Synthesis and acaricidal activity of 4-pyrimidinyloxy- and 4- pyrimidinylaminoethylphenyl dioxolanes and oxime ethers

Article abstract of DOI:10.1002/(SICI)1526-4998(200001)56:1<94::AID-PS105>3.0.CO;2-3

Novel types of mitochondrial respiration inhibitors at complex I, with emphasis on acaricidal activity, have been designed and prepared. The synthetic approach to these 4-pyrimidinylphenyl ethyl ethers and amines with a specific ketal or oxime function in the phenyl side chain is outlined. Bioassays demonstrate their high potential against important spider mites, like Tetranychus urticae and Panonychus ulmi. Structure-activity relationship studies and several biological parameters are discussed. (C) 2000 Society of Chemical Industry.

Full text of DOI:10.1002/(SICI)1526-4998(200001)56:1<94::AID-PS105>3.0.CO;2-3

Pest Management Science
Pest Manag Sci 56:94±100 (2000)
Synthesis and acaricidal activity of
4-pyrimidinyloxy- and
4-pyrimidinylaminoethylphenyl dioxolanes
and oxime ethers
Clemens Lamberth,* Elke Hillesheim, Denis Bassand and Fritz Schaub
Novartis Crop Protection AG, Research Department, Schwarzwaldallee 211, CH-4002 Basel, Switzerland
Abstract: Novel types of mitochondrial respiration inhibitors at complex I, with emphasis on acaricidal
activity, have been designed and prepared. The synthetic approach to these 4-pyrimidinylphenyl ethyl
ethers and amines with a speci®c ketal or oxime function in the phenyl side chain is outlined. Bioassays
demonstrate their high potential against important spider mites, like Tetranychus urticae and
Panonychus ulmi. Structure±activity relationship studies and several biological parameters are
discussed.
# 2000 Society of Chemical Industry
Keywords: acaricide; respiration inhibitor; NADH:ubiquinone oxidoreductase; quinazoline; pyrimidine;
synthesis; SAN 1398 A
1
INTRODUCTION
line,16 4-chloro-5-methylthieno[2,3-d]pyrimidine,17
4-chloro-5-methoxy-6-methoxymethylpyrimidine18
and 4,5-dichloro-6-ethylpyrimidine19 were prepared
according to literature procedures.
The continuous search for new acaricides and in-
secticides, intensi®ed by resistance problems and the
need for new environmentally safe pesticides, has
focused recently on inhibitors of the respiratory
chain.1,2 Several modern acaricides, which reached
the market recently, such as fenazaquin,3 tebufen-
pyrad,4 fenpyroximate,5 pyridaben6 and pyrimidifen,7
as well as the natural product rotenone, interrupt
mitochondrial electron transport by inhibition of
NADH:ubiquinone oxidoreductase (complex I).8±12
Although several derivatives of fenazaquin (Fig 1; I)
have been described already,13,14 we found during the
course of a research programme that substitution of
fenazaquin's tert-butyl group by a dioxolane ring
(general structure II) or an oxime function (general
structure III) leads to new acaricides, which are highly
effective against spider mites of major importance, like
the two-spotted spider mite, Tetranychus urticae
(Koch), and the European red mite, Panonychus ulmi
(Koch). The new compounds display outstanding
contact activity on mobile stages of the mites and in
addition possess moderate ovicidal properties.
The synthetic pathways used to prepare the new
dioxolanes and oxime ethers are shown in Fig 2. 2-
Phenylethyl benzoate20 (1) was transformed by Frie-
del±Crafts acylation21 to the ketone 2,22,23 which
served as a key intermediate. Ketalization and deben-
zoylation then gave dioxolanylphenethanols 4. These
were either converted to the corresponding amine 5 via
a Mitsunobu reaction24,25 or linked to an appropriate
pyrimidine or quinazoline derivative to give 4-pyrimi-
dinyloxyethyl phenyl dioxolanes such as 33.
Representative procedures are given below.
