Pestic. Sci. 1989,25, 53-58

Studies on Pesticides based on Coumarin IV: Synthesis and Antifungal Activity of Twelve 4-(substituted

phenoxy)met hyl-6-met hyl Coumarins

Tushar Batra, Raj V. Singh, Naresh K. Sangwan, Mange1 S. Malik & Om. P. Malik

Department of Chemistry and Biochemistry, Haryana Agricultural University, Hisar-125 004, India

(Revised manuscript received 6 May 1988; accepted 11 May 1988)

ABSTRACT

Twelve 4-(substituted phenoxy)methyld-methyl coumarins were synthesised by the condensation of 4-chloromethyl-6-methyl coumarin with various phenols in the presence of potassium carbonate in dry acetone. The compounds were tested for their toxicity towards the mycelial growth of seven plant pathogenic fingi. Among the tested fungi, Pythium aphanidermatum, Colletotrichum falcatum, Drechslera oryzae, Alternaria alternata and Fusarium solani exhibited maximum sensitivity whereas Macrophomina phaseolina and Rhizoctonia solani were least sensitive to the test compounds. The 4-(4-tert-butylphenoxy)methyl and 444- nitrophenoxy)methyl analogues possessed greatest toxicity towards the majority of the tested fungi.

1 INTRODUCTION

The marked biological activit ie~l-~ possessed by some naturally occurring coumarin derivatives and previous work on substituted coumarins6-* prompted the extension of the study to explore the antifungal potential of coumarin derivatives with different substituents in the phenoxy moiety of the molecule. Synthesis of such 4-(substituted phenoxy)methyld-methyl coumarins (I; see Table 1) and their in vitro growth-inhibiting activity against various plant pathogenic fungi is described in this communication.

53

Pestic. Sci. 0031-613X/88/$03.50 0 1989 Society of Chemical Industry. Printed in Great Britain

R,

TABL

E 1

Phys

ical

and

Ana

lytic

al D

ata

of 4-

(sub

stitu

ted

phen

oxy)

met

hyl-6

-met

hyl

coum

arin

s

Com

poun

d"

Ri

R2

R3

R

, Yi

eld

M.P

IR

(KB

r)

NM

R (6

) ( %

) ("

C)

(cm-

') C

=O

C,-

H(s

) C

4-C

H,-O

(s)

Ar-

H(m

)

I1

111

IV

V

VI

VII

V

III

IX

X XI

XI1

XI11

H

H

H

CH

, C

H,

CH

, C

H,

H

H

CH

, H

H

H

H

c1 H

H

CI

CI

H

H

H

NO

2 H

H c1 c1 H

NO

2

H

74

H

85

H

82

CH

, 75

C

H,

85

H

84

H

72

H

86

H

80

CI

78

H

83

H

74

150-

52

190

170

2424

4

218

(Lit

2171

2)

224-

25

(Lit

225-

26")

22

627

223-

-24

220

230-

31

195-

97

205-

6

1710

6.

96

1720

6.

88

1730

6.

87

1710

6.

85

1720

6.

83

1730

7.

0 17

10

7.0

1720

7.

1

1710

7.

1 17

10

7.1

1730

6.

86

1710

7.

0

5.53

5.

33

5.40

5.

23

5.52

5.

50

5.40

5.40

5.40

5.

60

5.60

5.

60

7.0-

7.80

7G

7.80

6.

67.8

0 7.

0-7.

60

7.1-

7.80

7.

1-7.

