Design, synthesis and effect of the introduction of a propargyloxy group on the fungicidal activities of 1-substituted phenoxypropan-2-amino valinamide carbamate derivatives

Article abstract of DOI:10.1039/c6ra17908h

The cell walls of oomycetes are composed of cellulose, making cellulose synthase enzymes good targets for carboxylic acid amide fungicides. Valinamide carbamates are amino acid fungicides that represent excellent alternatives to conventional synthetic pesticides in terms of their ability to reduce the negative impacts of these compounds on human health and the environment. In a continuation of our research towards the development of new cellulose synthase inhibitors, we have developed a series of "stretched" analogues of iprovalicarb by the introduction of an additional OCH₂ linker. The bioassay results indicated that compounds containing a small group at the para-position of phenyl gave excellent fungicidal activities with EC₅₀ values ranging from 0.59 to 2.06 μmol L^-1. Most notably, the introduction of a propargyloxy group led to a pronounced increase in the fungicidal activity. Furthermore, compound 7o bearing a propargyloxy group was identified as the most promising candidate because of its excellent fungicidal potency against oomycete diseases and good fungicidal activity against non-oomycete diseases.

Full text of DOI:10.1039/c6ra17908h

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Design, Synthesis and Effect of the Introduction of a Propargyloxy
Group on the Fungicidal Activities of 1-Substituted
Phenoxypropan-2-Amino Valinamide Carbamate Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Jian-Qiang Li, Zhi-Peng Wang, Yang Gao and Wei-Guang Zhao*
DOI: 10.1039/x0xx00000x
The cell walls of oomycetes are composed of cellulose, making cellulose synthase enzymes good targets for carboxylic acid
amide fungicides. Valinamide carbamates are amino acid fungicides that represent excellent alternatives to conventional
synthetic pesticides in terms of their ability to reduce the negative impacts of these compounds on human health and the
environment. In a continuation of our research towards the development of new cellulose synthase inhibitors, we have
developed a series of “stretched” analogues of iprovalicarb by the introduction of an additional OCH2 linker. The bioassay
results indicated that compounds containing a small group at the para-position of phenyl gave excellent fungicidal
activities with EC50 values ranging from 0.59 to 2.06μmol L-1. Most notably, the introduction of a propargyloxy group led to
a pronounced increase in the fungicidal activity. Furthermore, compound 7o bearing a propargyloxy group was identified
as the most promising candidate because of its excellent fungicidal potency against oomycete diseases and good fungicidal
activity against non-oomycete diseases.
www.rsc.org/
commercially marketed throughout the world to date. Lamberth
11
Introduction
et al.10,
reported that mandelamide fungicides bearing an
OCH2 or CH2OCH2 linker between the 4ꢀchlorophenyl ring and
the 2ꢀpropargyloxyacetamide function of mandipropamid
exhibited improved levels of fungicidal activity. For example,
these “stretched” mandelamide systems showed improved
activity against P. infestans with an increase in activity from
0.1 to 0.02 mg Lꢀ1 versus the parent system.
Oomycetes can lead to the occurrence of several destructive
diseases in a range of important crop plants, such as late blight
on potatoes, blue mold on tobacco, and grape downy mildew.1
Fungicides are therefore vital for increasing the yield of food
production processes. However, the overuse of traditional
pesticides has led to several environmental issues during the
last decade, which have raised public concerns regarding their
use. The use of environmental friendly and biodegradable green
pesticides could address some of these environmental problems,
while maintaining crop yields. Amino acids are important
biochemical molecules that are critical to life. The valinamide
carbamates, which are amino acid fungicides, represent an
excellent alternative to conventional synthetic pesticides in
terms of their impact on human health and the environment.
The valinamide carbamates, including benthiavalicarb,2
iprovalicarb,3 and valifenalate,4 belong to one of three subꢀ
classes of carboxylic acid amide (CAA) fungicides (FRAC
code: 40),5 which were officially announced by the Fungicide
Resistance Action Committee (FRAC) in 2005.1 In terms of
their mode of action, these compounds target the cellulose
synthase enzymes found in oomycete plant pathogens.6, 7
Fig. 1 Structures of commercial valinamide carbamates fungicides
In our previous study,12ꢀ18 we reported the synthesis and
evaluation of the fungicidal activities of a series of mandelic
acid amide and valinamide carbamate derivatives. We also
found that “stretched” valinamide carbamate derivatives
bearing an OCH2 linker between both of their phenyl rings
exhibited much higher fungicidal activities against
Phytophthora capsici and Pseudoperonospora cubensis than
the corresponding lead compounds with two phenyl fragments.
