Synthesis and antiviral activity of novel a-aminophosphonates containing 6-fluorobenzothiazole moiety

Article abstract of DOI:10.1080/10426507.2017.1323895

A series of novel a-aminophosphonates containing 6-fluorobenzothiazole moiety derivatives were synthesized by one-pot reaction under microwave irradiation and their structures were characterized by IR, ¹H, ¹³C, and ³¹P NMR and element analysis data. Antiviral assays showed that some compounds possess good curative and protective activities against tobacco mosaic virus (TMV) in vivo at 500 μg/mL In particular, compounds diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(phenyl)methyl]phosphonate (4b), diethyl [(6-methoxybenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4j) and diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl]phosphonate (4q) exhibited remarkable antiviral activities than Ribavirin against TMV and PVY. Compound diphenyl [(6-fluorobenzo[d]thiazol- 2-ylamino)(4-methoxyphenyl)methyl]phosphonate (4q) showed similar curative and protective activity against potato virus Y (PVY) to Dufulin.

Full text of DOI:10.1080/10426507.2017.1323895

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and antiviral activity of novel
a-aminophosphonates containing a 6-
fluorobenzothiazole moiety
Dandan Xie, Awei Zhang, Dengyue Liu, Limin Yin, Jingbo Wan, Song Zeng &
Deyu Hu
To cite this article: Dandan Xie, Awei Zhang, Dengyue Liu, Limin Yin, Jingbo Wan, Song Zeng
& Deyu Hu (2017): Synthesis and antiviral activity of novel a-aminophosphonates containing a
6-fluorobenzothiazole moiety, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2017.1323895
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1323895
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Date: 04 May 2017, At: 02:50

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Synthesis and antiviral activity of novel a-aminophosphonates containing a
6-fluorobenzothiazole moiety
Dandan Xie1, Awei Zhang2, Dengyue Liu3, Limin Yin4, Jingbo Wan5, Song Zeng6, 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, Huaxi District, Guiyang 550025, China
*Author to whom correspondence should be addressed; e-mail: dyhu@gzu.edu.cn; Tel.:
+86-851-8829-2170; Fax: +86-851-8829-2170.
1E-Mails: xddxed@163.com(D.D.X);
2E-Mails: awzhang15@163.com(A.W.Z);
3E-Mails: 18230826058@163.com(D.Y.L);
4E-Mails: 18585062530@163.com(L.M.Y);
5E-Mails: 18727431942@163.com(B.J.W);
6E-Mails: zengsong123@126.com(S.Z)
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ABSTRACT
A series of novel α-aminophosphonates containing a 6-fluorobenzothiazole moiety derivatives
were synthesized by a one-pot reaction under microwave irradiation. The structure of the
products was characterized by IR, 1H, 13C and 31P NMR spectroscopy and elemental analysis
data. Antiviral assays showed that some compounds possess good curative and protective
activities against tobacco mosaic virus (TMV) in vivo at 500 μg/mL In particular, diethyl
[(6-fluorobenzo[d]thiazol-2-ylamino)(phenyl)methyl]phosphonate (4b), diethyl
[(6-methoxybenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4j) and diphenyl
[(6-fluorobenzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl]phosphonate (4q) exhibited
remarkable antiviral activities against TMV and PVY, compared with Ribavirin. Diphenyl
[(6-fluorobenzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl]phosphonate (4q) showed
similar curative and protective activity against potato virus Y (PVY) to Dufulin.
Graphical Abstract
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Keywords
a-aminophosphonates, 6-fluorobenzothiazole, microwave chemistry, multicomponent reaction,
antiviral activity
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Introduction
Phosphonic acids are an important class of organophosphorus structures found in many
synthetic and natural occurring products with a remarkable spectrum of biological activities [1].
As analogs of phosphonic acids, α-aminophosphonate derivatives have received much attention
due to their potential biological activities in agrochemicals, such as antibacterial [2-4], antifungal
[5, 6], and antiviral [7, 8]. In our previous work, several series of α-aminophosphonate
derivatives were synthesized and exhibited good antiviral activities [9, 10]. Based on these
studies we had found that α-aminophosphonates containing the benzo[d]thiazole group (Fig. 1,
Dufulin) displayed excellent antiviral activity and have since been commercialized as antiviral
agents for controlling plant virus diseases [11]. Then we have made great efforts to optimize the
structure of Dufulin and discovered that the skeleton of α-aminophosphonates derivatives
containing diphenylphosphates exhibited better antiviral activity than α-aminophosphonates
containing dialkylphosphates [12, 13]. Therefore, we believe that introducing
diphenylphosphates into the skeleton of Dufulin may enhance the antiviral activity.
