A general, versatile synthesis of 2 H -pyrrolo[3,4-c ]quinolines via tosylmethylisocyanide reaction

A new synthetic procedure for obtaining 2 H -pyrrolo[3,4-c ]quinolines is reported. The synthetic pathway utilizes TosMIC reaction to prepare appropriate nitroarylpyrrylcarboxylic esters, which on treatment with Fe-AcOH undergo reduction of nitro group with concomitant intramolecular cyclization to give title derivatives. The procedure proved general and more profitable than those previously reported in the literature. The synthesis of still unknown parent compound 4 via TosMIC is described. 2 H -Pyrrolo[3,4-c ]quinolines substituted at 1 and 3 positions have been obtained by making use of methyl-TosMIC.


Introduction
The presence of heterocyclic structures in many natural and synthetic products endowed with biological activities makes account for the large amount of searches devoted in the past years to the synthesis of novel polycyclic systems containing one or more heteroatoms.
Various 5,6,6 tricyclic pyrrole annulated rings, including pyrroloquinoxalines and pyrroloquinolines, have been used as lead chemical structures for developing chemotherapeutic agents and drugs acting on Central Nervous System.][4] Our decennial interest in the chemistry of pyrrole annulated heterocyclic systems [5][6][7][8][9] and our recent involvement in a work project on potential ligands of 5-HT receptors led us to explore new routes for obtaining 2H-pyrrolo [3,4-c]quinoline derivatives.
As a first approach, we describe a smooth two steps synthesis of 2H-pyrrolo [3,4-c]quinolin-4(5H)-one 2 (Scheme 1) starting from ethyl 2-nitrocinnamate, which was treated with toluene-4sulfonylmethylisocyanide (TosMIC) 10,11 in the presence of sodium hydride, to afford pyrrole 1. 12 Powdered iron-acetic acid reduction of the last compound gave directly the quinolinone 2 by intramolecular cyclization of the intermediate amino ester.Preparation of the parent tricyclic system 4 was promptly achieved from 2 by lithium aluminum hydride reduction of carbonyl to methylene with formation of 4,5-dihydro-2H-pyrrolo [3,4c] The herein described synthetic approach was employed to prepare a number of novel 2Hpyrrolo [4,5-c]quinolines bearing substituents in the benzene ring as well as at positions 1, 2, 3 and 4 in the pyrrolopyridine moiety.
Alkylation at 2-position of pyrroloquinolinone 10 with methyl iodide in the presence of anhydrous potassium carbonate, followed by lithium aluminum hydride reduction and manganese dioxide oxidation, afforded 2-substituted derivatives 11a, 12a and 13a.2,3-Substituted pyrroloquinolines 11b, 12b and 13b were synthesized by a similar pathway starting from pyrrole derivative 9d, obtained by reaction of methylTosMIC on 5-chloro-2-nitrocinnamate, followed by alkylation with methyl iodide in alkaline medium.
Introduction of a phenyl group in 2-position of the pyrroloquinoline system can be obtained by direct arylation of 2 with phenylboronic acid in the presence of Cu(II) in typical Suzuki reaction conditions to obtain 14.However, the yields of the above phenylation were not satisfactory neither when the traditional conditions (21%) were used or when the microwaveassisted reactions were performed (14%).
4-Chloroderivatives 16a and 16b, obtained by chlorination with phosphorus oxychloride of intermediate lactams 10 and 11a, respectively, were easily transformed into 4-methoxy and In conclusion, the examples here reported, although not exhaustive, point out the utility of TosMIC and its methyl derivative in the simple and profitable new approach to 2H-pyrrolo [3,4c]quinoline derivatives, which are undoubtedly useful for the design of new drugs acting on central nervous system.

