Novel ultrasound-promoted parallel synthesis of trifluoroatrolactamide library via a one-pot passerini/hydrolysis reaction sequence and their fungicidal activities

Article abstract of DOI:10.1021/co400111r

An ultrasound-promoted one-pot Passerini/hydrolysis reaction sequence has been developed for the synthesis of trifluoroatrolactamide derivatives using a diverse range of trifluoroacetophenones and isonitriles in acetic acid. Parallel synthesis in a centrifuge tube using a noncontact ultrasonic cell crusher was used in this study as an efficient method for the rapid generation of combinatorial trifluoroatrolactamide libraries, and subsequent biochemical evaluation of the resulting compounds indicated that they possessed excellent broad-spectrum fungicidal activities. N-(4-chlorophenyl)-2-(4-ethylphenyl)-3,3, 3-trifluoro-2-hydroxypropanamide and N-(4-chlorophenyl)-3,3,3-trifluoro-2- hydroxy-2-(4-methoxyphenyl)propanamide, in particular, showed significant fungicidal activities against all of the fungal species tested in the current study.

Full text of DOI:10.1021/co400111r

Research Article
pubs.acs.org/acscombsci
Novel Ultrasound-Promoted Parallel Synthesis of
Trifluoroatrolactamide Library via a One-Pot Passerini/Hydrolysis
Reaction Sequence and Their Fungicidal Activities
Shu-Jing Yu,† Cong Zhu,† Qiang Bian,‡ Can Cui,† Xiu-Jiang Du,† Zheng-Ming Li,†,‡
and Wei-Guang Zhao*,†,‡
‡
†State Key Laboratory of Elemento-Organic Chemistry and National Pesticide Engineering Research Center (Tianjin), Nankai
University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An ultrasound-promoted one-pot Passerini/hydrolysis
reaction sequence has been developed for the synthesis of
trifluoroatrolactamide derivatives using a diverse range of trifluor-
oacetophenones and isonitriles in acetic acid. Parallel synthesis in a
centrifuge tube using a noncontact ultrasonic cell crusher was used in
this study as an efficient method for the rapid generation of
combinatorial trifluoroatrolactamide libraries, and subsequent bio-
chemical evaluation of the resulting compounds indicated that they
possessed excellent broad-spectrum fungicidal activities. N-(4-chlorophenyl)-2-(4-ethylphenyl)-3,3,3-trifluoro-2-hydroxypropa-
namide and N-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-2-(4-methoxyphenyl)propanamide, in particular, showed significant
fungicidal activities against all of the fungal species tested in the current study.
KEYWORDS: parallel synthesis, ultrasound-promoted, trifluoroatrolactamide library, one-pot Passerini/hydrolysis reaction,
fungicidal activities
available for preparing α-acyloxy amides9 because of its high
atom economy and chemical efficiency. This reaction also
provides scaffolds that are ideal for parallel synthesis and
INTRODUCTION
■
α-Hydroxyacetamides represent an interesting structural class
that has recently been the subject of considerable levels of
combinatorial chemistry. Although the reaction is suitable for
attention. Depsides and depsipeptides,1 which are both
the synthesis of a wide variety of mandelamide derivatives, it
members of this particular class, show promising biological
generally proceeds at a particularly slow rate (2 weeks), and
properties, including antibacterial, antiviral, antifungal, anti-
HIV, and anti-inflammatory activities. Some compounds
bearing an α-hydroxyacetamide moiety have become successful
sometimes even fails to provide the desired atrolactamide
derivatives. We recently developed a rapid, eco-friendly, and
high-yielding procedure for sterically congested Passerini
commercial products as medicines and pesticides. Bicalutamide,
reactions to occur with ultrasound irradiation under solvent-
for example, is currently the leading antiandrogen used for the
free conditions.10 Herein, we describe the results of our recent
treatment of prostate cancer,2 whereas mandipropamid is the
related studies toward the development of a methodology for
the ultrasound-promoted parallel synthesis of a library of
first mandelamide fungicide against foliar diseases caused by
Oomycetes.3 The distinguished activity of mandelamides 1
against fungal diseases was first reported in 1986,4 and it was
trifluoroatrolactamide derivatives via a one-pot Passerini/
hydrolysis reaction sequence and the subsequent evaluation
subsequently found by Agrevo (now Bayer) and Novartis (now
Syngenta) that the deacetyl mandelamides 25 and 3,6
respectively, exhibited excellent levels of activity against plant
pathogens, especially oomycetes diseases. Atrolactamide may be
regarded either as a methylated mandipropamid or as an acyclic
of their fungicidal activities (Scheme 1).