Although it has been reported19 that individual valinamide
carbamate compounds bearing an OCH2 linker between their
Mandipropamid,8ꢀ10 which was developed by Syngenta, is
the only mandelic acid amide fungicide to have been
phenyl ring (pꢀCl and pꢀCN) and amide group possess good
fungicidal activities, we describe herein the synthesis and
fungicidal evaluation of a series of “stretched” iprovalicarb
derivatives bearing an OCH2 or CH2OCH2 linker between the
phenyl ring and the valinamide function of iprovalicarb. We
have also shown for the first time that the introduction of a
* State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering, Nankai University, Tianjin 300071,
China. E-mail: zwg@nankai.edu.cn.
Electronic Supplementary
DOI: 10.1039/x0xx00000x
Information
(ESI)
available.
See
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Journal Name
propargyloxy group had a positive effect on the antioomycetic according to a previously reported procedure. Compound 10
activity. was successfully prepared using the method described above
for the synthesis of . The subsequent alkylation of compound
10 with various benzyl bromides gave the desired products
7
R
O
H
O
H
N
O
O
N
O
N
( )n
11a–g.
N
H
H
O
O
O
H
O
N
O
O
O
n = 0, 1
O
NH2
iprovalicarb
O
H
N
LiAlH4
NH2
HO
O
6
OH
N
H
Fig. 2 Design of the target compounds
OH
O
O
9
8
10
Results and discussion
Br
O
R
H
N
O
O
Chemistry
N
H
R
O
A series of “stretched” compounds bearing an OCH2 linker 7a–
was synthesized as shown in Scheme 1. The precursor
compounds 3a–m 4a–m and 5a–m were synthesized
according to a previously reported procedure. All of the aryloxy
acetophenones were prepared by the alkylation of the
11a-g
Scheme 2. Synthetic route to compounds 11a-g
o
,
,
All of the synthesized compounds were characterized by 1H and
13C NMR and HRꢀMS. All of the spectral and analytical data
were consistent with the assigned structures.
Fungicidal Activity
3
corresponding substituted phenols with chloroacetone in DMF
in the presence of potassium carbonate and sodium iodide. The
oximes
4
were subsequently prepared by the addition of
at
The in vitro fungicidal activities of compounds 7a–o and 11a–g
towards Phytophthora capsici are shown in Table 1 (reported as
EC50 values in ꢁmol Lꢀ1). The EC50 values were obtained from
Petri dish trials and represent the concentrations at which the
test compounds inhibited the growth of the fungus by 50%.
NH2OH·HCl and NaOH to the aryloxy acetophenones
3
room temperature. The result of a previous study showed that
the hydrogenation of oximes over palladium on carbon
provided facile access to the corresponding amines in high
yield. However, the hydrogenation of the oximes
conditions failed to afford the corresponding amines
overcome this issue, the oximes were instead reduced with
LiAlH4 in dry THF to give the corresponding amines in good
yields. Amine 5m was subsequently debenzylated using Pd/C
and H2 to give amine 5n. LꢀValine was treated with isopropyl
chloroformate under basic conditions in THF to give the mixed
4
under these
Most of the valinamide carbamates
7 bearing an OCH2 bridge
5. To
showed excellent fungicidal activity against Phytophthora
capsici, especially for the paraꢀsubstituted compounds. Once
again, the experimental data confirmed that the paraꢀsubstituted
compounds exhibited stronger activity than their meteꢀ or
orthoꢀsubstituted counterparts. In contrast to previously
reported valinamide fungicides, the methylꢀ and chloroꢀ
substituted compounds prepared in the current study were not
the most active examples from this series. The EC50 values of
