Design, synthesis, and biological evaluation of various α-substituted benzylpyrroles based on the structures of insecticidal chlorfenapyr and natural pyrrolomycins

Article abstract of DOI:10.1021/jf501377t

On the basis of the structures of chlorfenapyr and dioxapyrrolomycin, a series of 2-benzylpyrroles with a hydroxyl, an alkyloxy, an acyloxy, an alkylsulfanyl, or an oxime moiety at the α-position of benzyl were designed and synthesized. Their insecticidal, acaricidal, and fungicidal activities were extensively investigated. The structure-activity relationship showed that benzylpyrroles bearing shorter α-alkyloxy groups gave better activities against most of the insect species; the alkylation of pyrrole usually gave increased activity. Among all compounds, (4-bromo-2-(α-(2,2,2- trifluoroethoxy)-4-chlorobenzyl)-1-(ethoxymethyl)-5-(trifluoromethyl) -1H-pyrrole-3-carbonitrile) (5′j) exhibited the most outstanding insecticidal activities against oriental armyworm (IC₅₀ = 10 mg L^-1), diamondback moth (0.07 mg L^-1), corn borer (50 mg L^-1), and mosquito (0.04 mg L^-1), which are very close to those of chlorfenapyr (5, 0.08, <25, and <0.025 mg L^-1, respectively). In addition, some compounds also exhibited a broad or selective fungicidal spectrum.

Full text of DOI:10.1021/jf501377t

Article
pubs.acs.org/JAFC
Design, Synthesis, and Biological Evaluation of Various α‑Substituted
Benzylpyrroles Based on the Structures of Insecticidal Chlorfenapyr
and Natural Pyrrolomycins
Qiaoqiao Ma, Yuxiu Liu,* Pengxiang Zhang, Yongqiang Li, Lixia Xiong, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People’s Republic of China
ABSTRACT: On the basis of the structures of chlorfenapyr and dioxapyrrolomycin, a series of 2-benzylpyrroles with a hydroxyl,
an alkyloxy, an acyloxy, an alkylsulfanyl, or an oxime moiety at the α-position of benzyl were designed and synthesized. Their
insecticidal, acaricidal, and fungicidal activities were extensively investigated. The structure−activity relationship showed that
benzylpyrroles bearing shorter α-alkyloxy groups gave better activities against most of the insect species; the alkylation of pyrrole
usually gave increased activity. Among all compounds, (4-bromo-2-(α-(2,2,2-trifluoroethoxy)-4-chlorobenzyl)-1-(ethoxymethyl)-
5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile) (5′j) exhibited the most outstanding insecticidal activities against oriental
armyworm (IC50 = 10 mg L−1), diamondback moth (0.07 mg L−1), corn borer (50 mg L−1), and mosquito (0.04 mg L−1), which
are very close to those of chlorfenapyr (5, 0.08, <25, and <0.025 mg L−1, respectively). In addition, some compounds also
exhibited a broad or selective fungicidal spectrum.
KEYWORDS: chlorfenapyr, dioxapyrrolomycin, 2-benzylpyrrole, insecticidal activity, acaricidal activity, fungicidal activity
mentioned compound may also likely keep the fungicidal
activity. To our delight, compound 2 and its N-alkylation
product 3 were synthesized and found to have considerable
insecticidal and/or acaricidal activity.10
INTRODUCTION
■
Using natural products as lead compounds to develop new
pesticides with a novel structure and mechanism is one of the
most effective drug design methods.1,2 Dioxapyrrolomycin
(Figure 1), isolated from the metabolites of the microorganism
Streptomyces by the American Cyanamid Co. in 1987, is the first
chiral pyrrole toxin found to have insecticidal, acaricidal, and
fungicidal activities.3 Chlorfenapyr is such a commercial
arylpyrrole insecticide/acaricide optimized from dioxapyrrolo-
mycin.4−7 In fact, after chemical structure modification,
chlorfenapyr has obvious changes in the skeleton compared
with dioxapyrrolomycin. First, there is a carbon atom between
the benzene ring and pyrrole ring in dioxapyrrolomycin,
whereas in chlorfenapyr the benzene ring and pyrrole ring are
directly connected. Second, the substituents on both the
benzene ring and pyrrole ring of the two compounds are
significantly different. Third, chlorfenapyr has an ethoxymethyl
group on the pyrrole N, which is a necessary structural
modification to solve the tough problem that the chlorfenapyr
parent compound (1) has an intolerable phytotoxicity to the
plants applied.7
Though dioxapyrrolomycin and chlorfenapyr have some
differences in their skeletons, their insecticidal mechanisms are
the same. Both dioxapyrrolomycin and the chlorfenapyr parent
compound (1), acting as uncouplers of oxidative phosphor-
ylation,8 can uncouple respiratory electron transport in
mitochondria and hinder ADP conversion to ATP.9 Chlorfe-
napyr, as a precursor pesticide, shows same effect because it
could be converted to 1 inside the insect body.8 Thus, we
speculated that when we retain all the substituents on the
benzene and pyrrole rings of 1 but insert a methylene group
between the two rings (compound 2, Figure 1), such an
alteration in the structure would not change the insecticidal
mechanism and insecticidal/acaricidal activity, and the
Dioxapyrrolomycin contains a dioxane moiety in the
structure; from another point of view, there is an oxygen-
containing substituent on the methylene between the benzene
ring and pyrrole ring. The presence of oxygen is thought to
provide the possibility for the molecule to form a hydrogen
bond with the target in the respiratory electron transport chain
and therefore to give improved biological activity. Thus, in this
paper, choosing compound 2 as the skeleton structure, we
designed and synthesized a series of compounds with a
hydroxyl group (4) and various alkyloxy groups (5) on the
methylene and investigated the influence of different
substituents on the insecticidal, acaricidal, and fungicidal
activities; we also synthesized (α-(acyloxy)benzyl)pyrroles 6,
α-sulfanyl compounds 7, and α-oxime ether compounds 8 to
test their bioactivity. For (α-(alkyloxy)benzyl)pyrroles 5 with
higher insecticidal activity, we further introduced an ethox-
ymethyl group onto the nitrogen atom of the pyrrole ring to get
5′ to compare the resulting changes in biological activity
(Scheme 1). Herein, we present the synthesis and variety of
bioactivities of the compounds mentioned above in detail. The
structure−activity relationships are also discussed.
