Biological evaluation and simple method for the

Journal of Saudi Chemical Society (2013) xxx, xxx–xxx

King Saud University

Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Biological evaluation and simple method for the synthesis of tetrahydrobenzo[a]xanthenes-11-one derivatives Ali Akbari a b

a,*

, Asghar Hosseini-Nia

b

Department of Chemistry, Faculty of Science, University of Jiroft, P.O. Box 8767161167, Jiroft, Iran Department of Plant Protection National Research Station of Ornamental Plants, P.O. Box 37815-137, Mahallat, Iran

Received 5 June 2013; revised 4 September 2013; accepted 24 September 2013

KEYWORDS Antibacterial activity; Tetrahydrobenzo[a] xanthenes-11-one

Abstract A simple method for the synthesis of Tetrahydrobenzo[a]xanthenes-11-one derivatives in the presence of BF3.SiO2, and its antibacterial activity was assessed against Pseudomonas syringae, Xanthomonas citi and Pectobacterium carotovorum. The structure of the isolated compounds has been determined by means of 1H/13C NMR and FT-IR spectroscopy. The reactions were carried out in water at room temperature for 5 h. This method has some advantages such as good to excellent yield, mild reaction condition, ease of operation and workup, high product purity and green process. ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.

1. Introduction Benzoxanthene moiety in the structure of molecules causes important biological activities such as antileukemic [1], insecticidal [2], antifungal [3], free radical scavenging activity [4], antimycobacterial [5], antiplasmodial [6–8], antitumor [6], apoptotic effects [9], antiproliferative [10], antimalarial [11], antioxidant [12], anticancer [13]. Silica supported boron trifluoride, BF3.SiO2, which is easy to prepare and shows unusually high acidity which can be controlled by activation temperature, and exhibits consider* Corresponding author. Tel.: +98 3483260061; fax: 3483260065. E-mail address: [email protected] (A. Akbari). Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

+98

able catalytic activity [14], enables better accessibility of the reactants to the active sites. The BF3.SiO2 is used in several organic transformations, such as in Claisen–Schmidt condensations [17,15], in syntheses of 14-aryl or alkyl-14Hdibenzo[a,j]xanthenes [16], 1,2,4,5-tetrasubstituted imidazoles [17,15], in the polymerization of styrene [18], the preparation of polyfunctionalized piperidin-4-ones [19], a-amino phosphonates [20], quinoxalines [21,22], and 3,4-dihydropyrimidin-2(1H)-ones [21,22]. The first multi-component reaction (MCR) was reported by Strecker in 1850 for the synthesis of amino acids [23]. In recent years, multi-component reactions (MCRs) have occupied an important part in modern synthetic organic chemistry due to their valued features such as convergence, productivity, facile execution, and generally high yield of products [24–28]. Pectobacterium carotovorum is a bacterium of the family enterobacteriaceae; it formerly was a member of the genus Erwinia. The species is a plant pathogen with a diverse host range, including potato, African violet, and other agriculturally and scientifically important plant species. It

1319-6103 ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University. http://dx.doi.org/10.1016/j.jscs.2013.09.009 Please cite this article in press as: A. Akbari, A. Hosseini-Nia, Biological evaluation and simple method for the synthesis of tetrahydrobenzo[a]xanthenes-11-one derivativesa]xanthenes-11-one derivatives –>, Journal of Saudi Chemical Society (2013), http://dx.doi.org/10.1016/j.jscs.2013.09.009

2

A. Akbari, A. Hosseini-Nia HO O CHO + R1

R1

O +

R2

60 °C R2

O

BF3.SiO2

R2

O

R2

Scheme 1

causes soft rot and blackleg of potato and vegetables, as well as slime flux on many different tree species [29,30]. Xanthomonas can infect a wide variety of species including pepper, rice, citrus, cotton, tomato, broccoli, cabbage, and soybeans. Some types of Xanthomonas cause localized leaf spot or leaf streak while others spread systemically and cause black rot or leaf blight disease ([31,32]. Pseudomonas syringae is responsible for causing diseases on over 180 plant species including fruit trees, vegetable crops and flowers. Pathovars of main economic importance in Europe are the pvs syringae, morsprunorum, avii and persicae, causing bacterial canker on sweet and sour cherry, plum, peach and apricot as well as in wild cherry [33,34]. 2. Materials and methods 2.1. General The materials were purchased from Sigma–Aldrich and Merck and were used without any additional purification. Products were characterized by FT-IR, 1H-NMR and comparison of their physical properties was done with those reported in the literature. FT-IR spectra were run on a Bruker, Eqinox 55 spectrometer. A Bruker (DRX-500 Avanes) NMR was used to record the 1H NMR spectra. 2.2. Preparation of BF3.SiO2 3.7 g of BF3 (7.0 ml of BF3.Et2O) was added dropwise to a mixture of 6.3 g of silicagel and 10 ml of chloroform. The mixture was stirred for 1 h at room temperature. The resulted sus-

