Novel Substituted Anilinopyrimidine ... - American Chemical Society

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Chapter 12

Novel Substituted Anilinopyrimidine Compounds: Design, Synthesis, and Fungicidal Activity Jichun Yang, Baoshan Chai, Huichao Li, Zhinian Li, and Changling Liu* State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Co. Ltd., No. 8 Shenliao East Road, Shenyang, P.C. 110021 *E-mail: [email protected]

Anilinopyrimidinones exhibited moderate fungicidal activity against cucumber downy mildew (CDM) or wheat powdery mildew (WPM) in previous research. To improve their bioactivity, a series of novel anilinopyrimidine analogs were designed and synthesized using ‘Intermediate Derivatization Method’. Preliminary bioassays demonstrated that most of the compounds exhibited weak to moderate activities against downy mildew. But surprisingly, some compounds synthesized showed moderate to good fungicidal activities against powdery mildew. The relationship between structure and fungicidal activity was also discussed. Compounds 7a-4 exhibited potent fungicidal activity against powdery mildew and effective in the control of powdery mildew on wheat, strawberry, tomato, cucumbers at 250-300 mg/L in field trials.

Pyriminostrobin (SYP-11277) is a novel acaricide of methoxyacrylate class developed by our group with terminal group replacement method (TRM) which was one important type of Intermediate Derivatization Method (IDM) (1–8). TRM focuses on novel key intermediates that have the potential to replace terminal moieties of known agrochemicals, pharmaceuticals, or natural products. These unique intermediates are synthesized through chemical reactions starting

© 2015 American Chemical Society In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


from raw chemicals. So a number of anilinopyrimidinone compounds 1 were synthesized in the process of discovery of pyriminostrobin. Bioassay indicated that compounds 1 showed moderate fungicidal activities against cucumber downy mildew (CDM) or wheat powdery mildew (WPM), especially compound 2 provided 60% control of CDM at 25 mg/L (3, 4, 9). To improve its bioactivity, a series of novel anilinopyrimidine analogs 3 were designed and synthesized using IDM based on the structural features of commercial fungicides dimethirimol, ethirimol and bupirimate, which are major fungicides in control of powdery mildew (Figure 1). Many of the compounds represented by 3 provided more than 90% control of WPM or CDM at 100 mg/L. Several sufficiently active compounds were evaluated in field tests to assess the potential for commercial development.

Figure 1. Structure Design and Some Known Fungicides

Synthesis Synthesis of different sub-classes of compounds of generic structure 3 will be discussed. When R3 was CH3, anilinopyrimidinones 6 were prepared in 88–95% yield by the reaction of substituted guanidines 5 with substituted ß-keto esters 4 in refluxing toluene for 8–12 h. The substituted guanidines 5 were purchased from commercial sources or prepared by treating corresponding amine hydrochlorides with cyanamide and Na2CO3. ß-Keto esters 4 were prepared by condensation of ethyl acetoacetate with R4X (haloalkanes, halobenzenes or benzyl halides) in 85–90% yield. For further optimization, compounds 7 were synthesized by the reaction of anilinopyrimidinones 6 with R5X such as haloalkanes, propargylic halides, ethyl chloroacetate, methyl chlorofonmate, ethyl chloroformate, isopropyl chlorocarbonate, dimethylsulfamoyl chloride, and dimethylcarbamyl chloride under basic conditions (Scheme 1).

164 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Scheme 1. General Synthesis Methods for Compounds 7

Compound 11 was prepared by condensation of the phenylguanidine carbonate 9 with 2-acetylbutyrolactone 10 in toluene in 85% yield, and compounds 12 were obtained by treating of 11 with R5X as the same procedure as compounds 7 (Scheme 2).


Compounds 14 with 5 or 6- membered rings were prepared by condensation of the phenylguanidine carbonate 9 with 2-carbethoxycyclopentanone or 2-carboethoxycyclohexanone 13 in toluene in 80% and 85% yields respectively, and compounds 15 were obtained by the reaction of 14 with R5X with the same procedure as compounds 7 (Scheme 3).



