Design, Synthesis, and StructureâActivity Relationship of New

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Design, Synthesis and Structure-activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety Aiying Guan, Changling Liu, Wei Chen, FAN YANG, Yong Xie, Jinbo Zhang, Zhinian Li, and Ming-an Wang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b05580 • Publication Date (Web): 25 Jan 2017 Downloaded from http://pubs.acs.org on January 30, 2017

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Page 1 of 41

Journal of Agricultural and Food Chemistry

1

Design, Synthesis and Structure-activity Relationship

2

of New Pyrimidinamine Derivatives Containing an

3

Aryloxy Pyridine Moiety

4 5

Aiying Guan†,‡, Changling Liu*,‡, Wei Chen‡, Fan Yang‡, Yong Xie‡, Jinbo

6

Zhang‡, Zhinian Li‡, Mingan Wang*,†

7 8 9 10

†

Department of Applied Chemistry, China Agricultural University, Beijing

100193, People’s Republic of China ‡

State Key Laboratory of the Discovery and Development of Novel Pesticide,

11

Shenyang Sinochem Agrochemicals R&D Co. Ltd., Shenyang 110021,

12

People’s Republic of China

13 14 15

*Corresponding author (Tel: +86-(0)10-62734093; E-mail:

16

[email protected])

17

1

ACS Paragon Plus Environment


18

ABSTRACT

19

The pyrimidinamine diflumetorim is an ideal template for the discovery of

20

agrochemical lead compounds due to its unique mode of action, novel

21

chemical structure and lack of reported resistance. In order to develop a new

22

pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a

23

series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety

24

were designed and synthesized by employing the recently reported

25

intermediate derivatization method (IDM). The structures of all compounds

26

were identified by 1H NMR, elemental analyses, HRMS and X-ray diffraction.

27

Bioassays demonstrated that some of the title compounds exhibited excellent

28

fungicidal activities against CDM. Compound 9 gave the best activity (EC50 =

29

0.19 mg/L), which is significantly better than the commercial fungicides

30

diflumetorim, flumorph and cyazofamid. The relationship between structure

31

and fungicidal activity of the synthesized pyrimidinamines was explored. The

32

study showed that compound 9 is a promising fungicide candidate for further

33

development.

34 35

KEYWORDS: intermediate derivatization method (IDM), fungicidal activities,

36

cucumber downy mildew, structure-activity relationship

2


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Page 3 of 41


37

INTRODUCTION

38

Agrochemicals play an important role in modern agriculture by increasing both

39

crop quality and yield while improving living standards. Fungicides are a major

40

section of crop protection products, which are applied widely to major crops

41

such as rice, corn, fruits and vegetables. In 2014 the global market for

42

fungicides was valued at $16,365 million, equivalent to 25.9% of the global

43

agrochemical market; this represents an increase of 4.4% in comparison with

44

2013.1 However, with the widespread application of fungicides, the

45

development of resistance is inevitable. Based on the report from the

46

Fungicide Resistance Action Committee (FRAC), fungicides with known

47

modes of action are classified according to target sites into more than 50

48

groups. Among these, it was reported that over 40 target sites have already

49

developed medium to high resistance risk to many familiar classes of

50

fungicides which involved the vast majority of fungicide structures.2 The

51

discovery of fungicide candidates with innovative structures is urgently needed

52

to address this problem. Pyrimidinamines, which act as mitochondrial complex

53

I electron transport inhibitors (MET I), are one of the few types of fungicides

54

without reported resistance.2 Diflumetorim is the representative pyrimidinamine

55

fungicide targeting MET I, its structure is significantly different from

56

commercially available fungicides, and also different from MET I inhibitors that

57

are insecticides. More importantly, it has no cross resistance with the existing

58

conventional fungicides, and is safe to non-target organisms.3a These

3



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59

properties suggest that pyrimidinamines may be promising templates for the

60

discovery of new fungicide candidates.

61

The diaryl ether moiety is commonly found in many molecules of agricultural

62

importance such as pyrethroid insecticides, (aryloxy)phenoxypropionate

63

herbicides and triazole fungicides such as difenoconazole.3 Additionally, the

64

pyridine moiety is found in several fungicides, insecticides/acaricides and

65

herbicides.4 The introduction of a pyridine ring in place of a phenyl ring usually

66

leads to pesticides that have lower toxicity and higher systemicity or

67

selectivity.5 2-Chloro-5-(chloromethyl)pyridine and substituted nicotinic acids

68

bearing reactive groups such as Cl, COOH and chloromethyl, are promising

69

intermediates of low cost and toxicity, which can be readily modified to give

70

structural diversity.

71

In this study, we sought to develop new pyrimidinamine derivatives with

72

improved fungicidal activity by employing intermediate derivatization method

73

(IDM), a recently reported highly efficient approach to discover agrochemical

74

candidates.6-20 2-Chloro-5-(chloromethyl)pyridine or 6-chloronicotinic acid

75

derivatives were used as starting materials to obtain key intermediates which

76

produced a series of pyrimidinamine derivatives containing an aryloxy pyridine

77

moiety

78

structure−activity relationships of these compounds are discussed below.

79

MATERIALS AND METHODS

80

All chemicals such as starting materials and reagents were commercially

(Figure

1).

The

detailed

synthesis,

bioassay

4


results,

and

Page 5 of 41


81

available (Sinopharm Chemical reagent Co. Ltd., Shanghai, China) and used

82

without further purification except as indicated. Melting points were determined

83

on a Büchi M-569 melting point apparatus (Büchi Labortechnik AG, Flawil,

84

Switzerland) and are uncorrected. 1H NMR spectra were recorded with a

85

Mercury 300 MHz spectrometer (Varian, Palo Alto, CA) with deuterochloroform

86

as the solvent and tetramethylsilane (TMS) as the internal standard. Elemental

87

analyses were determined on a Yanaco MT-3CHN elemental analyzer

88

(Yanaco, Kyoto, Japan). Mass spectra were acquired with an Agilent

89

Accurate-Mass-Q-TOF MS 6520 system (Agilent Technologies, Milford, MA)

90

equipped with an electrospray ionisation (ESI) source. X-ray structure

91

determination was recorded with XtaLAB mini (Rigaku, The Woodlands, TX).

92

All plant and bacteria materials were obtained from the Agrochemical

93

Discovery Department in Shenyang Sinochem Agrochemicals R&D Co. Ltd

94

(Shenyang, China).

95

The general synthetic methods for compounds 1-37 are shown in Figures 2, 3

96

and 5-9 and their structures are listed in Tables 1-4. The silica gel

97

chromatography was performed with a column of 254 mm x 26 mm i.d.

