Synthesis and fungicidal activity of N-2-(3-methoxy-4-propargyloxy) phenethyl amides. Part 3: Stretched and heterocyclic mandelamide oomyceticides

Article abstract of DOI:10.1002/ps.1308

Novel analogues of mandipropamid have been designed and prepared. The synthetic approach to these stretched and heterocyclic mandelamides is outlined. Biological data demonstrate their high efficacy against important plant diseases like tomato and potato

Full text of DOI:10.1002/ps.1308

Pest Management Science
Pest Manag Sci 63:57–62 (2007)
Synthesis and fungicidal activity
of N-2-(3-methoxy-4-propargyloxy)
phenethyl amides. Part 3: stretched and
heterocyclic mandelamide oomyceticides†
Clemens Lamberth,1∗ Hans-Joachim Kempf2 and Miroslav Krizˇ3
1Syngenta AG, Crop Protection Research, Chemistry, Schwarzwaldallee 215, CH-4058 Basel, Switzerland
2Syngenta AG, Crop Protection Research, Biology, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
3Synkola Consortium, Mlynska dolina, areal PvF UK, 84215 Bratislava, Slovakia
Abstract: Novel analogues of mandipropamid have been designed and prepared. The synthetic approach to these
stretched and heterocyclic mandelamides is outlined. Biological data demonstrate their high efficacy against
important plant diseases like tomato and potato late blight (Phytophthora infestans De Bary) and grape downy
mildew (Plasmopara viticola Berliner & de Toni). Structure–activity relationship studies are discussed.
 2006 Society of Chemical Industry
Keywords: mandipropamid; fungicide; Phytophthora infestans; Plasmopara viticola; glyceric acid amide; Passerini
reaction
viticola Berliner & de Toni (grape downy mildew) and
Pseudoperonospara cubensis Rostow (cucumber downy
mildew). Mandipropamid is highly active against spore
germination, but it also inhibits mycelial growth and
sporulation.8 Locking rapidly and tightly to the wax
layer of the plant surface,9 mandipropamid provides
a rainfast and long-lasting barrier to fungal diseases.
It is reported here that mandipropamid analogues
with a spacer in between the 4-chlorophenyl ring
and the 2-propargyloxyacetamide function (‘stretched
mandelamides’), such as 5, and with a aromatic
heterocycle replacing the phenyl ring of the mandelic
acid moiety (‘heterocyclic mandelamides’), such as 6,
display strong fungicidal activity against oomycetes
diseases.
1
INTRODUCTION
The distinguished activity of mandelamides with
dialkoxylated phenethylamine moieties against fungal
diseases was first discovered in the field of human
pathogens by Yu and Van Scott in the mid-1980s.1
They found that 1 (Fig. 1), which is the acetylated
adduct of mandelic acid and homoveratrylamine,
has significant activity against skin disorders such
as fungal mycosis and psoriasis. In the early
1990s, this structural motif was taken up by
chemists at Agrevo (now Bayer), who found that
the mandelamide SX 623 509 (2) has activity against
plant pathogens, especially oomycetes diseases.2,3 At
Novartis (now Syngenta), the replacement of the
ethoxy group of 2 by a propargyloxy function resulted
in the mandelamide 3 with enhanced fungicidal
efficacy.4 Similar experiences, that the replacement
of methoxy or ethoxy groups by propargyloxy
leads to increases in biological activity, have also
been reported in the pharmaceutical literature for
compounds with antibacterial5 and leishmanicidal6
activity. The introduction of a further propargyl
group into the mandelic acid moiety increased the
fungicidal activity dramatically, leading finally to
Syngenta’s new oomycete fungicide mandipropamid
(4),7,8 which is the first derivative of the chemical
class of mandelamide fungicides to be commercialized.
