Synthesis of benzylaminopyrimidines and their fungicidal activities against wheat brown rust and barley powdery mildew

Article abstract of DOI:10.1002/(SICI)1096-9063(1998110)54:3<223::AID-PS814>3.0.CO;2-R

Members of a new class of fungicide containing benzyl-aminopyrimidine as a core structure were synthesized and their fungicidal potencies against wheat brown rust, Puccinia recondita, and barley powdery mildew, Erysiphe graminis, were assessed. Among these fungicides, N-(fluoroalkoxy or fluorophenoxybenzyl)-4-pyrimidinamines showed notable preventive activities. The potency of the new pyrimidines was increased when a difluoromethoxy or tetrafluorophenoxy group was introduced at the 4- or 3-position of the phenyl moiety and a methyl or ethyl group was introduced at the benzyl position. Structure-activity relationships are discussed.

Full text of DOI:10.1002/(SICI)1096-9063(1998110)54:3<223::AID-PS814>3.0.CO;2-R

Pestic. Sci. 1998, 54, 223È229
Synthesis of Benzylaminopyrimidines and Their
Fungicidal Activities against Wheat Brown Rust
and Barley Powdery Mildew
Yoshinori Yamanaka,1 Masaru Moritomo,1 Katsutoshi Fujii,1 Toshinobu
Tanaka,1 Yasuhisa Fukuda1 & Keiichiro Nishimura2*
1 Ube Laboratory, Ube Industries, Ltd., Ube, Yamaguchi 755-8633, Japan
2 Research Institute for Advanced Science and Technology, Osaka Prefecture University, Sakai, Osaka
599-8570, Japan
(Received 15 May 1998; accepted 16 July 1998)
Abstract: Members of
a
new class of fungicide containing benzyl-
aminopyrimidine as a core structure were synthesized and their fungicidal
potencies against wheat brown rust, Puccinia recondita, and barley powdery
mildew, Erysiphe graminis, were assessed. Among these fungicides, N-
(Ñuoroalkoxy or Ñuorophenoxybenzyl)-4-pyrimidinamines showed notable pre-
ventive activities. The potency of the new pyrimidines was increased when a
diÑuoromethoxy or tetraÑuorophenoxy group was introduced at the 4- or 3-
position of the phenyl moiety and a methyl or ethyl group was introduced at the
benzyl position. StructureÈactivity relationships are discussed. ( 1998 Society of
Chemical Industry
Pestic. Sci., 54, 223È229 (1998)
Key words: benzylaminopyrimidines; wheat brown rust; barley powdery
mildew; fungicides
1
INTRODUCTION
We have found N-benzyl-4-pyrimidinamines to have
a broad spectrum of pesticidal activity.5 Among them,
compounds with a Ñuoroalkoxy or Ñuorophenoxy
group on the phenyl ring have highly fungicidal activity.
Some of them have potent preventive and therapeutic
activities against wheat brown rust and barley powdery
mildew. Here we describe the synthesis and the
structureÈactivity relationship of this class of fungicides.
A number of fungicides with speciÐc modes of action
have been developed. Sterol 14a-demethylation inhibi-
tors (DMIs), including azole fungicides, a type of sterol
biosynthesis inhibitor (SBI), are the largest group of
modern fungicides.1
In the last two decades, the development of resistance
to these compounds has severely hampered the chemi-
cal control of fungi. Resistance to DMIs is one of the
most crucial topics, and compounds with alternative
modes of action are sought. For example, amine-type
fungicides such as fenpropimorph and fenpropidin are a
class of SBI, and their modes of action are di†erent
from those of DMIs.2,3 A new class of carbocation-
mimetic ergosterol biosynthesis inhibitor has also been
reported.4 These fungicides can be used as substitutes
for DMIs.
2
MATERIALS AND METHODS
2.1 Compounds
The test compounds are listed in Tables 1È4. Their
structures were conÐrmed by 270 MHz-[1H]NMR
spectroscopy (GX270, JEOL, Tokyo, Japan) in deutero-
chloroform using tetramethylsilane as the internal stan-
dard or by mass spectroscopy (M-80, Hitachi, Tokyo,
Japan). Melting points were measured with a melting
* To whom correspondence should be addressed.