compounds 7f (R = 4ꢀCH3) and 7i (R = 4ꢀCF3) were 22.5 and
11.7 ꢁmol Lꢀ1, respectively. Compounds containing a sterically
bulky alkyl group, e.g. 7h (EC50 = 56.4 ꢁmol Lꢀ1), showed
much lower levels of fungicidal activity. In contrast,
compounds containing a halogen group showed much higher
levels of fungicidal activity. The EC50 values of compounds 7b
(R = 4ꢀF), 7d (R = 4ꢀCl), and 7e (R = 4ꢀBr) were 2.06, 1.89 and
2.38 ꢁmol Lꢀ1, respectively. Compounds bearing small alkyloxy
groups achieved the highest activity of all of the compounds in
the valinamide family. The EC50 values of compounds 7j (R =
4ꢀOCH3) and 7l (R = 4ꢀOCF3) were 1.53 and 1.36 ꢁmol Lꢀ1,
respectively. Interestingly, the introduction of a propargyloxy
group at the paraꢀposition of the phenyl ring led to a
pronounced increase in fungicidal activity. The most active
compound 7o had an EC50 value of 0.59 ꢁmol Lꢀ1 (threeꢀfold
greater than that of the known compound 7d (R = 4ꢀCl) and
twoꢀfold greater than that of compound 7l (R = 4ꢀOCF3))
against Phytophthora capsici. The propargyloxy group has been
reported to play an important role in the fungicidal activity of
mandipropamide.10 However, there have been no reports to date
suggesting that the introduction of a propargyloxy group can be
used as a strategy for increasing the fungicidal activity of any
other CAA fungicides (i.e., valinamide carbamate and cinnamic
4
5
anhydride
The subsequent treatment of
6, which was used without purification or isolation.
6
with triethylamine and amines
5
in tetrahydrofuran gave the title compounds 7a–n in 80–86%
yields (Scheme 1). The propargylation of compound 7n (R1 =
OH) with propargyl bromide in the presence of K2CO3 under
reflux conditions for 10 h gave the corresponding ether 7o
(Scheme 1).
Scheme 1. Synthetic route to compounds 7a–n and 7o
A series of “stretched” compounds bearing a CH2OCH2 linker
11a–g was synthesized as shown in Scheme 2. Aminopropanol
9
was prepared by the reduction of Lꢀalanine with LiAlH4
2 | J. Name., 2012, 00, 1-3
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Table 1. Fungicidal activities of compounds 7a–o and 11a–g against Phytophthora capsici (in vitro) along with their
predicted activities
Substituents
R1
EC50
No.
y = a + bx
r2
0
ꢁmol Lꢀ1 95% CI*
7a
7b
H
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
y = 2.4517 + 3.6457x 0.9650
y = 5.1629 + 1.2016x 0.9755
y = 3.2447 + 1.8472x 0.9973
14.8
2.06
25.2
1.89
2.38
22.5
38.5
56.4
11.7
1.53
15.6
1.36
2.40
48.2
0.59
99.7
96.3
90.9
108
13.5ꢀ16.4
1.33ꢀ3.19
21.3ꢀ29.7
1.11ꢀ3.26
1.04ꢀ5.47
19.4ꢀ25.5
32.8ꢀ45.1
44.5ꢀ71.6
8.93ꢀ14.9
1.01ꢀ2.32
12.1ꢀ20.2
1.17ꢀ1.57
2.10ꢀ2.92
37.1ꢀ62.9
0.41ꢀ0.87
56.5ꢀ173
58.4ꢀ163
71.5ꢀ115
67.6ꢀ158
62.4ꢀ174
57.5ꢀ150
11.7ꢀ19.2
0.49ꢀ0.80
0.69ꢀ1.03
p
ꢀF
ꢀF
7c
o
7d
p
ꢀCl
ꢀBr
ꢀCH3
ꢀCH3
ꢀtꢀBu
ꢀF3C
y = 5.813 + 5.3012x
y = 5.3748 + 5.509x
0.9857
0.9937
7e
p
7f
p
y = 2.6767 + 2.6063x 0.9863
y = 2.9982 + 1.7720x 0.9883
y = 3.1965 + 1.3407x 0.9850
y = 4.2399 + 1.8009x 0.9991
y = 2.0601x + 5.3874 0.9733
y = 3.9365 + 1.4030x 0.9835
y = 5.5047 + 2.0758x 0.9776
y = 4.9551 + 1.7729x 0.9883
y = 3.7098 + 1.0486x 0.9932
y = 9.2377 + 6.6440 x 0.9917
y = ꢀ3.7477 + 5.9951x 0.9866
y = ꢀ4.0438 + 5.6919x 1.0360
y = 1.0083 + 2.7566x 0.9975
y = ꢀ4.0638 + 6.2018x 0.9917
y = ꢀ3.8533+ 4.0541x 0.9856
y = ꢀ4.1271 + 6.1156x 0.9565
y = 2.1463 + 3.7225x 0.9906
y = 9.1342 + 6.3811x 0.9349
y = 6.2088 + 2.1245x 0.9966
7g
m
7h
p
7i
p
7j
p
ꢀCH3O
ꢀCH3O
7k
o
7l
p
ꢀCF3O
ꢀBnO
ꢀOH
7m
7n
p
p
7o
p
ꢀHCCCH2O
11a
11b
11c
11d
11e
11f
11g
H
pꢀF
m ꢀF
oꢀF
p
ꢀCl
ꢀCH3
ꢀCF3O
106
p
90.4
15.0
0.59
0.84
p
Dimethomorph
Iprovalicarb
* CI: confidence interval.
