Fungicidal Activity of 2-Dichlorophenyl-3-triazolylpropyl Ethers
J. Agric. Food Chem., Vol. 48, No. 6, 2000 2549
solid (0.30 g, 30% yield): mp 86-87 °C; NMR (CDCl3) δ 1.88
(2 H, m, CH2), 3.5-3.8 (6 H), 3.95 (1 H, m, CH), 4.53 (2 H, m,
CH2O), 7.13 (1 H, d, J ) 8 Hz, H-6′), 7.19 (1 H, dd, J ) 8 and
Hz, H-5′), 7.4 (1 H, d, J ) 2 Hz, H-3′), 7.88 and 7.94 (2 H, 2 s,
triazole); MS, m/z (%) 331 (M+, 10), 329 (18), 294 (21), 174 (61),
172 (100), 137 (15).
g, 6.0 mmol) were added in small portions in 30 min. The
mixture was stirred at room temperature overnight and
filtered. The solvent was evaporated, and the crude residue
was purified by column chromatography. The title compound
10a was obtained as a white solid: 0.86 g, 55%, mp 122-125
°C; NMR (CDCl3) δ 4.50 (2 H, s, CH2Br), 4.98 (2 H, s, OCH2),
5.07 (2 H, s, OCH2), 6.8-7.5 (13 H).
P r oced u r e E. Syn th esis of Com p ou n d 5. A solution of
methylmagnesium iodide obtained by treating Mg (0.7 g, 29
mmol) with methyl iodide (1.8 mL, 29 mmol) in anhydrous
ethyl ether (30 mL) was added dropwise with 2,4-dichloroac-
etophenone (5 g, 26.4 mmol) in ethyl ether (20 mL); the
temperature was maintained under 20 °C with a cool bath.
The mixture was then refluxed for 7 h, cooled, and treated
with NH4Cl (3 g in 5 mL of water). After extraction with ethyl
ether (2 × 30 mL), the organic phase was dried, evaporated,
and purified by column chromatography (hexane/ethyl acetate
9:1) to give 2-(2,4-dichlorophenyl)propan-2-ol, 11, as a colorless
oil (3.5 g, 65% yield): NMR (CDCl3) δ 1.73 (6 H, s, CH3), 2.45
(OH), 7.20 (1 H, d, J ) 2 Hz, H-3′), 7.38 (1 H, dd, J ) 9 and 2
Hz, H-5′), 7.68 (1 H, d, J ) 9 Hz, H-6′). This compound was
heated at reflux for 5 h in acetic anhydride (10 mL). The
mixture was poured into water (15 mL) and extracted with
ethyl acetate. The organic phase was dried and evaporated,
and the residue was purified by column chromatography to
give 2-(2,4-dichlorophenyl)-2-acetoxypropane, 12 (2.38, 56%
yield): NMR (CDCl3) δ 1.83 (6 H, s, CH3), 2.05 (3 H, s, COCH3),
7.2-7.5 (3 H, arom). This compound (1.1 g, 4.5 mmol) was
distilled bulb to bulb at 200 °C to give 2-(2,4-dichlorophenyl)-
prop-1-ene, 13, as a colorless oil (0.8 g, 95% yield): NMR
(CDCl3) δ 2.06 (3 H, m, CH3), 4.98 (1 H, m, CdCH), 5.23 (1 H,
m, CdCH), 7.0-7.4 (3 H, arom). This compound (0.8 g, 4.3
mmol) in 1,1,2,2,-tetrachloroethane (8 mL) was treated with
N-bromosuccinimide (0.91 g, 5.1 mmol) and a catalytic amount
of dibenzoylperoxide. The mixture was heated under reflux for
4 h and then filtered. The solvent was evaporated, and
purification by column chromatography gave 0.81 g of a 57:43
mixture of 3-bromo-2-(2,4-dichlorophenyl)prop-1-ene, 15, and
1-bromo-2-(2,4-dichlorophenyl)prop-1-ene, 14. This mixture
(0.50 g) was added with anhydrous triethylamine (0.2 mL, 2.82
mmol) and 1,2,4-triazole (0.25 g, 3.76 mmol) in ethyl acetate
(15 mL). The mixture was heated at reflux for 40 h, then
treated with HCl (1 M, 10 mL), and extracted with ethyl
acetate (3 × 10 mL). The organic layer was washed with NaOH
(1 M), dried and evaporated. Compound 5 was purified by
column chromatography (220 mg, 47%); NMR (CDCl3) δ 5.15
(2 H, s, CH2-triaz), 5.31 (1 H, s, dCH), 5.45 (1 H, s, dCH),
7.00 (1 H, d, J ) 8 Hz, H-6), 7.20 (1 H, dd, J ) 8 Hz, H-6),
7.20 (1 H, dd, J ) 8 and 2 Hz, H-5), 7.44 (1 H, J ) 2 Hz, H-3),
7.95 and 8.00 (2 H, 2 s, triazole); MS, m/z (%) 253 (M+, 12),
220 (29), 218 (100), 136 (11).
