Design, synthesis, and antiviral activity of α-aminophosphonates bearing a benzothiophene moiety

Article abstract of DOI:10.1080/10426507.2013.829837

A series of α-aminophosphonates containing a benzothiophene moiety was designed and synthesized. All synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, ³¹P NMR, infrared spectroscopy, and elemental analysis. The half-leaf method was used to determine the in vivo efficacy of α-aminophosphonates bearing a benzothiophene moiety against the tobacco mosaic virus (TMV). Bioassay results showed that all compounds exhibited certain anti-TMV activity at 500 μg/mL concentration. Compound 2f exhibited a curative effect of up to 48.1% against TMV, which was almost similar to that obtained from the standard ningnanmycin (51.9%). [Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures, and tables.]

Full text of DOI:10.1080/10426507.2013.829837

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Phosphorus, Sulfur, and Silicon and the Related
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Design, Synthesis, and Antiviral Activity of α-
Aminophosphonates Bearing a Benzothiophene moiety
Peiwei Zhang a , Chenghao Tang a , Zhiwei Chen a , Bo Wang a , Xiang Wang a , Linhong Jin a ,
Song Yang a & Deyu Hu a
a 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 , P. R. China
Accepted author version posted online: 23 Sep 2013.
To cite this article: Phosphorus, Sulfur, and Silicon and the Related Elements (2013): Design, Synthesis, and Antiviral Activity
of α-Aminophosphonates Bearing a Benzothiophene moiety, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2013.829837
To link to this article: http://dx.doi.org/10.1080/10426507.2013.829837
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Design, Synthesis, and Antiviral Activity of α-Aminophosphonates Bearing a
Benzothiophene moiety
Peiwei Zhang, Chenghao Tang, Zhiwei Chen, Bo Wang, Xiang Wang, Linhong Jin, Song Yang,
Deyu Hu*
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, P. R. China
E-Mails:zhangpeiwei880511@163.com(P.W.Z.);chtang1122@163.com(C.H.T);yan.zhilie(Z.W.
C);youxihema@gmail.com(B.W);Wangx8887256@163.com(X.W);fcc.jinlh@gzu.edu.cn(L.H.J.
); fcc.syang@gzu.edu.cn(S.Y.)
* Author to whom correspondence should be addressed; E-Mails: fcc.dyhu@gzu.edu.cn; Tel.:
+86-851-829-2170; Fax: +86-851-829-2170.
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Abstract
A series of α-aminophosphonates containing a benzothiophene moiety was designed and
synthesized. All synthesized compounds were confirmed by 1H NMR, 13C NMR, 31P NMR,
infrared spectroscopy, and elemental analysis. The half-leaf method was used to determine the in
vivo efficacy of α-aminophosphonates bearing a benzothiophene moiety against the tobacco
mosaic virus (TMV). Bioassay results showed that all compounds exhibited certain anti-TMV
activity at 500 µg/mL concentration. Compound 2f exhibited a curative effect of up to 48.1%
against TMV, which was almost similar to that obtained from the standard ningnanmycin (51.9%).
[Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental
files: Additional text, figures, and tables.]
Keywords: α-aminophosphonate, benzothiophene moiety, synthesis, tobacco mosaic virus,
anti-TMV activity.
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Introduction
Plant viruses bring about various detrimental effects on agriculture and horticulture [1]. Tobacco
mosaic virus (TMV), one of the most prevalent plant viruses in the world, is known to infect more
than 400 plant species belonging to 36 families, such as tobacco, tomato, potato, cucumber, and
several ornamental flowers. TMV can change plant phenotypes by destroying mitochondria and
thus impair plant quality. In some fields, nearly 90% to 100% of plants manifest mosaic or leaf
necrosis at harvest. Effectively controlling TMV remains a challenge. No chemical treatment
completely protects plants from TMV infection or eliminates TMV from infected plant tissues
under field conditions. Given the unsatisfactory cure rate (30% to 60%) of common antiviral
agents (e.g., Ningnanmycin and Ribavirin; Figure 1) and the associated huge economic losses of
tobacco companies, this plant virus is named “plant cancer” [2–4].
[Insert Figure 1]
Perhaps the most successful registered anti-plant viral agent, ningnanmycin (Figure 1) produces
a 51.9% in vivo curative effect at 500 µg/mL. Ningnanmycin is a microbial pesticide that destroys
the protein coat of TMV and builds plant host resistance. However, the use of ningnanmycin in
field trials is heavily limited by its photosensitivity and water stickiness. It has been reported that
many chemicals such as pyrazole derivatives [5,6], nucleotides [7], α-aminophosphonate
derivatives [8,9], 3-acetonyl-3-hydroxyoxindole [10], triazolyl compounds [11], oxidized
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polyamines [12], thiadiazoles [13], substituted phenylureas [14], and several natural products
[15–17] exhibit antiviral activity. However, only a few economically viable antiviral chemicals are
available for agricultural applications [18]. Thus, novel potent and structurally concise antiviral
agents should be developed.
Benzothiophene derivatives have a wide range of biological activity in pesticides, including
insecticide [19,20], antibacterial [21], antifungal [22], and anti-inflammatory [23] properties. One
example of these derivatives is benzo[b]thien-4-yl methylcarbamate (Mobam, Figure 1), which is
prepared by Mobil [24]. This compound exhibits a favorable combination of broad-spectrum
insecticidal activity and low mammalian toxicity. Moreover, the methyl 2-((tert-butoxycarbonyl)
amino)-3-(2,3-dimethylbenzo[b]thiophen-7-yl)-3-phenylacrylate reported by Ana et al. [21]
exhibits strong activity against Bacillus cereus, B. subtilis, and Candida albicans at a minimum
inhibitory concentration of 0.125 µg/mL. Many pesticides with potent bioactivity and
benzothiophene are widely used to control plant diseases [25–28]. With these increasing
applications, research on the synthesis and bioactivity of benzothiophene derivatives is gaining
interest from chemists and biologists.
