Synthesis of phenoxyphenyl pyridine and pyrazine carboxamides. Activity against Cydia pomonella (L.) eggs

Article abstract of DOI:10.1021/jf990404e

Several N-(4-phenoxyphenyl)pyridinecarboxamides and N-(4- phenoxyphenyl)pyrazinecarboxamides were synthesized from commercially available material, and their ovicidal activities against Cydia pomonella (L.) were tested. Some of the tested products showed a moderate activity when <24-h-old eggs were sprayed using a Potter tower. A significant increase in the length of the development period of the eggs was also observed in many cases. A clear correlation between both effects was noticed: the products that produced higher mortality also produced higher increase of the length of the development. These results seem to confirm our hypothesis that these compounds could be defined as a juvenile hormone analogues.

Full text of DOI:10.1021/jf990404e

J. Agric. Food Chem. 2000, 48, 83−87
83
Syn th esis of P h en oxyp h en yl P yr id in e a n d P yr a zin e Ca r boxa m id es.
Activity a ga in st Cyd ia pom on ella (L.) Eggs
Merce` Balcells,†,§ J esu´s Avilla,*,‡,§ J aume Profitos,† and Ramon Canela*,†,§
Department de Qu´ımica and Departament de Produccio´ Vegetal i Cie`ncia Forestal, Universitat de Lleida,
and AÅ rea de Proteccio´ de Conreus, Centre UdL-IRTA de R+D de Lleida, Rovira Roure 177,
25198 Lleida, Spain
Several N-(4-phenoxyphenyl)pyridinecarboxamides and N-(4-phenoxyphenyl)pyrazinecarboxamides
were synthesized from commercially available material, and their ovicidal activities against Cydia
pomonella (L.) were tested. Some of the tested products showed a moderate activity when <24-h-
old eggs were sprayed using a Potter tower. A significant increase in the length of the development
period of the eggs was also observed in many cases. A clear correlation between both effects was
noticed: the products that produced higher mortality also produced higher increase of the length of
the development. These results seem to confirm our hypothesis that these compounds could be defined
as a juvenile hormone analogues.
Keyw or d s: Cydia pomonella; codling moth; ovicide; insecticide; carbamate; J HA; IGR
INTRODUCTION
(Gelbic and Sehnal, 1973). In this case, the problem was
to know how the molecule fits into the enzyme. The best
way to match the ester group implies that a very huge
group must fit the active site of the supposed receptor
(Figure 1A). To avoid this problem, the picolinamide
could interact with the active site in the other way
round (Figure 1B). In this case the electrophilic carbon
of both the ester and the amide group could interact
with the active site of the receptor and only the pyridine
moiety must fit into the active site. A second hypothesis
supposes the amide group matches the epoxy moiety of
juvenile hormones (Figure 1C). In both cases, an es-
terase or an epoxide hydrolase could be inhibited by
strongly binding to the picolinamide compound. Thus,
the hydrolysis of endogenous juvenile hormone could be
avoided.
With these two possibilities in mind, the synthesis of
a set of new compounds was formulated. First of all,
we planned to study how the nitrogen position on the
ring affects activity by modifying the electrophilicity of
the amide carbon. Second, we increased the length of
our molecule by introducing either a new amide bond
or a carbamate bond. Substances containing a carbam-
ate group are known to be among the most active
juvenile hormone analogues (J HA) known (Masner et
al., 1983; Wimmer et al., 1997).
Codling moth [Cydia pomonella (L.), Lepidoptera:
Tortricidae] is a major pest of apples and pears, al-
though it can also attack other crops such as walnuts
and prunes. Its world distribution closely resembles the
distribution of apple trees, and it can cause heavy
economic losses, depending on the climatic region. The
larvae enter a fruit and fully develop inside it, rendering
the fruits unmarketable, although the larvae consume
only a small part of the fruit flesh (University of
California Statewide IPM Program, 1991). Many dif-
ferent chemicals have shown efficacy against this spe-
cies, both conventional insecticides (organophosphates,
carbamates, pyrethroids) and insect growth regulators
(chitin synthesis inhibitors, juvenile hormone analogues,
molting hormone agonists). However, the environmental
problems associated with the former and some resistant
populations developed to the latter (Croft and Riedl,
1991) stress the need for new compounds.
With that aim, we synthesized N-(4-phenoxyphenyl)-
2-pyridinecarboxamide (1a ) (Figure 1), testing its ovi-
cidal and larvicidal activities against C. pomonella.
Considering its activity, an insect juvenile hormone-like
activity was proposed (Canela et al., 1999). Although
there exist many potential sites for selective disruption
of endocrine function in insects (Mumby et al., 1979), it
is difficult to find a clear structure-activity relationship
(Schvartzapel et al., 1996). However, two hypotheses can
be considered when the structure of compound 1a is
matched with the juvenile hormone 0 (J H 0) structure.