Table 2. Fungicidal activities of selected compounds against Phytophthora capsici and Pseudoperonospora cubensis (in
vivo)
P. capsici (% control at given concentration mg L−1) P. cubensis (% control at given concentration mg L−1)
No.
cLog P
100
50
25
12.5
6.25
100
50
25
12.5
6.25
7b
100
100
100
100
87
100
100
100
100
35
82
100
88
80
66
49
62
21
30
26
79
70
85
81
84
81
84
78
86
ꢀ*
72
70
70
72
69
72
ꢀ
61
66
62
66
58
70
ꢀ
44
42
54
47
41
54
ꢀ
40
35
30
42
37
46
ꢀ
2.89
3.29
2.60
4.26
4.34
2.82
3.20
2.73
7d
7j
7l
79
74
30
7m
30
30
7o
100
100
100
100
100
100
100
100
100
92
iprovalicarb
dimethomorph
* no test.
100
100
82
74
54
37
27
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18
acid fungicides).17,
This result therefore provides clear 12.9, 14.7, 15.8, 16.4, 17.5 and 10.4 ꢁmol Lꢀ1 against S.
evidence that the inclusion of a propargyl group can have a sclerotiorum, respectively. Compound 7j also provided good
pronounced impact on the fungicidal activity of valinamide levels of activity against P. piricola with an EC50 value of 9.6
carbamate derivatives, although the extent of this effect is ꢁg/mL.
dependent on the other substituents. Steric congestion can lead
Table 3. Fungicidal spectrum test of selected compounds at
to a sharp reduction in the fungicidal activity, as demonstrated
in our previous study, where steric hindrance made it difficult
for a propargyl group to interact with the binding pocket of
cellulose synthase.
In contrast to compounds 7a–o, the inclusion of three linker
atoms to give compounds 11a–g appeared to be unsuitable for
good fungicidal activity. Most of the compounds belonging to
the latter of these two series showed poor fungicidal activity.
This result could be attributed to the adverse steric effect of the
CH2OCH2 bridge.
50 µg/mL
No.
