Design, synthesis and antifungal/insecticidal evaluation of novel cinnamide derivatives

Article abstract of DOI:10.3390/molecules16118945

Twenty novel cinnamamide derivatives were designed and synthesized using as lead compound pyrimorph, whose morpholine moiety was replaced by ss-phenylethylamine. All the compounds were characterized by their spectroscopic data. The fungicidal and insecticidal activities were also evaluated. The preliminary results showed that all the title compounds had certain fungicidal activities against seven plant pathogens at a concentration of 50 μg/mL, and compounds 11a and 11l showed inhibition ratios of up to 90% against R. solani. Most of the title compounds exhibited moderate nematicidal activities. In general, the morpholine ring may be replaced by other amines and a chlorine atom in the pyridine ring is helpful to fungicidal activity.

Full text of DOI:10.3390/molecules16118945

Molecules 2011, 16, 8945-8957; doi:10.3390/molecules16118945
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Design, Synthesis and Antifungal/Insecticidal Evaluation of
Novel Cinnamide Derivatives
Yumei Xiao 1, Xiaoli Yang 1, Bo Li 2, Huizhu Yuan 3, Shuqing Wan 2, Yanjun Xu 1,* and
Zhaohai Qin 1,*
1
College of Science, China Agricultural University, Beijing 100193, China
2
Lab of Insect Toxicology, South China Agricultural University, Guangzhou 510642, China
3
Institute of Plant Protection, Chinese Academ y of Agriculture Science, Beijing 10193, China
* Authors to whom correspondence should be addressed; E-Mails: qinzhaohai451@126.com (Z.Q.);
xyj323@126.com (Y.X.); Tel.: +86-10-62732958; Fax: +86-10-62732958.
Received: 12 August 2011; in revised form: 2 October 2011 / Accepted: 11 October 2011 /
Published: 25 October 2011
Abstract: Twenty novel cinnamamide derivatives were designed and synthesized using as
lead compound pyrimorph, whose morpholine moiety was replaced by β-phenylethylamine.
All the compounds were characterized by their spectroscopic data. The fungicidal and
insecticidal activities were also evaluated. The preliminary results showed that all the title
compounds had certain fungicidal activities against seven plant pathogens at a concentration
of 50 μg/mL, and compounds 11a and 11l showed inhibition ratios of up to 90% against
R. solani. Most of the title compounds exhibited moderate nematicidal activities. In general,
the morpholine ring may be replaced by other amines and a chlorine atom in the pyridine
ring is helpful to fungicidal activity.
Keywords: cinnamide; β-phenyl ethylamine; fungicidal activity; insecticidal activity
1. Introduction
Cinnamides constitute an important class of compounds with a variety of biological properties, such
as nervous central system depressant, anticonvulsant, muscle relaxant, antiallergic, antineoplastic and
anti-infective activities, etc. [1-7]. In the agrochemical field, their avian repellent, fungicidal and
herbicidal activities have also attracted the attention of many researchers [8,9], and several excellent

Molecules 2011, 16
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cinnamide fungicides, for example dimethomorph (1) [10], fluormorph (2) [11] and pyrimorph (3) [12,13],
have been successfully developed. Pyrimorph, containing a morpholine ring and a pyridine ring, is a
novel fungicide developed by our lab that exhibited excellent activity against oomycetes [14,15].
β-phenylethylamines are also very important bioactive molecules that can be found in many natural
and synthetic drugs. Mandipropamide (4), which controls foliar diseases caused by oomycetes, is a
typical representative of β-phenylethylamines derivitives used in agrochemistry [16,17]. Wan et al.
have reported the fungicidal activity of (E)-N-2-phenylethyl cinnamide (5) [18] and the insecticidal
activity of lansiumamide B (6) against B. xylophilus and Culex pipiens have also been disclosed [19,20]
(Figure 1).
Figure 1. Several cinnamide and β-phenylethylamine derivitives with fungicide or insecticidal activity.
F
Cl
Cl
N
O
O
O
MeO
MeO
N
O
MeO
MeO
N
N
O
O
O
2
1
3
O
H
O
N
O
O
N
H
N
H
O
Cl
4
5
6
Considering the important role of the cinnamoyl, pyridine ring and 2-phenylethylamine moieties in
pesticides, their combination might result in novel bioactive molecules. In this study, using pyrimorph
as lead compound, we have designed and synthesized a novel series of cinnamide derivatives in which
the morpholine moiety in pyrimorph was replaced by a phenethylamino group. All of the target
compounds were evaluated for fungicidal and nematicidal activity. Some title compounds showed good
fugicidal activity at 50 μg mL−1, and the compound 11b exhibited an LC50 of 113.8 μg mL−1 against
B. xylophilus.
2. Results and Discussion
2.1. Synthesis
The synthetic route to the title 20 compounds involves four-step reaction including Wittig-Horner
reaction as the key step (Scheme 1). The Wittig-Horner reaction usually gives a mixture of E/Z isomers,
but the ratio is quite different depending to the structure of substrates, reaction temperature, solvent,
catalyst and so on. In our synthetic route, the reaction of compound 8 with ethyl diethoxyphosphinic
acetate predominantly generated the more stable cis-intermediate 12 rather than the trans-form. Tis is
attributed to the fact that in the cis-form the electron-rich carbonyl oxygen has a tendency to donate
electrons to the electron-deficient pyridine ring, which leads to the formation of the more stable