MATERIALS AND METHODS
■
1
Instruments. H NMR and 13C NMR spectra were obtained at
400 MHz using a Bruker AV400 spectrometer in CDCl3 or DMSO-d6
Received: March 22, 2014
Revised: June 3, 2014
Accepted: June 10, 2014
Published: June 10, 2014
© 2014 American Chemical Society
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Figure 1. Structures of dioxapyrrolomycin, chlorfenapyr, and designed benzylpyrroles.
Scheme 1. Preparation of Target Compounds
solution with tetramethylsilane as the internal standard. Chemical shift
values (δ) are given in parts per million. In the 13C NMR data, four
peaks in one set of parentheses means that they are assigned to one
carbon which is split by three adjacent F atoms. HRMS data were
obtained on an FTICR-MS instrument (Ionspec 7.0 T). The melting
points were determined on an X-4 binocular microscope melting point
apparatus and are uncorrected. The yields were not optimized.
4-Bromo-2-(α-hydroxyl-4-chlorobenzyl)-5-(trifluoromethyl)-
1H-pyrrole-3-carbonitrile (4). Method 1: A solution of 2 (0.50 g,
1.38 mmol) in dichloromethane (180 mL) was heated to reflux until
all solid was dissolved. After this solution was cooled to room
temperature, a solution of freshly distilled sulfonyl chloride (0.23 g,
1.70 mmol) in dichloromethane (10 mL) was added, and the reaction
mixture was stirred at room temperature for 12 h. Saturated sodium
bicarbonate aqueous solution (100 mL) was added, and the mixture
was stirred for another 0.5 h. The organic layer was separated and
washed with water and brine, dried over anhydrous magnesium sulfate,
and concentrated to give 4 as a white solid (0.49 g, 90%): mp 158−
159 °C; 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 7.39 (d, J = 8.4
Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.00 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 142.8, 137.6, 135.6, 129.6, 128.0, (123.6, 120.9, 118.2,
115.6), (119.2, 118.8, 118.4, 118.0), 112.5, 101.7, 95.9, 69.0; HRMS
(ESI) m/z calcd for C13H6BrClF3N2O (M − H)− 376.9315, found
376.9310.
anhydrous magnesium sulfate, and concentrated to give 4-bromo-2-(4-
chlorobenzoyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (10) as a
1
white solid (0.49 g, 94%): H NMR (400 MHz, CDCl3) δ 11.19 (s,
1H), 7.84 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H); HRMS (ESI)
m/z calcd for C13H3BrClF3N2O (M − H)− 374.9153, found 374.9153.
To a solution of 10 (1.0 g, 2.65 mmol) in THF (30 mL) was added
NaBH4 (0.15 g, 3.95 mmol), and the reaction mixture was stirred at
room temperature for 12 h. The mixture was quenched with water, the
solvent evaporated, and then the mixture extracted with dichloro-
methane. The organic layer was separated, washed with water and
brine, dried over anhydrous magnesium sulfate, filtered, and then
concentrated. The residue was purified by silica gel using petroleum
ether/ethyl acetate as the eluent to give 4 as a white solid (0.50 g,
50%).
4-Bromo-2-(α-chloro-4-chlorobenzyl)-5-(trifluoromethyl)-
1H-pyrrole-3-carbonitrile (9). Method 1: A solution of 2 (0.50 g,
1.38 mmol) in dichloromethane (180 mL) was heated to reflux until
all solid was dissolved. After this solution was cooled to room
temperature, a solution of freshly distilled sulfonyl chloride (0.23 g,
1.70 mmol) in dichloromethane (10 mL) was added, and the reaction
mixture was stirred at room temperature for 12 h. Then the mixture
was successively washed with water (3 × 100 mL) and brine, dried
over anhydrous magnesium sulfate, an dconcentrated to give 9 as a
1
white solid (0.51 g, 92%): mp 120−122 °C; H NMR (400 MHz,
Method 2: To a solution of 2 (0.50 g, 1.38 mmol) in a mixed
solvent of dichloromethane (50 mL) and DMF (5 mL) was added
freshly distilled sulfonyl chloride (0.46 g, 3.40 mmol) in dichloro-
methane (10 mL), and the reaction mixture was stirred at room
temperature for 12 h. Then water (100 mL) was added to the mixture,
and the resulting mixture was stirred for another 0.5 h. The organic
layer was separated and washed with water and brine, dried over
CDCl3) δ 9.23 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz,
2H), 6.20 (s, 1H).
Method 2: To a solution of 4 (0.50 g, 1.32 mmol) in
dichloromethane (40 mL) was added freshly distilled sulfonyl chloride
(0.46 g, 3.40 mmol) in dichloromethane (10 mL), and the reaction
mixture was refluxed for 8 h. Then the mixture was successively
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washed with water (3 × 100 mL) and brine, dried over anhydrous
magnesium sulfate, and concentrated to give 9 (0.47 g, 90%).
Synthesis of (α-Alkoxybenzyl)pyrrole (5). General Proce-
dure. To a solution of the corresponding alcohol (4.5 mmol) in THF
(40 mL) was added NaH (0.10 g, 4.1 mmol). After the mixture was
refluxed for 1.5 h, crude 9 (0.60 g, 1.51 mmol) was added, and the
mixture was refluxed for another 3 h. After the solvent was evaporated,
the residue was dissolved in dichloromethane (50 mL), washed with
water (3 × 25 mL) and brine, dried over anhydrous magnesium
sulfate, and then concentrated. The crude was purified by silica gel
using petroleum ether/ethyl acetate (10:1) as the eluent to give 5 as a
white solid.