Several aminophosphonates often display interesting bioactivity, such as antibacterial [29,30],
antifungal [31], plant virucidal [32,33], and herbicidal [34,35] activities. Several of these
derivatives are commercialized as pesticides. Phosfolan, glyphosate, and dufulin protect certain
plants from severe diseases and pests (Figure 1). In our previous work, we have designed and
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synthesized α-aminophosphonates with fluorine and heterocyclic moiety; these derivatives exhibit
moderate antiviral bioactivity against TMV and antitumor activity [36–39]. Nevertheless, to the
best of our knowledge, there has been no report on synthesis of α-aminophosphonates derivatives
containing benzothiophene moiety and antiviral activity against TMV, our group were planned to
introduce the benzothiophene groups to the α-aminophosphonates and gained a series of novel
α-aminophosphonates derivatives.
In view of the growing demand for the development of effective and environmentally benign
antiviral agents to protect crops from the deadly pests and virus, we envisioned that the
introduction of benzothiophene moiety into the parent α-aminophosphonate scaffold might lead to
the generation of novel agents with high bioactivities (Fig. 1). In this study, we mean to design and
synthesize a series of α-aminophosphonates derivatives containing benzothiophene moiety, and
then test the antiviral activity against TMV. The half-leaf method was used to determine the in vivo
efficacy of α-aminophosphonates bearing a benzothiophene moiety against the tobacco mosaic
virus (TMV). Bioassay results showed that all compounds exhibited certain anti-TMV activity at
500 µg/mL concentration. Compound 2f produced a curative effect of up to 48.1% against TMV,
almost similar to that obtained from standard ningnanmycin (51.9%). This study demonstrated that
α-aminophosphonate derivatives with a benzothiophene moiety can be used to develop potential
agrochemicals. To our knowledge, this study is the first one on the anti-TMV activity of
α-aminophosphonate derivatives with a benzothiophene moiety.
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Results and Discusssion
Chemistry
The synthetic route to the title compounds is illustrated in Figure 2. The intermediate 1 imine
was prepared by treating substituted 2-aminobenzothiazole and
benzo[b]thiophene-3-carbaldehyde with readily available starting materials. The reaction mixture
was refluxed for 10 h and then cooled down to room temperature. The solvent was removed under
reduced pressure, and the crude product was purified by recrystallization to yield pure imines
1a–1f. The intermediates 1 were dissolved in toluene solution, and different substituted
phosphonate reactions at 109 °C yielded the final compounds (2a–2p).
[Insert Figure 2]
All synthesized compounds (2a to 2p) were confirmed by 1H NMR, 13C NMR, 31P NMR,
infrared (IR) analysis, and elemental analysis (Table 2). The IR spectrum of all synthesized
compounds showed broad absorption bands at around 3500 cm−1 to 3200 cm−1 for -NH and 1235
cm−1 to 1200 cm−1 for P=O, with distinguishing benzene ring broad absorption peaks at 1650 cm−1
to 1500 cm−1. The 1H-NMR spectrum showed two characteristic peaks near δ 8.16 ppm to 8.07
ppm for the -NH proton and near δ 6.88 ppm to 5.99 ppm for the P-CH proton. A broad multiplet
was observed at δ 6.75 ppm to 7.84 ppm for the -ArH proton, and a singlet near δ 3.79 ppm to 3.81
ppm for the methyl (Ar-OCH3) proton signals.
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[Insert Table 2]
Anti-TMV activity
The half-leaf method was used to determine the in vivo efficacy of the title compounds against
TMV. The bioassay results showed that all compounds exhibited certain anti-TMV activity at 500
µg/mL concentration. Compound 2f produced a curative effect of up to 48.1% against TMV,
almost similar to that obtained from the standard ningnanmycin (51.9%).
Experimental
Chemistry
Materials and Instrumentation
Benzo[b]thiophene-3-carbaldehyde was purchased from Accela ChemBio Co. Ltd.
Substituted 2-aminobenzothiazole was purchased from Adamas. Unless otherwise stated, all
reagents and reactants were purchased from commercial suppliers, and melting points were
uncorrected and determined with an XT-4 binocular microscope (Beijing Tech Instrument, China).
1H-NMR, 13C-NMR, and 31P-NMR spectra were recorded at room temperature on a JEOL ECX
500 NMR spectrometer operated at 500 MHz for 1H-NMR, 125 MHz for 13C-NMR, and 200 MHz
for 31P-NMR using CDCl3 as the solvent and tetramethylsilane as the internal standard. IR spectra
were recorded in KBr on a Bruker VECTOR 22 spectrometer, and elements were analyzed with an
Elemental Vario-III CHN analyzer. The course of reactions was monitored by thin-layer
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chromatography (TLC) performed on silica gel GF 254. The Supplemental Materials contains
sample spectra for 2f and 2l (Figures S 1 – S 6)
Synthesis of compounds
Benzo[b]thiophene-3-carbaldehyde (1.0 equiv.) in toluene (5 mL) was slowly added with
constant stirring to a 50 mL three-necked round-bottom flask containing substituted
2-aminobenzothiazole (1.0 equiv.) and anhydrous toluene (10 mL). The reaction mixture was
refluxed for 10 h and then cooled down to room temperature. The solvent was removed under
reduced pressure, and the crude product was purified by recrystallization using
N,N-dimethylethanamine/acetone/petroleum ether to yield pure imines 1a–1f. Phosphonate (0.6
mmol) in one portion was added to a solution of imines 1a–1f (0.5 mol) in toluene (5.0 mL) at
room temperature. The reaction mixture was refluxed for 8 h, the mixture was concentrated, and
the residue was directly purified by preparative TLC (hexane/ethyl ether, 5:1 to 1:1) to yield
products 2a–2p.
