Synthesis and antifungal activity of novel 1-(1H-benzoimidazol-1-yl)propan- 2-one oxime-ethers containing the morpholine moiety

Article abstract of DOI:10.1007/s11164-012-0708-5

A series of 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one oxime-ethers have been synthesized from 2-chloromethyl-1H-benzoimidazole, morpholine, bromoacetone, hydroxylamine, and a haloalkane (or benzyl halide). Their structures were elucidated by IR, ¹H NMR, elemental analysis, and MS. Antifungal activity against Botrytis cinerea, Sclerotinia sclerotiorum, and Beans sclerotia was evaluated by the mycelium growth-rate method; the results indicated that many of the target compounds have excellent antifungal activity, even higher than that of the control fungicide (carbendazim).

Full text of DOI:10.1007/s11164-012-0708-5

Res Chem Intermed (2013) 39:1735–1743
DOI 10.1007/s11164-012-0708-5
Synthesis and antifungal activity of novel
1-(1H-benzoimidazol-1-yl)propan-2-one oxime-ethers
containing the morpholine moiety
•
Shaofang Zhou Fubo Li Peizhi Zhang Lin Jiang
•
•
Received: 11 May 2012 / Accepted: 26 June 2012 / Published online: 14 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A series of 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-
2-one oxime-ethers have been synthesized from 2-chloromethyl-1H-benzoimidaz-
ole, morpholine, bromoacetone, hydroxylamine, and a haloalkane (or benzyl
1
halide). Their structures were elucidated by IR, H NMR, elemental analysis, and
MS. Antifungal activity against Botrytis cinerea, Sclerotinia sclerotiorum, and
Beans sclerotia was evaluated by the mycelium growth-rate method; the results
indicated that many of the target compounds have excellent antifungal activity, even
higher than that of the control fungicide (carbendazim).
Keywords Benzimidazole ꢀ Oxime-ether ꢀ Morpholine ꢀ Synthesis ꢀ
Antifungal activity
Introduction
Benzimidazole derivatives have a broad range of biological activity, for example
antifungal [1], antibacterial [2], antiviral [3], antitumor [4], and antiparasitic [5], and
thus are extensively used in agriculture and as pharmaceuticals. For example,
approximately twenty benzimidazole fungicides including carbendazim, benomyl,
and thiabendazole have been developed [6]. In addition, a series of 2-substituted
benzimidazole compounds containing the oxime-ether moiety were synthesized and
evaluated for their antifungal activity in our previous research [7]. The results
showed many had high activity.
S. Zhou ꢀ P. Zhang ꢀ L. Jiang (&)
College of Chemistry and Material Science, Shandong Agricultural University,
Tai’an 271018, China
e-mail: jiangl@sdau.edu.cn
F. Li
College of Plant Protection, Shandong Agricultural University, Tai’an 271018, China
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S. Zhou et al.
Oxime-ether derivatives have attracted much attention because of their
widespread biological activity, for example insecticidal [8], fungicidal [9], and
herbicidal [10]. For example, pyrifenox and dimoxystrobin are both efficient oxime-
ether fungicides [11, 12]. Moreover, the morpholine ring is a traditional and
promising heterocycle with excellent bioactivity, and is often present in compounds
used in agriculture. In recent years, many excellent morpholine fungicides, for
example dimethomorph and fenpropimorph, have been developed and introduced as
commercial pesticides [13]. Motivated by these findings, and in continuation of our
interest in the synthesis and bioactivity of benzimidazole derivatives, we designed
and synthesized a series of benzimizdazol-1-yl propan-2-one oxime-ethers
containing the morpholine moiety, and evaluated their activity against three fungi.
The synthetic pathway is shown in Scheme 1.
Experimental section
Melting points were recorded on an X-5 melting point apparatus with microscope
and are uncorrected. IR spectra were recorded on a Shimadzu IR-440 infrared
spectrophotometer, as KBr disks or CHCl3 films. 1H NMR spectra were recorded on
a Bruker AM-400 spectrometer with CDCl3 as solvent and TMS as internal
standard, chemical shifts are reported in ppm (parts per million) values. APCI–MS
spectra were acquired on a Micro Mass Agilent 6410 spectrometer. Elemental
analysis was performed with an Elementary Vario EL III analyzer.