First, the amide group from compound 1a can match
the ester group of the juvenile hormone. The introduc-
tion of an amide group instead of an ester group
produced an increase of ovicidal activity against C.
pomonella in some of the compounds tested by Gelbic
EXPERIMENTAL PROCEDURES
Ch em ica ls. 3-Pyridinecarboxylic acid (nicotinic acid), 4-py-
ridinecarboxylic acid (isonicotinic acid), pyrazinecarboxylic
acid, 4-aminophenyl phenyl ether, 4,4′-di(aminophenyl) ether,
1,1′-carbonyldiimidazole, acetic anhydride, and triethylamine
were purchased from Fluka (Sigma-Aldrich Qu´ımica S.A.,
Alcobendas, Spain), and allyl chloroformate was purchased
from Aldrich (Sigma-Aldrich Qu´ımica S.A.). 2-Pyridinecar-
boxylic acid (picolinic acid) and silica gel 60 (0.040-0.063 mm)
were purchased from Merck (Merck KGaA, Darmstadt, Ger-
many). Fenoxycarb was a gift of CIBA-Geigy (now Novartis)
and was recrystallized twice from ethyl ether saturated with
hexane.
* Author to whom correspondence may be addressed (e-mail
canela@quimica.udl.es or avilla@lleida.irta.es).
† Department de Qu´ımica.
‡ Department de Produccio´ Vegetal i Cie`ncia Forestal.
§ AÅ rea de Proteccio´ de Conreus.
Ap p a r a tu s. Synthesized compound were identified by 1H
NMR, IR, and MS. 1H NMR spectra were recorded either with
10.1021/jf990404e CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/28/1999

84 J. Agric. Food Chem., Vol. 48, No. 1, 2000
Balcells et al.
F igu r e 1. Possible action modes of N-(4-phenoxyphenyl)-2-pyridinecarboxamide (1a ) as J H mimetic.
a Varian Gemini 200 (200 MHz) or with a Varian Unity-300
(300 MHz) spectrometer. Infrared and mass spectra were
determined with Phillips PU9700 and HP5989 spectrometers,
respectively.
7.65, 1.20, 0.93 Hz), 8.62 (ddd, 1H, J ) 7.83, 1.71, 0.93 Hz),
10 (s, 1H); IR (KBr) 3304, 1671, 1512 cm-1; MS, m/z 290 (100)
(M+), 261 (4), 197 (5), 186 (8), 156 (4), 129 (5), 106 (12), 79
(95). C18H14N2O2 Anal. Calcd: C, 74.47; H, 4.86; N, 9.65.
Found: C, 74.42; H, 4.88; N, 9.64.
Melting points are uncorrected.
1b: 1H NMR (CDC13) δ 7.00-7.13 (m, 5H), 7.35 (m, 2H),
7.45 (ddd, 1H, J ) 8.18, 4.80, 0.87 Hz), 7.60 (dd, 2H, J ) 9.00,
1.98 Hz), 8.00 (s, 1H), 8.21 (dd, 1H, J ) 8.18, 1.71 Hz), 8.77
(dd, 1H, J ) 4.80, 1.71 Hz), 9.09 (d, 1H, J ) 0.87 Hz); IR (KBr)
3380, 1650, 1500 cm-1; MS, m/z 290 (43) (M+), 261 (4), 184
(9), 129 (7), 106 (100), 78 (37), 51 (21); mp 154.5-156.5 °C
(Tomlison, 1989).
Syn th esis of 4-(4-Acetyla m in op h en oxy)a n ilin e (6). 4,4′-
Di(aminophenyl) ether (2.01 g, 10 mmol) was dissolved in 50
mL of dry tetrahydrofuran (THF) (Leonard et al., 1995). Then
0.945 mL (10 mmol) of acetic anhydride, dissolved in 10 mL
of THF, was added dropwise to this solution. The solution was
continuously stirred, and the temperature was kept below 30
°C during the addition. After 1 h, the reaction mixture was
neutralized to pH 7-8 by the addition of 50 mL of water and
solid NaHCO3. The reaction mixture was extracted with ethyl
acetate. The resulting organic layer was extracted with 2 M
HCl. The remaining acidic aqueous solution was neutralized
to pH 7-8 by addition of solid NaHCO3 and finally extracted
again with ethyl acetate. The new organic phase was dried
over anhydrous magnesium sulfate, filtered, and evaporated.
The residue was purified by flash chromatography (SiO2, 1:1
chloroform/ethyl acetate) to afford compound 6 (0.85 g, 35%
yield).
