Synthesis and bioactivities of α-aminophosphonate derivatives containing benzothiazole and thiourea moieties

Article abstract of DOI:10.1080/10426507.2011.575422

The synthesis of a series of novel α-aminophosphonate derivatives containing benzothiazole and thiourea moieties from substituted 2-aminobenzothiazoles and synthetic intermediates O,O'-dialkylisothiocyanat- (phenyl)methylphosphonates under microwave irradiation has been demonstrated. Several salient features, such as good to excellent yields, shorter reaction times, milder reaction conditions, and simple purification procedures, make the present synthetic protocol highly attractive to access the title compounds. Bioassays indicated that most of the compounds possessed broad-spectrum insecticidal and antiviral activities against Tobacco Mosaic Virus (TMV) in vivo. Interestingly, in comparison with control insecticide Avermectin, two compounds displayed remarkably high in vitro insecticidal activities against Plutella xylostella. Furthermore, according to the results from preliminary bioassay, all were associated with moderate to good anti-TMV activities. [Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: Tables S1-S4. Figures S1-S52.] Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/10426507.2011.575422

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Synthesis and Bioactivities of α-
Aminophosphonate Derivatives
Containing Benzothiazole and Thiourea
Moieties
Jing-Zi Liu a b , Bao-An Song a , Pinaki S. Bhadury a , De-Yu Hu a &
Song Yang a
a Center for Research and Development of Fine Chemicals, State
Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Guiyang,
People's Republic of China
b Laboratory of Medicinal Chemistry, Zunyi Medical College, Zunyi,
People's Republic of China
Published online: 06 Dec 2011.
To cite this article: Jing-Zi Liu , Bao-An Song , Pinaki S. Bhadury , De-Yu Hu & Song Yang (2012)
Synthesis and Bioactivities of α-Aminophosphonate Derivatives Containing Benzothiazole and
Thiourea Moieties, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:1, 61-70, DOI:
10.1080/10426507.2011.575422
To link to this article: http://dx.doi.org/10.1080/10426507.2011.575422
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Phosphorus, Sulfur, and Silicon, 187:61–70, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.575422
SYNTHESIS AND BIOACTIVITIES
OF α-AMINOPHOSPHONATE DERIVATIVES CONTAINING
BENZOTHIAZOLE AND THIOUREA MOIETIES
Jing-Zi Liu,1,2 Bao-An Song,1 Pinaki S. Bhadury,1 De-Yu Hu,1
and Song Yang1
1Center for Research and Development of Fine Chemicals, State Key Laboratory
Breeding Base of Green Pesticide and Agricultural Bioengineering, Key
Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Guiyang, People’s Republic of China
2Laboratory of Medicinal Chemistry, Zunyi Medical College, Zunyi, People’s
Republic of China
GRAPHICAL ABSTRACT
R
O
N
N (E)
O
R
R
O
S
(E)
O
O
O
O
(E)
N
O
OH
CHO
P
R
· H2O
HP
NH3·H2O
°
°
70 C--75 C
1
2
R
R
R
O
O
P
O
P
Et3N, CS2
O
NH3·H2O
O
O
O
O
P
R
R
R
O
O
NH2
Cl3COCOCCl3, Et2O
NH3· OTs
N=C=S
5a
3
d
4
R1
S
NH2
N
d
S
R1
O
P
S
N
O
R
R
6a
N
H
N
O
H
MW
7a
p
R1 = 6-F, 4-Me, 6-OMe, 6-OEt; R = Et, n-Pr, i-Pr, n-Bu
Abstract The synthesis of a series of novel α-aminophosphonate derivatives containing ben-
zothiazole and thiourea moieties from substituted 2-aminobenzothiazoles and synthetic inter-
mediates O,Oꢁ-dialkylisothiocyanat-(phenyl)methylphosphonates under microwave irradiation
has been demonstrated. Several salient features, such as good to excellent yields, shorter re-
action times, milder reaction conditions, and simple purification procedures, make the present
synthetic protocol highly attractive to access the title compounds. Bioassays indicated that
most of the compounds possessed broad-spectrum insecticidal and antiviral activities against
Received 29 January 2011; accepted 9 May 2011.
We are grateful for the generous financial support received from National Key Program for Basic Research
(Nos. 2010CB126105, 2010CB134504), and National Natural Science Foundation of China (No. 20872021).
Address correspondence to Bao-An Song, Center for Research and Development of Fine Chemicals, State
Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China.
E-mail: songbaoan22@yahoo.com
61

62
JING-ZI LIU ET AL.
Tobacco Mosaic Virus (TMV) in vivo. Interestingly, in comparison with control insecticide
Avermectin, two compounds displayed remarkably high in vitro insecticidal activities against
Plutella xylostella. Furthermore, according to the results from preliminary bioassay, all were
associated with moderate to good anti-TMV activities.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Tables S1–S4. Figures S1–S52.]
