Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel difluoromethylated heterocyclic acid moieties

Article abstract of DOI:10.1007/s00706-017-2101-y

Abstract: Novel fungicidally active succinate dehydrogenase inhibitors have been prepared, which either carry a difluoromethyl and methyl-bearing pyrazoline, pyrrole, or thiophene ring in the acid component, mimicking similar-substituted pyrazole carboxamides. As five-membered heterocyclic systems with such a special substitution pattern are barely known, unique synthesis routes had to be developed, which rely, e.g., on the van Leusen pyrrole synthesis and the halogen dance reaction. Synthesis and biological activity against selected Ascomycete pathogens of these difluoromethylated pyrazoline, pyrrole, and thiophene derivatives are reported.

Full text of DOI:10.1007/s00706-017-2101-y

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-017-2101-y
ORIGINAL PAPER
Synthesis of fungicidally active succinate dehydrogenase inhibitors
with novel difluoromethylated heterocyclic acid moieties
Harald Walter1 Clemens Lamberth1 Camilla Corsi1
•
•
Received: 20 October 2017 / Accepted: 13 November 2017
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2017
Abstract
Novelfungicidallyactivesuccinate dehydrogenaseinhibitorshavebeenprepared, whicheither carryadifluoromethylandmethyl-
bearing pyrazoline, pyrrole, or thiophene ring in the acid component, mimicking similar-substituted pyrazole carboxamides. As
five-membered heterocyclic systems with such a special substitution pattern are barely known, unique synthesis routes had to be
developed, which rely, e.g., on the van Leusen pyrrole synthesis and the halogen dance reaction. Synthesis and biological activity
against selected Ascomycete pathogens of these difluoromethylated pyrazoline, pyrrole, and thiophene derivatives are reported.
Graphical abstract
Keywords Fungicide Á Thiophene Á Pyrrole Á Pyrazoline Á Succinate dehydrogenase inhibitor
Introduction
commercialized active ingredients of this compound class
[1–5]. Although the chemical scope of the amine part is
relatively broad and reaches from aniline derivatives over
benzylamine derivatives to phenethylamine derivatives, the
structure–activity relationship requirements of the acid
portion seem to be much more restricted. The oxathiine ring
system of carboxin (1), the very first complex II inhibitor
which was launched in the 1960s, bears a methyl group next
to its carboxyl function. A first breakthrough towards a
broader spectrum was the introduction of boscalid (2), which
carries a chloro-substituent in the ortho-position of the car-
boxamide function. However, the evolution of 50 years
SDHI optimization culminated in a CHF2 group next to the
acid function being optimum for fungicidal efficacy. This is
demonstrated by the highly successful 3-(difluoromethyl)-1-
methyl-1H-pyrazole-4-carboxylic acid as structural motif of
the very recent commercialized products benzovindiflupyr
The succinate dehydrogenase inhibitors (SDHIs, also called
complex II inhibitors) are currently the fastest growing
broad-spectrum mode of action class on the fungicide mar-
ket, being applied against all kinds of phytopathogens
including seed- and soilborne diseases, such as take-all dis-
ease and fusarium head blight, many different foliar cereal,
fruit, and vegetable diseases, such as molds and stem rots,
leaf and net blotch, powdery mildew and rusts including the
important well as Asian soybean rust. Their historical name
‘‘carboxamides’’ points to the fact that the central amide
function is the only common ground of the so far 20
& Clemens Lamberth
clemens.lamberth@syngenta.com
1
Chemical Research, Syngenta Crop Protection AG,
Schaffhauserstrasse 101, 4332 Stein, Switzerland
123

H. Walter et al.
Fig. 1 Different commercialized succinate dehydrogenase inhibitors
(3), bixafen (4), fluxapyroxad (5), isopyrazam (6), pydi-
flumetofen (7), and sedaxane (8) (Fig. 1).
Results and discussion
Although the synthesis of 3-(difluoromethyl)-1-methyl-
1H-pyrazole-4-carboxylic acid has been thoroughly opti-
mized and well described in the meantime [6–10], other
difluoromethylated heterocyclic carboxylic acids are rarely
known. In this paper, we report the synthesis of the
fungicidally active SDHIs 9–11, for which we developed
the synthesis of three completely novel difluoromethylated
heterocycles, which are 3-(difluoromethyl)-1-methylpyra-
zoline and 3-(difluoromethyl)-pyrrole with a carboxylic
function in position 4 as well as 3-(difluoromethyl)-5-
methylthiophene-2-carbonyl fluoride (Fig. 2).