Syn t h esis of 4-[3-(Ben zyloxy)b en zyloxy]b en zylb r o-
m id e, 10b. Alcohol 6b (1.34 g, 6.25 mmol) was dissolved in
dry dichloromethane (45 mL) at 0 °C. Tetrabromomethane
(3.11 g, 9.37 mmol) and triphenylphosphine (2.46 g, 9.37 mmol)
were added, and the mixture was kept at room temperature
for 22 h. The mixture was then filtered with suction, dried,
and concentrated. Compound 7b was purified by column
chromatography: 1.16 g, 67% yield, mp 45-47 °C; NMR
(CDCl3) δ 4.42 (2 H, s, CH2Br), 5.05 (2 H, s, OCH2), 6.8-7.7 (9
H). The mixture obtained by adding this compound (1.08 g,
3.90 mmol), methyl 4-hydroxybenzoate (0.593 g, 3.90 mmol),
and K2CO3 (1.348 g, 9.75 mmol) in 2-butanone (65 mL) was
refluxed for 6 h and then filtered. The filtrate was washed with
ethyl acetate, and the organic phase was washed with water
(2 × 20 mL), dried, and evaporated to give an amber yellow
thick oil, which was chromatographed to give 8b as a white
solid: 0.78 g, 57% yield, mp 73-75 °C; NMR (CDCl3) δ 3.90
(3 H, s, OCH3), 5.07 (4 H, s, OCH2), 6.8-7.5 (11 H), 8.0 (2 H,
m). Under nitrogen, LiAlH4 (3.4 mL, 1 M solution in THF, 3.36
mmol) was dissolved in anhydrous THF (35 mL). Compound
8b (0.78 g, 2.24 mmol) dissolved in THF (25 mL) was added
dropwise at 0 °C, and then the mixture was stirred at reflux
for 5.30 h. After addition of ethyl acetate (1 mL) and H2SO4
(10%, 1 mL), the solution was filtered and evaporated. Ethyl
acetate (30 mL) and water (30 mL) were added to the residue.
The organic phase was dried and evaporated to give 9b as a
colorless oil, which solidified slowly: 0.68 g, 95% yield, mp 66-
67 °C; NMR (CDCl3) δ 4.62 (2 H, s, CH2OH), 5.02 (2 H, s,
OCH2), 5.07 (2 H, s, OCH2), 6.8-7.5 (13 H). Compound 9b (0.68
g, 2.12 mmol) was treated with tetrabromomethane (1.054 g,
3.18 mmol) and triphenylphosphine (0.384 g, 3.18 mmol) as
indicated above, giving the title compound 10b as a color-
less thick oil: 0.54 g, 66% yield; NMR (CDCl3) δ 4.50 (2 H, s,
CH2Br), 5.02 (2 H, s, OCH2), 5.07 (2 H, s, OCH2), 6.8-7.5 (13
H).
