide 3d, which is not totally soluble in acetone, was performed in dry DMF and the salt 9d was isolated by removing the solvent and treating the residue with ethyl acetate in an ultrasonic bath.The salts 9 were used in the next step without further purification.

Figure 2 .
Figure 2. Amines obtained as secondary products in the reduction step.

Table 1 . Yields for compounds 9 and 10
a Ring numbering employed in NMR analysis.b Yields of isolated pure products.

Table 2 .
Yields for compounds 5 b Yields of isolated pure products.

.
Melting points were determined in open capillary tubes on a Stuart Scientific SMP3 melting point apparatus.IR spectra were obtained on a Perkin-Elmer FTIR spectrum 2000 spectrophotometer.1Hand13CNMRspectra were recorded on Varian Gemini 200, Varian Unity 300/500 MHz or Varian Mercury VX-300 systems at room temperature.Chemical shifts are given in ppm () downfield from TMS. Coupling constants (J) are in Hertz(Hz)and signals are described as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; h, heptuplet; m, multiplet; br, broad; ap, apparent.Low resolution mass spectra (MS) were recorded on a Hewlett-Packard 5988A (70eV) spectrometer using Electronic Impact (EI) or Atmospheric Pressure Chemical Ionization (APCI) and high resolution analysis (TOF) was performed on an Agilent 6210 timeof-flight LC/MS.All reagents were obtained from commercial sources and were used without further purification.TLC analyses were performed on silica gel (Kieselgel 60 F254, Macherey-Nagel) and spots were visualized under UV light.Column chromatography was carried out on silica gel 60 (40-63 m, Merck) columns, using the eluent reported in each case.