This reaction was achieved from commercially available or
readily synthesizable starting materials such as substituted 2,2,2-
trifluoroacetophenones 5 (Figure 2), substituted isonitriles 6
famoxadone,7 which is a highly active, broad-spectrum
(Figure 3), and acetic acid under ultrasound irradiation. Upon
completion of the Passerini reaction, the reaction mixture was
fungicide from a new class of chemicals, the oxazolidinediones.
Furthermore, the huge success of fluorine-containing drugs will
directly hydrolyzed by the addition of aqueous sodium
hydroxide and methanol under ultrasound irradiation to afford
compounds 4 (Scheme 2).
undoubtedly stimulate continued research toward the use of
fluorine in medicinal chemistry for drug discovery.8 With this in
mind, we have designed a small molecule library of
trifluoroatrolactamides 4 Figure 1.
The Passerini reaction is one of the oldest multicomponent
Received: September 6, 2013
Revised: October 17, 2013
reactions in organic synthesis and is one of the best methods
© XXXX American Chemical Society
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Figure 1. Structures of some compounds with α-hydroxyacetamide moieties.
Scheme 1. Step-by-Step Procedure for Research and Development of Compounds with Fungicidal Activity
Figure 2. Diversity of the substituted 2,2,2-trifluoroacetophenones 5{1−6}.
Figure 3. Diversity of the substituted isonitriles 6{1−15}.
Scheme 2. Ultrasound Irradiation-Promoted Parallel Synthesis of Trifluoroatrolactamides 4
different dehydration agents have been reported in the
literature for the synthesis of isonitriles, including chlorodime-
thylformiminium chloride,11 phosphoryl chloride,12 phos-
gene,13 and diphosgene.14 Unfortunately, most of these
methods suffer from several disadvantages, including the
RESULTS AND DISCUSSION
■
During our study toward the synthesis of trifluoroatrolacta-
mides 4, we explored a variety of different methods for the
synthesis of substituted isonitriles 6 involving the dehydration
of formamides with a range of dehydration agents. Several
B
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extreme toxicity and cumbersome handling of the dehydration
agents, or the high cost and general availability of the reagents.
Triphosgene is an excellent alternative as a dehydrating agent to
phosgene and diphosgene because it is supplied as a solid and
therefore much easier to handle. Furthermore, the use of
triphosgene as a dehydration agent generally leads to higher
yields than phosphoryl chloride. For example, the yield of
benzyl isocyanide was 59.3% with triphosgene compared with
37.1% with phosphoryl chloride (Scheme 3).
compound 7a. Single-crystal X-ray diffraction of 8a showed an
unexpected oxazolidinone ring structure (Figure 4), which was
Scheme 3. Synthesis of Substituted Isonitriles 6
Figure 4. Molecular structure of 8a.
most likely formed by the nucleophilic attack of the amide
nitrogen on the acetyl carbonyl carbon of the Passerini product
7a. Moreover, intermolecular O3−H−O2 hydrogen bonding
interactions were also observed in the crystal structure. This
hydrogen bonding scheme was repeated along the b axis leading
to the formation of a one-dimensional chain polymer.
