Synthesis and herbicidal activities of benzothiazole N,O-acetals

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4065–4068

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl

Synthesis and herbicidal activities of benzothiazole N,O-acetals Zhiqin Ji ⇑, Fengxing Zhou, Shaopeng Wei College of Plant Protection, Northwest A&F University, Yangling, Shaanxi 712100, China

a r t i c l e

i n f o

Article history: Received 7 July 2015 Revised 18 August 2015 Accepted 20 August 2015 Available online 20 August 2015 Keywords: Synthesis Herbicidal N,O-acetals Benzothiazole

a b s t r a c t A new series of N,O-acetals were prepared via a simple one-pot reaction by the condensation of 2-aminomethybenzothiazole with aldehydes and alcohols. The title compounds were obtained in moderate to good yields in the presence of acid catalyst. Bioassay results indicated that some synthesized compounds had good herbicidal activity against both dicotyledon and monocotyledon weeds. This investigation provided a new type of herbicidal lead compounds, as well as its facile preparation method. Ó 2015 Elsevier Ltd. All rights reserved.

With the widely spread use of herbicides, the occurrence of herbicide-resistant weeds has increased dramatically during the past decades, and which suggests a great need for the development of novel herbicidal chemicals.1 As a versatile scaffold with diverse bioactivity, benzothiazole moiety has been successfully incorporated into many agro-chemicals, and it is still attracting more attention from chemists.2–5 Here are several examples of benzothiazole-containing chemicals which were used as herbicides (Fig. 1). Mefenacet, which belongs to the family of anilide herbicides, is a pre-emergence herbicide used to control graminaceous and some dicotyledonous weeds. Its mode of action is most like that of the chloroacetamides among the herbicide classes known to inhibit the growth of cell division and enlargement.6 Benazolin is a postemergent herbicide used to control annual broad-leaved weeds, and it exhibits auxin-like activity.7 Benzthiazuron belongs to urea herbicides, and it is a photosynthesis inhibitor.8 Fenthiaprop-ethyl belongs to aryloxyphenoxypropionic herbicides, and it targets on the acetyl-coA carboxylase (ACC), a key enzyme for the biosynthesis of fatty acid.9 Although these chemicals could be also classified as benzothiazole herbicides according to their chemical structures, they have entirely different modes of action. To better reflect their activity, these benzothiazole herbicides are more commonly classified by their active groups such as amide, urea or carboxylic acid groups. As a key enzyme related to the biosynthesis of chlorophyll in plant, protoporphyrinogen oxidase (PPO) is the target of several chemical families of herbicides such as N-phenyl phthalimides, oxadiazoles, diphenylethers, and so on. Benzothiazole moiety has ⇑ Corresponding author. Tel./fax: +86 029 87093987. E-mail address: [email protected] (Z. Ji). http://dx.doi.org/10.1016/j.bmcl.2015.08.051 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

been widely in the development of new PPO inhibitors in recent years.10–13 For example, two series of benzothiazole-containing chemicals (Fig. 2, formulas I and II) were designed based on the structures of Oxadiazon and Flumioxazin, two commercial herbicides targeted on PPO, and some of these compounds exhibited stronger inhibitory effect against PPO than its commercial inhibitors.14,15 In a program of screening fungicidal ingredients via the derivation of 2-amino-4-methylbenzothiazole (the key intermediate of fungicide tricyclazole), N-(methoxymethyl)-4-methyl benzo[d]thiazol-2-amine, a novel N,O-acetal, was occasionally obtained with high yield in our laboratory. In the following field trials, we found that the obtained N,O-acetal only exhibited selective depigmentation effect against Fusarium graminearum, whereas it had obvious phytotoxicity on tested plant. Attracted by this phenomenon, our interest was transferred from antifungal to herbicidal activity. To best understand the relationship between structure and activity, more N,O-acetal analogues were synthesized and evaluated for their herbicidal activities. Furthermore, although many 2-position derivatives of benzothiazole have been reported in literatures, the readily synthesized title compounds which featured N–C–O–C moiety at 2-postion are a novel type of chemicals. We herein report for the first time an efficient synthesis of a series of novel N,Oacetal derivatives of benzothiazole. All synthesized N,O-acetals were subjected to evaluate their herbicidal activities against Setaria viridis and Amaranthus retroflexus. It was reported that primary aromatic amines reacted at room temperature with paraformaldehyde and sodium alkoxide in the corresponding alcohol as solvent to afford N,O-acetals in good yields.16 In that investigation, the prepared N-(alkoxymethyl)arylamines were unstable compounds under room temperature and