Characterization of final compounds (2a–2p)
Diphenyl(benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonat
e
(2a)
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IR (KBr, cm−1): v 3225 (−NH str.), 1252 (C=N str.), 1211 (P=O str.), 1025 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.16 (d, J = 5.7 Hz, 1H, NH), 7.79–7.84 (m, 2H, Ar-H), 7.50 (d, J = 9.2
Hz, 1H, Ar-H), 7.36–7.42 (m, 2H, Ar-H), 7.05–7.19 (m, 9H, Ar-H), 6.81–6.91 (m, 4H, Ar-H), 6.59
(d, J = 18.3 Hz, 1H, P-CH), 3.81 (s, 3H, Ar-OCH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 163.6
(Ar-C), 155.5 (Ar-C), 146.0 (Ar-C), 140.2 (Ar-C), 137.9 (Ar-C), 132.3 (Ar-C), 129.8 (Ar-C),
129.6 (Ar-C), 129.3 (Ar-C), 127.3 (Ar-C), 127.2 (Ar-C), 125.5 (Ar-C), 125.3 (Ar-C), 124.8
(Ar-C), 124.6 (Ar-C), 122.7 (Ar-C), 122.4 (Ar-C), 120.7 (Ar-C), 120.6 (Ar-C), 120.4 (Ar-C),
120.3 (Ar-C), 120.0 (Ar-C), 113.4 (Ar-C), 105.3 (Ar-C), 55.9 (P-CH), 48.7 (OCH3); 31P-NMR
(200 MHz, CDCl3, ppm): δ 13.7.
Diphenyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2b)
IR (KBr, cm−1): v 3213 (−NH str.), 1271 (C=N str.), 1203 (P=O str.), 1157 (P-O-C str.);1H-NMR
(500 MHz, CDCl3, ppm): δ 8.15 (d, J = 8.0 Hz, 1H, NH), 7.83 (d, J = 8.1 Hz, 1H, Ar-H), 7.72 (d, J
= 2.9 Hz, 1H, Ar-H), 7.59 (d, J = 8.6 Hz, 1H, Ar-H), 7.36–7.50 (m, 4H, Ar-H), 7.23 (s, 1H, Ar-H),
7.06–7.20 (m, 8H, Ar-H), 6.75 (d, J = 8.0 Hz, 1H, Ar-H), 6.61 (dd, J1 = 9.2 Hz, J2 = 9.8 Hz, 1H,
P-CH); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.5 (Ar-C), 165.4 (Ar-C), 150.3 (Ar-C), 149.9
(Ar-C), 140.0 (Ar-C), 137.6 (Ar-C), 132.5 (Ar-C), 129.7 (Ar-C), 129.5 (Ar-C), 128.9 (Ar-C),
127.2 (Ar-C), 127.1 (Ar-C), 127.0 (Ar-C), 126.1 (Ar-C), 125.6 (Ar-C), 125.3 (Ar-C), 124.8
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(Ar-C), 124.5 (Ar-C), 122.7 (Ar-C), 122.2 (Ar-C), 120.6 (Ar-C), 120.5 (Ar-C), 120.3 (Ar-C),
120.3 (Ar-C), 120.2 (Ar-C), 120.1 (Ar-C), 48.4 (P-CH); 31P-NMR (200 MHz, CDCl3, ppm): δ
13.5.
Bis(2-ethoxyethyl) (benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)
phosphonate (2c)
IR (KBr, cm−1): v 3523 (−NH str.), 1338 (C=N str.), 1223 (P=O str.), 1022 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.0 Hz, 1H, NH), 7.83-7.86 (m, J = 8.1 Hz, 1H, Ar-H), 7.76
(d, J = 2.8 Hz, 1H, Ar-H), 7.34–7.46 (m, 3H, Ar-H), 7.07 (d, J = 2.9 Hz, 1H, Ar-H), 6.86 (dd, J1 =
2.9 Hz, J2 = 2.3 Hz, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 6.11 (dd, J1 = 5.7 Hz, J2 = 6.3 Hz, 1H, P-CH),
4.13–4.29 (m, 4H, P-OCH2), 3.79 (s, 3H, Ar-OCH3), 3.37–3.57 (m, 8H, P-OCH2CH2OCH2CH3),
1.10-1.13 (m, 6H, OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 163.6 (Ar-C), 155.3 (Ar-C),
146.2 (Ar-C), 140.0 (Ar-C), 137.9 (Ar-C), 132.0 (Ar-C), 130.3 (Ar-C), 125.8 (Ar-C), 124.6
(Ar-C), 124.3 (Ar-C), 122.6 (Ar-C), 122.5 (Ar-C), 119.8 (Ar-C), 113.4 (Ar-C), 105.1 (Ar-C), 69.4
(P-OCH2CH2), 69.3 (P-OCH2CH2), 69.2 (P-CH), 66.7 (OCH2CH3), 66.6 (OCH2CH3), 66.3
(P-OCH2), 55.8 (P-OCH2), 50.7 (Ar-OCH3), 16.0 (OCH2CH3); 31P-NMR (200 MHz, CDCl3,
ppm): δ 20.9.
