Synthesis, structure and biological activities of 2,2-dichloro-1-(4- ethoxyphenyl)-cyclopropanyl substituted piperidin-1-yl Ketone

Article abstract of DOI:10.14233/ajchem.2013.14040

Ten new amide-type compounds, which are pyrethroids containing piperidine, are synthesized from 1-(4-ethyoxyphenyl)-2,2- dichlorocyclopropane-1-carboxylic acid and substituted piperidine. Their structures were confirmed by ^1H NMR, MS and elemen

Full text of DOI:10.14233/ajchem.2013.14040

Asian Journal of Chemistry; Vol. 25, No. 7 (2013), 4067-4070
http://dx.doi.org/10.14233/ajchem.2013.14040
Synthesis, Structure and Biological Activities of 2,2-Dichloro-1-(4-ethoxyphenyl)-
cyclopropanyl Substituted Piperidin-1-yl Ketone
*
NA-BO SUN , JIAN-ZHONG JIN, CHAO LEI and WEI KE
College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou, 310015, P.R. China
*Corresponding author: E-mail: nabosun@gmail.com
(Received: 10 May 2012;
Accepted: 28 January 2013)
AJC-12757
Ten new amide-type compounds, which are pyrethroids containing piperidine, are synthesized from 1-(4-ethyoxyphenyl)-2,2-
1
dichlorocyclopropane-1-carboxylic acid and substituted piperidine. Their structures were confirmed by H NMR, MS and elemental
analysis. The crystal structure of 4a and 4h were determined by X-ray diffraction analysis. The bioassay results indicated that they
showed moderate activity.
Key Words: Pyrethroid, Cycloprothrin, Piperidine, Synthesis, Structure.
INTRODUCTION
EXPERIMENTAL
Cyclopropane derivatives, as a kind of highly bioactive
compounds, have been studied broadly1. At the end of 1940s,
cyclopropane compounds, such as pyrethroids, were marketed
as low toxic insecticides. Since the first pyrethroids insecticide-
Allethrin was found, a large variety of pyrethroids derivatives
have been synthesized and lots of them, such as deltamethrin,
cypermethrin, bifenthrin, fenvalerate, tefluthrin etc. are com-
mercially available2. From then on, many biologically active
and structurally stable cyclopropane compounds had been
synthesized3.
In recent years, synthesis of broader spectrum and highly
bioactive substituted cyclopropane compounds, especially
heterocycle substituted ones, becomes the main stream in the
agriculture chemistry field. Also, from the structure-activity
relationships of these pyrethroids, it is showed that the ester
group was replaced by other functional groups, such as amide
group from numerous reports. Due to the amide group exhibited
the good biological activity, such as herbicidal activity, fungicidal
activity, insecticide activity, etc.4. In line with our continuous
efforts to synthesize bioactive lead compounds for crop protec-
tion, the title compounds were designed by introducing amide
and piperidine pharmacophore into the cyclopropane scaffold
and their biologicial activity tested. Then, the single crystal of
the title compound was determined. The preliminary biological
test showed that the synthesized compound has moderate
fungicidal activity.
Melting points were determined by an X-4 apparatus and
uncorrected. H NMR spectra were measured on a Bruker
1
Avance 400 DMX instrument using TMS as an internal
standard and CDCl3 as the solvent. Mass spectra were recorded
on a HP 5989B mass detector instrument. Elemental analyses
were performed on a Carlo erba EA1110 elemental analyzer.
All the reagents are of analytical grade or freshly prepared
before use.