Molecules 2011, 16
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intermediate and the cis-product 9. The deduction was confirmed by the crystal structure of 11b, which
was determined by X-ray diffraction analysis (Figure 2 and Table 1).
It can be seen from Figure 1 that the carbonyl and the pyridine ring bearing a chlorine atom are
oriented towards the same side, so we can conclude that compound 11b is the Z-isomer.
Scheme 1. Synthetic route to the title compounds 11.
X
N
O
O
X
COCl
X
O
(EtO)2PCH2COOEt
Ph-R
AlCl3
R
N
N
O
OEt
NaH
R
7
8
9
X
N
X
N
1. NaOH/MeOH
2. H+
1. SOCl2
O
OH
H2N
2.
R1
R
R1
R
N
H
10
11
11 a X=Cl, R=4-Me, R1=H
11 c X=Cl, R=3,4-Me, R1=H
11 e X=Cl, R=4-MeO R1=H
11 b X=Cl, R=4-Et,
11 d X=Cl, R= 2,4-Me, R1=H
11 f X=Cl, R=4-Me, R1=3,4-2MeO
R1=H
R
O
H
-O
EtO
EtO
P
X
11 g X=Cl, R=3,4-Me, R1=3,4-MeO 11 h X=Cl, R=2,4-2Me, R1=3,4-2MeO
11 i X=Cl, R=4-t-Bu, R1=3,4-MeO 11 j X=Cl, R=4-Me, R1=4-OH
C
N
O
EtO
11 K X=Cl, R=4-Et,
11 m X=Cl,R= 2,4-Me R1=4-OH
11 o X=H, R=4-Me R1=H
R1=4-OH
11 l X=Cl, R=3,4-2Me, R1=4-OH
11 n X=Cl, R=4-t-Bu , R1=4-OH
12
11 p X=H, R=4-Et,
R1=H
11 q X=H, R=3,4-Me R1=H
11 r X=H, R=3,4-2Me, R1=3,4-2MeO
11 t X=H, R=3,4-2Me, R1=4-OH
11 s X=H, R=4-Me, R1=4-OH
Figure 2. Crystal structure of 11b.

Molecules 2011, 16
8948
Table 1. Crystal structure and data refinement parameters.
Compound
Empirical formula
Formula weight
Crystal system/space group
Orthorhombic
a / Å
11b
C24H23ON2C
391.2
Triclinic, P-1
8.6568(17)
b / Å
13.927(3)
c / Å
18.507(4)
α / °
90°
β / °
90°
γ / °
90°
2056.1(7)
V / Å3
Z
4
D calc (g/cm3)
μ (mm−1)
1.263
0.202
Crystal size (mm)
Color/shape
Temp (K)
0.50 × 0.36 × 0.36
Colorless/ rectangle
173(2)K
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Largest difference peak/hole
2.39 < θ < 25.00°
20946
7232
7232 / 0 / 505
1.062
R1 = 0.0481, wR2 = 0.1187
R1 = 0.0514, wR2 = 0.1213
0.686 and −0.312 e.A−3
2.2. Biological Activity
The fungicidal activity of the target compounds was tested in vitro against seven kinds of common
plant pathogens including R. solani, P. parasitica, B. cinerea, S. sclerotiorum, V. mali, P. asparagi and
C. lindemuthianum). As shown in Table 2, most of the title compounds at 50 μg·mL−1 indicated
moderate to high activity in the initial screening against the tested pathogens except P. parasitica and
V. mali, and the inhibition ratios of 11a and 11l reached 90% against R. solani. The antifungal activity
is basically in the following order: 11a > 11o, 11b > 11p, 11c > 11q, 11g > 11r, 11j > 11s, 11l > 11t.
That is to say, compounds bearing a chlorine atom in the pyridine ring indicated higher inhibition rates
against the seven fungi than those with no chlorine atom in the ring. The results also showed that the
morpholine ring of the lead compound pyrimorph could be replaced by β-phenylethylamine.
As structural analogs of lansiumamide B (6), the nematicidal activity of title compounds was tested
against Bursaphelenchus xylophilus. The data is presented in the form of mean mortality and corrected
mortality (%) in Table 3. Next, the LD50 ofcompounds 11b, 11c and 11f were determined and the results
are listed in Table 4.

Molecules 2011, 16
8949
The results of Tables 3 and 4 indicated that the twenty novel cinnamide derivatives displayed
moderate insectidal activity. Compound 11b indicated the highest nematicidal activity, and theLC50 is
113.8 μg mL−1 against B. xylophilus. Compounds 11m and 11q also exhibited good mortality.
Table 2. Fungicidal activity of the title compounds (inhibition rate, %).
R.
P.
B.
S.
V.
P.
C.
Compd.
solani parasitica cinerea sclerotiorum mali asparagi lindemuthianum
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
11r
93.88
22.45
76.77
4.52
13.55
82.58
23.81
35.48
14.84
72.9
67.74
90.97
13.55
9.03
15.48
9.68
24.41
26.77
1.61
11.29
−2.42
0
14.17
22.58
−8.06
−18.5
28.23
−18.5
−25
−13.7
−17.7
5.65
−9.68
−14.5
−17.7
14.52
-
14.52
63.71
37.9
44
50
67
43
55
59
33
40
48
33
37
54
38
50
43
48
15
52
47
64
-
37
44
72
24
42
42
28
68
53
29
17
44
27
29
16
45
2.7
11
5.3
27
79
100
70
100
48
20
52
31
−6.3
42
36
29
18
29
24
−6.3
26
−7.8
36
30
59.70
34.33
35.82
22.39
31.34
39.55
23.88
29.10
23.13
55.22
32.09
17.16
42.54
32.84
44.03
28.36
23.88
16.42
28.36
55.97
66.50
59.7
34.33
55.97
47.01
43.28
55.22
23.88
42.54
22.39
16.42
24.63
35.82
21.64
39.55
32.84
37.31
17.16
28.36
28.36
38.81
-
3.87
5.81
10.32
16.13
97.20
100
18
68
11s
11t
−2.3
−2.3
-
100
88
pyrimorph
carbendazim
chlorothalonil 75.48
azoxystrobin 89.03
38
95
80
82.09
82.09
92
Table 3. Nematicidal Activity of the title compounds.
24 h
48 h
72 h
Compd. Mortality
Corrected
Mortality
(%)
Corrected
Mortality
(%)
Corrected
mortality (%)
35.35 ± 0.39
67.87 ± 1.41
45.15 ± 1.82
27.91±1.18
42.01 ± 1.48
43.97 ± 1.71
21.64 ± 1.03
38.09 ± 1.71
45.15 ± 1.96
14.20 ± 1.36
(%)
mortality (%)
15.80 ± 1.79
17.95 ± 0.95
14.73 ± 0.72
22.97 ± 1.29
13.65±0.36
13.29 ± 0.72
8.63 ± 0.00i
19.02 ± 1.87
4.33 ± 0.62
7.56 ± 1.64
mortality (%)
28.13 ± 1.28
26.29 ± 1.84
21.49 ± 1.30
24.44 ± 1.84
38.82 ± 1.33
38.45 ± 0.97
17.81 ± 1.58
34.02 ± 0.98
38.82 ± 0.74
12.65 ± 0.64
11a
11b
11c
11d
11e
11f
11g
11h
11i
21.67 ± 1.67
23.67 ± 0.88
20.67 ± 0.67
28.33 ± 1.20
19.67 ± 0.33
19.33 ± 0.67
15.00 ± 0.00
24.67 ± 1.67
11.00 ± 0.57
14.00 ± 1.53
5.00 ± 1.15
33.33 ± 1.67
29.00 ± 1.08
31.67 ± 1.67
44.67 ± 1.20
44.33 ± 0.88
25.67 ± 1.33
40.33 ± 0.88
44.67 ± 0.67
21.00 ± 0.58
45.00 ± 1.89
72.67 ± 1.20
53.33 ± 1.40
38.67 ± 1.86
50.67 ± 2.96
52.33 ± 1.33
33.33 ± 0.88
47.00 ± 1.45
53.33 ± 1.67
27.00 ± 1.15
11j

