Two alternatives for the synthesis of pyrrolo[1,2-a ]quinoxaline derivatives

The 4,5-dihydropyrrolo[1,2-a ]quinoxaline system was prepared through two different reaction sequences. The first method is based on the intramolecular reductive amination of the corresponding nitrophenylpyrrole-carbaldehyde intermediate, whereas an alternative synthesis involves as key step, the intramolecular substitution of an aromatic fluoride by a secondary amine


Results and Discussion
Following previous work of our laboratory on the synthesis of pyrrolo[2,1-c][1,4]benzoxazines 11 we report here two different and useful synthetic approaches to the synthesis of pyrrolo [1,2a]quinoxalines from the corresponding commercially available 2-substituted anilines (Scheme 1).

Scheme 1
The key starting intermediates 2 and 3 11 were prepared by reacting 2-nitroaniline or 2fluoroaniline with 2,5-dimethoxytetrahydrofuran (DMTHF) in the presence of glacial acetic acid by a modified Paal-Knorr procedure [12][13] known as the Clauson-Kaas reaction 14 in 88% and 85% yield, respectively.The introduction of a formyl group at C-2 of the condensed heterocyclic system, under Vilsmeier-Haak conditions, affords the aldehydes 4 and 9 in acceptable yields (70% for 4 and 85% for 9) (Scheme 2 and 3).

Scheme 2
The nitroaldehyde 4 was reductively cyclized using catalytic hydrogenation; optimum yield (65% for compound 5) was obtained using Ni-Raney in methanol, under hydrogen atmosphere, for a period of time less than 12 h.Prolonged hydrogenation reaction time (more than 12 h) leads exclusively to reduced hexahydropyrroloquinoxaline 7 in 76% yield.When 10% Pd/C was used as catalyst in ethyl acetate, a mixture of the desired pyrrolo-quinoxaline 5 (30%) and the analogue 6 (11%) was obtained (Scheme 2).
Methylation of the pyrrolo-quinoxaline 5 was carried out in acetone with CH 3 I in the presence of K 2 CO 3 at room temperature to give the N-methylquinoxaline 1 in good yield (80%).In this alkylation process, traces of the corresponding quinoxalium iodide were also isolated (8).It is noteworthy that the compound 1 was previously prepared by Mannich reaction from N-(2-(methylamino)phenyl)pyrrole in only 22% yield. 15he pyrrolo-quinoxaline 1 was preferably prepared in higher yields by an alternative synthesis (method 2) in which 2-fluoroaniline was chosen as starting material.The formylation of the N-(2-fluorophenyl)pyrrole 3 and subsequent treatment with methylamine, followed by reduction of the intermediate imine with NaBH 4 provided the secondary amine 10 in good yield (Scheme 3).Several attempts were made to optimize the intramolecular cyclization: first treatment of the methylamine 10 in refluxing toluene under the coupling reaction conditions 16 catalyzed by Pd[P(o-tolyl) 3 ] 2 Cl 2 /BINAP/ Cs 2 CO 3 gave the pyrrolo-quinoxaline 1 in low yields (< 30 %).Further insight into this reaction was obtained by treatment of the amine 10 with Cs 2 CO 3 (1 eq) as a base without catalyst.The absence of reaction under these conditions suggests the implication of catalyst and ligand in the cyclization process or that the solvent is inadequate for the nucleophilic aromatic substitution.
The pyrrolo-quinoxaline 1 was successfully obtained by treatment of the methylamine 10 with NaH in DMF by direct intramolecular nucleophilic displacement of the fluoride anion by the secondary amine (93%).Other bases as anhydrous Cs 2 CO 3 and K 2 CO 3 in excess (5 eq) in DMF gave the quinoxaline in low yields (45% and 39% respectively).These results revealed that an excess of base is necessary and that DMF is the appropriate solvent for the intramolecular aromatic nucleophilic substitution.

Conclusion
The two synthetic methods described herein allow the preparation of the pyrrolo-quinoxaline 1 in each three steps, but whereas the method 1 provide the pyrrolo-quinoxaline in 36% overall yield, the second sequence involving formylation, reductive amination and cyclization give the desired compound in 66% overall yield.It is interesting to note that method 1 provides next to the desired dihydropyrrolo-quinoxaline, also the pyrrolo-quinoxaline 6 and the hexahydropyrroloquinoxaline 7, interesting and useful intermediates in organic synthesis and in medicinal chemistry.

Experimental Section
General Methods.Melting points were obtained on an MFB-595010M Gallenkamp apparatus in open capillary tubes and are uncorrected.IR spectra were obtained using a FTIR Perkin-Elmer 1600 Infrared Spectrophotometer.Only noteworthy IR absorptions are listed (cm -1 ). 1 H and 13 C NMR spectra were recorded on a Varian Gemini-200 (200 and 50.3 MHz respectively) or Varian Gemini-300 (300 and 75.5 MHz) Instrument using CDCl 3 as solvent with tetramethylsilane as internal standard or (CD 3 ) 2 CO.Other 1 H-NMR spectra and heterocorrelation 1 H-13 C (HMQC and HMBC) experiments were recorded on a Varian VXR-500 (500 MHz).Mass spectra were recorded on a Helwett-Packard 5988-A.Column chromatography was performed with silica gel (E.Merck, 70-230 mesh).Reactions were monitored by TLC using 0.25 mm silica gel F-254 (E.Merck).Microanalysis was determined on a Carlo Erba-1106 analyser.All reagents were of commercially quality or were purified before use.Organic solvents were of analytical grade or were purified by standard procedures.Commercial products were obtained from Sigma-Aldrich.

Method 2. N-Methyl-4,5dihydropyrrolo[1,2-a]quinoxaline (1). Procedure a).
To a suspension of Cs 2 CO 3 (130 mg, 0.40 mmol), BINAP (0.5 mol %) and Pd[P(o-tolyl) 3 ] 2 Cl 2 (0.1 mol %) in toluene (1 mL) the corresponding methylamine 10 (80 mg, 0.39 mmol) was added and the resulting mixture was stirred and heated at 100 ºC under argon for 12 h.The mixture was cooled to room temperature, the solvent was removed and the crude product was purified by silica gel column chromatography using hexane / ethyl acetate 90:10 as eluent.The title compound was isolated as a white solid in 23 % yield (17 mg, 0.02 mmol).Procedure b).To a solution of methylamine 10 (160 mg, 0.78 mmol) in freshly distilled DMF (4 mL), NaH (50 mg, 2.08 mmol) was slowly added under an argon atmosphere.The resulting mixture was heated at 100 ºC for 48 h.The crude reaction mixture was cooled to room temperature and diluted with water and ice (30 mL), and then 2N HCl was added until pH 5-6.The mixture was extracted with ether (3x20 mL).Then the organic phase was washed with water, dried over Na 2 SO 4 , filtered and the solvent was removed under vacuum.The crude reaction mixture was purified by silica gel chromatography column using a mixture of hexane/ethyl acetate 90:10 as eluent.An amount of 133.5 mg (0.73 mmol) 93% of the title compound as a white solid was obtained.Following the above indicated conditions and using Cs 2 CO 3 or K 2 CO 3 (excess 5 equiv) instead of NaH the same quinoxaline 1 was obtained in 45 and 39% yield, respectively.