1,3-Dipolar cycloadditions of acridine with nitrile oxides

Site-and regio-isomeric mono-cycloadducts 9 are formed in the reactions of mesito-1b and dichloromesitonitrile oxide 1c with acridine 6 in a 1:2 ratio, while the reaction of 1b and 6 in a 10:1 ratio afforded, besides the mono-cycloadduct 9b and traces of the corresponding oxime 10b, the bis-cycloadduct 12 with the opposite regiochemistry to that of the mono-cycloadducts 9 and the adduct 13


Introduction
Intermolecular reactions of heteroaromatics with 1,3-dipoles have provided an interesting way for the synthesis of complex heterocyclic systems, with high levels of regio-and stereochemical control.Previously, one of us found that pyridine, in apolar solvents, adds to benzonitrile oxide 1a to give two bis-cycloadducts 1 4 (26%) and 5 (9%), which arise from the addition of a second molecule of 1,3-dipole to the highly reactive dienamine moiety of the initial mono-cycloadduct 3 (Scheme 1).The formation of 3 has been rationalised in terms of a pseudo-pericyclic 2 process involving the formation of an initial zwitterion 2, originating from the attack of the heterocyclic nitrogen atom on the dipole carbon, which undergoes a subsequent electrocyclic closure to the corresponding mono-cycloadduct 3.

Scheme 1
In a search for direct evidence of the proposed intermediates, we explored the possibility of increasing their stability by appropriate modifications of the reactants.After having trapped the mono-cycloadduct 3 by exposing pyridine to two different nitrile oxides, 3 we have succeeded in stabilizing the zwitterion 2 with respect to the reactants by providing a delocalization of negative charge 4 or by reducing the loss of aromaticity involved in the cycloaddition process. 1,5  an extension of this research, we now report our investigation of the reactivity of acridine 6 towards benzo-1a, mesito-1b, and dichloromesito-nitrile 1c oxides.Two reaction pathways have been observed: the first one is related to the nucleophilicity of the acridine nitrogen atom and then to the possible isolation of a zwitterion 7, whose stability should be improved by delocalization of the positive charge on the three aromatic rings.The acridine nitrogen atom, even if less nucleophilic than that of pyridine or quinoline, 6 appears to be associated to a good value of electron density 7 and then to a good nucleophilicity, as is supported by the large number of acridinium salts prepared by alkylation, which is favoured by the use of polar solvents. 8he second mode of reactivity of acridine is the dipolarophilic activity of the diene system included in its benzenoid structure.Because the nitrogen atom in acridine does not keep an external position, its cyclohexadiene ring could add to nitrile oxides, as does anthracene, 9 to give site-and regio-isomeric mono-cycloadducts; this latter aspect arises from our recent studies on polycyclic aromatic hydrocarbons (PAHs) [9][10][11] and aza-analogues of phenanthrene. 12cridine participates in many nucleophilic addition reactions, which lead to acridan products through nucleophilic attack at the C-9 carbon followed, in many instances, by an oxidation process. 6The predicted position of electrophilic attack is, on the contrary, at the C-4 position and is in agreement with the experimentally observed products. 13To the best of our knowledge, however, there are no literature reports concerning cycloaddition reactions of acridine where this acts as a 2π component.