Molecules 2011, 16
8950
Table 3. Cont.
24 h
48 h
Corrected
mortality
(%)
72 h
Corrected
mortality
(%)
Compd.
Mortality
(%)
Corrected
mortality (%)
Mortality
(%)
Mortality
(%)
11k
11l
11m
11n
11o
11p
11q
11r
11s
11t
6
20.67 ± 0.67
10.67 ± 0.33
18.33 ± 1.02
26.67 ± 0.67
15.67 ± 0.67
14.00 ± 1.00
33.67 ± 0.88
1.67 ± 0.88
14.67 ± 1.45
18.00 ± 1.15
100.00±0.00
6.97 ± 1.06 2
14.73 ± 0.72
3.97 ± 0.36
12.22 ± 1.18
21.17 ± 0.95
9.34 ± 0.92
7.56 ± 1.07
28.70 ± 0.95
13.65 ± 0.95
8.27 ± 1.56
11.86 ± 1.24
40.00 ± 1.15 33.60 ± 1.28 52.33 ± 1.45 43.97 ± 1.71
23.00 ± 1.00 14.86 ± 1.11 35.33 ± 1.60 23.99 ± 1.06
50.00 ± 1.15 44.71 ± 1.28 61.00 ± 1.08 54.16 ± 1.44
34.67 ± 1.45 27.76 ± 1.61 41.67 ± 1.67 31.44 ± 1.96
23.00 ± 1.00 14.86 ± 1.11 30.33 ± 0.33 18.11 ± 0.39
17.00 ± 1.53 8.23 ± 1.69 22.33 ± 0.88 8.71 ± 1.04
52.67 ± 1.20 47.67 ± 1.32 65.67 ± 1.67 49.07 ± 1.96
24.33 ± 1.20 16.33 ± 1.33 31.33 ± 0.67 19.29 ± 0.79
24.67 ± 1.45 16.70 ± 1.61 31.33 ± 1.33 19.29 ± 0.79
30.00 ± 1.52 22.60 ± 1.78 42.33 ± 1.45 32.22 ± 1.71
100.00±0.00 100.00±0.00 100.00±0.00 100.00±0.00 100.00±0.00
CK
9.50 ± 1.05 2 13.02 ± 0.88 2
Note. The corrected mortality = an average value ± standard error, which is the result after 72 hours
of administration. In this column, the same character means no prominent difference at 5% level
(LSD).
Table 4. Toxicity of selected compounds against Bursaphelen-chus xylophilusat.
Regression
equation
Correlation
coefficient
0.99
LD50
(mg/L)
300.56
173.77
113.79
429.66
314.58
252.36
305.34
178.50
126.18
8.38
6.36
5.38
18.88
8.98
7.23
95% Confidence
limit (mg/L)
241.33–373.00
165.11–182.88
95.27–135.90
285.32–646.99
231.32–429.57
170.43–373.67
232.32–401.02
139.51–228.41
80.47–180.78
7.77–9.03
Time
Compd.
24 h
48 h
72 h
24 h
48 h
72 h
24 h
48 h
72 h
24 h
48 h
72 h
24 h
48 h
72 h
Y = 0.41 + 1.85x
Y = 0.14 + 2.17x
Y = 0.59 + 2.14x
y = 0.15 + 1.84x
y = 0.02 + 2.00x
y = 0.37 + 1.92x
y = 0.74 + 1.71x
y = 1.89 + 1.38x
y = 2.28 + 1.30x
y = 0.26 + 5.70x
y = 0.44 + 5.67x
y = 0.62 + 6.00x
y = 2.58 + 1.75x
y = 3.35 + 1.73x
y = 3.27 + 2.00x
11b
0.99
0.99
0.97
0.98
0.95
0.98
0.98
0.94
0.96
0.95
0.96
0.94
0.98
0.99
11c
11f
6
5.90–6.84
4.96–5.78
10.56–33.75
8.30–9.73
6.43–8.12
Avermec
tins
3. Experimental
3.1. General: Instruments and Methods
The melting points were determined on an XT-4 microscope melting point apparatus (Beijing Tech
1
Instruments Co., Beijing, China) and are uncorrected. H-NMR spectra were obtained at 300 MHz