Data for 4-bromo-2-(α-(cyclohexyloxy)-4-chlorobenzyl)-5-(tri-
fluoromethyl)-1H-pyrrole-3-carbonitrile (5h): yield 75%; white
solid; mp 102−103 °C; 1H NMR (400 MHz, CDCl3) δ 9.38 (s,
1H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 5.71 (s, 1H),
1.97−1.95 (m, 1H), 1.85−1.83 (m, 1H), 1.78−1.75 (m, 2H), 1.60−
1.51 (m, 1H), 1.47−1.33 (m, 2H), 1.31−1.18 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 142.0, 135.6, 134.0, 128.3, 127.2, (122.6, 119.9,
117.2, 114.5), (118.0, 117.6, 117.2, 116.8), 111.6, 100.4, 95.1, 75.7,
71.3, 31.7, 30.6, 24.4, 23.0, 22.8; HRMS (ESI) m/z calcd for
C19H16BrClF3N3O2 (M − H)− 459.0092, found 454.0084.
Data for 4-bromo-2-(α-(prop-2-ynyloxy)-4-chlorobenzyl)-5-(tri-
fluoromethyl)-1H-pyrrole-3-carbonitrile (5i): yield 67%; white solid;
1
mp 127−129 °C; H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 7.41
Data for 4-bromo-2-(α-methoxy-4-chlorobenzyl)-5-(trifluoro-
(d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.84 (s, 1H), 4.31 (d, J =
16.0 Hz, 1H), 4.06 (d, J = 16.0 Hz, 1H), 2.57 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 141.3, 135.8, 134.3, 129.5, 129.0, (123.5, 120.9, 118.2,
115.5), (119.4, 119.0, 118.6, 112.2), (101.62, 101.59, 101.56, 101.54),
96.7, 77.6, 73.8, 56.1; HRMS (ESI) m/z calcd for C16H7BrClF3N2O
(M − H)− 414.9466, found 414.9462.
methyl)-1H-pyrrole-3-carbonitrile (5a): yield 63%; white solid; mp
1
51−53 °C; H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 7.40 (d, J =
8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.40 (s, 1H), 3.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 141.1, 134.4, 130.1, 128.4, 127.5, (122.6,
119.9, 117.2, 114.5), (118.5, 118.1, 117.7, 117.3), 111.4, 100.3, 95.2,
76.3, 56.2; HRMS (ESI) m/z calcd for C14H13BrClF3N3O (M +
NH4)+ 409.9877, found 409.9867.
Data for 4-bromo-2-(α-(2,2,2-trifluoroethoxy)-4-chlorobenzyl)-5-
(trifluoromethyl)-1H-pyrrole-3-carbonitrile (5j): yield 70%; yellow
solid; mp 107−109 °C; 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H),
7.45 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.72 (s, 1H), 3.95−
3.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.0, 136.4, 133.6,
129.9, 128.7, (127.5, 124.7, 122.0, 119.2), (123.4, 120.7, 118.1, 115.4),
(120.0, 119.6, 119.2, 118.8), 112.0, 101.7, 97.2, 76.7, 66.5, 66.2, 65.8,
65.5; HRMS (ESI) m/z calcd for C15H6BrClF6N2O (M − H)−
458.9340, found 458.9335.
Data for 4-bromo-2-(α-ethoxy-4-chlorobenzyl)-5-(trifluorometh-
yl)-1H-pyrrole-3-carbonitrile (5b): yield 80%; white solid; mp 118−
119 °C; 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 7.40 (d, J = 8.0
Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.52 (s, 1H), 3.60−3.48 (m, 2H),
1.28 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.5, 135.0,
134.1, 128.3, 127.4, 111.5, 100.3, 95.1, 74.4, 64.3, 14.0; HRMS (ESI)
m/z calcd for C15H15BrClF 3N3O (M + NH4)+ 424.0034, found
424.0040.
Data for 4-bromo-2-(α-(2,2,2-trichloroethoxy)-4-chlorobenzyl)-5-
(trifluoromethyl)-1H-pyrrole-3-carbonitrile (5k): yield 70%; white
solid; mp 112−113 °C; 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H),
7.45 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 5.90 (s, 1H), 4.15
(d, J = 11.2 Hz, 1H), 4.10 (d, J = 11.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 140.1, 136.3, 134.0, 129.8, 128.7, (120.8, 118.1), (119.6,
119.2), 112.0, 101.8, 97.3, 95.8, 80.4, 77.0; HRMS (ESI) m/z calcd for
C15H7BrCl4F3N2O (M − H)− 506.8453, found 506.8450.
Data for 4-bromo-2-(α-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-
4-chlorobenzyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (5l):
yield 76%; white solid; mp 106−108 °C; 1H NMR (400 MHz,
CDCl3) δ 9.16 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz,
1H), 5.96 (s, 1H), 4.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
137.1, 136.2, 130.8, 129.0, 128.3, (124.5, 121.7, 118.9, 116.1), (123.8,
121.0, 118.2, 115.4), (122.2, 119.6, 116.9, 114.2), (119.7, 119.3, 118.9,
118.5), 110.4, (100.91, 100.88, 100.85, 100.82), 97.4, 77.1, (72.8, 72.6,
72.2, 71.9, 71.6, 71.2, 70.9); HRMS (ESI) m/z calcd for
C16H6BrClF9N2O (M − H)− 526.9214, found 526.9215.
Data for 4-bromo-2-(α-propoxy-4-chlorobenzyl)-5-(trifluoro-
methyl)-1H-pyrrole-3-carbonitrile (5c): yield 65%; yellow oil; 1H
NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H),
7.31 (d, J = 8.4 Hz, 2H), 5.50 (s, 1H), 3.45 (t, J = 6.4 Hz, 2H), 1.74−
1.55 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H); HRMS (ESI) m/z calcd for
C16H17BrClF3N3O (M + NH4)+ 438.0190, found 438.0193.
Data for 4-bromo-2-(α-isopropoxy-4-chlorobenzyl)-5-(trifluoro-
methyl)-1H-pyrrole-3-carbonitrile (5d): yield 86%; white solid; mp
1
62−64 °C; H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 7.38 (d, J =
8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.63 (s, 1H), 3.73−3.67 (m,
1H), 1.22 (dd, J = 12.4, 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
142.8, 136.5, 135.1, 129.4, 128.3, (120.9, 118.3), (119.0, 118.6, 118.2,
117.8), 112.5, 101.5, 96.2, 72.7, 70.9, 22.8, 21.4; HRMS (ESI) m/z
calcd for C16H12BrClF3N2O (M − H)− 418.9779, found 418.9786.