Keywords α-Aminophosphonate derivatives; thiourea moiety; benzothiazole moiety; synthe-
sis; microwave irradiation; bioactivity
INTRODUCTION
α-Aminophosphonates, structural analogues to natural amino acids, exhibit diverse
biological activities such as plant virucides,1–3 plant growth regulators, herbicides, fungi-
cides, and antitumor agents. Numerous synthetic studies and bioactivities screening of
α-aminophosphonates analogues were undertaken in recent years to evaluate their suitabil-
ity as antiviral agents of plant virus.4–6
On the other hand, benzothiazoles belong to an important class of heterocyclic com-
pounds due to their diverse medicinal and pesticidal applications. Some commercial dyes,
such as thioflavin, and pharmaceutical drugs, such as riluzole, have benzothiazoles as a
structural modifier. They exhibit broad range of biological activities, such as antibacte-
rial, fungicidal, herbicidal, and anti-HIV7–9 and are often employed as selective antitumor
agents against inter alias breast, ovarian, colon, and renal cell lines.10–12 It is also well
documented in the literature13 that development of suitable synthetic methodologies for
their preparation in pure form has been a topic of great interest in the last 20 years.14–16
In this context, in our previous investigation,17–19 benzothiazole derivatives bearing an
α-aminophosphonate moiety, as demonstrated in the newly designed dufulin(O,Oꢁ-diethyl-
α-(4-methylbenzothiazole-2-ylamino)-(2-fluorophenyl)phosphonate), was proven to be an
effective antiviral agent, which was indeed a breakthrough achieved in this area. The results
showed dufulin-induced pathogenesis-related (PR) gene up-regulation in tobacco and in-
creased the activity of the tobacco defense enzyme and chlorophyll content.18 Plastid–lipid-
associated protein and chloroplast cysteine synthase were also related with SA ssalicylic
acid (SA) content.19 In addition, systemic-acquired resistance (SAR) was activated by SA
signal molecule. Since thioureas and their derivatives are also associated with significant
functional and biological activities and have low toxicity, minimal residues, and impart
special biomimetic effects based on hydrogen bonding, we had earlier prepared these com-
pounds containing a phosphonate moiety to demonstrate their utility as potent antiviral
and antitumor agents.20–22 In view of the growing demand for the development of effec-
tive and environmentally benign antiviral agents to protect crops from the deadly pests
and virus, we envisioned that the introduction of benzothiazole moiety into the parent α-
aminophosphonate scaffold through thioureido unit might lead to the generation of novel
agents with high bioactivities. Unfortunately, conventional nucleophilic addition reactions
designed for this purpose suffer from serious drawbacks such as heating over a long period,
low yields, possible thermal decomposition of desired products, and formation of side reac-
tion products thereby making the separation process extremely troublesome. As application
of microwave energy can accelerate an organic reaction and offers several other advantages

SYNTHESIS OF α-AMINOPHOSPHONATE DERIVATIVES
63
over conventional techniques,23 herein we undertook the synthesis of the title compounds
under microwave irradiation for shortening reaction times and improving reaction yields.
The test result indicated that microwave irradiation could enhance the reaction rate and
yield compared to the conventional mode. The structures of compounds 7a–p were firmly
established by IR, 1H, 13C, 19F, and 31P-NMR and elemental analysis. Preliminary bioassay
tests showed that the anti-PC3 cells activities of title compounds were low (8.5%–41.5%),
but some of the synthesized compounds displayed excellent insecticidal and good antiviral
activities against Tobacco Mosaic Virus (TMV) in vivo. To the best of our knowledge,
this is the first report on the synthesis, insecticidal, and anti-TMV bioactivities of title
compounds.
RESULTS AND DISCUSSION
We synthesized novel α-aminophosphonate derivatives 7a–p containing benzothia-
zole and thiourea moieties by reacting substituted aminobenzothiazoles 6a–d with O,Oꢁ-
dialkylisothiocyanato(phenyl)methylphosphonates 5a–d, which were obtained through
multistep synthesis as shown in Scheme 1. The microwave reaction conditions for the
final step leading to the synthesis of title compounds were optimized for various reaction
parameters, for example, temperature, reaction time, and power input, by taking 7a as the
model. According to the test results, the reaction time was considerably shortened from 24
h to 30 min and the yields were increased from 19.3%–46.6% to 40.2%–81.4% when the
reaction was switched to microwave irradiation mode from conventional heating. Under
optimized conditions, the products were obtained in dry CH3CN at a reaction temperature
of 90 ◦C, and a reaction time of 30 min with a power input of 120 W.
R
O
N
N (E)
O
R
R
O
S
(E)
O
O
O
O
(E)
N
O
OH
CHO
P
R
· H2
O
HP
NH3·H2
O
°
°
70 C--75 C
1
2
R
R
R
O
O
P
O
P
Et3N, CS2
O
O
R
O
NH3·H2O
O
O
P
R
R
O
O
NH2
Cl3COCOCCl3, Et2
O
NH3· OTs
N=C=S
5a
3
d
4
R1
S
NH2
N
d
R1
S
O
P
S
N
O
R
R
6a
N
H
N
O
H
MW
7a
p
R1 = 6-F, 4-Me, 6-OMe, 6-OEt; R = Et, n-Pr, i-Pr, n-Bu
Compd.
