o-Nitroaryl-bis(5-methylfur-2-yl)methanes as Versatile Synthons for the Synthesis of Nitrogen-Containing Heterocycles

2-Nitroaryldifurylmethanes 1a and 1b, readily available by condensation of 2-nitrobenzaldehyde and 6-nitroveratraldehyde with 2-methylfuran, were transformed into indole, cinnoline and benzothiazine-3,1 derivatives. The reduction of 2-nitroaryldifurylmethanes gave the corresponding anilines 2a,b or indole 3 depending on the reaction conditions. A plausible mechanism for the last reaction involving intramolecular heterocyclic addition between a nitroso-group and a furan ring is proposed. Diazotisation of the amine 2b gave a cinnoline derivative - a product of intramolecular oxidative furan ring opening. Treatment of isothiocyanates 7a,b with perchloric acid resulted in a new rearrangement with furan ring migration leading to the 4-Hbenzothiazine-3,1 derivatives.


Introduction
Difurylarylmethanes are of interest to the flavour manufacturring [1], the food industry [2], agrochemistry [3] and dyes and polymer chemistry [4,5].However, until recently this readily available class of compounds was not practically utilised in organic synthesis, although the availability in a difurylarylmethane molecule of suitably located functional groups is a favourable condition for transformations affecting the furan ring.
In developing methods for the synthesis of 2hydroxyaryldifurylmethanes, we have established that these compounds, under acidic conditions, undergo recyclisation to the benzofuran carbonyl derivatives [6], which in their turn can be cyclised with the formation of tetracyclic derivatives (Scheme 1).
In this paper we present our preliminary results on the study of conversions of o-nitroaryldifurylmethane derivatives into nitrogen-containing heterocycles, continuing our search into the use of aryldifurylalkanes as synthons.

Results and Discussion
Earlier, the treatment of o-nitroarylbis-(5-alkylfur-2yl)methanes with triethylphosphite was shown to give carbazole.The authors believed, that the reaction proceeded via nitrene attack on the furan ring with an unsaturated ketone as intermediate (Scheme 2) [7].
It appears that the optimum method for the synthesis of the starting o-nitroaryldifurylmethanes 1a, 1b is the perchloric acid catalysed condensation of the appropriate o-nitrobenzaldehydes and 2-methylfuran in dioxane (Scheme 3) [8].
By the reduction of compounds 1a, 1b in methanol with zinc dust in the presence of hydrochloric acid, or with a hydrazine hydrate -Pd/C system, the corresponding anilines 2a, 2b were obtained in good yields.Different results were observed in the SnCl 2 promoted reduction of the compounds 1a, 1b in acidic media.Compound 1b under this conditions gave the corresponding aniline 2b, wherwas the reduction of o-nitrophenyldifurylmethane 1a led to the formation of an unsaturated ketone 3. It was originally supposed that a key intermediate in this conversion is the hydroxylamine 4 [9], which under acid conditions forms a nitrenium cation or its equivalent with subsequent oxidative furan ring opening (scheme 4).It appears, however, that the authentic hydroxylamine 4, obtained from the nitrocompound 1a by Zn reduction in the presence of NH 4 Cl or complex Sn thiophenolates [10], does not form the ketone 3 under acid conditions.On the other hand, we have established, that the purification of the hydroxylamine 4 by column chromatography and storage at room temperature gave compound 5, contaminated with a small quantity of ketone 3.
These facts have enabled us to assume, that a true intermediate of the reaction is the corresponding nitroso compound A, formed by the slow oxidation of the hydroxylamine 4 with oxygen from the air.To check this idea, compound 4 was refluxed in toluene and the tricyclic compound 5 was isolated from the reaction mixture; its structure was supported by IR-and NMR-spectroscopy and mass-spectrometry data.The same compound was obtained in an 80 % yield by the oxidation of the hydroxylamine 4 with K 2 Cr 2 O 7 at a temperature of 0-5 °C for 10 minutes.
The mechanism of the formation of compound 5 probably includes an intramolecular Diels-Alder reaction between the furan ring and the nitroso-group with subsequent opening of the ether bridge in the initial strained adduct.Diels-Alder heterocycloaddition is well known and recently this methodology was exploited as the key step in the synthesis of mitomycin, as reported by Danishefsky [11].
Since cycloadduct 5 and ketone 3 have different oxidation levels, a reductant is required for the conversion of 5 into 3.Thus, compound 5 can be reduced by the system SnCl 2 + HCl rather smoothly to give ketone 3. It is noteworthy, that in the case of FeCl 3 promoted oxidation of the hydroxylamine 4, ketone 3 was directly formed.It seems probable that under these conditions the in situ formed FeCl 2 serves itself as the reducing agent.It is also possible, that the cycloadduct 5 can oxidize the hydroxylamine 4 under acidic conditions and the conversion as a whole proceeds catalytically.
The other example is the synthesis of a cinnoline derivative as a result of an intramolecular electrophilic attack of diazonium group on the furan ring.Earlier attempts to obtain cinnolines failed due to strong resinification of the reaction mixture caused by the action of aqueous solutions of NaNO 2 and HCl [11].By carrying out the diazotisation reaction under mild conditions (isoamylnitrite, Me 3 SiCl, acetonitrile), we succeeded in obtaining the cinnoline derivative 6 in high yield (Scheme 5).Finally, using a standard procedure, we have obtained isothiocyanates 7a, 8b which under the action of perchloric acid are transformed into 4H-bensothiazines-3,1 (8a, 8b).A possible mechanism of this conversion consists of intramolecular ipso-substitution of one of the furan rings by the protonated isothiocyano-group with subsequent alkylation of the sulphur-atom by a carbenium cation, arising from C-C bond fission (Scheme 6).The described results open up new possibilities in the application of difurylarylalkanes as synthons for condensed polycyclic heterocyclic compound synthesis.