Mandipropamid is highly effective against most
foliar oomycete pathogens such as the economically
important plant diseases Phytophthora infestans De
Bary (potato and tomato late blight), Plasmopara
2
MATERIALS AND METHODS
2.1 Chemical synthesis
The synthetic pathways used to prepare the stretched
mandelamide 5 are shown in Fig. 2. 4-Chlorophenol
(7) is alkyated with 3-chlorolactic acid without protec-
tion of the acid’s hydroxy and carboxy functions.10 The
resulting glyceric acid derivative 8 is then transformed
into the α-hydroxy amide 12 by peptide coupling
with the phenethylamine 9,7 Castro’s reagent and
Hunig’s base. Finally, 12 can be converted into the
desired stretched mandelamide 5 by alkylation with
propargyl bromide under basic conditions. In an alter-
native synthesis of 5, 4-chlorophenol (7) is reacted
with bromoacetaldehyde diethyl acetal, which after
¨
∗ Correspondence to: Clemens Lamberth, Syngenta AG, Crop Protection Research, Chemistry, Schwarzwaldallee 215, CH-4058 Basel, Switzerland
E-mail: clemens.lamberth@syngenta.com
†Part 2: Anti-oomycetic mandelamides. Pest Manag Sci 62:446-451 (2006)
(Received 15 May 2006; revised version received 5 July 2006; accepted 24 July 2006)
Published online 31 October 2006; DOI: 10.1002/ps.1308
 2006 Society of Chemical Industry. Pest Manag Sci 1526–498X/2006/$30.00

C Lamberth, H-J Kempf, M Krizˇ
12, which can be propargylated to 5 as described above.
This special multicomponent condensation was also
applied to the concise synthesis of heterocyclic man-
delamides, such as 6, starting from the corresponding
heterocyclic aldehydes. The stereoselective synthesis
of enantiopure stretched or heterocyclic mandelamides
would be possible via the diastereoselective Passerini
reaction with a galacturonic acid derivative as acid
component.17
O
O
H
N
O
O
O
O
1
OH
H
N
O
O
Cl
Cl
2.1.1 3-(4-Chlorophenoxy)-2-hydroxypropionic acid
(8)
A mixture of 4-chlorophenol (7, 9.3 g, 72 mmol) and
3-chlorolactic acid (5.0 g, 40 mmol) in 40 mL of 3.3
M aqueous sodium hydroxide solution was heated
to reflux for 2 h. The mixture was cooled to room
temperature and acidified to pH 3 with concentrated
aqueous hydrochloric acid. The resulting crystals were
filtered and dissolved in hot water and the hot solution
was adjusted to pH 1 with concentrated sulfuric acid.
Upon cooling, the product was collected in crystalline
form. Yield: 4.8 g (22 mmol, 55%). 1H NMR (d6-
DMSO): δ 3.93 (d, 2H, OCH2), 4.14 (t, 1H, CHOH),
6.76 (d, 2H, CH arom.), 7.12 (d, 2H, CH arom.).
2
OH
H
N
O
O
O
Br
3
O
2.1.2 3-(4-Chlorophenoxy)-2-hydroxy-N-[2-(3-
methoxy-4-prop-2-ynyloxyphenyl)ethyl]propionamide
(12)
H
N
O
O
O
(Benzotriazol-1-yloxy)tris(dimethylamino)
phos-
Cl
phonium hexafluorophosphate (BOP, Castro’s rea-
gent, 9.5 g, 21 mmol) was added slowly to a solu-
tion of 8 (4.3 g, 20 mmol), 2-(3-methoxy-4-prop-2-
ynyloxyphenyl)ethylamine hydrochloride7 (9, 5.0 g,
21 mmol) and N-ethyldiisopropylamine (10 g,
78 mmol) in 70 mL of N,N-dimethylformamide. This
reaction mixture was stirred at room temperature for
16 h, poured into water and extracted 3 times with ethyl
acetate. The combined organic phases were washed
with brine, dried over magnesium sulfate and concen-
trated. The residue was purified by chromatography
on silica gel (ethyl acetate + hexane, 7 + 3 by volume).
