Synthesis of Isocoumarins and their Biological Activities

Synthesis of Isocoumarins and their Biological Activities

Synthesis of Isocoumarins and their Biological Activities KAZUYUKI MAEKAWA*AND HIROMICHI YOSHIKAWA Fac. of Engin. Kyushu Kyoritsu Univ., Kitakyushu* a...

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Synthesis of Isocoumarins and their Biological Activities KAZUYUKI MAEKAWA*AND HIROMICHI YOSHIKAWA Fac. of Engin. Kyushu Kyoritsu Univ., Kitakyushu* and Dept. ofAgric. Kyushu Univ., Fukuoka, 812 Japan

Abstract3-(Hydroxyphenyl)-isocoumarins, 3-aminoisocoumarins, 3-acetoxy-4-acetylisocoumarins, 4-carboxy(or carboethoxy)isocoumarins, and other various ring substituted isocoumarins were synthetized through different routes. The constitution of the synthetized compounds was confirmed by IR, NMR and mass spectrometry. Many isocoumarin derivatives so far synthetized showed interesting effects on plants. In particular, isocoumarins having 4-carboxyl- or 4-carboethoxyl group exhibited auxin-like activity on radish and rice plants at low concentrations. Among other isocoumarins, a considerable selectivity in their bioactivity was also observed. In general,radishes were more susceptible than rice and barnyard grass. However some isocoumarins affected more strongly on the rice than the radishes. On the other hand, the isocoumarins with a 3-methyl group showed both plant growth regulating activity and fungicidal activity. Thus, the development of some non-persistent and selective pesticides may be expected in this series.

INTRODUCTION A lot of isocoumarin derivatives are naturally obtained as secondary metabolites of plants and fungi, and some of them possess interesting bioactivities. For example, diaporthin is a strong phytotoxin(Ref.l)and sclerins are thought to be a plant growth regulating substance(Refs.2,3). Lunularic acid isolated from Lunulavia oruoiata which exists widely in liverworts and lower plants,is thought to function as a growth inhibitor like absisic acid in higher plants (Refs.4,5). This compound seemed to be biogenetically originated from hydrangenol, 3-(4-hydroxyphenyl)-8-hydroxy-3,4-dihydroisocoumarin. On the other hand, 3-(hydroxyphenyl)-isocoumarins possess similar structures to those of bioactive isoflavonoids such as formenetin, diadzein and others (Refs. 6,7). From these facts, the authors interested in the bioactivities of isocoumarin derivatives and synthetized some derivatives of isocoumarins in order to survey the relationships between structure and activity. The present paper deals with the synthesis, structure, phytotoxic and fungicidal activity of isocoumarin derivatives. In the isocoumarin synthesis, homophthalic acids are the most convenient intermediates, since they can be converted to several types of isocoumarins (Fig. 1 ) . But the general synthetic pathway of homophthalic acids is not known. Consequently, the authors inevitably investigated some synthetic pathways of homophthalic acids. SYNTHESIS OF HOMOPHTHALIC ACIDS i ) , Homophthalic acid derivatives bearing substituents on the ring were prepared by the ortho-carboxvlation method proposed by Smith and Kan (Ref.8), In the cases of cyclizations of 3-methyl- and 3-methoxyphenylacetyl isothiocyanates, the direction of cyclization was clarified by their NMR spectra, after being converted into dimethyl ester and 3-methylisocoumarin respectively. ii), 2,4-Dichloro- and 2,5-dichloro- and 2-bromo-3,4-dimethoxybenzbic acids were respectively treated with ethyl acetoacetate in the presence of sodium hydride and a catalytic amount of cuprous bromide according to Bruggink and McKillop (Ref.9). In every case, corresponding substituted homophthalic acids were obtained in a fairly good yield after hydrolysis with alkali. However, 2-chloro-6-methoxybenzoic acid did not react under the same condition.

104

105

Synthesis of isocoumarins

dii), 3-Hydroxy-, 3-hydroxy-6-methyl- and 3-hydroxy-4,6-dimethylhomophthalic acids were synthetized from 7-hydroxyindanon derivatives according to the procedure of Wagatsuma et al.(Ref.10). Many of naturally occurring bioactive isocoumarins, e.g. mellein, diaporthin have a hydroxyl group at 8 position ( correspond to the 3-position of homophthalic acid). SYNTHESES OF ISOCOUMARIN DERIVATIVES a ) , A variety of 3-acetoxy-4-acetylisocoumarins (II) were prepared from substituted homophthalic acids and acetic anhydride in the presence of pyridine (Ref.11,12).When homophthalic acid was refluxed with acetic anhydride or propionic anhydride without pyridine, 3-methyl-or 3-ethylisocoumarin was obtained in a moderate yield. It seems to be possible to introduce an alkyl group resulting from an acid anhydride to the 3-position of isocoumarins by this procedure. The 3-acetoxy-4-acetylisocoumarin (Π ) is easily hydrolyzed under alkaline condition and afford O-carboxyphenyl acetone derivatives(IH) in good yields. The ketocarboxylic acTds (ΠΊ) could be recyclized to 3-methylisocoumarins with concentrated mineral acids. In particular, a catalytic amount of perchloric acid in ethyl acetate was the best cyclizing reagent for this reaction (Ref.13).