Data for 4-bromo-2-(α-butoxy-4-chlorobenzyl)-5-(trifluorometh-
yl)-1H-pyrrole-3-carbonitrile (5e): yield 74%; white solid; mp 72−74
°C; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.39 (d, J = 8.4 Hz,
1H), 7.31 (d, J = 8.4 Hz, 1H), 5.50 (s, 1H), 3.54−3.36 (m, 1H), 1.63
(dt, J = 13.6, 6.8 Hz, 1H), 1.49−1.27 (m, 1H), 0.91 (t, J = 7.6 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 141.6, 135.0, 134.1, 128.3,
127.3, (122.6, 119.9, 117.2, 114.6), (117.9, 117.5, 117.1, 118.3), 100.3,
95.1, 74.6, 68.6, 30.5, 18.2, 12.8; HRMS (ESI) m/z calcd for
C17H19BrClF3N3O (M + NH4)+ 452.0347, found 452.0339.
Data for 4-bromo-2-(α-(3-chloropropoxy)-4-chlorobenzyl)-5-(tri-
fluoromethyl)-1H-pyrrole-3-carbonitrile (5m): yield 40%; white solid;
mp 71−73 °C; 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.40 (d, J
= 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.54 (s, 1H), 3.73−3.60 (m,
4H), 2.19−2.03 (m, 2H); HRMS (ESI) m/z calcd for
C16H11BrCl2F3N2O (M − H)− 452.9389, found 452.9385.
Data for 4-bromo-2-(α-(hexyloxy)-4-chlorobenzyl)-5-(trifluoro-
methyl)-1H-pyrrole-3-carbonitrile (5f): yield 80%; yellow oil; 1H
NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H),
7.31 (d, J = 8.4 Hz, 2H), 5.50 (s, 1H), 3.54−3.35 (m, 2H), 1.70−1.56
(m, 2H), 1.38−1.21 (m, 6H), 0.88 (t, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 143.0, 136.6, 136.0, 130.1, 129.1, (121.6, 118.9),
(119.5, 119.1), 113.1, 102.1, 97.2, 76.2, 70.7, 32.2, 30.1, 26.4, 23.3,
14.7; HRMS (ESI) m/z calcd for C19H18BrClF3N2O (M − H)−
461.0249, found 461.0245.
Data for 2-(α-(benzyloxy)-4-chlorobenzyl)-4-bromo-5-(trifluoro-
methyl)-1H-pyrrole-3-carbonitrile (5n): yield 71%; white solid; mp
117−118 °C; 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 7.43−7.37
(m, 5H), 7.34−7.28 (m, 4H), 5.58 (s, 1H), 4.62 (d, J = 11.2 Hz, 1H),
4.45 (d, J = 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.1,
135.0, 134.5, 134.3, 128.4, 127.8, 127.62, 127.58, 127.3, (122.5, 119.8,
117.2, 114.5), (118.4, 118.0, 117.6, 117.2), 111.4, (100.43, 100.40,
100.38, 100.35), 95.4, 73.4, 70.2; HRMS (ESI) m/z calcd for
C20H11BrClF3N2O (M − H)− 466.9779, found 466.9778.
Data for 4-bromo-2-(α-((diethylamino)oxy)-4-chlorobenzyl)-5-
(trifluoromethyl)-1H-pyrrole-3-carbonitrile (5o): yield 60%; white
solid; mp 104−106 °C; 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H),
7.39 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.85 (s, 1H), 2.88−
2.76 (m, 4H), 1.00 (t, J = 7.2 Hz, 6H); HRMS (ESI) m/z calcd for
C17H18BrClF3N3O (M + H)+ 450.0190, found 450.0198.
Data for 4-bromo-2-(α-(2-methoxyethoxy)-4-chlorobenzyl)-5-
(trifluoromethyl)-1H-pyrrole-3-carbonitrile (5g): yield 72%; yellow
1
solid; mp 65−67 °C; H NMR (400 MHz, CDCl3) δ 11.26 (s, 1H),
7.37 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.61 (s, 1H), 4.01−
3.89 (m, 1H), 3.80−3.71 (m, 1H), 3.70−3.62 (m, 1H), 3.60−3.54 (m,
1H), 3.50 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.1, 135.0,
134.2, 128.2, 127.7, (122.8, 120.1, 117.4, 114.8), (118.2, 117.8, 117.4,
117.0), 111.6, (100.3, 100.2), 95.1, 75.6, 70.7, 68.3, 58.1; HRMS (ESI)
m/z calcd for C16H17BrClF3N3O2 (M + NH4)+ 454.0139, found
454.0131.
Alternative Method for 5b. To a solution of 9 (0.55 g, 1.38
mmol) in ethanol (40 mL) was added sodium bicarbonate (0.35 g,
4.15 mmol), and the mixture was refluxed for 1 h. After the solvent
was evaporated, the residue was dissolved in ethyl acetate (50 mL),
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washed with water (3 × 25 mL) and brine, dried over anhydrous
magnesium sulfate, and concentrated to give 5b as a white solid (0.52
g, 93%).
Data for (E)-4-bromo-2-(α-(((4-nitrobenzylidene)amino)oxy)-4-
chlorobenzyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (8a):
yield 53%; yellow solid; mp 211−213 °C; 1H NMR (400 MHz,
DMSO-d6) δ 13.94 (s, 1H), 8.67 (s, 1H), 8.28 (d, J = 8.8 Hz, 2H),
7.88 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz,
2H), 6.54 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 150.1, 148.3,
142.2, 137.3, 135.9, 133.6, 129.0, 128.9, 128.3, 124.1, (124.0, 121.3,
118.6, 115.9), (118.8, 118.4), 113.3, 100.7, 95.3, 79.0; HRMS (ESI)
m/z calcd for C20H15BrClF3N5O3 (M + NH4)+ 543.9993, found
543.9972.