7a
R1
R
Compd.
R1
R
Compd.
6-F
6-F
6-F
6-F
Et
7e
7f
4-CH3
4-CH3
4-CH3
4-CH3
Et
7i
7b
n-Pr
i-Pr
n-Bu
n-Pr
i-Pr
n-Bu
7j
7k
7l
7c
7g
7h
7d
Scheme 1 Intermediate α-aminophosphonate 4 was prepared according to the procedure in the literature.28
The screening and optimization of reaction conditions under Microwave assisted and the synthetic results for
compounds 7a–p are provided in the Supporting Materials (available online).
All of the products were unequivocally characterized by Infrared (IR) and nuclear
magnetic resonance (NMR) spectral data and elemental analysis. The characteristic IR
absorption bands for N-H (3142–3291, s cm−1), C S (1337–1355 cm−1), P O (1202–1265
cm−1), and P O C (1010–1059 cm−1) confirmed the presence of the respective functional

64
JING-ZI LIU ET AL.
groups. In 1H NMR spectra, all aromatic protons revealed the expected multiple near δH =
6.95–7.72 ppm. The N–H protons of compounds 7a–p appeared weak peaks considerably
downfield in the region of δH = 9.42–12.48 ppm due to the existence of hydrogen bonding
with the thioureido moiety. The chemical shift of PCH appeared near δH = 6.19–6.28 ppm
range as a doublet of doublets due to the presence of CH moiety adjacent to a phosphorus
atom. The chemical shifts of OCH2 generally appeared in the region of δH = 3.45–5.02
ppm. The 31P NMR spectral data showed the presence of a phosphorus atom and appeared
around δP = 19.5–22.3 ppm as singlet or doublets. The fluorine resonance appeared at
δF = 118.2–118.6 ppm in the corresponding fluorine NMR spectra. All the nonequivalent
carbon atoms were identified in 13C NMR, and the typical low intense carbon resonance
frequencies at δC = 178.4–183.0 ppm in the 13C NMR spectra of 7a–p also confirmed the
presence of C S double bond.
Antiviral Activity
Antiviral activities of 7a–p were investigated. The results obtained for anti-TMV
activities are given in Table 1. Ningnanmycin was used as the reference antiviral agent. The
data provided in Table 1 indicate that the title compounds 7a–p showed curative rates of
29.5%–52.9%. The compounds 7a, 7c, 7e, 7f, 7i, 7j, and 7n displayed moderate curative
bioactivities of up to 43.8%, 46.6%, 45.7%, 42.8%, 44.9%, 41.4%, and 43.1%, respectively,
against TMV at 500 µg/mL. The compound 7b (R1 = F, R = n-Pr) exhibited similar curative
activity (52.9%) as that of the standard reference (55.4%), but the rest of the compounds
revealed relatively lower curative activities. These data also indicate that these changes as
a substituent on the aryl and phosphite moieties can affect the curative activity of 7a–p. In
general, as expected, the aminophosphonate derivatives incorporating benzothiazole and
thiourea moieties also provided good antiviral activities.
Insecticidal Activity
The insecticidal activity results of title compounds 7a–p against Plutella xylostella
are given in Table 2. Avermectin was used as the reference insecticidal agent. The data in
Table 2 indicate that compounds 7a–p displayed moderate to good insecticidal bioactivities
(corrected mortality of 43%–84%) at 100 µg/mL. The corrected mortalities of compounds
7b (R1 = F, R = n-Pr) and 7l (R1 = OMe, R = n-Bu) at 84% and 78%, respectively, at
100 µg/mL have similar effect as the control drug avermectin (corrected mortality 82%).
Table 1 Curative effect of the new compounds 7a–p against TMV in vivo
Compd.
Concn. (µg/mL)
Curative effect (%)
Compd.
Concn. (µg/mL)
Curative effect (%)
7a
7b
7c
7d
7e
7f
7g
7h
500
500
500
500
500
500
500
500
500
43.8
52.9
46.6
33.4
45.7
42.8
31.8
37.5
55.4
7i
7j
7k
7l
7m
7n
7o
7p
500
500
500
500
500
500
500
500
44.9
41.4
32.1
29.5
32.8
43.1
35.9
34.6
Ningnamycin

SYNTHESIS OF α-AMINOPHOSPHONATE DERIVATIVES
65
Table 2 Insecticidal activity of compounds 7a–p against Plutella Xylostella at 100 µg/mL
Compd.
Mortality (%) Corrected mortality (%) Compd. Mortality (%) Corrected mortality (%)
7a
7b
7c
7d
7e
7f
7g
7h
69
85
74
56
52
56
45
49
5
67
84
71
55
51
53
43
48
–
7i
7j
7k
7l
7m
7n
7o
7p
65
70
59
80
58
61
54
68
64
68
57
78
56
60
52
66
ck
Avermectin
83
82
It was found that most of title compounds possessed broad-spectrum insecticidal
and antiviral activities against TMV in vivo. These results are promising, the syntheses
are original and well conducted, and biological activities are very interesting. Especially,
compound 7b (R1 = F, R = n-Pr) with both good insecticidal (the corrected mortalities is
84% at 100 µg/mL) and anti-TMV (the curative effect is 52.9% at 500 µg/mL) bioactivities,
is valuable for further research and development.