Chemical synthesis
Because of the fact that 3-(difluoromethyl)-1-methyl-1H-
pyrazole is part of six successful active ingredients, we
wanted to prepare some novel analogs, which are closely
related by structure to it. One isosteric replacement, which
came immediately to our mind, was to exchange the
pyrazole ring by its partially saturated pyrazoline (dihy-
dropyrazole) derivative. So far, difluoromethylated pyra-
zolines have been only rarely described in the scientific
literature. Although there have been some methods known
for the synthesis of N-methylpyrazoline-4-carboxylic acid
Fig. 2 The three target compounds 9–11 with novel difluoromethylated heterocyclic acid portions
123

Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel…
derivatives, such as the 1,3-dipolar cycloaddition of N-
methylnitrilimines to acrylates [11] and of a-silylni-
trosamines to fumarates [12], or the transformation of N-
dimethylaminopyrroles with dimethyl acetylenedicar-
boxylate [13], we decided to use the 4,4-difluoroacetoac-
etate 13 for our synthesis, as this important building block
of the manufacturing routes of benzovindiflupyr (3),
isopyrazam (6), pydiflumetofen (7), and sedaxane (8) is
readily available as a mixture of methyl and ethyl esters in
only one step by Claisen condensation of N,N-dimethyld-
ifluoroacetamide (12) with ethyl acetate [1, 3, 7]. This b-
ketoester 13 was then converted in a Mannich-type reaction
with methylhydrazine and an aqueous solution of
formaldehyde in the presence of catalytic amounts of
hydrochloric acid in boiling ethanol to the Mannich adduct
14, which cyclizes spontaneously to the desired 3-(difluo-
romethyl)-1-methylpyrazoline ester 15 as major product.
The isomeric 5-(difluoromethyl) substituted pyrazole, in
which the methyl group is linked to the ring nitrogen next
to the difluoromethyl function was formed in less than
10%. After saponification of ester 15 to the pyrazoline acid
16, subsequent transformation into the acid chloride and
amidation with 40-chlorobiphenyl-2-amine delivered the
target compound 9 (Scheme 1) [14].
synthesis route [15]. We used diethyl maleate (17) as
starting material, which was converted with TosMIC into
the 3,4-dicarbethoxy-substituted pyrrole 18. The synthesis
of this diester has been described already by Paal–Knorr
cyclization of a 2,3-diformylsuccinate [16], by a three-
component condensation of methylamine with two equiv-
alents of ethylpropiolate [17] and by dehydrogenation of
the corresponding pyrrolidine with manganese dioxide
[18], but never by the van Leusen pyrrole synthesis with
TosMIC [19–23], as reported herewith by us. One of the
two ester functions of 18 were then saponified to the car-
boxylic acid 19 and transformed into the acid chloride,
which underwent a Rosenmund reduction to the aldehyde
20. The saponification of the remaining ester of 20 deliv-
ered the pyrrole derivative 21. Both aldehyde and car-
boxylic acid functions of 21 were converted with
diethylaminosulfur trifluoride (DAST) [24, 25] to the
difluoromethyl-substituted pyrrole acid fluoride 22 [15],
which delivered the desired target compound 10 by ami-
dation with 40-chlorobiphenyl-2-amine (Scheme 2) [26].
Finally, we also wanted to check, which results a
difluoromethyl- and methyl-substituted thiophene analog of
the successful pyrazole carboxylic acid part of products 3–
8 would deliver in our assays. As it was the case for
pyrazolines and pyrroles, also difluoromethylated thio-
phenes are completely unknown so far. We started the
synthesis of target compound 11 bearing the sulfur atom
adjacent to the carboxamide function with the regioselec-
tive bromination of 2-methylthiophene (23). The resulting
2-bromo-5-methylthiophene (24) was subjected to a
lithium diisopropylamide (LDA)-induced halogen dance
reaction [27–31], in which the migrated carbanion could be
Another ring system, which would be closely related to
the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic
acid moiety of the commercial fungicides 2–7, is the cor-
responding pyrrole, in which one of the two ring nitrogen
of the pyrazole has been replaced by a carbon atom. Also
difluoromethylated pyrrole derivatives are, as it was the
case for the pyrazoline scaffold, not known in the literature
at all; therefore, we had to develop a completely new
Scheme 1
123

H. Walter et al.
Scheme 2
trapped with carbon dioxide delivering the thienyl acid 25.