On the other hand, since a fluorinated corticosteroid was found to have increased
biological activity with the non-fluorinated parent steroid [14, 15] in 1954, organo-fluorine
compounds attracted more and more attention due to the special physical and chemical properties
of fluoro substituents, such as steric hindrance, strong electronegativity and good permeability
[16, 17]. Once fluorine contained groups were introduced into organic compounds, there may be
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profound and unexpected improves in biological activity of these compounds [18, 19].
Moreover, the important role of fluorine reflected in the number of fluorine-containing
agrochemical has more than tripled in the past few decades [20].
Keeping these considerations in mind, we aim to introduce fluoro substituens into the
benzothiazole ring of Dufulin for enhancing the activity and to synthesized a series of novel
6-fluorobenzothiazol or diphenyl phosphate containing a-aminophosphonates. The synthetic
route is depicted in Fig. 2. The structures of the compounds were confirmed by 1H NMR, 13C
NMR, 19F NMR, 31P NMR spectroscopy and elemental analysis. Preliminary bioassays indicated
that some compounds exhibit good antiviral activities against TMV and PVY.
Results and discussion
Chemistry
A typical method for the synthesis of this type of a-aminophosphonates consists in the
one-pot reaction of aldehydes, 2-amine benzothiazoles, and dialkyl phosphate by
Kabachnik-Fields reaction under microwave irradiation.[21-23] Ionic liquids, such as
[bmim][BF4], [bmim][BF6] and [bmim][SbF6] are widely used as solvent.[24, 25]. However,
ionic liquids have some limitations such as high price and water sensitivity.[26]. Therefore, first
of all we have optimized the reaction conditions including solvent, reaction temperature, and
reaction time. As shown in Table 1, the choice of solvent proved crucial to the reaction outcome
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as no reaction was observed in acetonitrile, DMSO and ethyl alcohol, whereas in toluene an
overall yield of 9.4% resulted. It is worth noting that this yield was significantly low. With the
increase of reaction temperature, the yield was relatively higher, but no substantial improvement
was observed when the reaction system was heated from 150 °C to 160 °C (Table 1, entry 13 and
14). Hence, it seemed better to perform the reaction at 150 °C instead of a lower or higher
temperature. When the reaction time was prolonged from 20 to 40 min, the yield increased from
46.8 % to 66.5% (Table 1, entry 13 and 16). When the reaction time was further prolonged to 60
min, there was a further slight improvement of yield (67.9 %, Table 1, entry 17). Therefore,
compared with acetonitrile, DMF, DMSO, pyridine, ethyl alcohol and toluene, it turned out that
the best solvent was NMP, the best reaction temperature was 150 °C, and the best reaction time
was 40 min. Using theses optimized conditions, the compounds 4a–4v were prepared.
The structures of the synthesized compounds were characterized by IR and NMR
spectroscopy, and elemental analyses. The IR spectra of products 4m exhibited bands at ca.
3264.7 cm1, indicating the presence of NH. The 1207.5 cm1 band was assigned to be due to the
P=O stretching mode. Bands at 953.8 cm1 belong to the C-O stretching mode of the P-O-C
group. In the 1H NMR spectra, all phenyl proton showed multiplets at 6.89-7.75 ppm. The
chemical shift of the PC-H ptoton was 6.41 ppm, and appeared as dd peak due to the coupling of
the P atom and N-H. The products showed the N-H proton at 9.44 ppm due to the existence of a
hydrogen bridge between P=O of phosphonate and NH of the 6-fluorobenzothiazol group in 4m
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which shifts the N-H signal to lower field. All carbon atoms in the compounds have been
identified and the total number of protons calculated from the integration curve agrees with the
value expected for the molecular formula. The calculated analytical data for 4m
(C26H19F2N2O3PS, Mol. Wt: 508.48, : C, 61.42; H, 3.77; N, 5.51) agree with the experimental
values (C, 60.98; H, 3.72; N, 5.60).
Antiviral activity
In this study, the antiviral activities of the target compounds 4a–4v against TMV and PVY
were evaluated by using the previous methods.[27] The results are summarized in Table 2 and
Table 3, respectively. As show in Table S 1 (Supplemental Materials), some compounds
exhibited good antiviral in vivo activity against TMV at 500 μg/mL. Compounds 4n and 4t
exhibited potent curative activities against TMV with values of 48.2% and 47.2%, respectively,
at 500 μg/mL, which are better than Ribavirin (38.3%) and similar to Dufulin (47.2%).
