The trifluoromethyl transformation synthesis, crystal structure and insecticidal activities of novel 2-pyrrolecarboxamide and 2-pyrrolecarboxlate

Article abstract of DOI:10.1016/j.bmcl.2012.09.036

Two series of 2-phenylpyrroles: 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole- 2-carboxamide (5a-5d) and 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2- carboxylate (6a-6c) were synthesized by a novel trifluoromethyl transformation. The result of insecticidal bioassays indicated that 6a-6c had moderate larvicidal activity against oriental armyworm and 6b also had good acaricidal activity, so 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxylate derivatives were expected to become lead compounds for new pesticides.

Full text of DOI:10.1016/j.bmcl.2012.09.036

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6858–6861
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The trifluoromethyl transformation synthesis, crystal structure and
insecticidal activities of novel 2-pyrrolecarboxamide and 2-pyrrolecarboxlate
⇑
⇑
Yongqiang Li, Pengxiang Zhang, Qiaoqiao Ma, Haibin Song, Yuxiu Liu , Qingmin Wang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2012
Revised 10 September 2012
Accepted 12 September 2012
Available online 20 September 2012
Two series of 2-phenylpyrroles: 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxamide (5a–5d)
and 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxylate (6a–6c) were synthesized by a novel
trifluoromethyl transformation. The result of insecticidal bioassays indicated that 6a–6c had moderate
larvicidal activity against oriental armyworm and 6b also had good acaricidal activity, so 3-bromo-5-
(4-chlorophenyl)-4-cyanopyrrole-2-carboxylate derivatives were expected to become lead compounds
for new pesticides.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Insecticidal activity
Acaricidal activity
Trifluoromethyl
Pyrrolecarboxamide
Pyrrolecarboxylate
Dioxapyrrolomycin ( Fig. 1) was isolated from a Streptomyces
strain by the researchers from American Cyanamid Co. in 1980s
and found to have insecticidal and acaricidal activities.1 It has also
reported as an antibiotic in Japan.2,3 It was not developed as a can-
didate pesticide because of its super high toxicity to mammals.
Extensive structural modification was used to overcome the defect
of toxicity. Afterwards, series of compounds were synthesized, of
which compound 1 possessed outstanding insecticidal activity
against tobacco cutworm, two-spotted spider mite and potato
leafhopper, etc.4 However, evaluation of bioactivity showed
compound 1 had intolerable toxicity to crops. An ethoxymethyl
group was introduced onto the nitrogen atom of compound 1,
therefore got rid of the undesirable phytotoxic properties but
retained high insecticidal activity.5–8 This compound was finally
commercialized as an insecticide/acaricide by American Cyanamid
Co. with its trade name as Chlorfenapyr.
We have been focusing on novel Chlorfenapyr analogues as sub-
stitute for years. In our previous work, we paid more attention on
modifying substituent on the nitrogen atom of pyrrole 1 and found
some of the compounds A and B exhibited excellent insecticidal
activities.9,10 After that, we turned our direction onto the substitu-
ent on other positions of compound 1. Recently, we happened to
find a novel synthetic method that can convert trifluoromethyl
group to the corresponding carboxamide, thus the method was
compounds and speculated mechanism. Furthermore, their insecti-
cidal activities against oriental armyworm (Mythimna separata)
and acaricidal activities against eggs, larvae and adults of spider
mite (Tetranychus cinnabarinus) were assayed and discussed.
As illustrated in Scheme 1, the initial aim of the reaction of
4-bromo-2-(4-bromophenyl)-5-(trifluoromethyl)pyrrole-3-carbo-
nitrile (2) with aniline in the presence of CuI was to prepare diphe-
nyl amine via Ullmann coupling reaction,11 which was carried out
in microwave synthesizer to shorten the reaction time. However,
the Ullmann coupling product was not formed, while unexpected
N-phenyl 5-(4-bromophenyl)-3-cyanopyrrole-2-carboxamide (3a)
was separated, and its structure was verified by NMR, high
resolution mass spectrum and the X-ray single-crystal diffraction
(Fig. 2).12
Similarly, the reaction of compound 2 or 1 with 4-trifluoro-
methylaniline afforded pyrrolecarboxamide 3b or 4, respectively.
In all these reactions the original 5-trifluoromethyl group of
pyrrole of 2 or 1 was replaced by carboxamide, and the original
bromide at the 4-position of pyrrole (i.e., 3-position in compound
3 or 4) was missing. The drop of bromine can be explained as
CuI-catalyzed debromonation. As expected, in the absence of CuI,
compounds 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-car-
boxamides (5a–5d) and 3-bromo-5-(4-chlorophenyl)-4-cyanopyr-
role-2-carboxamides (6a–6c) were prepared from compound 1
with corresponding amines or alcohols under similar condition
(Scheme 2).
applied to synthesize
a series of 2-pyrrolecarboxamide and
2-pyrrolecarboxlate (3–6). Herein, we report the synthesis of the
As far as we know, the reaction that converting trifluoromethyl
group to corresponding carboxamide or carboxylate has seldom
been reported so far. In 2010, Gavin O’Mahony reported
⇑
Corresponding authors. Tel./fax: +86 22 23503952.
E-mail addresses: wang98h@263.net, wangqm@nankai.edu.cn (Q. Wang).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.036