Previously, several different electrophiles have been added
to the lithium salt in thiophene position 2 resulting from the
halogen dance reaction of 2-bromo-5-methylthiophene (24)
[32, 33], but so far never carbon dioxide delivering a car-
boxylic acid. The synthesis of the trisubstituted thiophene
derivative 25 has been described already [34, 35], but not
via a halogen dance reaction as in our approach. Another
lithiation, this time with butyl lithium, led by exchange of
the bromo-substituent with a formyl function to 26, which
was subsequently converted with excess of bis(2-
powdery mildew), Pyrenophora teres (barley net blotch),
and Zymoseptoria tritici (wheat leaf blotch), all belonging
to the family of Ascomycota, as fungal test species.
Because 9–11 bear exactly the same amine portion as
boscalid (2), this commercial product was used as refer-
ence. As shown in Table 1, all three novel succinate
dehydrogenase inhibitors show at the very low rate of
20 ppm interesting efficacy. It seems that the pyrazoline
derivative 9 and the pyrrole carboxamide 10 have a
strength in the control of powdery mildew, whereas the
thiophene 11 shows a similar profile as its pyridine analog
boscalid, because both compounds show excellent control
of the leaf spot diseases P. teres and Z. tritici.
methoxyethyl)aminosulfur
trifluoride
(Deoxo-fluor)
[24, 25] to the difluoromethylated thiophene-2-carboxyl
acid fluoride 27 (Scheme 3).
Biological evaluation
Conclusion
The three target compounds 9–11 have been evaluated for
their fungicidal activity against different phytopathogens.
As we were especially interested in the control of cereal
diseases, we chose Blumeria graminis (wheat and barley
We have introduced three novel difluoromethylated acid
motifs into the family of succinate dehydrogenase inhibi-
tors. These previously unknown pyrazoline, pyrrole, and
thiophene derivatives have been prepared on completely
123

Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel…
Scheme 3
Table 1 Fungicidal activity of the target compounds against different cereal pathogens
Compound
Blumeria graminis (cereal powdery mildew) Pyrenophora teres (barley net blotch) Zymoseptoria tritici (wheat leaf blotch)
9
80
70
30
50
30
70
80
30
35
80
70
10
11
2 (boscalid) 20
Results are given in % activity at 20 ppm
different routes from simple starting materials, such as
N,N-dimethyldifluoroacetamide, diethyl maleate, and
2-methylthiophene, either using a Mannich reaction, a van
Leusen pyrrole synthesis, or a halogen dance reaction as
the key step. These novel specifically substituted five-
membered ring carboxamides show potent activity against
the economically important Ascomycete phytopathogens
B. graminis, P. teres, and Z. tritici.
CH3CN/MeOH 4:1 ? 0.04% HCOOH (5%)—2 min—
CH3CN/MeOH 4:1 ? 0.04% HCOOH (5%)—0.8 min;
ACQUITY SQD Mass Spectrometer from Waters, ioniza-
tion method: electrospray (ESI), polarity: positive ions,
capillary 3.00 kV, cone 20.00 V, extractor 3.00 V, source
temperature 150 °C, desolvation temperature 400 °C, cone
gas flow 60 dm3/h, desolvation gas flow 700 dm3/h. Ana-
lytical thin-layer chromatography (TLC) was performed
using silica gel 60 F524 precoated plates. Preparative flash
chromatography was performed using silica gel 60
(40–63 lm, E. Merck). Unless otherwise stated, all reac-
tions were carried out under anhydrous conditions in an
inert atmosphere (nitrogen or argon) with dry solvents.
Experimental
All new compounds were characterized by standard spec-
1
troscopical methods. H NMR spectra were recorded on a
Varian Unity 400 spectrometer at 400 MHz using CDCl3
as solvent and tetramethylsilane as internal standard.
Chemical shifts are reported in ppm downfield from the
standard (d = 0.00), coupling constants in Hz. LC–MS
spectra were determined using the following apparatus:
ACQUITY UPLC from Waters, Phenomenex Gemini C18,
Synthesis protocols
Ethyl 4,4-difluoro-3-oxobutanoate (13) A 21% solution of
sodium ethoxide in ethanol (32 cm3, 0.1 mol) was added
dropwise to a solution of 11.2 g 2,2-difluoro-N,N-dimethyl-
acetamide (12, 91 mmol) in 150 cm3 of ethyl acetate. The
resulting mixture was stirred for 1 h at 80 °C, then cooled
to room temperature, poured on ice-water, acidified with
¨
3 mm particle size, 110 Angstrom, 30 9 3 mm column,
1.7 cm3/min., 60 °C, H2O ? 0.05% HCOOH (95%)/
123

H. Walter et al.
2 N hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with brine, dried over
sodium sulfate, and evaporated under in vacuo. The residue
was purified by distillation under reduced pressure to
deliver 13.2 g ethyl 4,4-difluoro-3-oxo-butanoate (13,
79 mmol, 87%) as a colorless oil. B.p.: 50–53 °C
N-[2-(4-Chlorophenyl)phenyl]-3-(difluoromethyl)-1-methyl-
4,5-dihydro-1H-pyrazole-4-carboxamide (9, C18H16ClF2N3O)
3-(Difluoromethyl)-1-methyl-4,5-dihydro-1H-pyrazole-4-
carboxylic acid (0.1 g, 0.6 mmol) was dissolved in 2 cm3
of dichloromethane containing one drop of N,N-dimethyl-
formamide.
