Synthesis, antiviral and antifungal bioactivity of 2-cyano-acrylate derivatives containing phosphonyl moieties

Article abstract of DOI:10.3390/12050965

Alkyl 2-cyano-3-methylthio-3-phosphonylacrylates were synthesized by the reaction of alkyl 2-cyano-3,3-dimethylthioacrylates with dialkyl phosphites. The structures of the new compounds were characterized by elemental analyses, IR, ¹H-, ¹³

Full text of DOI:10.3390/12050965

Molecules 2007, 12, 965-978
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Synthesis, Antiviral and Antifungal Bioactivity of
2-Cyano-acrylate Derivatives Containing Phosphonyl Moieties
Yin-Pu Lv, Xian-You Wang, Bao-An Song*, Song Yang, Kai Yan, Guang-Fang Xu, Pinaki S
Bhadury, Fang Liu, Lin-Hong Jin and De-Yu Hu
Center for Research and Development of Fine Chemicals, Guizhou University, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guiyang, 550025, P. R.
China
* Author to whom correspondence should be addressed; E-mail: songbaoan22@yahoo.com,
Tel.: (+86) 851 3620521, Fax: (+86) 851 3622211
Received: 2 March 2007; in revised form 25 April 2007 / Accepted: 25 April 2007 / Published:
9 May 2007
Abstract: Alkyl 2-cyano-3-methylthio-3-phosphonylacrylates were synthesized by the
reaction of alkyl 2-cyano-3,3-dimethylthioacrylates with dialkyl phosphites. The structures
1
of the new compounds were characterized by elemental analyses, IR, H-, 13C- and
31P-NMR spectral data. These compounds were tested in vitro against pathogenic fungi,
namely, Fusarium graminearum, Cytospora mandshurica and Fusarium oxysporum.
Amongst all compounds, 2d and 2t were found to be effective against the tested fungi at 50
µg/mL. A half-leaf method was used to determine the in vivo protective, inactivation and
curative efficacies of the title products against tobacco mosaic virus (TMV). Title
compounds 2a and 2b were found to possess good in vivo curative, protection and
inactivation effects against TMV with inhibitory rates at 500 mg/L of 60.0, 89.4 and 56.5
and 64.2, 84.2 and 61.2 %, respectively. To the best of our knowledge, this is the first
report on the antiviral and antifungal activity of alkyl 2-cyano-3-methylthio-3-
phosphonylacrylates.
Keywords: 2-Cyanoacrylate; phosphonyl moiety; antiviral activity; antifungal activity;
synthesis.

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Molecules 2007, 12
Introduction
Cyanoacrylates, a class of highly potent herbicidal compounds, are known to disrupt
photosynthetic electron transportation at a common binding domain on the 32 kDa polypeptide of the
photosystem II (PSII) reaction center [1,2]. A large number of reports on the synthesis of cyanoacrylate
derivatives exist due to their wide range of biological activities [3-6]. Some derivatives can serve not
only as agrochemicals such as herbicides, insecticides, fungicides and plant virucides, but also as
medicines such as antitumor agents. In our previous work, we designed and synthesized some chiral
cyanoacrylates with antiviral activity by replacing the methylthio moiety of some 2-cyano-3-methyl-
thio-3-substituted-phenylacrylates with (R)- or (S)-1-phenylethylamine groups. The (E) configuration
of the reported chiral products was confirmed by X-ray single-crystal structure analysis. The bioassays
showed that a chiral compound containing a 4-nitrophenyl moiety [(E)-ethyl 3[(S)-1-phenylethyl-
amino]-3-(4-nitrophenylamino)-2-cyanoacrylate] exhibited good protection activity against TMV in
vivo [7]. On the other hand, phosphonyl compounds, in general, have received wide attention in
modern medicinal and pesticide chemistry. They are ideal for use in drug design due to their good
bioactivity [8,9], low toxicity, and the ease of substitution with conventional heterocyclic ring groups
[10-12]. In 2001 Chen et al. reported an efficient method for the synthesis of ethyl 2-cyano-3-methyl-
thio-3-(diethoxyphosphonyl)acrylate under microwave irradiation conditions [13]. No reports on the
fungitoxicity and antiviral activity of alkyl 2-cyano-3-methylthio-3-phosphonylacrylates have been
published in the chemical or biological literature. In order to extend our research work on
cyanoacrylates as antiviral agents and fungicides, we have designed and synthesized some novel
cyanoacrylate derivatives 2a-2t containing phosphonyl moieties. The synthetic route is shown in
Scheme 1. Diethyl phosphite or higher homologues were employed in the reaction due to their ease of
preparation. The structures of 2 were established by well defined IR, NMR and elemental analysis. The
results of bioassay revealed that some compounds of the above series have good anti-TMV and
antifungal activity.
Scheme 1. Synthesis of compounds 2a-2t.
O
OR2
O
H P
NC
OR2
OR2
SMe
OR2
NC
SMe
SMe
OR2
NaOH
NC
P
+
CS2
CNCH2CO2R1
+
R1OOC
Me2SO4
R1OOC
P
NaH/THF
R1OOC
SMe
OR2
O
2
1
2a R1=C2H5,
2c R1=C2H5,
R2=C2H5;
R2=n-C3H7;
2b R1=C2H5,
2d R1=C2H5,
R2=i-C3H7;.
R2=n-C4H9;
2e R1=C2H4OC2H5, R2=C2H5;
2g R1=C2H4OC2H5, R2=n-C3H7;
2i R1=C2H4OCH3, R2=C2H5;
2k R1=C2H4OCH3, R2=n-C3H7;
2f R1=C2H4OC2H5, R2=i-C3H7 ;
2h R1=C2H4OC2H5, R2=n-C4H9;.
2j R1=C2H4OCH3, R2=i-C3H7;
2l R1=C2H4OCH3, R2=n-C4H9;
R2=C2H4OC2H5;.
2o R1=C2H4OC2H5, R2=C2H4OCH3; 2p R1=C2H4OC2H5 , R2=C2H4OC2H5;
2m R1=C2H5,
R2=C2H4OCH3; 2n R1=C2H5,
2q R1=CH3 ,
2s R1=CH3 ,
R2=C2H5 ;
R2=n-C3H7;
2r R1=CH3 ,
2t R1=CH3 ,
R2=i-C3H7;.
R2=n-C4H9;