7a
FV1 CA2 PP3 AS4 GZ5 SS6 BC7 TC8
48.1 57.1 65.0 72.7 73.1 75.0 61.0 67.2
46.2 52.9 90.9 63.2 66.7 90.9 81.4 86.3
42.3 35.3 100 68.4 66.7 86.4 81.4 88.2
50.0 47.1 63.6 68.4 66.7 90.9 83.7 92.2
47.4 36.8 68.4 63.2 53.3 90.2 76.1 88.2
38.5 47.1 79.5 63.2 60.0 84.1 79.1 86.3
42.3 47.1 100 63.2 66.7 88.6 83.7 92.2
42.3 5.9 100 63.2 66.7 95.5 79.1 86.3
46.2 41.2 100 63.2 73.3 93.2 79.1 88.2
50.0 35.3 100 68.4 53.3 90.9 76.7 84.3
46.2 35.3 90.9 68.4 66.7 90.9 79.1 84.3
33.3 31.6 35.7 76.2 47.1 91.0 90.2 79.1
33.3 36.8 44.6 71.4 38.2 90.2 76.1 68.7
38.1 47.4 46.4 76.2 52.9 90.2 84.8 90.3
52.4 63.2 25.0 71.4 41.2 90.2 76.1 73.1
7b
7c
7d
7e
A further in vivo assay was conducted in a greenhouse to
estimate the fungicidal activities of the most active compounds
against P. capsici and P. cubensis. The results of our previous
study17, 18 revealed that the high cLogP values of the valinamide
carbamate derivatives led to a significant decrease in their in
vivo fungicidal potency against P. capsici, because of their poor
absorption through the root. As shown in Table 2, the cLogP
values of most of the compounds prepared in this study were in
the range of 2.6–3.3, except for compounds 7l and 7m bearing
trifluoromethoxy and benzyloxy moieties, respectively. Most of
these compounds exhibited very good in vivo fungicidal activity,
with a strong association between their EC50 value and in vivo
fungicidal potency against P. capsici and P. cubensis.
Compound 7o displayed high levels of control of 79 and 46%
against P. capsici and P. cubensis at 6.25 ꢁg mL−1, respectively,
and showed higher levels of antioomycetic activity than
dimethomorph (85 and 27%) and iprovalicarb (70%) at the
same concentration. However, high cLogP compounds, e.g. 7l
and 7m, showed much lower fungicidal activity for root
irrigation treatments (P. capsici) than leaf spray (P. cubensis).
Interestingly, these compounds showed good broadꢀ
spectrum fungicidal activities against nonꢀoomycete diseases at
50 ꢁg/mL, with almost all of them inhibiting the growth of S.
sclerotiorum by more than 90%, which was similar to that of
chlorothalonil. Compound 7j showed the highest level of
activity towards P. piricola at 100%, which was greater than
that of chlorothalonil (Table 3).
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
11a
11b
11d
11f
11g
ꢀ
ꢀ
23.8 58.1 45.5 61.9 93.4 69.0 62.2
23.8 58.1 50.0 59.5 90.8 66.7 58.1
28.6 48.4 45.5 38.1 88.2 69.0 62.2
28.6 64.5 72.7 71.4 93.4 73.8 64.9
23.8 58.1 54.5 61.9 93.4 69.0 67.6
ꢀ
ꢀ
ꢀ
chlorothalonil
83
75
92
74
73
96
96
96
1
2
3
FV: Fusarium vasinfectum
;
CA: Cercospora arachidicola;
PP:
Physalospora piricola; 4 AS: Alternaria solani; 5 GZ: Gibberella zeae; 6 SS:
7
8
Sclerotinia sclerotiorum; BC: Botrytis cinerea; TC: Thanatephorus
cucumber; 9 PC: Phytophthora capsici (PC)
.
Table 4. EC50 values of fiveteen selected compounds against
We subsequently determined the EC50 values of a selection
of the synthesized compounds against a variety of different
four different fungi (µmol L-1)
fungi, and the results are listed in Table 4. These compounds
and 11 showed fungicidal activities against S. sclerotiorum
7
No.
7b
SS1
7.28
22.1
ꢀ
PP2
36.1
ꢀ
BC3
TC4
ꢀ
ꢀ
ꢀ
similar to or higher than those of the control compound
Chlorothalonil (21.8 ꢁmol Lꢀ1). Compounds 7b
,
7h
, 7i, 7j, 7o,
7d
16.3
15.9
11a, 11d, 11e and 11g gave EC50 values of 7.28, 7.62, 11.5,
7g
34.5
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ethanol, and the resulting solution was flushed with N2.
Palladium on carbon (0.2 grams, 10% wt) was added to the
solution, and the resulting mixture was hydrogenated under 15
atm of H2 pressure for 12 h. The mixture was then filtered to
remove the catalyst, and the filtrate was concentrated under
vacuum to afford a yellow residue, which was purified by flash
column chromatography to give the desired product (0.95 g,
73.1%. M.p.: 72–74 °C.