98

(Synthware glass Co. Ltd., Beijing, China) using 100-140 mesh silica gel

99

(Sinopharm Chemical reagent Co. Ltd., Shanghai, China).

100

Synthesis of

101

5-chloro-N-((6-(4-chlorophenoxy)pyridin-3-yl)methyl)-6-ethylpyrimidin-4-

102

amine, 26. (General procedure for compounds 1, 2, 25 and 26) (Figure 2)

5



Page 6 of 41

103

Synthesis of 6-(4-chlorophenoxy)nicotinonitrile (M-1, R = Cl)

104

Sodium hydride (1.03 g, 70%, 30 mmol) was added into a solution of

105

4-chlorophenol (2.57 g, 20 mmol) in 30 mL of DMF, the reaction mixture was

106

stirred

107

6-chloronicotinonitrile (2.76 g, 20 mmol), and then the reaction mixture was

108

heated to 100 oC for another 10 h. After reaction completion, the mixture was

109

poured into water and extracted with ethyl acetate. The extract was dried over

110

anhydrous magnesium sulfate and concentrated under reduced pressure to

111

give intermediate M-1 as a pale brown solid: 4.27 g (93%).

112

Synthesis of (6-(4-chlorophenoxy)pyridin-3-yl)methanamine (M-2, R = Cl)

113

To a solution of M-1 (2.31 g, 10 mmol), Raney nickel (1.0 g) and 10 mL of 25%

114

aqueous ammonia in 50 mL ethanol, hydrogen was introduced, then the

115

reaction mixture was stirred at room temperature for 3-15 h and monitored by

116

TLC until the reaction was complete, Raney nickel was filtered, and the

117

solution was concentrated under reduced pressure to give M-2 as a jade-green

118

sticky liquid: 2.55 g (95%).

119

To a solution of M-2 (0.24 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5

120

mmol) in 10 mL DMF was added 4,5-dichloro-6-ethylpyrimidine (0.16 g, 1.0

121

mmol), prepared according to literature methods.21,22 Then the reaction

122

mixture was heated to 80 oC for 2 h, and monitored by TLC until the reaction

123

was complete. The reaction mixture was poured into water and extracted with

124

ethyl acetate. The organic phase was washed successively with water and

at

room

temperature

for

4

h,

followed

6


by

addition

of

Page 7 of 41


125

saturated brine, dried, filtered and evaporated under reduced pressure. The

126

residue was purified via silica gel chromatography with ethyl acetate/60-90 °C

127

petroleum ether (1:3, v/v) as eluent to obtain 0.28 g compound 26 as a white

128

solid: 0.28 g (75%), m.p. 86 oC. 1H NMR (300MHz, CDCl3) δ 1.31 (t, J=7.5Hz,

129

3H, CH2CH3), 2.80 (q, 2H, CH2CH3), 4.68 (d, J=6.0 Hz, 2H, CH2), 5.71 (bs, 1H,

130

NH), 6.91 (d, J=8.4Hz, 1H, pyridine 3-H), 7.07 (d, J=8.7Hz, 2H, Ph-2,6-2H),

131

7.34 (d, J=8.7Hz, 2H, Ph-3,5-2H), 7.72 (dd, J=8.4,2.7Hz, 1H, pyridine 4-H),

132

8.16 (s, 1H, pyridine 6-H), 8.44 (s, 1H, pyrimidine 2-H). Anal. Calcd (%) for

133

C18H16Cl2N4O: C, 57.61; H, 4.30; N, 14.93. Found: C, 57.53; H, 4.33; N, 14.89.

134

HRMS m/z 374.0698 [M + H]+ (calcd [M + H]+ 374.0701).

135

Synthesis of

136

5-chloro-N-(2-(6-(4-chlorophenoxy)pyridin-3-yl)ethyl)-6-methylpyrimidin-

137

4-amine, 9. (General procedure for compounds 3-24) (Figure 3)

138

Synthesis of methyl 6-(4-chlorophenoxy)nicotinate (M-3, R = Cl)

139

To a solution of 4-chlorophenol (25.6 g, 0.2 mol) in 350 mL DMF was added

140

70% sodium hydride (103 g, 3.0 mol) in portions. The reaction mixture was

141

stirred for 4 h at room temperature, and then methyl 6-chloronicotinate (34.2 g,

142

0.2 mol) was added in portions. Next the reaction temperature was raised to

143

100 oC and maintained for 10 h, and monitored by TLC until the reaction was

144

complete. The resulting solution was poured into water and extracted with

145

ethyl acetate. The organic phase was successively washed with water and

146

saturated brine, dried, filtered and evaporated under reduced pressure, the

7



147

cooled residue was filtered and washed with petroleum ether, to obtain

148

intermediate M-3 as a brown solid: 42.0 g, m.p. 65 oC.

149

Synthesis of (6-(4-chlorophenoxy)pyridin-3-yl)methanol (M-4, R = Cl)

150

To a solution of M-3 (52.6 g, 0.2 mol) in 500 mL anhydrous ether was added

151

dropwise 65% Red-Al (74.5 g, 0.24 mol) in toluene at 0 oC. The reaction

152

mixture was stirred for 4 h at room temperature, cooled to 0 oC, and 10%

153

sodium hydroxide solution prepared fresh was added dropwise until the

154

reaction solution was clarified. Then the reaction temperature was raised to 35

155

o

C to react for 2 h, and monitored by TLC until the reaction was complete. The

156

solution was poured into water and extracted with ethyl acetate. The organic

157

phase was successively washed with water and saturated brine, dried, filtered

158

and evaporated under reduced pressure. The residue was purified via silica

159

gel chromatography with ethyl acetate/60-90 °C petroleum ether (1:3, v/v) as

160

eluent to obtain M-4 as a white solid: 42.2 g, m.p. 101 oC.

161

Synthesis of 5-(chloromethyl)-2-(4-chlorophenoxy)pyridine (M-5, R = Cl)

162

To a solution of M-4 (23.5 g, 0.1 mol) in 350 mL dichloromethane was

163

dropwise added thionyl chloride (17.9 g, 0.15 mol) at 0 oC. The reaction

164

mixture was stirred for 4 h at room temperature, and monitored by TLC until

165

the reaction was complete, excess thionyl chloride was evaporated and the

166

residue was poured into water and extracted with ethyl acetate. The organic

167

phase was successively washed with water, saturated sodium bicarbonate

168

solution and saturated brine, dried, filtered and evaporated under reduced

8


Page 8 of 41

Page 9 of 41


169

pressure, to obtain M-5 as a white solid: 22.8 g, m.p. 79 oC.