4066

Z. Ji et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4065–4068

S

O S

O

N

N

N

Cl

OH Benazolin

Mefenacet

N

Cl

O

S

O O

N H

S O N

N H

OH

O O Fenthiaprop-ethyl

Benzthiazuron

Figure 1. Commercial benzothiazole-containing herbicides and their active groups.

X

Cl O

O

O O

O Cl

N

N

N RS

O

O O

N

N

S

F

N

N

O

N

O Flumioxazin

I

Oxadiazon

Y

S N

O

SR

II

Figure 2. Benzothiazole-containing PPO inhibitors based on the structures of commercial herbicides.

needed to be stored at low temperature to avoid decomposition. Recently, a synthetic route that using microwave irradiation to obtain stable N,O-acetals and N,S-acetals from 2-amino-1,4naphthoquinones was proposed.17 According to the literature, N,O-acetals could be readily prepared by the condensation of 2-amino-1,4-naphthoquinones with paraformaldehyde using alcohols simultaneously as both solvent and reactant, and N,S-acetals were obtained using various thiols in chloroform. In this study, N-(methoxymethyl)-4-methylbenzo[d]thiazol2-amine (4a) was firstly obtained by the condensation of 2-amino4-methybenzothiazole with formaldehyde using methanol simultaneously as both solvent and reactant in the presence of acid catalyst. The reaction could proceed smoothly under ambient condition without the assistance of microwave radiation, but the presence of catalytic amount of acid was crucial to the success. The reaction progress was monitored by silica gel TLC, and the results indicated that the preparation of N,O-acetal was a two-step reaction. Firstly, a spot with lower Rf value than starting material was observed at the beginning of the reaction. Then the second spot with high Rf value appeared gradually, and it was identified as the target compound finally. The structure of the intermediate was not identified because it was unstable during the isolation procedure, but it could be deduced as Schiff base produced by the reaction between primary amine with aldehyde. Then the addition of methanol across the imine bond resulted in the formation of N,O-acetal finally. Speaking objectively, 4a is not a purposely designed compound, but its herbicidal activity, facile synthetic route and novel chemical moiety inspired us to learn more about the relationship between structure and activity of this type of N,O-acetals. To evaluate the influence of different alkoxy groups on the herbicidal activity, compounds 4a–4g were prepared by the reaction

O

S NH 2 N

R1

H 2

1

HO R2 3

of 2-amino-4-methybenzothiazole with formaldehyde and the corresponding alcohols according to the synthetic route illustrated in Scheme 1. Among them, 4a and 4b were synthesized in methanol and ethanol, respectively. Other compounds were prepared using tetrahydrofuran (THF) as solvent. Meanwhile, it was observed that the presence of catalytic amount of formic acid or acetic acid was crucial to the reaction. To evaluate the influence of introducing different aldehydes on the activity, compounds 4h–4l were prepared by using acetaldehyde and butyraldehyde as reactant, respectively. Starting from 2-amino-benzothiazole and 4(or 6)-substituted2-amino-benzothiazoles, 8a–8j were obtained in moderate to good yields by using the synthetic route illustrated as Scheme 2. It implies that the simple synthetic strategy is applicable to the preparation of N,O-acetal analogues from a variety of substituted-2-amino-benzothiazoles. Tricyclazole is a protective fungicide by inhibiting melanin formation in fungi.18 Fungal melanin is a type of dark brown to black pigments deposited in cell walls, and it is usually formed by oxidative polymerization of phenolic compounds with protein or carbohydrates.19 Melanin protect cells against attack by environmental factors such as ultraviolet light, lytic enzymes, and function as an essential component of appressorium-based penetration of plant cells.20 In view of their structural similarity, the depigmentation effect of 4a against Curvularia lunata and Fusarium graminearum, two species of plant pathogenic fungi, was evaluated firstly. As depicted in Figure 3, the melanin biosynthesis in C. lunata was almost totally inhibited by tricyclazole at the concentration of 25 lg mL 1, whereas 4a showed no inhibitory effect at the same concentration. On the contrary, the pigment production in F. graminearum was hardly affected by the presence of tricyclazole, but it could be thoroughly inhibited by 4a. According to the literature, the red pigments produced by Fusarium species are auro-