'«V
^ C O O H ^ ^ C H X O N H ,

VI

•COOH

M 0 & C H 3 — * Φ Ε.COOH IV

.COOMe

OOH

H0C III

NH2

VII

I

COOMe

Ac

II

vm i H 0

COOH

Rz^NfH-cocH 3 COOEt

X

OOH

COOEt

XI

IX

Fig.l Syntheses of isocoumarins b ) , Syntheses of 4-carboethoxy-3-methylisocoumarins. The cyclization of ethyl 2-(2-carboxy-4, or -5, or -4,5-substituted phenyl)acetoacetate (X) was carried out under an acidic condition. As cyclizing reagents, a catalytic amount of p-toluenesulfonic acid in dry benzene was superior in the yield.The ester group in the molecule was scarcely hydrolyzed in this reaction. c ) , Syntheses of 4-carboxyisocoumarins.The Stobbe condensation of the active méthylène group of dimethyl homophthalate with ethyl formate in the presence of sodium methoxide gave dimethyl a-formylhomophthalate(VIII). The formylated compound was subjected to hydrolysis and ring closure by heating with cone. hydrochloric acid at 100°C. The product was not 4-carboethoxyisocoumarin but 4-carboxyisocoumarin (IX). By this method, ring substituted 4-carboxyisocoumarins were prepared from the corresponding homophthalic acids. d ) , 3-(Hydroxyphenyl)isocoumarins(V) were directly prepared from homophthalic acids and phenols by heating at 120°C for 1-2 hrs with anhydrous stannic chloride (Ref.14). As for this reaction, there are two possible ways leading to the formation of 2-carboxybenzylphenylketone derivatives(a), which are cyclized to isocoumarins, and of 2-benzoylphenylacetic acid derivatives(b). However, pathway(a) predominated under the condition used. On the other hand, in this electrophilic substitution, phenylacetyl carbonium ion can attack free ortho or para, positions of the hydroxyl group of phenols. Indeed we could obtain both derivatives. e ) , Syntheses of 3-amino- and 3-acetylaminoisocoumarins. Homophthalic acids were treated with dicyclohexylcarbodiimide in ethyl acetate. After removing dicyclohexylurea, ammonia gas was passed into the organic layer with stirring to afford homophthalamic acid ammonium salt. The homophthalamic acid(VI) thus obtained was treated again with a slight excess of dicyclohexylcarbodiimide to afford 3-aminoisocoumarin (VII). The reaction of 2-carboxybenzyl cyanide (ΧΠ) with acetyl chloride in the presence of pyridine afforded 3-acetylamino-

106

K. Maekawa and H. Yoshikawa

isocoumarin(XIII) which was identical with the product prepared from 3-aminoisocoumarin and acetyl chloride. The structural elucidation of these products was performed by elemental analysis, deriving to corresponding isocarbostyrils (Ref.15), IR, NMR, mass spectrometry. BIOLOGICAL ACTIVITIES OF ISOCOUMARIN DERIVATIVES 1) The phytotoxic activity of synthetized isocoumarins on radishes, rice and barnyard grass was examined as a manner described previously (Ref.16). The activity was evaluated after 6-9 days by measuring the rate of growth on both the stem and root. The effective compounds were enumerated in Table 1. TABLE 1 Effective compounds on plants

* Compd. No.

R

47 68 59 61 66 48 6 10 24

0

41 43

3

R

4

R

COOH COOH Me COOEt Me COOEt

5

Me

6

Cl

R7

R

8

2'

Me

OH

OH

31

41



Me

6?

Action

Me

s. i. s. i. s. i.

Cl OMe OMe Cl

Me

0 0 0 0 0

R

i.

OH

Me Me

s. : stimulation i. : inhibition

Me

OH

R. : root S. : stem

Me

OH OH Me

Me

Me

OH

Me

s. s.

Me

i.

s. s.

i.of R. i.of R.

gothic : strong italic : specific

A number of isocoumarins was phytotoxic. In particular, compounds No.47, 59, 66 and 68 were highly effective. No.47 caused strong growth stimulating effect on radishes below a concentratin of 10 ppm as shown in Fig. 2. However,

Fig.2 Effects of some isocoumarins on radish seedling even at a concentration of 100 ppm, it scarcely influenced the rice and barnyard grass. No. 59 inhibited the growth of radishes at a concentration of 30 ppm, while it considerably stimulated the elongation of the root at low levels of concentration. This compound seemed to inhibit the differentiation and the growth of the adventitious roots in the low concentration and to make the main root continue growing. The length of the main root of the treated rice reached to 250 I against that of control. No. 61 exhibited considerable inhibition upon the growth of radishes,but the monocotyledonous plant was scarcely affected. No. 68, an isomer of No.59, was also phytotoxically active to radish, rice and barnyard grass at a low concentration. However, No.68 stimulated the growth of stem and root of radish and the growth of the rice root at lower concentrations. While it did not affect the growth of barnyard grass.