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Molecules 2007, 12
Results and Discussion
In order to optimize the reaction conditions for the syntheses of compounds 2a-2t, the effects of
various solvents, molar reagent ratios, reaction times and reaction temperatures on the reaction
synthesis of 2b were examined. The results are summarized in Table 1. Cyanoacrylate 2b was obtained
from 1 in poor yield (Table 1, entries 1-3) in solvents such as DMF, acetone and CH3CN, but when
tetrahydrofuran (THF) was chosen as solvent, the yield of 2b increased from 11.2 % to 55.0 % (Table
1, entries 1, 4). Next we also examined the effect on the reaction of the molar ratios of the reactants.
When the molar ratio of 2-cyano-3,3-(dimethylthio)- acrylate to O, O’-di-i-propylphosphite to sodium
hydride was increased from 1:1:1 to 1:3:1, 1:3:2, 1:3:3 and 1:3:4 eq, compound 2b was obtained in 0,
12.0, 20.0, 55.0 and 49.5 % yield, respectively (Table 1, entries 4-8). With regard to the reaction time 0,
23.0 and 55.0 % yields of 2b were noted after 4, 8 and 16 h, respectively (Table 1, entries 9, 10, 4).
When the reaction time was prolonged further to 20 h, no significant improvement was obtained (56.0
%, Table 1, entry 11), as compared to that seen after 16 h (55.0 %, Table 1, entry 4). As for the reaction
temperature, a lower yield was observed at lower temperature (Table 1, entry 12). It could also be seen
that the yield was significantly lower when the reaction was performed at 40-45 °C (Table 1, entry 13),
compared to that seen at room temperature (Table 1, entry 4).
Table 1. Synthesis of 2b under different reaction conditions.
Reaction
Entry
Solvent
Ratio a
Time (h)
Yield (%) b
temperature
1
2
DMF
acetone
CH3CN
THF
1:3:3
1:3:3
1:3:3
1:3:3
1:3:1
1:3:2
1:1:1
1:3:4
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
16
16
16
16
16
16
16
16
4
r.t
11.2
19.0
34.9
55.0
12.0
20.0
0
r.t
3
r.t
4
r.t
5
THF
r.t
6
THF
r.t
r.t
7
THF
8
THF
r.t
49.5
0
9
THF
r.t
10
11
12
THF
8
r.t
23.0
56.0
23.0
13.0
THF
20
16
16
r.t
THF
0-5°C
40-45°C
13
THF
a
Ratio of 2-cyano-3,3-dimethylthioacrylate:O,O’-di-i-propylphosphite:sodium hydride
b
Isolated yield based on 2-cyano-3,3-dimethylthioacrylate
Antifungal Bioassay: Inhibitory effects of cyanoacrylate derivatives on phytopathogenic fungi
The three fungi used in the fungicidal bioassay, Fusarium graminearum, Cytospora mandshurica
and Fusarium oxysporum, were tested by the poison plate technique. The results of preliminary
bioassays were compared with that of a commercial agricultural fungicide, hymexazol. As indicated in

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Molecules 2007, 12
Table 2, the new compounds 2d and 2t exhibited promising antifungal activity, inhibiting growth of F.
graminearum at 64.5 and 49.7 %, C. mandshurica at 60.4 and 51.3 % and F. oxysporum at 65.0 and
41.1 %, respectively, which is a little lower than that of hymexazole (73.2 % against F. graminearum,
58.9 % against C. mandshurica, and 65.5 % against F. oxysporum at 50 µg/mL). Marked loss of
activity was observed with other compounds such as 2a-2c and 2e-2s.
Table 2. Inhibition effects of the title compounds on fungi.
Inhibition rate (%)
Conc.
Compd.
Fusarium
graminearum
11.14±0.21
37.30±0.56
4.94±0.49
31.40±0.78
8.31±0.57
37.10±1.08
64.50±0.40
93.30±4.28
22.04±0.90
41.44±1.21
35.22±1.78
55.64±3.01
7.79±0.57
40.0±2.15
4.68±0.56
25.41±0.73
5.45±0.73
16.3±0.64
0.97±0.11
20.00±0.21
10.09±0.76
31.03±0.90
21.08±0.98
34.01±1.67
3.93±0.22
27.31±0.99
12.22±1.01
24.04±0.62
3.75±0.52
21.08±0.65
4.45±0.55
28.10±0.69
Cytospora
mandshurica
11.00±0.25
24.00±0.77
1.34±0.65
Fusarium
oxysporum
18.21±0.11
26.03±0.99
8.08±0.98
36.83±1.24
13.47±1.24
41.02±1.30
65.03±1.22
92.75±2.52
26.71±0.90
32.13±1.09
46.11±3.34
68.9±1.19
6.29±0.97
48.80±1.33
5.99±0.87
36.53±1.27
1.20±0.89
20.06±0.97
9.99±0.22
30.99±1.09
19.39±0.44
40.22±1.45
12.11±1.02
32.00±0.69
23.09±0.88
41.90±2.01
11.91±0.42
35.69±1.90
4.01±0.55
29.07±0.65
6.52±0.56
35.59±0.69
(µg/mL)
50
500
50
2a
2b
2c
2d
2e
2f
500
50
35.03±0.84
13.10±0.78
31.82±1.45
60.43±0.63
90.59±1.59
32.01±0.78
36.77±1.45
41.09±3.21
66.09±2.55
-0.80±0.72
49.47±1.01
-3.21±0.85
23.26±0.84
-2.67±0.67
8.29±0.76
500
50
500
50
500
50
500
50
2g
2h
2i
500
50
500
50
500
50
11.27±0.45
26.78±0.44
32.20±0.55
36.38±1.32
30.07±0.67
29.51±1.02
14.23±0.51
16.08±0.55
9.97±0.88
2j
500
50
2k
2l
500
50
500
50
2m
2n
2o
2p
500
50
500
50
36.09±0.55
10.61±0.69
48.28±0.96
24.93±0.76
47.21±0.95
500
50
500