Syn th esis of Allyl N-[4-(4-Am in op h en oxy)p h en yl]ca r -
ba m a te (7). 4,4′-Di(aminophenyl) ether (2.01 g, 10 mmol) was
dissolved in 50 mL of dry THF (Leonard et al., 1995), and 2.78
mL (20 mmol) of dry triethylamine (Leonard et al., 1995) was
added. Next, 1.06 mL (10 mmol) of allyl chloroformate,
dissolved in 10 mL of THF, was added dropwise to this
solution. The solution was continuously stirred, and the
temperature was kept below 30 °C during the addition. After
1 h, stirring was stopped. One hour later the reaction mixture
was filtered and the filtrate was evaporated. The residue was
dissolved again in hot chloroform and then allowed to cool to
room temperature. The cold organic solution was again filtered
and evaporated. The residue was purified by flash chroma-
tography (SiO2, 93:7 chloroform/ethyl acetate) to afford com-
pound 7 (0.77 g, 27% yield).
1c: 1H NMR (CDC13) δ 7.00-7.13 (m, 5H), 7.34 (m, 2H),
7.49 (ddd, 1H, J ) 7.83, 7.65, 1.2 Hz), 7.60 (d, 2H, J ) 8.85
Hz), 7.70 (dd, 1H, J ) 4.41, 1.65 Hz), 7.95 (s, 1H), 8.30 (dd,
1H, J ) 7.65, 1.62 Hz), 8.62 (dd, 1H, J ) 7.65, 1.65 Hz), 8.80
(dd, 2H, J ) 4.41, 1.62 Hz), 10 (s, 1H); IR (KBr) 3360, 3290,
1650, 1490 cm-1; MS, m/z 290 (100) (M+) 184 (58), 129 (9),
106 (92), 78 (19); mp 146-148 °C. C18H14N2O2 Anal. Calcd:
C, 74.47; H, 4.86; N, 9.65. Found: C, 74.43; H, 4.87; N, 9.64.
1d : 1H NMR (CDC13) δ 7.00-7.13 (m, 5H), 7.34 (m, 2H),
7.76 (dd, 2H, J ) 8.97, 2.16 Hz), 8.60 (dd, 1H, J ) 2.43, 1.50
Hz), 8.82 (d, 1H, J ) 2.43 Hz), 9.52 (d, 1H, J ) 1.50 Hz), 9.84
(s, 1H); 8.30 (ddd, 1H, J ) 7.65, 1.20, 0.93 Hz), 8.62 (ddd, 1H,
J ) 7.83, 1.71, 0.93 Hz), 10 (s, 1H); IR (KBr) 3360, 1670, 1490;
MS, m/z 291 (100) (M+), 211 (4), 184 (31), 107 (12), 80 (39), 53
(6); mp 158-160 °C. C17H13N3O2 Anal. Calcd: C, 70.10; H, 4.50;
N, 14.42. Found: C, 70.05; H, 4.51; N, 14.40.
2a : 1H NMR (acetone-d6) δ 2.02 (s, 3H), 6.96-7.10 (m, 4H),
7.64 (d, 2H, J ) 9.00 Hz), 7.67 (ddd, 1H, J ) 7.68, 4.77, 1.20
Hz), 7.95 (dd, 2H, J ) 9.06, 2.22 Hz), 8.10 (dt, 1H, J ) 7.68,
1.71 Hz), 8.27 (dpt, 1H, J ) 7.68, 1.20, 1.05 Hz), 8.72 (ddd,
1H, J ) 4.77, 1.71, 1.05 Hz), 10.30 (s, 1H), 10.5 (s, 1H); IR
(KBr) 3312, 3280, 1665, 1503 cm-1; MS, m/z 347 (77) (M+),
305 (47), 269 (3), 214 (22), 197 (7), 151 (10), 109 (40), 79 (100),
43 (30); mp 195-197 °C. C20H17N3O3 Anal. Calcd: C, 69.15;
H, 4.93; N, 12.10. Found: C, 69.12; H, 4.94; N, 12.08.
1
Syn th esis of N-(4-P h en oxyp h en yl)-2-p yr id in eca r boxa -
m id e (1a ). Typ ica l P r oced u r e. 2-Pyridinecarboxylic acid
(1.50 g, 12.18 mmol), 1,1′-carbonyldiimidazole (1.97 g, 12.15
mmol), and dry dimethylformamide (DMF) (Leonard et al.,
1995) (25 mL) were stirred for 1 h. Then 4-aminophenyl phenyl
ether (2.25 g, 12.15 mmol) dissolved in dry DMF (3 mL) was
added. The mixture was stirred for 3 days. Then, 50 mL of
water was added, and the resulting precipitate was collected
by vacuum filtration. The solid (2.61 g, 73%) was recrystallized
twice, first with chloroform and then with methanol render-
ing: 1.14 g of white crystals (mp 91-3 °C, 32% yield) (Canela
et al., 1999).