A
solution of 78 mg oxalyl chloride
1
(18 mbar); H NMR (400 MHz, CDCl3): d = 1.32 (t, 3H,
(0.6 mmol) in 2 cm3 of dichloromethane was added at
room temperature. This mixture was stirred for 1 h at room
temperature and then slowly added to a mixture of 0.11 g
40-chlorobiphenyl-2-amine (0.6 mmol) and 85 mg triethy-
lamine (0.8 mmol) in 2 cm3 of dichloromethane. The
reaction mixture was stirred for 16 h at room temperature,
then poured on water and extracted with dichloromethane.
The organic layer was washed with brine, dried over
sodium sulfate, and evaporated under reduced pressure.
The residue was purified by chromatography on silica gel,
using ethyl acetate/heptane 1:3 as eluent, to deliver
40 mg N-[2-(4-chlorophenyl)phenyl]-3-(difluoromethyl)-
J = 7.5 Hz), 4.34 (q, 2H, J = 7.5 Hz), 5.40 (s, 2H), 5.98
(t, 1H, J = 54.0 Hz) ppm; LC–MS: tR = 1.85 min; MS:
m/z = 167 ([M?1]?).
Ethyl 3-(difluoromethyl)-1-methyl-4,5-dihydro-1H-pyrazole-4-
carboxylate (15, C8H12F2N2O2) Ethyl 4,4-difluoro-3-
oxobutanoate (5.0 g, 30 mmol) was dissolved in 35 cm3 of
ethanol and the solution was cooled to 0 °C. A 37% aqueous
solution of formaldehyde (2.5 g, 30 mmol) was added and
the mixture was stirred for 15 min at 0 °C. Methylhydrazine
(1.4 g, 30 mmol) was added and the reaction mixture was
heated to reflux. After reaching the reflux temperature,
0.5 cm3 of concentrated hydrochloric acid was added, then
refluxing was continued for 16 h. Subsequently the mixture
was cooled to room temperature and evaporated in vacuo.
The remainder was taken up in water and extracted with ethyl
acetate. The organic layer was washed with water, dried over
sodium sulfate and evaporated under reduced pressure. The
remainder was purified by chromatography on silica gel,
using ethyl acetate and hexane 1:2 as eluents to deliver 1.5 g
ethyl 3-(difluoromethyl)-1-methyl-4,5-dihydro-1H-pyra-
zole-4-carboxylate (15, 7.3 mmol, 24%). 1H NMR
(400 MHz, CDCl3): d = 1.14 (t, 3H, J = 7.3 Hz), 2.77 (s,
3H), 3.53–3.61 (m, 1H), 3.76–3.80 (m, 1H), 4.07 (q, 2H,
J = 7.4 Hz), 5.67 (t, 1H, J = 54.2 Hz), 6.48 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3): d = 14.8, 15.4, 17.3, 39.0,
44.9, 129.1, 143.2, 158.7 ppm; LC–MS: tR = 2.01 min;
MS: m/z = 207 ([M?1]?).
1-methyl-4,5-dihydro-1H-pyrazole-4-carboxamide
(9,
1
0.2 mmol, 35%). H NMR (400 MHz, CDCl3): d = 2.83
(s, 3H), 3.59–3.68 (m, 2H), 5.72 (t, 1H, J = 54.5 Hz), 6.44
(s, 1H), 7.12–7.22 (m, 5H), 7.31–7.43 (m, 3H) ppm; 13C
NMR (100 MHz, CDCl3): d = 24.7, 108.3, 110.0, 113.2,
117.5, 117.9, 121.8, 123.6, 124.8, 126.1, 129.2, 129.7,
130.4, 133.3, 134.02, 135.1, 136.7, 160.6 ppm; LC–MS:
tR = 1.73 min; MS: m/z = 364 ([M?1]?).