170

Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)acetonitrile (M-6, R = Cl)

171

To a solution of sodium cyanide (2.69 g, 55 mmol) dissolved in 300 mL

172

dimethyl sulfoxide was added M-5 (13.9 g, 50 mmol) and 18-Crown-6 (0.69 g,

173

2.63 mmol) at 40 °C. The reaction mixture was raised to 80 oC to react for 2 h,

174

and monitored by TLC until the reaction was complete. The residue was

175

poured into water, extracted with toluene, the organic phase was successively

176

washed with water and saturated brine, dried, filtered and evaporated under

177

reduced pressure. The residue was purified via silica gel chromatography with

178

ethyl acetate/60-90 °C petroleum ether (1:3, v/v) as eluent to obtain M-6 as a

179

white solid: 11.2 g, m.p. 101 oC.

180

Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)ethanamine (M-7, R = Cl)

181

To a solution of M-6 (2.44 g, 10 mmol), Raney nickel (1.0 g) and 10 mL of 25%

182

aqueous ammonia in 50 mL ethanol was introduced hydrogen gas, then the

183

reaction mixture was stirred at room temperature for 3-15 h and monitored by

184

TLC until the reaction was complete. Raney nickel was filtered, and the

185

solution was concentrated under reduced pressure to give M-7 as a jade-green

186

sticky liquid: 2.30 g (95%).

187

To a solution of M-7 (0.25 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5

188

mmol) in 10 mL DMF was added 4,5-dichloro-6-methylpyrimidine (0.16 g, 1.0

189

mmol). Then the reaction temperature was raised to 80 oC and maintained for

190

2 h, and monitored by TLC until the reaction was complete. The mixture was

9



191

poured into water and extracted with ethyl acetate. The organic phase was

192

successively washed with water and saturated brine, then dried, filtered and

193

evaporated under reduced pressure. The residue was purified via silica gel

194

chromatography with ethyl acetate/60-90 °C petroleum ether (1:4, v/v) as

195

eluent to obtain compound 9 as a colorless oil: 0.28 g (74%). 1H NMR

196

(300MHz, CDCl3) δ 2.46 (s, 3H, CH3), 2.91 (t, J=6.9Hz, 2H, CH2CH2NH), 3.75

197

(q, 2H, CH2CH2NH), 5.43 (bs, 1H, NH), 6.89(d, J=8.4Hz, 1H, pyridine 3-H),

198

7.07 (d, J=6.6Hz, 2H, Ph-2,6-2H), 7.35 (d, J=6.6Hz, 2H, Ph-3,5-2H), 7.58 (dd,

199

J=8.4,2.7Hz, 1H, pyridine 4-H), 8.03 (s, 1H, pyridine 6-H), 8.39 (s, 1H,

200

pyrimidine 2-H). Anal. Calcd (%) for C18H16Cl2N4O: C, 57.61; H, 4.30; N, 14.93.

201

Found: C, 57.59; H, 4.26; N, 14.99. HRMS m/z 374.0694 [M + H]+ (calcd [M +

202

H]+ 374.0701).

203

The crystal structure of target compound 9 was also determined by X-ray

204

diffraction analyses. Its crystal structure is shown in Figure 4.

205

Synthesis of

206

5-chloro-4-((6-(4-chlorophenoxy)pyridin-3-yl)methoxy)-6-methylpyrimidin

207

e, 27. (General procedure for compounds 27 and 28) (Figure 5)

208

To a solution of (6-(4-chlorophenoxy)pyridin-3-yl)methanol (M-4) (0.23 g, 1.0

209

mmol) and potassium carbonate (0.21 g, 1.5 mmol) in 10 mL DMF was added

210

4,5-dichloro-6-methylpyrimidine (0.16 g, 1.0 mmol). Then the reaction

211

temperature was raised to 80 °C and maintained for 2 h, and monitored by TLC

212

until the reaction was complete. The mixture was poured into water and

10


Page 10 of 41

Page 11 of 41


213

extracted with ethyl acetate. The organic phase was successively washed with

214

water and saturated brine, dried, filtered and evaporated under reduced

215

pressure. The residue was purified via silica gel chromatography with ethyl

216

acetate/60-90 °C petroleum ether (1:4, v/v) as eluent to obtain compound 27

217

as a colorless oil: 0.28 g (77%). 1H NMR (300MHz, CDCl3) δ 2.43 (s, 3H, CH3)

218

5.07 (s, 2H, CH2), 6.92 (d, J=8.4Hz, 1H, pyridine 3-H), 7.06 (d, J=8.4Hz, 2H,

219

Ph-2,6-2H), 7.35 (d, J=8.4Hz, 2H, Ph-3,5-2H), 7.81 (dd, J=8.4,2.1Hz, 1H,

220

pyridine 4-H), 8.06 (s, 1H, pyridine 6-H), 8.17 (s, 1H, pyrimidine 2-H). Anal.

221

Calcd (%) for C17H13Cl2N3O2: C, 56.37; H, 3.62; N, 11.60. Found: C, 56.42; H,

222

3.59; N, 11.68. HRMS m/z 361.0391 [M + H]+ (calcd [M + H]+ 361.0385).

223

Synthesis of

224

N-(1-(6-(4-(tert-butyl)phenoxy)pyridin-3-yl)ethyl)-5-chloro-6-ethylpyrimidi

225

n-4-amine, 30. (General procedure for compounds 29 and 30) (Figure 6)

226

Compound 30 was obtained according to a literature method as a colorless oil

227

in 49% yield.23 1H NMR (300MHz, CDCl3) δ 1.26 (t, J=7.5Hz, 3H, CH2CH3),

228

1.33 (s, 9H, t-Bu), 1.61 (d, J=6.9Hz, 3H, CHCH3), 2.78 (q, 2H, CH2CH3), 5.36

229

(q, 1H, CHCH3), 5.52 (bs, 1H, NH), 6.87 (d, J=8.4Hz, 1H, pyridine 3-H), 7.05 (d,

230

J=6.9Hz, 2H, Ph-2,6-2H), 7.39 (d, J=6.9Hz, 2H, Ph-3,5-2H), 7.67 (dd,

231

J=8.4,2.7Hz, 1H, pyridine 4-H), 8.22 (s, 1H, pyridine 6-H), 8.39 (s, 1H,

232

pyrimidine 2-H). Anal. Calcd (%) for C19H19ClN4O: C, 64.31; H, 5.40; N, 15.79.