2.1.1 2-(4-acetylphenyl)ethyl benzoate (2)
Anhydrous aluminum chloride (263g, 1.98mol) was
suspended in dichloromethane (1800ml). After cool-
ing the mixture to 0°C, acetyl chloride (81g; 1.0mol)
and 2-phenylethyl benzoate20 (1; 212g; 0.94mol)
were added one after the other. The reaction mixture
was stirred for 16h at room temperature, and then
poured into a mixture of crushed ice (500ml) and
concentrated hydrochloric acid (900ml). After separa-
tion of the phases, the aqueous layer was extracted
with ethyl acetate. The combined organic layers were
washed with water and aqueous potassium bicarbo-
nate solution (100g litre 1), dried over magnesium
2
MATERIALS AND METHODS
2.1 Chemical synthesis
The quinazoline and pyrimidine derivatives 4-chloro-
quinazoline,15 4-chloro-5,6,7,8-tetrahydroquinazo-
* Correspondence to: Clemens Lamberth, Novartis Crop Protection AG, Research Department, Schwarzwaldallee 211, CH-4002 Basel,
Switzerland
(Received 10 November 1998; revised version received 9 September 1999; accepted 7 October 1999)
# 2000 Society of Chemical Industry. Pest Manag Sci 1526±498X/2000/$17.50
94

Synthesis and activity of new acaricides
rated in vacuum. Yield: 17.7g (67mmol, 79%).
[1H]NMR (deuterochloroform): ꢀ=7.42 (d, 2H),
7.20 (d, 2H), 4.15 (m, 1H), 3.93±3.80 (m, 4H),
2.87 (t, 2H), 1.69±1.22 (m, 9H), 0.95 (t, 3H).
2.1.4 2-[4-(4-butyl-2-methyl-1,3-dioxolan-2-
yl)phenyl]ethylamine (5)
To a solution of compound 4 (9.5g; 36mmol),
triphenylphosphine (10g; 38mmol) and phthalimide
(5.9g; 40mmol) in tetrahydrofuran (400ml), was
added dropwise diethyl azodicarboxylate (7.3g;
42mmol). The reaction was stirred for 1h at room
temperature. The solvent was removed in vacuum and
the residue dissolved in diethyl ether‡hexane. The
resulting precipitate was washed with the same
mixture of solvents, the combined ®ltrate was evapo-
rated in vacuum and the residue suspended in ethanol
1
(40ml). Methylamine solution (330g litre in etha-
nol; 40ml) was added slowly. The reaction mixture
was stirred for 3h at room temperature, and then
evaporated in vacuum. Yield: 6.8g (26mmol, 72%).
[1H]NMR (deuterochloroform): ꢀ=7.44 (d, 2H),
7.21 (d, 2H), 4.32 (m, 1H), 4.08 (t, 2H), 3.89±3.83
(m, 2H), 2.95 (t, 2H), 1.70 ±1.27 (m, 9H), 0.96 (t,
3H).
Figure 1. Structures of compounds discussed
sulfate and evaporated in vacuum. The residue was
recrystallized from ethyl acetate‡hexane. Yield: 165g
(0.62mol, 66%), mp 90.5±91.5°C. [1H]NMR
(deuterochloroform): ꢀ=8.04±7.35 (m, 9H), 4.56 (t,
2H), 3.15 (t, 2H), 2.60 (s, 3H).
2.1.5 4-[2-(benzoyloxy)ethyl]acetophenone oxime (6)
Compound 2 (250g, 0.93mol) was suspended in
ethanol (1100ml). Hydroxylamine hydrochloride
(97g, 1.4mol) and anhydrous sodium acetate (114g;
1.4mol) were added and the reaction stirred for 2h at
60°C. The mixture was cooled to room temperature,
then poured on to crushed ice (500ml) and extracted
with ethyl acetate. The combined organic layers were
washed with water, dried over magnesium sulfate and
evaporated in vacuum. Yield: 194g (0.69mol, 74%).
[1H]NMR (deuterochloroform): ꢀ=8.04±7.27 (m,
9H), 4.55 (t, 2H), 3.10 (t, 2H), 2.29 (s, 3H).
2.1.2 2-[4-(4-butyl-2-methyl-1,3-dioxolan-2-
yl)phenyl]ethyl benzoate (3)
1,2-Hexanediol (11.8g; 0.1mol) and 4-toluenesulfo-
nic acid monohydrate (0.5g) were added to a solution
of compound 2 (26.8g; 0.1mol) in toluene (200ml).
The resulting mixture was heated at re¯ux for 7h using
a Dean±Stark trap, then cooled and poured into a
mixture of crushed ice, (100ml) and aqueous potas-
sium bicarbonate solution (100g litre 1; 100ml).