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Bis(2-ethoxyethyl)
(benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phos- phonate (2d)
IR (KBr, cm−1): v 3244 (−NH str.), 1291 (C=N str.), 1230 (P=O str.), 1029 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.0 Hz, 1H, NH), 7.83 (d, J = 8.0 Hz, 1H, Ar-H), 7.79 (s,
1H, Ar-H), 7.35–7.48 (m, 5H, Ar-H), 7.21–7.23 (m, 1H, Ar-H), 6.19 (d, J = 21.2 Hz, 1H, P-CH),
4.14–4.27 (m, 4H, P-OCH2), 3.36–3.55 (m, 8H, P-OCH2CH2OCH2CH3), 1.11 (t, J = 8.6 Hz, 6H,
OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.6 (Ar-C), 150.7 (Ar-C), 140.1 (Ar-C),
138.0 (Ar-C), 137.9 (Ar-C), 132.3 (Ar-C), 130.2 (Ar-C), 127.0 (Ar-C), 126.3 (Ar-C), 126.0
(Ar-C), 124.8 (Ar-C), 124.5 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 120.4 (Ar-C), 120.1 (Ar-C), 69.5
(P-OCH2CH2), 69.4 (P-OCH2CH2), 69.3 (P-CH), 66.7 (OCH2CH3), 66.6 (OCH2CH3), 66.5
(P-OCH2), 50.6 (P-OCH2), 15.1 (OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 20.7.
Diethyl (benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2e)
IR (KBr, cm−1): v 3209 (−NH str.), 1252 (C=N str.), 1232 (P=O str.), 1034 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.1 Hz, 1H, NH), 7.84–7.87 (m, 2H, Ar-H), 7.34–7.48 (m,
3H, Ar-H), 7.21 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 6.86 (d, J = 8.0 Hz, 1H, Ar-H), 6.06 (d, J = 18.3
Hz, 1H, P-CH), 3.79 (s, 3H, Ar-OCH3), 3.73–4.28 (m, 4H, OCH2CH3), 1.26 (t, J = 13.7 Hz, 3H,
OCH2CH3), 1.02 (t, J = 14.3 Hz, 3H, OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 164.0
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(Ar-C), 155.3 (Ar-C), 146.2 (Ar-C), 140.2 (Ar-C), 138.0 (Ar-C), 132.1 (Ar-C), 130.4 (Ar-C),
126.2 (Ar-C), 124.7 (Ar-C), 124.4 (Ar-C), 122.6 (Ar-C), 119.8 (Ar-C), 113.4 (Ar-C), 105.2
(Ar-C), 63.8 (P-OCH2), 63.5 (P-OCH2), 55.9 (Ar-OCH3), 50.2 (P-CH), 16.6 (OCH2CH3), 16.2
(OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.1.
Diethyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2f)
IR (KBr, cm−1): v 3213 (−NH str.), 1271 (C=N str.), 1203 (P=O str.), 1020 (P-O-C str.);1H-NMR
(500 MHz, CDCl3, ppm): δ 8.09 (d, J = 8.1 Hz, 1H, NH), 7.20–8.09 (m, 8H, Ar-H), 6.16 (d, J =
20.6 Hz, 1H, P-CH), 3.70–4.30 (m, 4H, OCH2CH3), 1.25 (t, J = 6.6 Hz, 3H, OCH2CH3), 1.02 (t, J
= 6.9 Hz, 3H, OCH2CH3); 13C-NMR (125 MHz, CDCl3,ppm): δ 165.8 (Ar-C), 150.7 (Ar-C), 140.1
(Ar-C), 137.9 (Ar-C), 132.5 (Ar-C), 130.3 (Ar-C), 126.9 (Ar-C), 126.3 (Ar-C), 124.8 (Ar-C),
124.4 (Ar-C), 122.8 (Ar-C), 122.5 (Ar-C), 120.4 (Ar-C), 119.9 (Ar-C), 63.9 (P-CH), 50.0
(P-OCH2), 48.8 (P-OCH2), 16.5 (OCH2CH3), 16.2 (OCH2CH3); 31P-NMR (200 MHz, CDCl3,
ppm): δ 20.9.
Diethyl (benzo[b]thiophen-3-yl((6-ethoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2g)
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IR (KBr, cm−1): v 3217 (−NH str.), 1265 (C=N str.), 1226 (P=O str.), 1020 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.0 Hz, 1H, NH), 7.83 (d, J = 12.1 Hz, 2H, Ar-H),
7.35–7.47 (m, 3H, Ar-H), 7.06 (s, 1H, Ar-H), 6.86 (d, J = 9.2 Hz, 1H, Ar-H), 6.66 (s, 1H, Ar-H),
5.99 (d, J = 21.2 Hz, 1H, P-CH), 4.14–4.28 (m, 2H, Ar-OCH2CH3), 3.71–4.02 (m, 4H,
P-OCH2CH3), 1.39 (t, J = 13.8 Hz, 3H, Ar-OCH2CH3), 1.27 (t, J = 13.8 Hz, 3H, P-OCH2CH3),
1.02 (t, J = 14.3 Hz, 3H, P-OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 163.7 (Ar-C), 154.6
(Ar-C), 146.0 (Ar-C), 140.1 (Ar-C), 137.8 (Ar-C), 131.9 (Ar-C), 130.2 (Ar-C), 126.1 (Ar-C),
124.6 (Ar-C), 124.3 (Ar-C), 122.7 (Ar-C), 122.4 (Ar-C), 119.8 (Ar-C), 114.1 (Ar-C), 105.9
(Ar-C), 64.1 (P-OCH2CH3), 63.6 (P-OCH2CH3), 50.3 (P-CH), 49.1 (Ar-OCH2CH3), 16.4
(P-OCH2CH3), 16.1 (P-OCH2CH3), 14.9 (Ar-OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ
21.1.
