Design, synthesis, and biological activities of novel 2-alkylpyrrole derivatives

Article abstract of DOI:10.1002/jhet.1835

To investigate the alkyl analog of insecticide chlorfenapyr, two series of 2-alkyl-4-bromo-5-(trifluoromethyl)pyrrole-3-carbonitriles were synthesized with a cycloaddition as the key step. The target products were characterized by ¹H-NMR spectroscopy, elemental analysis, or HRMS. The insecticidal, herbicidal, and antifungal activities of the target compounds were evaluated and found that these compounds did not show much insecticidal activity, but compounds 4, 10, and 11 had very good fungicidal activities against Alternaria solani and Fusarium oxysporum. Moreover, compound 4 had an outstanding inhibition effect against pigweed.

Full text of DOI:10.1002/jhet.1835

1
410
Design, Synthesis, and Biological Activities of Novel 2-Alkylpyrrole
Derivatives
Vol 51
Yongqiang Li, Ziwen Wang, Pengxiang Zhang, Yuxiu Liu,* Lixia Xiong, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, People’s Republic of China
E-mail: wang98h@263.net; liuyuxiu@nankai.edu.cn
Received June 12, 2012
*
DOI 10.1002/jhet.1835
Published online 25 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
To investigate the alkyl analog of insecticide chlorfenapyr, two series of 2-alkyl-4-bromo-5-(trifluoromethyl)
pyrrole-3-carbonitriles were synthesized with a cycloaddition as the key step. The target products were
1
characterized by H-NMR spectroscopy, elemental analysis, or HRMS. The insecticidal, herbicidal, and
antifungal activities of the target compounds were evaluated and found that these compounds did not show much
insecticidal activity, but compounds 4, 10, and 11 had very good fungicidal activities against Alternaria solani
and Fusarium oxysporum. Moreover, compound 4 had an outstanding inhibition effect against pigweed.
J. Heterocyclic Chem., 51, 1410 (2014).
INTRODUCTION
-Bromo-2-(4-chlorophenyl)-1-ethoxymethyl-5-(trifluoromethyl)
at the other positions as precursors of insecticides/miticides
[4].
4
As a continuation of our research on design, synthesis, and
pyrrole-3-carbonitrile (Fig. 1, A), marketed as chlorfenapyr
by American Cyanamid [1], was contrived by modifying
the structure of the precursor compound B (Fig. 1). The study
on mechanism of action showed that compound B could
obstruct the action of oxidation–phosphatization as an
uncoupler, whereas chlorfenapyr could not uncouple the
oxidation–phosphatization [2], but chlorfenapyr could be
activated by the oxidative removal of ethoxymethyl group
on 1-position to change into compound B and therefore
exhibit insecticidal activity in vivo[3], so chlorfenapyr actu-
ally acted as a proinsecticide of compound B. Many modifi-
cations towards chlorfenapyr occurred at 1-position;
however, none of the analogically structural compounds
exhibited superiority over chlorfenapyr. To generate a new
lead compound with more superior property, there is a great
need to discover some novel pyrrole containing modification
bioactive studies of heterocyclic compounds containing
pyrrole ring, two series of 2-alkyl-4-bromo-5-(trifluoromethyl)
pyrrole-3-carbonitriles were synthesized and evaluated for
their insecticidal, herbicidal, and antifungal activities. To
the best of our knowledge, the introduction of alkyl group
or cycloalkyl group into the 2-position of compound B
has never been reported because of the synthetic difficulty.
Herein, we would like to report the synthesis and bioactivities
of the target compounds.
RESULTS AND DISCUSSION
Synthesis. The title compounds 4 and 5 and compounds
10 and 11 were synthesized, respectively, using the depicted
routes in Schemes 1 and 2.
©
2014 HeteroCorporation

September 2014
Design, Synthesis, and Biological Activities of Novel 2-Alkylpyrrole Derivatives
1411
NC
Br
NC
Br
In the procedure, the cyclohexylglycine had to be synthesized
using two steps, in which benzaldehyde (6) firstly was
converted to phenylglycine (7), and then reduction of 7
gave intermediate 8 using Pd-C as catalyst.