EXPERIMENTAL
The melting points of the products were determined on a XT-4 binocular microscope
(Beijing Tech Instrument Co., China) and were not corrected. The IR spectra were recorded
on a Bruker VECTOR 22 spectrometer in KBr disks. 1H, 13C, 31P, and 19F NMR (solvent
CDCl3) spectra were performed on a JEOL-ECX 500 NMR spectrometer at room temper-
ature using TMS as 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.
Preparation of Intermediate 5
According to the procedure given in literature,21 the key intermediate O,Oꢁ-
dialkylisothio-cyanato(phenyl)methylphosphonate 5 was prepared in 67.4%–78.6% yield
by the reaction of 4 bearing different alkyl substituents with bis(trichloromethyl)carbonate
(BTC) as shown in Scheme 1.
Preparation of Title Compounds 7a–p Under Conventional
Heating Mode
A mixture of substituted 2-aminobenzothiazole 6a–d (1.0 mmol), tetrabutyl am-
monium bromide (1.0 mmol), and O,Oꢁ-dialkylisothiocyanato(phenyl)methylphos phonate
◦
5a–d (2 mmol) in dry acetonitrile (10 mL) was refluxed and stirred at 80 C for 24 h.
The progress of the reaction was monitored by TLC, the solvent was removed by evapora-
tion, and the crude product was purified by thin-layer chromatography using a mixture of
dichloromethane, acetic ether, and n-hexane (V/V/V = 4:1:2) as developing solvent to give
the title compounds 7a–p.

66
JING-ZI LIU ET AL.
Microwave-Aassisted Preparation of Title Compounds 7a–p
A mixture of substituted 2-aminobenzothiazole 6a–d (1.0 mmol) and O,Oꢁ-dialkyl
isothiocyanato(phenyl)methylphosphonate 5a–d (2 mmol) in dry acetonitrile (5 mL) was
transferred in a microwave tube, which was then sealed and placed under a pressurized
atmosphere inside the Discovery Synthesizer and subjected to microwave irradiation at 120
◦
W for 30 min at a temperature of 90 C. Upon completion of the reaction, the solvent
was removed under reduced pressure and the crude product was purified by thin-layer
chromatography using a mixture of dichloromethane, acetic ether, and n-hexane (V/V/V =
4:1:2) as a developing solvent to give the title compounds 7a–p in 40.2%–81.4% yields.
O,Oꢀ-Diethyl (3-(6-fluorobenzo[d]thiazol-2-yl)thioureido)(phenyl)methyl
◦
phosphonate (7a). White solid, mp = 215–216 C; yield 71.3%; IR (ν cm−1): 3279,
3142 (NH), 2974, 1609, 1534, 1458, 1342 (C S), 1244 (P O), 1110, 1022(P O C),
698; 1H NMR (500 MHz, CDCl3): δ 7.55–7.07 (m, 8H, Ar–H), 6.23 (dd, 1H, J = 9.20 Hz,
NCH-P), 4.26–3.90 (m, 4H, 2OCH2), 1.37, 1.21 (t, 6H, J = 6.8 Hz, 2CH3); 13C NMR (125
MHz, CDCl3): δ = 179.2, 172.2, 160.3, 145.2, 134.1, 128.8, 128.3, 128.1, 120.9, 114.1,
107.6, 64.1, 54.3, 16.3; 31P NMR (200 MHz, CDCl3): δ = 22.3; 19F NMR: δ = −118.2
ppm; Anal. Calcd. for C19H21FN3O3PS2 (453): C, 50.32; H, 4.67; N, 9.27. Found: C, 50.11;
H, 4.76; N, 9.48.
O,Oꢀ-Dipropyl (3-(6-fluorobenzo[d]thiazol-2-yl)thioureido)(phenyl)methy
lphosphonate (7b). White solid, mp = 206–207 ◦C; yield 53.8%; IR (ν cm−1): 3260,
3150 (NH), 2968, 1611, 1547, 1458, 1355 (C S), 1217 (P O), 1013 (P O C), 696; 1H
NMR (500 MHz, CDCl3): δ = 11.29 (s, 1H, N-H), 9.49 (s, 1H, N-H), 7.65–7.06 (m, 8H,
Ar H), 6.28 (dd, 1H, J = 8.60 Hz, NCH-P), 4.19–3.80 (m, 4H, 2OCH2), 1.72–1.58 (m, 4H,
2CH2), 0.93, 0.84 (t, 6H, J = 5.75 Hz, 2CH3); 13C NMR (125 MHz, CDCl3): δ = 179.3,
160.4, 158.5, 145.2, 134.3, 132.4, 128.8, 128.5, 121.1, 114.1, 107.4, 69.6, 55.4, 24.1, 9.8;
31P NMR (200 MHz, CDCl3): δ = 22.1; 19F NMR: δ = −118.6 ppm; Anal. Calcd. for
C21H25FN3O3PS2 (481): C, 52.38; H, 5.23; N, 8.73. Found: C, 52.49; H, 5.51; N, 8.52.