233

Found: C, 64.22; H, 5.44; N, 15.80. HRMS m/z 410.1878 [M + H]+ (calcd [M +

234

H]+ 410.1873).

11



Page 12 of 41

235

Synthesis

236

1-(5-chloro-6-methylpyrimidin-4-yl)-3-(2-(6-(4-chlorophenoxy)pyridin-3-yl)

237

ethyl)urea, 31. (Figure 7)

238

Synthesis of 2-(4-chlorophenoxy)-5-(2-isocyanatoethyl)pyridine (M-10)

239

To a 0 oC solution of triphosgene (3.5 mL) in dichloromethane (25 mL) and

240

saturated NaHCO3 (25 mL) was added

241

2-(6-(4-chlorophenoxy)-pyridin-3-yl)ethanamine (M-7) (0.74 g, 3.0 mmol). The

242

reaction mixture was stirred at room temperature for 2.5 h and then the layers

243

are separated. The organic layer was dried over anhydrous MgSO4 and

244

concentrated under reduced pressure to half volume. Dichloromethane (20 mL)

245

was added to obtain M-10 as a solution in dichloromethane.

246

To a 0 oC solution of 5-chloro-6-methylpyrimidin-4-amine (0.28 g, 2.0 mmol) in

247

dichloromethane (5 mL) was added isocyanate M-10 prepared above and then

248

N,N-diisopropylethylamine (DIPEA) (3 mL).24 The reaction mixture was stirred

249

at room temperature for 1 h and then diluted with ethyl acetate and washed

250

with saturated NH4Cl and brine. The organic layer was dried over anhydrous

251

MgSO4, filtered and concentrated under reduced pressure. The residue was

252

purified via silica gel chromatography with ethyl acetate/60-90 °C petroleum

253

ether (1:2, v/v) as eluent to obtain compound 31 as a white solid: 0.33 g (40%).

254

1

of

H NMR (300MHz, CDCl3) δ 2.48 (s, 3H, CH3), 2.73 (t, J=6.9Hz, 2H,

255

NHCH2CH2), 3.46-3.51 (m, 2H, NHCH2CH2), 4.92(bs, 1H, NHCH2CH2), 6.85 (d,

256

J=8.4Hz, 1H, pyridine 3-H), 7.03 (d, J=8.1Hz, 2H, Ph-2,6-2H), 7.33 (d, J=8.1Hz,

12


Page 13 of 41


257

2H, Ph-3,5-2H), 7.54 (d, J=7.2Hz, 1H, pyridine 4-H), 7.96 (s, 1H, pyridine 6-H),

258

8.32 (s, 1H, pyrimidine 2-H). Anal. Calcd (%) for C19H19ClN4O: C, 64.37; H,

259

5.30; N, 15.79. Found: C, 64.31; H, 5.40; N, 15.79. HRMS m/z 417.0755 [M +

260

H]+ (calcd [M + H]+ 417.0759).

261

Synthesis

262

5-Chloro-N-(2-(2-(4-chlorophenoxy)pyridin-3-yl)ethyl)-6-ethylpyrimidin-4-

263

amine, 35. (General procedure for compounds 32-35) (Figure 8)

264

The procedures for preparing intermediates (M-11 to M-15) and desired

265

compound 35 were analogous to those for the corresponding intermediates

266

(M-3 to M-7) and compound 9, only replacing the starting materials, methyl

267

6-chloronicotinate

268

2-chloronicotinate (1.71 g, 10 mmol) and 4,5-dichloro-6-ethylpyrimidine (1.76 g,

269

10 mmol) respectively.

270

5-Chloro-N-(2-(2-(4-chlorophenoxy)pyridin-4-yl)ethyl)-6-ethylpyrimidin-4-

271

amine, 37. (General procedure for compounds 36 and 37) (Figure 9)

272

The procedures for preparing intermediates (M-16 to M-20) and desired

273

compound 37 were analogous to those for the corresponding intermediates

274

(M-3 to M-7) and compound 9, only replacing the starting materials, methyl

275

6-chloronicotinate

276

2-chloroisonicotinate

277

4,5-dichloro-6-ethylpyrimidine(1.76 g, 10 mmol) respectively.

278

Fungicidal assay

of

and

and

4,5-dichloro-6-methylpyrimidine,

4,5-dichloro-6-methylpyrimidine, (1.86

g,

10

13


with

with

mmol)

methyl

ethyl and


279

Each of the test compounds (4 mg) was first dissolved in 5 mL

280

acetone/methanol (1:1, v/v), then 5 mL of water containing 0.1% Tween 80

281

was added to generate a 10 mL stock solution of concentration 400 mg/L.

282

Serial test solutions were prepared by diluting the above solution (testing

283

range 3.13-400 mg/L).

284

Evaluations of fungicidal activity of the synthesized compounds against

285

cucumber downy mildew (CDM) was performed as follows: cucumber seeds

286

(Cucumis sativus L.) were grown to the one-leaf and one-heart stage, then the

287

test solution was sprayed on the host plant with a home-made sprayer. After

288

24 h, the leaf of host plant was inoculated with Sporangium suspension of the

289

fungus Pseudoperonospora cubensis cultured by Shenyang Sinochem

290

Agrochemicals R&D Co. Ltd. (Shenyang, China) at a concentration of 5x105

291

spores/mL using PS289 Procon Boy WA double action 0.3 mm airbrush (GSI,

292

Tokyo, Japan). The cucumber plants were stored in a humidity chamber (24±1

293

o

C, RH>95%, dark) and then transferred into a greenhouse (18-30 oC,

294

RH>50-60%) 24 h after infection. Three replicates were carried out. The

295

activity of each compound was estimated by visual inspection after 7 d and

296

screening results were reported in the range 0% (no control) to 100%

297

(complete control). The inhibitory activity (%) was estimated as: [(viability of

298

the blank control-viability of the treatment) / viability of the blank control] x 100.

299

The ED50 values were calculated by Duncan's new multiple range method

300

using DPS version 14.5.

14


Page 14 of 41

Page 15 of 41


301

The fungicidal test results of compounds 1-37 against CDM are listed in Tables

302

1-4.

303

RESULTS AND DISCUSSION

304

Synthesis. According to the schemes shown in Figures 2-9, 37 title

305

compounds were synthesized with yields of 40-80%. Chemical structures of

306

compounds 1-37 are shown in Tables 1-4. The synthesized compounds were

307

characterized by 1H NMR and elemental analyses/HRMS. The chemical

308

structure of lead compound 9 was unequivocally determined by x-ray

309

crystallography (Figure 4). All spectral and analytical data were consistent with

310

the assigned structures.