The Passerini reaction of trifluoroacetophenones, acetic acid
and isonitriles normally requires 2 weeks to proceed to
completion under conventional conditions (<40% yield). In
contrast, the same reaction can proceed to completion in only
24 h under solvent-free conditions. Furthermore, under
ultrasound irradiation conditions at the same temperature
with the power set at 1200 W (pulse-on time, 2 s; pulse-off
time, 2 s), the same reaction can reach completion in 15−45
min with a much higher yield. It has been reported Passerini
reactions using aqueous hydrochloric, hydrobromic, sulfuric,
nitric, phosphoric,15 or trifluoroacetic acid with pyridine-type
bases16 proceed smoothly to affords α-hydroxy amide
derivatives directly. These reactions, however, did not take
place under the same reaction condition to give the expected
products 4, with the isocyanides being completely hydrolyzed
to give the corresponding N-substituted formamides in the
presence of aqueous acid or trifluoroacetic acid.
Furthermore, a minor impurity 8 (i.e., compound 7a and 8a
in a 3:0.09 NMR ratio) was regularly observed by TLC when
we prepared the Passerini products using trifluoroacetophe-
nones as starting materials. HRMS analysis of this material
indicated that it corresponded to the expected product 7a,
whereas the 1H NMR of 8a did not contain a CONH signal at
6.3 ppm or a COCH3 signal at 2.3 ppm, and the methyl signal
was seen at 1.6 ppm, instead of 2.3 ppm. Furthermore, the
methylene proton resonances of the benzyl group were divided
into two sets of doublets at 4.71 and 4.27 ppm. The 13C NMR
spectrum of 8a showed a single carbonyl group (at 165 ppm).
When we tried to grow a single crystal of compounds 7a by the
slow evaporation solution growth technique at room temper-
ature, we only formed single crystals of compounds 8a. We
subsequently established that compounds 7a and 8a could be
very slowly converted into each other in solution, and that
heating or the addition of an organic base did not accelerate the
conversion process (Scheme 4). This result demonstrated that
compound 8a possessed better thermodynamic stability than
This ring closing phenomenon in the Passerini reaction has
not been reported previously for a three-component
intermolecular Passerini reaction, although a similar phenom-
enon has been reported for an intramolecular Passerini reaction
conducted in the presence of catalytic amine.17 Given the
novelty of this particular result, we decided to study this ring
closing reaction in greater detail. Our initial results revealed that
when the reaction was carried out at 60 °C, the 7a/8a ratio
went up to 3:7.24 after 40 min. When tributyl amine (0.2
equiv) was used as the amine at 40 °C, we obtained a ratio of
3:2.07 of 7a/8a (NMR ratio). When the temperature was
increased to 60 °C under the same conditions, the ratio of 7a/
8a went up to 3:26.6. Furthermore, when 1 equiv of tributyl
amine was used at 60 °C, the ratio of 7a/8a increased further to
3:50.0. Further increases in the amount of catalyst did not lead
to an increase in the ratio of 7a/8a (Table 1).
Table 1. Effects of the Temperature and Catalyst Charge on
a
the Ultrasound-promoted Passerini Reaction
b
c
entry
temperature (°C)
catalyst (equiv)
7a/8a
yield (%)
1
2
3
4
5
6
7
40
60
40
60
60
60
60
3:0.09
3:7.24
3:2.07
3:26.6
3:38.4
3:50.0
3:50.0
65
63
69
61
60
63
62
0.2
0.2
0.5
1.0
1.5
a
General reaction conditions: 1-(Isocyanomethyl)-4-methoxybenzene
(0.1 mmol), acetic acid (0.15 mmol), and 2,2,2-trifluoro-1-phenyl-
b
ethanone (0.15 mmol), 15 min. Determined by 1H NMR analysis of
c
−CH3 resonance signal. Isolated yield.