Syn th esis of En a n tiom er s (+)-3a a n d (-)-3a . These were
prepared following procedure A starting from (R)-(+)-2 and
(S)-(-)-2, respectively. Compound (R)-(+)-3a was obtained in
70% yield and had [R]D ) +52 (c 1, MeOH). Compound (S)-
(-)-3a was obtained in 53% yield and had [R]D ) -51.7 (c 1,
MeOH). The optical purity was >95% and was determined by
an LIS experiment adding a percentage from 5 to 25% of tris-
[3-(heptafluoropropyl)hydroxymethylene-(+)-camphorate)-eu-
ropium(III)].
Syn t h esis of 4-[4-(Ben zyloxy)b en zyloxy]b en zylb r o-
m id e, 10a . 4-Benzyloxybenzyl chloride, 7a (2.1 g, 9.02 mmol),
methyl 4-hydroxybenzoate (1.37 g, 9.02 mmol), and anhydrous
potassium carbonate (3.11 g, 22.5 mmol) were stirred overnight
at room temperature in 2-butanone (90 mL) and then heated
for 6 h. The solids were filtered, and the solvent was evapo-
rated in part. The mixture was partitioned in 0.1 N HCl and
ethyl acetate and then extracted with ethyl acetate. After
drying, the solvent was evaporated to give an oil, which was
purified by column chromatography giving 1.62 g (52% yield)
of methyl ester 8a : mp 137 °C; NMR (CDCl3) δ 3.90 (3 H, s,
OCH3), 5.02 (2 H, s, OCH2), 5.07 (2 H, s, OCH2), 6.8-7.5 (11
H), 8.0 (2 H, m). This compound (1.62 g, 4.65 mmol) in THF
(40 mL) was dropped in 25 min in a solution of LiAlH4 (6.5
mL, 1 M solution in THF) in THF (38 mL). The mixture was
heated at reflux for 4 h, ethyl acetate (1 mL) was added, and
then 5% H2SO4 was added until pH 1 was obtained. The
organic layer was separated, and the aqueous one was
extracted with ethyl acetate. The combined extracts were dried
and evaporated to give alcohol 9a pure enough for the
subsequent step (1.30 g, 88% yield, mp 124-126 °C): NMR
(CDCl3) δ 4.62 (2 H, s, CH2OH), 4.98 (2 H, s, OCH2), 5.07 (2
H, s, OCH2), 6.8-7.5 (13 H). This compound (1.30 g, 4.06 mmol)
was dissolved in dichloromethane (45 mL) and cooled at 0 °C,
and then CBr4 (1.99 g, 6.0 mmol) and triphenylphosphine (1.57
Syn th esis of En a n tiom er s (+)-4a a n d (-)-4a . These were
prepared as described above for compounds (+)-3a and (-)-
3a . Enantiomer (+)-4a was obtained in 37% yield and had [R]D
) +45.5 (c 1, MeOH). Enantiomer (-)-4a was obtained in 64%
yield and had [R]D ) - 44.9 (c 1, MeOH). For both compounds
the optical purity, determined by a similar LIS experiment,
was >95%.
P a r tition Coefficien ts. The log P (where P is the octanol-
water partition coefficient) was obtained as described by
Arnoldi and Merlini (1990) using reversed-phase chromatog-
raphy (Braumann, 1986) by comparison with 13 reference
compounds having known log P values (Nys and Rekker, 1974).
Retention times were determined on a Hewlett-Packard HPLC
equipped with a quaternary pump HP-1050 with a Rheodyne
injector (20 µL loop) with an UV-visible detector HP-1050 or
a Waters Lambda Max model 481. Methanol for HPLC was
purchased from Baker, and water for HPLC was produced with
a Milli-Q water purification system (Millipore). Analyses were
performed on a Merck column LiChrospher 100 RP18 (250 ×
4 mm, 5 µm), and the flow rate was 1 mL/min. As the log P
values of the compounds fall in a large range, it was necessary
to use three different eluents [methanol/water, 20:80 (4h and
4i), 70:30 (compound 5), and 80:20 (all others)] and different
groups of standards.