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International Journal of ChemTech Research CODEN (USA): IJCRGG, ISSN: 0974-4290, ISSN(Online):2455-9555 Vol.10 No.1 pp 01-06, 2017
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The Evalution of Antibacterial Activity of the (E)-(3-Methoxy-2-Nitroprop-1-Enyl)Benzene Compounds
Periyasamy Amudha1, Palaniappan Matheswaran2,Nagappan Sivakumar*1,Vadivelu Balasubramanian1
1Department Chemistry, AMET University Chennai 603 112, India
2vidhyaVikas College of Engineering and Technology, Tiruchengode, Namakkal, India
Abstract : A simple and convenient synthetic route for the synthesis of (E)-(3-methoxy-2-nitroprop-1-enyl)benzene using Baylis-Hillman chlorides in presence of potassium carbonate and hydroquinone. Baylis-Hillman adducts derived from aldehydes and nitroethylene except the initial report by Baylis and Hillman. This strategy opens new opportunities for the preparation of libraries of a wide variety of new nitro derivatives for biological screening.
Keywords : Baylis-Hillman reaction; O-alkylation, potassium carbonate, THF, nitro compound and methanol.
Introduction
During the past ten years the Baylis-Hillman reaction has seen enormous growth in terms of the components such as electrophile, activated olefin and catalyst.1-3 A variety of activated olefins are explored by various research groups, however nitroolefins are not utilized much, as an activated olefinic component. So far there is no report available in the literature for the synthesis of Baylis-Hillman adducts derived from aldehydes and nitroethylene except the initial report by Baylis and Hillman. The reason for the nitroethylene to be unexplored may be due to its relatively more reactivity which would lead to polymerization.
Therefore, we have undertaken a research program for the synthesis and examining the possible applications of the trisubstitutedallyl halides derived from nitroolefins in various organic reactions.4-6 We envisaged that the chloro derivative of Baylis-Hillman adducts derived from aldehydes and nitroethylene may be very useful starting material for a variety of applications in organic synthesis.7Baylis-Hillman adducts and its derived compounds are extensively utilized in the synthesis of biologically active molecules, heterocycles and manynatural products.8-10 In particular chloro and acetate derivatives of Baylis-Hillman adducts are widely utilized for various organic transformations11.
Antibacterial activity:
In vitro antibacterial inhibitory activities of the (E)-(3-methoxy-2-nitroprop-1-enyl)benzene compounds were determined by microdilution broth assay method using resazurin as an indicator. Nutrient-broth was used to culture the bacterial strains to a final inoculum size of 5 × 105 CFU/mL. The (E)-(3-methoxy-2-nitroprop-1-enyl)benzene compounds were dissolved in DMSO to a concentration of 10 mg/mL. Serially diluted these compounds solutions were added to successive wells in a 96-well microtitre plate and incubated with respective micro-organism for 18 h at 37°C. After the incubation period, 10 μL of 0.01% resazurin solution was added and incubated for 2 h. The color change was assessed visually. Growth of organism changed the color from blue to pink. Growth and sterility controls were also maintained during the experiment. Test compounds serially diluted
with DMSO were also kept in the 96-well microtitre plates (uninoculated dilution) to determine whether they precipitated out during the course of the experiments. One entire column had antibiotics as a positive control (Amphiciline). A blank assay with ethanol alone was taken into account to discount any possible effect of the solvent.
The minimum inhibitory concentration (MIC) of the (E)-(3-methoxy-2-nitroprop-1-enyl)benzene compounds were performed by microtitre dilution assay. The optical density was measured at 575 nm for all the tested human pathogenic bacteria. The MIC for all the six compounds was found at 0.625µg/ml against the test organisms. Interestingly, all the newly synthesized (E)-(3-methoxy-2-nitroprop-1-enyl)benzenecompounds showed excellent antibacterial activity against the Gram negative organism E. coli. Moreover, the methoxy compounds (1a-f) moderately inhibited the growth of P aeruginosa. Among the ten compounds, 1a, 1b and 1d were showed good antibacterial activity against all the test pathogens. (Table 1)
Entry |
(E)-(3-methoxy-2-nitroprop-1-enyl)benzene |
Antibacterial activity |
||
Staphylococcus aureus |
Pseudomonas aeruginosa |
Escherichia coli |
||
Control/DMSO |
0.6731 |
0.8141 |
0.9316 |
|
1 |
1a |
0.1870 |
0.6684 |
0.1675 |
2 |
1b |
0.1551 |
0.6213 |
0.1559 |
3 |
1c |
0.5815 |
1.1627 |
0.1451 |
4 |
1d
|
1.0916 |
0.2728 |
0.1360 |
Scheme 1
Encouraged by this result, we prepared a variety of Baylis Hillman adducts derived from nitroolefins and successfully converted them into the desired chloro derivatives 3a–j in very good yields.
