Microwave irradiation for accelerating the synthesis of acridine and xanthene derivatives from dimedone

Microwave (MW) irradiation activated the reaction of dimedone with aniline or p-chloroaniline in formic acid to give the acridine derivatives 2a and 2 b , respectively, which can be derivatized as the bisoximes 3 and bisphenylhydrazone 4 . However, under the same reaction conditions 2-aminopyridine gave the xanthene derivative 6 and not the expected acridine derivative 2c . When 2-aminopyridine was allowed to react under MW irradiation with dimedone in presence of benzaldehyde in ethanol it gave the bis(dimedonyl)methane derivative 10 . Cyclization of 10 has been enhanced under MW irradiation to give the xanthene derivative 9 in improved yield and in less time than the conventional heating. The structures of products were confirmed from the analysis of their IR, 1 H-NMR and mass spectra. The antimicrobial activity has been investigated for compounds 3 , 4 , 6 and 10.


Introduction
Chemical and pharmaceutical industries are facing constraints regarding the environmental aspects and saving energy.A major concern to overcome such problems in organic synthesis has considered the use of microwave (MW) irradiation as a source of energy.This led to a dramatic increase of the number of publications using MW in organic synthesis 1,2 .Recently, we became interested in using MW for accelerating organic reactions whereby varied numbers of heterocycles and carbohydrates has been achieved [1][2][3] .
Acridine derivatives have a wide spectrum of biological activities as antibacterial, antimalarial, anticancer and mutagenic properties, principally connected with their ability to inhibit the enzymes acting on nucleic acids 4 .Our protocol was designed for a comparative study for constructing some acridine and xanthene derivatives from dimedone under the influence of ARKAT subsequently cyclized to give 6.It seems that the basic properties of 2-aminopyridine played a role on catalyzing both formylation and its condensation with 1 rather than its involvement in the reaction to form 2c (Scheme 1).Various fused heterocyclic compounds containing the dihydropyridine moiety were conventionally synthesized by the cyclocondensation of 1 with aminoheterocycles and aromatic aldehydes [11][12][13][14][15][16] .Such approach looks attractive for the synthesis of fused partially hydrogenated pyridoquinoline derivative such as 7.However, under the same reaction conditions, boiling equimolar amounts of dimedone (1), 2-aminopyridine and benzaldehyde in absolute ethanol, neither the pyridoquinoline derivative 7 nor the acridine derivative 8 were formed.The elemental analysis of the isolated product indicated the absence of nitrogen, and agreed with the molecular formula C 23 H 28 O 4 .Its 1 H NMR spectrum showed the presence of five protons in the aromatic region indicating the presence of a phenyl group and the absence of a pyridine moiety.The presence of four methyl groups, resonated as two singlets a δ 0.98 and 1.17, and four methylene protons at δ 2.39-2.48were consistent with the presence of two dimedone units.A signal for the enolic OH proton was observed at δ 11.92 and a singlet for the CHPh appeared at δ 5.54.Accordingly, the isolated product was assigned the structure 10.It was readily confirmed ARKAT by its conversion to 3,3,6,6-tetramethyl-9-phenyl-octahydro-xanthene-1,8-dione 17 (11) by boiling with dilute hydrochloric acid in ethanol.

Me
The formation of the bis(dimedonyl)methane derivative 10 may have taken place either through formation of the Schiff's base 13, whose C=N has spontaneously added dimedone (1) to form the adduct 12. Subsequent elimination of the 2-aminopyridine moiety, rather than cyclization to the pyridoquinoline 7, afforded the intermediate 9 which upon reaction with dimedone gave 10; such mode of reaction has been noted in the reaction of dimedone with some arylideneanilines [18][19][20] .Further support for this rationale can be drawn from the elimintation of the 5-aminopyrazole moiety from the product of addition of its benzylidene derivatives to ethyl cyanoacetate 21 ; the donor/acceptor effect of substituents on the benzylidene moiety influences to a significant extent the reactivity of the azomethine carbon 19 .Alternatively, the 1:1 adduct 9 may be formed as a key step in the condensation of dimedone and benzaldehyde, followed by subsequent Michael addition of another molecule of dimedone.Attempted synthesis of 9 by microwave irradiation of equimolar amount of dimedone and benzaldehyde in acetic anhydride in the presence of catalytic amount of sodium acetate afforded 10 rather than 9; a spontaneous reaction of the presumably formed 9 with dimedone has taken place to give 10.Although such condensation was described in the literature 20 , it is unsuccessful for all aldehydes 21 (Scheme 2).
The above results indicated that in contrary to other amino heterocyclic compounds, 2aminopyridine did not react, in a similar manner, with dimedone to give the pyridoquinoline analogue.Moreover, the use of MW in performing the above reactions provided similar pathways to the conventional heating, but in much reduced times and better yields.
The antimicrobial activity against Staphylococcus aureus, Candida albicans, Escherichia coli and Psudominus aureus for compounds 3a,b, 4, 6 and 10 was evaluated by agar diffusion technique using Ampicilin and Chlotrimazole as references (Table 1).
Although the oxime derivative 3a showed a lower activity (IZ 22) against Staphlococcus aureus, the 10-p-chlorophenyl derivative 3b exhibited no activity.However, both compounds showed a lower inhibition (IZ 16) relative to Chlotrimazole against Candida albicans.The bishydrazone 4 showed lower activity compared to ampicilin (IZ 23) against Staphylococcus aureus and it exhibits a compatible inhibition (IZ 22) relative to Chlotrimazole.On the other hand, the xanthene derivative 6 showed that it possess a potential antimicrobial activity (IZ 34 and 28) relative to ampicilin (IZ 35) and Chlotrimazole (IZ 23), respectively against Staphlococcus aureus and Candida albicans, respectively.However, the uncyclized product 10 showed a lower inhibition activities.None of the tested compounds showed inhibition activity against Escherichia coli and Psudominus aureus.In conclusion MW irradiation activated the reaction of dimedone with aromatic amines in formic acid to give the acridine derivatives.However, under the same reaction conditions 2aminopyridine gave a xanthene derivative containing three dimedonyl moities and not the expected acridine derivative.When 2-aminopyridine was allowed to react under MW irradiation with dimedone in presence of benzaldehyde in ethanol it gave the bis(dimedonyl)methane derivative.The MW has improved the yields in less time than the conventional heating.

Table 1 .
The antimicrobial activity of selected compounds