Table 1

pension was filtered. The obtained solid was washed with chloroform and dried in a domestic microwave oven for 20 min in power 100. 2.3. General procedure for the synthesis of tetrahydrobenzo [a]xanthenes-11-one derivatives under aqueous condition A mixture of 2-naphthol (2 mmol), aldehyde (2 mmol), 1,3-diketone (2 mmol), BF3.SiO2 (0.05 g), was heated at 60 C. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with ethanol and filtered to recover the catalyst. The filtrate was evaporated and the crude product was recrystallized from iso-propanol to afford the pure Tetrahydrobenzo[a] xanthenes-11-one derivatives in 88–97% yields. All products were identified by comparison of their physical and spectral data with those of authentic samples. 2.4. In vitro antibacterial screening 2.4.1. Preparation of plates and microbiological assays Inoculation of test bacteria (Xanthomonas campestris pvs, P. syringae and P. carotovorum) was prepared by inoculating a loopful of organism in a 10 ml nutrient broth and incubated at 37 C for 24 h. each till a moderate turbidity was developed. 0.10 ml of this suspension was thoroughly mixed with 25 ml of nutrient agar medium in each. Petri plates were pre-sterilized and set aside. After the cooling, the seeded agar plate was used for testing compounds by the disc diffusion method. The sterilized paper discs were dipped in each compound solution. These discs were placed in the plates at equidistant. The central disc without any compound was taken as control. The Petri plates were then incubated at 37 C for 24 h. After the recommended period, zones of inhibition were measured. After solidification of medium, 0.10 ml of spore suspension was spread by a sterilized spreader in a specific zone. The compounds were dissolved in DMSO solvent in 200 ppm concentration. The paper discs were dipped in each compound solution for 5 min. Then these paper discs were placed equidistant in the plates. The central disc dipped in DMSO solvent without compound

The synthesis of 9,9-dimethyl-12-(4-nitrophenyl)-8,9,10,12-tetrahydrobenzo-[a]xanthen-11-one.a

Entry

Catalyst (mol %)

Solvent

Conditions

Time (min)

Yieldb %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2 BF3.SiO2

Chloroform Chloroform Ethanol Ethanol Water Water Solvent-free Solvent-free Solvent-free Solvent-free Solvent-free Solvent-free Solvent-free Solvent-free Solvent-free

r.t. Reflux r.t. Reflux r.t. Reflux r.t. 35 C 35 C 60 C 60 C 60 C 60 C 60 C 60 C

30 30 30 30 30 30 30 30 15 10 15 15 15 15 15

Scarce 63 Scarce 60 Scarce 58 Scarce 79 67 75 94 69 94 93 93

a b

(20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (30) (10) (20) (20) 2nd run (20) 2nd run

4-Nitrobenzaldehyde (2 mmol, 0.31 g), dimedone (2 mmol, 0.30 g), b-naphthol (2 mmol, 0.29 g). Isolated yield.

Please cite this article in press as: A. Akbari, A. Hosseini-Nia, Biological evaluation and simple method for the synthesis of tetrahydrobenzo[a]xanthenes-11-one derivativesa]xanthenes-11-one derivatives –>, Journal of Saudi Chemical Society (2013), http://dx.doi.org/10.1016/j.jscs.2013.09.009

3 Table 2

The synthesis of tetrahydrobenzo-[a]xanthen-11-one derivatives in the presence of BF3.SiO2 via 1.a R1

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 a

3- BrC6H4 4-CH(CH3)2C6H4 2,3-OHC6H3 C6H5 4-ClC6H4 4-BrC6H4 4-NO2C6H4 3-NO2C6H4 4-OHC6H4 4-OMeC6H4 C6H5 4-ClC6H4 4-NO2C6H4 4-MeC6H4

Yield (%)a

Me Me Me Me Me Me Me Me Me Me H H H H

m.p.(C) found

88 85 89 96 97 93 92 88 94 97 96 97 92 97

m.p.(C) reported

lit

17

181–183 161–162 243–244 151–153 178–180 181–183 178–180 167–168 222–223 206–207 186–187 202–204 236–238 207–208

185–187 160–16224 243–24524 151–15332 178–17917 187–18929 178–18032 167–17017 222–22429 205–20729 188–18917 197–19917 234–23531 205–20831

Aldehyde (2 mmol), 1,3-diketone (2 mmol), BF3.SiO2 (0.05 g) for 15 min.