4-Bromo-2-(α-ethoxy-4-chlorobenzyl)-1-(ethoxymethyl)-5-
(trifluoromethyl)-1H-pyrrole-3-carbonitrile (5′b). To a stirred
solution of 5b (0.40 g, 1.24 mmol) in THF (20 mL) under an ice−salt
bath was added sodium hydride (0.12 g, 6.19 mmol) in batches. After
the mixture was stirred at room temperature for 10 min, chloromethyl
ethyl ether (0.35 g, 3.71 mmol) was added, and the mixture was
refluxed for 2.5 h. Then the solvent was removed by evaporation, and
the residue was redissolved in ethyl acetate, successively washed with
water and brine, dried over sodium sulfate, and concentrated give 5′b
Data for (E)-4-bromo-2-(α-((((4-(dimethylamino)benzylidene)-
amino)oxy)-4-chlorobenzyl)-5-(trifluoromethyl)-1H-pyrrole-3-car-
1
1
as a white solid (0.50 g, 85%): mp 61−63 °C; H NMR (400 MHz,
bonitrile (8b): yield 50%; white solid; mp 86−88 °C; H NMR (400
CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 5.77 (s,
1H), 5.27 (d, J = 10.4 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 3.63 (q, J =
6.8 Hz, 2H), 3.25 (hept, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H), 1.06
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.7, 135.3,
133.5, 128.0, 126.6, (122.8, 120.7, 117.4, 114.7), (120.7, 120.4, 120.0,
119.6), 111.9, 101.9, 101.9, 99.0, 74.8, 73.9, 65.0, 63.4, 13.9, 13.5;
HRMS (ESI) m/z calcd for C18H21BrClF3N3O2 (M + NH4)+
482.0452, found 482.0448.
MHz, CDCl3) δ 9.49 (s, 1H), 8.15 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H),
7.39 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz,
2H), 6.34 (s, 1H), 3.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
152.3, 141.4, 140.5, 135.3, 135.1, 129.3, 128.9, 128.8, (120.9, 118.2),
(119.8, 119.4, 119.0, 118.6), 112.4, 112.1, 101.4, 97.9, 40.3; HRMS
(ESI) m/z calcd for C22H18BrClF3N4O (M + H)+ 525.0299, found
525.0299.
Data for (E)-4-bromo-2-(α-(((3,3-dimethylbutan-2-ylidene)-
4-Bromo-1-(ethoxymethyl)-2-(α-(2,2,2-trifluoroethoxy)-4-
chlorobenzyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile
(5′j). The synthetic procedure was according to that of 5′b using 5j as
amino)oxy)-4-chlorobenzyl)-5-(trifluoromethyl)-1H-pyrrole-3-car-
1
bonitrile (8c): yield 68%; white solid; mp 97−99 °C; H NMR (400
MHz, CDCl3) δ 9.88 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4
Hz, 2H), 6.22 (s, 1H), 1.91 (s, 3H), 1.10 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 167.1, 140.6, 134.4, 134.0, 128.1, 127.7, (125.6, 119.9,
117.2, 114.5), (118.8, 118.4, 118.0, 117.6), 111.3, (100.03, 100.00),
97.0, 75.8, 36.6, 26.4, 10.2; HRMS (ESI) m/z calcd for
C19H19BrClF3N3O (M + H)+ 476.0347, found 476.0353.
1
the starting material: yield 90%; colorless oil; H NMR (400 MHz,
CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.89 (s,
1H), 5.21 (d, J = 10.4 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 3.87 (q, J =
8.4 Hz, 2H), 3.25 (q, J = 6.8 Hz, 2H), 1.00 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 140.5, 134.5, 133.2, 128.4, 127.1, (126.7,
123.9, 121.1, 118.3), (122.7, 120.0, 117.4, 114.7), (121.2, 120.8, 120.5,
120.1), 111.4, 102.2, 99.4, 75.2, 74.9, (66.2, 65.9, 65.5, 65.2), 63.7,
13.4; HRMS (ESI) m/z calcd for C18H18BrClF6N3O2 (M + NH4)+
536.0170, found 536.0163.
4-Bromo-2-(α-(2,2,2-trifluoroethoxy)-4-chlorobenzyl))-5-
(tris(2,2,2-trifluoroethoxy)methyl)-1H-pyrrole-3-carbonitrile
(11). To a solution of 9 (0.05 g, 0.13 mmol) in trifluoroethanol (15
mL) was added sodium bicarbonate (0.10 g, 0.94 mmol), and the
mixture was refluxed for 5 h. After the solvent was evaporated, the
residue was dissolved in dichloromethane (25 mL), washed with water
(3 × 25 mL) and brine, dried over anhydrous magnesium sulfate, and
then concentrated to give 11 as a white solid (0.08 g, 90%): 1H NMR
(400 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz,2H), 7.26 (d, J = 8.4 Hz,
2H), 5.60 (s, 1H), 3.93 (q, J = 8.0 Hz, 6H), 3.80 (q, J = 8.0 Hz, 2H).
Biological Assay. All bioassays were performed on representative
test organisms reared in the laboratory. Each bioassay was replicated
three times at 25 1 °C for the statistical requirements. Mortalities
were evaluated according to a percentage scale of 0−100%, in which
0% indicates no activity and 100% indicates total kill. When the
mortality of the blank control was less than 5%, the test result was
directly used. However, if the mortality of the blank control was less
than 20%, the test result was corrected by means of V = ((X − Y)/X)
× 100 (V = value of the corrected mortality, X = livability of the blank
control, and Y = livability of the treated organisms). To calculate IC50,
at least two mortalities at different concentrations had to be lower than
50%. The IC50 was taken from a graph plotting mortality (y-axis)
against compound concentration (x-axis); the IC50 value is the
concentration where the mortality crosses 50%.
(4-Bromo-3-cyano-5-(trifluoromethyl)-1H-pyrrol-2-yl)(4-
chlorophenyl)methyl Isobutyrate (6). To a solution of sodium
isobutyrate (0.28 g, 2.51 mmol) in dichloromethane (40 mL) was
added the appropriate amount of molecular sieves, and the mixture
was refluxed for 0.5 h. After compound 9 (0.50 g, 1.26 mmol) was
added, the mixture was refluxed for another 1.5 h. Then the molecular
sieves were filtrated, and the filtrate was washed with water (3 × 25
mL) and brine, dried over anhydrous magnesium sulfate, and then
concentrated. The crude was purified by silica gel using petroleum
ether/ethyl acetate (5:1) as the eluent to give 6 as a white solid: yield
1
71%; mp 101−102 °C; H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H),
7.40 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 2.76
(hept, J = 7.0 Hz, 1H), 1.25 (d, J = 4.0 Hz, 3H), 1.23 (d, J = 4.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 176.5, 139.3, 135.7, 133.9,
129.6, 128.1, (123.4, 120.7, 118.0, 115.4), (120.2, 119.8, 119.4, 119.0),
112.1, 102.1, 97.7, 69.1, 34.1, 18.9, 18.6; HRMS (ESI) m/z calcd for
C17H17BrClF3N3O2 (M + NH4)+ 466.0139, found 466.0147.