Diethyl 1-methylpyrrole-3,4-dicarboxylate (18) A solution
of 19.5 g p-toluenesulfonylmethyl isocyanide (TosMIC,
0.1 mol) in 200 cm3 of N-methylpyrrolidone was added
during 1 h at 0 °C to a suspension of 60% sodium hydride
(8.8 g, 0.2 mol) in 150 cm3 of N-methylpyrrolidone. The
resulting suspension was stirred for further 30 min at 0 °C,
then a solution of 17.2 g diethyl maleate (17, 0.1 mol) in
50 cm3 of N-methylpyrrolidone was slowly added. The
reaction mixture was stirred for 2 h at 0 °C and for 1 h at
10 °C, then 28.4 g methyl iodide (0.2 mol) was added and
stirring was continued for further 3 h at room temperature.
Subsequently the reaction mixture was cooled to 0 °C and
quenched by addition of 100 cm3 of saturated aqueous
ammonium chloride solution. The resulting mixture was
poured on brine and extracted with ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, and
evaporated under reduced pressure. The remainder was puri-
fied by chromatography on silica gel, using ethyl acetate/
heptane 1:4 as eluent, to deliver 12.7 g diethyl 1-methylpyr-
role-3,4-dicarboxylate (18, 56 mmol, 56%). M.p.: 48–50 °C;
1H NMR (400 MHz, CDCl3): d = 1.33 (t, 6H, J = 5.3 Hz),
3.66 (s, 3H), 4.27 (q, 4H, J = 5.2 Hz), 7.18 (s, 2H) ppm; LC–
MS: tR = 1.95 min; MS: m/z = 226 ([M?1]?).
3-(Difluoromethyl)-1-methyl-4,5-dihydro-1H-pyrazole-4-car-
boxylic acid (16, C6H8F2N2O2) Aqueous sodium hydroxide
solution (1 N, 1.5 cm3, 1.5 mmol) was added to a solution
of 0.15 g ethyl 3-(difluoromethyl)-1-methyl-4,5-dihydro-
1H-pyrazole-4-carboxylate (0.7 mmol) in 2 cm3 of diox-
ane. The reaction mixture was stirred for 2 h at room
temperature, then acidified to pH 2 by addition of con-
centrated hydrochloric acid. The solvent was removed
under reduced pressure and the remainder extracted with
ethyl acetate. The organic layer was washed with brine,
dried over sodium sulfate, and evaporated to deliver 0.1 g
3-(difluoromethyl)-1-methyl-4,5-dihydro-1H-pyrazole-4-
carboxylic acid (16, 0.6 mmol, 85%). 1H NMR (400 MHz,
CDCl3): d = 2.69 (s, 3H), 3.51–3.59 (m, 1H), 3.78–3.86
(m, 1H), 5.73 (t, 1H, J = 55.1 Hz), 6.50 (s, 1H), 12.31 (bs,
1H) ppm; LC–MS: tR = 1.54 min; MS: m/z = 179
([M?1]?).
4-Ethoxycarbonyl-1-methylpyrrole-3-carboxylic acid (19, C9-
H11NO4) A mixture of 12.7 g diethyl 1-methylpyrrole-
3,4-dicarboxylate (18, 56 mmol) and 3.3 g powdered
123

Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel…
1
potassium hydroxide (50 mmol) in 140 cm3 of ethanol was
heated for 4 h to 80 °C. Subsequently the reaction mixture
was stirred for 16 h at room temperature and then evapo-
rated under reduced pressure. The residue was taken up in
ethyl acetate, stirred for 15 min, and filtered. The filtrate
was diluted with water and the phases were separated. The
aqueous phase was acidified to pH 2 by addition of 2 N
hydrochloric acid. The resulting suspension was filtered
and the solid remainder was washed with cold water and
dried in high vacuum to deliver 7.1 g 4-ethoxycarbonyl-1-
methylpyrrole-3-carboxylic acid (19, 36 mmol, 64%).
M.p.: 160–162 °C; 1H NMR (400 MHz, CDCl3): d = 1.41
(t, 3H, J = 5.3 Hz), 3.73 (s, 3H), 4.39 (q, 2H, J = 5.4 Hz),
7.33 (d, 1H, J = 2.5 Hz), 7.47 (d, 1H, J = 2.5 Hz), 13.66
(bs, 1H) ppm; 13C NMR (100 MHz, CDCl3): d = 14.5,
36.3, 59.1, 114.3, 121.5, 121.9, 127.4, 163.8, 165.6 ppm;
LC–MS: tR = 0.96 min; MS: m/z = 198 ([M?1]?).
23 mmol, 92%). M.p.: 176–179 °C; H NMR (400 MHz,
DMSO-d6): d = 3.84 (s, 3H), 7.63 (d, 1H, J = 2.6 Hz), 7.74
(d, 1H, J = 2.5 Hz), 10.22 (s, 1H), 12.72 (s, 1H) ppm; LC–
MS: tR = 0.87 min; MS: m/z = 154 ([M?1]?).