Diethyl (benzo[b]thiophen-3-yl((6-methylbenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2h)
IR (KBr, cm−1): v 3215 (−NH str.), 1230 (C=N str.), 1213 (P=O str.), 1018 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.0 Hz, 1H, NH), 7.84 (d, J = 7.2 Hz, 2H, Ar-H), 7.34–7.47
(m, 4H, Ar-H), 7.08 (d, J = 8.6 Hz, 1H, Ar-H), 6.65 (s, 1H, Ar-H), 6.01 (dd, J1 = 8.6 Hz, J2 = 8.0
Hz,1H, P-CH), 3.74–4.25 (m, 4H, P-OCH2CH3), 2.37 (s, 3H, Ar-CH3), 1.26 (t, J = 6.9 Hz, 3H,
P-OCH2CH3), 1.03 (t, J = 6.9 Hz, 3H, P-OCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 164.7
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(Ar-C), 149.9 (Ar-C), 140.2 (Ar-C), 137.9 (Ar-C), 131.8 (Ar-C), 131.2 (Ar-C), 130.3 (Ar-C),
127.0 (Ar-C), 126.2 (Ar-C), 124.7 (Ar-C), 124.4 (Ar-C), 122.5 (Ar-C), 120.9 (Ar-C), 119.1
(Ar-C), 63.8 (P-OCH2CH3), 63.5 (P-OCH2CH3), 55.9 (P-CH), 49.0 (Ar-CH3), 16.6 (P-OCH2CH3),
16.2 (P-OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.0.
Diethyl (benzo[b]thiophen-3-yl((4-methylbenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2i)
IR (KBr, cm−1): v 3244 (−NH str.), 1259 (C=N str.), 1211 (P=O str.), 1024 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.16 (d, J = 7.5 Hz, 1H, NH), 7.89 (d, J = 2.9 Hz, 1H, Ar-H), 7.84 (d, J
= 7.4 Hz, 1H, Ar-H), 7.34–7.43 (m, 3H, Ar-H), 6.96–7.00 (m, 3H, Ar-H), 6.10 (dd, J1 = 8.6 Hz, J2
= 8.6 Hz, 1H, CH), 4.20–4.29 (m, 2H, P-OCH2CH3), 3.75–4.07 (m, 2H, P-OCH2CH3), 2.37 (s, 3H,
Ar-CH3), 1.28 (t, J = 7.2 Hz, 3H, P-OCH2CH3), 1.03 (t, J = 6.9 Hz, 3H, P-OCH2CH3); 13C-NMR
(125 MHz, CDCl3, ppm): δ 164.6 (Ar-C), 151.0 (Ar-C), 140.1 (Ar-C), 138.2 (Ar-C), 130.9 (Ar-C),
130.6 (Ar-C), 129.3 (Ar-C), 126.6 (Ar-C), 126.3 (Ar-C), 124.7 (Ar-C), 124.4 (Ar-C), 122.7
(Ar-C), 122.5 (Ar-C), 121.8 (Ar-C), 118.2 (Ar-C), 63.8 (C-N), 49.9 (POCH2CH3), 48.6
(POCH2CH3), 18.5 (Ar-CH3), 16.6 (P-OCH2CH3), 16.2 (P-OCH2CH3); 31P-NMR (200 MHz,
CDCl3, ppm): δ 21.2.
Diethyl (benzo[b]thiophen-3-yl(benzo[d]thiazol-2-ylamino)methyl)phosphonate (2j)
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IR (KBr, cm−1): v 3201 (−NH str.), 1232 (C=N str.), 1201 (P=O str.), 1014 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.11–8.12 (m, 1H, NH), 7.84–7.89 (m, 2H, Ar-H), 7.26–7.59 (m, 6H,
Ar-H), 7.05–7.09 (m, 1H, Ar-H), 6.12 (d, J = 21.2 Hz, 1H, CH), 4.15–4.31 (m, 2H, POCH2CH3),
3.97–4.06 (m, 1H, POCH2CH3), 3.73–3.82 (m, 1H, POCH2CH3), 1.26 (t, J = 9.2 Hz, 3H,
POCH2CH3), 1.03 (t, J = 9.7 Hz, 3H, POCH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.6
(Ar-C), 152.1 (Ar-C), 140.2 (Ar-C), 138.0 (Ar-C), 131.2 (Ar-C), 130.3 (Ar-C), 126.2 (Ar-C),
125.8 (Ar-C), 124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.6 (Ar-C), 121.9 (Ar-C), 120.8
(Ar-C), 119.4 (Ar-C), 63.8 (C-N), 63.6 (P-OCH2CH3), 48.9 (P-OCH2CH3), 16.5 (P-OCH2CH3),
16.2 (P-OCH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.0.
