Synthesis of acridan-fused quinoxalines

The synthesis of acridan-fused quinoxalines, 10,14b-dihydro-1,6,14b-triazanaphth[ a ]- aceanthrylenes, 10,14b-dihydro-1,2,6,14b-tetraazanaphth[ a ]aceanthrylene, 10,14b-dihydro-1,5,6,14b-tetraazanaphth[ a ]aceanthrylene and the acridan-fused pyrazine, 2,3-dicyano-8,12b-dihydro-1,4,12b-triazabenz[ a ]aceanthrylene, is described.


Introduction
Quinoxaline 1 structural units are found frequently in biologically active substances, as recently well summarised. 2 Quinoxalines fused to other heterocyclic systems have been of particular interest, for example antiviral indolo[2,3-b]quinoxalines 3,4 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-isopropyliminophenazine (chlofazimine) for treatment of leprosy, 5 and the potent Lck inhibitor N-(2-chloro-6-methylphenyl)-7,8-dimethoxyimidazo [1,5-a]quinoxalin-4-amine (BMS 238497). 6The quinoxaline framework also figures largely in materials chemistry, 7 again, as well summarised previously. 2 The standard route for the ring synthesis of quinoxalines involves the acid or Lewis acid catalysed double condensation of a 1,2-diketone with an ortho-phenylenediamine.Many protocols, differing mainly in the acidic catalyst used, have been described and are well summarized in a report 2 which introduced bismuth(III) triflate as a catalyst for carrying out the condensation in water.Other combinations utilize the reaction of an ortho-phenylenediamine with 1,2-difunctionalised components at a lower oxidation state, for example 2-hydroxy-ketones, but these require the presence of an oxidant (sometimes just air).There are many examples of the use of isatins (1H-indole-2,3-diones), which are, chemically speaking, -keto-amides, in the ring synthesis of quinoxalines, 8 the earliest of which dates back to 1947. 9e have previously described our investigations on the synthesis of some cyclooctane-based pyrazines and quinoxalines. 10Here we detail our preparations of some acridan-fused quinoxalines.The route is notable for the use of fused isatins as -ketoamides, not 1,2-diketones, in the quinoxaline ring formation.

Results and Discussion
Our route began with the assembly of the fused isatins 4a and 4b (Scheme 1).Acridones 1a and 1b were prepared by a standard route 11 involving copper(II) oxide catalysed reactions of aniline/2-methylaniline with 2-chlorobenzoic acid, then sulfuric acid promoted ring closure.The acridones were efficiently reduced to the acridans (9,10-dihydroacridines) 2a and 2b by treatment with sodium dissolving in n-butanol at 110 °C. 12Attempts to follow earlier work and use lithium aluminium hydride 13 or sodium amalgam 14 resulted only in mixtures of starting material and product.The acridans were unstable substances and spectroscopic measurements were made rapidly as were the subsequent reactions of these two aromatic amines.
Reaction of the acridans with oxalyl chloride generated amide-acid chlorides 3a and 3b which were ring closed to 4a and 4b by aluminium(III) chloride treatment at room temperature, conditions which are milder than those used previously 15 for a ring closure to 4a.Scheme 1. Synthesis of 6H-pyrrolo[1,2,3-de]acridine-1,2-diones.Two methods were investigated for the reaction of the arylamine-1,2-diamines with 4: (i) heating at reflux in acetic acid or (ii) heating at 160 °C in acetic acid/methanol (1:9) with ultrasound irradiation.The second of these methods is to be preferred since better yields were obtained in shorter reaction times.Reaction of 4b with 2,3-diaminomaleonitrile 5 gave the pentacyclic pyrazine derivative 6 (Scheme 2).An alternative and reasonable structure for the condensation product, 7, was clearly eliminated on the grounds of molecular weight, absence of IR carbonyl or NH peaks, and the absence of an NMR signal for N-hydrogen.These criteria also apply to the structure determinations of the other condensation products, 9 and 10/11, described below.Scheme 2. Synthesis of 12-methyl-8H-pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine-2,3dicarbonitrile (6).
The hexacyclic quinoxalines 9a and 9b were similarly obtained by reactions of 4a and 4b, respectively, with ortho-phenylenediamine 8a (Scheme 3).Isomeric mixtures were obtained from the reactions between 4a and 4b with 4-methylbenzene-1,2-diamine 8b; compounds 9c/9d and 9e/9f were formed in a 1:1 and 1:3 ratio respectively, but could not be separated by chromatography.The ratios were determined by examination of the integrations of the 1 H NMR methyl signals, but we were not able to determine in the isomeric pair 9e/9f, which is the major product.

Experimental Section
General.Melting points were recorded on a Philip Harris C4954718 apparatus and are uncorrected. 1H and 13 C NMR spectra were recorded on a Bruker Avance AQS 300 MHz spectrometer, at 300 MHz and 75 MHz respectively.Chemical shifts δ are in parts per million (ppm) measured in CDCl3 and DMSO-d6 as solvents and relative to TMS as the internal standard.Infrared spectra were recorded on a Thermonicolet-Nexus 670 FT-IR instrument.High resolution mass spectra were recorded on an Agilent Technology (HP), MS Model: 5973 Network Mass, selective Detector Ion source: Electron Impact (EI) 70 eV, ion source temperature: 230 ºC Analyzer: quadrupole, and relative abundances of fragments are quoted in parentheses after the m/z values.A Cole-Parmer 600-Watt Ultrasonic Processor with US probe was used for the ultrasonication and the reactions were carried out in a round-bottom flask.

General procedure for synthesis of 2-(acridin-10(9H)-yl)-2-oxoacetyl chlorides
Oxalyl chloride (5.5 mmol, 0.7 g) was added dropwise to a solution of the dihydroacridine (2.7 mmol) in benzene (10 mL) at 5 o C. The mixture was stirred for 2 h at room temperature, then the benzene was evaporated leaving the residue as solid.It was not necessary to purify crude product for subsequent reaction.

General procedures for synthesis of fused quinoxalines Method 1:
A mixture of the dione (0.21 mmol) and ortho-phenylenediamine (0.21 mmol, 0.023 g) in acetic acid-methanol (1:9, 10 mL) was irradiated with ultrasound at 160 o C for the appropriate time.After completion of reaction a precipitate had appeared.The solid obtained was filtered off, washed with water and dried.