80

7.2-

8.0

6.7-

8.0

7'2-8

.1

7'2-8

.3

7.1-

8.4

7.1-

8.6

tn

Q s

5' ? x s i" iz 4

-. x- ? .o

@

All t

he c

ompo

unds

are

cry

stal

lised

fro

m x

ylen

e + he

xane

. t 4

-. x-

Sttidies on pesticides bused on coumurin I V 5s

2 MATERIALS AND METHODS

2.1 Synthesis and characterisation of the compounds

The melting points are uncorrected. Homogeneity of the compounds was routinely checked on silica gelG TLC plates using benzene +methanol as the mobile phase. Infrared spectra were recorded on a Perkin-Elmer 157 Infracord and NMR on Varian A 60D or R-32 (90 MHz) instruments using deuterochloroform + trifluoroacetic acid with tetramethylsilane as internal reference. The chemical shift values are expressed in 6 units. Only those data have been mentioned which have a direct bearing in the assignment of the structure. Satisfactory microanalyses have been obtained for all compounds, and are given in Table 1 along with other physical and analytical data.

2. I .I 4-Chloromethyl-6-methyl coumarin A mixture of ethyl 4chloroacetoacetate (0.01 mole) and p-cresol (0.01 mole) was stirred in an ice-bath during the addition of six volumes of 73% sulphuric acid (1.65 gm ml-l). The mixture was kept at room temperature for 24-36 h and progress of the reaction was monitored by TLC. When complete, the mixture was poured over crushed ice, the solid product collected, washed with water, dried and crystallised to afford 4-chloromethyl-6-methyl coumarin in good yield.

2. I .2 General method of preparation of 4-(substituted phenoxy) methyl-6- methyl coumarins (ZZ-XIII)

A mixture of 4-chloromethyl-6-methyl coumarin (001 mole) substituted phenol (001 mole), anhydrous potassium carbonate (0.02 mole) in dry acetone (30 ml) was refluxed for 16 h. The acetone was evaporated at reduced pressure, the residue triturated with cold water, the solid collected by filtration, thoroughly washed with water, dried and crystallised from xylene + hexane to give the desired compounds in good yields.

4-Chloromethyl-6-methyl coumarin on further treatment with various phenols viz. p-tert-butylphenol, 3,4-xylenol, 2,3-xylenol, 2,5-xylenol, 4chloro-3,5-xylenol, p-bromophenol, p-chlorophenol, ochlorophenol, 3,4dichlorophenol, 2,4,5- trichlorophenol, p-nitrophenol and o-nitrophenol gave the corresponding 4- (substituted phenoxy)methyld-methyl coumarins (11-XIII), respectively. In the NMR spectrum of 4-chloromethyl-6-methyl coumarin the C3-H and CH2C1 protons appeared as singlets at 6 6.6 and 4.7, respectively. The inhibition of long range coupling of such systems is influenced by the electronegativity and inductive effect of the attached group^.^^'^ A singlet for C6-CH3 protons was observed at 6 2.55, while the aromatic protons ranged from 6 74-7.7 as a multiplet. The presence of the coumarin moiety was confirmed by the characteristic absorption at 1720cm-' in the IR spectrum."J2 In the NMR spectrum of 4-(4-tert- butylphenoxy)methyl-6-methyl coumarin (11), C,H, C,<H20 and C6-CH3 protons appeared as singlets at 6.96,5.33 and 2.53, respectively. Another singlet for 9 protons of the tert-butyl group was assigned at 6 1.37. A similar pattern of proton splitting was observed in all the compounds.

TA

BL

E 2

Fu

ngito

xici

ty o

f 4-

(sub

stitu

ted

phen

oxy)

met

hyl-

6-m

ethy

l cou

mar

ins

Com

poun

d EC

,, (p

g m

l-')

aga

inst

no

, ~

__

__

P.

aph

ani-

de

rmat

um

C. f

alca

tum

A

. alte

rnat

a D

. ory

zae

F. s

olan

i M

. pha

solin

a R.

sol

ani

11

111

IV

V

VI

VII

V

III

IX

X XI XI1

XI11

5 79

<1

>

100

2 >

100

>

100

<1

63

46

>

100 86

> 10

0

46 1.84

~

74

> 1

00

Y 43 3.68

1

1 >

100

> 1

00

Y a

>lo

o

> 1

00

>loo

1.84

<1 1.