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Molecules 2007, 12
Table 2. Cont.
50
500
50
7.03±0.60
42.15±0.79
11.71±0.96
44.03±0.81
9.84±0.61
53.40±0.92
49.67±0.65
81.97±2.91
73.2±1.41
100±0.66
0
15.38±0.61
57.82±1.11
23.87±0.75
64.72±1.26
35.01±0.72
65.78±1.29
51.30±0.70
75.33±1.71
58.89±1.16
95.33±1.87
0
3.26±0.44
33.58±0.68
9.52±0.57
52.13±0.84
13.53±0.48
56.64±0.90
41.05±0.51
69.42±1.23
65.51±1.76
93.18±3.76
0
2q
2r
2s
2t
500
50
500
50
500
50
Hymexazol a
DMSO b
500
a reference compound; b control.
Figure 1 shows the inhibition of mycelial growth of isolated hypha of F. oxysporum by compound
2d at different concentrations (100, 50, 25, 10, and 1 µg/mL) as compared to control, when tested in
vitro. Almost complete inhibition of mycelial growth was observed at 100 and 50 µg/mL
concentrations as compared to control (full growth).
Figure 1. Effect of various concentrations of 2d on the growth of isolated hypha of F.
oxysporum (100, 50, 25, 5 and 1 µg/mL).
Key (µg/mL): 1, 100; 2, 50; 3, 25; 4, 5; 5, 1; and C, control.
Micro-observation results
Microphotography of the hyphal morphology of F. oxysporum treated with 100 µg/mL of 2d
(Figure 2) showed a series of changes, i.e. the cell of the hyphal divarication increased, hyphal knots
appeared, and hypha bulged partially, compared with control.

970
Figure 2. Microphotograph (800×) of hyphal morphology of F. oxysporum treated with 2d.
Molecules 2007, 12
ck
Preliminary antiviral activity assay
2d
The results of the in vivo bioassay against TMV are given in Table 3. Ningnanmycin was used as
reference antiviral agent. The data provided in the table indicate that the introduction of
dialkylphosphonyl moieties in cyanoacrylates might improve their protective activities. The title
compounds 2a-2t showed protection rates of 40.8-61.2 %. When R1 and R2 are Et, the resulting
compound 2a displayed a lower protective activity (56.5 %) than that of the reference compound (62.6
%). The highest protective activity was achieved when R1 is Et and R2 is i-Pr (compound 2b). A
protective rate of 61.2 %, equivalent to ningnanmycin, against TMV at 500 µg/mL was recorded in this
case. From the data in Table 3, it may be observed that the title compounds 2a-2t possess significant
potential inactivation bioactivities, with values of 89.4, 84.7, 76.3, 80.3, 74.2, 79.6, 73.8, 70.8, 80.0,
77.9, 79.0, 78.2, 81.2, 80.2, 68.9, 67.3, 60.0, 70.0, 80.2 and 61.0 % at 500 µg/mL, respectively. Among
these compounds, 2a (R1 and R2 are Et) is much more active against TMV than the other ones, with an
inactivation rate of 89.4 %, equivalent to ningnanmycin (92.6 %) against TMV at 500 µg/mL. The data
also indicate that a change in the substituent might also affect the curative activity of the title
compounds 2a-2t. Compound 2a (R1 and R2 are Et) and compound 2b could cure TMV up to 60.0 %
and 64.2 % at 500 µg/mL. The other compounds have a relatively lower curative activity than 2a and
2b.
Table 3. The Protective, inactivation and curative effects of the new compounds against
TMV in vivo.
Concentration
(mg/L)
500
Protective
Effect (%)
56.5*±1.4
61.2*±3.2
53.0*±1.8
53.4*±0.7
45.0*±1.1
47.9*±1.7
40.8*±5.4
46.5*±2.3
Inactivation
Effect (%)
89.4**±2.0
84.7**±1.0
76.3*±2.4
80.3**±3.4
74.2*±3.4
79.6**±1.6
73.8*±3.0
70.8*±1.4
Curative
Effect(%)
60.0*±0.9
64.2*±1.9
45.8*±1.0
41.2*±2.1
54.7*±2.2
28.4±4.4
Agents
2a
2b
2c
2d
2e
2f
500
500
500
500
500
2g
2h
500
41.8*±5.5
31.4*±1.7
500

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Molecules 2007, 12
Table 3. Cont.
2i
2j
500
500
500
500
500
500
500
500
500
500
500
500
500
50.1*±3.0
43.2*±5.4
45.7*±1.9
51.2*±1.1
50.0*±2.0
49.7±8.0
80.0**±2.0
77.9*±0.9
79.0*±0.7
78.2*±0.9
81.2*±1.6
80.2**±1.2
68.9*±5.3
67.3*±2.4
60.0*±3.1
70.0*±1.9
80.2**±2.0
61.0*±5.1
92.6**±1.0
36.6*±4.4
42.1*±3.8
44.3*±6.4
42.0*±1.5
50.0*±1.0
51.2*±1.0
33.3*±4.9
33.3±8.9
2k
2l
2m
2n
2o
2p
2q
2r
2s
48.9*±0.9
47.6*±1.0
45.6*±0.4
50.9*±1.1
51.2*±0.9
46.6*±5.5
62.6*±2.1
10.9±6.0
36.7*±6.7
41.4*±9.9
24.1±8.7
2t
Ningnamycin
53.9*±2.3
All results are expressed as mean ± SD; n= 3 for all groups; * P<0.05, **P<0.01.
Conclusions
A series of novel cyanoacrylate derivatives 2a-2t containing phosphonyl moieties were synthesized
by treatment of alkyl 2-cyano-3,3-dimethylthioacrylates and dialkyl phosphites with NaH in THF
solvent. This method is easy and gields the title compounds in moderate yields. The structures were
verified by spectroscopic data. In the antifungal bioassay, the title compounds 2d and 2t were found to
possess the highest activity against three kinds of fungi in vitro. The bioassay results showed that these
title compounds exhibited moderate to good anti-TMV bioactivity. Title compounds 2a and 2b showed
better biological activity than their structurally related analogues 2c-2t.
Acknowledgements
The authors wish to thank the National Key Project for Basic Research (Grant No. 2003CB114404,
2005CCA01500) and Key Technologies R&D Program (Grant No. 2006BAE01A02-5) and the
National Natural Science Foundation of China (Grant No. 20672024) for their financial support.
Experimental
General
The melting points of the products were determined on an XT-4 binocular microscope (Beijing
Tech Instrument Co., P.R. China) and were not corrected. The IR spectra were recorded on a Bruker
1
13
VECTOR 22 spectrometer in KBr disks. H-, C- and 31P-NMR spectra (solvent CDCl3) were
recorded on a JEOL-ECX 500 NMR spectrometer at room temperature using TMS as an internal
standard. Elemental analysis was performed on an Elementar Vario-III CHN analyzer. Analytical TLC
was performed on silica gel GF254. Column chromatographic purification was carried out using silica
gel. All reagents either belonged to analytical reagent grade or were chemically pure. THF was dried,