The intermediates 2-chloromethyl-1H-benzimidazole 1 and 2-(4-morpholinom-
ethyl)-1H-benzimidazole 2 were prepared in our laboratory in accordance with Ref.
[14]. All other solvents and chemicals were of reagent grade and were used without
further purification.
b
O
O
a
O
HN
O
N
N
N
N
Br
N
Cl
N
N
H
N
H
O
1
2
3
b
b
O
O
a
a
N
N
N
N
N
.
HONH2 HCl
RX
d
N
e
H
R
N
N
O
O
5a-j
4
Scheme 1 Synthetic route to the target compounds 5a–j
123

Synthesis and antifungal activity
1737
Synthesis of 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one 3
Bromoacetone (1.63 g, 12 mmol) in acetone (5 mL) was added dropwise at room
temperature to a stirred mixture of 2 (2.18 g, 10 mmol) and anhydrous potassium
carbonate (1.66 g, 12 mmol) in acetone (20 mL). The reaction mixture was then
heated under reflux, with stirring, for 7 h until the starting materials had been
consumed. The mixture was left to cool, and the precipitate was isolated by filtration
and washed with acetone. The filtrate was evaporated under reduced pressure to
remove the solvent and a brown solid was obtained. This was recrystallized from
ethyl acetate–hexane to give the intermediate 3 as colorless needle crystals. Yield
1
85 %; mp 180–181 °C. H NMR (400 MHz, CDCl3): 2.23 (s, 3H, CH3), 2.47 (m,
4H, Ha), 3.60 (m, 4H, Hb), 3.77 (s, 2H, Hd), 5.03 (s, 2H, He), 7.16–7.76 (m, 4H,
ArH); IR (KBr) v: 3040, 1726, 1686, 1618, 1111 cm-1. Anal. calcd for
C15H19N3O2: C, 65.92; H, 6.95; N, 15.37; Found: C, 65.68; H, 6.85; N, 15.60.
Synthesis of 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime 4
A mixture of 3 (1.00 g, 4 mmol) and hydroxylamine hydrochloride in 50 % ethanol
solution (10 mL) was stirred at room temperature for 15 min, then KOH (0.56 g,
12 mmol) in water (2 mL) was added dropwise, followed by reaction for another
5 h. After completion of the reaction, the solid was collected by filtration, washed
with water, dried, and purified by recrystallization from EtOH–H2O to yield
compound 4 as pale yellow crystals. Yield 82 %; mp 223–225 °C. 1H NMR
(400 MHz, CDCl3): 1.57 (s, 0.64H, CH3, Z isomer), 1.85 (s, 2.36H, CH3, E isomer),
2.46–2.48 (t, 3.15H, J = 4.4 Hz, Ha, E isomer), 2.54–2.57 (t, 0.85H, J = 4.4 Hz,
Ha, Z isomer), 3.60–2.63 (m, 3.15H, Hb, E isomer), 3.64–3.67 (t, 0.85H, Hb,
Z isomer), 3.74 (s, 1.55H, Hd, E isomer), 3.78 (s, 0.45H, Hd, Z isomer), 5.03 (s,
1.58H, He, E isomer), 5.24 (s, 0.42H, He, Z isomer), 7.24–7.76 (m, 4H, ArH,
Z ? E isomers), 8.93 (s, 0.20H, OH, Z isomer), 9.05 (s, 0.80H, OH, E isomer); IR
(KBr) v: 3416, 3060, 1625, 1613, 1132, 1012 cm-1. Anal. calcd for C15H20N4O2: C,
62.49; H, 6.99; N, 19.43. Found: C, 62.65; H, 6.74; N, 19.30.
General procedure for synthesis of 1-(2-(4-morpholinomethyl)-1H-
benzoimidazol-1-yl)propan-2-one oxime-ethers 5a–j
A mixture of 4 (10 mmol) and KOH (0.56 g, 12 mmol) in ethanol (10 mL) was
stirred at room temperature for 15 min, then haloalkane or benzyl halide (12 mmol)
in ethanol (10 mL) was added dropwise. The reaction mixture was heated under
reflux with stirring for 5–7 h until the reaction was complete. After filtration to
remove the resulting precipitate, the filtrate was evaporated on a rotary evaporator.
The oil was collected and purified by flash column chromatography on silica gel
with 1:3 (v/v) ethyl acetate–petroleum ether (bp 60–90 °C) as eluent to give the
target compounds 5a–j.