4-(Difluoromethyl)-1-methylpyrrole-3-carbonyl fluoride (22,
C7H6 F3NO) A solution of 11.0 g diethylaminosulfurtri-
fluoride (DAST, 68 mmol) in 10 cm3 of dichloromethane
was slowly added at 0 °C to a solution of 2.6 g 4-formyl-1-
methylpyrrole-3-carboxylic acid (21, 17 mmol) in 70 cm3
of dichloromethane. The reaction mixture was stirred for
30 min at 0 °C and for 16 h at room temperature, then
taken up in ethyl acetate, and washed with water and brine.
The organic layer was washed with water and brine, dried
over sodium sulfate, and evaporated under reduced pres-
sure. The remainder was purified by chromatography on
silica gel, using ethyl acetate/heptane 1:2 as eluent, to
deliver 1.95 g 4-(difluoromethyl)-1-methylpyrrole-3-car-
1
Ethyl 4-formyl-1-methylpyrrole-3-carboxylate (20, C9H11-
NO3) A solution of 8.0 g oxalyl chloride (63 mmol) in
20 cm3 of dichloromethane was slowly added at room tem-
perature to a solution of 11.8 g 4-ethoxycarbonyl-1-methyl-
pyrrole-3-carboxylic acid (19, 60 mmol) and 7 drops of N,N-
dimethylformamide in 60 cm3 of dichloromethane. The
reaction mixture was stirred for 2 h at room temperature and
then heated to reflux for 1 h. Subsequently it was cooled to
room temperature and evaporated under reduced pressure to
deliver the crude 4-ethoxycarbonyl-1-methylpyrrole-3-car-
boxylic acid chloride. This acid chloride was dissolved in
200 cm3 of tetrahydrofuran. After addition of 7.7 g N,N-di-
isopropylethylamine (Hu¨nig’s base, 60 mmol), the mixture
was treated with hydrogen in the presence of a 10% palladium
on charcoal at 5 °C for 5 h. The catalyst was filtered off and
the solvent removed in vacuo. The remainder was purified by
chromatography on silica gel, using tert-butyl methyl ether/
heptane 1:5 as eluent, to deliver 7.1 g ethyl 4-formyl-1-
methylpyrrole-3-carboxylate (20, 39 mmol, 65%). M.p.:
bonyl fluoride (22, 11 mmol, 64%). M.p.: 53–55 °C; H
NMR (400 MHz, CDCl3): d = 3.75 (s, 3H), 6.79–7.17 (m,
2H), 7.38 (d, 1H, J = 2.6 Hz) ppm; LC–MS: tR = 1.62 -
min; MS: m/z = 178 ([M?1]?).
N-[2-(4-Chlorophenyl)phenyl]-4-(difluoromethyl)-1-methylpyr-
role-3-carboxamide (10, C19H15ClF2N2O)
0.23 g 4-(difluoromethyl)-1-methylpyrrole-3-carbonyl flu-
A mixture of
oride (22, 1.3 mmol), 0.27 g 40-chlorobiphenyl-2-amine
(1.3 mmol),
and
0.2 g
1,4-diazabicyclo[2]octane
(DABCO, 1.9 mmol) in 5 cm3 of acetonitrile was heated
to 110 °C for 3 h. The reaction mixture was cooled to
room temperature, taken up in ethyl acetate, washed with
water, dried over sodium sulfate, and evaporated under
reduced pressure. The residue was purified by chro-
matography on silica gel, using ethyl acetate/heptane 1:2
as eluent, to deliver 0.29 g N-[2-(4-chlorophenyl)phenyl]-
4-(difluoromethyl)-1-methylpyrrole -3-carboxamide (10,
1
0.8 mmol, 62%). M.p.: 175–177 °C; H NMR (400 MHz,
CDCl3): d = 3.66 (s, 3H), 6.77–6.96 (m, 2H), 7.19–7.45
(m, 8H), 8.27–8.32 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 36.9, 109.2, 111.7, 114.0, 117.9, 118.5,
122.3, 123.2, 124.1, 124.6, 128.5, 129.2, 130.1, 130.8,
131.6, 134.0, 134.9, 136.8, 161.6 ppm; LC–MS:
tR = 1.81 min; MS: m/z = 361 ([M?1]?).
1
75–76 °C; H NMR (400 MHz, CDCl3): d = 1.36 (t, 3H,
J = 5.3 Hz), 3.72 (s, 3H), 4.33 (q, 2H, J = 5.3 Hz), 7.25 (d,
1H, J = 2.6 Hz), 7.30 (d, 1H, J = 2.6 Hz), 10.39 (s, 1H)
ppm; LC–MS: tR = 1.55 min; MS: m/z = 182 ([M?1]?).