311

Structure-Activity Relationships (SAR).

312

Discovery of lead compounds 3 and 4

313

Initially, in order to verify the feasibility of our design concept, mimicking the

314

skeleton of diflumetorim, the starting materials, phenol and

315

6-chloronicotinonitrile, were employed to obtain the key intermediate

316

(6-phenoxypyridin-3-yl)methanamine, from which we obtained compounds 1

317

and 2. These compounds can be considered as diflumetorim analogs in which

318

the phenyl moiety is replaced with a pyridinyl moiety. The bioassay results

319

indicated that the synthesized compounds had activity against four important

320

fungal diseases, CDM, cucumber grey mold (CGM), wheat powdery mildew

321

(WPM) and southern corn rust (SCR),25 particularly against CDM. The activity

322

of compound 1 (R1 = CH3) against CDM was very weak (EC50 > 400 mg/L)

15



323

compared with diflumetorim (EC50 = 23.06 mg/L), however, compound 2 (R1 =

324

C2H5) displayed activity equal to diflumetorim (EC50 = 23.17 mg/L). On the

325

basis of these results, CDM was selected as the test target for optimization.

326

Next, taking inspiration from the structure of insecticide flufenerim, which is

327

similar to diflumetorim,26 we synthesized compounds 3 and 4 with Alk =

328

CH2CH2 (Table 1). These two compounds exhibited higher fungicidal activity

329

than the corresponding analogs with Alk = CH2 (7.33 mg/L and 7.02 mg/L

330

respectively versus 23.06 mg/L), which encouraged us to synthesize additional

331

analogs.

332

Optimization of lead compounds 3 and 4

333

Using compounds 3 and 4 as a starting point for additional analogs, we next

334

turned our attention to modifications in the phenyl ring including changes of

335

substituent position, numbers of substituents, the electronic properties and

336

spatial characteristics of the substituent groups (Table 2). First, six compounds,

337

5-10, were synthesized to evaluate the position effect of the substituent on

338

fungicidal activity using the chlorine atoms as probes. When a single chlorine

339

was present in the ortho-position of phenyl ring (compounds 5 and 6), there

340

was no improvement in fungicidal activity. When a single chlorine was present

341

in the meta-position of phenyl ring (compounds 7 and 8), the fungicidal activity

342

decreased significantly. When a single chlorine was present in the

343

para-position (compounds 9 and 10), we observed a significant increase in

344

fungicidal activity; compounds 9 and 10 gave much lower EC50 values of 0.19

16


Page 16 of 41

Page 17 of 41


345

mg/L and 2.65 mg/L, respectively, versus initial leads 3 and 4 (7.33 mg/L and

346

7.02 mg/L), especially compound 9 displayed superior control to the

347

commercial fungicides flumorph and cyazofamid, indicating that single

348

substitution at the para-position probably has a positive effect on bioactivity.

349

Next, we further selected typical electron-donating groups CH3 and OCH3, and

350

electron-withdrawing group CF3 to carry out some fine modification on

351

para-position of phenyl ring to investigate the electronic properties of

352

substituents. We synthesized six compounds, 11 and 12 with the electron

353

donating group (CH3), 13 and 14 with the electron donating group (OCH3), 15

354

and 16 with the electron withdrawing group (CF3) respectively (Table 2). The

355

bioassay results showed that these six compounds 11 to 16 were less

356

efficacious than compounds 9 and 10 (3.13 - 11.65 mg/L versus 0.19 mg/L,

357

2.65 mg/L), indicating that higher electron donating or withdrawing group has

358

possibly a negative effect on bioactivity. Then in order to assess the effect of

359

substituent numbers specifically relating to double substituted phenyl on

360

fungicidal activity, we employed some low cost and commonly used phenol

361

intermediates bearing two substituents to prepare compounds 17 to 24 (Table

362

2). Compound 18 with Rn of 2-CH3-4-Cl showed low fungicidal activity with

363

30.25 mg/L EC50 and the other compounds of this type 17, 19 to 23 were also

364

less active, with EC50 values ranging from 3.75 mg/L to 10.44 mg/L. However,

365

compound 24 (Table 2) with Rn = 2-Cl-4-CF3 showed promising activity (EC50

366

of 1.10 mg/L) which is approaching of compound 9 and may be considered for

17



367

exploring new compounds with improved activity. So far, the result of the

368

optimization of compounds 3 and 4 is identification of compound 9 with para-Cl

369

group on phenyl ring as the optimized structure, the third lead compound with

370

greatly improved fungicidal activity.

371

Effect of linker between pyrimidine and pyridine groups on fungicidal

372

activity

373

To determine if changing the linker between pyrimidine and pyridine groups

374

(X-Alk) would bring enhanced fungicidal activity, we synthesized and screened

375

a series of compounds 25 to 31 (Table 3). When CH2CH2 was replaced with

376

CH2 on Alk and keeping the X group fixed as NH, both compounds 25 which

377

gave EC50 of 7.91 mg/L and 26 which showed EC50 of 5.79 mg/L were much

378

less efficacious than compound 9 which gave EC50 of 0.19 mg/L. These results

379

were consistent with the conclusion obtained above. When introducing O-CH2

380

into X-Alk instead of NH-CH2CH2, both compounds 27 and 28 exhibited a

381

sharply reduced efficacy compared with the lead compound 9 (more than 400

382

mg/L for compound 27, 137.8 mg/L for compound 28 versus 0.19 mg/L for

383

compound 9). The branched Alk in diflumetorim was employed in compounds

384

29 and 30 with Alk = CH(CH3). The replacement of CH2 with CH(CH3) did not

385

enhance fungicidal activity. The introduction of t-Bu into the para-position on

386

phenyl suggests that the presence of a group with large spatial effect probably

387

leads to considerable reduction in activity. A possible explanation for the lower

388

activity associated with large substituents is that such substituents would block

18


Page 18 of 41

Page 19 of 41


389

the interaction of target enzyme with these bulky compounds.10 Additionally,

390

we considered a urea bridge, an extensively utilized moiety in herbicides.3c We

391

designed NH(CO)NH substructure for X group based on compound 9 to

392

achieve compound 31. However, disappointedly, compound 31 had hardly any

393

fungicidal activity with a very high EC50 value of more than 400 mg/L.