Molecules 2011, 16
8951
using a Bruker Avance DPX 300 spectrometer in CDCl3 or DMSO-d6 solution, with tetramethylsilane
as the internal standard. Chemical-shift values (δ) were given in parts per million (ppm). Mass spectra
were obtained at Agilent 1100 series LC/MSD Trap. IR spectra data (cm−1) were determined on
VECTOR2 (KBr). The determination of unit cell and data collection was performed on a Rigaku raxis
Rapid IP Area Detector by using a graphite-monochromatized diffraction meter with MoKa radiation.
Elemental analyses were carried out on an Elementar Vario EL instrument. All analytically pure
reagents were purchased from Bailingwei or Beijing Chemical Reagent Co., and the solvents were
dried by standard methods in advance and distilled before use.
3.2. General Synthetic Procedures for the Preparation of Compounds 10a–10j
A mixture of 70% sodium hydride (15 mmol) and tetrahydrofuran (THF, 10 mL) was added
dropwise to the solution of ethyl diethoxyphosphinic acetate in THF (3 mL, 10 mmol) at 0 °C under
stirring. After the evolution of hydrogen ceased, compound 9 in THF (6 mL, 5 mmol) was added
dropwise and the mixture was stirred at r.t. for a further 10 h. Water (30 mL) was added slowly and the
mixture was extracted with ethyl acetate (10 mL × 4). The combined organic phase was washed with
water, dried with anhydrous magnesium sulphate, filtered, and evaporated to dryness in vacuo to give
ethyl 3-(pyrid-4-yl)cinnamate as a colorless oil. The oil was dissolved in methanol (30 mL) and NaOH
solution (7.5 mL, 2 mol/L), and was stirred at r.t. for further 10 h. The reaction mixture was evaporated
to remove the solvent in vacuo, and the mixture was extracted twice with ethyl ether (20 mL) after
water (40 mL) was added. The aqueous layer was then acidified to pH 2-3 and extracted with ethyl
ether (20 mL × 3) again. The combined organic phase was treated successively by washing with water,
drying with anhydrous Na2SO4, filtering, evaporating to dryness and recrystallizing from glacial HOAc,
to give compounds 10 as white powders.
3-(2-Chloropyridin-4-yl)-3-p-tolylacrylic acid (10a, C15H12O2NCl, X = Cl, R = 4-Me). Yield 91%, Mp.
1
191~192 °C. H-NMR (CDCl3), δ2.30 (s, 3H, CH3), 6.50 (s, 1H, =CH), 7.17–7.34 (m, 6H, Ar-H),
8.38(d, J = 5.07 Hz, 1H, pyridine-H), 12.36 (brs, 1H, OH).
3-(2-Chloropyridin-4-yl)-3-(4-ethylphenyl) acrylic acid (10b, C16H14O2NCl, X = Cl, R = 4-Et). Yield
72%, Mp. 152~153 °C. 1H-NMR (CDCl3), δ1.21 (m, 3H, 2CH3), 2.59 (m, 2H, CH2), 6.50 (s, 1H, =CH),
7.08–7.35 (m, 6H), 8.38–8.44 (m, 1H, pyridine-H), 12.40 (brs, 1H, OH).
3-(2-Chloropyridin-4-yl)-3-(3,4-dimethylphenyl) acrylic acid (10c, C16H14O2NCl, X = Cl, R = 3,4-Me).
Yield 96%, Mp. 201~202 °C. 1H-NMR (CDCl3), δ2.20 (s, 6H, ), 6.61 (s, 1H, =CH), 6.98–7.17 (m, 3H,
Ph-H), 7.81–7.83 (dd, 2H, pyridine-H), 8.89 (d, J = 1.29 Hz, 1H, pyridine-H), 8.92 (s, 1H, OH).
3-(2-Chloropyridin-4-yl)-3-(2,4-dimethylphenyl) acrylic acid (10d, C16H14O2NCl, X = Cl, R = 2,4-Me).
1
Yield 85%, Mp. 189~191 °C. H-NMR (CDCl3), δ2.10 (s, 3H, CH3), 2.13 (s, 3H, CH3), 6.63 (s, 1H,
=CH), 6.98 (d, J = 2.03 Hz, 1H), 7.01–7.18 (m, 4H, Ph-H), 7.84 (dd, 2H, pyridine-H), 8.75 (d, J = 3.57 Hz,
1H), 12.38 (brs, 1H, OH).
3-(2-Chloropyridin-4-yl)-3-(4-methoxyphenyl) acrylic acid (10e, C16H14O3NCl, X = Cl, R = 4-OMe).
Yield 68%, Mp. 168~170 °C. 1H-NMR(CDCl3), δ3.80 (s, 3H, CH3), 6.51 (s, 1H, =CH), 7.06–7.22 (m,