4-Formyl-1-methylpyrrole-3-carboxylic acid (21, C7H7NO3)-
A solution of 2.1 g potassium hydroxide (31 mmol) in
22 cm3 of water was added to a solution of 4.6 g ethyl
4-formyl-1-methylpyrrole-3-carboxylate (20, 25 mmol) in
90 cm3 of ethanol. The reaction mixture was heated for 2 h to
80 °C, then cooled to room temperature and evaporated under
reduced pressure. The residue was taken up in water and
extracted with ethyl acetate. The aqueous phase was acidified
to pH 2 by addition of 2 N hydrochloric acid to pH 2. The
resulting suspension was filtered and the solid remainder was
washed with cold water and dried in high vacuum to deliver
3.6 g 4-formyl-1-methylpyrrole-3-carboxylic acid (21,
2-Bromo-5-methylthiophene (24) A solution of 48.0 g
bromine (0.3 mol) in 260 cm3 of dioxane was slowly
added to a solution of 29.4 g 2-methylthiophene (23,
0.3 mmol) in 140 cm3 of dioxane. The reaction mixture
was stirred for 3 h at room temperature, then cooled to
0 °C. A saturated aqueous sodium bicarbonate solution
was then carefully added and the mixture was extracted
with ethyl acetate. The organic layer was dried over
sodium sulfate and evaporated under reduced pressure.
The remainder was purified by distillation to deliver
123

H. Walter et al.
37.2 g 2-bromo-5-methylthiophene (24, 0.21 mol, 70%).
1
dropwise at 0 °C to a solution of 2.05 g 3-formyl-5-
methylthiophene-2-carboxylic acid (26, 12 mmol) in
80 cm3 of dichloromethane. The reaction mixture was
stirred for 1 h at 0 °C and 2 h at room temperature, then
poured on ice-water. The phases were separated, the
organic layer was washed with water, dried over sodium
sulfate, and evaporated under reduced pressure. The
remainder was purified by chromatography on silica gel,
using dichloromethane/heptane 2:1 as eluent, to deliver
B.p.: 68–70 °C (20 mbar); H NMR (400 MHz, CDCl3):
d = 2.42 (s, 3H), 6.51 (d, 1H, J = 3.6 Hz), 6.83 (d, 1H,
J = 3.6 Hz) ppm; LC–MS: tR = 1.65 min; MS: m/
z = 176, 178 ([M?1]?, [M?3]?).
3-Bromo-5-methylthiophene-2-carboxylic acid (25, C6H5-
BrO2S) A 1.6 M solution of butyllithium in hexane
(105 cm3) was slowly added at -30 °C to a solution of
18.4 g diisopropylamine (0.18 mol) in 150 cm3 of
tetrahydrofuran. The mixture was stirred for 30 min at
- 30 °C, then cooled to – 70 °C. At this temperature a
solution of 24.8 g 2-bromo-5-methylthiophene (24,
0.14 mol) in 60 cm3 of tetrahydrofuran was slowly added.
The reaction mixture was stirred for 2 h at – 70 °C, then a
stream of carbon dioxide was introduced at the same
temperature for 1 h. The addition of carbon dioxide was
continued as the mixture warmed up to room temperature.
The reaction mixture was acidified to pH 2 by addition of
1 N hydrochloric acid and extracted with ethyl acetate. The
organic layer was washed with water and brine, dried over
sodium sulfate, and evaporated under reduced pressure.
The remainder was purified by chromatography on silica
gel, using ethyl acetate/heptane 1:3 as eluent, to deliver
20.5 g 3-bromo-5-methylthiophene-2-carboxylic acid (25,
66%). M.p.: 190–196 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.47 (s, 3H), 6.98 (s, 1H), 13.19 (bs, 1H) ppm; 13C
NMR (100 MHz, CDCl3): d = 15.3, 108.7, 125.5, 129.8,
141.4, 156.3 ppm; LC–MS: tR = 1.13 min; MS: m/
z = 220, 222 ([M?1]?, [M?3]?).
1.2 g
3-(difluoromethyl)-5-methylthiophene-2-carbonyl
fluoride (27, 6.1 mmol, 51%). 1H NMR (400 MHz,
CDCl3): d = 2.60 (s, 3H), 7.03–7.28 (m, 2H) ppm; LC–
MS: tR = 1.95 min; MS: m/z = 195 ([M?1]?).