7h
7i
7.62
11.5
12.9
ꢀ
29.4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
7j
26.1
ꢀ
ꢀ
7l
ꢀ
15.8
ꢀ
7n
36.7
14.7
15.8
25.8
16.4
17.5
25.3
10.4
21.8
ꢀ
ꢀ
27.5
7o
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
11a
11b
11d
11e
11f
11g
ꢀ
ꢀ
General procedure for the synthesis of the isopropyl ((2S)-3-
methyl-1-oxo-1-((1-substituted phenoxypropan-2-yl)amino)butan-
2-yl)carbamates 7a–n. 4ꢀMethylmorpholine (6 mmol) was added
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
to
a
solution of (S)ꢀ2ꢀ((isopropoxycarbonyl)amino)ꢀ3ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
methylbutanoic acid (5 mmol) in anhydrous tetrahydrofuran (20
mL), followed by ethyl chloroformate (5 mmol), and the
resulting mixture was stirred at 0 °C for 1 h. A solution of
Chlorothalonil
27.5
4.14
6.39
1
2
3
amine
5 (6 mmol) in anhydrous tetrahydrofuran (10 mL) was
SS: Sclerotinia sclerotiorum; PP: Physalospora piricola; BC:
Botrytis cinerea; 4 TC: Thanatephorus cucumber
.
then added to the reaction in a dropꢀwise manner, and the
resulting mixture was stirred at room temperature for 10 h. The
reaction mixture was then filtered and the filtrate concentrated
under vacuum to give a residue, which was extracted with ethyl
acetate (3 × 20 mL). The combined organics were washed with
brine (2 × 15 mL), dried over anhydrous sodium sulfate, and
concentrated in vacuo to give the crude product, which was
purified by flash column chromatography to give the desired
Experimental
Materials and methods
1H and 13C NMR spectra were measured on a Bruker ACꢀ
P500 instrument ((Bruker, Fallanden, Switzerland) using TMS
as internal standard and CDCl3 as a solvent. Melting points
were determined on an Xꢀ4 binocular microscope melting point
apparatus (Beijing Tech Instruments, Beijing, China) and were
uncorrected. HRMS were recorded on an Ionspec 7.0ꢀT
Fourierꢀtransform ionꢀcyclotron resonance (FTICR) mass
spectrometer (Bruker, Billerica, USA). All of the reagents were
purchased as the analytical grade.
General procedure for the synthesis of the 1-substituted
phenoxypropan-2-ones 3a–m. The intermediate phenoxypropanꢀ
2ꢀones were prepared according to a previously reported
method by the reaction of the corresponding substituted phenols
with αꢀchloroacetone.20 Analytical data for the characterization
of compounds 3a–m can be found in the Supporting
Information.
1
product 7a as a white solid (78.5%). M.p.: 89–91 °C; H NMR
(400 MHz, CDCl3) δ 7.36–7.23 (m, 2H, Arꢀ
3H, Arꢀ ), 6.25 (t, = 8.6 Hz, 1H, CHCON
25.3, 8.1 Hz, 1H, OCON ), 4.89 (dt, = 12.4, 6.1 Hz, 1H,
OC (CH3)2), 4.41 (d, = 3.3 Hz, 1H, CH2C CH3), 3.95 (qd,
= 9.4, 4.4 Hz, 3H, OCONHC + OC 2), 2.26–2.00 (m, 1H,
CHC (CH3)2), 1.33 (dd, = 6.8, 3.4 Hz, 3H, CHC 3), 1.23 (dd,
= 8.1, 6.4 Hz, 6H, OCH(C 3)2), 1.03–0.84 (m, 6H,
CHCH(C
3)2); 13C NMR (101 MHz, CDCl3) δ 170.66, 158.50,
H), 7.04–6.85 (m,
H
J
H), 5.24 (dd,
J =
H
J
H
J
H
J
H
H
H
J
H
J
H
H
156.28, 129.46, 121.13, 114.73, 70.30, 68.60, 60.37, 44.71,
31.07, 22.07, 19.24, 17.59; HRMS (MALDI) m/z Calcd for
C18H28N2O4Na+ [M + Na]+ = 359.1941, found 359.1945.
Analytical data for the characterization of compounds 7b–n
can be found in the Supporting Information.