After separation of the phases, the aqueous layer was
extracted with diethyl ether. The combined organic
layers were washed with aqueous potassium bicarbo-
nate solution (100g litre 1) and water, dried over
magnesium sulfate and evaporated in vacuum. Yield:
31.2g (85mmol, 85%). [1H]NMR (deuterochloro-
form): ꢀ=8.05±7.22 (m, 9H), 4.54 (t, 2H), 4.15 (m,
1H), 3.87 (m, 2H), 3.09 (t, 2H), 1.71±1.25 (m, 9H),
0.96 (t, 3H).
2.1.6. O-(isopropyl)-4-[2-
(benzoyloxy)ethyl]acetophenone oxime (7)
Sodium hydride (0.7g, 30mmol) was suspended in
N,N-dimethylformamide‡tetrahydrofuran (1‡1 by
volume; 30ml). A solution of compound 6 (7.0g;
25mmol) in N,N-dimethylformamide‡tetrahydro-
furan (1‡1 by volume; 40ml) was added dropwise.
The mixture was stirred for 1 at room temperature, 2-
chloropropane (2.0g, 25mmol) was added and the
reaction stirred for a further 16h at room temperature.
The mixture was diluted with water and extracted with
diethyl ether, the combined organic layers dried over
magnesium sulfate and evaporated in vacuum. The
residue was chromatographed on silica gel (hexane‡
diethyl ether, 1‡1 by volume). Yield: 5.5g (17mmol,
67%). [1H]NMR (deuterochloroform): ꢀ=8.04±7.24
(m, 9H), 4.55 (t, 2H), 4.42 (m, 1H), 3.11 (t, 2H),
2.23 (s, 3H), 1.33 (d, 3H), 1.30 (d, 3H).
2.1.3 2-[4-(4-butyl-2-methyl-1,3-dioxolan-2-
yl)phenyl]ethanol (4)
Compound 3 (31.2g; 85mmol) was stirred in 150ml
of a solution of potassium hydroxide (100g litre 1) in
methanol‡water (80‡20 by volume) for 2h at room
temperature. The mixture was concentrated in va-
cuum, diluted with water and extracted with ethyl
acetate. The combined organic layers were washed
with water, dried over magnesium sulfate and evapo-
Pest Manag Sci 56:94±100 (2000)
95

C Lamberth et al
Figure 2. Synthetic routes to novel 4-pyrimidinyloxy- and 4-pyrimidinylamino-ethylphenyl dioxolanes and oxime ethers.
2.1.7. O-(isopropyl)-4-(2-hydroxyethyl)acetophenone
oxime (8)
(m, 4H), 2.93 (t, 2H), 2.79 (q, 2H), 1.71±1.58 (m,
5H), 1.39 ±1.21 (m, 7H), 0.91 (t, 3H).
Compound 7 (5.0g; 15mmol) was stirred in a solution
of potassium hydroxide (100g litre 1) in methanol‡
water (80‡20 by volume) (100ml) for 2h at room
temperature. The mixture was concentrated in
vacuum, diluted with water and extracted with ethyl
acetate. The combined organic layers were washed
with water, dried over magnesium sulfate and evapo-
rated in vacuum. Yield: 2.7g (12mmol, 81%).
[1H]NMR (deuterochloroform): ꢀ=7.61 (d, 2H),
7.22 (d, 2H), 4.47 (q, 1H), 3.88 (t, 2H), 2.90 (t,
2H), 2.21 (s, 3H), 1.34 (d, 3H), 1.31 (d, 3H).
2.1.9 4-[2-[4-(4-butyl-2-methyl-1,3-dioxolan-2-
yl)phenyl]ethoxy]quinazoline (33)
Sodium hydride (1.6g, 65mmol) was suspended in
1,2-dimethoxyethane (50ml) and cooled to 0°C. A
solution of compound 4 (14.3g; 54mmol) in 1,2-
dimethoxyethane (100ml) was added dropwise. The
reaction was stirred for 1h at room temperature and
cooled again to 0°C, then 4-chloroquinazoline15
(9.7g; 59mmol) added in portions. The mixture was
stirred for 16h at room temperature, cooled to 0°C,
diluted with water and extracted with ethyl acetate.
The combined organic layers were washed with water,
dried over magnesium sulfate and evaporated in
vacuum. The residue was chromatographed on silica
gel (hexane‡ether; 8‡2 by volume). Yield: 17.3g
(44mmol, 82%). [1H]NMR (deuterochloroform):
ꢀ=8.80 (s, 1H), 8.18±7.31 (m, 8H), 4.79 (t, 2H),
4.18 (m, 1H), 3.86 (m, 2H), 3.21 (t, 2H), 1.74±1.20
(m, 9H), 0.90 (t, 3H).