O,Oꢀ-Diisopropyl
(3-(6-fluorobenzo[d]thiazol-2-yl)thioureido)(phenyl)
◦
methylphosphonate (7c). White solid, mp = 232–233 C; yield = 67.2%; IR (ν
cm−1): 3269 (NH), 2976, 1610, 1541, 1456, 1242, 1204 (P=O), 1103, 1011(P O C),
1
851, 696; H NMR (500 MHz, CDCl3): δ = 11.43 (s, 1H, N-H), 9.42 (s, 1H, N-H),
7.72–7.01 (m, 8H, Ar-H), 6.23 (dd, 1H, J = 8.55 Hz, NCH-P), 5.02–4.92 (m, 2H, 2OCH),
1.35, 0.88 (d, 12H, J = 26.35 Hz, 4CH3); 13C NMR (125 MHz, CDCl3): δ = 179.3,
160.3, 158.2, 145.2, 134.4, 128.6, 128.4, 127.6, 121.3, 114.0, 107.5, 73.6, 55.6, 24.3;
31P NMR (200 MHz, CDCl3): δ = 20.7; 19F NMR: δ = −118.4 ppm; Anal. Calcd. for
C21H25FN3O3PS2 (481): C, 52.38; H, 5.23; N, 8.73. Found: C, 52.55; H, 5.41; N, 8.49.
O,Oꢀ-Dibutyl (3-(6-fluorobenzo[d]thiazol-2-yl)thioureido)(phenyl)methyl
phosphonate (7d). White solid, mp = 123–125 ◦C; yield = 48.9%; IR (ν cm−1): 3291
(NH), 2959, 1609, 1528, 1456, 1442, 1346 (C S), 1192 (P O), 1028 (P O C), 694;
1H NMR (500 MHz, CDCl3): δ = 7.56–7.07 (m, 8H, ArH), 6.24 (dd, 1H, J = 9.15 Hz,
NCH-P), 4.21–3.86 (m, 4H, 2OCH2), 1.70–1.26 (m, 8H, 2CH2CH2), 0.85 (t, 6H, J = 8.0
Hz, 2CH3); 13C NMR (125 MHz, CDCl3): δ = 179.2, 160.4, 158.5, 144.9, 134.3, 129.0,
128.8, 128.5, 128.1, 121.1, 113.7, 107.7, 67.9, 65.9, 32.6, 18.8, 13.6; 31P NMR (200 MHz,
CDCl3): δ = 22.4; 19F NMR: δ = −118.4 ppm; Anal. Calcd. for C23H29FN3O3PS2 (509):
C, 54.21; H, 5.74; N, 8.25. Found: C, 54.53; H, 5.38; N, 8.51.
O,Oꢀ-Diethyl (3-(4-methylbenzo[d]thiazol-2-yl)thioureido)(phenyl)methyl
◦
phosphonate (7e). White solid, mp = 204–205 C; yield 55.7%; IR (ν cm−1): 3260

SYNTHESIS OF α-AMINOPHOSPHONATE DERIVATIVES
67
(NH), 2920, 1597, 1541, 1456, 1350 (C S), 1238, 1207 (P O), 1015 (P O C), 696; 1H
NMR (500 MHz, CDCl3): δ = 12.43 (br, s, 1H, NH), 10.46 (br, s, 1H, NH), 7.58–7.19
(m, 8H, ArH), 6.25 (dd, 1H, J = 8.60 Hz, NCH-P), 4.14–3.93 (m, 4H, 2OCH2), 2.73 (br,
s, 3H, ArCH3), 1.28, 1.15 (t, 6H, J = 7.15 Hz, 2CH3); 13C NMR (125 MHz, CDCl3):
δ = 178.4, 159.6, 146.5, 134.4, 130.6, 128.6, 127.3, 124.4, 118.3, 63.3, 54.0, 18.5, 16.1;
31P NMR (200 MHz, CDCl3): δ = 20.9 ppm; Anal. Calcd. for C20H24N3O3PS2 (449): C,
53.44; H, 5.38; N, 9.35. Found: C, 53.49; H, 5.62; N, 9.71.
O,Oꢀ-Dipropyl (3-(4-methylbenzo[d]thiazol-2-yl)thioureido)(phenyl)meth
ylphosphonate (7f). White solid, mp = 180–182 ◦C; yield 46.5%; IR (ν cm−1): 3265
(NH), 2968, 1598, 1543, 1352 (C S), 1206 (P O), 1013 (P O C), 698; 1H NMR (500
MHz, CDCl3): δ = 12.45 (br, s, 1H, N-H), 10.73 (br, s, 1H, N-H), 7.60–7.17 (m, 8H,
ArH), 6.28 (dd, 1H, J = 8.05 Hz, NCH-P), 4.02–3.81 (m, 4H, 2OCH2), 2.72 (br, s, 3H,
ArCH3), 1.65–1.52 (m, 4H, 2CH2), 0.87, 0.78 (t, 6H, J = 7.45 Hz, 2CH3); 13C NMR (125
MHz, CDCl3): δ = 178.7, 159.2, 148.1, 134.5, 130.7, 129.8, 128.8, 127.3, 124.3, 118.4,
68.7, 55.9, 24.0, 18.3, 10.2; 31P NMR (200 MHz, CDCl3): δ = 20.7 ppm; Anal. Calcd. for
C22H28N3O3PS2 (447): C, 55.33; H, 5.91; N, 8.80. Found: C, 55.42; H, 5.63; N, 8.89.