We decided to synthesize the O-alkylation derivatives from the corresponding Baylis Hillman adducts under mild reaction conditions. The treatment of Baylis–Hillman adduct 3a with with methanol in the presence of sodium hydride in tetrahydrofuran (THF) at room temperature, over a period of one hours successfully provided the desired (E)-(3-methoxy-2-nitroprop-1-enyl)benzene 5a in 64% yield according to the scheme 2
Scheme 2
Encouraged by this results we prepared variety of Baylis-Hillman adducts and successfully transformed them into their corresponding methoxy derivatives 5b-j, according to scheme 3.
Scheme 3
Table 1. Synthesis of (E)-(3-methoxy-2-nitroprop-1-enyl)benzene compounds from Baylis-Hillman derivatives
S.No Allyl Chloride Methoxy Yield
3a C6H5 5a 64
3b 2-Me 5b 67
3c 4-Me 5c 62
3d 2-MeO 5d 60
3e 4-MeO 5e 59
3f 3,4-(MeO)2 5f 54
3g 3,4-(OCH2O) 5g 62
3h 2-Cl 5h 56
3i 3-Cl 5i 52
3j 4-Cl 5j 61
aAll reactions were carried out with 4 mmol scale of allyl chloride (5a-j), bAll products gave satisfactory IR, 1H NMR (300 MHz), 13C NMR (75 MHz), mass spectral data and elemental analyses. cYields of the pure products (5a-j ) obtained after column chromatography (silica gel, (5a-j) 5% EtOAc in hexanes,
Typical experimental procedure for the synthesis of(E)-2-nitro-3-o-tolylprop-2-en-1-ol(1a)
To a stirred solution of 1-methyl-2-((E)-2-nitrovinyl)benzene (1 mmol) in THF (2 mL) at room temperature, was added imidazole (68 mg, 1eq) followed by the addition of DABCO (11.2 mg, 10 mol %) and 38 % aqueous formaldehyde, (2 mL, excess). The reaction mixture was stirred at room temperature for about 24 hours. After completion of the reaction (confirmed by TLC analysis), the reaction mixture was acidified with dill HCl (5 mL). The reaction mixture was diluted with ethyl acetate and the organic layer was extracted (3×10 ml). The combined organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. Then the organic layer was evaporated and crude liquid thus obtained was purified by silica gel column chromatography (eluting with 10 % ethyl acetate in hexanes) to afford pure 1a (0.90 g, 50%) as a yellow oil.
IR (KBr): 3423, 1653, 1522, 1326, 1023, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.61 (s, 1 H), 4.71 (d, J = 4.2 Hz,2 H), 7.48–7.58 (m, 5 H), 8.22 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.62, 129.14, 130.19, 130.96,131.31, 137.67, 149.44.
MS: m/z = 179 (M+).
Anal.Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.37; H, 5.08; N, 7.80.
Synthesis of (E)-(3-chloro-2-nitroprop-1-enyl)benzene
To a stirred solution of ((E)-2-nitro-3-phenylprop-2-en-1-ol (3a) (1.00 gm, 5.55 mmol) in DCM (20 mL), TiCl4 was added at room temperature. Then the reaction mixture was stirred well at room temperature for about 1 hours. After the completion of reaction (confirmed by TLC analysis), the reaction mixture was poured into water and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na2SO4 and solvent was evaporated. The crude product thus obtained was purified by column chromatography (2%, EtOAc / hexanes) to provide 3a in 62% (0.85 gm) yield, as a pale white crystalline solid
IR (KBr): 1637, 1519, 1328 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.79 (s, 2 H), 7.45–7.59 (m, 5 H),8.28 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 61.65, 129.15, 130.24, 131.10, 131.38, 138.99, 147.36.
MS: m/z = 197 (M+), 199 (M+ + 2).
Anal.Calcd for C9H8ClNO2: C, 54.70; H, 4.08; N, 7.09. Found: C,54.61; H, 4.04; N, 7.13.
Procedure for O-alkylation of BH derivatives:
To a solution of methanol (4) in THF, sodium hydride (0.5g, 1.46mmol) was added and stirred well for few minutes at room temperature. To this solution, (E)-(3-chloro-2-nitroprop-1-enyl)benzene (3a) (0.178g, 1.46mmol) in THF (10mL) was added dropwise and stirred well for 1hr. After the completion of the reaction (confirmed by TLC analysis), the reaction mixture was poured into water and the aqueous layer was extracted with ethyl acetate (3 x 10 ml). The combined organic layer was washed with brine (20 mL), and dried over anhydrous Na2SO4 and solvent was evaporated. The crude product thus obtained was purified by column chromatography (EtOAc / hexanes) to provide the compound 5a in 64% (0.21 g) yield, as a pale yellow crystalline solid.
Yield : 64 %
Time : 1 hr
mp : 110 – 112 oC
1H NMR : δ 3.49 (s, 3H), 5.14 (s, 2H), 6.96 - 7.90 (m, 5H), 8.29 (s, 1H)
13C NMR : δ = 57.41, 61.65, 129.15, 130.24, 131.10, 138.99, 147.36.
MS: m/z = 193
Anal.Calcd for C10H11ClNO3: C, 62.17; H, 5.74; N, 7.25, Found: C, 61.15; H, 5.71; N, 7.23.
References
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