99

a

> 1

00

> 1

00

> 10

0 1 3.6

a

1 >

loo

>

100

a

> 10

0 20 I 1

(1

93

32

92

>lo

o

> 1

00

> 1

00

> 1

00

23

>I0

0 >

100

> 1

00

>lo

o

> 1

00

93

28

93

> 10

0 32

>lo

o

> 10

0 >

100

>lo

o >

loo

86

"No

inhi

bitio

n at

100

pg

ml-

'

7j

S co 'c s r 3 s in s a -_

7?

Studies on pesticides based 011 coumarin 1 V 57

2.2 Test of fungitoxicity

The seven plant pathogenic fungi and the test method used were described earlier.6

3 RESULTS AND DISCUSSION

The results given in Table 2 reveal that coumarin derivatives exhibit differential activity against seven plant pathogenic fungi. The majority of these taxonomically different fungi are plurivorous plant pathogens which possess varying levels of sensitivity towards substituted coumarins. Although no single compound is effective against all the fungi, some appear to possess a strong non-specific fungitoxic potential against several fungi but their activity is determined largely by the position and chemical nature of the functional group/radical incorporated in the parent molecule. In general 4-(4-bromophenoxy)methyl-6-methyl coumarin (VII), 4-(4-chlorophenoxy)methyl-6-methyl coumarin (VIII) and 4-(3,4- dichlorophenoxy)methyl-6-methyl coumarin (X) were least active against the majority of the fungi. 4(-4-tert-butylphenoxy)methyl-6-methyl coumarin (11) and 4- (4-nitrophenoxy)methyl-6-methyl coumarin (XII) were most inhibitory to A . alternata, D. oryzae and F . solani which are morphologically and physiologically quite different from each other. It was observed that, in general, halo functionality (bromo or chloro) at position 4 in the phenoxy moiety resulted in almost complete loss of fungitoxicity, while the trichloroderivative (XI) was highly effective against F . solani and dematiaceous fungi such as D. oryzae. Thus compounds I1 and XI1 which exhibit a strong non-specific fungitoxicity towards various fungi, deserve further investigation for their possible use in plant disease control.

ACKNOWLEDGEMENTS

The authors would like to thank the Professor and Head, of the Department of Chemistry, Punjab University Chandigarh, Kurukshetra University for the spectral data and the Professor and Head, Dept of Chemistry and Biochemistry, HAU Hisar for necessary facilities. Thanks are also due to CSIR, New Delhi for financial assistance.

REFERENCES

1. Baldwin, R. E. Brit. J . Pharmacol., 3 (1948) 91. 2. Nakabayasi, T., Miyazaki, H. & Kokoroyama, T. J. Pharm. Soc. Japan, 73 (1953) 565. 3. Kitagawa, H. & Jto, Y. J . Pharm. Soc. Japan, 73 (1953) 107. 4. Nakabaysi, T. Chem. Abstr., 51 (1957) 14709. 5. Olson, R. Can. J . Biochem., 43 (1965) 1565. 6. Singh, R. V., Gupta, B. B., Malik, 0. P. & Kataria, H. R. Pestic Sci . , 20 (1987) 125-30. 7. Gupta, B. B., Singh, R. V., Malik, 0. P. & Kataria, H. R. Pestic. Sci., 21 (1987) 51-5. 8. Singh, R. V., Gupta, B. B., Abrol, V. & Malik, 0. P. Pestic. Sci., 1988 23 (1988) 103-7.

58 T. Burru. R . V. Srtigh. N . K . Satiywari, M . S . Malik, 0. P. Malik

9. Gasbisch, Jr, E. W. J . Am. Chem. Soc., 86 (1964) 5561. 10. Barnes, C. S. & Occdowit, J . L. Aust. J . Chem., 17 (1964) 975. 1 1. Socrates, G. Infra red Characteristics Group Frequencies, John Wiley and Sons, New

York, 1980, p. 57. 12. Kulkarni, M. V., Pujar, B. G. & Patil, V. D. Archiv der Pharmazie, 316 (1983) 15-20.