Dibutyl (benzo[b]thiophen-3-yl((6-ethoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2k)
IR (KBr, cm−1): v 3258 (−NH str.), 1252 (C=N str.), 1207 (P=O str.), 1031 (P-O-C str.);1H-NMR
(500 MHz, CDCl3, ppm): δ 8.07 (d, J = 8.1 Hz, 1H, NH), 7.84 (t, J = 2.9 Hz, 2H, Ar-H), 7.35–7.46
(m, 3H, Ar-H), 7.06 (s, 1H, Ar-H), 6.86 (d, J = 9.8 Hz, 1H, Ar-H), 6.80 (s, 1H, Ar-H), 6.02 (d, J =
21.2 Hz, 1H, CH), 4.20-4.32 (m, 2H, P-OCH2CH2CH2CH3), 4.00-4.12 (m, 2H,
P-OCH2CH2CH2CH3), 3.89-3.99 (m, 1H, P-OCH2CH2CH2CH3), 3.64–3.71 (m, 1H,
P-OCH2CH2CH2CH3), 1.54–1.60 (m, 2H, POCH2CH2CH2CH3), 1.38 (t, J = 13.7 Hz, 3H,
Ar-OCH2CH3), 1.26–1.33 (m, 4H, P-OCH2CH2CH2CH3), 1.04–1.11 (m, 2H, Ar-OCH2CH3), 0.79
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(t, J = 7.5 Hz, 3H, P-OCH2CH2CH2CH3), 0.71 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH2CH3); 13C-NMR
(125 MHz, CDCl3, ppm): δ 163.8 (Ar-C), 154.7 (Ar-C), 146.2 (Ar-C), 140.2 (Ar-C), 137.9 (Ar-C),
132.0 (Ar-C), 130.4 (Ar-C), 126.1 (Ar-C), 124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.5
(Ar-C), 119.8 (Ar-C), 114.1 (Ar-C), 106.0 (Ar-C), 67.4 (C-N), 67.1 (POCH2CH2CH2CH3), 64.2
(OCH2), 50.2 (Ar-OCH2CH3), 48.9 (P-OCH2CH2CH2CH3), 32.6 (P-OCH2CH2CH2CH3), 32.2
(P-OCH2CH2CH2CH3),18.7(P-OCH2CH2CH2CH3),18.5(Ar-OCH2CH3),15.0(P-OCH2CH2CH2C
H3),13.5 (P-OCH2CH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.2.
Dibutyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2l)
IR (KBr, cm−1): v 3234 (−NH str.), 1234 (C=N str.), 1209 (P=O str.), 1024 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.1 Hz, 1H, NH), 7.86 (t, J = 7.5 Hz, 2H, Ar-H), 7.36–7.49
(m, 4H, Ar-H), 7.22–7.24 (m, 2H, Ar-H), 6.07 (dd, J1 = 8.6 Hz, J2 = 8.6 Hz,1H, CH), 4.08–4.20
(m, 2H, P-OCH2CH2CH2CH3), 3.64–3.96 (m, 2H, P-OCH2CH2CH2CH3), 1.54–1.60 (m, 2H,
P-OCH2CH2CH2CH3), 1.30–1.33 (m, 2H, P-OCH2CH2CH2CH3), 1.04–1.11 (m, 4H,
P-OCH2CH2CH2CH3), 0.79 (t, J = 7.4 Hz, 3H, P-OCH2CH2CH2CH3), 0.71 (t, J = 6.9 Hz, 3H,
P-OCH2CH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 165.6 (Ar-C), 150.6 (Ar-C), 140.1
(Ar-C), 137.7 (Ar-C), 132.3 (Ar-C), 130.0 (Ar-C), 126.9 (Ar-C), 126.2 (Ar-C), 124.7 (Ar-C),
124.3 (Ar-C), 122.7 (Ar-C), 122.3 (Ar-C), 120.3 (Ar-C), 119.9 (Ar-C), 67.2 (C-N), 50.0
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(P-OCH2CH2CH2CH3), 48.7 (P-OCH2CH2CH2CH3), 32.4 (P-OCH2CH2CH2CH3), 32.1
(P-OCH2CH2CH2CH3), 18.6 (P-OCH2CH2CH2CH3), 18.4 (P-OCH2CH2CH2CH3), 13.4
(P-OCH2CH2CH2CH3), 13.3 (P-OCH2CH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.0.
Dibutyl (benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2m)
IR (KBr, cm−1): v 3207 (−NH str.), 1219 (C=N str.), 1199 (P=O str.), 1018 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.07 (t, J = 8.0 Hz, 1H, NH), 7.84 (t, J = 7.4 Hz, 3H, Ar-H), 7.35–7.48
(m, 3H, Ar-H), 7.07 (d, J = 2.3 Hz, 1H, Ar-H), 6.87 (d, J = 9.2 Hz, 1H, Ar-H), 6.06–6.11 (m, 1H,
CH), 4.10–4.21 (m, 2H, P-OCH2CH2CH2CH3), 3.91–3.94 (m, 1H, P-OCH2CH2CH2CH3 ), 3.79 (s,
3H, OCH3), 3.65–3.70 (m, 1H, P-OCH2CH2CH2CH3), 1.55–1.60 (m, 2H, P-OCH2CH2CH2CH3),
1.28–1.33 (m, 4H, P-OCH2CH2CH2CH3), 1.06–1.12 (m, 2H, P-OCH2CH2CH2CH3), 0.80 (t, J =
6.9 Hz, 3H, P-OCH2CH2CH2CH3), 0.71 (t, J = 7.4 Hz, 3H, P-OCH2CH2CH2CH3); 13C-NMR (125
MHz, CDCl3, ppm): δ 163.8 (Ar-C), 155.2 (Ar-C), 146.2 (Ar-C), 140.1 (Ar-C), 137.8 (Ar-C),
132.2 (Ar-C), 130.4 (Ar-C), 126.0 (Ar-C), 124.6 (Ar-C), 124.3 (Ar-C), 122.6 (Ar-C), 122.4
(Ar-C), 119.6 (Ar-C), 113.2 (Ar-C), 105.1 (Ar-C), 67.3 (C-N), 67.2 (P-OCH2CH2CH2CH3), 67.0
(P-OCH2CH2CH2CH3), 55.8 (OCH3), 32.5 (P-OCH2CH2CH2CH3), 32.2 (P-OCH2CH2CH2CH3),
18.6 (P-OCH2CH2CH2CH3), 18.4 (P-OCH2CH2CH2CH3), 13.5 (P-OCH2CH2CH2CH3), 13.4
(P-OCH2CH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.2.