2.1.8 N-4-[2-[4-(4-butyl-2-methyl-1,3-dioxolan-2-
yl)phenyl]ethyl]-5-chloro-6-ethyl-pyrimidin-4-amine
(11)
A mixture of compound 5 (2.1g; 7.9mmol), 4,5-
dichloro-6-ethylpyrimidine19 (1.8g; 10mmol) and
sodium carbonate (2.4g; 23mmol) in water (40ml)
was heated to re¯ux for 3h, then diluted with water
and extracted with ethyl acetate. The organic layer was
washed with water, dried over magnesium sulfate and
evaporated in vacuum. The residue was chromato-
graphed on silica gel (hexane‡ethyl acetate, 1‡1 by
volume). Yield: 2.3g (5.6mmol, 71%). [1H]NMR
(deuterochloroform): ꢀ=8.42 (s, 1H), 7.43 (d, 2H),
7.19 (d, 2H), 5.44 (bs, 1H), 4.17 (m, 1H), 3.92±3.70
2.1.10 O-(isopropyl)-4-[2-(5,6,7,8-
tetrahydroquinazolin-4-yloxy)ethyl]acetophenone oxime
(38)
To a solution of compound 8 (85g; 0.38mol) in
toluene (500ml) were added successively aqueous
96
Pest Manag Sci 56:94±100 (2000)

Synthesis and activity of new acaricides
sodium hydroxide (300g litre 1; 250ml) benzyl-
triethylammonium chloride (5.0g; 22mmol) and 4-
2.2 Formulations and standards
The test compounds were applied as 100g litre
1
chloro-5,6,7,8-tetrahydroquinazoline16
(70g;
emulsi®able concentrates in N,N-dimethyl formami-
de‡xylene, using Atlox 4851B as surfactant. Fenaza-
quin and tebufenpyrad (both>95%) were used
0.42mol) in portions. The mixture was stirred for 5h
at room temperature, then extracted with diethyl ether
and washed with water. The organic layer was dried
over magnesium sulfate and evaporated in vacuum.
The residue was chromatographed on silica gel
(hexane‡ethyl acetate; 7‡3 by volume). Yield:
120g (0.34mol, 90%). [1H]NMR (deuterochloro-
form): ꢀ=8.49 (s, 1H), 7.60 (d, 2H), 7.26 (d, 2H),
4.57 (t, 2H), 4.46 (q, 1H), 3.10 (t, 2H), 2.79 (t, 2H),
2.52 (t, 2H), 2.21 (s, 3H), 1.88±1.73 (m, 4H), 1.35
(d, 3H), 1.30 (d, 3H).
similarly as standards. Commercial hexythiazox
1
100g kg
WP (Trevi 10WP) and fenpyroximate
500g litre 1 SC (Kiron 50SC) were used as standards
in ®eld tests.
2.3 Biological assays
2.3.1 Acaricidal assays on two-spotted spider mite,
Tetranychus urticae (Koch)
For these biological assays, conducted in the labora-
Table 1. Acaricidal activity against Tetranychus urticae of 4-pyrimidinyloxy- and 4-pyrimidinylaminoethylphenyl dioxolanes
1
LC95 (mg litre
Contact
)
Ovicidal
6days
Compound No
R1
R2
R3
X
2±3days
8±10days
9
10
C2H5
Cl
CH2OCH2CH=
CH2OCH2C(CH3)
CH2
CH2
NH
O
1
0.3
2
2
>400
119
16
ÐCH
C2H5
ÐCH CHÐCH
=CHÐCH
=
=
CHÐ
Cl
=
2
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
CH2CH2CH2CH3
CH2OCH2CCH
CH2SCH2CH3
NH
O
3
=
CHÐ
3
3
>400
>400
84
ÐSÐ CHÐC(CH3)Ð
ÐCH CHÐCH CHÐ
ÐSÐ CHÐC(CH3)Ð
CH2OCH3 OCH3
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐCH CHÐCH CHÐ
O
6
4
=
=
CH2OCH2C(Cl)
CH2OCH2CH
CH2SCH2CH3
=
CH2
O
2
5
=
CH2
O
3
5
34
O
3
5
23
CH2OCH2CH
CH2OCH2CH
CH2OCH2CH
=
=
=
CH2
CH2
CH2
NH
O
8
8
>400
37
=
=
20
3
9
CH2OCH3
CH2OCH3
CH2OCH3
OCH3
OCH3
OCH3
O
10
10
11
11
11
12
12
12
13
13
14
14
15
17
18
22
22
32
11
13
74
37
CH2SCH3
O
8
12
CH2OCH(CH3)2
CH2OCH2CH2OCH3
CH2CH2CH2CH3
CH2OCH3
O
5
150
100
13
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐSÐCHÐC(CH3)Ð
O
20
29
7
O
ÐCH
ÐSÐCHÐC(CH3)Ð
ÐCH CHÐCH CHÐ
=CHÐCH
=
CHÐ
O
4
CH2SCH3
C6H5
CH2OCH2CH=
O
10
19
1
>400
105
29
=
=
O
ÐSÐCHÐCHÐ
CH2
O
