Synthesis of novel 2-aryl-2,3-dihydronaphtho[2,1-b ]furo[3,2-b ] pyridin-4(1 H )-ones of biological importance

2-Aryl-2,3-dihydronaphtho[2,1-b ]furo[3,2-b ]pyridin-4( 1H )-ones 5a-f were synthesized from 2-hydroxy-1-naphthonitrile 2 and characterized on the basis of chemical, analytical and spectral data. The compounds were screened for antibacterial and antifungal activity


Introduction
Naphthofuran nuclei are key structural moieties found in a large number of biologically important natural products, mainly belonging to the sesquiterpene and arylquinone classes. 1 Most of the natural naphthofurans such as (±)-laevigatin, 2 (+)-heritol 3 and balsaminone 4 possess interesting pharmacological and cytotoxic properties.Several synthetic compounds bearing this ring skeleton are associated with diverse biological activities such as antifungal, 5 antibacterial, 6 antiviral, 7 β-adrenolytic, 8 antitumour, 9 and anthelmintic. 10The wide pharmacological potential of these bioactive moieties has attracted many organic and medicinal chemists to develop efficient routes for their synthesis.Moreover, there has been considerable research work in the synthesis of angularly fused tetracyclic compounds owing to their close relationship with anticancer agents. 113][14] The conventional procedures are not fully satisfactory with regard to operational simplicity, cost of the reagent and isolated yield.6][17][18] Thus; the drive continues to find a better and improved methodology.In recent communications [19][20][21][22] we have demonstrated a very simple procedure for the synthesis of fused heterocyclic compounds proving the synthetic utility of MORE chemistry in routine organic synthesis.In view of the above reports and in continuation of research in the synthesis of pharmacologically potent naphtho [2,1-b]furan derivatives, we report in this paper the synthesis of 2-aryl-2,3-dihydronaphtho [

Results and Discussion
The key intermediate 2-hydroxy-1-naphthonitrile 2, was synthesized from 2-hydroxy-1naphthaldehyde. The compound 2 was prepared from an equimolar mixture of 2-hydroxy-1naphthaldehyde and hydroxylamine hydrochloride in formic acid and sodium formate.The reaction mixture was irradiated to microwave.The structure of 2 was confirmed by its IR spectrum, which exhibited strong absorption band at 2233 cm -1 due to the CN group and a broad absorption band at 3300 cm -1 due to the OH group.The 1 H NMR data revealed consistent with the structure.This is a novel method for the conversion of 2-hydroxy-1-naphthaldehyde into 2-hydroxy-1-naphthonitrile with 75% yield (Scheme 1).The nitrile compound 2 on reaction with chloroacetone in presence of potassium carbonate and dimethylformamide underwent Thrope-Ziegler cyclisation to produce compound 3 in moderate yield.In order to improve the yield, the same reaction between 2 and chloroacetone was carried out in microwave oven for 4-5 min, which resulted in considerable increase in yield to the extent of 85% (Scheme 2).
The structure of 3 was confirmed by its spectral data.The IR spectrum of 3 showed the absence of nitrile group, instead it exhibited two absorption bands due to symmetric and asymmetric stretching frequencies of primary amine at 3373 cm -1 and 3485 cm -1 and another band at 1630 cm -1 due to carbonyl group, which is intermolecular hydrogen bonded with adjacent NH 2 group. 1 H NMR spectrum of 3 showed a broad singlet integrating for 2 protons at δ 5.95 ppm, due to the NH 2 group (D 2 O exchangeable) and a singlet integrating for 3 protons at δ 2.55 ppm due to the CH 3 group.Other signals appeared in the aromatic region corresponding to 6 protons as multiplet at δ 7.58-8.63ppm, in particular C 5 & C 6 resonate as triplets δ 7.60 ppm (J=7 Hz) and δ 7.70 ppm (J=7 Hz) respectively.C 10 and C 11 resonate as doublet at δ 7.90 ppm (J=9 Hz), & δ 8.45 ppm (J=8 Hz), and C 4 & C 7 at δ 8.05-8.15ppm as a double doublet (J=8 Hz) of naphthofuran confirmed the structure.In order to further ascertain the structure, the mass & 13 C were also recorded.The 13 C NMR spectrum of this compound was in good agreement with the structure assigned.In the broad band decoupled 13 C spectrum of 3, a small peak at δ 189.17 was assigned to carbonyl carbon atom.The remaining small peaks appearing at 153. 04 As a set target to synthesize the title compounds, 3 was made to undergo Claisen-Schmidt condensation followed by intramolecular Michael addition with aromatic aldehyde in presence of ethanolic sodium hydroxide solution.The mixture was taken in a mortar and ground well for 10 min to get uniform mass.Then the reaction mixture was subjected to microwave irradiation in ethanol at low power-2 for 4 to 5 min exposure to give 2-Phenyl-2,3-dihydronaphtho[2,1b]furo[3,2-b]pyridin-4(1H)-ones 5 in 73% yield.We also noticed that, when the mixture was pounded to get uniform mass before exposure to microwave, the compound 3 underwent Claisen-Schmidt condensation to produce an intermediate i.e. 1-aminonaphtho[2,1-b]furan-2-yl-3-phenylprop-2-en-1-one 4a-f in 68-75% yield.This underwent intra molecular Michael types of addition in acetic acid media under microwave irradiation to give the title compounds 5a-f hitherto unknown in literature.The structures of 5a-f obtained by two pathways were confirmed by superimposing their 1 H NMR and mass spectral data.The sequence of reaction is cited in Scheme-3 and the products are tabulated in experimental section.
The IR spectrum of 4a showed two absorption bands at 3200 and 3350 cm -1 due to symmetric and asymmetric stretching frequencies of NH 2 group and another band at 1622 cm -1 due to carbonyl group.The 1 H NMR spectrum of 4a shows broad singlet at δ 6.2 due to NH 2 group (D 2 O exchangeable) was found to be little higher δ value than before (δ 5.85).Further, a singlet at δ 2.55 attributed to the COCH 3 group of compound 3 was found to be absent, instead two doublets appeared between δ 7.75 (J=8 Hz) and 7.90 (J=9 Hz) was due to the protons of the CO-CH=CH-R group (merged with aromatic protons).The spectrum of 5a was in well agreement to the assigned structure, showing absence of two sharp bands in the region of 3300-3400 due to the NH 2 group and appearance of bands in the region between 3300-3400 cm -1 , 3100-3400 cm -1 , 1629 cm -1 characteristic of tetrahydroquinoline, assignable to -NH and -C=O frequencies in the IR spectrum.In the 1 H NMR spectrum of 5a signals due to COCH=CHR and -NH 2 protons were not observed and instead a new peaks at δ 4.92-5.1 and at δ 2.64-3.1 as doublet of a doublet and two quartets respectively were observed due to -CH and -CH 2 protons of the nitrogen heterocycles.Similar observations were made in the case of tetrahydropyridine derivatives. 23ince the reactions took place well in microwave method, we would also like to disclose reaction features under conventional method.The results obtained pertaining to time & yields of both the methods are felt appropriate to discuss.So the results are given in the Table 1.In conclusion, the present protocol describes a simple and efficient method for the synthesis of angularly fused tetracyclic condensed heterocycles.