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Dipropyl
(benzo[b]thiophen-3-yl((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate (2n)
IR (KBr, cm−1): v 3196 (−NH str.), 1273 (C=N str.), 1228 (P=O str.), 1001 (P-O-C str.); 1H-NMR
(500 MHz, CDCl3, ppm): δ 8.10 (d, J = 8.1 Hz, 1H, NH), 7.91 (s, 1H, Ar-H), 7.83 (d, J = 13.0 Hz,
1H, Ar-H), 7.34–7.47 (m, 4H, Ar-H), 7.07 (s, 1H, Ar-H), 6.86 (d, J = 11.2 Hz, 1H, CH), 6.11 (dd,
J1 = 8.6 Hz, J2 = 9.2 Hz, 1H, CH), 4.05–4.15 (m, 2H, P-OCH2CH2CH3), 3.89–3.92 (m, 1H,
P-OCH2CH2CH3), 3.70 (s, 3H, OCH3), 3.61–3.67 (m,1H, P-OCH2CH2CH3), 1.58–1.64 (m, 2H,
P-OCH2CH2CH3), 1.35–1.41 (m, 2H, P-OCH2CH2CH3), 0.84 (t, J = 7.5 Hz, 3H,
P-OCH2CH2CH3), 0.68 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm):
δ 164.0 (Ar-C), 155.3 (Ar-C), 146.3 (Ar-C), 140.1 (Ar-C), 138.0 (Ar-C), 132.2 (Ar-C), 130.6
(Ar-C), 126.2 (Ar-C), 124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.6 (Ar-C), 119.7 (Ar-C),
113.3 (Ar-C), 105.2 (Ar-C), 69.2 (C-N), 55.9 (OCH3), 50.0 (P-OCH2CH2CH3), 48.7
(P-OCH2CH2CH3), 24.0 (P-OCH2CH2CH3), 23.7 (P-OCH2CH2CH3), 10.0 (P-OCH2CH2CH3), 9.9
(P-OCH2CH2CH3); 31P-NMR (200 MHz, CDCl3, ppm): δ 21.2.
Dipropyl (benzo[b]thiophen-3-yl((6-chlorobenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2o)
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IR (KBr, cm−1): v 3238 (−NH str.), 1232 (C=N str.), 1207 (P=O str.), 1001 (P-O-C str.);1H-NMR
(500 MHz, CDCl3, ppm): δ 8.10 (d, J = 8.0 Hz, 1H, NH), 7.93 (d, J = 2.3 Hz, 1H, Ar-H), 7.84 (d, J
= 7.5 Hz, 1H, Ar-H), 7.35–7.48 (m, 5H, Ar-H), 7.21–7.23 (m, 1H, Ar-H), 6.21 (dd, J1 = 9.2 Hz, J2
= 10.9 Hz, 1H, CH), 4.06–4.19 (m, 2H, P-OCH2CH2CH3), 3.89–3.94 (m, 1H, P-OCH2CH2CH3),
3.61–3.64 (m, 1H, P-OCH2CH2CH3), 1.59–1.65 (m, 2H, P-OCH2CH2CH3), 1.36–1.41 (m, 2H,
P-OCH2CH2CH3), 0.84 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH3), 0.68 (t, J = 7.5 Hz, 3H,
P-OCH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 150.8 (Ar-C), 140.1 (Ar-C), 140.0
(Ar-C), 137.7 (Ar-C), 132.5 (Ar-C), 130.4 (Ar-C), 126.8 (Ar-C), 126.3 (Ar-C), 126.1 (Ar-C),
124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 120.4 (Ar-C), 119.9 (Ar-C), 69.3 (C-N),
49.8 (P-OCH2CH2CH3), 48.5 (P-OCH2CH2CH3), 24.0 (P-OCH2CH2CH3), 23.7
(P-OCH2CH2CH3), 10.0 (P-OCH2CH2CH3), 9.9 (P-OCH2CH2CH3); 31P-NMR (200 MHz, CDCl3,
ppm): δ 21.1.
Dipropyl (benzo[b]thiophen-3-yl((6-methylbenzo[d]thiazol-2-yl)amino)methyl)phosphonate
(2p)
IR (KBr, cm−1): v 3523 (−NH str.), 1291 (C=N str.), 1259 (P=O str.), 1022 (P-O-C str.);1H-NMR
(500 MHz, CDCl3, ppm): δ 8.08 (t, J = 9.2 Hz, 1H, NH), 7.83–7.90 (m, 2H, Ar-H), 7.33–7.49 (m,
4H, Ar-H), 7.10 (t, J = 9.2 Hz, 2H, Ar-H), 6.08–6.14 (m, 1H, CH), 4.03–4.16 (m, 2H,
P-OCH2CH2CH3), 3.87–3.92 (m, 1H, P-OCH2CH2CH3), 3.61–3.66 (m, 1H, P-OCH2CH2CH3),
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2.37 (d, J = 11.5 Hz, 3H, Ar-CH3), 1.58–1.64 (m, 2H, P-OCH2CH2CH3), 1.35–1.41 (m, 2H,
P-OCH2CH2CH3), 0.85 (t, J = 7.5 Hz, 3H, P-OCH2CH2CH3), 0.68 (t, J = 14.8 Hz, 3H,
P-OCH2CH2CH3); 13C-NMR (125 MHz, CDCl3, ppm): δ 164.8 (Ar-C), 149.9 (Ar-C), 140.1
(Ar-C), 137.99 (Ar-C), 131.7 (Ar-C), 131.2 (Ar-C), 130.4 (Ar-C), 127.0 (Ar-C), 126.2 (Ar-C),
124.7 (Ar-C), 124.4 (Ar-C), 122.7 (Ar-C), 122.5 (Ar-C), 120.9 (Ar-C), 119.0 (Ar-C), 69.2 (C-N),
50.1 (P-OCH2CH2CH3), 48.9 (P-OCH2CH2CH3), 24.0(P-OCH2CH2CH3), 23.6(P-OCH2CH2CH3),
21.3(Ar-CH3), 10.0 (P-OCH2CH2CH3), 9.8 (P-OCH2CH2CH3); 31P-NMR (200 MHz, CDCl3,
ppm): δ 21.1.