HCOOH

S

THF/alcohol,rt

N

R2

NH O

1 4a~4l R

4a: R 1 = H, R2 = CH 3 ; 4b: R 1 = H, R2 = CH 2 CH 3; 4c: R 1 = H, R2 = CH(CH 3) 2; 4d: R1 = H, R 2 = CH 2CH2 CH3 ; 4e: R 1 = H, R2 = CH2 (CH2 )2 CH 3 ; 4f: R1 = H, R 2 = CH 2(CH 2) 3CH 3; 4g: R1 = H, R 2 = CH 2CH2 CH 2 (CH3 )2 ; 4h: R 1 = CH3 , R2 = CH 3; 4i: R 1 = CH 3, R2 = CH2 CH 3 ; 4j: R1 = CH 3 , R 2 = CH(CH3 )2 ; 4k: R1 = CH 2 CH 2CH3 , R2 = CH 3 ; 4l: R 1 = CH 2CH 2CH3 , R2 = CH 2 CH 3

Scheme 1. Synthesis of N,O-acetal derivatives of 2-amino-4-methylbenzothiazole.

4067

Z. Ji et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4065–4068 O

S R N 5

NH 2

H

H

HO CH 3 7

6

S

HCOOH

R

N H

N

CH 3OH, rt

O

8a~8j

R: 8a, -H; 8b, 4-OCH3 ; 8c, 4-Cl; 8d, 6-CH 3 ; 8e, 6-OCH 3; 8f, 6-OC2 H5 ; 8g, 6-F; 8h,6-Cl; 8i, 6-Br; 8j, 6-NO 2

Scheme 2. Synthesis of N-(methoxymethyl)benzothiazole derivatives.

A1

A2

A3

B1

B2

B3

Figure 3. Depigmentation of fungi after treatment with 4a and tricyclazole at 25 lg mL

fusarin, bikaverin or its analogues, which belong to the naphthoquinone group of polyketides.21,22 Although the pigments which are incorporated into the melanin polymers also belong to naphthoquinones in C. lunata, 4a exhibited selective depigmentation effect against F. graminearum.23 However, our main concern is the relationship between depigmentation effect and pathogenicity, not the mechanism of inhibition of pigment biosynthesis. To evaluate the protective efficacy 4a, a bioassay test was carried out by assessing the pathogenicity of F. graminearum on wheat as the literature described.22 But the results indicated that 4a had no obvious control efficiency against the infection by tested fungi. The inhibitory effect of 4a against the spore germination and mycelial growth of several strains of plant pathogenic fungi was also evaluated, but the results indicated that 4a only exhibited weak antifungal activity. The pre-emergent herbicidal activity herbicidal activity of title compounds against Setaria viridis and Amaranthus retroflexus was evaluated using pot culture assay. The application rate were 700 and 1400 g a.i./ha, respectively. A commercial pre-emergent herbicide, 60% Butachlor EC, was used as positive control and made application at the same rate. Fresh weight of the above ground tissues was measured after 14 d of treatment, and the inhibition rate was calculated by comparing to control values. The herbicidal activity of all tested compounds was listed in Table 1. As shown in Table 1, 4a exhibited herbicidal activity against both S. viridis and A. retroflexus. The mean inhibition rate against S. viridis were 52.6% and 83.2% at the application rate of 700 and 1400 g a.i./ha, respectively. And the corresponding inhibition rate against A. retroflexus were 67.8% and 93.0%, respectively. By contrast, the herbicidal activities of 4b–4g decreased dramatically, and some of them showed no inhibition against tested plant at all. It implied that the activity of N-alkoxymethyl derivatives was related with the type of introduced alcohols, and methanol was obviously more beneficial to the activity than other aliphatic alcohols. The