972
Molecules 2007, 12
deoxygenated and redistilled before use. Dialkyl phosphites and alkyl 2-cyano-3,3-(dimethyl-
thio)acrylates were prepared according to literature methods [14, 15].
General procedure for the preparation of title compounds 2a-2t.
A dry 100 mL round-bottom flask equipped with a magnetic stirrer and nitrogen inlet was charged
with sodium hydride (0.66 g, 55%, 15.2 mmol) in THF (15 mL) at 0~5 °C. Dialkyl phosphite (15.2
mmol) was than slowly added through a dropping funnel into the resulting solution over a period of 30
min. Alkyl 2-cyano-3,3-(dimethylthio)acrylate (5.0 mmol) in THF (20 mL) was then slowly added to
the above solution. The mixture was stirred for 16 h at room temperature. After removal of the solvent
under vacuum, the residue was dissolved in ice-cold water (40 mL) and acidified with dilute
hydrochloric acid (10%), extracted with ethyl acetate (3 × 20 mL) and the combined organic layer was
dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was subjected to
column chromatography using a mixture of petroleum ether and ethyl acetate (4:1) as eluent to give the
title compounds 2a-2t.
Yields and product characterization
1
Ethyl 2-cyano-3-methylthio-3-(diethoxyphosphonyl)acrylate (2a): yellow liquid; yield 52.0%; H-
NMR δ: 1.37~1.45 (m, 9H, ester CH3 + 2 × phosphonyl CH3), 2.76 (d, J = 6.8 Hz, 3H, SCH3),
4.32~4.35 (m, 6H, ester CH2 + 2 × phosphonyl CH2); 13C-NMR δ: 14.1 (ester CH3), 16.2
(2×phosphonyl CH3), 19.4 (SCH3), 62.7 (ester OCH2), 64.5 (2 × phosphonyl CH2), 106.2 (C=C C-2),
114.5 (CN), 162.1 (C=C C-3), 165.7 (C=O); 31P-NMR δ: 5.1; IR ν: 2983, 2214, 1745, 1251, 1018 cm-1;
Anal. Calcd. for C11H18NO5PS (307.5): C, 42.93; H, 5.58; N, 4.55. Found: C, 42.99; H, 5.90; N, 4.56.
1
Ethyl 2-cyano-3-methylthio-3-(di-i-propoxyphosphonyl)acrylate (2b): yellow liquid; yield 55.0%; H-
NMR δ: 1.36~1.38 (m, 15 H, 4 × phosphonyl CH3 + ester CH3), 2.73 (d, J = 6.9 Hz, 3H, SCH3), 4.33
(q, J = 7.2 Hz, 2H, ester CH2), 4.82~4.89 (m, 2H, 2 × phosphonyl CH); 13C-NMR δ: 14.1 (ester CH3),
19.4 (SCH3), 23.9 (4 × phosphonyl CH3), 63.1 (ester OCH2), 64.5 (2 × phosphonyl CH2), 74.2 (2 ×
phosphonyl CH), 106.9 (C=C C-2), 114.7 (CN), 162.1 (C=C C-3), 165.3 (C=O); 31P-NMR δ: 3.5; IR ν:
2980, 2212, 1718, 1504, 1246, 987 cm-1; Anal. Calcd. for C13H22NO5PS (335.1): C, 46.55; H, 6.56; N,
4.18. Found: C, 46.56; H, 6.61; N, 4.10.
1
Ethyl 2-cyano-3-methylthio-3-(di-n-propoxyphosphonyl)acrylate (2c): yellow liquid; yield 50.0%; H-
NMR δ: 0.98~1.02 (m, 6H, 2 × phosphonyl CH3), 1.37 (t, J = 7.5 Hz, 3H, ester CH3), 1.73~1.75 (m,
4H, 2 × phosphonyl CH2), 2.75 (d, J = 6.9 Hz, 3H, SCH3), 4.09~4.19 (m, 4H, 2 × phosphonyl CH2),
13
4.33 (q, J = 7.1Hz, 2H, ester CH2); C-NMR δ: 10.0 (2 × phosphonyl CH3), 14.1 (ester CH3), 19.5
(SCH3), 23.7 (2 × phosphonyl CH2), 63.3 (ester OCH2), 69.8 (2 × phosphonyl CH2), 106.5 (C=C C-2),
31
114.6 (CN), 162.1 (C=C C-3), 165.5 (C=O); P-NMR δ: 5.9; IR ν: 2970, 2214, 1735, 1463, 1251,
1006 cm-1; Anal. Calcd. for C13H22NO5PS (335.1): C, 46.55; H, 6.56; N, 4.18. Found: C, 46.56; H,
6.61; N, 4.18.