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S. Zhou et al.
O-Methyl 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5a
1
Pale yellow crystals; yield: 52 %; mp 115–117 °C. H NMR (400 MHz, CDCl3):
1.73 (s, 3H, CH3), 2.54–2.56 (t, J = 4.4 Hz, 4H, Ha), 3.66–3.69 (t, J = 4.4 Hz 4H,
Hb), 3.76 (s, 2H, Hd), 3.82 (s, 3H, OCH3), 5.02 (s, 2H, He), 7.26–7.75 (m, 4H, ArH);
IR (KBr) v: 3056, 1614, 1519, 1116, 1059 cm-1. Anal. calcd for C16H22N4O2: C,
63.55; H, 7.33; N, 18.53; Found: C, 63.78; H, 7.25; N, 18.82; APCI–MS m/z: 303.4
[M ? H]?.
O-Ethyl 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5b
1
Yellow oil; yield: 59 %. H NMR (400 MHz, CDCl3): 1.25–1.28 (t, J = 7.2 Hz,
2.36H, OCH2CH3, E isomer), 1.34 (t, J = 7.2 Hz, 0.64H, OCH2CH3, Z isomer),
1.54 (s, 0.65H, CH3, Z isomer), 1.74 (s, 2.35H, CH3, E isomer), 2.54–2.56 (m, 4H,
Ha, Z ? E-isomers), 3.67–3.70 (m, 4H, Hb, Z ? E isomers), 3.82 (s, 1.54H, Hd,
E isomer), 3.77 (s, 0.46H, Hd, Z isomer), 4.10–4.16 (q, J = 7.2 Hz, 1.54H,
OCH2CH3, E isomer), 4.18–4.24 (q, J = 7.2 Hz, 0.46H, OCH2CH3, Z isomer), 5.03
(s, 1.57H, He, E isomer), 5.25 (s, 0.43H, He, Z isomer), 7.23–7.77 (m, 4H, ArH,
Z ? E isomers); IR (CHCl3) v: 3051, 1613, 1519, 1116, 1051 cm-1; Anal. calcd for
C17H24N4O2: C, 64.53; H, 7.65; N, 17.71; Found: C, 64.25; H, 7.90, N, 17.85;
APCI–MS m/z: 317.2 [M ? H]?.
O-Propyl 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5c
Yellow crystals; yield: 56 %; mp 163–167 °C. 1H NMR (400 MHz, CDCl3):
0.84–0.88 (t, J = 7.2 Hz, 2.67H, O(CH2)2CH3, E isomer), 0.97–1.00 (t,
J = 7.2 Hz, 0.33H, O(CH2)2CH3, Z isomer), 1.53–1.56 (m, 1.75H, OCH2CH2CH3,
E isomer), 1.55 (s, 0.38H, CH3, Z isomer), 1.56–1.60 (m, 0.25H, OCH2CH2CH3,
Z isomer), 1.87 (s, 2.62H, CH3, E isomer), 2.80 (m, 0.50H, Ha, Z isomer), 2.90 (m,
3.50H, Ha, E isomer), 3.81 (m, 0.50H, J = 4.4 Hz, Hb, Z isomer), 3.83 (t,
J = 4.4 Hz, 3.50H, Hb, E isomer), 3.89 (t, J = 6.8 Hz, 1.75H, OCH2C2H5,
E isomer), 4.11 (t, J = 6.8 Hz, 0.25H, OCH2C2H5, Z isomer), 4.29 (s, 2H, Hd,
Z ? E isomers), 5.23 (s, 1.8H, He, E isomer), 5.37 (s, 0.20H, He, Z isomer),
7.41–7.89 (m, 4H, ArH, Z ? E-isomers); IR (KBr) v: 3060, 1613, 1116, 1064 cm-1
;
Anal. calcd for C18H26N4O2: C, 65.43; H, 7.93; N, 16.96; Found: C, 65.39; H, 8.12;
N, 16.79; APCI–MS m/z: 331.5 [M ? H]?.