Biological Data


The fungicidal activities of the title compounds are shown in Tables 1-4. Most compounds showed moderate fungicidal activities against cucumber downy mildew (CDM) or wheat powdery mildew (WPM). By changing the A, B, and C moieties of anilinopyrimidine compounds (Figure 2), and analyzing the greenhouse disease control data we were able to develop structure activity relationships.

Figure 2. General Formulae of Anilinopyrimidine Compounds

Previous studies demonstrated that compound 2 showed 60% control of CDM at 25 mg/L. First, moiety B (R1 = Ph, R2 = H) and C (R5 = H) were maintained, moiety A was changed (Table 1), but all compounds, except compound 6a-3, did not show good fungicidal activities against CDM, which were significantly inferior to compound 2. Some compounds showed some control of WPM. As the result shown in Table 1, we found that only the compounds 6a-3 and 2, of which each R3 was CH3 and R4 was CH2CH2OH or CH2(CH2)2CH3, showed good fungicidal activity against CDM. Then moiety A (R3 = CH3, R4 = CH2(CH2)2CH3) and C (R5 = H) were maintained, moiety B was changed (Table 2), and all R1 was substituted phenyl and R2 was maintained as H. The electron-withdrawing group and electron-donating group all be lead into phenyl ring. But the regularity of fungicidal activity still not been found. Only compound 6b-2 (R1 = 4-CF3O-Ph) had 90% control of CDM at 25 mg/L, which was superior to compound 2. As shown in Table 2, we found that the compounds 6b-2 and 2, of which R1 was 4-CF3O-Ph or Ph, showed good fungicidal activity against CDM at 25 mg/L. The Moiety C was changed for further studying structure activity relationships, while moieties A (R3 = CH3, R4 = CH2(CH2)2CH3) and B (R1 = Ph, R2 = H) were maintained. With cost and process considerations being taken into account, we found compound 2 with a simple phenyl substituent as the best group to maintain in the subsequent optimization. Bupirimate was generally used for control of powdery mildew of fruits and crops, which has SO2N(CH3)2 in the 4 position of structure. So compound 7a-1 was prepared by introducing the group SO2N(CH3)2 at 4-OH of compound 2, but the fungicidal activity was poor against CDM and WPM. The fungicidal activity improved when the group SO2N(CH3)2 was replaced by CON(CH3)2 (compound 7a-2), and especially 166 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


when replaced by CO2CH(CH3)2 (compound 7a-3), compound 7a-3 had better control of CDM and WPM than compound 7a-1, and it had superior control of WPM as expected, despite showing better control of WPM than compound 2, but worse control of CDM than compound 2. So a series of compound 7a-3 analogs were synthesized, that is, R5 was changed from the group CO2CH(CH3)2 to chloroformate derivatives, alkyl, propargyl, ethyl acetate, etc. Most compounds showed better control of WPM than CDM, except compound 7a-8 showed 80% control of CDM at 25 mg/L, better than compound 2. Especially compound 7a-4 (R5 = CO2CH3) displayed more outstanding control of WPM than Compound 7a-3, with 100% control of WPM at 6.25 mg/L.

Table 1. Biological Data of Compounds 6a and 14aa

#

R3

R4

CDM (% control at the given concentration in mg/L)

WPM (% control at the given concentration in mg/L)

400

100

50

400

100

50

6a-1

CH3

H

0

NT

NT

80

NT

NT

6a-2

CH3

CH3

0

NT

NT

40

NT

NT

6a-3

CH3

CH2CH2OH

100

0

NT

NT

NT

NT

6a-4

CH3

CH2-Ph

0

NT

NT

0

NT

NT

6a-5

CH3

Ph

0

NT

NT

0

NT

NT

6a-6

CH3

CH2CH2Br

0

NT

NT

30

NT

NT

6a-7

CH3

CH2(CH2)6CH3

0

NT

NT

0

NT

NT

14a-1

CH2CH2CH2

0

NT

NT

20

NT

NT

14a-2

CH2CH2CH2CH2

0

NT

NT

20

NT

NT

2

CH3

100

90

80

0

NT

NT

CH2(CH2)2CH3

a

CDM-cucumber downy mildew (Pseudoperonospora cubensis); WPM-wheat powdery mildew ((Erysiphe graminis); NT-Not Tested. the same as following tables.