4
O
H
O
O
N
O
O
Cl
Cl
5
1
Yield: 7.4 g (18 mmol, 93%). H NMR (CDCl3): δ
≡
2.52 (t, 1H, C CH), 2.83 (t, 2H, CH2CH2), 3.61
(q, 2H, CH2CH2), 3.89 (s, 3H, OCH3), 4.15 (d, 2H,
≡
OCH2), 4.43(t, 1H, CHOH), 4.76(d, 2H, CH2C C),
6.72–7.30 (m, 7H, CH arom.).
O
H
N
S
O
O
2.1.3 (4-Chlorophenoxy)acetaldehyde (10)
A mixture of 4-chlorophenol (7, 13 g, 0.1 mol)
in 15 mL of N,N-dimethylformamide was added
O
6
dropwise to
a vigorously stirred suspension of
sodium hydride (2.6 g, 0.11 mol) in 50 mL of
N,N-dimethylformamide. After 20 min at room
temperature, bromoacetaldehyde diethyl acetal (20 g,
0.1 mol) was added and the resulting mixture was
heated to 90 ◦C for 4 h. The reaction mixture was
poured on water and extracted with ethyl acetate. The
combined organic layer was washed with brine, dried
over magnesium sulfate and evaporated. The residue
was taken up in 250 mL of a mixture of acetone
Figure 1. Fungicidal mandelamides and other
α-hydroxycarboxamides.
acidic workup leads to the aryloxyacetaldehyde 10.11
This aldehyde is then further transformed with the
formamide 11,7,12 triphosgene, triethylamine and tita-
nium tetrachloride, using Seebach’s modification13,14
of the Passerini reaction,15,16 into the α-hydroxy amide
58
Pest Manag Sci 63:57–62 (2007)
DOI: 10.1002/ps

Synthesis and activity of mandipropamide analogues
OH
OH
OH
O
ClCH2CHOHCO2H, NaOH
O
Cl
Cl
Cl
Cl
7
8
BOP, EtN(iPr)2,
H2N
O
O
BrCH2CH(OEt)2, NaH
Cl3COCO2CCl3, NEt3, TiCl4,
H
9
O
N
H
O
OH
O
H
N
O
11
O
O
O
O
H
O
Cl
10
12
HC CCH2Br,
NaOH
O
H
N
O
O
O
O
5
Figure 2. Different synthetic approaches to the stretched mandelamide 5.
and water. Concentrated sulfuric acid (0.75 g) was
added and the mixture was heated to reflux for 16 h.
After cooling, the reaction mixture was poured on
ice and extracted 3 times with dichloromethane. The
combined organic layer was washed with 50 g L−1
aqueous sodium bicarbonate solution and dried
over magnesium sulfate. Evaporation of the solvent
delivered the product, which could be transformed in
the next step without further purification. Yield: 13 g
temperature did not exceed −70 ◦C. After comple-
tion of the addition, the reaction mixture was stirred
for 2 h at −40 ◦C. A solution of 10 (5.6 g, 33 mmol)
in 40 mL of dichloromethane was added dropwise at
−40 ◦C and the reaction mixture was stirred for 16 h
at room temperature. Subsequently the mixture was
quenched with 20 mL of 5 M hydrochloric acid and
stirred for 30 min at room temperature. The phases
were separated, the aqueous phase was extracted 3
times with dichloromethane and the combined organic
layer was washed with brine, dried over magne-
sium sulfate and evaporated. The remaining oil was
purified by chromatography (ethyl acetate + hexane,
1
(78 mmol, 78%). H NMR (CDCl3): δ 4.42 (d, 2H,
OCH2), 6.87–7.33 (m, 4H, CH arom.), 9.71 (t, 1H,
CHO).