Synthesis of (α-(Alkylsulfanyl)benzyl)pyrroles 7 and Benzyl-
pyrrole α-Oxime Ethers 8. The synthetic procedures were according
to that of 5 using compound 9 and 1.5−2 equiv of the corresponding
alkanethiol or oxime as the starting material.
Stock solutions of each test compound were prepared in
dimethylformamide at a concentration of 600 or 200 mg L−1 and
then diluted to the required concentration (100, 50, 25, 10, 5, 2, 1, 0.5,
0.25, 0.1, 0.05, 0.025, and 0.01 mg L−1) with water containing 0.1%
TW-20 (a type of emulsifier).
Insecticidal Activity. Insecticidal Activities against Oriental
Armyworm (Mythimna separata), Diamondback Moth (Plutella
xylostella), Cotton Bollworm (Helicoverpa armigera), Corn Borer
(Ostrinia nubilalis), Beet Armyworm (Spodoptera exigua), and
Bean Aphid (Aphis craccivora). The leaf-dip method was used. Leaf
disks (5 cm × 3 cm) were cut from fresh cabbage leaves (or other
leaves) and then dipped into the test solution for 3 s. After air-drying,
the treated leaf disks were placed individually into vertical tubes (or
Petri dishes), and the disks were infested with 10 larvae (for example,
2nd-instar diamondback moth larvae). The mortalities were evaluated
3 days after treatment.
Data for 4-bromo-2-(α-(ethylthio)-4-chlorobenzyl)-5-(trifluoro-
methyl)-1H-pyrrole-3-carbonitrile (7a): yield 90%; pale yellow solid;
mp 46−48 °C; 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.34 (d, J
= 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 5.32 (s, 1H), 2.64−2.28 (m,
2H), 1.28 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.4,
134.5, 133.6, 128.5, 127.9, (122.4, 119.8, 117.1, 114.4), (118.7, 118.3,
117.9, 117.5), 111.4, 100.3, 100.3, 97.1, 44.0, 25.9, 13.2; HRMS (ESI)
m/z calcd for C15H10BrClF3N2S (M − H)− 420.9394, found 420.9395.
Data for 4-bromo-2-(α-(tert-butylthio)-4-chlorobenzyl)-5-(tri-
fluoromethyl)-1H-pyrrole-3-carbonitrile (7b): yield 62%; pale yellow
1
solid; mp 147−149 °C; H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H),
7.32 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.27 (s, 1H), 1.32
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 141.5, 135.9, 133.3, 128.5,
127.8, (122.5, 119.8, 117.2, 114.5), (118.1, 117.7, 117.3, 116.9), 111.4,
100.6, 96.2, 45.1, 41.8, 29.9; HRMS (ESI) m/z calcd for
C17H19BrClF3N3S (M + NH4)+ 468.0118, found 468.0127.
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Scheme 2. Unexpected Reactions of 9 in Ethanol and Trifluoroethanol
Table 1. Insecticidal Activity (Mortality Rates, %) against Different Insects’ Larvae
a
b
c
Concentration of the tested compounds. The units are milligrams per liter. A dash means not tested. The assay was conducted at a concentration
of 600 mg L−1.
Insecticidal Activities against Mosquito (Culex pipiens pallens).
Twenty 4th-instar mosquito larvae were put into 10 mL of the test
solution. The mortalities were evaluated 8 days after treatment.
Acaricidal Activity Assay. The detailed assay method against the
eggs, larvae, and adults of the spider mite (Tetranychus cinnabarinus)
was described in the literature.10
phytopathogens, Fusarium oxysporium, Cercospora arachidicola Hori,
Physalospora piricola, Alternaria solani, Fusarium graminearum,
Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea,
Rhizoctonia solani, and Phytophthora capsici, at rate of 50 mg L−1.
In vivo assay: The compounds were evaluated in leaf-piece assays at
a rate of 200 mg L−1 for Corynespora cassiicola and B. cinerea on
cucumber, Blumeria graminis f. sp. tritici on wheat, S. sclerotiorum on
oilseed rape, R. solani on rice, and Phytophthora on pepper.
Fungicidal Activity Assay. In vitro assay: The compounds were
evaluated in mycelial growth tests in artificial media against 10
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a
Table 2. IC50 (mg L−1) of Compounds against Insects’ Larvae
a
b
The data in blue mean good to excellent activity, and the data in pink mean moderate activity. The concentrations were set as 600, 200, 100, 50,
25, 10, and 5 mg L−1 for calculation of IC50. In the rectangular coordinate system, a line was drawn with concentration as the abscissa and mortality
rate as the ordinate. The IC50 value was roughly read from the straight line that connected the two concentrations that gave mortality rates of just
c
more and just less than 50%. Other IC50 values were calculated in the same way. The concentrations were set as 600, 200, 100, 10, 1, 0.1, and 0.01
d
mg L−1 for calculation of IC50. The concentrations were set as 5, 2, 1, 0.5, 0.25, 0.1, 0.05, 0.025, and 0.01 mg L−1 for calculation of IC50.