107

Synthesis of isocoumarins

No.66 inhibited strongly the growth of radishes and also the root elongation of rice. The length of the treated root is about a half of that of control at a concentration of lppm. Even at a level of O.lppm, the root elongation of rice was still inhibited to some extent, while the root of radishes considerably elongated. From these results, it seems that the isocoumarins, which have carboxyl (or carboethoxyl)-group at 4-position, have strong phytotoxic activity. No.48, 6, 10 and 24 stimulated markedly the seedling growth of radishes. On the whole, radish was more susceptible to these isocoumarins than rice. Only few compounds, No. 41 and 43 were more effective on rice than on radishes. 2) Test for fungicidal activity on Asp.niger. The chemical to be tested was usually dissolved in a small amount of acetone and an aliquot of the solution was spotted on a filter paper of 6 mm in diameter. After spontaneous evaporation of the solvent, it was put on the surface of the agar medium in a Petri dish. In the Petri dish 3 or 4 samples were placed and spores of Asp.niger suspended in sterile water were sprayed on the plate medium. The activity was evaluated by inspecting the diameter of the inhibitory circle,after the incubation for 48 hrs at 30°C. Some isocoumarins(Table 2), No. 13, 52, 53, 54 and 55, were fungicidal. Among these compounds, No. 55 was the strongest. All of the examined isocoumarins, which have 3-methyl group, indicated the growth inhibiting effect on Asp.niger. Furthermore, No. 46 promoted the formation of spores of Asp.niger. This phenomenon is interesting because the isocoumarin can be easily converted to the analogue of lunularic acid. TABLE 2 Fungicidally active isocoumarins

to 3

Compd. No. 52 53 54 55 13

h Me Me

Me Me

R

4

R

5

Me

R

6

R

7

R

8

0 0

f 3» 4

OH OH

Me Me

Me OMe

Me

Me Me Me OH * stimulation for sporulation

46

2'

5' 6» Activity (MIC) 50Mg/ml 70 40 30 80 Me *

REFERENCES 1. A Boiler, E.Gäumann, E.Hardegger, F.Kugler, St.Naef-Roth and M.Rosner, Helv.Chim.Acta, £0, 875-880 (1957). 2. Y Satomura and A.Sato, Agric.Biol.Chem. 29, 337-344 (1965). t39 ( 1 9 6 8 ) . 3. T Sassa, H.Aoki, M.Namiki and K.Munakata, ibid., 32, 1432-14: L178 ( 1 9 6 9 ) . 4. I F.M.Valio, R.S.Burdon and W.W.Schwabe, Nature, 223, 1176-1] 2679-2685 (1971); idem. ibid. 11, 1 7 5 9 - 1 7 6 1 5. R J.Pryce, Phytochem., 10, — (1972). 6. S Tamura, C-F.Chang, A.Suzuki and S.Kumai, Agric.Biol.Chem. 33, 391-397 (1969). 7. C •F.Chang, A.Suzuki, S.Kumai and S.Tamura, ibid. 33, 398-408 (1969). 8. P A.S.Smith, and R.O.Kan, J.Amer.Chem.Soc. £2, 47Π-4754 (1960); idem, Org.Syn.Coll.Vol. 5, 1051-1057; ibid. ,5, 612-613 (1973). 9. A Bruggink and A.McKTllop, Tetrahedron, 31, 2607-2619 (1975). 10. S ,Wagatsuma, S.Higuchi, H.l'to, T.Nakano ,T.Naoi, K.Sakai, T.Matsui, Y. Takahashi, A.Nishi and S.Sano, Org.Prep.Proc.Int. _5, 65-70 (1973). 11. H ,L.Slates, S.Weber and N.L.Wendler, Chimia, 21, 468 (1967). 12. M «Matsui, K.Mori and Y.Ozawa, Agric.Biol.Chem. 30, 193-195 (1966). 13. B .E.Edwards and P.M.Pao, J.OrgTCïïëm. 31, 324-327(1965). 14. S •P.Inamdar, and R.N.Usgaonkar, J.Indian Chem.Soc. 43, 615-619 (1966). 15. A ,Rose and N.P.Buu-Hol, J.Chem.Soc.(C), 1968, 2205-2208. 16. K .Maekawa and J.Ohtani, Agric.Biol.Chem.~T07 791-799 (1976).

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