Table 2. Biological Data of Compounds 6ba

R1


#

a

R2



400

100

50

400

100

50

6b-1

3,5-di-Cl-Ph

H

100

0

0

100

0

0

6b-2

4-CF3O-Ph

H

100

100

90*

0

NT

NT

6b-3

4-F-Ph

H

0

NT

NT

0

NT

NT

6b-4

4-CF3-Ph

H

0

NT

NT

0

NT

NT

6b-5

4-CH3O-Ph

H

0

NT

NT

30

NT

NT

6b-6

4-CN-Ph

H

0

NT

NT

30

NT

NT

2

Ph

H

100

90

80

0

NT

NT

* indicates 25mg/L. the same as following tables.

It could be concluded that the general trend in WPM activity for R5 of moiety A (7a) was that : CO2CH3 > CO2CH(CH3)2 > CO2C2H5, CO2CH2CH(CH3)2, CO2CH2CH2CH3, CO2CH2CH2OCH3, CO2CH2-(tetrahydrofuran-2-yl), COC(CH3)3, CH2C≡CH, COC2H5, COC(CH3)3 > CO2CH(CH3)-Ph, CO2CH2-Ph > SO2(4-CH3-Ph), CO2SCH2CH=CH2, CON(CH3)2 > SO2N(CH3)2, CH2COCH3, CO-Ph, CH3 >> CO2(4-NO2-Ph), CO2(2-CH3O-Ph), CSNH(CH2)2CH3, H. Compounds 7b-1 and 7b-2 were prepared in order to optimize the WPM activity, but with disappointing results as 7a-4 still was the best compound. The fungicidal activities of compound 7a-4 were shown in Figure 3. Compound 7a-4 showed more than 50% inhibition effect to Rhizoctonia solani, Clttihmoloru ecgooprodslesoiie, Cytospora, Fulvia fulva, Alternaria solani, Phytophthora megasperma, Drechslera SoFokiniana, Fusarium oxysporumf, Fusarium oxysporum, Pythium aphanidermatum at 10 mg/L. Field trials were carried out on wheats, strawberries, tomatos and cucumbers separately, compound 7a-4 as a 20% emulsifiable concentrate (EC) was effective in the control of powdery mildew at 250-300 mg/L (Tables 5-8). Compound 7a-4 showed slightly higher control than the structurally related powdery mildew standard ethirimol at an equivalent dose.


Table 3. Biological Data of Compounds 7aa

R5


#

a



400

100

50

400

100

50

7a-1

SO2N(CH3)2

30

NT

NT

60

NT

NT

7a-2

CON(CH3)2

98

0

0

100

0

0

7a-3

CO2CH(CH3)2

95

10

0

100

100

98

7a-4

CO2CH3

95

20

0

100

100

100**

7a-5

CO2C2H5

95

20

0

95

98

50

7a-6

CO2CH2CH(CH3)2

95

0

0

100

90

25

7a-7

CO2CH2CH2CH3

70

NT

NT

100

95

70

7a-8

CO2CH2CH2OCH3

100

100

80*

100

100

70

7a-9

CO2CH2-(tetrahydrofuran-2-yl)

98

95

0

100

100

20

7a-10

CO2CH2-Ph

30

NT

NT

100

80

0

7a-11

CO2CH(CH3)-Ph

50

NT

NT

100

80

30

7a-12

SO2(4-CH3-Ph)

0

NT

NT

100

0

NT

7a-13

CO2(4-NO2-Ph)

0

NT

NT

0

NT

NT

7a-14

CO2(2-CH3O-Ph)