394

Activity of different position of pyrimidinamine group attached to

395

pyridine ring

396

To investigate the effect of different position of pyrimidinamine group attached

397

to pyridine ring on the activity of intact molecules, six positional isomers were

398

designed and synthesized (Table 4). Generally speaking, when

399

pyrimidinamine group was attached to the 3-position of the pyridine ring

400

(compounds 32 to 35), the fungicidal activity indicated the lowest, followed by

401

4-position analogues 36 and 37, showing obviously higher activity especially

402

compound 36 with EC50 of 6.49 mg/L, but still much lower than compound 9. In

403

addition, we noted that compounds with CH3 on R1 were much more active in

404

contrast with their counterparts of C2H5 in this series. The poor results of

405

compounds 32-37 in Table 4 suggested that when the pyrimidinamine group

406

was attached to the pyridine ring at 3- or 4-position, the fungicidal activity

407

diminished dramatically in this class of compounds.

408

Based on data presented in Tables 1-4, a clear-cut, well-defined relationship

409

between chemical structure and biological activity has taken shape by

410

examining the effect of the substituted position, the numbers of substituents,

19



411

the electronic properties and spatial characteristics of the substituent groups

412

on phenyl ring, linker between pyrimidine and pyridine groups, and the

413

different position of pyrimidinamine group attached to pyridine ring. The

414

para-position single chlorine substituted phenyl derivative, compound 9,

415

showed significantly improved fungicidal activity compared to the

416

commercialized controls. Compound 24 with Rn of 2-Cl-4-CF3 is a good

417

candidate for further exploration of new compounds with improved activity.

418

Variation in the linker between pyrimidine and pyridine groups did not enhance

419

fungicidal activity, while the 5-position where pyrimidinamine group is attached

420

to pyridine ring provided optimal activity.

421

From the above we can conclude that compound 9 is the optimal structure with

422

desired activity. It offers a control with EC50 value of 0.19 mg/L against CDM,

423

significantly higher than commercial fungicides diflumetorim, flumorph and

424

cyazofamid. Compound 9, which has also shown activities against CSR, WPM

425

and RB in addition to CDM,25 is a promising candidate for further development.

426

This study demonstrates the effectiveness of our design concept by using

427

intermediate derivatization method to discover bioactive compounds. The

428

discovery of new pyrimidinamine fungicides may delay the development of

429

resistance and contribute to resistance management. Further synthesis of

430

analogs, structure optimization studies and field trials of compound 9 are in

431

progress.

432

20


Page 20 of 41

Page 21 of 41


433

ACKNOWLEDGEMENT

434

We thank Dr. Mark Dekeyser (Canada) for assistance with manuscript

435

preparation.

436 437

SUPPORTING INFORMATION

438

Characterization for intermediates M-1, 3-7, 11-20, and compounds 1-8, 10-25,

439

28, 29, 32-37. This material is available free of charge via the Internet at

440

http://pubs.acs.org. The atomic coordinates for compound 9 have been

441

deposited at the Cambridge Crystallographic Data Centre. CCDC ID: 1501756

442

contains the supplementary crystallographic data for this paper. These data

443

can be obtained free of charge from The Cambridge Crystallographic Data

444

Centre via www.ccdc.cam.ac.uk/data_request/cif.

445 446

AUTHOR INFORMATION

447

Corresponding Author

448

*(M.W.) Tel: +86-(0)10-62734093. E-mail: [email protected].

449

*(C.L.) Tel: +86-(0)24-85869078. Fax: +86-(0)24-85869137. E-mail:

450

[email protected].

451

21



452

REFERENCES

453

(1) Mcdougall, P. Phillips McDougall AgriService; Phillips McDougall

454

AgriService: Midlothian, UK, May 2016; p 219.

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(3) (a) Liu, C. L. World Compendium of Fungicides; Chemical Industry Press:

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Beijing, China, 2006. (b) World Compendium of Insecticides; Chemical

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Industry Press: Beijing, China, 2012. (c) World Compendium of Herbicides;

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Chemical Industry Press: Beijing, China, 2002.

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Bioorg. Med. Chem. 2016, 24, 342–353.

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(5) Liu, C. L. Proceedings of Research and Development of New

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Agrochemicals; Chemical Industry Press Publishers: Beijing, 2002; pp 93-94.

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(6) Liu, C. L.; Guan, A. Y.; Yang, J, D.; Chai, B. S.; Li, M.; Li, H. C.; Yang, J. C.;

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Xie. Y. Efficient approach to discover novel agrochemical candidates:

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intermediate derivatization method. J. Agric. Food Chem. 2016, 64, 45-51.

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(7) Guan, A. Y.; Liu, C. L.; Yang, X. P.; Dekeyser, M. Application of the

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intermediate derivatization approach in agrochemical discovery. Chem. Rev.

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2014, 114, 7079-7107.

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(8) Liu, C. L. Approach and application of novel agrochemical innovation. Chin.

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(9) Liu, C. L. New agrochemical candidates from intermediate derivatization

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Wang, J. K., Ed.; Chemical Industry Press Publishers: Beijing, China, 2009; pp

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86-94.

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(10) Guan, A. Y.; Liu, C. L.; Huang, G.; Li, H. C.; Hao, S. L.; Xu, Y.; Li, Z. N.

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Design, synthesis, and structure-activity relationship of novel aniline

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derivatives of chlorothalonil. J. Agric. Food Chem. 2013, 61, 11929−11936.

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(11) Xie, Y.; Chi, H. W.; Guan, A. Y.; Liu, C. L.; Ma, H. J.; Cui, D. L. Design,

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synthesis,

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3-(pyridin-2-yl)benzenesulfonamide derivatives. J. Agric. Food Chem. 2014,

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62, 12491-12496.

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(12) Li, M.; Liu, C. L.; Yang, J. C.; Zhang, J. B.; Li, Z. N.; Zhang, H.; Li, Z. M.

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Synthesis and biological activity of new (E)-α-(methoxyimino)benzeneacetate

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derivatives containing a substituted pyrazole ring. J. Agric. Food Chem. 2010,

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58, 2664-2667.

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(13) Yang, J. C.; Li, M.; Wu, Q.; Liu, C. L.; Chang, X. H. Design, synthesis and

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insecticidal evaluation of aryloxy dihalopropene derivatives. Bioorg. Med.

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Chem. 2016, 24, 383-390.

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(14) Xie, Y.; Chi, H. W.; Guan, A. Y.; Liu, C. L.; Ma, H. J.; Cui, D. L. Synthesis

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novel

substituted


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and evaluation of substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives

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as potent herbicidal agents. Bioorg. Med. Chem. 2016, 24, 428-434.

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(15) Li, H. C.; Guan, A. Y.; Huang, G.; Liu, C. L.; Li, Z. N.; Xie, Y.; Lan, J.