To 1-(4-ethyoxyphenyl)-2,2-dichlorocyclopropane-1-
carboxylic acid (2.75 g, 10 mmol) was added thionyl chloride
(20 mL) and the mixture was refluxed for 2 h to give acid
chloride. To a mixture of compound 3 (8.8 mmol) and Et3N
(1.2 g,12 mmol) in CH2Cl2 (20 mL) was added 2. The mixture
was stirred for 10-25 h. The corresponding amide precipitated
immediately. The product was washed with HCl, dried and
was purified by chromatography on silica gel using petroleum
ether (60-90 ºC) and ethyl acetate as the eluent to afford the
title compounds 4a-4j.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl
piperidin-1-yl ketone (4a). Colourless crystal; yield, 92 %;
m.p., 121-123 ºC; 1H NMR (CDCl3) δ: 1.41(t, J = 7.2 Hz, 3H,
CH3), 1.49-1.59 (m, 6H, piperdine H), 1.99 (d, J = 7.2 Hz, 1H,
cyclopropane H), 2.35 (d, J = 7.2 Hz, 1H, cyclopropane H),
3.44-3.67 (m, 4H, piperdine H), 4.00-4.05 (m, 2H, CH3CH2O),
6.85-6.88 (m, 2H, Ph), 7.86-7.88 (m, 2H, Ph); Ms m/z (rela-
tive intensity/ %): 341([M-1]+, 100), 306 (48), 277 (56), 222

4068 Sun et al.
Asian J. Chem.
(30), 193 (53), 165 (29), 131 (86), 112 (30), 97 (32), 84 (41);
Anal. calcd. for C17H20NO2Cl2 (%): C 59.66, H 6.18, N 4.09,
found: C 59.88, H 6.21, N 4.02.
(63), 97 (35); Anal. calcd. for C19H25NO2Cl2 (%): C 61.62, H
6.80, N 3.78; found: C 61.69, H 6.84, N 3.75.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 3,3-
dimethylpiperidin-1-yl ketone (4g). White crystal; yield,
76.5; m.p. 110-112 ºC; 1H NMR (CDCl3) δ: 0.72 (s, 6H, CH3),
1.41 (t, J = 6.8 Hz, 3H, CH3CH2), 1.44-1.50 (m, 4H, piperi-
dine H), 1.97 (d, J = 6.8 Hz, 1H, cyclopropane H), 2.40 (d, J
= 7.2 Hz, 1H, cyclopropane H), 3.10 (t, J = 8.4 Hz, 2H, piperi-
dine H), 3.66 (s, 2H, piperidine H), 4.00-4.05 (m, 2H,
CH3CH2O), 6.85-6.87 (m, 2H, Ph), 7.49-7.51 (m, 2H, Ph); Ms
m/z (relative intensity/%): 369 ([M-1]+, 100), 334 (30), 306
(21), 270 (26), 222 (30), 193 (17), 165 (29), 140 (63), 131
(38), 112 (35), 97 (14), 84 (33);Anal. calcd. for C19H25NO2Cl2
(%): C 61.62, H 6.80, N 3.78, found: C 61.58, H 6.83, N 3.77.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 2,3-
dimethylpiperidin-1-yl ketone (4h). Colourless crystal; yield,
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 4-methyl-
piperidin-1-yl ketone (4b).Yellow crystal; yield, 64.6 %; m.p.,
1
82-84; H NMR (CDCl3) δ: 0.83 (d, J = 7.2 Hz, 3H, CH3),
1.40 (t, J = 7.2 Hz, 3H, CH3CH2O), 1.48-1.63 (m, 5H, piperdine
H), 1.99 (d, J = 7.2 Hz, 1H, cyclopropane H), 2.53 (d, J = 7.2
Hz, 1H, cyclopropane H), 3.57-3.70 (m, 4H, piperdine H),
4.01-4.05 (m, 2H, CH3CH2O), 6.80-6.82 (m, 2H, Ph), 7.85-
7.87 (m, 2H, Ph); Ms m/z (relative intensity/%): 355 ([M-1]+,
100), 320 (63), 291 (60), 222 (76), 193 (81), 165 (29), 131
(35), 112 (44), 97 (63); Anal. calcd. for C18H23NO2Cl2(%): C
60.68, H 6.51, N 3.93, found: C 60.59, H 6.58, N 3.90.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 3-
methylpiperidin-1-yl ketone (4c). Yellow crystal; yield,
60.5 %; m.p., 90-92 ºC; 1H NMR (CDCl3) δ: 0.88 (d, J = 7.2
Hz, 3H, CH3), 1.41 (t, J = 7.2 Hz, 3H, CH3CH2O), 1.45-1.56
(m, 5H, piperdine H), 1.98 (d, J = 7.2 Hz, 1H, cyclopropane
H), 2.48 (d, J = 7.2 Hz, 1H, cyclopropane H), 3.51-3.69 (m,
4H, piperdine H), 4.01-4.04 (m, 2H, CH3CH2O), 6.84-6.86
(m, 2H, Ph), 7.82-7.84 (m, 2H, Ph); Ms m/z (relative inten-
sity/%): 355 ([M-1]+, 100), 320 (32), 291 (66), 222 (26), 193
(36), 165 (71), 131 (35), 112 (56), 97 (30), 84 (71); Anal.
