Design, synthesis and insecticidal activity of biphenyl-diamide derivatives

Article abstract of DOI:10.1016/j.cclet.2015.12.011

Diamides acting on insect ryanodine receptors are an intensive research area now. In order to search for novel candidates, a series of diamides containing biphenyl substructure were designed and synthesized. Their insecticidal activities against armyworms (Mythimna sepatara) and aphis (Aphis craccivora) were screened. The compounds with 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl substituent were found to be insecticidal to armyworms with the similar symptoms to poisoning by flubendiamide. In this research, we presented a novel type of diamide insecticide as a lead compound for further optimization.

Full text of DOI:10.1016/j.cclet.2015.12.011

G Model
CCLET 3504 1–5
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
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Original article
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Design, synthesis and insecticidal activity of biphenyl-diamide
derivatives
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Q1 Ye Liu, Chao Lei, Xiao-Yong Xu, Xu-Sheng Shao , Zhong Li
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Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Diamides acting on insect ryanodine receptors are an intensive research area now. In order to search for
novel candidates, a series of diamides containing biphenyl substructure were designed and synthesized.
Their insecticidal activities against armyworms (Mythimna sepatara) and aphis (Aphis craccivora) were
screened. The compounds with 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl substituent were
found to be insecticidal to armyworms with the similar symptoms to poisoning by flubendiamide. In this
research, we presented a novel type of diamide insecticide as a lead compound for further optimization.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 29 April 2015
Received in revised form 24 July 2015
Accepted 22 October 2015
Available online xxx
Keywords:
Diamide
Insecticide
Ryanodine insecticide
Biphenyl
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1. Introduction
a 3-formamide substituent have been reported recently by 30
Syngenta [15,16], Bayer [17,18], Mitsui chemicals [19,20] etc 31
(Fig. 3). In these examples, the two amides groups were not 32
situated at adjacent positions as in the phthalic diamides or 33
9
Diamide insecticides are newly-developed agrochemicals for
pest control which are effective on lepidopterous insects
[1]. Compared to the naturally sourced alkaloid ryanodine from
Ryania speciosa [2,3], artificial insecticides are less toxic to fish and
mammals, because they selectively induce the release of Ca2+
through the insect ryanodine receptors (RyRs) [4,5], but have no
effect on mammalian RyRs [4,6]. The selectivity of diamide
insecticides may be the result of large species differences on the
RyRs binding sites [7]. With a new mode of action, the diamide
insecticides were favored for their safety to mammals, high
efficiency, and lack of cross-resistance to pyrethroids, benzoyl-
phenylureas, organophosphates, and carbamates [8,9].
Basically, there are two kinds of diamide insecticides classified
by chemical structures. One kind is the phthalic diamides,
represented by flubendiamide, discovered by Nihon Nohyaku
and jointly developed with Bayer CropScience [9]. The other kind is
the anthranilamides, including chlorantraniliprole and cyantrani-
liprole developed by Dupont [10] (Fig. 1). Based on the general
structure of phthalic diamide (Fig. 2), chemical modification of part
B and C gave several novel candidates as potential Ryanodine
insecticides [11–14]. From the variation of part A, benzamides with
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anthranilamides, but still showed high insecticidal activity.
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The biphenyl group occurs in pharmaceuticals and pesticides for 35
its bioactivity. For example, the commercialized bifenthrin, bifena- 36
zate, and recent patents use biphenyl substitute as a pesticidal 37
pharmacophore (Fig. 4) [21–24]. Encouraged by the above descrip- 38
tion, we used the biphenyl group as the replacement of part A to 39
discover more chemicals as insecticides. The two amides groups 40
were located at the ortho-position of each aromatic ring.
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Herein, a series of biphenyl-diamides were synthesized and 42
screened to investigate their insecticidal activity as a function of 43
structure changes. Compound 1s containing 3,5-dichloro-4- 44
(2,2,4,4-tetrafluoro-ethoxy)aniline shows growth inhibition to 45
armyworms (Mythimna sepatara). It was found that Compound 46
3s substituted with formyl methylamine shows 100% mortality to 47
armyworms at 100 mg Lꢀ1 (Schemes 1 and 2).
Q248
2. Experimental
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All melting points were obtained with a Bu¨chi Melting Point 50
B540 and are uncorrected. NMR spectra were recorded in DMSO-d6 51
(1H at 400 MHz and 13C at 100 MHz) using TMS as the internal 52
standard on a Bruker WP-400SY (400 MHz) spectrometer. Chemi- 53
*
Corresponding authors.
cal shifts are reported in
d (parts per million) values. High- 54
E-mail addresses: shaoxusheng@ecust.edu.cn (X.-S. Shao),
lizhong@ecust.edu.cn (Z. Li).
resolution mass spectra were recorded under electron impact 55
http://dx.doi.org/10.1016/j.cclet.2015.12.011
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Y. Liu, et al., Design, synthesis and insecticidal activity of biphenyl-diamide derivatives, Chin. Chem.
Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.011

