Photoinduced synthesis of new diisochromenochromen-4-ones and their antimicrobial activities.

The diisochromenochromen-4-one 3a-3b, 4a-4c, 5a-6a  & 7 have been prepared from the photocyclization reaction of bischromen-4-one 2a-2e. The later compounds are obtained from the O-alkylation of the suitable 3-hydroxy-2-aryl-4H-chromen-4-one 1a-1e with 4,4'-bischloromethyl-diphenyl in dry acetone, anhydrous K₂CO₃, and PTC (Bu₄N⁺I⁻) under refluxing conditions. The structures of compounds 2a-2e, 3a-3b, 4a-4c, 5a-6a  & 7 have been characterized from the rigorous analysis of their IR, ¹H-NMR, ¹³C-NMR, ESI-Mass, and elemental analysis. The antibacterial and antifungal activities of the synthesized products were also evaluated against the Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Aspergillus janus and Penicillium glabrum, respectively. Some of the tested compounds showed significant activity against the above-said microorganisms.

1. Introduction

Syntheses of six membered heterocyclic compounds have been the subject of major interest for researchers due to their significant biological activities [1-12]. The photochemical reaction of C=O compounds leads to the formation of many exotic carbocyclic and heterocyclic compounds, and these reactions are initiated through the intramolecular H-abstraction by the photoexcited carbonyl group from the γ and δ position to give 1, 4 and 1, 5-biradicals which finally collapse to the generation of many unique heterocyclic products [13-20]. 2-Aryl-3-alkoxy-chromen-4-one is such substrates which can undergo γ H-abstraction to provide pyran derivatives from the cyclisation reaction of 1, 4-biradical and 2-aryl ring [21-23]. The bischromen-4-one is the bichromophoric molecules which are formed by joining two chromen-4-one moieties together through the carbon chain of varying length and structure, and photochemical reaction of these compounds may produce some interesting heterocyclic compounds. Generally, the heterocyclic compounds are obtained via multistage reaction in the presence of specific reagents and reaction conditions. We are aiming hereby to synthesize bispyran derivatives under the influence of light. This aspect has prompted us to investigate the synthesis of diisochromeno-chromen-4-ones from the photochemical reaction of bischromen-4-one 2a-2e built around the diphenyl spacer moiety. The major interest behind this study was to investigate the simple method and antimicrobial evaluations of new diisochromeno-chromen-4-ones.

2. Results and Discussion

The compound 2a-2e required for this study was obtained from the O-alkylation of the suitable 3-hydroxy-chromen-4-one [24-26] with 4,4′-bischloromethyldiphenyl in the presence of anhydrous K2CO3 and Bu4N+I− (PTC) in dry acetone (Scheme 1). The reactions carried out in the absence of PTC provided very poor yield of the bischromen-4-ones and also involved very long reaction times. The monoalkoxy chromen-4-one formed in these reactions was removed by using column chromatography (60–120 mesh). The structures of 2a-2e were determined by means of their IR, 1H-NMR, and ESI-MS spectral data (see the appendix).

Scheme 1

The IR spectra of 2a-2e exhibited strong absorptions in the region of 1640–1650 cm−1 which indicated the presence of conjugated C=O group. The major feature of their 1H-NMR spectra was the appearance of sharp singlet at δ 5.11–5.35 which may be assigned to 3-OCH2 group. The downfield appearance of this proton could be ascribed to their benzylic nature and placement near an electronegative oxygen atom. 13C-NMR of these compounds revealed the most significant downfield signal at δ 176.13–175.01 (C=O group), another signal at δ 142.12–139.08 due to C-3 due of its direct linkage to oxygen atom, and remaining aromatic carbon atoms were resonating at δ 161.47–117.97. The most upfield resonance was found placed at δ 72.07–69.02 due to OCH2 group.

The photochemical reaction of bischromen-4-ones 2a-2e was carried out under inert atmosphere in dry MeOH and THF (1 : 1) with Pyrex-filtered light from a 125 W Hg arc lamp. The progress of the photoreactions was monitored by TLC, and after about 8–10 hrs most of the starting compound was transformed to new products (Scheme 2). The column chromatographic separation of the reaction mixtures yielded 3a-3b, 4a-4c, 5a, 6a, and 7 in moderate yields. The structure of these products became evident from the comparison of their IR, 1H-NMR, and 13C-NMR spectra with those of starting compound 2a-2e (see the appendix).

Scheme 2

The appearance of one IR absorption band in the carbonyl group region of 1630–1650 cm−1 indicates that these products are obtained involving the both side cyclization on the bischromen-4-one. The 1H-NMR spectra of 3a and 3b were quite informative which gave broad singlet at δ 6.81–6.78 (H-1), dd at δ 5.85–5.80 (H-3), and another dd at δ 5.30–5.25 (H-4). The noticeable signals were centered at δ 5.01–5.05 (H-5) and 3.40–3.45 (H-4a) having coupling value of 11.0 Hz which describes their cis disposition at C-4a and C-5. The four-proton multiplet found at δ 2.95–2.92 may be assigned to H-2a. 13C-NMR spectra of these compounds were also very helpful which showed resonances at δ 178.20–177.82 due to carbonyl group, at δ 39.00–38.80 and δ 32.00–31.05 due to C-4a and C-2, respectively. Another signal at δ 126.53 could be assigned to C-1 which was absent in their starting compounds.