O,Oꢀ-Diisopropyl (3-(4-methylbenzo[d]thiazol-2-yl)thioureido)(phenyl)
methylphosphonate (7g). White solid, mp = 236–237 ◦C; yield 52.8%; IR (ν cm−1):
1
3262 (NH), 2978, 1543, 1356, 1219 (P O), 1018 (P O C), 698; H NMR (500 MHz,
CDCl3): δ = 12.36 (br, s, 1H, N-H), 10.60 (br, s, 1H, N-H), 7.59–7.17 (m, 8H, ArH),
6.22 (s, 1H, NCH-P), 4.77–4.60 (m, 2H, 2OCH), 2.76–2.52 (m, 3H, ArCH3), 1.31, 0.96
(d, 12H, J = 6.35 Hz, 4CH3); 13C NMR (125 MHz, CDCl3): δ = 178.6, 171.0, 148.5,
134.6, 130.9, 128.9, 127.2, 126.8, 124.4, 118.5, 72.3, 57.9, 24.2, 18.5; 31P NMR (200
MHz, CDCl3): δ = 19.5 ppm; Anal. Calcd. for C22H28N3O3PS2 (477): C, 55.33; H, 5.91;
N, 8.80. Found: C, 55.28; H, 5.77; N, 8.65.
O,Oꢀ-Dibutyl (3-(4-methylbenzo[d]thiazol-2-yl)thioureido)(phenyl)meth
ylphosphonate (7h). White solid, mp = 134–136 ◦C; yield 40.2%; IR (ν cm−1): 3267,
3159 (NH), 2959, 1599, 1541, 1458, 1352 (C S), 1203 (P O), 1026 (P O C), 698; 1H
NMR (500 MHz, CDCl3): δ = 12.48 (br, s, 1H, N-H), 11.02 (br, s, 1H, N-H), 7.61–7.17 (m,
8H, ArH), 6.28 (dd, 1H, J = 8.60 Hz, NCH-P), 4.08–3.86 (m, 4H, 2OCH2), 2.73 (s, 3H,
ArCH3), 1.61–1.22 (m, 8H, 2CH2CH2), 0.79 (t, 6H, J = 7.35 Hz, 2CH3); 13C NMR (125
MHz, CDCl3): δ = 178.8, 159.7, 148.7, 134.3, 130.8, 128.6, 128.6, 127.3, 124.1, 118.6,
67.4, 56.1, 32.4, 19.0, 18.4, 13.5; 31P NMR (200 MHz, CDCl3) δ = 21.1 ppm; Anal. Calcd.
for C24H32N3O3PS2 (505): C, 57.01; H, 6.38; N, 8.31. Found: C, 57.34; H, 6.08; N, 8.52.
O,Oꢀ-Diethyl (3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)me
thylphosphonate (7i). White solid, mp = 195–196 ◦C; yield 74.6%; IR (ν cm−1): 3285
(NH), 2970, 2890, 1610, 1541, 1462, 1337 (C S), 1265, 1202 (P O), 1020 (P O C),
1
696; H NMR (500 MHz, CDCl3): δ = 7.55–6.96 (m, 8H, ArH), 6.21 (dd, 1H, J = 9.15
Hz, NCH-P), 4.21–3.92 (m, 4H, 2OCH2), 3.83 (s, 3H, OCH3), 1.34, 1.19 (t, 6H, J = 7.45
Hz, 2CH3); 13C NMR (125 MHz, CDCl3): δ = 179.0, 173.6, 157.0, 142.1, 134.3, 128.8,
128.4, 124.6, 120.9, 114.9, 104.5, 63.9, 55.9, 54.5, 16.4; 31P NMR (200 MHz, CDCl3):
δ = 21.5 ppm; Anal. Calcd. for C20H24N3O4PS2 (465): C, 51.60; H, 5.20; N, 9.03. Found:
C, 51.24; H, 5.45; N, 9.33.
O,Oꢀ-Dipropyl
(3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)
methylphosphonate (7j). White solid, mp = 202–204 ◦C; yield 69.1%; IR (ν cm−1):
3161 (NH), 2966, 1602, 1552, 1472, 1354 (C S), 1226, 1147 (P O), 1056 (P O C),
1
997, 822, 694; H NMR (500 MHz, CDCl3): δ = 7.56–6.95 (m, 8H, Ar-H), 6.27 (dd,

68
JING-ZI LIU ET AL.