calcd. for C18H23NO2Cl2 (%): C 60.68, H 6.51, N 3.93, found:
C 60.50, H 6.45, N 4.00.
1
90.0 %; m.p., 159-161 ºC; H NMR (CDCl3) δ: 0.85 (d, J =
6.8 Hz, 6H, CH3), 1.41 (t, J = 6.8 Hz, 3H, CH3CH2O), 1.58-
1.69 (m, 5H, piperidine H), 2.01 (d, J = 6.8 Hz, 1H, cyclopro-
pane H), 2.32 (d, J = 6.8 Hz, 1H, cyclopropane H), 2.60-2.81
(m, 3H, piperidine H), 3.98-4.04 (m, 2H, CH3CH2O), 6.84-
6.86 (m, 2H, Ph), 7.45-7.50 (m, 2H, Ph); Ms m/z (relative
intensity/%): 369 ([M-1]+, 100), 334 (19), 306 (17), 270 (8),
222 (30), 195 (22), 165 (37), 140 (68), 131 (44), 112 (47), 98
(20), 84 (34); Anal. calcd. for C19H25NO2Cl2 (%): C 61.62, H
6.80, N 3.78; found: C 61.55, H 6.84, N 3.74.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 2-
ethylpiperidin-1-yl ketone (4d). White crystal; yield, 93.5 %;
m.p., 134-137 ºC; 1H NMR (CDCl3) δ: 0.85 (t, J = 7.2 Hz, 3H,
CH3), 1.41 (t, J = 7.2 Hz, 3H, CH3CH2O), 1.50-1.63 (m, 8H,
piperdine H and CH2CH3), 1.90 (d, J = 7.2 Hz, 1H, cyclopro-
pane H), 2.41 (d, J = 7.2 Hz, 1H, cyclopropane H), 3.19-3.25
(m, 3H, piperdine H), 4.00-4.05 (m, 2H, CH2O), 6.85-6.87
(m, 2H, Ph), 7.49-7.51 (m, 2H, Ph); Ms m/z (relative inten-
sity/%): 369 ([M-1]+, 95), 340 (44), 220 (100), 195 (33), 162
(55), 140 (83), 131 (64), 84 (47);Anal. calcd. for C19H25NO2Cl2
(%): C 61.62, H 6.80, N 3.78, found: C 61.81, H 6.88, N 3.72.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 4-
ethylpiperidin-1-yl ketone (4e).White crystal; yield, 86.4 %;
mp, 125-128 ºC; 1H NMR (CDCl3) δ: 0.88 (t, J = 7.2 Hz, 3H,
CH3), 1.41 (t, J = 7.2 Hz, 3H, CH3CH2O), 1.2-1.62 (m, 7H,
piperdine H and CH2CH3), 1.90 (d, J = 7.2 Hz, 1H, cyclopro-
pane H), 2.41 (d, J = 7.2 Hz, 1H, cyclopropane H), 3.19-3.25
(m, 4H, piperdine H), 4.01-4.05 (m, 2H, CH3CH2O), 6.84-
6.86 (m, 2H, Ph), 7.45-7.47 (m, 2H, Ph); Ms m/z (relative
intensity/%): 369 ([M-1]+, 93), 340 (30), 295 (34), 220 (100),
162 (69), 140 (68), 131 (87), 102 (28); Anal. calcd. for
C19H25NO2Cl2 (%): C 61.62, H 6.80, N 3.78, found: C 61.75,
H 6.86, N 3.73.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 3,5-
dimethylpiperidin-1-yl ketone (4i). White crystal; yield, 64.8;
m.p., 126-129 ºC; 1H NMR (CDCl3) δ: 0.86 (d, J = 7.2 Hz, 6H,
CH3), 1.41 (t, J = 6.8 Hz, 3H, CH3CH2O), 1.61-1.69 (m, 4H,
piperidine H), 1.91 (d, J = 7.2 Hz, 1H, cyclopropane H), 1.91
(d, J = 7.2 Hz, 1H, cyclopropane H), 2.51-2.67 (m, 3H, piperi-
dine H), 3.99-4.07 (m, 2H, CH3CH2O), 6.85-6.87 (m, 2H, Ph),
7.42-7.49 (m, 2H, Ph); Ms m/z (relative intensity/%): 369 ([M-