1

. (A) C. Lunata, (B) F. graminearum; 1-check; 2-4a; 3-tricyclazole.

Table 1 Herbicidal activity of benzothiazole N,O-acetals Compounds

Mean inhibition rate (%) Setaria viridis

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 8a 8b 8c 8d 8e 8f 8g 8h 8i 8j Butachlor

Amaranthus retroflexus

700 g a.i./ha

1400 g a.i./ha

700 g a.i./ha

1400 g a.i./ha

52.6 26.4 22.5 — — — — — 25.8 26.1 — — 38.5 24.9 49.7 43.5 17.2 — 25.1 58.6 64.8 70.3 86.5

83.2 48.3 29.0 — — — — 18.6 35.2 33.8 18.6 — 62.2 30.6 78.2 64.6 21.4 — 32.6 82.7 88.2 92.7 100

67.8 30.2 27.7 16.8 — — — 35.8 55.3 58.6 — — 42.4 35.2 62.8 45.9 15.3 — 31.2 66.9 72.6 78.5 92.0

93.0 46.8 42.4 24.0 12.6 — — 59.7 83.2 63.3 20.7 — 69.0 69.5 85.4 63.7 19.6 16.0 57.4 87.4 95.8 100 100

‘—’, no activity.

herbicidal activity of 4i, 4j and 4k was weaker than that of 4a, but it was stronger than that of other N-alkoxymethyl derivatives, which implied that the activity was determined by the combined effect of introduced aldehydes and alcohols. To understand the relationship between the groups substituted at scaffold and herbicidal activity, the activity of 8a were compared

4068

Z. Ji et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4065–4068

to that of 8b–8j, as well as 4a. As shown in Table 1, 8e, 8f and 8g showed weaker inhibitory effect than 8a, whereas 8c, 8h, 8i and 8j exhibited stronger activity than 8a. It implied that introducing electron withdrawing groups at 6(or 4)-position was beneficial to the activity, but the introduction of fluorine atom at 6-position (8g) was an exception. Meanwhile, the activity reduced by introducing alkoxy groups at 6-position. Compounds 8b and 8d showed slightly less or equivalent activity than 8a, it revealed that the introduction of methoxy at 4-position or methyl at 6-position had little effect on the activity. However, introducing methyl group at 4-position (4a) increased the activity dramatically. In conclusion, we synthesized a series of novel benzothiazole N, O-acetals using a simple one-pot reaction by the condensation of 2amino-methybenzothiazole with aldehydes and alcohols. Bioassay results indicated that some synthesized compounds had good herbicidal activity against both dicotyledon and monocotyledon weeds. More importantly, because the N,O-acetal group is not an active groups which commonly distributed in commercial herbicides, so this investigation provided a new type of lead compounds for the development of herbicides. Further investigation on the mechanism of herbicidal activity, as well as QSAR studies of this type of chemicals is now carried out in our laboratory. Acknowledgments This study was supported part by the Grant of the National Natural Science Foundation of China (Nos. 31371973, 31301700), the Natural Science Foundation of Shaanxi Province (No. 2013JQ3003), and the Fundamental Research Funds for the Central Universities (QN2013009). Supplementary data Supplementary data (synthetic procedures and structural characterization, as well as bioassay tests) associated with this article