50

NT

NT

0

NT

NT

7a-15

CO2-Ph

100

98

85

100

0

0

7a-16

CO2SCH2CH=CH2

0

NT

NT

100

0

0

7a-17

COC2H5

30

NT

NT

100

50

30

7a-18

COC(CH3)3

50

NT

NT

100

98

40

7a-19

CO-Ph

100

15

0

70

NT

NT

7a-20

CSNH(CH2)2CH3

0

NT

NT

0

NT

NT

7a-21

CH2C≡CH

100

0

0

100

100

80

7a-22

CH2COCH3

98

30

10

40

NT

NT

7a-23

CH2CO2C2H5

0

NT

NT

0

NT

NT

7a-24

CH3

0

NT

NT

95

0

NT

2

H

100

90

80

0

NT

NT

** indicates 6.25mg/L. the same as following tables.



Table 4. Biological Data of Compounds 7b

R1

#


R2 400

100

50

7b-1

3,5-di-Cl-Ph

H

100

0

0

7b-2

4-CF3O-Ph

H

95

10

0

7a-4

Ph

H

100

100

100**

Figure 3. Fungicidal Activities of Compound 7a-4


Table 5. Field Trials Results for Compound 7a-4 Control of Wheat Powdery Mildewa I

II

III

average

250

66.7

70.1

69.4

68.8

125

61.6

54.2

52.0

55.9

62.5

42.7

39.5

36.0

39.4

ethirimol 25% SC

250

60.0

60.5

63.7

61.4

triadimefon 25% WP

125

92.5

91.2

93.9

92.5

compound 7a-4 20% EC


control after spraying (%)

concentration (8mg/L)

compound

a EC -- emulsifiable concentrate, SC -- Suspension concentrate, WP -- Wettable Powder. the same as following tables.

Table 6. Field Trials Results for Compound 7a-4 Control of Strawberry Powdery Mildewa I

II

III

average

600

90.6

90.2

89.6

90.1

300

84.9

75.5

75.4

79.3

150

73.3

72.7

63.1

70.4

ethirimol 25% SC

300

61.4

61.5

66.2

62.7

difenoconazole 10% SL

150

59.6

58.3

63.9

60.4

kresoxim-methyl 30% SC

150

92.1

92.1

86.1

90.5


a


concentration (mg/L)

compound

SL -- soluble concentrate, the same as following tables.


Table 7. Field Trials Results for Compound 7a-4 Control of Tomato Powdery Mildew I

II

III

average

450

79.6

83.6

86.7

83.3

300

70.2

81.9

82.1

78.2

150

63.4

66.6

81.1

70.5

difenoconazole 10% SL

150

70.6

80.9

78.1

76.5

azoxystrobin 25% SC

150

82.0

80.0

84.6

82.3





compound

Table 8. Field Trials Results for Compound 7a-4 Control of Cucumbers Powdery Mildew compound



I

II

III

average

600

93.1

96.3

97.3

95.6

300

85.4

89.3

85.0

86.6

150

79.6

84.1

82.0

81.9

ethirimol 25% SC

300

79.9

80.6

76.7

79.1

pyraclostrobin 25% EC

150

63.4

65.3

62.6

63.7

tebuconazole 43% SC

150

68.7

68.2

69.0

68.6


Conclusions The anilinopyrimidine compounds showed good fungicidal activity against CDM or WPM. Compounds had more better control of WPM with the general structure 3 substituted by R1 = Ph, R2 = H, R3 = CH3, R4 = CH2(CH2)2CH3 and OR5 = carbonates, especially compound 7a-4 showed 100% control of WPM at 6.25 mg/L and had good inhibition effect on a variety of diseases at 10 mg/L, as a 20% emulsifiable concentrate (EC) was effective in the control of powdery mildew on wheat, strawberry, tomato, cucumbers at 250-300 mg/L in field trials, little more potent than ethirimol at equivalent dose. The potential for commercial development is being assessed.

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Novel Substituted Anilinopyrimidine ... - American Chemical Society

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