2b: H NMR (dimethyl sulfoxide-d6) δ 2.02 (s, 3H), 6.96-
7.05 (m, 4H), 7.45-7.60 (m, 3H), 8.27 (dd, 1H, J ) 7.98, 1.65
Hz), 8.75 (dd, 1H, J ) 4.77, 1.65 Hz), 9.09 (d, 1H, J ) 2.19
Hz), 9.92 (s, 1H), 10.42 (s, 1H); IR (KBr) 3280, 3260, 1630,
1490 cm-1; MS, m/z 347 (38) (M+), 305 (31), 268 (4), 214 (13),
151 (9), 106 (100), 78 (52), 43 (56); mp 243-245 °C. C20H17N3O3
Anal. Calcd: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.09; H,
4.95; N, 12.06.
2c: 1H NMR (dimethyl sulfoxide-d6) δ 2.02 (s, 3H), 6.96-
6.99 (m, 4H), 7.57 (d, 2H, J ) 9.24 Hz), 7.75 (d, 2H, J ) 9.06
Hz), 7.84 (dd, 2H, J ) 4.41, 1.68 Hz), 8.77 (dd, 2H, J ) 4.41,
1.68 Hz), 9.95 (s, 1H), 10.5 (s, 1H); IR (KBr) 3260, 1640, 1490
cm-1; MS, rn/ z 347 (39) (M+), 305 (49), 268 (4), 214 (16), 151
(10), 106 (76), 78 (55), 43 (100); mp 269-271 °C. C20H17N3O3
Anal. Calcd: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.10; H,
4.95; N, 12.03.
Ch a r a cter iza tion of P h en oxyp h en yla n ilid e Der iva -
tives. 1a : 1H NMR (CDCl3) δ 7.00-7.13 (m, 5H), 7.34 (m, 2H),
7.49 (ddd, 1H, J ) 7.65, 7.83, 1.20 Hz), 7.76 (dd, 2H, J ) 9.06,
2.25 Hz), 7.91 (dt, 1H, J ) 7.65, 1.71 Hz), 8.30 (ddd, 1H, J )

Synthesis and Activity of Phenoxyphenylcarboxamide Derivatives
J. Agric. Food Chem., Vol. 48, No. 1, 2000 85
F igu r e 2. General synthetic route to phenoxyphenylcarboxamides.
Ta ble 1. P h en oxya n ilid e Der iva tives Syn th esized
1
2d : H NMR (dimethyl sulfoxide-d6) δ 2.02 (s, 3H), 6.96-
6.99 (m, 4H), 7.57 (d, 2H, J ) 9.24 Hz), 7.75 (d, 2H, J ) 9.06
Hz), 8.80 (dd, 1H, J ) 2.46, 1.44 Hz), 8.92 (d, 1H, J ) 2.46
Hz), 9.28 (d, 1H, J ) 1.44 Hz), 9.93 (s, 1H), 10.76 (s, 1H); IR
(KBr) 3320, 3310, 1650, 1490 cm-1; MS, m/z 348 (74) (M+),
compd
X
R1
% yielda
306 (100), 215 (23), 199 (5), 151 (9), 109 (40), 80 (60), 43 (38);
mp 217-219 °C. C19H16N4O3 Anal. Calcd: C, 65.51; H, 4.63;
N, 16.08. Found: C, 65.47; H, 4.66; N, 16.03.
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
6
2-pyridinecarbonyl
3-pyridinecarbonyl
4-pyridinecarbonyl
pyrazinecarbonyl
2-pyridinecarbonyl
3-pyridinecarbonyl
4-pyridinecarbonyl
pyrazinecarbonyl
2-pyridinecarbonyl
3-pyridinecarbonyl
4-pyridinecarbonyl
pyrazinecarbonyl
H
H
H
H
H
32
26
23
48
30
29
17
22
58
50
37
16
1
3a : H NMR (CDC13) δ 4.65 (dt, 2H, J ) 5.67, 1.32), 5.26
(dpq, 1H, J ) 10.41, 2.61, 1.29 Hz), 5.35 (dpq, 1H, J ) 17.22,
2.61, 1.29 Hz), 5.97 (ddt, 1H, J ) 17.22, 10.41, 5.67 Hz), 6.64
(s, 1H), 6.95-7.05 (m, 4H), 7.36 (d, 2H, J ) 8.79 Hz), 7.55
(ddd, 1H, J ) 7.56, 5.97, 1.23 Hz), 7.74 (dd, 2H, J ) 9.00, 2.19
Hz), 7.92 (dt, 1H, J ) 7.56, 1.71 Hz), 8.35 (ddd, 1H, J ) 7.56,
1.23, 1.08 Hz), 8.62 (ddd, 1H, J ) 5.97, 1.71, 1.08 Hz), 10 (s,
1H); IR (KBr) 3334, 3291, 1736, 1664, 1490 cm-1; MS, m/z 389
(51) (M+), 304 (36), 214 (10), 106 (48), 79 (93), 41 (100); mp
139.3-141.3 °C. C22H19N3O4 Anal. Calcd: C, 67.86; H, 4.92;
N, 10.79. Found: C, 67.79; H, 4.94; N, 10.76.