1]+, 100), 256 (95), 334 (33), 306 (29), 270 (36), 222 (36), 165
(37), 140 (67), 131 (46), 112 (39);Anal. calcd. for C19H25NO2Cl2
(%): C 61.62, H 6.80, N 3.78; found: C 61.66, H 6.85, N
3.72.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 4-tert-
butylpiperidin-1-yl ketone (4j).Yellow crystal; yield, 55.6 %;
m.p., 113-115 ºC; 1H NMR (CDCl3) δ: 0.80 (s, 9H, CH3), 1.41
(t, J = 7.2 Hz, 3H, CH3), 1.60-1.73 (m, 5H, piperdine H), 1.99
(d, J = 7.2 Hz, 1H, cyclopropane H), 2.35 (d, J = 7.2 Hz, 1H,
cyclopropane H), 2.93-3.01 (m, 4H, piperdine H), 4.00-4.05
(m, 2H, CH3CH2O), 6.85-6.87 (m, 2H, Ph), 7.44-7.48 (m, 2H,
Ph); Ms m/z (relative intensity/%): 397([M-1]+, 100), 362 (30),
334 (24), 298 (29), 222 (38), 168 (42), 131 (41), 102 (10);
Anal. calcd. for C21H29NO2Cl2 (%): C 63.31, H 7.34, N 3.52,
found: C 63.27, H 7.31, N 3.57.
2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl 2,6-
dimethylpiperidin-1-yl ketone (4f). Colourless crystal; yield,
56.2 %; m.p., 124-127 ºC; H NMR (CDCl3) δ: 1.11 (d, J =
7.2 Hz, 6H, CH3), 1.41 (t, J = 6.8 Hz, 3H, CH3CH2O), 1.58-
1.78 (m, 6H, piperidine H), 1.88 (d, J = 7.2 Hz, 1H, cyclopro-
pane H), 2.23-2.28 (m, 2H, piperidine H), 3.99-4.03 (m, 2H,
CH3CH2O), 6.84-6.88 (m, 2H, Ph), 7.53-7.55 (m, 2H, Ph); Ms
m/z (relative intensity/%): 369 ([M-1]+, 100), 258 (15), 234
(57), 222 (28), 195 (32), 165 (40), 140 (74), 131 (53), 112
Single crystal: The prism-shaped single crystal of the
title compound was obtained by recrystallization from EtOH
and CH2Cl2. The crystal with dimensions of 0.20 mm × 0.16
mm × 0.12 mm was mounted on a Bruker SMART 1000 CCD
area-detector diffractometer5 with a graphite-monochromated
MoKα radiation (λ = 0.71073Å) by using a Phi scan modes at
113 (2) K in the range of 2θ ≤ 55.0º. The calculations were
performed with SIR97 program and the empirical absorption
corrections were applied to all intensity data.
1

Vol. 25, No. 7 (2013)
Synthesis, Structure and Biological Activities of Substituted Piperidin-1-yl Ketone 4069
cyclpopropane and phenyl is 55.68 (17)º. In addition, X-ray
analysis reveals that there exist three intermolecular hydrogen
bonds in the crystal. The intermolecular hydrogen bond lengths
of C11-H···O1 is 3.322(2) Å.
RESULTS AND DISCUSSION
The 1-(4-ethyoxyphenyl)-2,2-dichlorocyclopropane-1-
carboxylic acid, prepared according the reference. Cyclopro-
panecarbonyl chloride was prepared from the cyclopropane
dicarboxylic acid and SOCl2, without isolation further reacted
with substituted peridines at room temperature as shown in
Scheme-I.