Results and Discussion
Reactions between acridine 6 and the nitrile oxides 1a-c were initially carried out by adding portionwise one equivalent of the nitrile oxide to a solution containing two equivalents of 6 in dry diethyl ether at 0 °C; after three hours, the reaction mixture was left to reach room temperature and to react until the 1,3-dipole was consumed.Under these conditions, no zwitterion 7 was obtained, but its initial formation can be deduced by the isolation of the dioxadiazine dimer 8 in 38.2% yields from 1a and 6 pre-formed in a neutral solution at 0 °C, in dimethylformamide. 14The production of 8 falls to 0.5% in the absence of acridine, in agreement with a literature report, 15 which attributes the abnormal dimerization of 1a to the dioxadiazine 8 to the initial formation of a zwitterion (Scheme 2).
In contrast, when reactions of 6 with 1a-c were carried out in refluxing dry toluene for two days, they provided the mono-cycloadducts 9b and 9c, in 12% and 14% yield, respectively, but not 9a (Scheme 2).No traces of other regio-and site-isomers were detected by 1 H-NMR analysis of the crude reaction mixtures.The structures of the dihydroisoxazolo-[4,5-a]-acridines 9b and 9c were assigned on the basis of 1 H-and 13 C-NMR spectra and confirmed through NOEDS experiments.In particular, for the regioisomer 9b, diagnostic resonances for H-11b and H-3a appear at δ4.98 as a doublet, and at 5.86 ppm as a double doublet of doublets, respectively; the H-4 and H-5 olefinic protons resonate as double doublets at 6.44 (J = 2.9 and 10.2 Hz) and 7.00 (J = 1.4 and 10.2 Hz) ppm, respectively.Irradiation of the H-11 proton, gives rise to positive NOE enhancements for H-11b (7.6%), H-10 (8.8%), and the methyl protons of the mesityl moiety at C-1 (1.4%).Moreover, by irradiating H-11b, NOE effects were observed for the methyl protons (6.2%), H-3a (11.9%), and H-11 (8.2%); in turn the irradiation of H-3a shows NOE effects for H-11b (9.0%) and H-4 (6.2%).The 13 C-NMR spectrum reveals signals for C-11b, C-3a and C-1 of the dihydroisoxazole ring at 52.12, 76.72 and 159.20 ppm, respectively.Further confirmation of the assigned structures was obtained by cleavage of the C-O bond of the dihydroisoxazole ring upon treatment with sodium ethoxide in ethanol, which afford the corresponding oximes 10b,c (Scheme 3). 16 The oximes 10b,c were resistant to acidic or basic hydrolysis and did not afford the corresponding ketones.Their structures were derived from the following spectroscopic observations.Compared to the compounds 9, the 1 H-NMR spectra of 10b,c show the lack of the H-11b and H-3a resonances and the appearance of the oxime proton in the range 10-11 ppm, exchangeable with deuterium oxide.In the 13 C-NMR spectra, the oxime carbon resonates at 160.82 ppm.
The oximes 10b,c were also isolated as exclusive products when the reactions between 6 and 1b,c in the previously used stoichiometric ratio, were performed directly in a simple domestic microwave oven under irradiation (600 W) for 60 sec; analogous results were also obtained when the reactions were conducted in the absence of solvent, in an oil bath preheated at 180°C, for 60 sec (Scheme 3).
These data and the obtention of 10b from 9b by heating at 180°C for 60 sec in the absence of solvent, indicate that the first step of the reaction is the cycloaddition leading to 9b,c: then the reorganisation of the dihydroisoxazole rings of 9b,c into the corresponding oxime 10b,c takes place owing to a thermal effect rather than by an irradiating effect by microwaves.
Thus, the 1 H-NMR spectrum of 12 shows distinct resonances for the methyl groups and aromatic protons of the two mesityl substituents (see Experimental), two doublets at 5.19 and 6.29 ppm for the dihydroisoxazole protons, and five signals for acridine protons.The assignments were made on the basis of NOEDS experiments.Thus, the irradiation of H-12b results in enhancements of the H-3a and H-12 resonances; in turn, positive NOE effects have been measured for H-12b and the methyl protons centred at 2.08 ppm, upon irradiation of the Besides the resonances of methyl protons in the range 2.26-2.44 ppm and mesityl protons at 6.88 and 6.93 ppm, the 1 H-NMR spectrum of 13 shows two doublets, a double triplet, a singlet and three multiplets for H-2-H-9 protons, in the range 7.52-8.05ppm and a very broad singlet at 6.92 ppm for the N-hydroxyl proton. 18The 13 C-NMR spectrum shows diagnostic signals for C-3 and C-5 at 160.75 and 115.21 ppm, and the IR spectrum shows a broad absorption band at 3352 cm -1 for OH or NH stretching. 19hile the dihydro-oxadiazole derivative 13 was an expected compound, since 6 is a very poor dipolarophile and then a second molecule of nitrile oxide preferentially adds to the C=N double bond of an initially formed adduct 9b, 20 formation of the bis-cycloadduct 12 cannot be rationalised directly on the basis of the isolated mono-cycloadduct.Tentatively, we assume that this compound could originate from the other, unisolated regioisomer 14b, which regioselectively undergoes addition of a second molecule of 1b to the C-4-C-5 double bond, followed by the loss of a hydrogen molecule (Scheme 6).In conclusion, contrary to expectation of its inertia, mainly owing to loss of its aromaticity, and high nitrogen-nucleophilicity, 6 reacts as a 2π   component towards nitrile oxides affording the mono-cycloadducts 9 in low yields, as do PAHs [9][10][11] and aza-analogues of phenanthrene. 12he reaction performed with 10 equiv. of the 1,3-dipole, led to two new products, 12 and 13, as well as the mono-cycloadduct 9b and traces of the oxime 10b.Moreover, semi-empirical calculations at the PM3 level, performed in order to rationalise the observed experimental results, are not completely in accord with the FMO theory: although the site-selectivity of the reactions is predicted correctly, the observed regioselectivity of mono-cycloadducts is inverted.An ab initio study is in progress, and will be reported in due course.

Experimental Section
General Procedures.Melting points were determined with a Kofler apparatus and are uncorrected.Elemental analyses were performed with a Perkin-Elmer elemental analyzer.IR spectra were recorded on a Perkin-Elmer Paragon 500 FT-IR Spectrometer using potassium bromide discs.NMR spectra were recorded on a Varian instrument at 200 or 500 MHz ( 1 H) and at 50 or 125 MHz ( 13 C) using deuteriochloroform or dimethyl sulfoxide-d 6 as solvent; chemical shifts are given in ppm (δ) from TMS as internal standard.Thin-layer chromatographic separations were performed on Merck silica gel 60-F 254 precoated aluminium plates.Preparative separations were by column-and flash chromatography using Merck silica gel 0.063-0.200mm and 0.035-0.070mm, respectively, with cyclohexane-ethyl acetate mixtures as eluent.Microwave irradiations were performed with a Moulinex FM 5745 A domestic oven at 600W.The identification of samples from different experiments was secured by mixed mps and superimposable IR spectra.

Hydrogenation of 9b with Raney nickel.
A suspension of 9b (2.0 mmol) and a spatula-tip (ca.200 mg) of Raney Nickel in ethanol (10 mL) were placed in a hydrogenation vessel, and shaken mechanically for 4 h under hydrogen (30 psi).The reaction mixture was then filtered through Celite ® and then concentrated under reduced pressure.The 1 H-NMR of the reaction mixture showed numerous products and was not separated.Cycloaddition reactions of 1 with 2b in 1:10 ratio.To a solution of 6 (4 mmol) in refluxing dry toluene (10 mL), 1b (40 mmol) was added portionwise in the same solvent (30 mL).The mixture was heated at reflux until the dipole was consumed (3 days).After removing the solvent, the reaction mixture was subjected to flash chromatography to give the mono-cycloadduct 9b (25%), the oxime 10b (3%), and two new cycloadducts 12 and 13, whose physical and spectral data are given below.