Y. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6858–6861
6859
Cl
O
NC
Br
CF3
NC
Br
NO2
H
Cl
Cl
Cl
Cl
CF3
N
Cl
N
H
N
H
O
CH2OC2H5
Chlorfenapyr
Dioxapyrrolomycin
1
Br
NC
Br
NC
Cl
CF3
O
Cl
CF3
N
N
O
O
O
R
OR
O
B
A
Figure 1. Chlorfenapyr and related compounds.
NC
Br
CF3
R1R2N
reaction
n
an
m
l
l
U
N
H
NC
Br
CF3
K2CO3, CuI
NMP MV
R1R2NH
+
X
NC
H
N
H
O
X
R1
N
H
N
2, X=Br
R2
1
, X=Cl
3, X=Br
4
, X= Cl
Scheme 1. Synthetic route of the compounds 3 and 4.
CF3-substituted anilines, phenols and 2-phenyl-4(5)-trifluoro-
methyl imidazoles could afford corresponding amide in the pres-
ence of alkaline.13 Heidelberger14 and Terenin15 also reported the
aminolysis of trifluoromethyl-substituted deoxyuridine or 3,4-
dihydropyrrolo-[1,2-a] pyrazines but with low yields. Comparably
more literature can be found on the alkaline hydrolysis of trifluoro-
methyl group to carboxylic acid or alcoholysis to orthoester if the
trifluoromethyl group is at a proper position of the benzene or het-
eroaromatic ring.16–30 Theoretically carboxamide or carboxylate
should be the hydrolysis product of trisubstitutedamino methyl
or trialkoxy methyl group. But C–F bond has great bond energy,
so the F atom in the CF3 group is difficult to be substituted via
an SN2-type mechanistic pathway. Based on the literature men-
tioned above, the reaction process of compound 1 to 5 or 6 was
proposed and illustrated in Scheme 3. Under microwave irritation
Figure 2. Molecular structure of compound 3a.
NC
NC
Br
CF3
NC
NC
Br
Br
K2CO3
+
R1
O
HN
Cl
Cl
Cl
Cl
R2
NMP,MV
N
H
R1
N
H
N
R2
1
5
Br
CF3
K2CO3
HOR1
+
O
O
R1
N
H
NMP, MV
N
H
1
6
Scheme 2. Synthetic route of the compounds 5 and 6.