Scheme 4. Conversion between the Two Passerini Products
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a
Table 2. Influence of Different Substituent Groups on the Passerini Ring Closing Reaction
b
c
entry
R1
R2
ratio of 7/8
yield (%)
1
2
3
4
5
6
H
NO2
Cl
3:0
48.7
76.5
78.2
66.1
48.3
50.0
H
3:0.42
3:1.64
3:1.30
3:1.60
3:1.82
H
MeO
MeO
MeO
MeO
Et
MeO
PhO
a
b
General reaction conditions: Isonitrile (0.1 mmol), acetic acid (0.15 mmol), and phenylethanone (0.15 mmol), 40 °C, 40 min. Determined by 1H
c
NMR analysis of the −CH3 resonance signal. Isolated yield.
To evaluate the influence of different substituents on
Passerini ring closing reaction, in terms of the selectivity and
the reaction time, a series of different isonitriles and
phenylethanones bearing different substituents were reacted
in the presence of acetic acid under ultrasound irradiation at 40
°C under solvent-free conditions. The substituents on the
isonitrile (R2) and the phenylethanone (R1) had a significant
effect on the 7/8 ratio. In the case of the nitro compounds 6,
bearing an electron-withdrawing substituent at the para-
position, a unique compound 7 was observed (Table 2, entry
1). When R1 was Cl, the 7/8 ratio was 3:0.42. The introduction
of an electron-donating substituent at the para-positions of
isonitrile (R2) or the phenylethanone (R1) led to a significant
increase in the 7/8 ratio (Table 2, entries 3−6).
Pleasingly, we found that the cyclized products 8 could be
readily hydrolyzed using an inorganic base. Upon completion of
the Passerini reaction, the reaction mixture could be directly
hydrolyzed in 2 h, following the addition of aqueous sodium
hydroxide and methanol at room temperature. When the
reaction was carried out under ultrasound irradiation
conditions, the reaction only required 15 min to proceed to
completion, with the ultrasound-assisted procedure therefore
providing an approximately 8-fold acceleration in the rate of the
reaction compared with the conventional procedure. Further
experiments showed that the title compounds could be readily
obtained via a one-pot Passerini/hydrolysis reaction sequence.
The structure of compound 4{1,8} was further confirmed by
single crystal X-ray diffraction analysis (Figure 5).
Although ultrasound irradiation has been successfully applied
to organic reactions for reducing synthesis time, as well as
improving yields,18 harnessing this method for the preparation
of combinatorial libraries can be technically challenging. It was
envisaged that this facile one-pot Passerini/hydrolysis reaction
sequence would be well suited to parallel combinatorial
synthesis. With this in mind, we describe a blend of parallel
ultrasound irradiation steps that allowed us to combine the
Passerini and hydrolysis reactions into a one-pot procedure for
the rapid preparation of trifluoroatrolactamide libraries in
inexpensive centrifuge tubes using a noncontact ultrasonic cell
crusher for ultrasound irradiation. The instrument could
accommodate centrifuge tubes of different sizes (0.5 and 10
mL) to allow for simultaneous parallel reactions. A noncontact
sonic horn was used to avoid the possibility of cross-
contamination, and the centrifuge tubes were sealed to avoid
the diffusion of any odor resulting from the isonitriles. The
yields obtained using the improved method were similar to
those obtained using the two-step contact sonic horn method.
There are several disadvantages associated with the routine
preparation of sizable libraries,19 including (i) these processes
can time-consuming and uneconomical in the sense that they
generally involve extensive and sometimes unnecessary
preparation and purification stages; and (ii) processes of this
type generally lead to the generation of large numbers of
compounds with unsuitable biological properties. With regard
to 2,2,2-trifluoroacetophenones and isonitriles, in particular,
there are only a limited number of these compounds available
commercially. With this in mind, it was only possible to
synthesize a limited orthogonal library (4 × 9 = 36
compounds) using four representative isonitriles and nine
representative trifluoroacetophenones. It was also possible to
construct a nonorthogonal library (11 compounds) using
several other building blocks to both increase the compound
diversity and evaluate the QSAR.