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Y. Liu et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
molecular sieve overnight. All other solvents and reagents were
used as obtained from commercial sources without further
purification.
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General procedure for compounds 1–8: The diphenic anhydride
was purchased from commercial source and recrystallized when
necessary. According to Ref. [25], A solution of 2,4,6-trimethylpyr-
idine (1.2 mmol) and aliphatic amine (1.2 mmol) in DMF (dimethyl
Formamide, 1 mL) was added dropwise to the diphenic anhydride
(1 mmol) in DMF (1 mL) at room temperature. After 2 h of stirring,
the solution was removed under reduced pressure. The residue
was dissolved in 10 mL EtOAc (ethyl acetate), then washed with
15% HCl and brine. The product was evaporated and crystallized in
EtOAc–petroleum ether.
Fig. 1. Commercialized diamide: flubendiamide, chlomathranilipole and
cyantraniliprole.
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(70 eV) condition using a MicroMass GCT CA 055 instrument.
Analytical thin-layer chromatography (TLC) was carried out on
precoated plates (silica gel 60 F254), and spots were visualized with
General procedure for the target compounds except 1c: Under
argon condition [26], p-TsCl (p-toluenesulfonyl, 1.2 mmol) in 2 mL
dichloromethanewasinjectedtothe2 mLdichloromethanemixture
of Compounds 1–6 (1 mmol) and 4-dimethylaminopyridine
˚
ultraviolet (UV) light. Dichloromethane was treated with a 4 A
Fig. 2. General structure of phthatic amides and diphenic amides.
Fig. 3. Insecticidal molecules with diamides subunit.
O
O
N
N
O
O
Cl
O
NH
HF2C
N
O
CF3
N
O
N
N
N
Cl
Bifenthrin
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OH
O
F3C
O
S
H
N
Cl
H
N
N
O
N
H
Cl
O
O
O
Cl
Bifenazate
WO 201413095
WO2013144096
Fig. 4. Biphenyl-containing pesticides.
Please cite this article in press as: Y. Liu, et al., Design, synthesis and insecticidal activity of biphenyl-diamide derivatives, Chin. Chem.
Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.011

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Scheme 1. Synthesis route of diphenic amides.
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(2.4 mmol) at reflux temperature. The aromatic amine or hetero-
aromatic amine (1.2 mmol) was injected to the reaction mixture 2 h
later. The mixturewasstirredforanother2 h. Afterremovingsolvent
in vacuo, the residue was quenched with EtOAc and water,
neutralized with sat. NaHCO3 solvent, the EtOAc layer was dried 81
over anhydrous Na2SO4 and concentrated. The residue was 82
chromatographed on silica gel (EtOAc–petroleum ether) to give 83
target compounds.
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Please cite this article in press as: Y. Liu, et al., Design, synthesis and insecticidal activity of biphenyl-diamide derivatives, Chin. Chem.
Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.011