N-[2-(4-Chlorophenyl)phenyl]-3-(difluoromethyl)-5-methylth-
iophene-2-carboxamide (11, C19H14ClF2NOS) A mixture of
0.38 g 3-(difluoromethyl)-5-methylthiophene-2-carbonyl
fluoride (27, 0.9 mmol), 0.19 g 40-chlorobiphenyl-2-amine
(0.9 mmol),
and
0.16 g
1,4-diazabicyclo[2]octane
(DABCO, 1.4 mmol) was heated without solvent to 110 °C
for 2 h. The reaction mixture was cooled to room tem-
perature, taken up in ethyl acetate, washed with water,
dried over sodium sulfate, and evaporated under reduced
pressure. The residue was purified by chromatography on
silica gel, using ethyl acetate/heptane 1:4 as eluent, to
deliver
0.24 g N-[2-(4-chlorophenyl)phenyl]-3-(difluo-
(11,
romethyl)-5-methylthiophene-2-carboxamide
1
0.6 mmol, 67%). M.p.: 149–151 °C; H NMR (400 MHz,
CDCl3): d = 2.49 (s, 3H), 7.03 (s, 1H), 7.18–7.52 (m, 8H),
8.31 (d, 1H, J = 11.6 Hz) ppm; 13C NMR (100 MHz,
CDCl3): d = 15.6, 107.4, 110.0, 112.2, 121.9, 125.0,
125.8, 128.8, 129.3, 130.1, 130.5, 131.7, 132.6, 134.1,
134.2, 136.2, 139.8, 143.3, 159.0 ppm; LC–MS:
tR = 1.76 min; MS: m/z = 378 ([M?1]?).
3-Formyl-5-methylthiophene-2-carboxylic acid (26, C7H6O3-
S) A 1.6 M solution of butyllithium in hexane (59 cm3)
was slowly added at – 75 °C to a solution of 10.0 g
3-bromo-5-methylthiophene-2-carboxylic acid (45 mmol)
in 220 cm3 of tetrahydrofuran. The mixture was stirred
30 min at - 75 °C, then a solution of 4.9 g N,N-
dimethylformamide (67 mmol) in 20 cm3 of tetrahydrofu-
ran was added dropwise. The reaction mixture was stirred
for 1 h at – 75 °C, then warmed to room temperature,
quenched by addition of 1 N hydrochloric acid, and taken
up in ethyl acetate. The phases were separated, the organic
layer was washed with brine, dried over sodium sulfate,
and evaporated under reduced pressure. The remaining
solid was crystallized from water/ethanol 9:1 to deliver
4.5 g 3-formyl-5-methylthiophene-2-carboxylic acid (26,
Biological assays
Blumeria graminis f. sp. hordei (Erysiphe graminis f. sp.
hordei)/barley/leaf disc preventative (powdery mildew
on barley)
Barley leaf segments cv. Hasso are placed on agar in
multiwell plate (24-well format) and sprayed with the
formulated test compound diluted in water. The leaf seg-
ments are inoculated by shaking powdery mildew infected
plants above the test plates 1 day after application. The
inoculated leaf segments are incubated at 20 °C and 60%
rh under a light regime of 24 h darkness followed by 12 h
light/12 h darkness in a climate chamber and the activity of
a compound is assessed as percent disease control com-
pared to untreated when an appropriate level of disease
damage appears on untreated check leaf segments
(5–7 days after application).
1
26 mmol, 58%). M.p.: 172–175 °C; H NMR (400 MHz,
CDCl3): d = 2.56 (s, 3H), 7.31 (s, 1H), 10.26 (s, 1H),
13.20 (bs, 1H) ppm; LC–MS: tR = 1.02 min; MS: m/
z = 171 ([M?1]?).
3-(Difluoromethyl)-5-methylthiophene-2-carbonyl
fluoride
solution of 10.6 g Deoxo-fluor
(27, C7H5F3OS)
A
(48 mmol) in 20 cm3 of dichloromethane was added
123

Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel…
Pyrenophora teres/barley/leaf disc preventative (net blotch)
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Jeschke P, Witschel M (eds) Modern crop protection compounds,
2nd edn. Wiley-VCH, Weinheim, p 639
Barley leaf segments cv. Hasso are placed on agar in a
multiwell plate (24-well format) and sprayed with the
formulated test compound diluted in water. The leaf seg-
ments are inoculated with a spore suspension of the fungus
2 days after application. The inoculated leaf segments are
incubated at 20 °C and 65% rh under a light regime of 12 h
light/12 h darkness in a climate cabinet and the activity of
a compound is assessed as disease control compared to
untreated when an appropriate level of disease damage
appears in untreated check leaf segments (57 days after
application).
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Acknowledgements We are grateful to S. Guelfi, D. Haerdi, R.
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