Chapter 23

Pyrimidine Fungicides: A New Class of Broad

Spectrum Fungicides

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Publication Date: May 14, 1998 | doi: 10.1021/bk-1998-0686.ch023

Zen-Yu Chang, PamelaJ.Delaney, John O'Donoghue, and RuPing Wang

Agricultural Products, Stine-Haskell Research Center, duPont and Company,
Building 300, Newark, DE 19714

Broad spectrum fungicidal activities were shown by a class of

pyrimidines substituted with nitrogen heterocycles. Biological data,
synthesis, and structure-activity relationships are discussed
The discovery of fungicidal activity of compounds 1, 2 (7) and 3 (Ferimzone) (2)
prompted us to undertake a major research program to explore the structure-activity of
this class of chemistry. Based on the common structural features of these three
compounds, we designed compounds represented by the general structure 4. We have
focused our optimization effort in the -ring, B-ring and the aromatic or benzyl
moieties shown in structure 4. Many of the compounds represented by 4 provided
100% control of economically important diseases such as wheat foot rot, wheat glum
blotch, andriceblast in our discovery screens at a 200 PPM rate. Several compounds
proved sufficiently active that they were evaluated in field tests to assess the potential
for commercial development.

1
228

n = 0, 1
4

1998 American Chemical Society

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

229
Synthesis

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Synthesis of different sub-classes of compounds of generic structure 4 will be

discussed. The -ring and the aromatic moiety come primarilyfromcommercial
sources and do not warrant much discussion. Rather, we will concentrate our
discussion in the variation of B-ring. Pyrazolines 5 with a 5-membered -ring were
prepared by condensation of the corresponding heterocyclic hydrazines with
substituted 3-chloropropiophenones or 3-N,N-dimethylpropiophenones (Scheme 1). 3N, N-Dimethy lpropiophenones were prepared via the Mannich reaction (3).

5
Scheme 1
Tetrahydropyridazines 6 with a 6-membered B-ring were prepared by
condensation of the hydrazines with substituted 4-chlorobutyrophenones. FriedelCrafts acylation of substituted benzenes with 4-chlorobutyrl chloride provided the
requisite butyrophenones (Scheme 2).

Scheme 2
1,4-Dihydropyridazines 7 were prepared by condensation of the pyrimidinylhydrazines with benzoylpropionic acids to give pyridazinones. Reduction with one
equivalent of lithium aluminum hydride (4) gave the intermediate aminal. Subsequent
treatment with methanesulfonyl chloride in pyridine afforded the desired 1,4dihydropyridazines 7 (Scheme 3).

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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230

Scheme 3
The synthesis of 1,6-dihydropyridazines is shown in Scheme 4. Condensation
of the pyrimidinylhydrazines with ,-diketones gave the corresponding hydrazones
as mixtures of E/Z isomers. Treatment of the mixtures with sodium hydride followed
by addition of vinyltriphenylphosphonium bromide (5) provided the 1,6-dihydro
pyridazines 8. The latter cyclization reaction did not work when the R group was 2pyridyl or 2-furanyl.

Bf
Scheme 4

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

231

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For the synthesis of 7-membered B-rings tetrahydrodiazepines 9, condensation

of the pyrimidinylhydrazines with substituted 5-chlorovalerophenones was followed
by treatment with sodium hydride (Scheme 5).

Scheme 5
The preparation of pyrazolines 5 in which the phenyl group is replaced by a
benzyl group is shown in Scheme 6. The requisite chloroketones were prepared by
coupling reactions between benzyl bromide and 3-chloropropionyl chloride catalyzed
by a palladium reagent and zinc powder (<5). Subsequent condensation with the
pyrimidinylhydrazine provided the desired benzylpyrazolines 10.

10
Scheme 6

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

232

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When condensations carried out using 5-chloro-l -pheny 1-2-pentanone prepared

analogously according to the butanones of Scheme 6 and 2,6-dimemylpyrimidinyl
hydrazine, the desired benzylpyridazine 11 was not isolated. Instead, cyclic hydrazine
12 with an exocyclic double bond was isolated (Scheme 7).

12
Scheme 7
Biological Data
The fungicidal activities of these compounds are shown in the Tables I-IV. The
Tables show preventive control though some of these compounds also demonstrated
curative efficacy (data not shown). The greenhouse disease control data were used to
develop structure-activity relationships. Many heterocycles in place of the pyrimidine
were also prepared via Schemes 1-6. These heterocycles include pyridine,
quinazoline, benzothiazole, benzoxazole, and pyridazine. The activities of these
compounds were generally less than those of the corresponding pyrimidines and the
data is not presented.
Structure-Activity Relationships
For the -ring, pyrimidine gave the best activity. For substitution on the pyrimidine
ring, 4,6-dimethyl- was better than 4-methyl and unsubstituted pyrimidine in overall
fungicidal activity when the rest of the molecules are otherwise the same.

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

233
For the B-ring, tetrahydropyridazines (Table II) gave better activity than
pyrazolines (Table I) and tetrahydrodiazepines (Table III). Among the 6-member
rings, the 1,4,5,6-tetrahydropyridazine ring was better than the two types of dihydropyridazines (Table IV)
In the pyrazoline series, the methylene group between the aromatic ring and firing afforded compounds at comparable fungicidal activities to those without the
methylene. However, since the synthesis was more difficult, only a few compounds
were prepared (Table I).