2.1.4 3-(4-chlorophenoxy)-2-hydroxy-N-[2-(3-
methoxy-4-prop-2-ynyloxyphenyl)ethyl]propionamide
(12)
1 + 4 by volume). Yield: 9.0 g (22.5 mmol, 72%).
1
≡
H NMR (CDCl3): δ 2.52 (t, 1H, C CH), 2.83 (t,
2H, CH2CH2), 3.61 (q, 2H, CH2CH2), 3.89 (s, 3H,
OCH3), 4.15 (d, 2H, OCH2), 4.43 (t, 1H, CHOH),
To a solution of N-[2-(3-methoxy-4-prop-2-ynyloxy-
phenyl)ethyl]formamide7,12 (11, 7.3 g, 31 mmol) in
80 mL of dichloromethane was added triethylamine
(7.6 g, 75 mmol). The mixture was cooled to
0–5 ◦C and a solution of bis(trichloromethyl) car-
bonate (triphosgene, 3.7 g, 12 mmol) in 40 mL of
dichloromethane was added dropwise at 5 ◦C. After
the addition was complete, the reaction was stirred
for 4 h at 5 ◦C. Subsequently, the reaction was cooled
down to −75 ◦C and a solution of titanium tetrachlo-
ride (6.5 g, 35 mmol) in 60 mL of dichloromethane
was added dropwise in such a way that the reaction
≡
4.76 (d, 2H, CH2C C), 6.72–7.30 (m, 7H, CH
arom.).
2.1.5 3-(4-Chlorophenoxy)-N-[2-(3-methoxy-4-prop-
2-ynyloxyphenyl)ethyl]-2-prop-2-ynyloxypropionamide
(5)
An 80% solution of propargyl bromide in toluene
(1.7 g, 11 mmol) was added slowly at room tempera-
ture to a mixture of 12 (3.5 g, 8.7 mmol), 300 g L−1
aqueous sodium hydroxide solution (4.4 mL, 44
mmol) and catalytic amounts of tetrabutylammonium
Pest Manag Sci 63:57–62 (2007)
59
DOI: 10.1002/ps

C Lamberth, H-J Kempf, M Krizˇ
Table 1. Variation of the spacer between the phenyl ring and the
α-propargyloxy-carboxamide function in the mandelic acid moiety of
mandipropamid (5)
bromide in 20 mL of dichloromethane. The reaction
mixture was stirred for 16 h at 40 ◦C. Subsequently the
mixture was evaporated and the residue was diluted
with water and dichloromethane. The phases were
separated and the aqueous layer was extracted 3
times with dichloromethane. The combined organic
phases were washed with brine, dried over magnesium
sulfate and evaporated. The remainder was purified
by chromatography (ethyl acetate + hexane, 1 + 4 by
volume). Yield: 1.8 g (4.1 mmol, 47%). 1H NMR
Cl
O
H
O
N
R
O
O
EC80 (mg L−1
)
a
≡
≡
(CDCl3): δ 2.39 (t, 1H, C CH), 2.43 (t, 1H, C CH),
2.72 (t, 2H, CH2CH2), 3.49 (q, 2H, CH2CH2), 3.80
Phytophthora
Plasmopara
≡
(s, 3H, OCH3), 4.01–4.33 (m, 5H, OCH2, CH2C C,
infestans (tomato viticola (grape
≡
CHO), 4.68 (d, 2H, CH2C C), 6.67–7.19 (m, 7H,
Compound
R
–
late blight)
downy mildew)
CH arom.).
4
13
14
5
15
16
17
18
0.1
26.3
>200
0.02
33.2
28.8
0.3
1.2
18.6
>200
0.6
20.7
100.5
20.4
CH2
O
OCH2
SCH2
2.2 Biological assays
2.2.1 Phytophthora infestans/tomato (late blight on
tomato)
Three-week-old tomato plants (Lycopersicon esculentum
Mill. cv. Roter Gnom) were treated with the
formulated test compound in a spray chamber. Two
days after application, plants were inoculated by
spraying a sporangial suspension (2 × 104 sporangia
mL−1) on the test plants. After an incubation period
of 4 days at 18 ◦C and 95% relative humidity (RH) in
a growth chamber, disease incidence was assessed.