Cl
CF3
Cl
CF3
N
CH OC H
2 5
N
H
2
Biological activities. Unfortunately, none of the target
compounds showed insecticidal activity against oriental
armyworm, only N-ethoxymethyl compound 5 exhibited
moderate acaricidal activities against spider mite, larvae of
spider mite, and eggs of spider mite (Table 1). However, it
was fortunate for us to discover some compounds having
good herbicidal and antifungal activities, which was rarely
reported in previous articles. For example, the target
compound 4 showed good herbicidal activities: 100%
inhibition effect against pigweed at the dose of 375 g/ha,
over 90% inhibition effect against sowthistle-leaf ixeris
and rape at 750g/ha (Table 2). Table 3 distinctly showed
that 2-alkylpyrrole derivatives 4, 10, and 11 all displayed
very good antifungal activities against Alternaria solani
and Fusarium oxysporum. Compound 4 also exhibited high
inhibition against Cercospora arachidicola, Macrophoma
kawatsukai, Fusahum graminearum in vitro at the
concentration of 50mg/mL, and Botrytis cinerea in vivo at
the concentration of 200 mg/mL.
A
B
Figure 1. Chemical structures of compounds A and B.
Scheme 1. Synthetic route of the title compound 4 and 5.
CN
O
NC
COOH
(
CF
3
CO)
2
O
O
Cl
N CH
CF
3
CF
3
NH
2
CH
3
CN
N
Et
3
3
CN
N
H
1
9%
53%
1
2
3
Br
Br
NC
NC
Br
2
DMF
2 2 5
ClCH OC H
CF
3
CF
3
N
CHCl
3
N
H
NaH THF
62%
CH OC H
2
2 5
70%
4
5
As shown in Scheme 1, treatment of alanine with
trifluoroacetic acid anhydride gave 4-methyl-2-trifluoromethyl-
1
2
,3-oxazol-5-one (2). Cycloaddition of compound 2 with
-chloroacrylonitrile in the presence of triethylamine
CONCLUSION
In summary, we designed and synthesized two new series
of 2-alkyl-4-bromo-5-(trifluoromethyl)pyrrole-3-carbonitriles.
The results of bioassay indicated that some compounds had
good herbicidal and antifungal activities; for example, com-
pounds 4, 10, and 11 had very good fungicidal activities
against A. solani and F. oxysporum. Moreover, compound 4
had an outstanding inhibition effect against pigweed.
Therefore, 2-alkylpyrroles might be regarded as precursor
compounds for new herbicide and fungicide development.
afforded substituted pyrrole (3). Bromination of 3 provided
the target compound 4. At last, N-alkylation of compound 4
gave the target compound 5 [5].
As the key step, the possible mechanism of cycloaddition
reaction according to Tian and coworker’s work [6] was
depicted in Figure 2. Dehydrogenation of compound 2 gave
intermediate 12. Addition of 12 with 2-chloroacrylonitrile
(13) afforded 14, which can cyclize to afford intermediate
16. Decarboxylation of 16 and further dechlorination reaction
gave target product 3. Intermediate 14 can also obtain a
proton to afford byproduct 15. To decrease the formation
of compound 15, more than two equivalent of ethylamine
was added.
The target compounds 10 and 11 (2-cycloalkylpyrrole
derivatives) were synthesized (Scheme 2) by using similar
synthetic route for the preparation of compounds 4 and 5.
EXPERIMENTAL
The melting points were determined on an X-4 binocular
microscope melting point apparatus manufactured by Beijing
Tech Instruments Co., (Beijing, China), and the thermometer
was uncorrected. H-NMR were obtained using a Bruker
AV300 spectrometer (Germany) or a Varian Mercury Plus 400
1
Scheme 2. Synthetic route of the title compound 10 and 11.
KOH/LiCl/TBAB/NH3 H O
COOH
2
COOH
NH2
Pd-C
CHO
CHCl /CH Cl
3
2
2
NH2
H2
55%
72%
6
7
8
CN
Cl
NC
O
NC
Br
(
CF CO) O
O
Br
89%
2
3
2
N
H
CF3
N
CF3
28%
N
H
CF
3
7
2%
9
10
11
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Y. Li, Z. Wang, P. Zhang, Y. Liu, L. Xiong, and Q. Wang
Vol 51
Figure 2. Possible mechanism of 2 to 3.