CH3CONH
CH3CONH
CH3CONH
CH3CONH
CH2CHCH2OCONH
CH2CHCH2OCONH
CH2CHCH2OCONH
CH2CHCH2OCONH
CH3CONH
7
H
CH2CHCH2OCONH
3b: 1H NMR (CDC13) δ 4.65 (dt, 2H, J ) 5.49, 1.47 Hz),
5.26 (dpq, 1H, J ) 10.47, 3.03, 1.47 Hz), 5.35 (dpq, 1H, J )
17.25, 3.03, 1.47 Hz), 5.97 (ddt, 1H, J ) 17.25, 10.47, 5.49 Hz),
6.96-7.10 (m, 4H), 7.56 (ddd, 1H, J ) 7.98, 4.80, 0.87 Hz),
7.63 (d, 2H, J ) 9.00 Hz), 7.86 (dd, 2H, J ) 9.09, 2.25 Hz),
8.36 (dd, 1H, J ) 7.98, 1.68 Hz), 8.77 (s, 1H), 8.78 (dd, 1H, J
) 4.80, 1.68 Hz), 9.20 (d, 1H, J ) 0.87 Hz), 9.85 (s, 1H); IR
(KBr) 3290, 1702, 1652, 1507 cm-1; MS, m/z 389 (29) (M+),
331 (4), 304 (24), 225 (12), 214 (11), 106 (100), 78 (40), 41 (90);
mp 215-217 °C. C22H19N3O4 Calcd: C, 67.86; H, 4.92; N, 10.79.
Found: C, 67.81; H, 4.93; N, 10.76.
a
After crystallization.
1630, 1490 cm-1; MS, m/z 242 (100) (M+), 200 (88), 171 (48),
108 (64), 93 (23), 80 (27), 65 (29), 43 (97); mp 129-131 °C.
C
14H14N2O2 Anal. Calcd: C, 69.41; H, 5.82; N, 11.56. Found:
C, 69.40; H, 5.80; N, 11.50.
7: 1H NMR (CDC13) δ 3.62 (br, 2H), 4.65 (dt, 2H, J ) 5.73,
1.38 Hz), 5.27 (dpq, 1H, J ) 10.40, 2.60, 1.38 Hz), 5.36 (dpq,
1H, J ) 17.20, 2.60, 1.38 Hz), 5.97 (ddt, 1H, J ) 17.22, 10.38,
5.73 Hz), 6.67 (dd, 2H, J ) 8.80, 2.20 Hz), 6.85 (dd, 2H, J )
8.80, 2.20 Hz), 6.91 (dd, 2H, J ) 9.00, 1.60 Hz), 7.28 (dd, 2H,
J ) 9.00, 1.60 Hz), 7.31 (s, 1H); IR (KBr) 3380, 3300, 1704,
1490 cm-1; MS, m/z 284 (100) (M+), 199 (55), 171 (24), 108
(36), 41 (69); mp 99.7-101.7 °C. C14H14N2O2 Anal. Calcd: C,
67.60; H, 5.67; N, 9.85. Found: C, 67.62; H, 5.65; N, 9.79.
Act ivit y on C. pom on ella E ggs. The population of C.
pomonella was collected from an unsprayed apple tree orchard
in 1992 at Lleida (northeastern Spain) and was reared on a
semisynthetic diet at room temperature under long-day condi-
tions (Pons et al., 1994). The adults were kept in cylindrical
rearing cages, where the substrate for egg laying was wax
paper (Waxtex Menominee Paper Co.).