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Table I. Biological data

Percent Disease Control at 200 PPM

#
1

2
3
4
5
6
7
8
9
10
11
12

Ri

Me
Me
Me
Me
Me
Me

Me
Me
Me
H
Me
Me

R
H
Me
Me
Me
Me
Me
Me
Me
H
H
H
Me
2

R
H
H
H
H
H
H
H
H
Me
H
H
H
3

n
0
0
0
0
0
0
0
0
0
1
1
1

Ar
1-naphthalenyl
1-naphthalenyl
2-Me-Ph
2-CI-Ph
3-CI-Ph
3-Me-Ph
4-Me-Ph
2-OMe-Ph
Ph
3-Me-Ph
3-Me-Ph
3-Me-Ph

WPM WLR
NT
NT
25
85
62
92
84
90
95
63
53
20
45
39
28
36
91
99
89
96
89
98
98
98

WFR WGB RCB

86
100
100
96
NT
100
87
100
NT
62
NT
100
NT
99
75
100
93
100
NT
100
96
84
100
NT
NT
NT
NT
0
93
0
74
49
97
61
100
91

NT - Not Tested.

WPM
WLR
WFR
WGB
RCB

Wheat Powdery Mildew (Erysiphe graminis)

Wheat Leaf Rust (Puccinia recondita)
Wheat Foot Rot (Pseudocercosporella herpotrichoides)
Wheat Glum Blotch (Septoria nodorum)
Rice Blast (Pyricularia oryzae)

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

234
For the aromatic group, phenyl appeared to be superior to heterocyclic
aromatic groups. In the tetrahydropyridazine series (Table II), alkyl and halo
substitutions on the phenyl ring were better than alkoxy and trifluoromethyl groups in
overall activities. A methyl or ethyl group as R group in the structure shown in Table
II also improved the activity. Compound 14 from Table II was the most active
compound and was therefore tested in the field. Unfortunately, the promising
greenhouse activity of this class of chemistry was not maintained in the field.

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Table II. Biological data

Ri

Ar

Percent Disease Control at 200 PPM

#

R,

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19

Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me

R
R
H
H
Me H
Me H
Me H
Me H
Me H
Me H
Me H
Me H
Me H
Me H
Me H
Me H
Me Me
Me Me
Me Et
Me Me
Me H
Me H
2

Ar
Ph
Ph
4-F-Ph
3-CI-Ph
4-CI-Ph
4-OH-Ph
4-OMe-Ph
4-OPh-Ph
2-Me-Ph
3-Me-Ph
4-Me-Ph
4-n-Pr-Ph
4-teff-Bu-Ph
Ph
Ph
Ph
3-Me-Ph
3-CF -Ph
2-thienyl
3

WPM WLR WFR WGB RCB

NT
NT
88
97
100
60
62
NT
96
99
61
NT
NT
89
38
98
97
92
100
21
100
100
91
100
100
NT
91
57
NT
79
66
100
99
85
98
90
72
100
86
79
90
87
100
80
41
94
100
85
99
98
74
97
100
89
100
92
98
99
99
100
NT
99
83
97
100
99
98
67
59
100
99
98
67
59
100
93
95
62
100
93
96
99
99
77
100
35*
71*
0* 100*
53*
57
46
100
100
67

* indicate disease control at 40 PPM.

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

235
Table III. Biological data

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Percent Disease Control at 200 PPM

WPM WLRWFRWGB RCB

X
1
2
3
4

4-CI
4-OMe
4-Me
H

89
60
79
96

83
66
70
83

100
39
41
33

*95
99
100
100

71
73
82
83

* indicate disease control at 40 PPM.

Table IV. Biological data

For compounds # 1 -4

#
1
2
3
4
5
6
7
8
9
10

For compounds # 5-7

For compounds #8-10

Percent Disease Control at 200 PPM

X
WPM WLR WFR WGB RCB

R
H
H
H
H
H
H
4-Me-Ph
Ph
4-Me-Ph
4-OMe-Ph

H
4-Me
4-OMe
3,4-diMe
H
3,4-diMe
4-Me
H
4-Me
4-OMe

96
89
66
91
0
60
57
24
NT
84

99
100
98
98
97
83
0
77
80
88

62
74
85
NT
0
0
0
0
48
61

NT
97
100
100
3
95
0
78
58
35

60
100
99
90
13
67
0
24
32
0

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

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236
Conclusions
The pyrimidinyltetrahydropyridazines discussed demonstrated broad spectrum of
fungicidal activity, especially against wheat foot rot, wheat glum blotch and rice blast,
in the greenhouse. Dimethyl substitution on the pyrimidinyl group boosted the
fungicidal activity. The greenhouse activity was not maintained in the field.
Acknowledgments

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The authors wish to thank those biologists who contributed to this work. We would
also like to thank John Daub, Ed Adams, Debbie Frasier and Simon Xu for sharing
ideas in this area of chemistry.
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Schweizer, E. E.; Kopay, C. M. J. Org. Chem. 1972, 37, 1561.
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In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 1998.