1H, J = 9.20 Hz, NCH-P), 4.13–3.85 (m, 4H, 2OCH2), 3.83 (s, 3H, OCH3),1.71–1.58
(m, 4H, 2CH2), 0.92, 0.84 (t, 6H, J = 7.45 Hz, 2CH3); 13C NMR (125 MHz, CDCl3):
δ = 178.7, 171.3, 156.59, 143.2, 134.3, 129.0, 128.6, 128.4, 128.0, 121.1, 114.9, 104.4,
69.3, 60.3, 55.8, 24.1, 10.0; 31P NMR (200 MHz, CDCl3): δ = 21.9 ppm; Anal. Calcd. for
C22H28N3O4PS2 (493): C, 53.53; H, 5.72; N, 8.51. Found: C, 53.29; H, 5.56; N, 8.84.
O,Oꢀ-Diisopropyl (3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)
methylphosphonate (7k). White solid, mp = 216–218 ◦C; yield 77.2%; IR (ν cm−1):
3163 (NH), 2976, 2830, 1603, 1552, 1472, 1339 (C S), 1265, 1225, 1148 (P O), 1059
1
(P O C), 984, 696; H NMR (500 MHz, CDCl3): δ = 7.72–6.95 (m, 8H, Ar-H), 6.19
(dd, 1H, J = 8.05 Hz, NCH-P), 4.87 (br, s, 2H, 2OCH), 3.83 (s, 3H, OCH3), 1.37, 0.92 (d,
12H, J = 6.30 Hz, 4CH3); 13C NMR (125 MHz, CDCl3): δ = 178.9, 158.7, 156.5, 143.1,
134.6, 129.0, 128.7, 128.1, 121.1, 114.7, 104.4, 73.4, 60.4, 55.8, 24.1; 31P NMR (200 MHz,
CDCl3): δ = 20.5 ppm; Anal. Calcd. for C22H28N3O4PS2 (493): C, 53.53; H, 5.72; N, 8.51.
Found: C, 53.24; H, 5.85; N, 8.44.
O,Oꢀ-Dibutyl
(3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)
methylphosphonate (7l). White solid, mp = 161–162 ◦C, yield 62.6%; IR (ν cm−1):
3258 (NH), 2957, 1609, 1551, 1466, 1354 (C S), 1265, 1213 (P O), 1028 (P O C),
827; 1H NMR (500 MHz, CDCl3): δ = 7.55–6.96 (m, 8H, Ar-H), 6.23 (dd, 1H, J = 6.85
Hz, NCH-P), 4.14 (br, s, 3H, OCH3), 3.88–3.83 (m, 4H, 2OCH2), 1.65–1.25 (m, 8H,
2CH2CH2), 0.83 (t, 6H, J = 7.45 Hz, 2CH3); 13C NMR (125 MHz, CDCl3): δ = 179.0,
158.7, 156.8, 143.4, 134.4, 128.8, 128.5, 121.1, 114.7, 104.4, 67.6, 61.0, 55.9, 32.4, 18.8,
13.7; 31P NMR (200 MHz, CDCl3): δ = 21.7 ppm; Anal. Calcd. for C24H32N3O4PS2
(521): C, 55.26; H, 6.18; N, 8.06. Found: C, 55.01; H, 6.39; N, 7.95.
O,Oꢀ-Diethyl (3-(6-ethoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)meth
ylphosphonate (7m). White solid, mp = 189–190 ◦C; yield 81.4%; IR (ν cm−1): 3265,
3146 (NH), 2978, 1607, 1541, 1458, 1352 (C S), 1204 (P O), 1022 (P O C), 827,
696; 1H NMR (500 MHz, CDCl3): δ = 7.55–6.95 (m, 8H, Ar-H), 6.23 (dd, 1H, J = 9.75
Hz, NCH-P), 4.21–4.04 (m, 6H, 3OCH2), 1.43, 1.21 (t, 9H, J = 7.45 Hz, 3CH3); 13C
NMR (125 MHz, CDCl3): δ = 183.0, 170.8, 155.9, 134.3, 128.8, 128.4, 120.9, 115.4,
105.2, 64.2, 60.5, 55.1, 14.9; 31P NMR (200 MHz, CDCl3): δ = 21.5 ppm; Anal. Calcd.
for C21H26N3O4PS2 (479): C, 52.60; H, 5.46; N, 8.76. Found: C, 52.73; H, 5.11; N, 8.49.
O,Oꢀ-Dipropyl (3-(6-ethoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)meth
ylphosphonate (7n). White solid, mp = 162–164 ◦C; yield 70.3%; IR (ν cm−1): 3269
(NH), 2970, 1607, 1545, 1460, 1353 (C S), 1263, 1207 (P O), 1061, 1013 (P O C),
696; 1H NMR (500 MHz, CDCl3): δ = 7.55–6.95 (m, 8H, Ar-H), 6.24 (dd, 1H, J = 8.60
Hz, NCH-P), 4.12–3.45 (m, 6H, 3OCH2), 1.71–1.55 (m, 4H, 2CH2), 1.44 (t, 3H, J =
6.90 Hz, CH3), 0.82 (t, 6H, J = 7.45 Hz, 2CH3); 13C NMR (125 MHz, CDCl3): δ =
178.8, 158.5, 156.0, 143.2, 134.3, 128.8, 128.4, 128.0, 121.1, 115.3, 105.1, 69.2, 65.9,
63.9, 55.3, 24.0, 14.7, 9.8; 31P NMR (200 MHz, CDCl3): δ = 21.5 ppm; Anal. Calcd. for
C23H30N3O4PS2 (507): C, 54.42; H, 5.96; N, 8.28. Found: C, 54.56; H, 5.73; N, 8.45.