Experimental
General 1 H NMR spectra were recorded on a Bruker AMX-400 400 MHz and Tesla 80 80 MHz spectrometers.IR spectra were obtained with a Specord M80 spectrometer.Low resolution mass-spectra were recorded on a Varian Model 112M mass spectrometer.

Bis(5-methylfur-2-yl)-2-aminophenylmethane (2a)
To a mixture of zinc dust (10 g), methanol (50 mL) and trimethylchlorosilane (4 mL) a solution of compound 1a (2.97 g, 10 mmol) in dioxane (15 mL) was added dropwise.The reaction mixture was stirred at room temperature until the starting compound was consumed (TLC -check), then filtered from the inorganic salts and excess of zinc dust.The filtrate was poured into water and extracted with ether.The ethereal layer was separated, dried over anhydrous sodium sulphate and evaporated to dryness.The residue was purified by column chromatography (silica gel, CH 2 Cl 2 /hexane) to give the pure amine 2a (1.87 g, yield 70 %). 1

Bis(5-methylfur-2-yl)-2-hydroxylaminophenylmethane (4)
To a stirred solution of 2-nitrophenyldifurylmethane 1a ( 0.5 g 1.68 mmol) in THF (6 mL), a solution of NH 4 Cl (0.1 g) in water (3.5 mL) was added followed by zinc dust (0.46 g).The mixture was stirred at room temperature until the starting nitrocompound was consumed (TLC -check).The reaction mixture was filtered from inorganic salts, the filter cake was washed with toluene (5 mL) and the water layer was extracted with toluene (10 mL).The combined organic fractions were dried over sodium sulphate, evaporated in vacuo to yield 0.38 g ( 80 %) of the hydroxylamine 4 as an oil.
As compound 4 is very unstable and easily destroyed by the action of acids and oxygen from the air, we consider it is not necessary to isolate the hydroxylamine 4. Compound 5 can be prepared from 4 in a one-pot procedure.(5) To a mixture of H 2 SO 4 (0.125 mL) and water (1.65 mL), cooled in an ice-bath, the solution of hydroxylamine 4 (0.38 g, 1.34 mmol) in THF (10 mL) (the previous reaction mixture) was added immediately followed by an addition of K 2 Cr 2 O 7 (0.12 g, 0.4 mmol) in water (3.5 mL).After 10 min the reaction mixture was extracted with ether, and the combined ethereal solutions were washed with NaHCO 3 solution, dried over Na 2 SO 4 and evaporated to dryness to give compound 5 (0.31 g, yield 82 % ) as an oil.IR (film, NaCl): 3380 cm -1 (b, OH).