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐCH2ÐCH2ÐCH2ÐCH2Ð
CH2OCH2CCH
CH2CH2CH2CH3
CH2OCH2C6H5
O
7
16
NH
O
5
>400
>400
47
ÐCH
ÐCH
ÐCH
ÐCH
=CHÐCH
=CHÐCH
=CHÐCH
=CHÐCH
=
=
=
=
CHÐ
CHÐ
CHÐ
CHÐ
19
36
49
26
7
CH2O(4Ð ClÐC6H5)
CHCH3
O
CH2OCH2CH
=
O
>400
80
CH2CH2CH2CH3
CH2OCH(CH3)2
CH2Cl
O
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐCH CHÐCH CHÐ
O
12
=
=
O
23
43
11
>500
74
42
ÐCH2ÐCH2ÐCH2ÐCH2Ð
Tebufenpyrad
CH2OCH2CH
=
CH2
O
20
17
Hexythiazox
14
Fenazaquin
173
Pest Manag Sci 56:94±100 (2000)
97

C Lamberth et al
Table 2. Acaricidal activity against Tetranychus urticae of 4-pyrimidinyloxy-ethylphenyl oxime ethers
1
LC95(mg litre
Contact
)
Ovicidal
6days
Compound no
37
R1
R2
R3
2±3days
8±10days
ÐCH
=
CHÐCH
=
CHÐ
CH2CH2OCH3
CH(CH3)2
9
13
13
9
9
25
124
284
37
38
39
40
41
42
43
44
45
46
47
ÐCH2ÐCH2ÐCH2ÐCH2Ð
CH2OCH3 OCH3
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐCH CHÐCH CHÐ
11
14
15
15
15
20
21
22
22
43
11
13
74
CH2CH2OCH3
CH2SCH3
=
=
CH2OCH3
CH2OCH3
17
19
13
46
40
60
50
11
>500
74
>400
76
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐCH2ÐCH2ÐCH2ÐCH2Ð
ÐCH2ÐCH2ÐCH2ÐCH2Ð
CH2CH2OCH3
CH2
CH2
56
CH2CH=
80
ÐCH
ÐCH
=
=
CHÐCH
CHÐCH
=
=
CHÐ
CHÐ
CH2C(Cl)
CH2C(CH3)
CH2C(CH3)
=
69
=
=
CH2
CH2
58
ÐCH2ÐCH2ÐCH2ÐCH2Ð
Tebufenpyrad
369
17
Hexythiazox
14
Fenazaquin
173
tory, a susceptible laboratory strain reared at Sandoz
Agro was used.
2.3.2 Acaricidal assay on European red mite,
Panonychus ulmi (Koch)
Direct contact activity of selected compounds on
Panonychus ulmi (Koch), European red mite, was
measured in the laboratory. Apple leaf discs (diameter:
35mm) infested with 10 adult mites or L4 larvae were
treated with the test compounds using a spray Potter
tower (2ml per treatment). Three replicates per
concentration, four concentrations (30, 6, 1.25 and
0.25mg litre 1) per test compound were used. The
treated leaf discs were stored in a climatic chamber at
25°C, 50% RH and 16h light. Mortality (%) was
recorded after two to three days to calculate the LC95
values (logit analysis).27
2.3.1.1 Contact activity
Bush bean plants (Phaseolus vulgaris L), two-leaf stage,
were infested with approximately 30mites two days
before treatment. A mixed population (eggs, nymphs
and adults) was treated in an application tunnel (spray
volume 1000litreha 1; four nozzles). Three replicates
per concentration, ®ve concentrations (100, 25, 6.25,
1.6, 0.4mg AI litre 1) per test series per test
compound were used. The treated plants were kept
at 25°C and 50% RH. in a climatic chamber with 16h
light. Rapid contact activity was evaluated after two or
three days. Slow contact activity was recorded eight or
ten days after treatment. Relative reduction of the mite
population was calculated according to Abbott.26
LC95 values were estimated using logit analysis.27
2.3.3 Toxicity to honey bee (Apis mellifera L)
Each test honey bee was treated individually by
applying 1ml test solution (in acetone) ventrally on
the thorax (topical application). Five different test
concentrations were used (20, 15, 10, 5, 2.5mg AI per
bee). Ten bees per replicate and three replicates per
concentration per compound were performed. A test
period of three days was used to record dead and
affected bees. Parathion-ethyl was used as standard of
known toxicity.