O-Isopropyl 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5d
Yellow oil; yield: 73 %. 1H NMR (400 MHz, CDCl3): 1.24 (d, J = 6.4 Hz, 4.80H,
OCH(CH3)2, E isomer), 1.30 (d, J = 6.4 Hz, 1.20H, OCH(CH3)2, Z isomer), 1.54
(s, 0.63H, CH3, Z isomer), 1.73 (s, 2.37H, CH3, E isomer), 2.54–2.56 (m, 4H, Ha,
123

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1739
Z ? E isomers), 3.67–3.69 (m, 4H, Hb, Z ? E isomers), 3.77 (s, 0.45H, Hd,
Z isomer), 3.82 (s, 1.55H, Hd, E isomer), 4.31 (m, 0.80H, OCH(CH3)2, E isomer),
4.40 (m, 0.20H, OCH(CH3)2, Z isomer), 5.03 (s, 1.60H, He, E isomer), 5.25 (s,
0.40H, He, Z isomer), 7.24–7.75 (m, 4H, ArH, Z ? E isomers); IR (CHCl3) v: 3056,
1617, 1116, 1009 cm-1; Anal. calcd for C18H26N4O2:C, 65.43; H, 7.93; N, 16.96,
Found: C, 65.27; H, 8.04; N, 17.20; APCI–MS m/z: 331.3 [M ? H]?.
O-Butyl 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5e
1
Pale yellow crystals; yield: 62 %; mp 84–85 °C. H NMR (400 MHz, CDCl3):
0.92–0.99 (m, 3H, O(CH2)3CH3, Z ? E isomers), 1.35–1.41 (m, 2H,
O(CH2)2CH2CH3, Z ? E-isomers), 1.39 (s, 0.29H, CH3, Z isomer), 1.64 (m, 2H,
O(CH2)2CH2CH3, Z ? E isomers), 1.73 (s, 2.71H, CH3, E isomer), 2.55 (m, 4H, Ha,
Z ? E isomers), 3.68 (m, 4H, Hb, Z ? E isomers), 3.77 (s, 0.25H, Hd, Z-isomer),
3.82 (s, 1.75H, Hd, E isomer), 4.06–4.10 (t, J = 6.8 Hz, 1.80H, OCH2C3H7,
E isomer), 4.14–4.18 (t, J = 6.8 Hz, 0.20H, OCH2C3H7, Z isomer), 5.03 (s, 1.80H,
He, E isomer), 5,25 (s, 0.20H, He, Z isomer), 7.24–7.76 (m, 4H, ArH, Z ? E-
isomers); IR (KBr) v: 3052, 1613, 1117, 1009 cm-1; Anal. calcd for C19H28N4O2:
C, 66.25; H, 8.19; N, 16.27; Found: C, 66.49; H, 8.05; N, 16.58; APCI–MS m/z:
345.4 [M ? H]?.
O-Benzyl 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5f
1
Pale yellow oil; yield: 62 %. H NMR (400 MHz, CDCl3): 1.54 (s, 0.85H, CH3,
Z isomer) 1.78 (s, 2.15H, CH3, E isomer), 2.43–2.49 (m, 4H, Ha, Z ? E isomers),
3.58–3.64 (m, 4H, Hb, Z ? E isomers), 3.70 (s, 1.32H, Hd, E isomer), 3.72 (s,
0.68H, Hd, Z isomer), 5.00 (s, 1.32H, OCH2Ar, E isomer), 5.18 (s, 0.68H, OCH2Ar,
Z isomer), 5.09 (s, 1.32H, He, E isomer), 5.27 (s, 0.68H, He, Z isomer), 7.18–7.74
(m, 9H, ArH, Z ? E isomers); IR (CHCl3) v: 3056, 1614, 1116, 1009, 745,
697 cm-1; Anal. calcd for C22H26N4O2: C, 69.82; H, 6.92; N, 14.80; Found: C,
69.58; H, 6.74; N, 14.89; APCI–MS m/z: 379.5 [M ? H]?.
O-(4-Fluorobenzyl) 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-
one oxime-ether 5g
1
White crystals; yield: 61 %; mp 82.6–84.7 °C. H NMR (400 MHz, CDCl3): 1.54
(s, 0.52H, CH3, Z isomer), 1.78 (s, 2.48H, CH3, E isomer) 2.47–2.48 (m, 4H, Ha,
Z ? E isomers), 3.60–3.64 (m, 4H, Hb, Z ? E isomers), 3.74 (s, 1.68H, Hd,
E isomer), 3.78 (s, 0.32H, Hd, Z isomer), 5.00 (m, 1.68H, OCH2Ar, E isomer), 5.14
(s, 0.32H, OCH2Ar, E isomer), 5.02 (s, 1.68H, He, E isomer), 5.25 (s, 0.32H, He,
Z isomer), 6.99–7.43 (m, 8H, ArH, Z ? E isomers); IR (CHCl3) v: 3052, 1604,
1116, 1010, 745 cm-1; Anal. calcd for C22H25FN4O2: C, 66.65; H, 6.36; N, 14.13;
Found: C, 66.42; H, 6.16; N, 14.35; APCI–MS m/z: 397.4 [M ? H]?.