The 47-member library was screened for in vitro antifungal
activity. The fungi tested were Fusarium vasinfectum (FV),
Cercospora arachidicola (CA), Physalospora piricola (PP),
Alternaria solani (AS), Gibberella zeae (GZ), Phytophthora
infestans (PI), Sclerotinia sclerotiorum (SS), Botrytis cinerea (BC),
Thanatephorus cucumeris (TC), and Phytophthora capsici (PC).
The results, as shown in Table 3, indicated that most of the
trifluoroatrolactamides 4 showed good broad-spectrum fungi-
cidal activities at 50 μg/mL. Almost all of the synthesized
compounds inhibited the growth of PP, SS and TC by more
Figure 5. Molecular structure of 4{1,8}.
D
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a
Table 3. Fungicidal Activities of the Trifluoroatrolactamides 4 at 50 μg/mL
percentage of fungal growth inhibition (%)
product
4{1,1}
FV
CA
PP
AS
GZ
PI
SS
BC
TC
PC
41.7
55.6
51.9
48.1
47.4
59.3
55.6
44.4
56.3
47.4
66.7
55.6
59.3
47.4
44.4
40.7
33.3
21.1
25.9
37.0
33.3
68.8
47.4
25.9
37.0
50.0
57.9
40.7
51.9
37.0
68.4
52.6
63.2
74.1
74.1
55.6
57.9
52.6
66.7
63.0
68.8
63.2
47.4
57.9
36.8
47.4
31.3
83.3
76.5
81.0
71.4
47.6
59.1
81.0
81.0
66.7
76.9
72.7
76.2
61.9
66.7
68.2
57.1
42.9
47.6
63.6
47.6
38.1
42.9
76.9
59.1
47.6
38.1
0.0
63.9
80.0
85.0
67.5
70.8
67.5
82.5
57.5
76.0
78.5
85.0
80.0
90.0
69.2
87.5
47.5
60.0
72.3
67.5
47.5
15.0
88.0
80.0
70.0
75.0
92.0
70.8
90.0
60.0
10.0
78.5
76.9
86.2
92.5
92.5
95.0
75.4
81.5
92.5
85.0
96.0
81.5
84.6
81.5
76.9
76.9
96.0
92.3
57.9
63.6
59.1
63.6
70.8
68.2
72.7
63.6
61.1
79.2
72.7
59.1
63.6
66.7
63.6
68.2
59.1
75.0
54.5
54.5
63.6
61.1
58.3
54.5
59.1
61.1
70.8
59.1
54.5
45.5
66.7
70.8
75.0
77.3
81.8
72.7
66.7
79.2
72.7
77.3
66.7
79.2
83.3
83.3
83.3
75.0
61.1
73.9
66.7
76.9
76.9
69.2
36.0
65.4
46.2
57.7
23.5
40.0
65.4
73.1
84.6
36.0
50.0
57.7
50.0
36.0
57.7
69.2
76.9
35.3
40.0
84.6
80.8
41.2
32.0
69.2
57.7
53.8
44.0
48.0
64.0
65.4
65.4
46.2
56.0
60.0
53.8
61.5
41.2
64.0
60.0
68.0
56.0
36.0
41.2
73.1
43.5
38.1
38.1
33.3
32.1
47.6
57.1
23.8
33.3
50.0
52.4
28.6
33.3
50.0
52.4
33.3
28.6
39.3
33.3
19.0
28.6
44.4
32.1
23.8
38.1
33.3
39.3
23.8
23.8
19.0
32.1
67.9
67.9
61.9
76.2
47.6
57.1
57.1
61.9
66.7
33.3
64.3
67.9
64.3
60.7
53.6
38.9
81.0
87.5
88.2
80.0
73.5
76.1
80.0
91.2
88.2
90.3
77.6
76.5
91.2
76.5
76.1
88.2
88.2
85.3
74.6
80.0
76.5
73.5
75.0
80.6
73.5
82.4