223
( 1998 Society of Chemical Industry. Pestic. Sci. 0031È613X/98/$17.50. Printed in Great Britain

224
Y oshinori Y amanaka et al.
TABLE 1
E†ects of Substituents on the Pyrimidine Ring (R and R ) and at the Benzyl Position (R )
1
2
3
on Preventive Activities against Wheat Brown Rust and Barley Powdery Mildew
Substituents
pI (M)
4
Compound
Position of
m.p. (¡C) or
(at ¡C)
No.
R
R
R
OC F
n
W BRa
BPMb
1
2
3
6 5
D
1
2
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
i-Pr
Cl
Cl
Me
Et
F
F
Cl
Cl
Cl
F
Cl
Cl
Cl
Br
Cl
Me
Me
Cl
Cl
Me
Et
H
Me
Et
Me
Me
Et
i-Pr
Et
Me
H
Et
Me
Me
4
4
4
4
4
4
4
4
4
4
4
4
4
3
3
117È119
1É5400 (26)
110È115
90È91
118È121
88È91
88È89
57È59
1É5401 (24)
86È88
4É15
2É93
\3É00c
3É33
3É35
4É93
4É65
3É96
3É59
3É40
3É16
\3É00c
\3É00c
3É68
4É92
4É09
3É46
4É97
3É04
4É93
5É35
4É66
4É15
3É40
3É96
\3É00d
\3É00c
4É09
3
4
5
6
7
8
9
10
11
12
13
14
15
62È65
128È132
120È125
1É5580 (22)
1É5522 (24)
3É95
4É75
a Wheat brown rust (Puccinia recondita).
b Barley powdery mildew (Erysiphe graminis).
c Rating 0 at the indicated concentration.
d Rating 2 at the indicated concentration.
TABLE 2
point apparatus (Buchi 535, Flawil, Switzerland).
Refractive indexes were measured with a refractometer
(3T, Atago-Abbe, Tokyo, Japan). Elemental analyses
were in accordance with the proposed structures.
E†ects of Para Substituents on the TetraÑuorophenoxy
Moiety on Preventive Activities against Wheat Brown Rust
and Barley Powdery Mildew
2.1.1 4-(2,3,5,6-T etraÑuorophenoxy)- and 3- or
4-(pentaÑuorophenoxy)benzylaminopyrimidines (1–23)
The synthetic routes for compounds 1–23 are shown in
Fig. 1. Typical examples of synthetic procedures are
described below.
pI (M)
4
Compound
m.p. (¡C) or
(at ¡C)
2.1.1.1 a-[RS]Ethyl-4-hydroxybenzylamine (a; R \
3
C H ; 4-OH). A solution of 4-hydroxypropiophenone
2 5
No.
R
n
W BRa
BPMb
4
D
(100 g; 0É67 mol), hydroxylamine hydrochloride (55 g;
16
8
H
F
CHF
CF
CHO
Ac
CH(OCH )
CN
NO
1É5518 (22)
57È59
1É5454 (22)
58È61
1É5734 (24)
1É5592 (24)
1É5589 (24)
1É5677 (24)
1É5712 (24)
4É03
3É96
3É99
4É04
4É66
4É69
4É23
3É51
3É5 mol) and potassium acetate (69 g; 0É7 mol) dis-
solved in a mixture of ethanol (80 ml) and water (20 ml)
was reÑuxed for 6 h. After cooling, most of the ethanol
was removed under reduced pressure. The residual solu-
tion was extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate. On concen-
tration, 4-hydroxypropiophenone oxime a†orded
colourless crystals, which was used for the next reaction
without further puriÐcation. Yield, 45 g (44%).
17
18
19
20
21
22
23
2
3É41
3
\3É00c
\3É00c
\3É00d
\3É00d
\3É00d
3É38
\3É00c
\3É00c
\3É00d
2 2
2
a Wheat brown rust (Puccinia recondita).
b Barley powdery mildew (Erysiphe graminis).
c Rating 2 at the indicated concentration.
d Rating 0 at the indicated concentration.