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S. Zhou et al.
O-(4-Iodobenzyl) 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one
oxime-ether 5h
1
Yellow crystals; yield: 57 %; mp 94–96 °C. H NMR (400 MHz, CDCl3): 1.53 (s,
0.45H, CH3, Z isomer), 1.77 (s, 2.55H, CH3, E isomer), 2.47 (m, 4H, Ha,
Z ? E isomers), 3.64 (m, 4H, Hb, Z ? E isomer), 3.71 (s, 2H, Hd, Z ? E isomers),
4.99 (s, 1.71H, OCH2Ar, E isomer), 5.00 (s, 1.71H, He, E isomer), 5.11 (s, 0.29H,
OCH2Ar, Z isomer), 5.24 (s, 0.29H, He, Z isomer), 7.01–7.28 (m, 8H, ArH,
Z ? E isomers); IR (KBr) v: 3051, 1617, 1116, 1007, 745 cm-1; Anal. calcd for
C22H25IN4O2: C, 52.39; H, 5.00; N, 11.11; Found: C, 52.28; H, 4.92; N, 11.39;
APCI–MS m/z: 505.1 [M ? H]?.
O-(4-Chlorobenzyl) 2-(4-morpholinomethyl)-1H-benzimidazol-1-yl acetone
oxime-ether 5i
1
White crystals; yield: 59 %; mp 88–91 °C. H NMR (400 MHz, CDCl3): 1.54 (s,
0.46H, CH3, Z isomer), 1.78 (s, 2.54H, CH3, E isomer), 2.46–2.47 (m, 4H, Ha,
Z ? E isomers), 3.63 (m, 4H, Hb, Z ? E isomers), 3.72 (s, 2H, Hd, Z ? E isomers),
4.99 (s, 1.72H, OCH2Ar, E isomer), 5.02 (s, 1.72H, He, E isomer), 5.13 (s, 0.28H,
OCH2Ar, Z isomer), 5.25 (s, 0.28H, He, Z isomer), 7.20–7.74 (m, 8H, ArH,
Z ? E isomers); IR (KBr) v: 3052, 1617, 1117 745 cm-1; Anal. calcd for
C22H25ClN4O2: C, 63.99; H, 6.10; N, 13.57; Found: C, 63.74; H, 6.18; N, 13.74;
APCI–MS m/z: 413.5 [M ? H]?.
O-(2,4-Dichlorodobenzyl) 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-
yl)propan-2-one oxime-ether 5j
Yellow oil; yield: 40 %. 1H NMR (400 MHz, CDCl3): 1.82 (s, 3H, CH3,
Z ? E isomers), 2.47–2.49 (m, 4H, Ha, Z ? E isomers), 3.63–3.65 (m, 4H, Hb,
Z ? E isomers), 3.75 (s, 1.50H, Hd, E isomer), 3.77 (s, 0.50H, Hd, Z isomer), 5.0 (s,
1.50H, OCH2Ar, E isomer), 5.04 (s, 0.50H, OCH2Ar, Z isomer), 5.14 (s, 1.50H, He,
E isomer), 5.24 (s, 0.50H, He, Z isomer), 7.20–7.74 (m, 7H, ArH, Z ? E isomers);
IR (CHCl3) v: 3062, 1615, 1116, 1010, 746 cm-1; Anal. calcd for C22H24Cl2N4O2:
C, 59.07; H, 5.41; N, 12.52; Found: C, 58.92; H, 5.33; N, 12.79; APCI–MS m/z:
447.5 [M ? H]?.
Antifungal activity assays
The in-vitro fungicidal activity of the target compounds 5a–j against Beans
sclerotia, Botrytis cinerea, and Sclerotinia sclerotiorum was evaluated by use of the
mycelium growth-rate method [15]. The culture medium was obtained by mixing a
solution of 5 with potato dextrose agar (PDA), on which fungus cakes were placed.