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Y. Liu et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Scheme 2. Insecticidal activity of target compounds to armyworms.
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Procedure for the preparation of compound 1c: Compound 1c
was synthesized according to Ref. [27]. Diphenic anhydride
(2 mmol) and 4-nitroaniline (2.4 mmol) were heated to reflux in
chloroform for 3 h. After removing solvent in vacuo, the residue
was resolved in EtOAc, then washed with NaHCO3 and brine. The
intermediate was recrystallized in EtOAc–petroleum ether. The
mixture of mono-acid intermediate 20-((4-nitrophenyl)carba-
moyl)-[1,10-biphenyl]-2-carboxylic acid (1.0 mmol) and 4-
dimethylaminopyridine (2.4 mmol) was heated (2.4 mmol) in
dichloromethane to reflux, then injected with p-TsCl (1.2 mmol)
and 2 mL dichloromethane for 2 h. Then, isopropylamine
(1.2 mmol) was added to the reaction flask, followed by stirring
for another 2 h. After removing the solvent in vacuo, the residue
was quenched with EtOAc and water. After this was neutralized
with sat. NaHCO3 solvent, the EtOAc layer was dried over
anhydrous Na2SO4 and concentrated. The residue was chromato-
graphed on silica gel (EtOAc–petroleum ether) to give target
compound.
synthesize sulfonyl-O-acryl mixed anhydrides as an alternative
routine. The mixed anhydrides reacted with amines to give the
final products. However, in preparing Compound 1c, treatment of
mixed anhydride with the p-nitroaniline could not give the
expected diamide. This might be caused by the low nucleophilicity
of the p-nitroaniline. Compound 1c was prepared under different
reaction conditions via amidation sequence. The p-nitroaniline was
introduced under refluxing chloroform with diphenic anhydride to
form the mono-amide intermediate 20-((4-nitrophenyl)carba-
moyl)-[1,10-biphenyl]-2-carboxylic acid. Then, this mono-amide
intermediate was treated with p-toluenesulfonyl, followed by
i-propylamine to give compound 1c.
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3.2. Insecticidal activity
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The insecticidal activities of the target compounds were
evaluated against armyworms (M. sepatara). Compounds 3s, 4s
and 9s containing 3,5-dichloro-4-(2,2,4,4-tetrafluoro-ethoxy)ani-
line group were insecticidal with mortality from 75% to 100% at
500 mg Lꢀ1. When R1 was i-propyl, the compound 1s showed
growth inhibition to armyworms at 500 mg Lꢀ1, while compound
8s with a larger aliphatic group is inactive. These differences
suggested that the smaller size of substituent R1 was favorable to
bioactivity. When R2 was some other aromatic amine or
heterocyclic ring, the compounds were inactive. This indicated
that the insecticidal activities of these compounds do not depend
on the electrical properties of the substituent. Compound 3s with
the shortest aliphatic chain showed LD50 value of 58.7 mg Lꢀ1 to
armyworm. Compound 3s showed the best water solubility of
compounds 3s, 4s, and 9s. A tentative inference was that the
different insecticidal activities of compound 3s, 4s, and 9s might be
related to their physiochemical property which could affect drug
absorption and delivery.
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3. Results and discussion
3.1. Synthesis
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The synthetic route of the designed structures was shown in
Fig. 2. Refluxing 2,2-biphenyldicarboxylic acid in acetic anhydride
gave the diphenic anhydride with a good yield. Using diphenic
anhydride as staring material, the Compounds 1–8 were synthe-
sized with yields from 55% to 90%, depending on the part of the
aliphatic amines. The second amine was much more difficult to
introduce into the core structure. The commonly-used amidation
methods, such as acylation or condensation, usually lead to the
formation of by-product 5H-dibenzo[c,e]azepine-5,7(6H)-dione.
Thus, we used the p-toluenesulfonyl and Compounds 1–8 to
Please cite this article in press as: Y. Liu, et al., Design, synthesis and insecticidal activity of biphenyl-diamide derivatives, Chin. Chem.
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A series of novel diphenic diamides were designed and
synthesized. The insecticidal activities were assayed to give a
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.12.011.
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Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.011