Experimental Section
General Procedures.Melting points were determined on a glass disk with an electrical bath and are uncorrected. 1H NMR (400 MHz) spectra were run in CDCl 3 solutions.Chemical shifts are expressed in δ ppm.IR spectra were taken as neat for liquid compounds and as KBr pellet for solids.Elemental analysis was done by a Perkin-Elmer auto analyzer at IISc Bangalore.Column chromatography was performed on silica gel (60-120 mesh, SRL, India).Chloroacetone and dimethylformamide were distilled before use.The microwave-assisted procedures were carried out in a domestic Whirlpool Microwave oven operating at 1000 W.
Antimicrobial Screening.The in vitro antimicrobial activity was carried out against 24 hrs old cultures of two bacteria and two fungi by cup-plate method. 24Compounds 4a-f and 5a-f has been tested for their antibacterial activity against Pseudomonas aerugenosa and Staphylococcus aureus and antifungal activity against Aspergillus niger and Candida albicans.Nutrient agar and potato dextrose agars were used to culture the bacteria and fungus respectively.The compounds were tested at varied concentration.The minimum inhibition concentration was found to be of 0.005 mol / ml in DMF against all organisms.The solution of chloramphenicol (2 mg/ ml) and fluconazole (2 mg/ ml) were prepared in sterilized water and used as standards for comparison of antibacterial and antifungal activities respectively.The compounds were tested at varied concentration.The minimum inhibition concentration was found to be 0.001mol/ ml in DMF against all organisms.Inhibition was recorded by measuring the diameter of the inhibition zone at the end of 24 hrs for bacteria at 28 o C and 48 h for fungus at 35 o C. Each experiment was repeated thrice and the average of the three independent determinations were recorded.The protocols were summarized in (Table 2).The compounds 5d, 4d and 5f showed promising activity against P. aerugenosa and the 5b, 5c and 5e against S. aureus.The compounds 5e, 5d and 5f against A. niger and 5d, 5f and 5b against C. albicans exhibited significant activity.Highly active (inhibition zone > 12 mm); Moderately active (inhibition zone 9-12 mm); Slightly active (inhibition zone 6-9 mm); Inactive -inhibition zone < 6 mm).

2 Scheme 3 .
Scheme 1 , 141.09, 136.27, 130.32, 128.83 and 114.14 were attributed to C 2 , C 9 , C 8 , C 12 , C 13 and C 3 carbon atoms respectively which are quaternary carbon atoms.The large peak at 131.28, 129.61, 127.71, 124.89 and 122.07 were assigned to C 10 , C 7 , C 4 , C 6 and C 5 carbon atoms of naphthalene ring respectively.As expected C 11 of naphthalene nucleus exhibited a large peak at 113.27.Methyl carbon atom exhibited a medium peak at δ 25.86 ppm.Finally mass spectrum of 3 also confirmed the structure.It exhibited a molecular ion peak at m/z 225 corresponding to its molecular weight.Other peaks appearing at m/z 210, 182, 154, 127 and 77 were in accordance with the fragmentation pattern of an assigned structure.

Table 1 .
Relative percentage of products formed under two methods (Column purified yields are reported)