Molecules 2011, 16
8952
4H, Ph-H), 7.40 (dd, 2H, Pyridine-H), 8.75 (d, J = 3.57 Hz, 1H, Pyridine-H), 12.46 (brs, 1H, OH).
3-(4-tert-Butylphenyl)-3-(2-chloropyridin-4-yl)-acrylic acid (10f, C17H16O2NCl, X = Cl, R = 4-t-Bu).
Yield 55%, Mp. 176~177 °C. 1H-NMR(CDCl3), δ1.32 (s, 9H, 3CH3), 6.23 (s, 1H, =CH), 7.08–7.20 (m,
4H, Ph-H), 7.40 (dd, 2H, Pyridine-H), 8.45 (d, J = 5.01 Hz, 1H, Pyridine-H), 12.36 (brs, 1H, OH).
3-(Pyridin-4-yl)-3-p-tolylacrylic acid (10g, C15H13O2N, X = H, R = 4-Me). Yield 83%, Mp. 221~222 °C.
1H-NMR (CDCl3), δ2.40 (s, 3H, CH3), 6.48 (s, 1H, =CH), 7.09–7.23 (m, 6H, Ar-H), 8.55–8.60 (m,
2H, pyridine-H), 11.89 (brs, 1H, OH).
3-(4-Ethylphenyl)-3-(pyridin-4-yl)-acrylic acid (10h, C16H15O2N, X = H, R = 4-Et). Yield 59%, Mp.
205~206 °C. 1H-NMR (CDCl3), δ1.14–1.25 (m, 3H, CH3), 2.50–2.67 (m, 2H, CH2), 6.48 (s, 1H, =CH),
6.90–7.14 (m, 4H), 7.20–7.25 (m, 2H), 11.89 (brs, 1H, OH).
3-(3,4-Dimethylphenyl)-3-(pyridin-4-yl)acrylic acid (10i, C16H15O2N, X = H, R = 3,4-Me). Yield 77%,
Mp. 238~240 °C. 1H-NMR (CDCl3), δ2.20 (d, J = 14.55 Hz, 3H, CH3), 2.27 (d, J = 3.54 Hz, 3H, CH3),
6.48 (s, 1H, =CH), 6.90–7.14 (m, 3H, Ph-H), 7.20–7.25 (m, 2H, pyridine-H), 8.52–8.58 (m, 2H,
pyridine-H), 11.90 (brs, 1H, OH).
3-(2,4-Dimethylphenyl)-3-(pyridin-4-yl) acrylic acid (10j, C16H15O2N, X = H, R = 2,4-2Me). Yield
1
62%, Mp. 207~208 °C. H-NMR (CDCl3), δ2.05 (s, 3H, CH3), 2.33 (s, 3H, CH3), 6.20 (s, 1H, =CH),
7.00–7.08 (m, 3H, Ph-H), 7.30 (dd, 2H, pyridine-H), 8.52 (dd, 2H, pyridine-H), 9.99 (brs, 1H, OH).
3.3. General Synthetic Procedures for Compounds 11a–11t
Thionyl chloride (6.95 mmol) was added dropwise to the mixture of compound 10 (3.66 mmol) and
DMF of catalytic amount in CH2Cl2 (20 mL) and then stirred continuously for eight hours at 0 °C. The
reaction mixture was evaporated to remove the solvent and excess thionyl chloride in vacuo and the
residue was dissolve using CH2Cl2 (20 mL). β-Phenylethamine (4.13 mmol) and triethylamine
(catalytic amount) in CH2Cl2 (10 mL) was added to the residue at 0 °C. The reaction mixture was
stirred at r.t. for further 10 h, and then was washed with hydrogen chloride (1 mol/L), saturated
potassium carbonate solution and water, dried over anhydrous MgSO4, and concentrated to give the
crude product. Recrystallization from methanol afforded the title compounds.
3-(2-Chloropyridin-4-yl)-N-phenethyl-3-p-tolylacrylamide (11a, X = Cl, R = 4-Me, R1 = H), Yield
59%, Mp. 158–160 °C,1H-NMR (CDCl3), δ2.35 (s, 3H, CH3), 2.74 (t, 2H, CH2), 3.51(q, 2H, CH2),
5.60 (brs, 1H, NH), 6.28 (s, 1H, =CH), 7.04–7.33 (m, 11H, Ar-H), 8.37 (dd, 1H, J = 6.87, 6.40 Hz,
pyridine-H). MS m/z (ESI) 377.2 [M+H]+ Anal. Calc. for C23H21ON2Cl (376.13): C, 73.30; H, 5.62; N,
7.43; found:C, 73.22; H, 5.62; N, 7.50.
3-(2-Chloropyridin-4-yl)-3-(4-ethylphenyl)-N-phenethylacrylamide (11b, X = Cl, R = 4-Et, R1 = H).
1
Yield 88%, Mp. 142–143 °C, H-NMR (CDCl3), δ1.23 (t, 3H, CH3), 2.65 (q, 2H, CH2), 2.74 (t, 2H,
CH2), 3.50 (q, 2H, CH2), 5.60 (brs, 1H, NH), 6.29 (s, 1H, =CH), 7.07–7.33 (m, 11H, Ar-H), 8.37 (dd,
J = 6.78. 6.39 Hz, 1H, pyridine-H ). MS m/z (ESI) 391.2[M+H]+. Anal. Calc. for C24H23ON2Cl
(390.15): C, 73.74; H, 5.93; N, 7.17; found C, 73.61; H 5.84; N 7.24.