499

Design, synthesis and structure-activity relationship of novel diphenylamine

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derivatives. Bioorg. Med. Chem. 2016, 24, 453-461.

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(16) Guan, A.Y.; Liu, C. L.; Li, M.; Zhang, H.; Li, Z. N.; Li, Z. M. Design,

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synthesis and structure-activity relationship of novel coumarin derivatives. Pest

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Manag. Sci. 2011, 67, 647-655.

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(17) Chai, B. S.; Liu, C. L.; Li, H. C.; He, X. M.; Luo, Y. M.; Huang, G.; Zhang,

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H.; Chang, J. B. Design, synthesis and acaricidal activity of novel strobilurin

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derivatives containing pyrimidine moieties. Pest Manag. Sci. 2010, 66,

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1208-1214.

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(18) Chai, B. S.; Liu, C. L.; Li, H. C.; Zhang, H.; Liu, S. W.; Huang, G.; Chang, J.

509

B. The discovery of SYP-10913 and SYP-11277: novel strobilurin acaricides.

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Pest Manag. Sci. 2011, 67, 1141-1146.

511

(19) Li, M.; Liu, C. L.; Li, L.; Yang, H.; Li, Z. N.; Zhang, H.; Li, Z. M. Design,

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synthesis and biological activities of new strobilurin derivatives containing

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substituted pyrazoles. Pest Manag. Sci. 2010, 66, 107-112.

514

(20) Li, M.; Liu, C. L.; Zhang, J.; Wu, Q.; Hao, S. L.; Song, Y. Q. Design,

515

synthesis and structure-activity relationship of novel insecticidal

516

dichloro-allyloxy-phenol derivatives containing substituted pyrazol-3-ols. Pest

517

Manag. Sci. 2013, 69, 635-641.

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(21) Liu, C. L.; Sun, X. F.; Zhao, J.; Wang, L. Z.; Li, K. K.; Zhang, J. B.; Chen, X.

519

M.; Guan, A. Y.; Song, Y. Q.; Lan, J.; Ma, S.; Ru, L. J. Pyrazolyl pyrimidinamine

520

compound and application thereof. PCT Int. Appl. WO 2015085935, June 18,

521

2015.

522

(22) Wang, L. Z.; Sun, X. F.; Lan, J.; Zhang, J. B.; Wang, B.; Guan, A. Y.; Zhou,

523

J. Z.; Yang, F.; Song, Y. Q.; Liu, C. L. Substituted pyrimidinamine compound

524

and uses thereof. CN Patent 104292169, Jan 21, 2015.

525

(23) Drumm, J. E. III.; Lett, R. M.; Stevenson, T. M. Preparation of fungicidal

526

and miticidal and arthropodicidal aminopyrimidine agrochemicals. PCT Int.

527

Appl. WO 9507278, Mar 16, 1995.

528

(24) Barlaam, B.; Fennell, M.; Germain, H.; Green, T.; Hennequin, L.;

529

Morgentin, R.; Olivier, A.; Ple, P.; Vautier, M.; Costello, G. New heterocyclic

530

analogues

531

selective c-Src kinase inhibitors. Bioorg. Med. Chem. Lett. 2005, 15,

532

5446-5449.

533

(25) Guan, A. Y.; Yang, F.; Wang, J. F.; Chen, W.; Fan, X. X.; Wang, X. L.; Chen,

534

X, M.; Li, K. K.; Li, Z. N.; Liu, C. L. Substituted aryloxyl pyridine compound and

535

uses thereof. CN Patent 105732585, July 6, 2016.

536

(26) Ghanim, M.; Lebedev, G.; Kontsedalov, S.; Ishaaya, I. Flufenerim, a novel

537

insecticide acting on diverse insect pests: biological mode of action and

538

biochemical aspects. J. Agric. Food Chem. 2011, 59, 2839-2844.

of

4-(2-chloro-5-methoxyanilino)quinazolines

25


as

potent

and


539

FIGURE CAPTIONS

540 541

Figure 1. An overview of the design of new pyrimidinamine derivatives

542

containing an aryloxy pyridine moiety

543

Figure 2. Synthetic route to compounds 1, 2, 25 and 26

544

Figure 3. Synthetic route to compounds 3-24

545

Figure 4. X-ray single-crystal diffraction of compound 9.

546

Figure 5. Synthetic route to compounds 27 and 28

547


548

Figure 7. Synthetic route to compound 31

549

Figure 8. Synthetic route to compounds 32-35

550


26


Page 26 of 41

Page 27 of 41


TABLES Table 1. Chemical Structures and Fungicidal Activity of Pyrimidinamine Derivatives Containing Aryloxy Pyridine Moiety (compounds 1 to 4)

a

compound

R1

Alk

EC50 (mg/L)

95% da

1

CH3

CH2

>400

/b

2

C2H5

CH2

23.17

15.86-33.86

3

CH3

CH2CH2

7.33

3.33-16.12

4

C2H5

CH2CH2

7.02

3.12-15.80

diflumetorim

23.06

16.13-32.95

flumorph

7.77

6.48-9.32

cyazofamid

1.01

0.62-1.63

confidence limit. b the value could not be measured accurately.

27



Page 28 of 41

Table 2. Chemical Structures and Fungicidal Activity of Pyrimidinamine Derivatives Containing Aryloxy Pyridine Moiety (compounds 5 to 24)

a

EC50 (mg/L)

95% da

H

7.33

3.33-16.12

C2H5

H

7.02

3.12-15.80

5

CH3

2-Cl

13.10

3.27-52.39

6

C2H5

2-Cl

26.40

17.75-39.26

7

CH3

3-Cl

>400

/b

8

C2H5

3-Cl

>400

/b

9 (Lead 3)

CH3

4-Cl

0.19

0.14-0.26

10

C2H5

4-Cl

2.65

1.61-4.35

11

CH3

4-CH3

3.13-6.25

/b

12

C2H5

4-CH3

5.50

3.57-8.50

13

CH3

4-OCH3

5.54

3.75-8.16

14

C2H5

4-OCH3

11.65

9.26-14.66

15

CH3

4-CF3

3.13-6.25

/b

16

C2H5

4-CF3

3.13-6.25

/b

17

CH3

2-CH3-4-Cl

9.44

3.34-26.65

18

C2H5

2-CH3-4-Cl

30.25

19.62-46.65

19

CH3

2,4-Cl2

9.11

3.15-26.35

20

C2H5

2,4-Cl2

10.44

3.93-27.72

21

CH3

2,5-Cl2

6.61

4.67-9.37

22

C2H5

2,5-Cl2

3.75

2.33-6.04

23

CH3

2-Cl-4-CF3

6.47

4.57-9.16

24

C2H5

2-Cl-4-CF3

1.10

0.80-1.52

diflumetorim

23.06

16.13-32.96

flumorph

7.77

6.48-9.32

cyazofamid

1.01

0.62-1.63

compound

R1

Rn

3 (Lead 1)

