Synthesis of 3-(4'-Bromo phenyl)-5-(aryl substituted) isoxazolines Compounds computational studies and Biological activity

 

N.P. Lachoriya,  Dilesh Indorkar, S.P. Shrivastava, O.P. Chourasia and S.N. Limaye

Department of Chemistry, Dr. H. S. Gour Central University, Sagar (M.P.)-470003

*Corresponding Author E-mail: dileshindorkar@yahoo.in

 

 

 

ABSTRACT:

The recent synthesis of 1-(aryl substituted)–3–(4'-Bromo phenyl) Prop–1–ene–3–ones prepared by p–bromo acetophenone (1 mol.) in ethanol (25 ml), aromatic aldehyde reaction 01 the solution was added 3–(4'-Bromo phenyl)-5–(aryl substituted) isoxazoles sodium acetate (0.01 mol.) dissolved in a minimum amount of hot glacial acetic acid was added to a solution of NH2OH.HCl (0.01 mol) in ethanol (10 ml). This solution was added to a solution of 1-(aryl substituted) -3-(4'-Bromophenyl) prop-1-ene–3–one.1-(aryl substituted)-3-(4'-Bromophenyl)-pop-1-ene-3-ones (0.01 mol), NH2OH.HCl (0.02 mol) and KOH (0.02 mol) in ethanol (25 ml) were refluxed on water bath for four hours. The reaction mixture was then cooled and acidified with glacial acetic acid. The resulting solid was washed with water and recrystallized from rectified spirit new compounds was 3-(4'-Bromo phenyl)-5-(aryl substituted) isoxazolines. respectively. Analysis in the PC-model values and Antibacterial , Antifungal activity This new route of synthesis has been proposed.

 

KEY WORDS: Azoles, Oxazoles, Isoxazole ,isoxazolines Benzoxazine.

 

INTRODUCTION:

The present work is in conjugation with our ongoing program me on the utilizing of readily obtainable starting materials for the synthesis of heterocyclic systems [1].One of the most important features of ion (4H)-1, 3-Benzoxazinone chemistry is their use as key starting materials for further transformations [2]. They are indeed useful intermediates in organic synthesis affording through reaction with nitrogen nucleophiles 4(3H) quinazolinones. With the aim of extending information on the reactivity of 4H-3,1-benzoxazinones [3] and also. Synthesizing from them new heterocyclic systems, potentially with biological activity .and in continuation of our work on the behavior of stable benzoxazinones [4-5]. Synthesis and pharmacology of isoxazolines.as highly selective antagonists at M (4) muscarinic receptors have been reported [6-7].The a, b-unsaturation present in chalcones has given way to many novel reactions. Among them the isoxazoles and isoxazolines were reported to be active fungicides, insecticides[8], antibacterial, antitubercular [9] and anti-inflammatory etc.

 

Synthesis of isoxazoles and isoxazolines has been reported by the action of NH2 OH. HCl on hydroxy chalcones and flavanones, Borkhade et al. synthesized isoxazolines from o‑hydroxy chalcones and corresponding flavanones. Gimil Aziz et al.[11] synthesized isoxazoles from fluorochalcones. Jamode reported the synthesis of 3, 5-diaryl isoxazolines using ethylenediamine from 2’‑hydroxy chalcones, flavanones and 3‑arylidine flavanones. Rajput and Jamode [12] have synthesized 3,5‑diarylisoxazolines from hydroxy‑3‑chlorochalcones in ethanol containing piperidine. C. Kedar has reported the synthesis of 3‑5, diarylisoxazoles in C2H5OH in presence of alkali. Kakade [13] synthesized 3, 5 diaryl isoxazoles in DMSO using NH2OH.HCl.

 

 EXPERIMENTAL:

1-(aryl substituted)–3–(4'-Bromo phenyl) Prop–1–ene–3–ones

To a solution of p–bromo acetophenone (1 mol.) in ethanol (25 ml), aromatic aldehyde (1 mol.) was added and stirred well. Later NaOH (30%, 20 ml) was added keeping the temperature below 10oC.