Molecules 2011, 16
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3-(2-Chloropyridin-4-yl)-3-(3,4-dimethylphenyl)-N-phenethylacrylamide (11c, X = Cl, R = 3,4-Me,
R1 = H). Yield 93%, Mp. 162–163 °C, 1H-NMR(CDCl3), δ 2.21 (q, 3H, CH3), 2.26 (t, 3H, CH3), 2.74
(t, 2H, CH2), 3.50 (q, 2 H, CH2), 5.60 (brs, 1H, NH), 6.28 (s, 1H, =CH), 6.87–7.33 (m, 10H, Ar-H),
8.33 (dd, J = 6.63, 6.81 Hz, 1H, pyridine-H). MS m/z (ESI) 391.2 [M+H]+. Anal. Calc. For
C24H23ON2Cl (390.15): C, 73.73; H, 5.93; N 7.17; found: C 73.74; H, 5.93; N, 7.20.
3-(2-Chloropyridine-4-yl)-3-(2,4-dimethylphenyl)acrylamide (11d, X = Cl, R = 2,4-2Me, R1 = H).
1
Yield 68%, Mp. 160–161 °C, H-NMR (CDCl3), δ2.01 (q, 3H, CH3), 2.30 (t, 3H, CH3), 2.77 (t, 2H,
CH2), 3.53 (q, 2H, CH2), 5.45 (brs, 1H, NH), 6.05 (s, 1H, =CH), 6.98–7.32 (m, 10H, Ar-H), 8.33 (dd,
J = 7.5, 7.5 Hz, 1H, pyridine-H). MS m/z (ESI) 391.20 [M+H]+. Anal. Calc. for C24H23ON2Cl (390.15):
C, 73.74; H 5.93; N, 7.17;. found: C, 73.72; H, 5.93; N, 7.22.
3-(2-Chloropyridin-4-yl)-3-(4-methoxyphenyl)-N-phenethylacrylamide (11e, X = Cl, R = 4-MeO, R1 = H).
1
Yield 71%, Mp. 185–186 °C, H-NMR (CDCl3), δ2.74 (t, 2H, CH2), 3.50 (q, 2H, CH2), 3.80 (s, 3H,
CH3O), 5.45 (brs, 1H, NH), 6.24 (s, 1H, =CH), 6.83–7.33 (m, 11H, Ar-H), 8.37 (dd, J = 5.70. 5.67 Hz,
1H, pyridine-H). MS m/z (ESI) 393.13[M+H]+. Anal. Calc. for C23H21O2N2Cl (392.13): C, 70.71; H,
5.39; N, 7.13; found：C, 70.32; H, 5.34; N, 7.20.
3-(2-Chloropyridin-4-yl)-N-(3,4-dimethoxyphenethyl)-3-p-tolylacrylamide (11f, X = Cl, R = 4-Me,
R1 = 3,4-MeO). Yield 77%, Mp. 181–182 °C, 1H-NMR (CDCl3), δ2.30 (t, 3H, CH3), 2.36 (q, 2H, CH2),
3.21 (q, 2H, CH2), 3.71 (s, 3H, CH3O), 3.73 (s, 3H, CH3O), 6.58 (s, 1H, =CH), 6.67–7.25 (m, 9H,
Ar-H), 8.23 (brs, 1H, NH), 8.38 (dd, J = 6.54, 6.54 Hz, 1H, pyridine-H). MS m/z (ESI) 437.2 [M+H]+.
Anal. Calc. for C25H25O3N2Cl (436.16): C, 68.72; H, 5.77; N, 6.41; found: C, 68.30, H, 5.78; N, 6.35.
3-(2-Chloropyridin-4-yl)-N-(3,4-dimethoxyphenethyl)-3-(3,4-dimethylphenyl)acrylamide (11g, X = Cl,
R = 3,4-Me, R1 = 3,4-MeO). Yield 81%, Mp. 157–159 °C, 1H-NMR (CDCl3), δ2.20 (s, 3H, CH3), 2.26
(s, 3H, CH3), 2.68 (t, 2H, CH2), 3.52 (q, 2H, CH2), 3.85 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 5.50 (brs,
1H, NH), 6.28 (s, 1H, =CH), 6.62–7.18 (m, 8H, Ar-H), 8.38 (dd, J = 5.4, 4.8 Hz, 1H, pyridine-H). MS
m/z (ESI) 451.2 [M+H]+. Anal. Calc. for C26H27O3N2Cl (450.17): C, 69.25; H, 6.03; N, 6.21; found,: C,
69.01; H, 5.99; N, 6.20.
3-(2-Chloropyridin-4-yl)-N-(3,4-dimethoxyphenethyl)-3-(2,4-dimethylphenyl)acrylamide (11h, X = Cl,
R = 2,4-Me, R1 = 3,4-MeO). Yield 77%, Mp. 111–113 °C, 1H-NMR (CDCl3), δ1.99 (d, 3H, CH3), 2.02
(d, 3H, CH3), 2.34 (t, 2H, CH2), 3.51 (q, 2H, CH2), 3.84 (s, 3H, CH3O), 3.85 (s, H, CH3O), 5.50 (brs,
1H, NH), 6.05 (s, 1H, =CH), 6.58–7.14 (m, 8H, Ar-H), 8.39 (dd, J = 6.18, 6.39 Hz, 1H, pyridine-H).
MS m/z (ESI) 451.2 [M+H]+. Anal. Calc. for C26H27O3N2Cl (450.17): C, 69.25; H, 6.03; N, 6.21;
found: C, 69.10; H, 6.03; N, 6.20.
3-(4-tert-Butylphenyl)-3-(2-chloropyridin-4-yl)-N-(3,4-dimethoxyphenethyl)acrylamide (11i, X=Cl,
1
R=4-t-Bu, R1 = 3,4-2MeO). Yield 53%, Mp. 146–148 °C, H-NMR (CDCl3), δ1.33 (t, 9H, C(CH3)3),
2.70 (t, 2H, CH2), 3.48 (q, 2H, CH2), 3.84 (s, 3H, CH3O), 3.86 (s, 3H, CH3O), 5.50 (brs, 1H, NH), 5.57
(t, 1 H, =CH), 6.63–7.38 (m, 9H, Ar-H ), 8.38 (dd, J = 7.02, 6.93 Hz, 1H, pyridine-H). MS m/z (ESI)