CH3

4 (Lead 2)

confidence limit. b the value could not be measured accurately. 28


Page 29 of 41


Table 3. Chemical Structures and Fungicidal Activity of Pyrimidinamine Derivatives containing Aryloxy Pyridine Moiety (compounds 25 to 31)

compound

R1

X

Alk

R

EC50 (mg/L)

95% da

9 (Lead 3)

CH3

NH

CH2CH2

Cl

0.19

0.14-0.26

25

CH3

NH

CH2

Cl

7.91

3.97-15.77

26

C2H5

NH

CH2

Cl

5.79

4.02-8.36

27

CH3

O

CH2

Cl

>400

/b

28

C2H5

O

CH2

Cl

137.84

51.51-368.85

29

C2H5

NH

CH(CH3)

H

18.76

11.87-29.66

30

C2H5

NH

CH(CH3) t-Bu

69.54

40.44-119.59

31

CH3

NH(CO)NH

CH2CH2

>400

/b

diflumetorim

23.06

16.13-32.96

flumorph

7.77

6.48-9.32

cyazofamid

1.01

0.62-1.63

a

Cl


29



Page 30 of 41

Table 4. Chemical Structures and Fungicidal Activity of Pyrimidinamine Derivatives containing Aryloxy Pyridine Moiety (compounds 32 to 37) R1 Cl

N

4 N

N H

3

O N

5

R

compound

R1

position of pyrimidinamine group attached to pyridine ring

9 (Lead 3)

CH3

5-position

Cl

0.19

0.14-0.26

10

C2H5

5-position

Cl

2.65

1.61-4.35

32

CH3

3-position

H

60.84

44.32-83.53

33

C2H5

3-position

H

326.58 179.20-595.16

34

CH3

3-position

Cl 232.59 177.24-305.23

35

C2H5

3-position

Cl

>400

/b

36

CH3

4-position

Cl

6.49

2.45-17.19

37

C2H5

4-position

Cl

92.14

71.00-119.57

diflumetorim

23.06

16.13-32.96

flumorph

7.77

6.48-9.32

cyazofamid

1.01

0.62-1.63

a

R

EC50 (mg/L)

95% da


30


Page 31 of 41


FIGURE GRAPHICS

Figure 1

R

O

O

Cl

NC

N R=ClCH2 or COOH

N

starting material

N H3C F

HN

OCF3 Cl N H

Cl

key intermediate

CH3

N

F N

H3C

insecticide flufenerim

O

F

N

fungicide diflumetorim

R1

high active compounds

R1

Cl

N N

X

N

H2N

optimization

O

Alk N

Rn

Cl

N N

N H

O N

lead compounds

31



Page 32 of 41

Figure 2

HO NC

Cl

NaH/DMF, 100 oC

N

R1

R1

N

Cl

N N

N H

NC

R

R

N O

N

R

N O

Cl Cl

K2CO3/DMF 80 oC

[M-1]

Raney-Ni/ NH3.H2O/ethanol room temperature H2N

[H]

R

N O [M-2]

Compounds 1, 2, 25 and 26

32


Page 33 of 41


Figure 3

HO O H3C

O

Rn

O

H3C

N

O

N

Rn

o

Cl

NaH/DMF, 100 C

O [M-3] anhydrous ether/ Red-Al toluene, 0 oC

Cl

N

Rn O

SOCl2

HO

N

CH2Cl2, 0 oC

Rn O

[M-5] 18-Crown-6/ DMSO, 40 oC NC

[M-4]

NaCN

[H]

N

Rn O [M-6]

H2N

N

Raney-Ni/ NH3.H2O/ethanol room temperature

O Cl N

Cl

N

[M-7]

R1 N

R1

Rn

Cl

K2CO3/DMF 80 oC N

O Rn

N

N H

Compounds 3-24

33



Figure 4

34


Page 34 of 41

Page 35 of 41


Figure 5

35



Page 36 of 41

Figure 6

CH3

HO

O

CH3

R

O

N K2CO3/DMF, 100 oC

Cl

O

R1

R1 Cl

N N

Cl

N

N H

N

CH3 R

N O

R

N

Cl

CH3

[M-8]

CH3COONH4 /sodium cyanoborohydride /methanol room temperature

K2CO3/DMF H2N 80 oC

R

N O [M-9]

Compounds 29 and 30

36


Page 37 of 41


Figure 7

37



Page 38 of 41

Figure 8

H3C

O

O

R H3C

HO

O

O O

Cl o

NaH/DMF, 100 C

N

HO Red-Al

O

anhydrous ether/toluene R 0 oC [M-11]

N

N

R [M-12]

CH2Cl2, 0 oC SOCl2 NH2

NC [H] O N

[M-15]

R1

K2CO3/DMF N 80 oC N N

Cl O

NaCN 18-Crown-6/ R DMSO 40 oC [M-14]

Raney-Ni/ N NH3.H2O/ R ethanol room temperature Cl Cl

N

R1

NH Cl O N

R

Compounds 32-35

38


O N

R [M-13]

Page 39 of 41


Figure 9

H 3C

HO

O

Cl H C 3

Cl

O

O

O

NaH/DMF 100 oC

N

O N

OH

Red-Al

O

anhydrous Cl ether/toluene 0 oC [M-16]

N

Cl [M-17]

CH2Cl2, 0 oC H 2N

[H] O N [M-20]

K2CO3/DMF N 80 oC

R1

Raney-Ni/ NH3.H2O/ ethanol room temperature

O N

NaCN 18-Crown-6/ Cl DMSO 40 oC [M-19]

Cl N

R1

Cl

CN

Cl

Cl

N N

NH Cl N

O

Compounds 36 and 37

39


SOCl2

Cl O N

Cl [M-18]


GRAPHIC FOR TABLE OF CONTENTS

40


Page 40 of 41

Page 41 of 41


CH3

O R N

R=ClCH2 or COOH

Cl

N

Cl H 2N

N

Cl

N

N H

O N

Compound 9

Cl

Intermediate Derivatization Method COMPOUND EC50 (mg/L) against CDM Compound 9 0.19 Diflumetorim 23.06 Flumorph 7.77 Cyazofamid 1.01


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