90.0
76.1
82.4
80.0
79.4
73.1
80.0
83.6
70.6
88.2
88.2
74.6
80.0
76.5
85.3
90.3
74.6
80.6
80.0
80.6
79.1
90.3
96.4
58.6
76.9
76.9
65.4
67.2
76.9
69.2
73.1
64.3
70.3
65.4
61.5
73.1
75.0
76.9
65.4
73.1
60.9
61.5
65.4
65.4
67.9
68.8
65.4
73.1
71.4
67.2
69.2
69.2
73.1
70.3
70.3
73.4
84.6
73.1
73.1
70.3
71.9
80.8
80.8
67.9
71.9
84.4
75.0
70.3
68.8
67.9
96.1
55.3
64.5
64.5
71.0
83.9
71.0
64.5
61.3
90.8
71.4
80.6
61.3
45.2
69.6
93.5
77.4
71.0
57.1
64.3
64.3
64.3
53.8
71.4
57.1
57.1
70.2
53.8
71.4
28.6
57.1
53.8
71.4
71.4
64.3
46.2
57.1
57.1
57.1
77.8
53.8
64.3
71.4
69.4
69.2
64.3
64.3
57.1
57.7
53.8
69.2
78.6
78.6
64.3
61.5
61.5
71.4
78.6
75.0
80.8
61.5
61.5
57.7
53.8
72.2
82.6
4{2,1}
4{3,1}
4{4,1}
4{1,2}
4{2,2}
4{3,2}
4{4,2}
4{5,2}
4{1,3}
4{2,3}
4{3,3}
4{4,3}
4{1,4}
4{2,4}
4{3,4}
4{4,4}
4{1,5}
4{2,5}
4{3,5}
4{4,5}
4{4,6}
4{1,7}
4{2,7}
4{3,7}
4{4,7}
4{1,8}
4{2,8}
4{3,8}
4{4,8}
4{5,8}
4{1,9}
4{6,9}
4{2,9}
4{3,9}
4{4,9}
4{5,9}
4{1,10}
4{2,10}
4{3,10}
4{4,10}
4{1,11}
4{1,12}
4{1,13}
4{1,14}
4{1,15}
4{4,15}
chlorothalonil
100
74.2
71.0
67.7
90.8
83.9
64.5
74.2
77.6
75.0
64.5
64.5
61.3
82.1
85.7
50.0
47.6
52.4
47.6
59.1
77.3
72.7
81.0
85.7
81.0
54.5
72.7
76.2
81.0
76.9
77.3
81.8
72.7
72.7
54.5
84.6
75.0
100
90.3
90.3
77.4
87.5
71.4
90.3
87.1
91.8
76.8
91.1
92.9
78.6
75.0
90.8
96.1
a
FV, Fusarium vasinfectum; CA, Cercospora arachidicola; PP, Physalospora piricola; AS, Alternaria solani; GZ, Gibberella zeae; PI, Phytophthora
infestans; SS, Sclerotinia sclerotiorum; BC, Botrytis cinerea; TC, Thanatephorus cucumeris; PC, Phytophthora capsici.
than 70%. For example, compounds 4{5,2}, 4{2,4}, 4{4,6},
4{2,9}, 4{3,9}, 4{2,10}, 4{4,10}, 4{1,12}, 4{1,13}, and 4{4,15}
inhibited the growth of TC by more than 90%. Compounds
4{4,3}, 4{4,7}, 4{2,8}, 4{2,9}, 4{3,9}, 4{4,9}, 4{2,10}, 4{4,10},
and 4{4,15} inhibited the growth of PP by more than 90%.
Thirty of the compounds inhibited the growth of SS by more
than 80%. Interestingly, the inhibition rates of 4{1,5} and
4{6,9} toward TC were up to 100% at 50 μg/mL and were
therefore similar that of the control compound chlorothalonil,
which is a commercially available fungicide. Compounds
4{6,9}, 4{2,9}, 4{3,9}, and 4{4,15} in particular showed
excellent broad-spectrum fungicidal activities, which were also
similar to those of the control compound chlorothalonil.