 

The mixture was stirred well and kept at room temperature for 12 hour. Then it was rendered acidic with dil. HCl and poured over crushed ice. The solid thus obtained was washed with water and recrystallized from absolute alcohol.

 

3–(4'-Bromo phenyl)-5–(aryl substituted) isoxazoles:

Anhydrous sodium acetate (0.01 mol.) dissolved in a minimum amount of hot glacial acetic acid was added to a solution of NH2OH.HCl (0.01 mol) in ethanol (10 ml). This solution was added to a solution of 1-(aryl substituted) -3-(4'-Bromophenyl) prop-1-ene–3–one (0.01 mol) in ethanol (15 ml). The mixture was refluxed on sand bath for three hours, concentrated and poured over crushed ice and neutralized with NaOH. The precipitate formed was washed with water and recrystallized from absolute alcohol. The yields, melting points, elemental analysis and spectral data are given in tables. The purity of the compounds was checked by TLC.

 

3-(4'-Bromo phenyl)-5-(aryl substituted) isoxazolines:

A mixture of 1-(aryl substituted)-3-(4'-Bromophenyl)-pop-1-ene-3-ones (0.01 mol), NH2OH.HCl (0.02 mol) and KOH (0.02 mol) in ethanol (25 ml) were refluxed on water bath for four hours. The reaction mixture was then cooled and acidified with glacial acetic acid. The resulting solid was washed with water and recrystallized from rectified spirit. The yields, melting prints, elemental analysis and spectral data are given in tables. The purity of the compounds was checked by TLC.

 

RESULTS AND DISCUSSION:

Melting point were determined in open capillaries on a Campbell apparatus and are uncorrected (Table 5) .The IR spectra were recorded on a Perkin-Elmer 297 spectrophotometer and 1HNMR spectra on a Bruker 80 MHz instrument (CDRI, Lucknow). Elemental analysis was found satisfactory for the compounds. Physical data of the compounds are given as Table.

 

 

Reaction sequence- 01

 

Table: 01Compound BPIsox-01

Name

3-(4'-Bromophenyl)-5-(4''-chloro phenyl) isoxazole

Mol.Wt.

334.59

 

 

M.P.°C

150

Yield ( %)

60%

Mol.For.

C15H9NOClBr

Elemental Analysis

C %

H %

N %

Found

Calcu.

Found

Calcu.

Found

Calcu.

53.81

53.84

2.69

2.79

4.17

4.19

Table 2. Characterization of Infrared data:

Type

Vibration mode

Frequency (cm-1)

Isoxazole ring

C=N Str.

1487.8

N─O Str.

1282.1

C=C Str.

1588.6

β─C─H Str.

1148.0

Aromatic ring

Ar─Br

531.3

C=C bend

682.1

1,4 ─Disubstituted Benzene ring

 

─C─H o.o.p bending

822.2

─C=C Str.

1656.0

Ar─Cl

778.8

 

Table 3 :NMR data

Signal no.

Chemical shift in δ ppm

Multiplicity

Relative no. of protons

Inference

1.

6.4256

Multiplet

04

Br substituted ring

2.

6.6313

Multiplet

05

Benzene ring

3.

4.3968

Singlet

01

-CH of Isoxazole ring

 

Table 4; Variation in the melting points for substituted 7-methoxy-isoxazine  derivatives.

Compound Code

Substituent

M.P. (oC)

Mebenzx-1

2-Cl

90

Mebenzx-2

3-Cl

95

Mebenzx-3

4-Cl

102

Mebenzx-4

2-NO2

110

Mebenzx-5

3-NO2

100

Mebenzx-6

4-NO2

115

Mebenzx-7

2,4-diNO2

120

Mebenzx-8

4 - Br

105

 

 

Table 5; Variation in IR frequencies for the methoxy- isoxazine derivatives of series.