Conclusion
New types of α-aminophosphonate derivatives with a benzothiophene moiety were designed
and synthesized, and the anti-TMV activity of compounds 2a to 2p was evaluated in vitro. The
synthesized compounds exhibited weak to good anti-TMV activity. In particular, compound 2f
produced a curative effect of up to 48.1% against TMV at 500 µg/mL concentration. When the
aminophosphonate group had an ethyl substituent, the compound exhibited significantly higher
activity than the other compounds. To our knowledge, this study is the first one on the synthesis
and anti-TMV activity of α-aminophosphonate derivatives with a benzothiophene moiety.
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Acknowledgements
This work was supported by the National Key Project for Basic Research (Grant
No.2010CB126105) and the National Key Technologies R & D Program of China (Grant No.
2011BAE06B05-6) and the Special Fund for Agro-Scientific Research in the Public Interest
(Grant No. 201203022).
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Table Captions
Table 1: Physical and analytical data on newly synthesized compounds 2a–2p
Figure Captions
Figure 1: Chemical structures of ningnanmycin, commercialized pesticide α-aminophosphonates,
and benzothiophene derivatives
Figure 2: Schematic diagram of synthesis of final compounds (2a–2p)
N
O
O
NH2
O
H
H
O
C
HOH2C
HO
N
N
N
CONH2
N
N
H
N
NH2
CH2OH
O
OH
HO
OH
N
O
Ningnanmycin
O
Ribavirin
O
O
H
S
N
P
P
O
O
HO
OH
N
OH
S
Phosfolan
N
Glyphosate
F
S
H H
N C
H
S
P
O
N
O
O
O
O
Dufulin
Mobam
Figure: 1: Chemical structures of Ningnanmycin, Ribavirin, the commercialized pesticide of
α-aminophosphonates and benzothiophene derivatives
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N
S
CHO
H
N
R1
C
N
a
R1
NH2
S
S
S
1a-f
R2
O
O
R2
H
P
N
S
O
R1
C N
H
b
S
2a-p
Figure 2: Schematic diagram for synthesis of final compounds; a: PhCH3, CH3COOH, reflux,
10h; b: HPO(OR2)2, PhCH3, reflux, 8h; 2 (a-p): R1, R2= a. 6-OCH3, Ph; b. 6-Cl, Ph; c. 6-OCH3,
CH2CH2OEt; d. 6-Cl, CH2CH2OEt; e. 6-OCH3, Et; f. 6-Cl, Et; g. 6-OCH2CH3, Et; h. 6-CH3, Et; i.
4-CH3, Et; j. H, Et; k. 6-OCH2CH3, n-Bu; l. 6-Cl, n-Bu; m. 6-OCH3, n-Bu; n. 6-OCH3, n-Pr; o.
6-Cl, n-Pr, p. 6- CH3, n-Pr
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Table 1: Physical and analytical data of the newly synthesized compounds 2a-p
Elemental Analysis
Entry
Mol. Formula
Yield%
M.W
Found (%)
Calculated (%)
C
H
N
C
H
N
C29H23N2O4PS2
C28H20ClN2O3PS2
C25H31N2O6PS2
C24H28ClN2O5PS2
C21H23N2O4PS2
C20H20ClN2O3PS2
C22H25N2O4PS2
C21H23N2O3PS2
C21H23N2O3PS2
C20H21N2O3PS2
C26H33N2O4PS2
C24H28ClN2O3PS2
C25H31N2O4PS2
C23H27N2O4PS2
C22H24ClN2O3PS2
C23H27N2O3PS2
65
68
57
42
62
51
42
46
54
52
50
47
57
40
62
52
558.08
562.03
550.14
554.09
462.08
466.03
476.10
446.09
446.09
432.07
532.16
522.10
518.15
490.11
494.07
474.12
61.92
60.18
54.69
51.32
54.66
51.37
55.42
56.86
56.49
55.86
58.10
55.08
57.82
56.00
53.52
58.06
4.32
4.14
6.02
5.62
5.56
4.61
5.47
5.38
5.26
5.42
6.52
5.86
6.39
5.58
5.04
5.51
4.98
5.12
5.26
5.20
6.00
5.96
6.02
6.42
6.47
6.53
5.47
5.46
5.49
5.67
5.89
5.88
62.35 4.15
59.73 3.58
54.53 5.67
51.93 5.08
54.53 5.01
51.44 4.32
55.45 5.29
56.49 5.19
56.49 5.19
55.54 4.89
58.63 6.24
55.11 5.40
57.90 6.02
56.31 5.55
53.38 4.89
58.21 5.73
5.01
4.98
5.09
5.05
6.06
6.00
5.88
6.27
6.27
6.48
5.26
5.36
5.40
5.71
5.66
5.90
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
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