Table 1
Insecticidal and acaricidal activities of compounds 4, 5, 10, and 11 against oriental armyworm, spider mite, larvae of spider mite, and eggs of spider mite.
À1
[
Mortality (%) at different concentration (mg kg )].
Oriental armyworm
Spider mite
200 100
Larvae of spider mite
Eggs of spider mite
Compd.
200
100
200
100
200
100
4
5
0
0
0
0
100
—
—
—
—
—
0
100
0
0
100
—
79
—
—
100
0
100
0
0
100
—
78
—
—
100
0
100
0
0
100
—
85
—
—
100
1
1
0
1
Chlorfenapyr
Table 2
Herbicidal activities of compounds 4 [inhibitions (%) at different doses (g/ha), postemergence treatment].
Rape Redroot amaranth Sowthistle-leaf ixeris Morning glory Piemarker
375
64.3
Pigweed
Compd.
750
91.3
750
375
750
375
750
375
750
375
750
100
375
100
4
69.1
58.1
92.7
71.6
51.2
14.8
0
—
Table 3
Antifungal activities of compounds 4, 10, and 11 (inhibitions (%), in vitro).
5
0 mg/mL
200 mg/mL
Cercospora
arachidicol
Alternaria
solani
Macrophoma
kawatsukai
Fusahum
oxysporum
Fusahum
graminearum
Psilocybe
cubensis
Botrytis
cinerea
Blumeria
graminis
Compd.
4
1
1
73.6
49.6
31.2
90.8
98.1
98.3
100
36.2
63.4
100
99.3
98.8
80.6
10.3
30.1
30
60
70
80
0
0
0
0
0
0
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Design, Synthesis, and Biological Activities of Novel 2-Alkylpyrrole Derivatives
1413
spectrometer (US) in CDCl solution with TMS as the inter-
crude product. Finally, the crude product was recrystallized using
petroleum ether and ethyl acetate to afford compound 5 (0.61g) as a
3
nal standard in parts per million (d). Elemental analyses were
determined on a Yanaco CHN Corder MT-3 elemental ana-
lyzer (Japan). IR spectra were recorded with an Nicolet
MAGNA-560 FTIR spectrometer. HRMS was obtained
depending on Ionspec 7.0 T Fourier Transform Ion Cyclotron
Resonance Mass Spectrometry (FTICR-MS) (US). All of the
reagents were analytically or chemically pure, which were
dried and distilled according to standard methods in advance
before use.
ꢀ
1
white solid, yield 62%, mp 49–50 C. H-NMR (400 MHz, CDCl
3
):
HH = 7.2 Hz, 2H), 2.50 (s, 3H), 1.20
(t, JHH = 7.2Hz, 3H); Anal. Calcd for C10 OF Br: C, 38.61; H,
3.24; N, 9.00. Found: C, 38.50; H, 3.28; N, 8.91.
Phenylglycine (7) [8]. To the mixture of KOH (38 g,
0.68 mol), LiCl (9.6 g, 0.23 mol), tetrabutyl ammonium bromide
3
5.31 (s, 2H), 3.49 (q,
J
3
H N
10 2
3
(3.6 g, 0.01 mol), concentrated ammonia (60 mL), and CH
2
Cl
2
ꢀ
(30 mL) was blown ammonia gas for 5 min at 0 C, and then a
solution of benzaldehyde (12 g, 0.11 mol) and chloroform
(20.3 g, 0.17 mol) in methylene dichloride (30 mL) was added
4
-Methyl-2-trifluoromethyl-1,3-oxazol-5-one (2).