The oxime (30 g; 0É18 mmol) and 5%-palladium
carbon (5 g; N. E. Chemcat. Co., Tokyo, Japan) were

Fungicidal activities of benzylaminopyrimidines
225
TABLE 3
E†ects of Substituents on the Pyrimidine Ring (R ) and at the Benzyl Position (R )
1
3
and of the Position of the OCHF Group on Preventive Activities against Wheat
2
Brown Rust and Barley Powdery Mildew
Substituents
pI (M)
4
Compound
Position of
m.p. (¡C) or
(at ¡C)
No.
R
R
OCHF
n
W BRa
BPMb
1
3
2
D
24
25
26
27
28
29
Me
Me
Et
Et
Me
Me
Me
Me
Me
Me
Et
3
4
3
4
2
4
1É5538 (23)
56È58
1É5471 (23)
1É5442 (20)
1É5456 (18)
1É5471 (24)
4É80
4É20
4É82
4É82
3É05
4É54
3É36
4É20
3É82
4É82
3É36
4É22
Et
a Wheat brown rust (Puccinia recondita).
b Barley powdery mildew (Erysiphe graminis).
placed with concentrated hydrochloric acid (5 ml) and
ethanol (100 ml) in a 300-ml stainless steel autoclave.
Hydrogen gas was introduced into the vessel. The inter-
nal pressure was kept at 30 kg cm~2 by the intro-
duction of the gas during the reaction. After being
maintained at 50¡C for 5 h, the mixture was Ðltered and
the Ðltrate was concentrated in vacuo. Distillation of the
residue gave 21 g (79% yield) of the desired product as a
colourless crystal. M.p. 163È165¡C (ref. 6, m.p. 167¡C).
[1H]NMR (d ppm): 1É25 (3H, t, J \ 8 Hz), 2É80 (2H, q,
J \ 8 Hz), 4É20 (1H, m), 6É92 (2H, d, J \ 8 Hz), 7É52
(2H, d, J \ 8 Hz), 7É68 (2H, m).
2.1.1.2 5-Chloro-6-ethyl-N-(a-[RS]ethyl-4-hydroxy-
benzyl)pyrimidin-4-amine (b; R \ Cl, R \ R \ C H ;
2
1
3
2 5
4-OH). To a solution of a-[RS]ethyl-4-hydroxybenzyl-
amine (5É0 g; 33 mmol), triethylamine (7É3 g; 72 mmol)
and 4,5-dichloro-6-ethylpyrimidine7h10 (7É0 g; 40 mmol)
in ethanol (50 ml), a catalytic amount of 4-(N,N-
dimethylamino)pyridine was added. The mixture was
reÑuxed for 8 h. After cooling, the ethanol was removed
under reduced pressure. The residue was dissolved in
toluene (30 ml) and extracted with sodium hydroxide
solution (80 g litre~1; 50 ml). The aqueous layer was
made neutral by the slow addition of hydrochloric acid
(2 M; 50 ml). The solution was extracted with ethyl
acetate and dried over sodium sulfate. By removing the
solvent under reduced pressure, the desired product
(5 g, 52%) was obtained as colourless crystals. M.p.
133È135¡C. [1H]NMR (d ppm): 0É94 (3H, t, J \ 7 Hz),
1É26 (3H, q, J \ 7 Hz), 1É92 (2H, m), 2É83 (2H, m),
5É08 (1H, q, J \ 7 Hz), 5É72 (1H, d, J \ 7 Hz), 6É81
(1H, m), 7É18 (2H, d, J \ 8 Hz), 7É32 (2H, d, J \
8É8 Hz), 8É40 (1H, m).
TABLE 4
E†ects of Substituents on the Pyrimidine (R ) and Phenyl (R )
1
4
Rings on Preventive Activities against Wheat Brown Rust
and Barley Powdery Mildew
Substituents
pI (M)
4
Compound
m.p. (¡C)
No.
R
R
or n (at ¡C)
W BRa BPMb
1
5
D
25
30
31
32
33
34
27
35
36
37
38
39
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
H
3-Cl
3-OMe
3-OCHF
3,5-(Me)
2-F
H
3-Cl
3-OMe
3-OCHF
3,5-(Me)
56È58
4É20
4É24
4É30
4É02
3É36
4É82
4É82
4É26
4É85
4É13
4É25
4É84
4É20
2É84
3É64
4É61
4É23
3É92
4É82
2É86
4É55
4É64
4É45
4É24
1É5536 (25)
1É5498 (24)
1É5246 (24)
1É5510 (25)
71È72
1É5442 (20)
1É5397 (23)
1É5458 (24)
1É5218 (24)
1É5456 (24)
1É5343 (26)
2
2.1.1.3 5-Chloro-6-ethyl-N-[a-[RS]ethyl-4-(2,3,5,6-
2
tetraÑuorophenoxy)benzyl]pyrimidin-4-amine (16).