The detailed assay method was described in the literature.10
During the multiple repeated tests, it was also found that the
amount of sulfonyl dichloride had to be changed depending on
the degree of solvent dryness and even the humidity of the air
because insufficient sulfonyl dichloride resulted in incomplete
reaction, while excess sulfonyl dichloride produced more α,α-
dichlorinated benzylpyrrole, and both circumstances made the
reaction systems complicated. Therefore, preparing 9 directly
from 2 was not always the quickest and the most convenient
method. The preparation of 9 was then adopted as an
alternative route (Scheme 1, route with purple arrows). 2 was
first transformed to dichlorinated benzylpyrrole by using excess
sulfonyl dichloride (3 equiv) in a mixed solvent of dichloro-
methane and dimethylformamide (0.5 g of 2 in 50 mL of
dichloromethane and 5 mL of DMF) and after hydrolysis gave
benzoylpyrrole 10. Then 10 was reduced by NaBH4 to (α-
hydroxybenzyl)pyrrole 4. Finally, 4 was treated with 1.3 equiv
of sulfonyl dichloride to obtain α-monochlorinated benzylpyr-
role 9. This route needs three steps from compound 2, 4 had
much better solubility than 2, and the chlorination step was not
RESULTS AND DISCUSSION
■
Synthesis. Benzylpyrrole 2, prepared according to our
previous method,10 was reacted with 1.3 equiv of sulfonyl
dichloride to obtain α-monochlorinated benzylpyrrole 9. As a
key intermediate, 9 was treated with different nucleophiles such
as sodium bicarbonate aqueous solution, sodium alkoxide,
sodium carboxylate, thiol sodium salt, or oxime sodium salt to
afford 4, 5, 6, 7, or 8, respectively (Scheme 1). 5 was further
allowed to react with chloromethyl ethyl ether to obtain N-
substituted compound 5′. (α-(Aryloxy)benzyl)pyrroles or more
(α-(acyloxy)benzyl)pyrroles were to be synthesized, but they
were too unstable during the workup.
Note that, due to the poor solubility of 2 in dichloromethane,
the preparation of intermediate 9 required a lot of solvent (0.50
g of 2 requires about 180 mL of warm dichloromethane), and
adding dimethylformamide to increase the solubility was only
to find an increased amount of α,α-dichlorinated benzylpyrrole.
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Table 3. Acarcidal Activity (Mortality Rates, %) against Spider Mite (T. cinnabarinus Boisduval)
a
b
The data in blue mean good to excellent activity. Concentration of tested compounds. The units are milligrams per liter. A dash means not tested.
so uncontrollable; thus, the purity of crude 9 prepared from 4
was better than that from 2, which made the following
nucleophilic substitution step clearer and the product easier to
purify. Another thing to remember is that compound 9 is
sensitive to alkaline aqueous solution, so whether it was
prepared from 2 or 4, during the workup the reaction mixture
should be washed with sufficient water to remove excess
sulfonyl dichloride but not with sodium bicarbonate aqueous
solution.
Here we also mention some other experimental phenomena
we encountered. (α-Alkoxybenzyl)pyrroles 5 were generally
prepared from 9 and the corresponding sodium alkoxide, which
were prepared in advance. Accidentally, we found (α-
ethoxybenzyl)pyrrole 5b also formed when 9 was refluxed in
ethanol in the presence of sodium bicarbonate. The simpler
procedure was then expected to be applied to other alcohols.
However, when 9 was refluxed in trifluoroethanol, orthoester
11 was unexpectedly separated in high yield. In the structure of
11 not only the α-chloro atom but also the three fluorine atoms
in the trifluoromethyl group on the pyrrole ring were replaced
by trifluoroethoxyl (Scheme 2). The formation of the
orthoester was thought to be via the repeated ion-participating
F− elimination and nucleophilic addition/rearomatization
courses, which had been elucidated in detail in our previously
published paper.11 It seemed that an alcoholic solvent, a high
reaction temperature (at least higher than the boiling point of
dichloromethane), and a large excess amount of sodium
bicarbonate jointly promoted the formation of the orthoester.
Bioactivity. The α-substituted benzylpyrroles were de-
signed from insecticidal/acaricidal chlorfenapyr and dioxapyr-
rolomycin, so their insecticidal, acaricidal, and fungicidal
activities were all assayed.
Insecticidal Activity. Table 1 shows the data of insecticidal
activity against the larvae of oriental armyworm (M. separata),
diamondback moth (P. xylostella), cotton bollworm (H.
armigera), corn borer (O. nubilalis), beet armyworm (Sp.
exigua), bean aphid (A. craccivora), and mosquito. Chlorfenapyr
is included as a control.
As shown in Table 1, at 600 mg L−1, most of the compounds
exhibited 100% mortality against oriental armyworm, diamond-
back moth, and mosquito, and half of them gave 100%
mortality against cotton bollworm and corn borer. However,
for beet armyworm and bean aphid, no compounds gave the
desired activity. Therefore, against those five species, the
insecticidal activities at lower concentrations were determined,
and the IC50 (the concentration of compounds resulting in 50%
mortality) values of each species were roughly calculated (Table
2).
Table 2 shows clear structure−activity relationships for each
insect species. For oriental armyworm, α-H-substituted (2), α-
hydroxy-substituted (4), α-chloro-substituted (9), and most α-
alkyloxy-substituted (5a−n) benzyl pyrroles gave moderate to
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a
Table 4. In Vitro Fungicidal Activity against Phytopathogens
a
The data in blue mean good to excellent activity. FO = F. oxysporium, CH = C. arachidicola Hori, PP = Phys. piricola, AS = Al. solani, FG = F.
b
graminearum, PI = Phyt. infestans, SS = S. sclerotiorum, BC = B. cinerea, RS = R. solani, and PC = Phyt. capsici. A dash means not tested.
excellent activity, except those bearing long or hindered alkyl
groups such as 5e (X = OBu-n), 5f (X = OHex-n), 5h (X =
OHex-c), and 5l (X = OCH(CF3)2). Compound 6 bearing an
isobutyryloxy group at the α-position of benzylpyrrole also gave
poor activity due to both steric and stereoelectronic effects. The
α-alkylsulfanyl compounds 7a and 7b had structure−activity
relationships different from those of α-alkyloxy compounds, as
7b (X = SBu-t) had a more hindered substituent than 7a (X =
SEt) but exhibited much higher activity. Data for oxime ethers
8a−c showed that an electron-withdrawing group played a
significant role in the activity, as 8a (4-NO2C6H4CHNO)
gave much better activity than 8b (X = 4-Me2NC6H4CH
NO). In comparing N-ethoxymethyl compounds 3, 5′b, and 5′j
with corresponding NH compounds 2, 5b, and 5j, the two
types of structures did not show significant differences in the
activity against oriental armyworm.