To a
solution of trifluoroactic anhydride (47g, 0.22mol) in acetonitrile
ꢀ
(
100mL) was added alanine (10 g, 0.11mol) at 30 C.
dropwise over 1 h. The mixture was stirred and synchronously
ꢀ
The mixture was refluxed for 0.5 h and then cooled to RT. The
solvent was removed via rotatory evaporator; then, the residue
was taken into ethyl acetate (100 mL) and made neutral with
connected with ammonia gas for 6 h at 0 C. Then, H
2
O (60 mL)
was added, and the layer was separated. The aqueous layer was
washed with CH Cl and concentrated in vacuo until inorganic
2
2
saturated Na
2
CO
3
solution. The mixture was washed with water
salt was precipitated. The solid was filtered off, and the pH
value of filtrate was adjusted to 4–6 with dilute hydrochloride to
obtain the crystal of compound 7 at 0 C. The crude product was
collected by filtration, washed with water, ethanol, and ethyl
ether in turn, and dried to give compound 7 (12.3, 72%) as a
white solid, which was directly used for the next step without
further structural identification.
(
3Â 30mL) and brine (30mL), dried over anhydrous MgSO
4
,
ꢀ
and concentrated in vacuo to obtain a yellow to pale oily liquid,
1
gross yield 19%. H-NMR (400 MHz, CDCl ): 6.10–6.07 (m,
3
1
H), 2.40 (s, 3H).
-Methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (3). The
solution of the compound 2 (3.2 g, 0.019 mol), 2-chloroacrylonitrile
2
(
(
2.5g, 0.029 mol), and NEt
40 mL) was refluxed for 2 h and then cooled to RT. The mixture
3
(3.8 g, 0.038 mol) in acetonitrile
Cyclohexylglycine (8). The solution of phenylglycine (10 g,
0.066 mol) and 10% Pd-C (2 g) in acetic acid (100 mL) was
stirred under hydrogen at 100 atm at 120 C for 72 h, then
ꢀ
was concentrated in vacuo, and the residue was taken into ethyl
acetate (100mL); then, the mixture was washed with water
cooled to RT, and reduced the pressure to 1 atm. The mixture
was filtered and concentrated in vacuo. The residue was taken
into ethanol (100 mL) and refluxed for 30 min, and then
propylene oxide was added. The mixture was refluxed for
another 10 min, cooled to RT, filtered, washed with ethyl ether,
and dried to afford compound 8 (5.7 g, 55%) as a white solid,
which was directly used for the next step without further
structural identification.
(
3Â 30mL) and brine (30mL), dried over anhydrous MgSO
4
,
and concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel using petroleum ether/
ethyl acetate (3:1, v/v) as the eluent to afford gross product.
Finally, the crude product was recrystallized using petroleum
ether and ethyl acetate to afford compound 3 (1.7g) as a slight
ꢀ
1
yellow solid yield 53%, mp 134–135 C. H-NMR (400 MHz,
CDCl ): 12.85 (s, 1H), 7.00 (s, 1H), 2.34 (s, 3H); Anal. Calcd for
C H N F : C, 48.28; H, 2.89; N, 16.09. Found: C, 48.15; H, 3.18;
7 5 2 3
4-Cyclohexyl-2-trifluoromethyl-1,3-oxazol-5-one (9). Compound
9 was synthesized according to the similar synthetic procedure
3
1
N, 15.72.
-Methyl-4-bromo-5-(trifluoromethyl)pyrrole-3-carbonitrile
4). To the solution of compound 3 (1.4 g, 0.008 mol) and N,N-
for compound 2. Yellow oily liquid, yield 72%. H-NMR
3
2
(400 MHz, CDCl
3
): 6.08 (s, 1H), 2.78 (t, JHH = 11.2 Hz, 1H), 2.08–
3
(
2.00 (m, 2H), 1.88–1.83 (m, 2H), 1.76–1.73 (d, J = 11.2 Hz, 1H),
HH
dimethylformamide (0.6 g, 0.008 mol) in chloroform was added
1.53–1.23 (m, 5H); HRMS Calcd for C H NO F : 258.0712.
10
12
2 3
dropwise the solution of bromine (1.9 g, 0.012 mol) in chloroform
Found: 258.0713.
(
50 mL). The mixture was refluxed for 1 h and cooled to RT, to
2-Cyclohexyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (10).
