Synthesis of Ring-Opened Analogues of Oxysterol-Binding Protein-Inhibiting Piperidinyl-thiazole Fungicides

Article abstract of DOI:10.1055/s-0036-1588473

Novel aminoethyl-, aminopropyl-, and aminobutyl-substituted thiazole-4-carboxamides have been prepared which are ring-opened analogues of piperidinyl-thiazole fungicides. Depending of the chain length, completely different synthetic approaches had to be chosen which vary from a Sonogashira coupling with a 2-bromothiazole derivative to a thiazole ring construction from different β- and δ-amino acids.

Full text of DOI:10.1055/s-0036-1588473

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
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S. Sulzer-Mosse et al.
Letter
Synlett
Synthesis of Ring-Opened Analogues of Oxysterol-Binding Pro-
tein-Inhibiting Piperidinyl-thiazole Fungicides
Sarah Sulzer-Mossea
Clemens Lamberth*a
Peter Kubiznab
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a Syngenta Crop Protection AG, Chemical Research,
Schaffhauserstrasse 101, 4332 Stein, Switzerland
clemens.lamberth@syngenta.com
b Synkola s.r.o., Mlynska dolina (CH-2), Ilkovičova 6,
84215 Bratislava, Slovak Republic
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Received: 07.03.2017
Accepted after revision: 20.05.2017
Published online: 29.06.2017
prostaglandin receptors EP2/EP4,10,11 histamine H2 receptor
agonists,12 and antitrypanosomal compounds.13 This quali-
fication for biological activity gave us confidence that we
can also reach the desired fungicidal efficacy if we combine
the 2-(3-aminopropyl)thiazole-4-carboxylic acid scaffold
via consecutive amidations with the 5-methyl-3-trifluoro-
methylpyrazole acetic acid and 1-aminotetraline end
groups of 2. In this paper we describe the preparation of
novel ring-opened analogues of piperdinyl-thiazole fungi-
cides (Figure 1).
DOI: 10.1055/s-0036-1588473; Art ID: st-2017-b0164-l
Abstract Novel aminoethyl-, aminopropyl-, and aminobutyl-substitut-
ed thiazole-4-carboxamides have been prepared which are ring-opened
analogues of piperidinyl-thiazole fungicides. Depending of the chain
length, completely different synthetic approaches had to be chosen
which vary from a Sonogashira coupling with a 2-bromothiazole deriva-
tive to a thiazole ring construction from different β- and δ-amino acids.
Key words ring opening, piperidine, thiazole, heterocycle, fungicide,
crop protection
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N
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Oxathiapiprolin (1), one of the latest introductions to
the fungicide market, controls very efficiently devastating
plant diseases, such as potato and tomato late blight caused
by Phytophthora infestans and grape downy mildew with
Plasmopara viticola as causal agent, at formerly unimagin-
ably low use rates of 10–20 g/ha.1,2 Its powerful fungicidal
activity is based on a completely novel mode of action,
which is the inhibition of the fungal oxysterol-binding pro-
tein. One of the final manipulations within the fascinating
invention pathway of oxathiapiprolin (1) was the introduc-
tion of the isoxazoline ring as cyclic peptide mimic of the
amide function in the precursor 2, which itself is highly ac-
tive.1,2 Recently, we have reported the synthesis and fungi-
cidal activity of analogues of 2, in which the amide function
linked to the thiazole has been reversed.3 Another modifi-
cation of 2, which we had planned, was to cut its piperidine
ring along its axis of symmetry, leading to compounds such
as 3, in which a flexible 3-aminopropyl chain is linking the
unchanged pyrazole acetic acid and thiazole carboxamide
moieties.