A
solution of 5-chloro-6-ethyl-N-(a-[RS]ethyl-4-hydroxy-
benzyl)pyrimidin-4-amine (2É0 g; 6É9 mmol) and pot-
assium hydroxide (0É6 g; 10 mmol) dissolved in N,N-
dimethylformamide (50 ml) was held at 50¡C for 30 min
under stirring. The solution was allowed to cool to
room temperature, pentaÑuorobenzene (2É3 g; 14 mmol)
was added and the mixture held at room temperature
2
2
Et
2-F
a Wheat brown rust (Puccinia recondita).
b Barley powdery mildew (Erysiphe graminis).

226
Y oshinori Y amanaka et al.
Fig. 1. Synthetic routes for compounds 1È23.
for 4 h. The mixture was poured into water and
extracted with toluene. The organic layer was washed
with water and dried over anhydrous sodium sulfate.
Toluene was evaporated under reduced pressure. The
residue was puriÐed by column chromatography on
silica gel with toluene ] ethyl acetate (10 ] 1 by
N-dimethylamino)pyridine was added. The mixture was
reÑuxed for 8 h. After cooling, the reaction mixture was
washed with water, and the organic layer was dried
over anhydrous sodium sulfate. After the removal of the
solvent under reduced pressure, the residue was puriÐed
by column chromatography (Wako Gel C200) using
toluene ] ethyl acetate (5 ] 1 by volume) as an eluent
to give 2É0 g (42% yield) of the desired product as
colourless crystals. M.p. 57È59¡C, [1H]NMR (d ppm):
0É95 (3H, t, J \ 7É6 Hz), 1É25 (3H, q, J \ 7É2 Hz), 1É90
(2H, m), 2É78 (2H, q, J \ 7É2 Hz), 5É12 (1H, q,
J \ 7É2 Hz), 5É58 (1H, m), 6É92 (2H, d, J \ 8É8 Hz), 7É28
(2H, d, J \ 8É8 Hz), 8É37 (1H, s). CI-MS m/e: 458, 428.
Compounds 1È7, 9È15 and 17È23 were prepared by
similar procedures. Their physical properties are listed
in Tables 1 and 2.
volume) to give 1É8 g (60% yield) of light yellow oil. N22
D
1É5518. [1H]NMR (d ppm): 0É95 (3H, t, J \ 8 Hz), 1É24
(3H, t, J \ 8 Hz), 1É92 (2H, q, J \ 8 Hz), 2É81 (2H, q,
J \ 8 Hz), 5É14 (1H, q, J \ 8 Hz), 5É58 (1H, m), 6É92
(2H, d, J \ 8 Hz), 7É15 (1H, m), 7É29 (2H, d, J \ 8 Hz),
8É38 (1H, s). [19F]NMR (d ppm): [153É0 (2F, s),
[138É7 (2F, s).
2.1.1.4 a-[RS]Ethyl-4-pentaÑuorophenoxybenzylamine
(c; R \ C H ; R \ F; 4-O-PhF ). A solution of 4-
3
2 5
4
5
pentaÑuorophenoxypropiophenone5 (10 g; 32 mmol),
ammonium acetate (15 g; 195 mmol) and sodium
cyanoborohydride (1É5 g; 24 mmol) dissolved in ethanol
(100 ml) was stirred at 50¡C for 5 h. After the solution
was cooled, concentrated hydrochloric acid (40 ml) was
added and the ethanol was removed under reduced
pressure. The residue was made alkaline by the addition
of sodium hydroxide solution (80 g litre~1; 250 ml) and
was then extracted with toluene. After the removal of
the solvent under reduced pressure, the resultant oil was
puriÐed by column chromatography (Gel C-200, Wako,
Osaka, Japan) with toluene ] ethyl acetate ] ethanol
(5 ] 5 ] 1 by volume) to give the desired product (4 g,
39% yield) as a colourless oil. CI-MS m/e: 318, 301, 273.