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479.20[M+H]+. Anal. Calc. for C28H31O3N2Cl (478.20): C, 70.21; H, 6.52; N, 5.85;. found: C, 69.90;
H, 6.50; N, 5.90.
3-(2-Chloropyridin-4-yl)-N-(4-hydroxyphenethyl)-3-p-tolylacrylamide (11j, X = Cl, R = 4-Me,
R1 = 4-OH). Yield 94%, Mp. 233–234 °C, 1H-NMR (DMSO), δ 2.30 (s, 3H, CH3), 2.36 (s, 3H, CH3),
2.51 (t, 2H, CH2), 3.21 (t, 2H, CH2), 6.56 (s, 1H, =CH), 6.63–7.29 (m, 8H, Ar-H), 7.17–7.30 (m, 2H,
pyridine-H), 8.07 (brs, 1H, NH), 8.38 (d, J = 5.25 Hz, 1H, pyridine-H), 9.18 (brs, 1H, OH). MS m/z
(ESI) 391.2 [M-H]+ Anal. Calc. for C23H21O2N2Cl (392.13): C, 70.31; H, 5.39; N, 7.13; found: C,
69.95; H, 5.33; N, 7.16.
3-(2-Chloropyridin-4-yl)-3-(4-ethylphenyl)-N-(4-hydroxyphenethyl)acrylamide (11k, X = Cl, R = 4-Et,
R1 = 4-OH). Yield 88%, Mp. 231–232 °C, 1H-NMR (DMSO), δ1.15–1.23 (m, 3H, CH3), 2.45–2.52 (m,
2H, CH2), 2.60–2.67 (m, 2H, CH2), 3.15–3.22 (m, 2H, CH2), 6.64 (s, 1H, =CH), 6.65–7.29 (m, 8H,
Ar-H), 7.17–7.30 (m, 2H, pyridine-H), 8.06 (brs, 1H, NH), 8.38 (d, J = 5.25 Hz, 1H, pyridine-H) 9.18
(s, 1 H, OH). MS m/z (ESI) 405.20 [M-H]+ Anal. Calc. for C24H23O2N2Cl (406.14): C, 70.84; H, 5.70;
N, 6.88; found: C, 70.57; H, 5.70; N, 6.81.
3-(2-Chloropyridin-4-yl)-3-(3,4-dimethylphenyl)-N-(4-hydroxyphenethyl)acrylamide (11l, X = Cl,
R = 3,4-Me, R1 = 4-OH). Yield 95%, Mp. 159–161 °C, 1H-NMR (DMSO), δ2.27 (s, 3H, -CH3), 2.30 (s,
3H, -CH3), 2.51 (t, 2H, -CH2), 3.19 (t, 2H, -CH2), 5.76 (s, 1H, =CH), 6.54–7.21 (m, 9H, Ar-H), 8.21(brs,
1H, -NH), 8.36 (d, 1H, J = 5.07 Hz, pyridine-H), 9.18 (brs, 1H, OH). MS m/z (ESI) 405.3 [M-H]+ Anal.
Calc. for C24H23O2N2Cl (406.14): C, 70.84; H, 5.70; N, 6.88; found: C, 70.59; H, 5.70, N, 6.78.
3-(2-Chloropyridin-4-yl)-3-(2,4-dimethylphenyl)-N-(4-hydroxyphenethyl)acrylamide (11m, X = Cl,
R = 2,4-Me, R1 = 4-OH). Yield 89%, Mp. 244–246 °C, 1H-NMR (DMSO), δ2.04 (s, 6H, -CH3), 2.56 (t,
2H, -CH2), 3.21 (t, 2H, -CH2), 6.14 (s, 1H, =CH), 6.66–7.19 (m, 9H, Ar-H ), 8.26 (brs, 1H, -NH), 8.31
(dd, J = 5.4, 5.1Hz, 1 H, pyridine-H), 9.10 (brs, 1H, -OH). MS m/z (ESI) 405.1 [M-H]+. Anal. Calc. for
C24H23O2N2Cl (406.14): C, 70.84; H, 5.70; N, 6.88; found: C, 70.53; H, 5.60; N, 6.79.
3-(4-tert-Butylphenyl)-3-(2-chloropyridin-4-yl)-N-(4-hydroxyphenethyl)acrylamide (11n, X = Cl,
R = 4-t-Bu, R1 = 4-OH). Yield 45%, Mp. 205–207 °C, 1H-NMR (DMSO), δ1.28 (s, 9H, 3CH3), 2.50 (t,
2H, CH2), 3.21 (t, 2H, CH2), 6.57 (s, 1H, =CH), 6.63–7.95 (m, 10H, Ar-H), 8.23 (brs, 1H, NH), 8.37
(dd, J = 6.90, 6.60 Hz, 1H, pyridine-H), 9.19 (brs, 1H, OH). MS m/z (ESI) 433.20 [M-H]+. Anal. Calc.
for C26H27O2N2Cl (434.18): C, 71.80; H, 6.26; N, 6.44; found: C, 71.54; H, 6.03; N, 6.21.
N-phenethyl-3-(pyridin-4-yl)-3-p-tolylacrylamide (11o, X = H, R = 4-Me, R1 = H). Yield 58%, Mp.
191–192 °C, 1H-NMR (DMSO), δ2.35 (s, 3H, CH3), 2.70 (t, 2H, -CH2), 3.46 (m, 2H, -CH2), 5.42 (brs,
1H, -NH), 6.32 (s, 1H, =CH), 7.06–7.31 (m, 11H, Ar-H), 8.60 (m, 2H, pyridine-H). MS m/z (ESI)
343.20[M+H]+. Anal. Calc. for C23H22ON2 (342.17): C, 80.67; H, 6.48; N, 8.18; found: C, 80.63; H,
6.46; N, 8.26.
3-(4-Ethylphenyl)-N-phenethyl-3-(pyridin-4-yl)acrylamide (11p, X = H, R = 4-Et, R1 = H). Yield 56%,
Mp. 135–137 °C, 1H-NMR (CDCl3), δ1.21 (t, 3H, CH3), 2.36 (q, 2H, CH2), 2.63 (t, 2H, CH2), 3.46 (q,
2H, CH2), 5.41 (brs, 1H, NH), 6.32 (s, 1H, =CH), 7.06–7.31 (m, 12H, Ar-H), 8.61 (dd, J = 1.65, 1.65 Hz,