6860
Y. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6858–6861
- F-
Br
Br
NC
NC
Br
NC
Br
CF3
base
Nu-
F
F
F
Cl
Cl
Cl
Cl
Cl
N
N
N
H
F
F
C
1
NC
Br
NC
- F-
Cl
NC
Nu-
Br
- F-
F
F
F
F
N
N
N
Nu
Nu
Br
Nu
Nu
NC
Path A
OH-
- HNu
H+
OH
Nu
Cl
Cl
NC
Br
N
E
NC
Br
Nu
Br
Nu
Cl
O
N
Cl
NC
N
H
Nu-
Nu
D
Nu
H2O
Nu
Nu
Path B
5, 6
N
H
F
- 2 HNu
Nu
Scheme 3. Proposed formation of 5 and 6.
crystal diffraction (Fig. 3).12 Therefore we verified our assumption
and provide an alternative method to prepare pyrrolecarboxylate 6
(Scheme 4).
Synthesized compounds 3–6 and reference compound Chlorfe-
napyr and 1 were tested for their insecticidal activity against orien-
tal armyworm and acaricidal activities against spider mite
according method described in literature.9,10,32
The data in Table 1 show that pyrrolecarboxamide compounds
3b, 4, 5a, 5c and 5d had no insecticidal activity against oriental
armyworm at 200 mg LÀ1, which indicates that when trifluoro-
methyl group was changed to amide group, the bioactivity dramat-
ically decreased whatever bromine atom is at the 3-position of
pyrrole ring or not. The substituent on the amide nitrogen plays
an important role on the activity; though 5a, 5c and 5d gave no
insecticidal activity at 200 mg LÀ1, N-cyclohexyl compound 5b
showed 80% insecticidal activity at the same concentration. The
pyrrolecarboxylate compounds 6b and 6c exhibited relatively good
activity against oriental armyworm at high concentrations (200 mg
LÀ1, 100 mg LÀ1); at lower concentration (50 mg LÀ1), compound 6c
still remained 100% insecticidal activity; but all the activity
dropped to 0 at the concentration of 25 mg LÀ1 whereas the com-
mercial Chlorfenapyr and compound 1 remaining 100%.
Just like the insecticidal activity against oriental armyworm, the
acaricidal activities of most of compounds also vanished when CF3
group was replaced by amide or ester. Ethyl ester compound 6b
gave better acaricidal activity than methyl ester 6a and benzyl es-
ter compound 6c but much lower than compound 1, which indi-
cates that the substituent at 2-position of pyrrole is very
important for the compounds’ activity.
Figure 3. Molecular structure of compound 6a.
or higher temperature and in the presence of Na2CO3, trifluoro-
methyl pyrrole compound 1 firstly undergoes an elimination of
hydrogen fluoride by an E1cB mechanism assisted by the N atom
of pyrrole ring to afford an electrophilic intermediate C, then it is
attacked by a nucleophile to restructure pyrrole ring; by repeating
process, the reaction gives compound D, which can be attacked
either by OHÀ (Path A)13 or by NuÀ (Path B)31, and then the result-
ing trisubstituted compound E or F is converted to amide or car-
boxylate by elimination of HNu.
Of the two paths, we are more apt to agree with path B. Though
we did not separate F from the reaction mixture irritated by micro-
wave, we did get the trimethoxymethyl pyrrole 7 when compound
1 was refluxed in methanol in the presence of sodium hydroxide.
The orthoester 7 converted to methyl carboxylate 6a in the later
hydrolysis, the structure of which was verified by the X-ray single
In summary, we have developed a new organic synthetic meth-
od about trifluoromethyl group converting to corresponding car-
boxamide or carboxylate, and this method has been used to yield
a series of 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carbox-
NC
Br
NC
Br
NC
Br
CF
H+
MeOH
O
OMe
OMe
Cl
Cl
Cl
N
H
6a
3NaOH
N
H
N
H
1
OMe
OMe
7
Scheme 4. Alternative method for 6a.

Y. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6858–6861
6861
Table 1
Insecticidal and acaricidal activities of compounds 3–6 against oriental armyworm, spider mite, larvae of spider mite, and eggs of spider mite (Mortality (%) at concentration
(mg kgÀ1).)
R1
R2
Oriental armyworm
Spider mite
200 100
Larvae of spider mite
Eggs of spider mite
200
100
50
25
200
100
200
100
3b
4
H
H
p-CF3-phenyl
p-CF3-phenyl
0
0
—
—
—
—
—
—
0
0
—
—
0
0
—
—
0
0
—
—
5a
5b
5c
5d
6a
6b
6c
1
H
H
p-CF3-phenyl
Cyclohexyl
Ethyl
Benzyl
—
—
—
—
0
80
0
—
—
—
—
100
100
100
100
100
—
—
—
—
40
60
100
100
100
0
0
0
0
60
78
0
100
100
—
—
—
—
—
40
—
100
100
0
0
0
0
40
76
0
100
100
—
—
—
—
—
52
—
100
100
0
0
0
0
0
81
0
100
100
—
—
—
—
—
54
—
100
100
—
—
—
0
0
0
100
100
Ethyl
H
Methyl
Ethyl
Benzyl
—
0
100
100
100
100
100
Chlorfenapyr
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This work was supported by the National Key Project for Basic
Research (2010CB126106), the National Natural Science Founda-
tion of China(21072109, 21121002) and the National Key Technol-
ogy Research and Development Program (2011BAE06B05). We also
thank China Agricultural University to supply some of chemical re-
agents and the National Key Technology Research and Develop-
ment Program (2012BAK25B03-3).
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Supplementary data (experimental detail, characterization of
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were provided) associated with this article can be found, in the on-
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