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Molecules 2007, 12
1
Ethyl 2-cyano-3-methylthio-3-(di-n-butoxyphosphonyl)acrylate (2d): yellow liquid; yield 45.6%; H-
NMR δ: 0.94~0.97 (m, 6H, 2 × phosphonyl CH3), 1.37 (t, J =7.2 Hz, 3H, ester CH3), 1.39~1.46 (m, 4H,
2 × phosphonyl CH2), 1.73~1.77 (m, 4H, 2 × phosphonyl CH2), 2.74 (d, J =6.9 Hz, 3H, SCH3),
13
4.23~4.34 (m, 6H, 2 × phosphonyl CH2 + ester CH2); C-NMR δ: 13.5 (2 × phosphonyl CH3), 13.6
(ester CH3), 18.7 (2 × phosphonyl CH2), 18.8 (SCH3), 32.3 (2 × phosphonyl CH2), 62.8 (ester CH2),
68.0 (2 × phosphonyl CH), 106.4 (C=C C-2), 114.5 (CN), 162.1 (C=C C-3), 165.6 (C=O); 31P-NMR δ:
5.5; IR ν: 2960, 2214, 1735, 1465, 1259, 1028 cm-1; Anal. Calcd. for C15H26NO5PS (363.1): C, 49.57;
H, 7.16; N, 3.86. Found: C, 49.54; H, 7.21; N, 3.69.
Ethoxyethyl 2-cyano-3-methylthio-3-(diethoxyphosphonyl)acrylate (2e): yellow liquid; yield 49.7%;
1H-NMR δ: 1.22 (t, J = 6.9 Hz, 3H, ester O-C-CH3), 1.38~1.45 (m, 6H, 2 × phosphonyl CH3), 2.75 (d,
J = 8.6 Hz, 3H, SCH3), 3.57 (q, J = 6.3 Hz, 2H, ester OCH2), 3.72~3.74 (m, 2H, ester CH2), 4.30~4.32
(m, 4H, 2 × phosphonyl CH2), 4.39~4.41 (m, 2H, ester CH2); 13C-NMR δ: 15.2 (ethoxy CH3), 16.3 (2
× phosphonyl CH3), 19.6 (SCH3), 64.6 (2 × phosphonyl CH2), 65.9 (ester OCH2), 66.9 (ethoxy OCH2),
31
67.8 (ester CH2O), 106.0 (C=C C-2 ), 114.5 (CN), 162.2 (C=C C-3), 164.9 (C=O); P-NMR δ: 5.15;
IR ν: 2953, 2992, 2852, 2214, 1714, 1444, 1249, 1120, 1012 cm-1; Anal. Calcd. for C13H22NO6PS
(351.1): C, 44.43; H, 6.27; N, 3.99. Found: C, 44.44; H, 6.31; N, 3.89.
Ethoxyethyl 2-cyano-3-methylthio-3-(di-i-propoxyphosphonyl)acrylate (2f): yellow liquid; yield 57.5%;
1H-NMR δ: 1.22 (t, J = 6.9 Hz, 3H, ester O-C-CH3), 1.41~1.45 (m, 12H, 4 × phosphonyl CH3), 2.72 (d,
J = 14.3 Hz, 3H, SCH3), 3.57 (q, J = 6.9 Hz, 2H, ester OCH2), 3.72~3.73 (m, 2H, ester OCH2),
4.39~4.41 (m, 2H, ester CH2), 4.82~4.89 (m, 2H, 2 × phosphonyl CH); 13C- NMR δ: 15.1 (ethoxy
CH3), 19.7 (SCH3), 23.8 (4 × phosphonyl CH3), 65.7 (ester CH2), 66.7 (ethoxy OCH2), 67.7 (ester
CH2O), 74.2 (2 × phosphonyl CH), 106.6 (C=C C-2), 114.5 (CN), 162.0 (C=C C-3), 166.8 (C=O);
31P-NMR δ: 4.76; IR ν: 2978, 2933, 2214, 1732, 1454, 1251, 1118, 987 cm-1; Anal. Calcd. for
C15H26NO6PS (379.4): C, 47.44; H, 6.85; N, 3.69. Found: C, 47.48; H, 6.91; N, 3.51.
Ethoxyethyl 2-cyano-3-methylthio-3-(di-n-propoxyphosphonyl)acrylate (2g): yellow liquid; yield
55.6%; 1H-NMR δ: 0.98~1.00 (m, 6H, 2 × phosphonyl CH3), 1.21 (t, J =6.9 Hz, 3H, ester O-C-CH3),
1.73~1.80 (m, 4H, 2 × phosphonyl CH2), 2.75 (d, J = 9.1 Hz, 3H, SCH3), 3.57 (q, J = 7.2 Hz, 2H, ester
OCH2), 3.72~3.74 (m, 2H, ester CH2), 4.16~4.20 (m, 4H, 2 × phosphonyl CH2), 4.39~4.41 (m, 2H,
ester CH2); 13C-NMR δ: 10.1 (2 × phosphonyl CH3), 15.2 (ethoxy OCH3), 19.6 (SCH3), 23.7 (2 ×
phosphonyl CH2COP), 65.9 (ester OCH2), 66.3 (ethoxy OCH2), 67.8 (ester CH2O), 70.0 (2 ×
phosphonyl CH2OP), 106.1 (C=C C-2), 114.5 (CN), 162.0 (C=C C-3), 164.9 (C=O); 31P-NMR δ: 5.43;
IR ν: 2968, 2897, 2214, 1745, 1456, 1381, 1238, 1116, 995 cm-1; Anal. Calcd. for C15H26NO6PS
(379.4): C, 47.44; H, 6.85; N, 3.69. Found: C, 47.40; H, 6.81; N, 3.55.
Ethoxyethyl 2-cyano-3-methylthio-3-(di-n-butoxyphosphonyl)acrylate (2h): yellow liquid; yield 54.7%;
1H-NMR δ: 0.94~0.96 (m, 6H, 2 × phosphonyl CH3), 1.22 (t, J = 6.9 Hz, 3H, ester O-C-CH3),
1.42~1.44 (m, 4H, 2 × phosphonyl CH2), 1.69~1.76 (m, 4H, 2 × phosphonyl CH2), 2.75 (d, J =
10.3Hz, 3H, SCH3), 3.57 (q, J = 7.5 Hz, 2H, ethoxy OCH2), 3.72~3.74 (m, 2H, ester OCH2), 4.23~4.25
(m, 4H, 2 × phosphonyl CH2), 4.39~4.41 (m, 2H, ester CH2); 13C-NMR (δ: 13.6 (2 × phosphonyl CH3),
15.2 (ethoxy OCH3), 18.8 (2 × phosphonyl CH2), 19.6 (SCH3), 32.4 (2 × phosphonyl CH2), 65.9 (ester

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Molecules 2007, 12
CH2), 66.9 (ethoxy OCH2), 67.8 (2 × phosphonyl CH2), 68.3 (ester CH2O), 106.1 (C=C C-2), 114.5
31
(CN), 162.0 (C=C C-3), 164.8 (C=O); P-NMR δ: 5.44; IR ν: 2960, 2872, 2214, 1732, 1714, 1249,
1056 cm-1; Anal. Calcd. for C17H30NO6PS (407.1): C, 50.11; H, 7.37; N, 3.44. Found: C, 50.13; H,
7.42; N, 3.26.
Methoxyethyl 2-cyano-3-methylthio-3-(diethoxyphosphonyl)acrylate (2i): yellow liquid; yield 60.1%;
1H-NMR δ: 1.36~1.45 (m, 6H, 2 × phosphonyl CH3), 2.75 (d, J = 7.5 Hz, 3H, SCH3), 3.41 (s, 3H,
methoxy CH3), 3.68~3.70 (m, 2H, ester CH2), 4.25~4.32 (m, 4H, 2 × phosphonyl CH2), 4.39~4.42 (m,
2H, ester CH2); 13C-NMR δ: 16.2 (2 × phosphonyl CH3), 19.5 (SCH3), 59.2 (methoxy), 64.6 (2 ×
phosphonyl CH2), 65.6 (ester CH2), 69.8 (ester CH2O), 105.8 (C=C C-2), 114.4 (CN), 161.9 (C=C
C-3), 165.0 (C=O); 31P-NMR δ: 5.11; IR ν: 2916, 2214, 1732, 1444, 1249, 1122, 1012 cm-1; Anal.
Calcd. for C12H20NO6PS (337.1): C, 42.71; H, 5.93; N, 4.15. Found: C, 42.73; H, 5.98; N, 4.05.
Methoxyethyl 2-cyano-3-methylthio-3-(di-i-propoxyphosphonyl)acrylate (2j): yellow liquid; yield
58.1%; 1H-NMR δ: 1.36~1.42 (m, 12H, 4 × phosphonyl CH3), 2.72 (d, J = 13.2 Hz, 3H, SCH3), 3.40 (s,
3H, ester OCH3), 3.68~3.70 (m, 2H, ester CH2), 4.39~4.40 (m, 2H, ester OCH2), 4.82~4.89 (m, 2H, 2
× phosphonyl CH); 13C-NMR δ:19.7 (SCH3), 24.0 (4 × phosphonyl CH3), 59.0 (methoxy OCH3), 65.9
(ester CH2), 70.0 (ester CH2), 74.1 (2 × phosphonyl CH), 106.4 (C=C C-2), 114.4 (CN), 162.0 (C=C
31
C-3), 165.8 (C=O); P-NMR δ: 5.10; IR ν: 2981, 2933, 2214, 1747, 1454, 1249, 1000 cm-1; Anal.
Calcd. for C14H24NO6PS (365.1): C, 46.01; H, 6.57; N, 3.83. Found: C, 45.92; H, 6.39; N 3.83.
Methoxyethyl 2-cyano-3-methylthio-3-(di-n-propoxyphosphonyl) acrylate (2k): yellow liquid; yield
55.3%; 1H-NMR δ: 0.98~1.00 (m, 6H, 2 × phosphonyl CH3), 1.73~1.80 (m, 4H, 2 × phosphonyl CH2),
2.75 (d, J = 7.5 Hz, 3H, SCH3), 3.42 (s, 3H, methoxy OCH3), 3.69~3.70 (m, 2H, ester OCH2),
4.13~4.21 (m, 4H, 2 × phosphonyl CH2), 4.40~4.42 (m, 2H, ester CH2); 13C-NMR δ: 10.0 (2 ×
phosphonyl CH3), 19.5 (SCH3), 23.7 (2 × phosphonyl CH2), 59.2 (methoxy OCH3), 65.6 (ester CH2),
69.8 (2 × phosphonyl CH2OP), 69.9 (ester CH2), 105.9 (C=C C-2), 114.4 (CN), 162.1 (C=C C-3),
165.0 (C=O); 31P-NMR δ: 5.38; IR ν: 2968, 2897, 2214, 1724, 1465, 1247, 1000 cm-1; Anal. Calcd. for
C14H24NO6PS (365.1): C, 46.01; H, 6.57; N, 3.83. Found: C, 45.82; H, 7.42; N 3.83.
Methoxyethyl 2-cyano-3-methylthio-3-(di-n-butoxyphosphonyl)acrylate (2l): yellow liquid; yield
1
51.0%; H-NMR δ: 0.94~0.97 (m, 6H, 2 × phosphonyl CH3), 1.41~1.44 (m, 4H, 2 × CH2), 1.69~1.76
(m, 4H, 2 × CH2-C-O-P=O), 2.74 (d, J = 8.0 Hz, 3H, SCH3), 3.41 (s, 3H, ester OCH3), 3.68~3.70 (m,
13
2H, ester CH2), 4.20~4.24 (m, 4H, 2 × phosphonyl CH2), 4.40~4.42 (m, 2H, ester CH2); C-NMR δ:
13.5 (2 × phosphonyl CH3), 18.6 (2 × phosphonyl CH2), 18.7 (SCH3), 32.2 (2 × phosphonyl CH2), 59.2
(methoxy OCH3), 65.6 (ester CH2), 68.2 (2 × phosphonyl CH2OP), 69.8 (ester CH2), 105.8 (C=C C-2),
31
114.4 (CN), 161.9 (C=C C-3), 165.0 (C=O); P-NMR δ: 5.39; IR ν: 2956, 2872, 2214, 1734, 1458,
1253, 1002 cm-1; Anal. Calcd. for C16H28NO6PS (393.1): C, 48.84; H, 7.12; N, 3.56. Found: C 48.80,
H, 7.17; N, 3.43.
Ethyl 2-cyano-3-methylthio-3-[di-(2-methoxyethoxy)phosphonyl]acrylate (2m): yellow liquid; yield
1
60.0%; H-NMR δ: 1.36~1.38 (m, 3H, ester CH3), 2.78 (d, J =10.9 Hz, 3H, SCH3), 3.39 (s, 6H, 2 ×
phosphonyl CH3), 3.62~3.67 (m, 4H, 2 × phosphonyl CH2), 4.31~4.40 (m, 6H, 2 × phosphonyl CH2 +