Compound 10 was synthesized according to the similar synthetic
which saturated Na CO solution (10 mL) was added, and then
2
3
ꢀ
the mixture was stirred for 30 min. Chloroform and part of the
water was removed using rotatory evaporator, and then the
remaining mixture was filtered and recrystallized using petroleum
ether and ethyl acetate to afford compound 4 (1.4 g) as a white
procedure for compound 3. White solid, yield 28%, mp 158–159 C.
1
H-NMR (400 MHz, CDCl ): 12.69 (s, 1H), 7.01 (s, 1H), 2.79–2.71
3
3
(m, 1H), 1.82–1.16 (m, 4H), 1.68 (d, JHH = 12.4 Hz, 1H), 1.64–1.53
(m, 2H), 1.36–1.27 (m, 2H), 1.27–1.17 (m, 1H); Anal. Calcd for
ꢀ
solid, yield 70%, mp 208–210 C. IR: n 3232, 2233, 1587, 1300,
C H N F : C, 59.50; H, 5.41; N, 11.56. Found: C, 59.32; H, 5.59;
12 14 2 3
À1
1
1
2
1
174, 711 cm
.38 (s, 3H); Anal. Calcd for C
1.07. Found: C, 33.21; H, 1.62; N, 10.93.
-Methyl-4-bromo-1-ethoxymethyl-5-(trifluoromethyl)pyrrole-
-carbonitrile (5) [7]. To a stirred solution of compound 4 (0.8 g,
.0031 mol) in THF (20 mL) was added 50% NaH under iced salt
;
H-NMR (400MHz, CDCl ): 13.26 (s, 1H),
N, 11.66.
3
7
H N F
4 2 3
Br: C, 33.23; H, 1.59; N,
2-Cyclohexyl-4-bromo-5-(trifluoromethyl)pyrrole-3-carbonitrile
(11). Compound 11 was synthesized according to the similar synthetic
ꢀ
2
procedure for compound 4. White solid, yield 89%, mp 203–206 C.
1
3
3 HH
3
0
H-NMR (400 MHz, CDCl ): 13.06 (s, 1H), 2.75 (t, J =12Hz,
1H), 1.82–1.76 (m, 4H), 1.69–1.53 (m, 3H), 1.35–1.16 (m, 3H);
Anal. Calcd for C12 Br: C, 44.88; H, 3.77; N, 8.72. Found: C,
bath until no gas was emitted. Then, the mixture was warmed to RT
and stirred for 10 min, and then chloromethyl ethyl ether (0.6 g,
13 2 3
H N F
44.51; H, 4.08; N, 8.65.
0.006 mol) was added dropwise. The mixture was refluxed for 0.5 h,
Biological tests.
The insecticidal activity against oriental
cooled to RT, and then concentrated in vacuo. The residue was
taken into ethyl acetate (50 mL), washed with water (3 Â 30 mL)
armyworm, the acaricidal activity against spider mite, eggs of
spider mite, and larvae of spider mite were tested using reported
methods in previous literatures [9]. Likewise, the herbicidal
and antifungal activities were also tested using the previously
reported methods [10]. The insecticidal and acaricidal experiments
4
and brine (30 mL), dried over anhydrous MgSO , concentrated in
vacuo, and purified by column chromatography on silica gel using
petroleum ether and ethyl acetate (5:1, v/v) as the eluent to afford
Journal of Heterocyclic Chemistry
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Y. Li, Z. Wang, P. Zhang, Y. Liu, L. Xiong, and Q. Wang
Vol 51
including control and chlorfenapyr for comparative purpose were
rigorously carried out in three replicate under the same conditions.
Assessments were made on a dead/alive basis, and mortality rates
were estimated using Abbott’s formula [11]. Evaluations are
based on a percentage scale of 0–100, which 0 equals no activity
and 100 equals total kill or inhibition. The results of insecticidal,
acaricidal, herbicidal, and fungicidal activities were listed in
Tables 1–3, respectively.
1
723.
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Acknowledgments. This work was supported by the National Key
Project for Basic Research (2010CB126100) and the National Natural
Science Foundation of China (21072109) and the National Key
Technology Research and Development Program (2012BAK25B03-3).
We also thank China Agricultural University to supply some of
chemical reagents.
2
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[
7
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet