EHOOPrÁHH^ECRAa XHMH3, 2014, moM 40, № 2, c. 234-247
SYNTHESIS, INSECTICIDAL, AND FUNGICIDAL SCREENING
OF SOME NEW SYNTHETIC QUINOLINE DERIVATIVES © 2014 M. R. E. Alya, b, #, M. M. Ibrahima, c, A. M. Okaeld, Y. A. M. H. Gherbawy ef
aChemistry Department, Faculty of Science, Taif University, Alhawyah-Taif, 888 Kingdom of Saudi Arabia bChemistry Department, Faculty of Applied Science, Port Said University, Port Said, 42522 Egypt cChemistry Department, Faculty of Science, Kafr El Sheikh University, Kafr El Sheikh, 33516 Egypt dPlant Protection Research Institute, ARC, Dokki, Cairo, Egypt eBiology Department, Faculty of Science, Taif University, Alhawyah-Taif, KSA fBotany Department, Faculty of Science, South Valley University, Qena, Egypt Received August 13, 2013; in final form, October 7, 2013
This paper describes the synthesis of a series of quinolines graphted with hydrazones, pyrazoles, pyridazine, phthalazine, triazepinone, semicarbazide, and thiomorpholide moieties and four metal complexes. These derivatives were screened against Fusarium oxysporum and the red palm weevil (RPW) Rhynchophorus ferrugineus Oliver (coleopteran: Curculionidae) as palm pathogens. Only chlorinated quinolines were active against these organisms with hydrazones being good fungicides, while those modified with pyrazoles and pyrazines showed moderate insecticidal activity. A unique trihydroxylated hydrazone was active against both organisms, while another hydrazone, the most potent fungicide in this series, exhibited insecticidal activity only upon com-plexation with Zn2+ ions.
Keywords: quinoline, hydrazones, fungicidal, insecticidal, red palm weevil.
DOI: 10.7868/S013234231402002X
INTRODUCTION
Date crop damage arising from attack of date palms Phoenix dactylifera (Palmae) by the destructive red palm weevil (RPW) Rhynchophorus ferrugineus (Olivier) [1] and fungal infection with Fusarium oxysporum [2] is a growing problem worldwide. Other palm species of economic significances are also harmed by RPW, particularly in Southern Asia. The larval stage of RPW feeds within the trunk, which frequently reduces the crop and finally kills the tree [3, 4]. While F. oxy-sporum is treated with ordinary fungicides, for instance, fluconazole [5], management control of RPW is more complicated due to the concealed nature of the larvae [1]. Chlorpyrifos 48% EC (Brand Name: Chlo-rozan), an organophosphate pesticide, is a common pesticide involved in RPW control [6]. These pesticides, however, increase the production cost and cause environmental hazards, which restricts its utility, and continuous use of the eco-tolerant grades lead to the development of resistant pests [7]. Therefore, alternatives are under investigation, including biocontrol based on nematodes, viruses, and bacteria; integrated pest management (IPM) with pheromones and pesticides; and finally, application of biotechnology
# Corresponding author (phone: +966 56 26 94 753; e-mail: mrea34@hotmail.com).
through gene transduction to produce pest resisting palm generations [8]. However, the progress in these tactics is not sufficient yet to control these infections and chemical interference is still of great demand. Therefore, in continuation of our ongoing program to suggest solutions to local agricultural problems in the Middle East and worldwide as well based on synthetic quinolines, we extended this project to the date crop problem. In a previous work [9], a structurally diverse quinoline series were prepared, of which compound (I) (Scheme 1) was quite effective against Aphids gossipy (Glover) that harms the Egyptian cotton crop. This derivative was contracted to be intensively investigated in fields by Syngenta Agro S.A.E.
In the present work, special emphasis was given to chloroquinolines having basic graphts at position-4. This type of quinolines has special interest as chloro-quine was evolved as one of the breakthroughs in antimalarial therapy [10]. Pharmacological potential of the same category was also reported in anticancer research [11, 12]. In pesticide research, the hydrazone moiety is a highly efficient pharmacophore [7] that is widely used in pesticide design. Hydramethylnon [13] and metaflumizone [14] are commercial examples of this class of pesticides (Scheme 1).
i ,N
N
Cl
F ^ F
Fluconazole
r
Cl
O
Cl
Chlorpyrifos
H
N T
S
H
Cl'
=N /= '
N
N
H
CF,
O.
(I)
F,C
OCF,
CN
CF,
Chloroquine
Hydramethylnon
Metaflumizone (Z-isomer)
NC
V=N
Cl
CF,
N 1
H
=N ci
Cl
R = Et Ethoprole R = CF3 Fipronil
Chlorantraniliprole Scheme 1. Structure of selected fungicides and pesticides.
On the other hand, phenyl pyrazoles are important class of pesticides including ^-aryl pyrazoles, for instance, ethiprole and fipronil, that effectively control pests on corn and soya bean [15]. ^-Heteroarylpyra-zoles, particularly those containing a chloropyridyl moiety, such as chlorantraniliprole, are common larvi-cides [16]. These two classes of pesticides prompted us to choose the quinoline derivative 6-chloro-4-hy-draqzino-2-methylquinoline [17, 18] as readily accessible and reliable scaffold to develop a series of hy-drazones, as well as isosteric analogues of ^-chloro-pyridylpyrazoles, to be tested against both RPW and F. oxysporum on the way to find an integrated solution for palm infections. Another acetylanilinoquin-oline derivative was chosen to get a set of thiomor-pholide and semicarbazide architectures for the same objective. It is to be mentioned that beside the wide application of quinolines in biological, industrial, and
material science researches [19], quinoline-based agrochemicals are known for hydroxyquinolines only and devoted for herbicidal applications [20].
RESULTS AND DISCUSSION
Chemistry
Substrate (III) [17, 18] was condensed with 1.1 equivalents of the relevant carbonyl compounds (IIa—k) and cinnamaldehyde in refluxing EtOH (Scheme 2 and Table 1). Generally, crystalline pure hydrazones (IVi—k) and (V) were obtained in good yields. All compounds showed a recognizable molecular ion peak corresponding to the exact mass of each derivative. 1HNMR spectra recorded in DMSO-J6 showed broad singlet for the NH-proton at about 5 11.0 ppm due to H-bonding while the imine proton was observed at about 5 8.5 ppm if not overlapped with aro-
matic protons. The quinolyl-2-methyl protons could not be seen due to overlap with DMSO protons at about 5 2.5 ppm. However, its carbon could be seen in the 13C NMR as in the case of (IVb) at about 5 23 ppm. In the IR spectra, all compounds showed bands at about 1616 and 1637 cm-1 corresponding to the C=N
stretching and N—H deformation vibrations, respectively. The N—H stretching band was weak at about 3200 cm-1 and this band in the IR spectrum, as well as its signal at 6 11.0 ppm in the 1H NMR in the case of cinnamaldehyde suggested structure (V) rather than the Michael condensation product (VI) in this case.
Cl
R2
R3
O.
H ,nh2
N 2
Cl
+
R R4 (Ila—k)
N CH3 (III) b .
R3
H .N^^Ph N
Cl
TH3 ^ N ^CH3
(IVa-k) (V) (VI)
Scheme 2. Reagents and conditions: (a) EtOH, rfx; (b) Cinnamaldehyde, EtOH, rfx.
Compound (III) was cyclocondensed with some toacetate in refluxing EtOH giving rise to the pyrazole 1,3-dielectophiles like acetyl acetone and ethylace- derivatives (VII) and (VIII) in good yields (Scheme 3).
Table 1. Structure and some physical data of compounds (IVa—k) and (V)
Entry R R1 R2 R3 R4 Yield, % M.p., °C
(IVa) H H H H H 82 239
(IVb) H H H OMe H 80 230-2
(IVc) H H H NO2 H 80 267
(IVd) H H H Cl H 65 243-5
(IVe) H OH H H H 72 260
(IVf) H H H OH H 67 230-4
(IVs) H H H CH3 H 81 256-8
(IVh) H H OH OMe H 81 242
(IVi) CH3 H H OH H 60 282
(IVJ) CH3 OH H H OH 77 253-5
(IVk) CH3 OH OH OH H 56 270-2
(V) - - - - - 56 240
O,
sf ^ Cl
Cl
N CH3 (VII)
Cl
Cl
N CH
3
(X)
H N
Cl
N CH3 (VIII)
H ,nh2
N
3
Cl
N CH (III)
X
O.
N y
N CH3 (IX)
O
N
H N ^
Cl
N
(XI)
(XII)
Scheme 3. Reagents and conditions: (a) acetylacetone, EtOH, rfx (93%); (b) ethylacetoacetate, EtOH, rfx (51%); (c) dimethylmaleic anhydride, EtOH, rfx (71%); (d) phthalic anhydride, EtOH, rfx (86%); (e) 2-methylbenzoxazolin-4-one, AcOH, rfx (74%).
b
d
e
In the IR of pyrazole (VII), all bands of the hydrazine group disappeared and smooth XH and 13C NMR spectra were obtained. Pyrazolone (VIII) is probable to be available in solution, mostly, in the enol form due to the weakness of the C=O signal in the 13C spectrum at 173 ppm and the presence of a broad phenolic proton at 12 ppm in the 1H NMR spectrum, while the NH signal was not observed. However, in solid state, as shown in the IR spectrum, the compound is mainly available in the keto form where a strong C=O absorption band and very weak N—H stretching bands were observed. The 13C NMR spectrum was much complicated, as 15 signals were observed for the 12 aromatic carbons, presumably, due to existence of rotamers.
Reaction of (III) with 3,4-dimethylmaleic anhydride, phthalic anhydride, and 2-methylbenzoxazine is believed to proceed via cyclocondensation affording pyridazin-4-one (IX), phthalazine-1,4-dione (X), and triazipeneone (XI), respectively (Scheme 3). These new-
ly formed ring structures at C-4 ofthe quinoline ring exist in two forms as seen from the XH NMR (Figs. 1—3) due to iminol-keto tautomerism. In all keto forms, SNH « ~ 9.5 ppm; H-3 of the quinoline ring is more deshield-ed, SH_3 « 6.5 ppm, compared with the iminol forms, SOH « 11.4 ppm, where SH_3 « 5.8 ppm.
This is interpreted by adaption of the keto-form of a perpendicular orientation at C-4 to avoid steric hindrance between the N—H and C5—H bonds. In this case, there is no resonance between the out-of-plane nitrogen atom lone-pair of electrons and the я-cloud of the quinoline ring. Thus, the H-3 become deshield-ed compared with the iminol-form which is free of hindrance between the prementiond bonds and the whole molecule is planar and lone-pair interaction with the я-cloud shields the H-3
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