EI-MS m/e: 301, 288.
2.1.2 DiÑuoromethoxybenzylaminopyrimidines (24È39)
The synthetic routes for 4-diÑuoromethoxybenzyl-
aminopyrimidines are shown in Fig. 2. Typical exam-
ples of synthetic procedures are described below.
2.1.2.1 4-DiÑuoromethoxypropiophenone ( f; R \
3
C H ; R \ H; 4-OCHF ). 4-Hydroxypropiophenone
2 5
5
2
(72 g; 480 mmol), chlorodiÑuoromethane (49É4 g;
571 mmol), potassium carbonate (66 g; 480 mmol) and
N,N-dimethylformamide (120 ml) were placed in a
300 ml-stainless steel autoclave and maintained at
100¡C for 3 h while stirring. After cooling, the reaction
mixture was poured into water. The mixture was
extracted with toluene and the organic layer was
washed three times with water. The solution was dried
over anhydrous sodium sulfate and concentrated in
vacuo. Distillation of the residue gave 40 g (42% yield)
of the desired product as a colourless oily product,
which became solid. M.p. 40É0È41É5¡C. [1H]NMR (d
ppm): 1É14 (3H, t, J \ 8É0 Hz), 2É80 (2H, q, J \ 7É2 Hz),
2.1.1.5 5-Chloro-6-ethyl-N-(a-[RS]ethyl-4-pentaÑuoro-
phenoxybenzyl)pyrimidin-4-amine (8). To a solution of
4,5-dichloro-6-ethylpyrimidine (2É1 g; 12 mmol), a-[RS]
ethyl-4-pentaÑuorophenoxybenzylamine
(3É5 g;
11 mmol) and triethylamine (1É5 g; 15 mmol) in N,N-
dimethylformamide (10 ml), a catalytic amount of 4-(N,

Fungicidal activities of benzylaminopyrimidines
227
Fig. 2. Synthetic routes for compounds 24È39.
6É49 (1H, t, J \ 74 Hz), 7É14 (2H, d, J \ 8É8 Hz), 7É34
(2H, d, J \ 8É8 Hz).
(100 ml) in the presence of Raney nickel (4 g), alu-
minium hydroxide (6 g; 77 mmol) and hydrogen gas.
Yield 2É13 g, 20%.
2.1.2.2 4-DiÑuoromethoxypropiophenone oxime (g;
R \ C H ; R \ H; 4-OCHF ). To a solution of 4-
Method 3. 4-DiÑuoromethoxypropiophenone (12 g;
60 mmol), liquid ammonia (12 g; 710 mmol), stabilized
Raney nickel (12É0 g; Nikki Chem Co., Tokyo, Japan,
N-103) and methanol (48 ml) were placed in a 300-ml
stainless steel autoclave, and heated with stirring for 3 h
at 120¡C. Hydrogen gas was then introduced into the
vessel to give the pressure of 40 kgf cm~2. The internal
pressure was kept constant by the introduction of
further hydrogen gas during the reaction. After being
stirred at 100¡C for 3 h, the mixture was Ðltered and the
Ðltrate was concentrated in vacuo. The residue was dis-
solved in toluene (30 ml) and extracted with hydro-
chloric acid (2 M, 36 ml). The aqueous layer was made
alkaline by the slow addition of sodium hydroxide
(3É17 g; 79 mmol). The layer was extracted with toluene.
Removal of the solvent under reduced pressure gave the
desired product (11É7 g; 97%) as a colourless oily
product.
3
2 5
5
2
diÑuoromethoxypropiophenone (400 g; 2É0 mol) and
hydroxylamine hydrochloride (222 g; 3É2 mol) dissolved
in ethanol (1 litre) and water (240 ml), sodium hydrox-
ide (280 g litre~1; 500 ml) was slowly added. The
resulting mixture was stirred at 60¡C for 4 h, the
ethanol was then removed under reduced pressure, and
the residue extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate. On con-
centration, it a†orded colourless crystals. They were
puriÐed by washing with hexane to give colourless crys-
tals (271 g, 63%). M.p. 78È80¡C. [1H]NMR (d ppm):
1É17 (3H, t, J \ 8É0 Hz), 2É80 (2H, q, J \ 8É0 Hz), 6É53
(1H, t, J \ 73É6 Hz), 7É46 (2H, d, J \ 8É8 Hz), 7É62 (2H,
d, J \ 8É8 Hz), 8É64 (1H, m).
2.1.2.3 a-[RS]Ethyl-4-diÑuoromethoxybenzylamine (h;
R \ C H ; R \ H; 4-OCHF ).
3
2 5
5
2
Method 1: 4-DiÑuoromethoxypropiophenone oxime
(910 g; 4É2 mol), Raney nickel (128 g; Kawaken Fine
Chem. Co., Tokyo, Japan, NDT-65), ethanol (6 litres),
and liquid ammonia (719 g; 42 mol) were placed in a
20-litre stainless steel autoclave. Hydrogen gas was
introduced into the vessel, and the internal pressure was
kept at 20 kg cm~2 by the introduction of further gas
during the reaction. After being kept at 100¡C for 7 h,
the mixture was cooled and Ðltered, and the Ðltrate was
concentrated in vacuo. Distillation of the residue gave
780 g (92% yield) of the desired product as a colourless
oil. B.p. 101¡C/5 mm Hg. [1H]NMR (d ppm): 0É85 (3H,
t, J \ 7É8 Hz), 1É65 (4H, m), 3É84 (1H, q, J \ 5É8 Hz),
6É48 (1H, t, J \ 72É5 Hz), 7É09 (2H, d, J \ 8É7 Hz), 7É30
(2H, d, J \ 8É7 Hz).
2.1.2.4 5-Chloro-6-methyl-N-(a-[RS]ethyl-4-diÑuoro-
methoxybenzyl)pyrimidin-4-amine (29). To a solution of
a-[RS]ethyl-4-diÑuoromethoxybenzylamine
(1É0 g;
5É0 mmol), triethylamine (0É73 g; 7É2 mmol) and 4,5-
dichloro-6-methylpyrimidine11 (0É9 g; 5É5 mmol) in
toluene (20 ml), a catalytic amount of 4-(N,N-dimethyl-
amino)pyridine was added. The mixture was reÑuxed
for 8 h. After cooling, the reaction mixture was washed
with water, and the organic layer was dried over anhy-
drous sodium sulfate. After the removal of the solvent
under reduced pressure, the residue was puriÐed by
column chromatography (Wako Gel C200) using
toluene ] ethyl acetate (5 ] 1 by volume) as an eluent
to give 1É1 g (67% yield) of a colourless oily product.
n24 1É5518. [1H]NMR (d ppm): 0É95 (3H, t,
D
Method 2. Using similar procedures to those of method
1, the desired product was prepared from 4-
diÑuoromethoxypropiophenone (10É8 g; 54 mmol) and
liquid ammonia (11É8 g; 700 mmol) in methanol
J \ 7É2 Hz), 1É25 (2H, q, J \ 7É2 Hz), 2É45 (3H, s), 5É12
(1H, q, J \ 7É2 Hz), 5É59 (1H, d, J \ 7É6 Hz), 6É49 (1H,
t, J \ 74 Hz), 7É08 (2H, d, J \ 8É8 Hz), 7É32 (2H, d,
J \ 8É8 Hz), 8É13 (1H, s).

228
Compounds 24È28 and 30È39 were prepared by
similar procedures. Their physical properties are listed
in Tables 3 and 4.
Y oshinori Y amanaka et al.
Marchal. One week later, the symptoms of the Ðrst leaf
were examined. The activity rankings of the test chemi-
cals were deÐned in the same way as for the activity
against wheat brown rust. The test was done with at
least two pots for each concentration of each com-
2.2 Biological tests
pound, as for the wheat brown rust. The pI values
4
were calculated as for the wheat brown rust and are
2.2.1 Preventive activity against wheat brown rust
listed in Tables 1È4.
In a plastic planting pot (6 cm diam. ] 10 cm), 10
wheat seedlings (T riticum aestivum L.) were grown at
28¡C. At the 1É5-leaf stage (on average) aqueous suspen-
sions of wettable powders of the test compounds at
given concentration were sprayed over the plants. Two
days later, the wheat plants were inoculated by a spore
suspension of wheat brown rust, Puccinia recondita
Rob. ex Desm., at 7 ] 104 spores ml~1. One week later,
the symptoms of the Ðrst leaf were examined. The activ-
ity rankings of the test chemicals were deÐned on a
scale of zero to Ðve, corresponding to 0È30, 31È60,
61È80, 81È94, 95È99 and 100% prevention, respectively.
The test was done with two pots for each concentration
of each compound. When the rankings of the two pots
were di†erent, the test was repeated until a reproducible
value was obtained. From a concentration-preventive
ranking relationship as exempliÐed in Fig. 3 for com-
pound 31, the concentration to give the activity ranking
4 was deÐned as I (M). The pI values, which are
3
RESULTS AND DISCUSSION
The preventive activities of pentaÑuorophenoxybenzyla-
minopyrimidines (1È15) against wheat brown rust and
barley powdery mildew are listed in Table 1. Most of
the compounds were more potent against the barley
powdery mildew than against the wheat brown rust.
Among the position isomers of pentaÑuorophenoxy
derivatives, the 4-position isomers seemed to be more
potent than the 3-position isomers (4 versus 14; 7 versus
15), although compound 4 was slightly less active than
compound 14 against wheat brown rust.
Among the 4-pentaÑuorophenoxy derivatives, the
methyl analogues on R were more potent than the
ethyl analogues (1 versus 2; 4 versus 5; 7 versus 8).
Further enlargement of the alkyl to isopropyl was unfa-
3
4
4
reciprocal log values of I , are given in Tables 1È4.
4
vourable to activity (9 versus 8). The unsubstituted
compound (R \ H) was less potent than the methyl
2.2.2 Preventive activity against barley powdery mildew
In a plastic planting pot (6 cm diam. ] 10 cm), 10
barley seedlings (Hordeum vulgare L. var. vulgare) were
grown at 28¡C. At the 1É5-leaf stage (on average)
aqueous suspensions of test compounds were sprayed
over the plants as before. Two days later, the barley
plants were inoculated by conidial spores of barley
powdery mildew, Erysiphe graminis DC f.sp.hordei
3
analogue (3 versus 4). Thus, there seemed to be an
optimum size for R . One of the most potent congeners
3
listed in Table 1 was compound 7. The conversion of R
2
from Cl (7) to F (6) did not signiÐcantly a†ect the
potency against either fungus. Conversions of R from
1
ethyl (7) to isopropyl (11) and of R from Cl (8) to Br
2
(10) gave less active compounds. Preventive activities
varied greatly among the isomers. Compounds 6 and 7
with R \ methyl were much more potent than the cor-
3
responding isomers 2 and 5 with R \ methyl. Another
1
isomer, 13, of compounds 5 and 7 was very weak and
did not give preventive e†ects at the highest concentra-
tion tested.
Even though compound 8 (R \ F) was not the most
4
potent compound among those listed in Table 1, it was
chosen as the target compound to examine the substit-
uent e†ect. Table 2 shows compound 8 and derivatives
16È23 with other substituents at the para position of the
tetraÑuorophenoxy moiety and their preventive activ-
ities against wheat brown rust and barley powdery
mildew. The CHF derivative (17) was as active as com-
2
pound 8. Compound 16 (R \ H) was as active as com-
4
pound 8 against wheat brown rust, and slightly less
active against barley powdery mildew. The introduction
of an electron-withdrawing CF group gave a slightly
3
less active compound, 18. Derivatives 19È23 with other
electron-withdrawing groups were weak against both
fungi.
Fig. 3. The preventative activity ranking, I , of compound 31
4
against wheat brown rust.

Fungicidal activities of benzylaminopyrimidines
229
Table 3 shows the e†ects of the position of another
position of the benzyl-benzene ring by electron-
withdrawing substituents such as OCHF and OC F
gave excellent fungicidal compounds.
electron-withdrawing group, OCHF , on the benzyl-
2
2
6 5
benzene ring and of substituents at R and R . Isomers
1
3
with the OCHF group in the 4-position were generally
more active than those with that group in the 3-position
2
REFERENCES
(25 versus 24 and 27 versus 26) or the 2-position (29
versus 28). The ethyl derivatives at R were generally
1
1. Koller, W., Antifungal agents with target sites in sterol
function and biosynthesis. In T arget Sites of Fungicide
Action, ed. W. Koller. CRC Press, Boca Raton, FL, 1992,
pp. 119È206.
more active than the methyl derivatives (26 versus 24;
27 versus 25). The derivative with R \ ethyl (29) was
3
slightly more potent than the equivalent methyl deriv-
ative (25) against wheat brown rust, but they showed
similar potencies against barley powdery mildew.
2. Baloch, R. I. & Mercer, E. I., Inhibition of sterol *8È*7-
isomerase and *14-reductase by fenpropimorph, tri-
demorph and fenpropidin in cell-free enzyme systems from
Saccharomyces cerevisiae. Phytochemistry, 26 (1987) 663È8.
3. Baloch, R. I., Mercer, E. I., Wiggins, T. E. & Baldwin,
B. C., Inhibition of ergosterol biosynthesis in Sac-
charomyces cerevisiae and Ustilago maydis by tridemorph,
fenpropimorph and fenpropidin. Phytochemistry, 23 (1984)
2219È26.
The e†ects of the further introduction of one or two
more substituent(s) to the benzene ring of compounds
25 and 27 are summarized in Table 4. The e†ects were
peculiar. The activity of compound 25 against wheat
brown rust was increased by the introduction of the 2-F
group (34) and that against barley powdery mildew was
4. Arnold, M. L., Duriatti, A. D., Jung, M., Katz, R. B. &
Liebeschuetz, J. W., Guanidinium and amidinium fungi-
cides: A new class of carbocation mimetic ergosterol bio-
synthesis inhibitors. Pestic Sci., 44 (1995) 341È55.
5. Obata, T., Fujii, K., Yoshiya, H. & Tsutsumiuchi, K., Syn-
thesis and insecticidal and acaricidal activity of new N-(a-
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increased by the introduction of the 3-OCHF group
2
(32). These modiÐcations, however, decreased the activ-
ity against the other fungus for each compound. The
introduction of 3-Cl (30) or 3-OCH (31) and the 3,5-
3
(CH ) group (33) to compound 25 did not signiÐcantly
3 2
change the activities against wheat brown rust and
barley powdery mildew, respectively. However, such
modiÐcations decreased the potency against the other
6. Couturier, P. L., Action of organomagnesium halides on
some hydroxy-benzamides. Study of the hydroxy ketones
obtained. Ann. chim. Ser. 11, 10 (1938) 559È629.
fungus. Among the derivatives with R \ ethyl (35È39)
1
7. Nishiwaki, T., 5-HalogenopyrimidinesÈIV. Extension on
the nature of pyrimidine substrates and the kind of N-
halogenosuccinimides. T etrahedron, 22 (1966) 2401È12.
8. Ube Industries Ltd., Japan Patent 279874, 1989.
9. Anderson, G. W., Halverstadt, I. F., Miller, W. H. &
Roblin, R. O., Study in chemotherapy. X. Antithyroid
compounds. Synthesis of 5- and 6-substituted 2-thiouracils
from b-oxoesters and thiourea. J. Amer. Chem. Soc., 67
(1945) 2197È200.
further introduction of substituents did not increase
activity. The introduction of a 3-OCH (36) or 2-F (39)
3
group maintained the highest potency against wheat
brown rust. These modiÐcations and the introduction of
a 3-OCHF (37) or 3,5-(CH ) (38) group, however,
2
3 2
slightly decreased the activity against barley powdery
mildew.
In summary, benzylaminopyrimidines showed
notable preventive activities against wheat brown rust
and barley powdery mildew. The preferable com-
bination of substituents on the pyrimidine ring seemed
to be a halogen atom and a small alkyl group. The
introduction of a small alkyl group at the benzyl posi-
tion gave potent compounds. Substitution at the 4-
10. Clark, J., Grantham, R. K. & Lydiate, J., Heterocyclic
studies. Part V. Desulphuration of heterocyclic thiols with
nickel boride. J. Chem. Soc., 1968C, 1122È4.
11. Yamanaka, H., Sakamoto, T., Nishimura, S. & Sagi, M.,
Study on pyrimidine derivatives. XXXIX. Site-selectivity
in the reaction of 5-substituted 4,5-disubstituted pyrim-
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Bull., 35 (1987) 3119È26.