SOCl2
C2H5O
C
COOH
Cl
C2H5O
C
COCl
Cl
Cl
Cl
1
2
R3
R2
R1
R2
R3
R1
HN
R6 R5
3
R4
R5
O
C
R4
N
C2H5O
C
Cl
Cl
R6
4
4a, R1=R2=R3=R4=R5=R6=H; 4b, R1=R2=R3=R5=R6=H, R4=CH3; 4c, R1=R3=R4=R5=R6=H,
R2=CH3 4d, R2=R3=R4=R5=R6=H, R1=CH2CH3 4e, R1=R2=R3=R5=R6=H, R4=CH2CH3;
4f, R2=R3=R4=R5=H, R1=R6=CH3; 4g, R1=R4=R5=R6=H, R2=R3=CH3 4h, R3=R4=R5=R6=H,
Fig. 2. Molecular structure of 4h
;
;
R1=R2=CH 4i, R1=R3=R4=R6=H, R2=R5=CH3; 4j, R1=R2=R3=R5=R6=H, R4=C(CH 3
3
)
3
Fungicidal activity: The in vivo fungicidal results of all
of the compounds against Rhizoctonia solani, Pseudo-
peronospora cubensis, Sphaerotheca fuliginea and Botrytis
cinerea were listed in Table-1. As shown in Table-1, all these
compounds did not display obvious fungicidal activities against
Rhizoctonia solani, Pseudo- peronospora cubensis, Sphaerotheca
fuliginea.Among them, these compounds displayed the highest
fungicidal activity against Botrytis cinerea. Compounds 4b,
4c, 4i have fair to moderate fungicidal activity against Botrytis
cinerea. at the concentration of 200 µg mL-1.
Scheme-I: Synthetic route of title compounds
Crystal structures of 4a: The crystal symmetry is mono-
clinic, space group P21/n, with a = 0.60819 (19) nm, b = 1.5592
(6) nm, c = 1.8000 (7) nm, α = 90º, β = 91.087 (14)º, γ = 90º,
V = 1.7066 (10) nm3, Z = 4,Dx = 1.332 Mg/m3, µ = 0.39 mm-1,
R = 0.035, wR = 0.081. The single crystal of the title compounds
was obtained and its structure is shown in Fig. 1. The torsion
angles of C2-C1-C4-O1 and C3-C1-C4-O1 are 65.82 (17)º
and 133.21 (14)º respectively. From the molecular structure,
it can be seen that the piperidine ring is in the e-bond positions
of chair conformation in the six membered ring.
TABLE-1
FUNGICIDAL ACTIVITIES OF 4 (INHIBITION/%)
Pseudo-
peronospora
cubensis
Sphaerotheca
fuliginea
Botrytis
cinerea
Rhizoctonia
solani
Compd.
0.00
3.11
0.00
6.74
8.79
1.63
0
0
0
0
0.00
6.53
7.58
0.00
3.21
6.39
0
0
0
0
17.25
45.36
59.85
28.61
30.80
21.53
0.00
0.00
43.66
34.86
0
0
0
0
0
0
0
0
0
0
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
ACKNOWLEDGEMENTS
This work was funded by the Program of Education
Department of Zhejiang Province, China (Y200803060).
Fig. 1. Molecular structure of 4a
Crystal structures of 4h: The crystal symmetry is mono-
clinic, space group P21/n, with a =1.1662 (5) nm, b = 1.6242
(8) nm, c = 1.1398 (5) nm, α = 90º, β = 115.078 (14)º, γ = 90º,
V = 1.9553 (10) nm3, Z = 4, Dx = 1.258 Mg/m3, µ = 0.34 mm-1, R
= 0.034, wR = 0.085. The single crystal of the title compounds
was obtained and its structure is shown in Fig. 2. The torsion
angles of C2-C1-C4-O1 and C3-C1-C4-O1 are-125.0(2)º and
-57.2(2)º respectively. From the molecular structure, it can be
seen that the piperidine ring is in the e-bond positions of chair
conformation in the six membered ring. The dihedral angle of
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