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2H, pyridine-H). MS m/z (ESI) 357.20 [M+H]+. Anal. Calc. for C24H24ON2 (356.19): C, 80.87; H, 6.79;
N, 7.86; found: C, 80.73; H, 6.80; N, 7.89.
3-(3,4-Dimethylphenyl)-N-phenethyl-3-(pyridin-4-yl)acrylamide (11q, X = H, R = 3,4-Me, R1 = H).
1
Yield 93%, Mp. 182–183 °C, H-NMR (CDCl3), δ2.21 (t, 3H, CH3), 2.36 (q, 3H, CH3), 2.63 (t, 2H,
CH2), 3.46 (m, 2H, CH2), 5.41 (brs, 1H, NH), 6.32 (s, 1H, =CH), 7.06–7.31 (m, 11H, Ar-H), 8.54 (dd,
J = 1.59, 1.59 Hz, 1H, pyridine-H). MS m/z (ESI) 357.20 [M+H]+. Anal. Calc. for C24H24ON2 (356.19):
C, 80.87; H, 6.79; N, 7.86; found: C, 80.85; H, 6.78; N, 7.90.
N-(3,4-Dimethoxyphenethyl)-3-(3,4-dimethylphenyl)-3-(pyridin-4-yl)acrylamide (11r,
X
=
H,
1
R = 3,4-Me, R1 = 3,4-2MeO). Yield 85%, Mp. 172–174 °C, H-NMR (CDCl3), δ 2.21 (t, 3H, CH3),
2.26 (s, 3H, CH3), 2.64 (t, 2H, CH2), 3.43 (q, 2H, CH2), 3.86 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 5.44
(brs, 1H, NH), 6.31 (s, 1H, =CH), 6.59–7.27 (m, 8H, Ar-H), 8.61 (dd, 2H, J = 1.53, 1.53 Hz, 2 H,
pyridine-H). MS m/z (ESI) 417.30[M+H]+. Anal. Calc. for C26H28O3N2 (416.21): C, 74.97；H, 6.78; N,
6.73; found: C, 74.60; H, 6.80; N, 6.63.
N-(4-Hydroxyphenethyl)-3-(pyridin-4-yl)-3-p-tolylacrylamide (11s, X = H, R = 4-Me, R1 = 4-OH).
1
Yield 88%, Mp. 244–246 °C, H-NMR (DMSO), δ2.30 (s, 3H, CH3), 2.50–2.53 (m, 2H, CH2),
3.15–3.22 (m, 2H, CH2), 6.51 (s, 1H, =CH), 6.66–7.20 (m, 11H, Ar-H), 8.14 (brs, 1H, NH), 8.51–8.55
(m, 1H, pyridine-H), 9.19 (brs, 1H, OH). MS m/z (ESI) 356.20[M-2H]+. Anal. Calc. for C23H22O2N2
(358.20): C, 77.07; H, 6.19; N, 7.93; found: C, 76.93; H, 6.17; N, 7.71.
3-(3,4-Dimethylphenyl)-N-(4-hydroxyphenethyl)-3-(pyridin-4-yl)acrylamide (11t, X = H, R = 3,4-Me,
1
R1 = 4-OH). Yield 96%, Mp. 159–161 °C, H-NMR (DMSO), δ2.01 (s, 3H, CH3), 2.11 (s, 3H, CH3),
2.50–2.53 (t, 2H, CH2), 3.15–3.22 (q, 2H, CH2), 6.70 (s, 1H, =CH), 6.66–7.20 (m, 10H, Ar-H), 8.23
(brs, 1H, NH), 8.51–8.55 (m, 1H, pyridine-H), 9.20 (brs, 1H, OH). MS m/z (ESI) 370.20 [M-2H]+.
Anal. Calc. for C24H24O2N2 (372.18): C, 77.39; H, 6.49; N, 7.52; found: C, 77.29; H, 6.44; N, 7.55.
Crystal data can be obtained from the Crystallographic Data Centre as supplementary publication
number CCDC 848237. Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
3.4. Bioassays
3.4.1. Fungicidal Activity Test
The fungicidal activity of the target compounds against R. solani, P. parasitica, B. cinerea,
S. sclerotiorum, V. mali, P. asparagi and C. lindemuthianum were evaluated using the mycelium
growth rate test [21]. Pyrimorph, carbendazim, chlorothalonil, azoxystrobin were used as controls.
Their relative inhibition ratio (%) h were calculated as equal to the (colony diameter of control −
colony diameter of treatment)/(colony diameter of control − mycelial disks diameter) × 100. This
experiment was conducted twice with four replicates.

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3.4.2. Nematicidal Activity
All the compounds were dissolved in acetone and diluted to a 200 mg L−1 solution with distilled
water. The solution (1.5 mL) was placed in a 24 holes cellplate with nematode solution (0.5 mL, nearly
five hundred nematodes of mixed ages), and the plate was put in a culture box at 25 °C. A distilled
water test was used as blank control and every test was replicated three times. The mortality of insects
was counted after 24, 48 and 72 hours of administration, and Abbotts formula was used to correct the
mortality relative to that of negative control.
4. Conclusions
Using pyrimorph as the lead compound, we designed and synthesized twenty novel cinnamamides
derivatives using Wittig-Horner reaction as the key step. X-ray data showed that the Wittig-Horner
reactions mainly gave the Z-isomer product. The preliminary bioassay results demonstrated that most
of the title compounds show a wide spectrum of activity against plant pathogens at 50 μg·mL−1.
Compounds 11a and 11l showed higher fungicidal activity than the other compounds. The title
compounds exhibited moderate nematicidal activity. Generally, the morpholine ring might be replaced
by other amines and a chlorine atom in the pyridine ring is helpful to fungicidal activity.
Acknowledgement
We gratefully thank the National Technology R&D Program in the 11th Five year plan of China
(grant No. 2006 BAE01A03-10) and the National Basic Research Science Foundation of China
(2010CB126100) for financial support of this research.
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Sample Availability: Samples of the compounds 11 are available from the authors.
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