CH(CH3)CH2
CH2OCH2
CH2CH2OCH2
32.0
45.9
a Concentration showing 80% activity in greenhouse trials.
Table 2. Variation of the phenyl substituent in the mandelic acid
moiety of stretched mandelamides
2.2.2 Plasmopara viticola/grape (grape downy
mildew)
Five-week-old grape seedlings (Vitis vinifera L. cv.
Gutedel) were treated with the formulated test
compound in a spray chamber. One day after
application, grape plants were inoculated by spraying
a sporangial suspension (4×104 sporangia mL−1) on
their lower leaf surface. After an incubation period of
6 days at 22 ◦C and 95% RH in a greenhouse, disease
incidence was assessed.
O
H
O
N
O
R
O
O
EC80 (mg L−1
)
a
Phytophthora
infestans (tomato viticola (grape
Plasmopara
Compound
R
late blight)
downy mildew)
19
20
21
5
H
7.8
38.7
26.3
0.02
10.5
15.8
0.1
41.6
18.6
17.8
14.8
56.2
40.0
32.0
2.0
38.7
19.8
0.6
1.6
5.1
3
RESULTS AND DISCUSSION
2-Cl
3-Cl
4-Cl
4-F
4-Br
4-CH3
3.1 Influence of the spacer between the phenyl
ring and the 2-propargyloxyacetamide function
in the mandelic acid moiety of mandipropamid
(4) on anti-oomycetic activity
22
23
24
25
26
27
28
29
30
31
Table 1 compares EC80 values of mandipropamid
(4) and its derivatives bearing different spac-
ers between the 4-chlorophenyl ring and the 2-
propargyloxyacetamide function on tomato late blight
and grape downy mildew. One-atom carbon or oxy-
gen spacers, as in 13 and 14, generally seem to be
unfavourable. However, the introduction of an addi-
tional linker atom leads to the highly active glyceric
acid amide 5 with an OCH2 bridge. Its impres-
sive efficacy, especially against P. infestans down to
0.02 mg L−1, was unrivalled by all other mandelamide
derivatives, and it is also very active against P. viti-
cola. The stretched mandelamide 17 with a three-atom
spacer is still highly active on tomato late blight, but it
1.8
3-CF3
53.7
42.8
48.1
2.9
5.3
34.6
60.4
3-F-4-Cl
3-CH3-4-Cl
3-CH3-4-Br
4-CH3CH2
4-CH3S
4-CH3O
a Concentration showing 80% activity in greenhouse trials.
has somehow lost the P. viticola efficacy. Four or more
linker atoms, as in 18, seem to be unsuitable.
60
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Synthesis and activity of mandipropamide analogues
Table 3. Replacement of the phenyl ring in the mandelic acid moiety
4
CONCLUSION
of mandelamides by a heterocycle
The introduction of a spacer between the phenyl
ring and the 2-propargyloxyacetamide function in the
mandelic acid moiety of mandipropamid (4) leads to
stretched mandelamides, some of which possess high
fungicidal activity. In particular, the application of an
OCH2 two-atom linker, converting the mandelamide
into a glyceric acid amide, results in extremely potent
oomyceticides. The replacement of the 4-chlorophenyl
ring of mandipropamid by different heterocycles
delivers heterocyclic mandelamides, of which mainly
the five-membered ring derivatives display the best
biological efficacy.
O
H
O
N
R
O
O
EC80 (mg L−1
)
a
Phytophthora
infestans
(tomato late
blight)
Plasmopara
viticola
(grape downy
mildew)
Compound
R
32
O
17.5
2.1
12.4
1.4
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