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Molecules 2007, 12
13
ester CH2); C-NMR δ: 14.0 (ester CH3), 19.2 (SCH3), 58.7 (phosphonyl OCH3), 62.7 (ester OCH2),
66.7 (2 × phosphonyl CH2OP), 71.0 (2 × phosphonyl CH2), 106.0 (C=C C-2), 114.7 (CN), 162.1 (C=C
31
C-3), 164.6 (C=O); P-NMR δ: 6.16; IR ν: 2985, 2926, 2212, 1714, 1446, 1367, 1242, 1014 cm-1;
Anal. Calcd. for C13H22NO7PS (367.1): C, 42.50; H, 5.99; N, 3.81. Found: C, 42.45; H, 6.04; N, 3.72.
Ethyl 2-cyano-3-methylthio-3-[di-(2-ethoxyethoxy)phosphonyl]acrylate (2n): yellow liquid; yield
57.6%; 1H-NMR δ: 1.20 (q, 6H, J = 7.1 Hz, 2 × phosphonyl CH3), 1.36~1.38 (m, 3H, ester CH3), 2.78
(d, J=10.8 Hz, 3H, SCH3), 3.52~3.55 (m, 4H, 2 × phosphonyl CH2), 3.65~3.70 (m, 4H, 2 ×
phosphonyl CH2), 4.31~4.40 (m, 6H, 2 x phosphonyl CH2 + ester CH2); 13C-NMR δ: 15.0 (SCH3), 66.5
(ester OCH2), 66.6 (2 × phosphonyl CH2), 66.9 (2 × phosphonyl CH2), 67.0 (2 × phosphonyl CH2),
31
106.0 (C=C C-2), 114.7 (CN), 162.2 (C=C C-3), 165.0 (C=O); P-NMR δ: 5.93; IR ν: 2970, 2868,
2212, 1720, 1446, 1367, 1244, 1016 cm-1; Anal. Calcd. for C15H26NO7PS (395.1): C, 45.56; H, 6.58; N,
3.39. Found: C, 45.51; H, 6.63; N, 3.54.
Ethoxyethyl 2-cyano-3-methylthio-3-[di-(2-methoxyethoxy)phosphoryl]acrylate (2o): yellow liquid;
1
yield 53.5%; H-NMR δ: 1.21 (t, 3H, J = 6.9 Hz, CH3 of ethoxy), 2.77 (d, JPH = 17.0Hz, 3H, SCH3),
3.38 (s, 6H, 2×OCH3), 3.55~3.74 (m, 8H, 2×CH2C-O of phosphonyl + COOCCH2 of ester + CH2 of
13
ethoxy), 4.24~4.41 (m, 6H, 2×CH2O of phosphonyl + COOCH2 of ester); C-NMR δ:15.1 (CH3 of
ethoxy), 19.3 (SCH3), 58.7 (2×OCH3), 59.0 (CH2 of ethoxy), 66.1 (OCH2 of ester), 66.8 (2×CH2O of
phosphonyl), 67.8 (OCCH2 of ester), 71.1 (2×CH2C-O of phosphonyl), 105.7 (C-2 of C=C), 114.6
(CN), 162.1 (C-3 of C=C), 165.0 (C=O); 31P-NMR δ: 6.11; IR ν: 2927, 2214, 1747, 1456, 1371, 1253,
1033 cm-1; Anal. Calcd. for C15H26NO8PS (411.1): C 43.79; H 6.37; N 3.40. Found: C 43.76, H 6.43,
N 3.41.
Ethoxyethyl 2-cyano-3-methylthio-3-[di-(2-ethoxyethoxy)phosphoryl]acrylate (2p): yellow liquid;
yield 56.2%; 1H-NMR δ: 1.21~1.39 (m, 9H, 3×CH3), 2.78 (d, JPH = 17.1 Hz, 3H, SCH3), 3.50-3.59 (m,
6H, 3 × OCH2), 3.63~3.73 (m, 6H, 2 × phosphonyl CH2C-O + ester COOCCH2), 4.27~4.41 (m, 6H, 2
13
× phosphonyl CH2O + ester COOCH2); C-NMR δ: 15.1 (3 × ethoxy CH3), 19.3 (SCH3), 66.5 (3 ×
ethoxy OCH2), 66.8, 67.0 (ester OCH2 + 2 × phosphonyl CH2O), 68.9, 69.0 (ester OCCH2 + 2 ×
phosphonyl CH2C-O), 105.8 (C=C C-2), 114.6 (CN), 162.1 (C=C C-3), 165.1 (C=O); 31P-NMR δ:
6.30; IR ν: 2974, 2214, 1747, 1583, 1485, 1253, 1035 cm-1; Anal. Calcd. for C17H30NO8PS (439.1): C
46.46; H 6.88; N 3.19. Found: C 46.60, H 6.95, N 3.26.
1
Methyl 2-cyano-3-methylthio-3-(diethoxyphosphonyl)acrylate (2q): yellow liquid; yield 61.0%; H-
NMR δ: 1.33~1.45 (m, 6H, 2 × phosphonyl CH3), 2.77 (d, JPH= 13.7 Hz, 3H, SCH3), 3.88 (d, JPH = 7.5
13
Hz, 3H, OCH3), 4.01~4.34 (m, 4H, 2 × phosphonyl CH2); C NMR δ: 16.2 (2 × phosphonyl CH3),
19.5 (SCH3), 53.7 (OCH3), 64.5 (2 × phosphonyl CH2), 105.5 (C=C C-2), 114.6 (CN), 162.6 (C=C
C-3), 165.3 (C=O); 31P-NMR δ: 5.0; IR ν: 2983, 2214, 1749, 1255, 1037 cm-1; Anal. Calcd. for
C10H16NO5PS (293.1): C 40.95, H 5.50, N 4.78. Found: C 40.91, H 5.47, N 4.81.
Methyl 2-cyano-3-methylthio-3-(di-i-propoxyphosphonyl)acrylate (2r): yellow liquid; yield 58.2%; 1H-
NMR δ: 1.35~1.44 (m, 12H, 4 × phosphonyl CH3), 2.74 (d, JPH = 6.9 Hz, 3H, SCH3), 3.87 (d, J = 8.1
Hz, 3H, OCH3), 4.83~4.89 (m, 2H, 2 × phosphonyl CH); 13C-NMR δ: 19.8 (SCH3), 23.9 (4 ×