Compound code

Substituent

isoxazine ring

Disubstituted Ring

C=N

C-O

  C-H(str)in  NCH2

C-H(bend)in  N-CH2

Ar-Cl,NO2,Br

C=C(str)

Mebenzx-1

2-Cl

1270.5

1052.8

2845.2

1468.4

773.9

1608.7

Mebenzx-2

3-Cl

1265.6

1056.7

2838.1

1462.4

769.8

1604.6

Mebenzx-3

4-Cl

1268.5

1048.8

2840.2

1459.2

764.7

1612.7

Mebenzx-4

2-NO2

1256.7

1052.8

2846.2

1471.4

1351.5

1599.7

Mebenzx-5

3-NO2

1262.6

1056.6

2839.1

1466.4

1346.5

1601.6

Mebenzx-6

4-NO2

1248.5

1056.8

2841.1

1466.5

1349.5

1610.7

Mebenzx-7

2,4-diNO2

1233.5

1059.7

2845.1

1356.4

1356.5

1602.7

Mebenzx-8

4 - Br

1261.6

1062.8

2842.1

1458.4

628.98

1610.7

 

Table 6; variation in Chemical shiftvalues for the methoxy-isoxazine derivatives series.

Compound code

Substituent

Benzene ring

O-CH2 of oxazine  Ring

N-CH2 of oxaine ring

Ar-OCH3

Mebenzx1

2-Cl

7.78

4.62

3.48

3.85

Mebenzx-2

3-Cl

7.69

4.81

3.61

3.89

Mebenzx-3

4-Cl

7.84

4.65

3.62

3.91

Mebenzx-4

2-NO2

7.85

4.75

3.56

3.86

Mebenzx-5

3-NO2

7.73

4.73

3.50

3.87

Mebenzx-6

4-NO2

7.71

4.42

3.49

3.86

Mebenzx-7

2,4-diNO2

7.70

4.56

3.51

3.78

Mebenzx-8

4 - Br

7.76

4.80

3.48

3.86

 

Table 7; Computer simulated PC Model data for marked bonds and their subsequent angles

Compound code

Substituent

B.L.     C-N

B.A.  N-C

Dihed. Ang.     C-N-C

Mol.         Vol.

VDW

Dip. Mom

MMX Energy

Mebenzx-1

2-Cl

1.460

120.67

162.37

276

8.03

4.197

36.398

Mebenzx-2

3-Cl

1.463

121.02

165.39

276

2.11

26.18

31.364

Mebenzx-3

4-Cl

1.463

121.02

166.70

276

10.304

2.479

40.103

Mebenzx-4

2-NO2

1.462

120.13

178.47

286

15.44

2.312

74.366

Mebenzx-5

3-NO2

1.463

121.05

173.00

286

11.47

1.895

24.747

Mebenzx-6

4-NO2

1.463

120.85

165.95

286

29.96

1.736

22.452

Mebenzx-7

2,4-diNO2

1.458

120.63

167.10

331

2.141

1.512

11.091

Mebenzx-8

4 - Br

1.461

121.16

167.76

323

10.74

1.089

29.206

 

 

The overall variations in the dipole moment and maximum minimization energy  values are in good agreement with the IR spectral frequencies for these compounds. This perfect co-relation between the theoretical data and the experimental characterization supports the satiric justifications extended for various substituent’s.

 

 

The validity of the PC Model simulated data has been examined separately by comparing these values with the electrical polarizability values obtained from the theoretical values as described by Hansch for various substituents at various position for the present set of synthesized compounds. The following table (Table 8) records the electrical polarizability for the said substituents of, along with their dipole moment values.

 

 

 

Table 8; Electrical polarizability as obtained by Hansch table for various derivatives of and their dipole moment values

Compound No.

Mebe-1

Mebe- 2

Mebe- 3

Mebe-4

Mebe-5

Mebe- 6

Mebe -7

Mebe- 8

Elec.Pol.

2.05

1.97

1.87

1.62

1.57

1.50

0.83

2.17

Dip.Mom.

4.197

2.618

2.479

2.312

1.895

1.736

1.512

1.089

 

Table- 9;   Antibacterial activity of methoxy isoxazine verivatives with Dipole moment values

Compound code

Dip.Mom

E. coli

Klebsiella pneumoniae

Pseudomonas alcaligens

Salmonella sp.