General synthetic procedure for the synthesis of 1-substituted
phenoxypropan-2-one oximes 4a–m. The intermediate oximes
were prepared according to a previously reported method by the
Procedure for the synthesis both diastereoisomers of isopropyl
((2S)-3-methyl-1-oxo-1-((1-(4-(prop-2-yn-1-yloxy)phenoxy)propan-
2-yl)amino)butan-2-yl)carbamate (7o). To
a
solution of
reaction of the corresponding ketone
3 with hydroxylamine
compound 7n (2.83 mmol) in dry acetone (30 mL) was added
anhydrous K2CO3 (4.26 mmol), and the resulting mixture was
stirred for 1 h. Propargyl bromide (4.3 mmol) was then added
to the mixture in a dropꢀwise manner over 30 min, and the
resulting mixture was heated at reflux for 10 h. The reaction
mixture was then cooled to ambient temperature, filtered, and
evaporated to dryness to give a brown oily residue. The residue
was dissolved in methylene chloride and washed with water (2
× 50 mL). The organic layer was then dried over anhydrous
Na2SO4 and evaporated under vacuum to give the crude product,
which was purified by flash column chromatography to give
diastereoisomer 7o as a white solid (80.9%). M.p.: 81–83 °C;
hydrochloride.21 Analytical data for the characterization of
compounds 4a–m can be found in the Supporting Information.
General procedure for the synthesis of the 1-substituted
phenoxypropan-2-amines 5a–m. Lithium aluminium hydride
(45.3 mmol) was suspended in 50 mL of ether at 0 °C. Oxime
4
(18.1 mmol) was then added to the mixture in small portions,
and the resulting mixture was heated at reflux for 3 h. The
mixture was then cooled to room temperature and slowly
treated with
a 2 N NaOH solution. The mixture was
subsequently filtered and evaporated to dryness to give a
yellow residue, which was purified by flash column
chromatography. Analytical data for the characterization of
compounds 5a–m can be found in the Supporting Information.
Procedure for the synthesis of the 4-(2-aminopropoxy)phenol
(5n). Amine 5m (2.0 g, 7.78 mmol) was dissolved in 50 mL of
1H NMR (300 MHz, CDCl3) δ 6.90–6.69 (m, 4H, Arꢀ
(s, 1H, CHCON ), 5.08 (s, 1H, OCON ), 4.90–4.73 (m, 1H,
OC (CH3)2), 4.57 (d, = 1.9 Hz, 2H, HCCC 2), 4.29 (s, 1H,
CH2C CH3), 3.82 (dd, = 13.8, 6.6 Hz, 3H, OCONHC
H), 6.03
H
H
H
J
H
H
J
H +
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ARTICLE
Journal Name
OC
1.24 (d,
OCH(C
H
2), 2.44 (s, 1H, OCH2CC
= 6.8 Hz, 3H, CHC
3)2), 0.92–0.77 (m, 6H, CHCH(C
H
H
), 2.06 (s, 1H, CHC
H(CH3)2), Physalospora piricola (PP), Alternaria solani (AS), Gibberella
J
H
3), 1.15 (t, J = 6.2 Hz, 6H, zeae (GZ), Sclerotinia sclerotiorum (SS), Botrytis cinerea (BC),
H
3)2); 13C NMR (101 and Thanatephorus cucumber (TC), as previously described.17,
23ꢀ25
MHz, CDCl3) δ 170.95, 156.30, 153.37, 152.06, 116.13, 115.39,
The results of these analyses are summarized in Tables 3
78.82, 75.41, 71.02, 68.58, 60.26, 56.54, 44.68, 31.37, 21.96, and 4.
19.18, 17.56; HRMS (MALDI) m/z Calcd for C21H30N2O5Na+ Fungicidal activity against Phytophthora capsici (in vivo). The in
[M + Na]+ = 413.2047, found 413.2049.