F
S
N
N
N
1
N
Oxathiapiprolin
F
F
N
O
O
O
O
F
N
N
S
2
N
F
N
F
O
F
N
N
S
3
N
F
F
N
F
Figure 1 Oxathiapiprolin (1), its amide bioisostere 2 and 3, the ring-
opened version of it
2-(3-Aminopropyl)thiazole-4-carboxylic acid deriva-
tives can be found as a structural motif in tubulin polymer-
ization inhibiting anticancer agents,4–9 dual agonists of
We started the synthesis of 3 with the Sonogashira cou-
pling of commercially available ethyl 2-bromothiazole-4-
carboxylate (4) with N-Boc-N-methylpropargylamine to de-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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S. Sulzer-Mosse et al.
Letter
Synlett
liver the alkyne 5. Other 2-alkynylthiazole derivatives have
been used as building blocks in the synthesis of nosihep-
tide14,15 and of analogues of epothilone E,16,17 complanadine
A,18 setileuton,19 and the glutamate receptor agonists MPEP
and MTEP.20 The ester saponification of 5 delivered the car-
boxylic acid 6, which was converted into the amide 7 under
standard peptide coupling conditions. Originally, we had
planned the removal of the Boc protecting group as next
step, but our reagent of choice, hydrochloric acid in diox-
ane, did not only cleave the carbamate but also added one
equivalent of HCl to the C–C triple bond, resulting in chlor-
ovinyl formation. Therefore we decided to hydrogenate first
the alkyne function of 7 to the saturated aminopropyl scaf-
fold of 8. Now the Boc group could be removed without any
undesired side reaction to deliver the secondary amine 9,
which was transformed by amidation with 5-methyl-3-tri-
fluoromethylpyrazole acetic acid into the target compound 3
(Scheme 1).
The same bromothiazole starting material 4 enabled
also the preparation of 13, a ring-opened derivative of the
corresponding piperazine-thiazole analogue of the piperi-
dine-thiazole 2 which also possesses excellent fungicidal
activity. In this regard, 4 was transformed with N,N′-di-
methylethylenediamine under the conditions of a copper-
catalyzed Buchwald–Hartwig amination to the thiazole de-
rivative 10. Two different amidation reactions, interrupted
by an ester saponification, delivered smoothly the desired
product 13, which carries, as also 3, a three-atom linker be-
tween the amide function and the thiazole ring (Scheme 1).
The aminopropylthiazole derivative 3 as well as some of
its analogues with different amines in place of the aminote-
traline showed excellent activity against the important
pathogens P. infestans and P. viticola down to the low dose
of 6 ppm. This convinced us that the piperidine ring of lead
compound 2 is not part of the pharmacophore, but rather a
spacer in the center core of the molecule which does not
O
CH2CN(Me)Boc CH,
O
O
2 N NaOH,
THF, r.t., 3 h
CuI, Pd(PPh3)2Cl2,
iPr2NH, THF, r.t., 16 h
N
OH
N
O
N
O
S
100%
55%
O
N
S
Br
S
O
N
6
5
4
O
O
MeNHCH2CH2NHMe,
CuI, Cs2CO3, DMF,
90 °C, 30 min
53%
61%
NH
HATU, EtNiPr2,
DMF, r.t., 16 h
O
N
O
O
O
H2, Pd/C,
MeOH
N
S
N
N
H
N
S
7
N
N
10
S
75%
O
N
O
N
8
OH
O
O
N
HCl, dioxane,
r.t., 16 h
89%
O
F
F
N
O
94%
BOP, EtNiPr2,
DMF, r.t., 16 h
F
OH
N
O
O
F
F
N
O
N
S
9
N
N
O
HATU, EtNiPr2,
MeCN, r.t., 16 h
F
N
S
3
N
N
S
H
N
N
78%
11
N
N
N
O
F
F
N
1 N NaOH,
THF, r.t., 5 h
O
F
N
94%
F
F
F
O
abs
N
OH
O
NH
N
S
BOP, EtNiPr2, DMF, r.t., 16 h
N
N
N
12
N
87%
N
S
O
F
N
N
F
13
N
F
O
F
F
N
F
Scheme 1 Synthesis of the fungicidally active compounds 3 and 13
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. Sulzer-Mosse et al.
Letter
Synlett
seem to be involved in target binding. Therefore we decided
to prepare further analogues of 3 with varied chain length.