O,Oꢀ-Diisopropyl (3-(6-ethoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)
methylphosphonate (7o). White solid, mp = 220–221 ◦C; yield 75.9%; IR (ν cm−1):
3275 (NH), 2978, 1611, 1533, 1460, 1342 (C S), 1265, 1225, 1198 (P O), 1063, 1010
1
(P O C), 696; H NMR (500 MHz, CDCl3): δ = 7.57–6.95 (m, 8H, Ar-H), 6.21 (dd,
1H, J = 6.85 Hz, NCH-P), 4.88 (s, 2H, OCH), 4.05 (q, 2H, J = 6.90 Hz, OCH2), 1.43
(t, 3H, J = 6.85 Hz, CH3), 1.37 (d, 12H, J = 5.15 Hz, 4CH3); 13C NMR (125 MHz,
CDCl3): δ = 179.0, 158.5, 155.9, 142.9, 134.6, 129.0, 128.4, 128.1, 121.0, 115.1, 105.2,

SYNTHESIS OF α-AMINOPHOSPHONATE DERIVATIVES
69
73.1, 64.1, 56.1, 24.4, 14.9; 31P NMR (200 MHz, CDCl3): δ = 20.5 ppm; Anal. Calcd. for
C23H30N3O4PS2 (507): C, 54.42; H, 5.96; N, 8.28. Found: C, 54.61; H, 5.65; N, 8.57.
O,Oꢀ-Dibutyl (3-(6-ethoxybenzo[d]thiazol-2-yl)thioureido)(phenyl)meth
ylphosphonate (7p). White solid, mp = 110–112 ◦C; yield 65.2%; IR (ν cm−1): 3265
1
(NH), 2959, 1607, 1545, 1460, 1263, 1211 (P O), 1061, 1028 (P O C), 814, 696; H
NMR (500 MHz, CDCl3): δ = 7.55–6.95 (m, 8H, Ar-H), 6.25 (dd, 1H, J = 9.15 Hz,
NCH-P), 4.13–3.45 (m, 6H, 3OCH2), 1.64–1.24 (m, 8H, 2CH2CH2), 1.42 (t, 3H, J = 6.85
Hz, CH3), 0.83 (t, 6H, J = 7.45 Hz, 2CH3); 13C NMR (125 MHz, CDCl3): δ = 178.9,
173.6, 156.2, 143.1, 134.3, 128.9, 128.7, 128.2, 127.8, 120.7, 115.3, 105.0, 67.6, 64.0,
54.3, 32.6, 18.6, 14.7, 13.2; 31P NMR (200 MHz, CDCl3): δ = 21.5 ppm; Anal. Calcd. for
C25H34N3O4PS2 (535): C, 56.06; H, 6.40; N, 7.84. Found: C, 56.12; H, 6.54; N, 7.61.
Antiviral Activity Assay
Purification of TMV. Using Gooding’s method,24 the upper leaves of Nicotiana
tabacum L. inoculated with TMV were selected and grounded in phosphate buffer and
then filtered through double-layer pledget. The filtrate was centrifuged at 10,000 g, trea◦ted
twice with PEG, and centrifuged again. The whole experiment was carried out at 4 C.
Absorbance values were estimated at 260 nm using an ultraviolet (UV) spectrophotometer.
virus concn. = (A260 × dilution ratio)/E10.c1m% 260 nm
.
Curative effect of compounds against TMV in vivo. Growing leaves of N. tabacum L.
of the same ages were selected. The TMV (with a concentration of 6 × 10−3 mg/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 counted and recorded
3–4 days after inoculation.25 For each compound, three repetitions were measured. The
inhibition rate of the compound was then calculated according to the following formula
(average: “av”):
Inhibition rate (%) =
Av. local lesion numbers of control (not treated with compound)−av. local lesion numbers smeared with drugs
× 100.
Av. local lesion numbers of control (not treated with compound)
(1)
Insecticidal Activity Assay
Insecticidal activities against Plutella xylostella of the title compounds 7a–p and
the control drug avermectin were tested by the leaf-dip method using the reported pro-
cedure.26,27 The solution for each test sample was prepared in dimethylformamide at a
concentration of 100 µg/mL. Leaf disks (6 cm × 2 cm) were cut from fresh cabbage
leaves and dipped into the test solution for 5 s. After air-drying, the treated leaf disks were
placed individually into glass tubes. Each dried and treated leaf disk was infested with 10
third-instar Plutella xylostella larvae. Percentage mortalities were evaluated 3 days after the
treatment. Leaves treated with water and dimethylformamide were provided as controls.
Each treatment was performed thrice.

70
JING-ZI LIU ET AL.
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