2.3.1.2 Ovicidal activity
A glue ring (diameter 2cm) was placed on the upper
side of a leaf from a bush bean plant, two-leaf stage.
Five to seven adult females were placed inside the glue
ring area and were allowed to lay eggs. The females
were removed after 24h and the eggs were sprayed
with four different concentrations (100, 25, 6.25,
1.6mg AI litre 1) using three replicates per concentra-
tion per test series. The treated plants were kept in a
climatic chamber at 25°C, 50% RH and 16h light.
After six days the percentage of unhatched eggs was
recorded. LC95 values were calculated using logit
analysis.27
2.3.4 Field trials
Field trials and small plot garden trials on apples were
conducted in the years 1994 and 1995 in the South of
France and in Switzerland. Test compounds were
formulated as 100g litre ECs. Doses of 5g, 7.5g and
1
10g AI hl were applied as a high-volume spray to
98
Pest Manag Sci 56:94±100 (2000)

Synthesis and activity of new acaricides
Table 3. Acaricidal activity against Panonychus ulmi, bee toxicity and field results of 4-pyrimidinyloxy- and 4-pyrimidinylaminoethylphenyl dioxolanes and oxime
ethers
Contact
P ulmi
Honeybees
2 days
Field trials
10 days 24 days
2±3 days
11 days
21 days
11 days
21 days
LC95 (mg LD50 (mg per
1
1
1
1
No.
litre
)
litre)
% ef®cacy at 5g AI hl
% ef®cacy at 7.5g AI hl
% ef®cacy at 10g AI hl
10
14
15
18
19
33
36
42
23
±
54
57
60
73
79
90
±
90
90
100
81
71
100
±
±
±
±
±
56
59
74
75
90
96
±
90
100
95
88
100
100
±
4.5
±
4
12
2
±
±
±
3
44
±
97
±
±
10
32
27
43
64
14
±
13/48
60
69
55
70
54
81
±
100
76
90
66
67
100
±
8
3
±
±
±
±
46
47
7
±
±
±
±
6
±
±
±
±
Fenazaquin
Tebufenpyrad
Fenpyroximate
Parathion-ethyla
10
5
42
88
88
±
95
98
99
±
60
96
±
95
98
±
±
±
±
±
±
0.13
±
±
±
±
a Toxic standard for bee toxicity studies.
run-off (three replicates per compound per concentra-
tion). Twenty-®ve leaves were collected randomly
from each tree 10 to 11 days and 21 to 24 days after
treatment. Relative reduction of the mite population
was calculated according to Abbott.26
A statistically signi®cant correlation was observed
between contact activity values on T. urticae (LC95 8±
10 days) and on P. ulmi (LC95 2±3 days) with
compounds 10, 14, 15, 18, 19, 33, 36, 42, 46 and 47
(r =0.83; df =8; P <0.01),28 which is not the case for
fenazaquin.
Small plot garden trials and ®eld trials in apple
orchards on P ulmi were conducted with compounds
10, 14, 15, 18, 19, 33, 36, 42, 46 and 47 (Table 3). In
these trials, the best compound, SAN 1398 A (33), was
at least as effective as the standards fenazaquin,
tebufenpyrad and fenpyroximate at the same applica-
tion rate (5±10g AI hl 1). On the bene®cial predatory
mite Typhlodromus pyri (Scheut), compound 33 had a
better selectivity than fenazaquin (30% mite reduction
versus 51%). Therefore 33 can be categorized as `low
toxicity to predatory mites'. In comparison with
fenazaquin and tebufenpyrad, this interesting acar-
icide displayed also the lowest toxicity (contact
activity) on worker honey bees. According to the
EPPO guideline 170 (1993),29 33 can be considered as
`low risk to honey bees'. Moreover, this compound
gave good control of Varroa jacobsoni (Oud), an
important ectoparasitic mite of the honey bee.