3c: 1H NMR (acetone-d6) δ 4.65 (dt, 2H, J ) 5.46, 1.57), 5.26
(dpq, 1H, J ) 10.44, 3.00, 1.59 Hz), 5.35 (dpq, 1H, J ) 17.22,
3.30, 1.59 Hz), 5.97 (ddt, 1H, J ) 17.22, 10.44, 5.46 Hz), 6.96-
7.02 (m, 4H), 7.62 (dd, 2H, J ) 9.03, 2.22 Hz), 7.86 (dd, 2H, J
) 9.09, 2.25 Hz), 7.90 (dd, 2H, J ) 4.41, 1.71 Hz), 8.77 (s, 1H),
8.80 (dd, 2H, J ) 4.41, 1.71 Hz), 9.80 (s, 1H); IR (KBr) 3275,
1700, 1665, 1488 cm-1; MS, m/z 389 (17) (M+), 331 (10), 310
(27), 304 (16), 225 (34), 214 (7), 170 (6), 106 (50), 78 (22), 41
(100); mp 221-223 °C. C22H19N3O4 Anal. Calcd: C, 67.86; H,
4.92; N, 10.79. Found: C, 67.82; H, 4.93; N, 10.74.
1
3d : H NMR (CDC13) δ 4.65 (dt, 2H, J ) 5.70, 1.38), 5.26
(dpq, 1H, J ) 10.41, 2.58, 1.28 Hz), 5.35 (dpq, 1H, J ) 17.22,
2.58, 1.38 Hz), 5.97 (ddt, 1H, J ) 17.22, 10.41, 5.70 Hz), 6.56
(s, 1H), 6.96-7.06 (m, 4H), 7.36 (d, 2H, J ) 8.73 Hz), 7.71
(dd, 2H, J ) 9.00, 2.22 Hz), 8.60 (dd, 1H, J ) 2.46, 1.53 Hz),
8.82 (d, 1H, J ) 2.46 Hz), 9.52 (d, 1H, J ) 1.53 Hz), 9.64 (s,
1H); IR (KBr) 3355, 3303, 1702, 1673, 1505 cm-1; MS, m/z 390
(51) (M+), 305 (45), 226 (5), 215 (15), 107 (27), 79 (49), 41 (100);
mp 170-172 °C. C21H18N4O4 Anal. Calcd: C, 64.61; H, 4.65;
N, 14.35. Found: C, 64.58; H, 4.62; N, 14.34.
Wax paper disks (9 mm in diameter) with <24-h-old codling
moth eggs were cut from the rearing cage and sprayed with 1
mL of a 5 mg/mL solution of the chemicals on pure acetone or
in acetone plus 18% dimethyl sulfoxide (DMSO). The applica-
tions were done with a Potter spray tower (Potter, 1952)
provided with a final nozzle, regulated at a pressure of 2 ×
104 N m-2 and allowing 5 s for settlement. After drying, the
disks were kept at 19 ( 1 °C in plastic Petri dishes with moist
filter paper. This temperature was chosen because it was
within the range for optimal development (Ferreira et al.,
6: 1H NMR (CD3OD) δ 2.02 (s, 3H), 3.62 (br, 2H), 6.96-
7.10 (m, 6H), 7.52 (d, 2H, J ) 9.00 Hz); IR (KBr) 3380, 3200,

86 J. Agric. Food Chem., Vol. 48, No. 1, 2000
Balcells et al.
F igu r e 3. General synthetic route to 4-phenoxyaniline precursors.
Ta ble 2. Mor ta lity a n d Len gth of Develop m en t P er iod of
<24-h -old C. pom on ella Eggs Top ica lly Sp r a yed w ith 1
m L of a 5 m g/m L Solu tion of P h en oxyp h en yl-
ca r boxa m id es (Gr ou p Com p ou n d s 1)a
Ta ble 3. Mor ta lity a n d Len gth of Develop m en t P er iod of
<24-h -old C. pom on ella Eggs Top ica lly Sp r a yed w ith 1
m L of a 5 m g/m L Solu tion of Acetyla m in op h en oxy-
p h en ylca r boxa m id es (Gr ou p Com p ou n d s 2)a
development
development
sample
control
acetone
1d
1c
1b
1a
mortality (%)
efficacy (%)
period (days)
sample
control
acetone + DMSO 37.4 ( 0.02 c
2c
2b
2a
2d
mortality (%)
efficacy (%) period (days)
0.8 ( 0.30 e
19.5 ( 0.01 d
29.2 ( 0.01 cd
33.4 ( 0.04 bcd
40.9 ( 0.09 bc
52.4 ( 0.31 bc
99.3 ( 0.27 a
9.2 ( 0.04 d
9.3 ( 0.04 d
9.7 ( 0.06 bc
10.0 ( 0.10 b
10.6 ( 0.02 a
10.8 ( 0.08 a
1.6 ( 0.26 d
9.5 ( 0.02 d
9.9 ( 0.00 c
52.7 ( 0.50 bc
57.6 ( 0.27 bc
67.3 ( 0.20 b
68.4 ( 0.12 b
10.1 ( 0.02 c
10.6 ( 0.07 b
26.3 ( 0.15 b
40.7 ( 0.43 b
99.1 ( 0.34 a
47.1 ( 0.35 b 10.9 ( 0.04 a
49.1 ( 0.18 b 11.0 ( 0.04 a
fenoxycarb
fenoxycarb
100.0 ( 0.00 a 100.0 ( 0.00 a
a
a
Mean and standard error of 5 replicates (20-30 eggs per
replicate). Efficacy calculated by Abbott’s formula. Figures followed
by the same letter within the same column were not significantly
different (Scheffe test, P > 0.05). Arcsin transformation was
carried out prior to analysis.