Table 3 Entry

1 2 3 4 5 6 7 8 9 10 11 12 13 14

R2

Analytical and antibacterial activity of compounds’ Zone of inhibition in (mm) P. carotovorum. R1

3- BrC6H4 4-CH(CH3)2C6H4 2,3-OHC6H3 C6H5 4-ClC6H4 4-BrC6H4 4-NO2C6H4 3-NO2C6H4 4-OHC6H4 4-OMeC6H4 C6H5 4-ClC6H4 4-NO2C6H4 4-MeC6H4

R2

Me Me Me Me Me Me Me Me Me Me H H H H

Molecular Formula

C25H21Br C29H30O2 C25H22O4 C25H22O2 C25H21Cl C25H21Br C25H21N C25H21N C25H22O3 C26H24O3 C23H18O2 C23H17Cl C23H17N C24H20O2

Molecular weight

433.34 410.55 386.44 354.44 388.89 433.34 399.44 399.44 370.44 384.47 326.39 360.83 371.39 340.41

was used as control. These Petri plates were kept for incubation period at 28 C for 3 days. After the completion of recommended period, the zones of inhibition were measured (Table 3). 3. Results and discussion In our continuing search for bioactive substances and in connection with our efforts towards the study of synthesis of Tetrahydrobenzo[a]xanthenes-11-one, we initiated an investigation on the bioactivities of these compound adducts against antibacterial. First, we described an efficient synthetic protocol for the preparation of these compounds that were shown to be active against X. campestris pvs, P. syringae and P. carotovorum. Initially, we have examined the synthesis of 9,9-dimethyl12-(4-nitro-phenyl)-8,9,10,12-tetrahydro-benzo[a]xanthen-11one using 4-nitrobenzaldehyde (2 mmol, 0.31 g), dimedone (2 mmol, 0.30 g), b-naphthol (2 mmol, 0.29 g) and BF3.SiO2 as the catalyst under various conditions (Scheme 1, Table 1). We have found that the best conditions are BF3.SiO2 (0.05 g) was heated at 60 C for 15 min (Table 1, entry 12).

Zone of inhibition in (mm) X. campestrispvs

P. syringae

P. carotovorum

22 ± 0.9 16 ± 0.7 36 ± 1.2 18 ± 1.1 29 ± 0.8 21 ± 0.6 20 ± 1.2 17 ± 0.9 28 ± 0.7 23 ± 1.1 21 ± 0.6 30 ± 1.2 23 ± 1.0 20 ± 0.8

24 ± 0.7 20 ± 1.1 38 ± 0.6 18 ± 1.0 28 ± 1.1 21 ± 0.9 19 ± 1.2 14 ± 0.8 27 ± 1.0 24 ± 1.2 18 ± 0.6 25 ± 1.2 20 ± 0.9 19 ± 1.0

17 ± 1.1 18 ± 1.2 33 ± 0.9 20 ± 1.0 25 ± 0.7 14 ± 1.3 18 ± 1.2 22 ± 1.1 27 ± 0.8 26 ± 1.2 21 ± 0.9 32 ± 1.0 25 ± 1.1 22 ± 0.8

Next, the synthesis of tetrahydrobenzo[a]xanthenes-11-one derivatives was studied and summarized in Table 2. In all cases, the three-component reaction proceeded smoothly to give the corresponding tetrahydrobenzo[a]xanthenes-11-one in moderate to good yields. In summary, we have described BF3.SiO2 is an efficient, catalyst for the synthesis of tetrahydrobenzo[a]xanthenes-11-one derivatives. All of the products were characterized by FT-IR and 1H-NMR. The applicability of a large scale process has been examined with 4-nitrobenzaldehyde (20 mmol, 3.08 g), dimedone (20 mmol, 2.95 g), b-naphthol (20 mmol, 2.91 g) which has given 9,9-dimethyl-12-(4-nitrophenyl)-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one in 90% yield. The in vitro antibacterial activity of synthesized novel class tetrahydrobenzo-[a]xanthen-11-one derivative was tested against some important bacteria by the disc diffusion method [35,36] using Mueller–Hinton agar No. 2 as the nutrient medium. In vitro antibacterial assay was performed against X. campestris pvs, P. syringae and P. carotovorum by using the disc diffusion method. The results obtained as zone of inhibition (mm) are presented in Table 3. The increase of the antibacterial activity with increasing numbers of hydroxyl groups in the molecule is observed, as


4 compounds 3 and 9, which bear 1 hydroxyl groups and Chloro group, show only moderate activity. The increase of the antibacterial activity with increasing numbers of another group in the molecule is not observed. In conclusion, we have demonstrated a simple method for the synthesis of tetrahydrobenzo-[a]xanthen-11-one derivatives using BF3.SiO2 as an eco-friendly, inexpensive and efficient reagent. Short reaction times, high yield, simplicity of operation and easy work-up are some advantages of this method. These promising results suggest that the evaluation of antibacterial activity should be extended to other structural types of tetrahydrobenzo-[a]xanthen-11-one derivatives.

A. Akbari, A. Hosseini-Nia

[10]

[11]

[12]

[13]

Acknowledgement [14]

The Research Council of University of Jiroft is gratefully acknowledged for the financial support for this work.

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