3
RESULTS AND DISCUSSION
As shown in Tables 1 and 2, the tested compounds
displayed superior contact activity in comparison to
the standards tebufenpyrad, hexythiazox and fenaza-
quin, whereas ovicidal activity was poor in many cases.
A few compounds, for example 11, 20, 33, 38 and 46
showed an interesting translaminar activity (not shown
in table). The persistence was overall within the range
of the standards.
The basic molecular skeleton represented in the
general formula of Tables 1 and 2 is necessary to reach
this level of activity. The large assortment of cyclic and
acyclic variations of R1 and R2 suggests that these
pyrimidine substituents are easily exchangeable. How-
ever, the replacement of the chlorine atom in
compounds 9 and 11 by a cyano group or the
introduction of a substituent into the 2-position of
the pyrimidine ring leads to completely inactive
compounds. In our experience, the combination
R1=C2H5, R2=Cl and X=NH results in very active
acaricides, which also, unfortunately, show high
mammalian toxicity. In comparison with these amines,
the employment of an oxygen atom in the linker
between the pyrimidine and phenyl rings has a positive
in¯uence on bee toxicity without reducing activity
against spider mites. In the cases of the ketals and the
oxime ethers, R3 is preferably a linear lipophilic
substituent with three to ®ve chain atoms.
4
CONCLUSION
Two new subclasses of substituted 4-hydroxy- and 4-
aminopyrimidines and -quinazolines have been dis-
covered which possess a remarkable pro®le of acar-
icidal activity and favourable ecotoxicological
properties. The best compound, SAN 1398 A (33),
performed as well as the common standard acaricides
for the control of Panonychus ulmi under standard ®eld
conditions. Due to its relative safeness to honey bees
Pest Manag Sci 56:94±100 (2000)
99

C Lamberth et al
tory complex I: mechanisms, pesticidal actions and toxicology.
Rev Pestic Toxicol 3:277±302 (1995).
and the predatory mite Typhlodromus pyri, 33 is an
excellent candidate for integrated pest control. A
further interesting feature of 33 might be its useful
activity against Varroa jacobsoni, an ectoparasite of the
honey bee, especially since Varroa has been reported to
be increasingly resistant to tau-¯uvalinate (Apistan1)
in Europe.30
11 Jewess PJ, Insecticides and acaricides which act at the rotenone-
binding site of mitochondrial NADH:ubiquinone oxidoreduc-
tase; competitive displacement studies using a 3H-labelled
rotenone analogue. Biochem Soc Trans 22:247±251 (1994).
12 Friedrich T, van Heek P, Leif H, Ohnishi T, Forche E, Kunze B,
Jansen R, Trowitzsch-Kienast W, Hoe¯e G, Reichenbach H
and Weiss H, Two binding sites of inhibitors in NADH:ubi-
quinone oxidoreductase (complex I). Eur J Biochem 219:691±
698 (1994).
13 Samaritoni JG and Babbitt GE, Synthesis of 2-(4-quinazoliny-
l)ethyl sul®des via addition of thiols to 4-vinylquinazolines. J
Heterocycl Chem 34:1263±1266 (1997).
ACKNOWLEDGEMENTS
The authors are very grateful to Drs F Kuhnen and K
Milzner for helpful discussions and to M GaberthuÈel,
M-C Bernhard, D Steiner and R Frey for excellent
technical assistance. Furthermore, we thank Dr F
Huggenberger and G Richli for carrying out the
garden and ®eld trials.
14 Hackler RE, Suhr RG, Sheets JJ, Hatton CJ, Johnson PL, Davis
LN, Edie RG, Kaster SV, Jourdan GP, Jackson JL and
Krumkalns EV, Chemistry and miticidal activity of fused
pyrimidine derivatives of fenazaquin. in Advances in the
Chemistry of Insect Control III, ed by Briggs GG, RSC,
Cambridge. pp 70±84 (1994).
15 SchoÈnowsky H and Sachse B, Chinazolinderivate, ihre Herstel-
lung und biologische Wirkung. Z Naturforsch 37b:907±911
(1982).
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