Culture was performed at 25 1 °C for 96 h. Carbendazim, a commercial
fungicide, was used as control, and sterile water was used as blank. Three replicates
were performed in antifungal activity assays. Inhibition was expressed as the mean
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Synthesis and antifungal activity
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Table 1 Antifungal activity as EC50 (lg/mL) of the target compounds 5a–j
Compound
R
EC50 (lg/mL)
B. Sclerotia
B. Cinerea-pers
S. Sclerotiorum
5a
CH3–
5.98 1.05
14.53 1.27
15.44 1.16
17.73 1.34
10.50 1.22
13.71 1.35
8.37 1.26
7.48 1.12
9.21 1.33
11.88 1.48
3.67 0.76
0.16 0.12
73.84 1.77
15.44 1.21
64.66 1.35
7.73 0.78
56.89 1.45
8.69 1.11
7.45 1.17
4.27 0.89
40.22 1.88
0.18 0.15
5.86 1.03
113.03 1.79
15.31 1.02
190.98 1.98
49.30 1.55
143.77 1.76
1.18 0.24
5b
CH3CH2–
5c
CH3CH2CH2–
(CH3)2CH–
n-C4H9–
5d
5e
5f
C6H5CH2–
5g
4-FC6H4CH2–
4-IC6H4CH2–
4-ClC6H4CH2–
2,4-Cl2C6H3CH2–
5 h
168.42 1.89
1.75 0.16
5i
5j
56.65 1.78
57.30 1.55
Carbendazim
B. sclerotia, B. cinerea pers, and S. sclerotiorum are Beans sclerotia, Botrytis cinerea, and Sclerotinia
sclerotiorum, respectively
of the values obtained in three independent experiments. Last, effective concen-
trations (EC50) that inhibited mycelium growth by 50 % and toxicity regression
equations were also obtained (Table 1). Inhibition was calculated by use of the
formula:
D0 ꢁ D1
Inhibition ¼
ꢂ 100 ð% Þ
D0
where D0 is the expansion diameter of the mycelia in the blank test, and D1 is the
expansion diameter of mycelia in the presence of the tested compounds (Table 1).
Results and discussion
The synthesis began by treating 2-chloromethyl-1H-benzimidazole 1 with morpho-
line to yield 2-(4-morpholinomethyl)-1H-benzimidazole 2. This was followed by
reaction with bromoacetone to give 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-
1-yl)propan-2-one 3. The intermediate 3 then reacted with hydroxylamine to
produce 1-(2-(4-morpholinomethyl)-1H-benzoimidazol-1-yl)propan-2-one oxime 4.
Last, compound 4 reacts with the haloalkane or benzyl halide to afford the target
1
compound 5. The structures of 5a–j were determined by H NMR, IR, elemental
analysis and MS.
Geometric isomers
There are two geometric isomers, E and Z, of the target compounds 5b–j because of
the presence of the C=N double bond. However, 5a has only the E isomer, because
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S. Zhou et al.
CH3 is the smallest alkyl group and there is minimum steric hindrance with another
CH3 in the molecule, making the E isomer more stable. In the E isomers, the alkoxy
(or benzyloxy) and benzimidazole moieties are on opposite sides of the C=N bond,
so their steric hindrance is smaller. As a result, the E isomer is more stable so the
1
amount formed is greater, which was confirmed from the H NMR spectrum. By
measuring the integrated area of the corresponding absorption peak of the same
1
proton in H NMR [16], it is estimate that the ratios of the two isomers (Z/E) are
from 1.0:2.5 to 1.0:9.3, which means the E isomer is the major geometric isomer.
For example, the ratios for 5b (R = C2H5), 5e (R = n-C4H9), 5f (R = CH2C6H5),
and 5i (R = CH2C6H4Cl-4) are 3.7, 9.3, 2.5, and 5.5, respectively, but there is no
good relationship between the ratio and the R group.