Experimental Section
General Procedures.Melting points were determined on a Büchi 530 melting point apparatus and are uncorrected.Infrared (IR) spectra (Nujol mulls) were recorded on a Perkin-Elmer Spectrum-one spectrophotometer. 1 H NMR spectra were recorded at 400 MHz on a Bruker AC 400 Ultrashield spectrophotometer using tetramethylsilane (Me 4 Si) as the internal reference standard.Microwave reactions were conducted using a CEM Discover Synthesis Unit.The machine consists of a continuous focused microwave power delivery system with operatorselectable power output from 0 to 300 W. Reactions were performed in glass vessels (capacity 5 mL) sealed with a septum.The pressure is controlled by a load cell connected to the vessel via a 14-gauge needle, wich penetrates just below the septum surface.The temperature of the contents of the vessel was monitored using a calibrated infrared temperature control mounted under the reaction vessel.All experiments were performed using a stirring option whereby the contents of the vessel are stirred by means of a rotating magnetic plate located below the floor of the microwave cavity and a Teflon-coated magnetic stir bar in the vessel.Column chromatographies were performed on alumina (Merck; 70-230 mesh) or silica gel (Merck; 70-230 mesh) column.All compounds were routinely checked by TLC using aluminium-baked silica gel plates (Fluka DC-Alufolien Kieselgel 60 F 254 ).Developed plates were visualized by UV light.Solvents were reagent grade and, when necessary, were purified and dried by standard methods.Concentration of solutions after reactions and extractions involved the use of rotary evaporator (Büchi) operating at a reduced pressure (ca.20 Torr).Organic solutions were dried over anhydrous sodium sulfate.Analytical results agreed to within ±0.40% of the theoretical values.All compounds were analysed for C, H, N, and, when present Cl.

4-(2-Nitrophenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (15)
. Method A. To a flask was added 1 (1.9 mmol, 500 mg), cupric acetate (2.9 mmol, 520 mg), phenylboronic acid (3.8 mmol, 460 mg), and pyridine (3.8 mmol, 300 mg) in that order, followed by 1,2dimethoxiethane (50 mL).The flask fitted with a male gas inlet and the mixture was allow to stir at reflux, open to air, for 72 h.After cooling, the mixture was diluted with tetrahydrofuran (70 mL), filtered off, and the solvent was evaporated under reduced pressure.The residue was chromatographed on silica gel column (ethyl acetate/n-hexane 1:2 as eluent) to furnish 15 (140 mg, 22%) as oil. 1  Method B. In a 5-mL glass tube were placed 1 (0.38 mmol, 100 mg), cupric acetate (1.9 mmol, 350 mg), phenylboronic acid (1.4 mmol, 140 mg) NMP-pyridine mixture (0.5:0.5 mL), and a magnetic stir bar.The vessel was sealed with a septum and placed into the microwave cavity.Microwave irradiation of 60 W was used, the temperature being ramped from room temperature to 120 °C.Once 120 °C was reached, the reaction mixture was held at this temperature for 3 x 50 sec (after each cycle, the reaction vessel was cooled and cupric acetate (1.9 mmol), phenylboronic acid (1.4 mmol), and NMP-pyridine (0.5:0.5 mL) were added).The reaction vessel was opened and the mixture was diluted with tetrahydrofuran (5 mL), filtered off, and the solvent was evaporated under reduced pressure.The residue was dissolved in ethyl acetate (20 mL), washed with 1N HCl (2 x 10 mL) then with brine (3 x 10 mL), dried, and evaporated.The crude product was chromatographed on silica gel column (ethyl acetate/n-hexane 1:2 as eluent) to furnish pure 15 (120 mg, 94%), with the same chemico-physical and spectral properties showed by the product obtained by method A.

4,8-Dichloro-2H-pyrrolo[3,4-c]quinoline (16a).
A mixture of 10 (1.8 mmol, 400 mg), N,Ndimethylaniline (0.5 mL), and phosphorus oxychloride (6 mL) was heated at reflux for 5 h.After cooling, the mixture was concentrated at reduced pressure and treated with chloroform and water.The organic layer was separated, washed with brine and dried.Removal of the solvent gave a residue which was chromatographed on silica gel (chloroform/ethyl acetate 4:1 as eluent) to afford pure 16a (100 mg, 22 %) which was used for the next reaction without characterization because of its instability.