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Molecules 2007, 12
phosphonyl CH3), 53.7 (OCH3), 74.4 (2 × phosphonyl CH), 106.3 (C=C C-2), 114.9 (CN), 162.7 (C=C
C-3), 166.3 (C=O); 31P-NMR δ: 4.90; IR ν: 2980, 2214, 1753, 1454, 1251, 999 cm-1; Anal. Calcd. for
C12H20NO5PS (335.1): C 44.85, H 6.27, N 4.36. Found: C 44.77, H 6.11, N 4.40.
Methyl 2-cyano-3-methylthio-3-(di-n-propoxyphosphonyl)acrylate (2s): yellow liquid; yield 56.3%;
1H-NMR δ: 0.98~1.00 (m, 6H, 2 × phosphonyl CH3), 1.72~1.80 (m, 4H, 2 × phosphonyl CH2C-O),
2.76 (d, JPH = 4.6 Hz, 3H, SCH3), 3.87 (d, J = 10.3Hz, 3H, OCH3), 3.99~4.21 (m, 4H, 2 × phosphonyl
13
CH2O); C-NMR δ: 10.1 (2 × phosphonyl CH3), 19.6 (SCH3), 23.8 (2 × phosphonyl CH2C-O), 53.8
(OCH3), 70.0 (2 × phosphonyl CH2O), 105.7 (C=C C-2), 114.6 (CN), 162.5 (C=C C-3), 165.4 (C=O);
31P-NMR δ: 5.3; IR ν: 2968, 2214, 1751, 1462, 1253, 1002 cm-1; Anal. Calcd. for C12H20NO5PS
(321.3): C 44.85, H 6.27, N 4.36. Found: C 45.01, H 6.18, N 4.38.
Methyl 2-cyano-3-methylthio-3-(di-n-butoxyphosphonyl)acrylate (2t): yellow liquid; yield 57.3%;
1H-NMR δ: 0.94~0.98 (m, 6H, 2 × phosphonyl CH3), 1.38-1.47 (m, 4H, 2 × phosphonyl CH2CCO),
1.65-1.77 (m, 4H, 2 × phosphonyl CH2CO), 2.75 (d, JPH = 4.6 Hz, 3H, SCH3), 3.87 (d, J = 10.3 Hz, 3H,
OCH3), 4.08~4.25 (m, 2H, 4H, 2 × phosphonyl CH2O); 13C-NMR δ: 13.6 (2 × phosphonyl CH3), 18.7
(2 × phosphonyl CH2CCO), 18.8 (SCH3), 32.2 (2 × phosphonyl CH2C-O), 53.8 (OCH3), 68.2 (2 ×
31
phosphonyl CH2O), 105.6 (C=C C-2), 114.6 (CN), 162.6 (C=C C-3), 165.3 (C=O); P-NMR δ: 5.3;
IR ν: 2960, 2214, 1743, 1462, 1255, 1020 cm-1; Anal. Calcd. for C14H24NO5PS (349.1): C 48.13, H
6.92, N 4.01. Found: C 48.46, H 7.04, N 3.91.
Antifungal bioassay
The antifungal activity of all synthesized compounds were tested against three pathogenic fungi.
namely Fusarium graminearum, Cytospora mandshurica and Fusarium oxysporum, by the poison
plate technique [16]. Compounds were dissolved in DMSO (1 mL) before mixing with potato dextrose
agar (PDA, 90 mL). The final concentration of compounds in the medium were fixed at 50 and 500
µg/mL. All types of fungi were incubated in PDA at 25±1 °C for 4 days to get new mycelium for the
antifungal assays, then a mycelia disk of approximately 4 mm diameter cut from culture medium was
picked up with a sterilized inoculation needle and inoculated in the center of the PDA plate. The
inoculated plates were incubated at 25±1 °C for 5 days. DMSO in sterile distilled water served as
control, while hymexazole severed as positive control. For each treatment, three replicates were
conducted. The radial growth of the fungal colonies were measured and the data were statistically
analyzed. The inhibitory effects of the test compounds on these fungi in vitro were calculated by the
formula I = (C-T/C) x 100, where C represents the diameter of fungi growth on untreated PDA, and T
represents the diameter of fungi on treated PDA while I represents the inhibition rate.
Hyphal morphology of F. oxysporum
Compound 2d (final conc. 100 µg/mL) was added to sterilized Czapek media (0.2 % NaNO3, 0.131
% K2HPO4·3H2O, 0.05 % KCl, 0.05 % MgSO4·7H2O, 0.00183 % FeSO4·7H2O, 3 % sucrose, pH 6.8)
[17] in which F. oxysporum had incubated for a few days. After incubating together at 27 oC for 24 h, it
was observed under microscope (Olympus 800 ×). Acetone (0.5 mL) served as the control.

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Molecules 2007, 12
Antiviral Biological Assays
Purification of tobacco mosaic virus: Using Gooding’s method [18], the upper leaves of Nicotiana
tabacum L inoculated with TMV were selected and were ground in phosphate buffer, then filtered
through double layer pledget. The filtrate was centrifuged at 10,000 g, treated twice with PEG and
centrifuged again. The whole experiment was carried out at 4 °C. Absorbance values were estimated at
0.1%,260nm
1cm
260 nm using an ultraviolet spectrophotometer. Virus concn = (A260 × dilution ratio)/ E
Protective effects of compounds on TMV in vivo: The compound solution was smeared on the left side
while solvent was served as control on the right side of growing Nicotiana tabacum. L leaves of the
same ages. The leaves were then inoculated with the virus after 12 hours. A brush was dipped in
tobacco mosaic virus of 6×10-3 mg/mL to inoculate the leaves, which were previously scattered with
silicon carbide. The leaves were then washed with water and rubbed softly along the nervature once or
twice. The local lesion numbers appearing 3-4 days after inoculation were counted [7]. Three
repetitions were conducted for each compound.
Inactivation effect of compounds on TMV in vivo: The virus was inhibited by mixing with the
compound solution at the same volume for 30 minutes. The mixture was then inoculated on the left
side of the leaves of Nicotiana tabacum. L., while the right side of the leaves was inoculated with the
mixture of solvent and the virus for control. The local lesion numbers were recorded 3-4 days after
inoculation [7]. Three repetitions were conducted for each compound.
Curative effect of compounds on TMV in vivo: Growing leaves of Nicotiana tabacum. L of the same
ages were selected. The tobacco mosaic virus (concentration of 6×10-3mg/mL) was dipped and
inoculated on the whole leaves. Then the leaves were washed with water and dried. The compound
solution was smeared on the left side and the solvent was smeared on the right side for control. The
local lesion numbers were then recorded 3-4 days after inoculation [7]. For each compound, three
repetitions were conducted to ensure the reliability of the results, which were measured according to
the following formula:
av local lesion numbers of control (not treated with compound) − av local lesion numbers smeared with drugs
Inhibition rate (%)=
av local lesion numbers without drugs
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Molecules 2007, 12
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Sample Availability: Samples of the compounds are available from authors.
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