Mean and standard error of 5 replicates (20-30 eggs per
replicate). Efficacy calculated by Abbott’s formula. Figures followed
by the same letter were not significantly different (Scheffe test, P
> 0.05). Arcsin transformation was carried out prior to analysis.
Ta ble 4. Mor ta lity a n d Len gth of Develop m en t P er iod of
<24-h -old C. pom on ella Eggs Top ica lly Sp r a yed w ith 1
m L of a 5 m g/m L Solu tion of Allyl P h en oxyp h en yl-
ca r ba m a tes (Gr ou p Com p ou n d s 3 a n d Com p ou n d 7)a
1994), and the length of development period might be sufficient
to detect significant differences. The eggs were checked daily
for larval emergence, until no more larvae emerged in three
consecutive days. Five replicates (20-30 eggs per replicate)
were carried out. Unsprayed eggs and pure acetone sprayed
or acetone plus 18% DMSO sprayed eggs were used as controls.
The insect growth regulator fenoxycarb (J HA) was used as a
standard.
Sta tistica l An a lyses. Analysis of variance was done using
the routine ANOVA of the statistical package SAS (SAS
Institute Inc., 1985). Percentage of mortality was arcsin
transformed [arcsinsqr (percentage mortality/100)] prior to
analysis. The Scheffe test was used to separate the means, at
a level of P ) 0.05. The efficacy of each chemical was calculated
by suing Abbot’s formula, when the mortality was significantly
different from the mortality of the acetone control. A subse-
quent ANOVA of the efficacy was carried out.
development
sample
control
mortality (%)
efficacy (%)
period (days)
1.6 ( 0.27 e
18.4 ( 0.05 d
25.3 ( 0.07 cd
34.4 ( 0.23 bcd
40.7 ( 0.25 bc
48.1 ( 0.73 bc
53.8 ( 0.55 b
9.3 ( 0.07 d
9.4 ( 0.02 d
9.5 ( 0.03 d
10.2 ( 0.05 c
acetone
3d
3b
3a
7
27.2 ( 0.56 bc 11.1 ( 0.05 b
35.0 ( 1.19 bc 11.3 ( 0.02 ab
42.5 ( 0.89 b
99.5 ( 0.52 a
3c
11.7 ( 0.03 a
fenoxycarb 99.5 ( 0.44 a
a
Mean and standard error of 5 replicates (20-30 eggs per
replicate). Efficacy calculated by Abbott’s formula. Figures followed
by the same letter were not significantly different (Scheffe test, P
> 0.05). Arcsin transformation was carried out prior to analysis.
Molecu la r Ca lcu la tion s. Calculations were done using
HyperChem release 5.0 for Windows (HyperChem Release 5.0
for Windows; Hypercube Inc., Gainesville, FL, 1996). Optimi-
zation of the different molecules was done using Molecular
Mechanics (MM+) with several starting conformations, and
then a semiempirical single point calculation using the AM1
parameters was carried out to obtain charges. Optimizations
with MM+ were done starting with several conformations for
each compound. The lowest energy conformer of each com-
pound was used as a starting point for AM1 calculations. With
juvenile hormone 0 we also optimized several starting confor-
mations. The most extended ones gave the lower energy values.
We used the lowest one to do a single-point calculation with
the AM1 method. Given distances are in angrstoms and were
obtained from the optimized structure.
anilines employed to synthesize the two series of
compounds, presenting an acetylamino (6) and an allyl
formylamino group (7), were prepared according to
conventional procedures (Figure 3). In both cases, the
monosubstituted compound was found together with the
starting material and the corresponding disubstituted
compound at the end of the reaction. Purification of the
crude reaction product yielded pure monoamines.
Mortality of <24-h-old C. pomonella eggs sprayed
with the synthesized substances (Table 1) and the
efficacy of these compounds are shown in Tables 2-4.
Several of the tested compounds (1a , 1b, 2a , 2d , 3a ,
and 3c) showed an ovicidal activity against C. pomonella
eggs significantly different from that of the controls; the
efficacy for these substances ranged from 26 to 50%. The
efficacy of the well-known ovicide fenoxycarb was 99-
100%.