For the different trifluoroatrolactamides bearing lipid chains
of different lengths (n), the fungicidal activities were basically in
the following order: 0 > 1 > 2. In the majority of cases, the
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Table 4. EC50Values of the Different Trifluoroatrolactamides 4 against Ten Different Fungi
EC50 (μg/mL)
product
4{3,2}
FV
CA
PP
AS
GZ
PI
SS
BC
TC
PC
8.9
4.6
4{5,2}
10.3
17.3
12.9
16.6
16.5
4{4,6}
4{4,7}
8.2
12.3
8.9
4{2,8}
9.3
4.2
4{2,9}
21.5
21.2
11.1
10.6
12.2
13.0
13.4
20.7
12.9
11.2
22.3
19.9
3.5
3.3
5.4
8.3
14.2
14.5
7.5
9.4
4{3,9}
9.3
6.2
22.2
4{4,9}
14.1
11.2
9.1
4{2,10}
4{3,10}
4{4,10}
4{4,15}
chlorothalonil
18.1
10.3
9.4
7.3
4.6
7.3
6.8
7.8
1.7
16.6
16.2
3.0
10.8
12.0
9.7
1.3
17.9
7.7
8.5
5.8
1.1
substituent group on the arylamine moiety (R2) did not have a
significant impact on the fungicidal activities of the compounds.
In contrast, the substituent group on the phenylethanone
moiety (R1) had some impact on the fungicidal activities of the
compounds, although these effects varied depending on the
fungus being tested. When R2 was 4-Cl, the fungicidal activities
against TC were in the following order: Me > Et ≈ MeO >
PhO ≈ H > Ph. Whereas, the fungicidal activities against PP
were of the following order: Et ≈ MeO ≈ Ph > Me > PhO ≈ H.
We then proceeded to determine the EC50 values of selection
of the synthesized compounds against a variety of different
fungi, and the results are listed in Table 4. Compounds 4{2,8},
4{2,9}, 4{3,9}, 4{4,10}, and 4{4,15} gave EC50 values of 9.3,
4.2, 9.3, 7.3, and 4.6 μg/mL respectively, against PP, whereas
compounds 4{3,2}, 4{5,2}, 4{4,7}, 4{2,9}, and 4{3,9} gave
EC50 values of 8.9, 4.6, 8.2, 8.9, and 6.2 μg/mL, respectively,
against SS. These compounds showed antifungal activities
similar to or higher than those of the control compound
chlorothalonil. Compounds 4{2,9} and 4{3,9} showed the
highest broad-spectrum fungicidal activities of all of the
compounds tested. For example, compound 4{2,9} gave EC50
values of 11.1, 4.2, and 13.0 μg/mL against CA, PP, and AS,
respectively, while compound 4{3,9} gave EC50 values of 10.6
and 13.4 μg/mL against CA and AS, respectively, which were
both greater than those of the control compound chlorotha-
lonil. Compound 4{2,9} gave EC50 values of 12.9, 8.9, and 3.5
μg/mL against GZ, SS, and BC, respectively, while compound
4{3,9} gave EC50 values of 9.3, 6.2, and 3.3 μg/mL against PP,
SS, and BC, respectively, which were similar to the antifungal
activities of chlorothalonil against the same fungi. Furthermore,
the fungicidal activities of compounds 4{2,9} and 4{3,9} were
evaluated in vitro against Pyricularia grisea, as well as being
evaluated in vivo against Pseudoperonospora cubensis and
Puccinia sorghi Schw. The inhibitory ratios of compound
4{2,9} were 100% and 80% against Pseudoperonospora cubensis
and Puccinia sorghi Schw at 400 μg/mL, respectively. The
inhibitory ratio of compound 4{3,9} against Pyricularia grisea at
25 μg/mL was 100%.
using ultrasonic irradiation. All the compounds synthesized in
the current study were evaluated for fungicidal activities, with
some of the compounds exhibiting excellent broad-spectrum
fungicidal activities against the fungal species tested.