In particular we were interested to check if the addition or
the removal of one methylene group would eventually in-
crease the fungicidal activity.
upon treatment with ethyl bromopyruvate underwent ring
condensation to the thiazole esters 22a,b. Then removal of
the Boc protecting group and subsequent amidation with
5-methyl-3-trifluoromethylpyrazole acetic acid delivered
24a,b. Finally another deprotection–amidation sequence,
the ester saponification to the carboxylic acid 25a,b and its
conversion with aminotetraline afforded 26a with one
methylene group more and 26b with one methylene group
less than the aminopropylthiazole derivative 3. In contrast
to their very active role model 3, both stretched and short-
ened analogues 26a,b displayed only weak fungicidal effica-
cy.
In conclusion, we have explored the scope around ana-
logues of piperidinyl-thiazole fungicides, in which the
piperidine ring has been replaced by a flexible alkyl chain
of different length. As it turned out, only compounds as 3,
which retain the three-carbon linker between the amide ni-
trogen atom and the thiazole ring of lead compound 2,
showed a sufficient level of fungicidal activity.
The synthesis of 26a, the derivative of 3 which is elon-
gated by one additional methylene group, started with the
ring-opening of N-methylpiperidone (14) to the δ-amino
acid 15 (Scheme 2). After Boc protection of the secondary
amine, the acid function of the resulting 16 was converted
via the primary amide 17 into the thioamide 21a. Com-
pound 21b, its corresponding equivalent with one methy-
lene group less in the alkyl chain compared to 3, could be
prepared in only two steps from N-cyanoethyl-N-methyl-
amine (18) by conversion of the amine into the tert-butoxy-
carbonyl (Boc) carbamate and subsequent reaction of the
nitrile to a thioamide. Also 21b has not been described in
the literature before, but its N-desmethyl analogue has been
used for the synthesis of DNA-cleaving agents.21,22 Com-
pounds 21a and 21b were then transformed by the same
sequence of five final steps. First the thioamide function
Boc2O,
NaOH,
r.t., 24 h
1. (COCl)2
2. aq. NH3
0 °C, 1.5 h
6 N HCl,
reflux, 40 h
O
O
O
O
O
N
O
O
N
NH2
O
N
OH
N
H
OH
99%
52%
98%
15
16
17
14
Lawesson's
reagent,
r.t., 20 h
98%
KOH,
t-BuOH, H2O
90 °C, 1 h
Boc2O,
Et3N,
r.t., 18 h
Lawesson's
reagent,
r.t., 3 h
O
O
S
n
O
O
O
N
N
NH2
N
H
N
H
NH2
O
N
NH2
88%
80%
69%
19
21a: n = 3
21b: n = 1
18
20
n = 3: 55%
n = 1: 62%
F
CH2BrC(=O)CO2Et
F
F
O
N
F
O
O
O
HCl in
F
F
N
OH
dioxane,
r.t., 20 h
O
N
N
O
O
N
O
N
O
N
N
O
N
S
N
S
n = 3: 81%
n = 1: 44%
S
99%
n
n
n
H
24a: n = 3: CDI, MeCN, reflux, 3 h
24b: n = 1: 1. (COCl)2, DMF, 2. Et3N
22a: n = 3: EtOH, 50 °C, 20 min
22b: n = 1: DMF, r.t., 16 h
23a: n = 3
23b: n = 1
n = 3: 99%
n = 1: 91%
2 N NaOH,
THF, r.t., 3 h
F
O
F
O
F
F
F
NH
O
N
N
N
O
F
N
N
OH
HATU, EtNiPr2, r.t., 2 h
N
N
N
N
S
S
n = 3: 74%
n = 1: 30%
n
n
25a: n = 3
25b: n = 1
26a: n = 3
26b: n = 1
Scheme 2 Synthesis of compounds 26a and 26b, analogues of experimental fungicide 3 with shortened or extended chain length
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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S. Sulzer-Mosse et al.
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Synlett
Acknowledgment
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The authors gratefully acknowledge the excellent synthetic contribu-
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588473.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D