The 1H-NMR spectrum of 4a-4c was very simple which produced most of the resonances in aromatic region at δ 8.30–6.95, and a significant singlet at δ 5.85–5.78 (2H) may be allotted to H-5. 13C-NMR of these compounds showed the suitable signals due to aromatic carbon in the region of δ 156.68–114.58, and the signals at δ 72.93–71.74 could be resulted by C-5.

Similarly the major features of 1H-NMR spectra of 5a-6a were the signals due to H-3a, H-11b, &H-4 which clearly resonating at δ 3.70–3.67 (2H, ddd), 5.11–5.06 (2H, d), and 5.48-5.45 (2H, d), respectively. The coupling value of J 3a,11b = 8.1 Hz and J 3a,4 = 10.0 Hz describes the cis relationship both between H-3a & H-11b and H-3a & H-4. In the 13C-NMR spectra, suitable resonances were found to be placed at δ 178.20–177.62, 83.30–82.10, 47.20–47.12 and 34.50–33.48 which may be very well represented by C=O, C-4, C-3a, and C-11b, respectively. The various spectral data also fully confirmed the structural features of the compound 7.

Mechanistically, the phototransformation of bischromen-4-ones 2a-2c may be occurring through the H-abstraction by the photoexcited C=O group from the 3-benzyloxy group to give 1,4-biradical which undergoes cyclization with the 2-aryl ring to provide 1,7-biradical. The later may suffer [1,7]-H shift to give 3a-3b while oxidation of the biradical produces 4a-4c (Scheme 3). Similarly, the formation of the products 5a-6a and 7 from the photocyclization of bischromon-4-ones 2c-2d may also be described.

Scheme 3

Mechanism of the photocyclizations of bischromon-4-ones 2a-2c.

3. Antimicrobial Activity

The antimicrobial activity of synthesized compounds was screened in vitro against selected pathogens which include Staphylococcus aureus (MTCC 96), Bacillus subtilis (MTCC 441), Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Klebsiella pneumoniae (MTCC 3384), and fungus strains were Aspergillus janus (2751) and Penicillium glabrum (4951). All the compounds were also screened for MIC by using serial tube dilution method [27] at concentration 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL against the above-said microorganisms, and observed minimum inhibitory concentration (MIC-μg/mL) values are given in Tables 1 and 2. Compounds 2a, 2d, and 2e showed significant activity against Escherichia coli and Klebsiella pneumoniae whereas 2b and 2c showed significant activity against Pseudomonas aeruginosa, Staphylococcus aureus, and Pencilluim glabrum. The photoproducts 3a, 3b, 4a, 5a, and 6a also exhibited significant activity against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Pencilluim glabrum, respectively. It is evident from the above study that 2-phenyl/thienyl/furanyl-bischromen-4-ones seem to be better antimicrobial agents than 2-tolyl/anisyl-bischromen-4-one derivatives. The importance of this work lies in the possibility that newly prepared compounds (2a, 2b, 2c, 2d, 3a, 3b, 4a, 5a, and 6a) might be more efficacious derivatives against the above-said bacterial and fungal strains.

Table 1

In vitro antimicrobial MIC (μg/mL) of compounds 2a-2b.

Compound No.	Gram-negative bacteria			Gram-positive bacteria		Fungi
	Escherichia coli	Klebsiella pneumonia	Pseudomonas aeruginosa	Staphylococcus aureus	Bacillus subtilis	Aspergillus janus	Penicillium glabrum
2a	12.5	12.5	50	25	25	50	25
2b	50	25	12.5	25	12.5	25	50
2c	25	25	12.5	12.5	25	25	12.5
2d	12.5	12.5	25	25	50	12.5	12.5
2e	12.5	12.5	12.5	25	25	25	12.5
Amoxicillin	3.12	3.12	3.12	3.12	3.12
Fluconozole	—	—	—	—	—	3.12	3.12

Table 2

In vitro antimicrobial MIC (μg/mL) of photoinduced compounds 3a-3b, 4a-4c, 5a-6a & 7.

Compound No.	Gram-negative bacteria			Gram-positive bacteria		Fungi
	Eschericha coli	Klebsiella pneumonia	Pseudomonas aeruginosa	Staphylococcus aureus	Bacillius subtilis	Aspergillus janus	Penicillium glabrum
3a	12.5	12.5	50	12.5	50	25	12.5
3b	25	25	25	25	12.5	12.5	12.5
4a	12.5	50	12.5	12.5	12.5	12.5	12.5
4b	50	25	25	50	25	50	25
4c	25	12.5	25	25	25	12.5	50
5a	12.5	25	12.5	25	25	25	50
6a	50	12.5	25	12.5	12.5	12.5	12.5
7	12.5	25	50	25	25	25	12.5
Amoxicillin	3.12	3.12	3.12	3.12	3.12
Fluconozole	—	—	—	—	—	3.12	3.12

4. Conclusion

This study provides the photochemical method for the preparation of new diisochromenochromen-4-one linked through the diphenyl moiety. The products have been obtained without using any specific and toxic reagent. The antimicrobial analysis of the prepared compounds has also been carried out and the importance of this work lies in the possibility that newly synthesized compounds (2a, 2b, 2c, 2d, 3a, 3b, 4a, 5a, and 6a) might be more efficacious derivatives against the tested bacterial and fungal strains. The investigations regarding the more biological studies of these bischromen-4-ones could be helpful in designing the potent antimicrobial agents.