Antifungal activity
As shown in Table 1, the EC50 values of the target compounds range from 5.98 to
17.73 lg/mL against Beans sclerotia, suggesting moderate to high antifungal
activity. However, their activity is lower than that of carbendazim, for which the
EC50 value is 3.67 lg/mL. Compounds 5a, 5c, 5e, and 5g–i have good antifungal
activity against Botrytis cinerea with EC50 values of 0.16–8.69 lg/mL; 5a,
especially, has excellent activity, higher than that of carbendazim (EC50 = 0.18 lg/
mL). Many of the target compounds, for example 5a, 5c, 5e, 5g, and 5i, have good
activity against Sclerotinia sclerotiorum, with EC50 values of 1.18–49.30 lg/mL;
among these, the EC50 values of 5a, 5g, and 5i are much higher than that of
carbendazim (EC50 = 57.30 lg/mL).
Analysis of the relationship between molecular structure and activity reveals that
compounds in which R is CH3, 4-FC6H4CH2, or 4-ClC6H4CH2, have high activity
against the three test fungi.
Conclusion
In summary, we have synthesized ten novel 1-(2-(4-morpholinomethyl)-1H-
benzoimidazol-1-yl)propan-2-one oxime-ethers containing the morpholine moiety,
by multi-step reactions, with yields of 40–73 %. The structures were determined by
1
IR, H NMR, MS, and elemental analysis, and the relative amounts of their Z and
E isomers were determined by 1H NMR. We also evaluated their in-vitro antifungal
activity against Beans sclerotia, Botrytis cinerea, and Sclerotinia sclerotiorum, and
found that many of the target compounds have excellent antifungal activity, even
higher than that of carbendazim. This study provides a useful reference in the search
for novel benzimidazole fungicides.
References
1. A. Mobinikhaledi, N. Foroughifar, M. Kalhor, M. Mirabolfathy, J. Heterocyclic Chem. 47, 77–80
(2010)
123

Synthesis and antifungal activity
1743
2. L. Keurulainen, O. Salin, A. Siiskonen, J.M. Kern, J. Alvesalo, P. Kiuru, M. Maass, J. Yli-Kauh-
aluoma, P. Vuorela, J. Med. Chem. 53, 7664–7674 (2010)
3. F. Xue, X.J. Luo, C.H. Ye, W.D. Ye, Y. Wang, Bioorg. Med. Chem. 19, 2641–2649 (2011)
4. S. Demirayak, I. Kayagil, L. Yurttas, Eur. J. Med. Chem. 46, 411–416 (2011)
5. A.A. Farahat, E. Paliakov, A. Kumar, A.M. Barghash, F.E. Goda, H.M. Eisa, T. Wenzler, R. Brun, Y.
Liu, W.D. Wilson, D.W. Boykin, Bioorg. Med. Chem. 19, 2156–2167 (2011)
6. Y. Zhang, S. Yang, B.A. Song, D.Y. Hu, Agrochemicals 47, 164–170 (2008)
7. L. Jiang, H. Wang, W. Mu, Z. Ji, P. Cao, Chin. J. Chem. 29, 539–543 (2011)
8. L.Z. Ling, A.P. Liu, C. Chen, Z.Z. Wei, D.S. Wang, D.L. Yin, X.G. Wang, Chin. J. Pestic. Sci. 8,
25–29 (2006)
9. X.F. Zhu, D.Q. Shi, Chin. J. Chem. 27, 565–568 (2009)
10. L. Chen, J.H. Yao, L.P. Yuan, J. Cao, Y. Huang, W. Xie, C.C. Ni, Z. Shen, X.L. Li, Y.B. Zhang, Acta
Chim. Sinica 65, 2583 (2007)
11. P. Leroux, A.S. Walker, Pest Manag. Sci. 67, 44–59 (2011)
12. A.S. Walker, C. Auclair, M. Gredt, P. Leroux, Pest Manag. Sci. 65, 906–915 (2009)
13. Y.B. Zhang, Y. Zhang, X.Y. Wu, New Developments in the World Pesticide. (Chemical Industry
Press, Beijing, 2010), p 242
14. H.M.F. Madkour, A.A. Farag, S.S. Ramses, N.A.A. Ibrahiem, Phosphorus. Sulfur Silicon 181,
255–265 (2006)
15. J.L. Sun, W. Mu, Pesticide Science Experimental Techniques and Guidance. Chemical Industry
Press, Beijing, 2009), pp. 228–229
16. L.L. Jiang, C.N. Chen, Y.F. Zhou, Q. Chen, G.F. Yang, Chin. J. Org. Chem. 29, 1392–1404 (2009)
123