Procedure for the synthesis of (S)-2-aminopropan-1-ol P. capsici were determined as previously described.17, 26 The
(9). The intermediate amino alcohol was prepared according results are summarized in Table 1.
to a previously reported method by the reduction reaction of Lꢀ Fungicidal activity against Pseudoperonospora cubensi (in vivo).
alanine with LiAlH4.22
The in vivo fungicidal activities of the synthesized compounds
Procedure for the synthesis of isopropyl ((S)-1-(((S)-1- against P. capsici were determined as previously described.17, 27
vivo fungicidal activities of the synthesized compounds against
9
hydroxypropan-2-yl)amino)-3-methyl-1-oxobutan-2-
The results are summarized in Table 2.
yl)carbamate (10). Intermediate 10 was prepared according to
the procedure reported in chapter 2.2.6 to give a white solid
(82.1%). M.p.: 179–181 °C; 1H NMR (400 MHz, CDCl3) δ
Conclusions
6.37 (d,
OCON
6.8 Hz, 1H, CH2C
OCONHC ), 3.69 (dd,
(dd, = 11.1, 5.8 Hz, 1H, OC
= 6.6 Hz, 1H, CHC
OCH(C 3)2), 1.21 (d,
6H, CHCH(C
156.51, 68.84, 66.65, 60.61, 47.83, 30.88, 22.06, 19.26, 17.95,
16.86; HRMS (ESI) m/z Calcd for C12H25N2O4 [M + H]+
261.1809, found 261.1810.
Procedure for the synthesis of isopropyl ((S)-1-(((S)-1-
(substituted benzyloxy)propan-2-yl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (11). To a stirred suspension of
NaH (0.23 g, 0.57 mmol, 60%) in DMF (10 mL) was added
intermediate 10 (1.0 g, 3.8 mmol) in a portionꢀwise manner at
−10 °C, and the resulting mixture was stirred for 20 mins at −10
°C. A solution of benzyl bromide (5.7 mmol) in DMF (10 mL)
was then added to the reaction in a dropꢀwise manner over 30
mins at −10 °C, and the resulting mixture was stirred for 6 h at
the same temperature. The mixture was then poured into 200
mL of ice water to give a white solid, which was collected by
filtration and purified by recrystallization from ethanol to give
J
H
= 6.8 Hz, 1H, CHCON
), 5.02–4.77 (m, 1H, OC
CH3), 3.93 (dt,
= 11.1, 3.6 Hz, 1H, OCH
H
H
), 5.31 (d,
(CH3)2), 4.09 (dt,
= 9.8, 5.0 Hz, 1H,
2CH), 3.56
), 2.12 (d,
= 6.2, 3.6 Hz, 6H,
3), 1.04–0.93 (m,
J
= 7.4 Hz, 1H,
In summary, we have designed and synthesized a series of 1ꢀ
substituted phenoxypropanꢀ2ꢀamino valinamide carbamates as
potential cellulose synthase inhibitors. The subsequent
evaluation of the fungicidal activities of these compounds
revealed that the introduction of an additional OCH2 linker into
iprovalicarb resulted in very good levels of fungicidal activity
J
= 10.9,
H
J
H
J
J
H2CH), 2.59 (s, 1H, OH
J
H
(CH3)2), 1.26 (dd, J
H
J
= 6.9 Hz, 3H, CHC
H
against Phytophthora capsici and Pseudoperonospora cubensis
.
H
3)2); 13C NMR (101 MHz, CDCl3) δ 171.97,
Most interestingly, the introduction of a propargyloxy group led
to a considerable increase in the fungicidal activity of the
“stretched” iprovalicarb. Compound 7o was identified as the
most promising candidate based on its excellent fungicidal
potency against oomycete diseases and good fungicidal activity
against nonꢀoomycete diseases. Further studies are currently
underway in our laboratory involving field trials.
+
=
Acknowledgements
We are grateful for financial support for this work from the
National Natural Science Foundation of China (21172124).
Notes and references
1
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1
compound 11a as a white solid (68.9%). M.p.: 145–147 °C; H
NMR (400 MHz, CDCl3) δ 7.49–7.19 (m, 5H, Ar-H), 6.12 (s,
1H, CHCON
OC (CH3)2), 4.53 (s, 2H, ArꢀC
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Y. Miyake, J. Sakai, I. Miura, K. Nagayama and M. Shibata,
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73.17, 72.84, 68.50, 60.30, 44.96, 31.24, 22.09, 19.18, 17.70;
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found 351.2277.
Analytical data for the characterization of compounds 7b–g
can be found in the Supporting Information.
Fungicidal Activities
5
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In vitro Fungicidal activity. The in vitro fungicidal activities of
the synthesized compounds were evaluated against Fusarium
vasinfectum
(FV),
Cercospora
arachidicola
(CA),
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