can be found, in the online version, at http://dx.doi.org/10.1016/j. bmcl.2015.08.051. References and notes 1. Beckie, H. J. Weed Technol. 2006, 20, 793. 2. Wheeler, M. H.; Bhatnagar, D.; Klich, M. A. Pestic. Biochem. Physiol. 1991, 41, 190. 3. Manninen, A.; Auriola, S.; Vartiainen, M.; Liesivuori, J.; Turunen, T.; Pasanen, M. Arch. Toxicol. 1996, 70, 579. 4. Koci, J.; Klimesova, V.; Waisser, K.; Kaustova, J.; Dahse, H. M.; Mollmann, H. M. Bioorg. Med. Chem. Lett. 2002, 12, 3275. 5. Sidoova, E.; Kralovam, K.; Loos, D. Molecules 1998, 3, 135. 6. Fedtke, C. Pestic. Sci. 1991, 33, 421. 7. Whatley, L. L.; Slife, F. W. Weed Sci. 1983, 31, 801. 8. Rajasekharan, R.; Sastry, P. S. Biochem. Cell Biol. 1990, 68, 567. 9. Zhu, X. L.; Zhang, L.; Chen, Q.; Wan, J.; Yang, G. F. J. Chem. Inf. Model. 2006, 46, 1819. 10. Wu, Q. Y.; Jiang, L. L.; Zuo, Y.; Wang, Z. F.; Xi, Z.; Yang, G. F. Chem. Biol. Drug Des. 2014, 84, 431. 11. Wu, Q. Y.; Jiang, L. L.; Yang, S. G.; Zuo, Y.; Wang, Z. F.; Xi, Z.; Yang, G. F. New J. Chem. 2014, 38, 4510. 12. Zuo, Y.; Yang, S. G.; Luo, Y. P.; Tan, Y.; Hao, G. F.; Wu, Q. Y.; Xi, Z.; Yang, G. F. Bioorg. Med. Chem. 2013, 21, 3245. 13. Zuo, Y.; Yang, S. G.; Jiang, L. L.; Hao, G. F.; Wang, Z. F.; Wu, Q. Y.; Xi, Z.; Yang, G. F. Bioorg. Med. Chem. 2012, 20, 296. 14. Jiang, L. L.; Zuo, Y.; Wang, Z. F.; Tan, Y.; Wu, Q. Y.; Xi, Z.; Yang, G. F. J. Agric. Food Chem. 2011, 59, 6172. 15. Jiang, L. L.; Tan, Y.; Zhu, X. L.; Wang, Z. F.; Zuo, Y.; Chen, Q.; Xi, Z.; Yang, G. F. J. Agric. Food Chem. 2010, 58, 2643. 16. Barluenga, J.; Bayón, A. M.; Asensio, G. J. Chem. Soc., Chem. Commun. 1983, 1109. 17. Jordão, A. K.; Novais, J.; Leal, B.; Escobar, A. C.; dos Santos, H. M., Jr.; Castro, H. C.; Ferreira, V. F. Eur. J. Med. Med. 2013, 63, 196. 18. Cunha, M. M.; Franzen, A. J.; Alviano, D. S.; Zanardi, E.; Alviano, C. S.; De Souza, W.; Rozental, S. Microsc. Res. Tech. 2005, 68, 377. 19. Kogej, T.; Wheeler, M. H.; Rizˇner, T. L.; Gunde-Cimerman, N. FEMS Microbiol. Lett. 2004, 232, 203. 20. Butler, M. J.; Gardiner, R. B.; Day, A. W. Mycologia 2009, 101, 296. 21. Frandsen, R. J.; Nielsen, N. J.; Maolanon, N.; Sørensen, J. C.; Olsson, S.; Nielsen, J.; Giese, H. Mol. Microbiol. 2006, 61, 1069. 22. Malz, S.; Grell, M. N.; Thrane, C.; Maier, F. J.; Rosager, P.; Felk, A.; Albertsen, K. S.; Salomon, S.; Boh, L.; Schäfer, W.; Giese, H. Fungal Genet. Biol. 2005, 42, 420. 23. Bell, A. A.; Wheeler, M. H. Phytopathology 1986, 24, 411.