EXPERIMENTAL PROCEDURES
■
1H and 13C NMR spectra were measured on a Bruker AC-P500
instrument using TMS as internal standard and CDCl3 as
solvent. Melting points were determined on an X-4 binocular
microscope melting point apparatus (Beijing Tech Instruments,
Beijing, China) and were uncorrected. HRMS were recorded
on an Ionspec 7.0-T Fourier-transform ion-cyclotron resonance
mass spectrometer.
The ultrasonic irradiation experiments were carried out in a
SL-1500W noncontact ultrasonic cell crusher, Nanjing, China;
the operating frequency was 25 kHz and the output power was
1500 W.
All chemicals and reagents were purchased from standard
commercial suppliers.
Typical Procedure for the Preparation of Trifluoroa-
trolactamide 4. Four different 2,2,2-trifluoroacetophenones 5
(0.75 mmol) were placed into different 5-mL centrifuge tubes,
and treated sequentially with acetic acid (0.75 mmol) and
isonitrile 6 (0.5 mmol) before being capped. The resulting
mixtures were then heated for 40 min at 40 °C under ultrasonic
irradiation before being treated sequentially with methanol (2
mL) and a 10% (w/w) sodium hydroxide solution (1 mL). The
resulting mixtures were then subjected to ultrasonic irradiation
using a cell crusher for 20 min at 40 °C before being allowed to
cool to room temperature. The mixtures were then evaporated
to dryness and the resulting residues extracted with ethyl
acetate. The combined organic phases were then washed with
brine and dried over magnesium sulfate before being
evaporated to dryness to give the crude product, which was
recrystallized from alcohol to give compound 4.
In conclusion, we have developed a three-component one-
pot Passerini/hydrolysis reaction sequence, involving trifluor-
oacetophenones, isonitriles, and acetic acid, as a novel method
for synthesis of trifluoroatrolactamide derivatives using a
noncontact ultrasonic cell crusher. This method is simple,
mild, and rapid and represents a practical strategy for the
synthesis of trifluoroatrolactamide derivatives in good yields
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectroscopic characterization for
compounds 4, and X-ray crystallographic information for
compounds 4{1,8} and 8a. This material is available free of
charge via the Internet at http://pubs.acs.org.
F
dx.doi.org/10.1021/co400111r | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
(16) Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E. New
Synthetic Technology for Efficient Construction of α-Hydroxy-β-
amino Amides via the Passerini Reaction 1. Org. Lett. 2000, 2 (18),
2769−2772.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: + 862223498368. Fax: + 862223505948. E-mail: zwg@
nankai.edu.cn.
(17) Marcaccini, S.; Miguel, D.; Torroba, T.; Garcia-Valverde, M. 1,4-
Thiazepines, 1,4-Benzothiazepin-5-ones, and 1,4-Benzothioxepin
Orthoamides via Multicomponent Reactions of Isocyanides. J. Org.
Chem. 2003, 68 (8), 3315−3318.
Notes
The authors declare no competing financial interest.
(18) Mason, T. J. Ultrasound in Synthetic Organic Chemistry. Chem.
Soc. Rev. 1997, 26 (6), 443−451.
ACKNOWLEDGMENTS
■
̌ ́
́ ̌ ́
(19) Soural, M.; Hlavac, J.; Funk, P.; Dzubak, P.; Hajduch, M. 2-
We are grateful for financial support for this work from the
National Natural Science Foundation of China (21172124), the
National Basic Research Science Foundation of China
(2010CB126105), and the National Key Technologies R&D
Program (2011BAE06B05).
Phenyl-substituted-3-hydroxyquinolin-4(1H)-one-carboxamides:
Structure−Cytotoxic Activity Relationship Study. ACS Comb. Sci.
2010, 13 (1), 39−44.
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