Several substances also produced a significant in-
crease in the length of the development period of the
eggs 1-2 days old. Tables 2-4 show that increase is
between 10 and 20%. Both effects were correlated: the
products that produced higher mortality also produced
higher increase in the length of the development period.
The insect growth regulator effect seems to be stronger
RESULTS AND DISCUSSION
The detailed chemical reactions used to prepare all
sets of compounds are shown in Figure 2. N,N′-Carbo-
nyldiimidazole (4) is a well-known reagent employed to
obtain carboxylic acid derivatives through the formation
of an imidazolide (5) (Fieser and Fieser, 1967). Although
yields were moderate, this procedure was chosen on the
basis of its methodological simplicity. The phenoxyphen-
ylcarboxamide derivatives (group compounds 1, 2, and
3) prepared are presented in Table 1. The two precursor

Synthesis and Activity of Phenoxyphenylcarboxamide Derivatives
J. Agric. Food Chem., Vol. 48, No. 1, 2000 87
Although the activity of the tested compounds is lower
than the activity shown by fenoxycarb, two facts are
pushing us to consider new modifications: (1) the
similar activity between 1a and some insect juvenile
hormones (Canela et al., 1999) and (2) the clear influ-
ence on the development period of C. pomonella eggs.
Thus, research is being carried out to examine the
influence of the carbamate group as well as of the
pyridine ring on the observed activity.
F igu r e 4. Possible action mode of allyl phenoxyphenylcar-
bamates (3) as J H mimetic.
LITERATURE CITED
than the biocidal effect. Thus, some products, which did
not increase the mortality, increased the length of the
development period.
Mortality caused by compound 1a was lower in the
tested conditions, 19 ( 1 °C, than in the conditions used
in our previous work, 25 ( 1 °C (Canela et al., 1999).
In that case egg hatching happens at day 5, so the
available detoxification period was shorter and the
activity higher.
Canela, R.; Balcells, M.; Dalmau, L.; Avilla, J . Activity of a
picolinphenoxyanilide against Cydia pomonella. Pestic. Sci.
1999, submitted for publication.
Croft, B. A.; Riedl, H. W. Chemical Control and Resistance to
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Ferreira, V. S.; Riedl, H.; Sarasu´a, M. J .; Avilla, J . Modeliza-
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Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
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Katagi, T.; Mikami, N.; Matsuda, T.; Miyamoto, J . Theoretical
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del fotoperiodo sobre la induccio´n de diapausa de Cydia
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These results seem to confirm the hypothesis pre-
sented in our previous publication (Canela et al., 1999).
In the three groups of obtained products, compounds
derived from picolinic acid present activities signifi-
cantly different from that of the control. However, only
in the first group of derivatives is efficiency, measured
as absolute value, higher than that of the other active
derivative. In the other groups there is always another
substance, with the nitrogen in a different ring position,
with absolute values of efficiency higher than those of
the corresponding picolinic derivative. This fact, and the
nonexistence of statistically significant differences among
the different active products, makes it difficult to draw
a final conclusion about the role of the position of the
nitrogen in the observed ovicidal activity.
Nevertheless, it is evident that the carbamate group
(Table 4) causes an increase of the development period
when the substance appears active. Considering these
results, the precursor 7 (Figure 3) was tested. As Table
4 shows, such a substance presented an efficiency
similar to that of the other two active products of this
group, causing an elongation of the development period
also.
In Figure 4 the extended structure of these substances
is compared with that of the J H 0. The coincidence of
the carbamate group with the carboxylate one of the
juvenile hormone, as well as that of the oxirane ring
with the amide, might explain the kind of observed
activity. Thus, the calculated distance between the
tertiary carbon supporting the epoxide group and the
carbon from the carboxylic group in the J H 0 optimized
conformation is 11.70 Å, very close to 11.74 Å (the
distance between both carboxamidic carbons in com-
pound 3a optimized conformation). Moreover, positive
charges are assigned to the indicated carbons in both
structures. The distance between the epoxy oxygen and
the carbonyl carbon at the other end (10.83 Å) in J H 0
was in the same range as that found by Katagi et al.
(10.70-11.86 Å) for insect juvenile hormone III struc-
tures optimized using an MNDO program (Katagi et al.,
1989). The lack of activity of some of the products tested,
despite having a very similar structure, would remain
without explanation. Logically, any structural modifica-
tion can alter the potential surface of the molecule,
varying its capacity to interact with the desired receptor
or another receptor different from this.
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Received for review April 12, 1999. Accepted October 21, 1999.
J F990404E