OCH2CF3), and 5k (X = OCH2CCl3) having the lowest IC50
values (<0.1 mg L−1), close to that of chlorfenapyr (0.08 mg
L−1).
The structure−activity relationships for cotton bollworm and
corn borer were very similar to each other. However, neither of
them had insecticidal ability comparable to that of chlorfenapyr.
For mosquito, most of the benzylpyrroles bearing shorter or
longer α-alkyloxy groups (5) gave moderate to excellent
activity, but the activity rule was not so distinct. The
compounds with an oxime ether moiety (8a−c) also showed
good activity. Notably, compounds 3, 5′b, and 5′j with an
ethoxymethyl group at the nitrogen of pyrrole all exhibited
higher activity than their corresponding parent compounds 2,
5b, and 5j, and the IC50 values for 5′b and 5′j (0.07 and 0.04
mg L−1, respectively) were close to that of chlorfenapyr (0.025
mg L−1).
Overall, benzylpyrroles bearing shorter α-alkyloxy groups
gave better activities against most of the insect species. The
alkylation of pyrrole usually gave increased activity. Among all
the compounds, 5b (X = OEt), 5i (X = OCH2CCH), 5j (X
= OCH2CF3), 5′j (X = OCH2CF3), and 5k (X = OCH2CCl3)
For diamondback moth, the compounds showed structure−
activity relationships very similar to those for oriental
armyworm. Benzylpyrroles with a shorter alkyloxy group at
the α-position also gave better activity, with 5b (X = OEt), 5i
(X = OCH2CCH), 5j (X = OCH2CF3), 5′j (X =
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a
Table 5. In Vivo Fungicidal Activity against Phytopathogens
a
The data in blue mean good to excellent activity. SS = S. sclerotiorum, RS = R. solani, BG = Bl. graminis; CC: Co. cassiicola; PH: Phytophthora; BC =
b
B. cinerea. A dash means not tested.
exhibited excellent insecticidal activity against both oriental
armyworm and diamondback moth; 5′j also showed an
eminent insecticidal effect against corn borer and mosquito.
Acaricidal Activity. Table 3 shows that few compounds
exhibited satisfactory acarcidal activity; only compounds 3, 9,
5b, 5i, 5j, and 5n maintained certain mortality at a
concentration of 100 mg L−1 against spider mite adults, larvae,
and/or eggs, and none of them were comparable to
chlorfenapyr. An interesting discovery is that though 5′b and
5′j had much lower activity than their parent products 5b and
5j, compound 3 gave much higher acarcidal activity than its
parent product 2.
Another thing to note is that no serious phytotoxicity was
observed during the insecticidal and acaricidal assays; even
those compounds without an ethoxymethyl group on the
pyrrole N, such as compounds 2 and 5, did not cause distinct
harm to the leaves of the test plants at different concentrations.
Fungicidal Activity. The compounds were designed
according to the structure of fungicidal dioxapyrrolomycin, so
their fungicidal activities were also assayed to see if they could
maintain fungicidal activity. The compounds were first
evaluated in mycelial growth tests in artificial media against
10 species of phytopathogens at a rate of 50 mg L−1. As shown
in Table 4, most of the designed (α-(alkyloxy)benzyl)pyrroles 5
and α-alkylsulfanyl compounds 7 gave more than 80%
inhibition against Phys. piricola (PP) and S. sclerotiorum (SS).
5a (X = OMe) had the broadest fungicidal spectrum, with more
than 80% inhibition against eight kinds of fungi. 5b (X = OEt),
5d (X = OPr-i), 5j (X = OCH2CF3), 5k (X = OCH2CCl3), and
5m (X = O(CH2)3Cl) also gave broad fungicidal activity against
at least five kinds of fungi.
Selected compounds were also tested for their fungicidal
activity in vivo at 200 mg L−1. Azoxystrobin, carbendazim,
thiram, and dimethomorph were respectively used as contrast
compounds for different fungi (Table 5). At the test
concentration, most compounds exhibit certain fungicidal
activity; especially 5a, 5d, 5g, 6, and 7a gave better and
broader fungicidal activity against at least three kinds of fungi.
In contrast, 5m showed some selectivity; it inhibited 87% of
Phytophthora, which was very close to the value for
dimethomorph. Thus, this kind of compound can be used as
a lead compound for further fungicide research and develop-
ment.
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benzoylpyrroles based on structures of insecticidal chlorfenapyr and
natural pyrrolomycins. Mol. Diversity 2014, DOI: 10.1007/s11030-
014-9515-9.
(11) Li, Y. Q.; Zhang, P. X.; Ma, Q. Q.; Song, H. B.; Liu, Y. X.; Wang,
Q. M. The trifluoromethyl transformation synthesis, crystal structure
and insecticidal activities of novel 2-pyrrolecarboxamide and 2-
pyrrolecarboxlate. Bioorg. Med. Chem. Lett. 2012, 22 (22), 6858−6861.
In summary, on the basis of the structures of chlorfenapyr
and dioxapyrrolomycin, a series of 2-benzylpyrroles with a
hydroxyl, an alkyloxy, an acyloxy, an alkylsulfanyl, or an oxime
moiety at the α-position of benzyl were designed and
synthesized. The structure−activity relationships showed that
benzylpyrroles bearing shorter α-alkyloxy groups gave better
activities against most of the insect species; the alkylation of
pyrrole usually gave increased activity. Several compounds were
identified with excellent insecticidal and/or fungicidal activities,
and the structure−activity relationship should be useful for
future new active compound design and development.
AUTHOR INFORMATION
Corresponding Authors
*Phone: +86-(0)22-23503792. Fax: +86-(0)22-23503792. E-
mail: liuyuxiu@nankai.edu.cn.
■
*Phone: +86-(0)22-23503952. Fax: +86-(0)22-23503952. E-
mail: wangqm@nankai.edu.cn.
Funding
This work was supported by the National Key Project for Basic
Research (Grant 2010CB126106), the National Natural
Science Foundation of China (Grants 21121002, 21372131,
and 21102077), and the Specialized Research Fund for the
Doctoral Program of Higher Education (Grant
20130031110017).
Notes
The authors declare no competing financial interest.
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