2%

4%

2%

4%

2%

4%

2%

4%

Mebenzx.1

1.089

10

12

13

16

11

14

8

10

Mebenzx2

1.512

11

12

13

14

13

14

9

10

Mebenzx.3

1.735

8

10

12

15

10

13

9

11

Mebenzx.4

1.895

10

11

11

14

8

10

12

13

Mebenzx.5

2.312

12

13

10

11

13

15

12

14

Mebenzx.6

2.479

14

17

15

18

12

15

14

16

Mebenzx.7

2.618

9

12

8

10

11

12

10

12

Mebenzx.8

4.197

12

16

16

19

10

13

13

16

 

Table 10;   Antifungal activity of methoxy isooxazine derivatives and its variation with  Dipole moment values.

Compound code

Dip.Mom

Penicillium citrinum

Aspergillus flavus

Rhizoctonia bataticola      

Aspergillus niger

2%

4%

2%

4%

2%

4%

2%

4%

Mebenz.1

1.089

11

13

13

15

11

13

13

15

Mebenz.2

1.512

9

11

10

15

9

11

10

15

Mebenz.3

1.735

17

20

15

18

17

20

15

18

Mebenz.4

1.895

10

12

9

13

10

12

9

13

Mebenz.5

2.312

9

10

14

10

9

10

14

10

Mebenz.6

2.479

10

11

12

14

10

11

12

14

Mebenz.7

2.618

9

14

10

10

9

14

10

10

Mebenz.8

4.197

10

12

10

15

10

12

10

15

 

 

CONCLUSION:           

The formation of 1, 3-methoxy-benzoxazine derivatives which indicate that the new approach enables the synthesis of 2, 3-disubstituted-1,3-Chlorobenzoxazines as the lactone 10, considered on useful intermediate preparation of new polycyclic systems. Directed ortho-lithiation of protected isoxazines allows facile go for 2, 3-disubstituted 1, 3-benzoxazines. Moreover, the removal of the N-protecting group in the alkylation provides the unprotected 1, 3-methoxy-benzoxazines as central scaffolds for designed pharmaceutical compounds.

 

REFERENCES:

1.        P.Novakov, I.IIiev, P.petrenko, J.Univ.Chem.Techno.Metall. 2006,41,134.

2.        S.Bhattacharya and P.Chaudhuri Curr.Med.Chem., 2008,15, 1762

3.        P.Vicini, M.Incerti, R.Loddo, Eur.J.Med.Chem. 2009,44,1801.

4.        H.S.Gunes and G.Cosar, Arzeim Forech.Drug Res., 1992, 42, 1045.

5.        S.Harikrishna S.P. Shrivastava and S.N.Limaye . J. Inst. Chemist.       20 06,48, 78.

6.        A. Dewan and D.K. Kakati,  Indian J. Ch em. Technol., 2007,14,635.

7.        A. Casey, P. Lambert and T.S.J. Elliott, Int. J. Antimic. Agents, 2007,29, 23.

8.        N. Marcovich, M. Reboredo, and M.I. Aranguren, Polymer,2000, 42, 815.

9.        V.N. Sonar and H.B. Hadimani, Indian J. Heterocycl. Chem., 1998,8,125.

10.     J.M. Sprague, A.H. Land, C. Ziegler, J.Am. Chem. Soc., 1946,68,2155.

11.     X. Sun. Y. Bai, B. Chen and Z. Zeng, Chin. J.Chem. 2009,27, 1397.

12.     R.J. Singh and D.K. Singh South African J. Chem. 2009, 62, 10

13.     D.K. Indorkar, O.P. Chourasia, and S.N. Limaye J. Chem. Asia 2011,02,2011.

 

 

 

 

 

Received on 03.09.2012        Modified on 15.09.2012

Accepted on 18.09.2012        © AJRC All right reserved

Asian J. Research Chem. 5(9): September, 2012; Page 1095-1098