Compounds 4a, 4d, 4e and 4f exhibited moderated curative activities, with values of 37.2%,
37.9%, 39.3%, 38.3%, respectively. Moreover, compounds 4b, 4j, and 4q exhibited excellent
inactivation activities against TMV with values of 81.1%, 84.2%, and 83.6%, respectively, at
500 μg/mL, which are better than Dufulin (78.6%) and superior to Ribavirin (70.2%). The
protective activities of compounds 4c, 4l and 4o at 500 μg/mL were 58.3%, 57.9% and 58.2%,
respectively, which is slightly better than Dufulin (56.7%) and superior to Ribavirin (50.6%). As
show in Table S 2 (Supplemental Materials), most of title compounds exhibited good antiviral
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activity against PVY at 500 μg/mL in vivo. Compounds 4o, 4r, and 4u displayed remarkable
protection activity against PVY, with value of 49.1%, 47.8%, 48.6%, respectively, which were
better than that of Dufulin (46.7%). Compounds 4g, 4p, and 4q showed good curative active
with values of 43.4%, 41.6%, and 44.9%, which are similar to Dufulin (43.0%).
Experimental
Materials and Instrumentation
NMR spectra were recorded on a JEOL-ECX 500 NMR spectrometer with TMS as internal
standard and DSMO-d6 as solvent at 500 (1H), 125 (13C), 202 (31P), and 471 (19F) MHz.
Elemental analyses were performed on an Elementar Vario-III CHN analyzer. IR spectra (KBr
pellets, wavelengths in cm1) were recorded on a Bruker VECTOR 22 spectrometer. The melting
points (mp) of the products were determined on an XT-4 binocular microscope (BeiJing Tech
Instrument Co., China). The compounds were synthesized by a monomodal microwave
(CEM-Discover), equipped with an infrared pyrometer for controlling the temperature, and
operating at a maximum power of 300W. All reagents were of analytical reagent grade or
chemically pure. All solvents were dried, deoxygenated, and redistilled before use. The
Supplemental Materials file contains sample 1H, 13C and 31P NMR of products 4a – 4v (Figures S
1 – S 84).
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General Procedure for the preparation of 4a–4v: 2-Aminobenzothiazole (1.0 mmol), aldehyde
(1.0 mmol), dialkyl phosphate (1.2 mmol) were successively added to 1.0 mL of NMP placed in
a round bottomed flask. The mixture was heated with stirring in a DiscoveryTM LabMate
instrument at 90 °C and a power of 60 W for 40 min. After the completion, the mixture was
diluted with water and extracted with ethyl acetate (20 mL × 3). The combined ethyl acetate
extracts were dried over anhydrous MgSO4, filtered, concentrated in vacuo, and the crude
product was purified by column chromatography on silica gel (100–200 mesh, petroleum
ether-EtOAc, V : V=1 : 3) to afford the pure a-aminophosphonates 4a–4v.
Characterization of 4a-4v
Diethyl [(4-chlorophenyl)(6-fluorobenzo[d]thiazol-2-ylamino)methyl]phosphonate (4a): White
solid, mp 166-168 °C, yield, 70.2 %. 1H NMR: δH = 9.09 (dd, J = 9.6, 3.8 Hz, 1H, NH), 7.63 (dd,
J = 8.7, 2.7 Hz, 1H, ArH), 7.53 (dd, J = 8.6, 2.0 Hz, 2H, ArH), 7.46 (d, J = 8.5 Hz, 2H, ArH),
7.37 (dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.06 (td, J = 9.1, 2.8 Hz, 1H, ArH), 5.65 (dd, J = 21.8, 9.6
Hz, 1H, CH), 4.11-3.82 (m, 4H, 2CH2), 1.15 (t, J = 7.0 Hz, 3H, CH3), 1.09 (t, J = 7.0 Hz, 3H,
CH3). 13C NMR: δC = 165.8 (d, 3JPC = 10.4 Hz), 158.0 (d, 1JFC = 237.1 Hz), 148.7, 135.5, 133.0,
3
132.5, 132.4(d, JFC = 11.6 Hz), 130.4, 130.3, 128.8, 128.8, 113.5 (d, 2JFC = 24.0 Hz), 108.5 (d,
2
2
2JFC = 27.2 Hz), 63.4 (d, JPC = 6.8 Hz), 63.1 (d, JPC = 7.1 Hz), 54.4 (d, 1JPC = 153.5 Hz), 16.8
3
3
31
19
(d, JPC = 5.0 Hz), 16.6 (d, JPC = 5.4 Hz). P NMR: 20.9. F NMR: 121.3. IR: 3225.1(NH),
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1227.2(C=N), 1054.2(P-O-C); Anal. calcd for C18H19N2FCl O3PS (428.84): C, 50.41; H, 4.47; N,
6.53; found: C, 50.46; H, 4.72; N, 6.67.
Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(phenyl)methyl]phosphonate (4b): White solid,
1
mp 178-180 °C, yield, 78.6 %. H NMR: δH = 9.04 (dd, J = 9.7, 3.4 Hz, 1H, NH), 7.58 (dd, J =
8.7, 2.7 Hz, 1H, ArH), 7.51-7.45 (m, 2H, ArH), 7.38-7.31 (m, 3H, ArH), 7.27 (t, J = 7.3 Hz, 1H,
ArH), 7.01 (td, J = 9.1, 2.7 Hz, 1H, NH), 5.60 (dd, J = 21.6, 9.7 Hz, 1H, CH), 4.05-3.73 (m, 4H,
2CH2), 1.11 (t, J = 7.0 Hz, 3H, CH3), 1.02 (t, J = 7.0 Hz, 3H, CH3). 13C NMR: δC = 165.9 (d, 3JPC
1
3
= 10.1 Hz), 157.9 (d, JFC = 237.0 Hz), 148.8, 136.3, 132.5, 132.4(d, JFC = 11.6 Hz), 128.8,
2
2
128.8,128.6, 128.6, 119.4, 119.3, 113.5 (d, JFC = 23.5 Hz), 108.5 (d, JFC = 27.2 Hz), 63.2 (d,
2JPC = 6.9 Hz), 63.0 (d, 2JPC = 6.7 Hz), 55.0 (d, 1JPC = 153.5 Hz), 16.8 (d, 3JPC = 5.1 Hz), 16.6 (d,
3JPC = 5.6 Hz). 31P NMR: 21.4. 19F NMR: 121.5. IR: 3234.1(NH), 1214.2(P=O),
1054.2(P-O-C); Anal. calcd for C18H20FN2O3PS (394.40): C, 54.82; H, 5.11; N, 7.10; found: C,
54.66; H, 4.90; N, 7.50.
Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(2-fluorophenyl)methyl]phosphonate (4c):
1
White solid, mp 143-145 °C, yield, 79.2 %. H NMR: δH = 9.17 (d, J = 9.6 Hz, 1H, NH), 7.64
(dd, J = 8.7, 2.7 Hz, 2H, ArH), 7.42 (dd, J = 8.8, 4.8 Hz, 2H, ArH), 7.27 (dd, J = 13.5, 6.0 Hz,
2H, ArH), 7.10-7.03 (m, 1H, ArH), 5.97 (dd, J = 21.5, 9.7 Hz, 1H, CH), 4.13-3.79 (m, 4H,
2CH2), 1.19 (t, J = 7.0 Hz, 3H, CH3), 1.06 (t, J = 7.0 Hz, 3H, CH3). 13C NMR: δC = 165.8 (d, 3JPC
1
3
1
= 9.6 Hz), 160.1 (dd, JFC = 245.9, JPC = 6.1 Hz), 158.0 (d, JFC = 237.3 Hz), 148.6, 132.4 (d,
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3JFC = 11.0 Hz), 130.5 (d, 2JPC = 6.8 Hz), 129.9, 125.1, 123.8 (d, 3JFC = 15.0 Hz), 119.6 (d, 3JFC =
2
8.8 Hz), 115.8 (d, 2JFC = 21.9 Hz), 113.6 (d, 2JFC = 23.6 Hz), 108.5 (d, JFC = 27.3 Hz), 63.5 (d,
2JPC = 6.9 Hz), 63.2 (d, 2JPC = 7.0 Hz), 47.8 (d, 1JPC = 158.3 Hz), 16.8 (d, 3JPC = 5.0 Hz), 16.5 (d,
3JPC = 5.4 Hz). 31P NMR: 20.6. 19F NMR: 116.8, 121.2. IR: 3244.4(-NH), 1228.7(P=O),
1054.2(P-O-C); Anal. calcd for C18H19F2N2O3PS (412.39): C, 52.43; H, 4.64; N, 6.79; found: C,
52.01; H, 4.39; N, 6.85.
Diethyl [(4-methylbenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4d):
White solid, mp 117-119 °C, yield, 72.6 %. 1H NMR: δH = 8.95 (d, J = 9.3 Hz, 1H, NH), 7.46 (t,
J = 5.5 Hz, 2H, ArH), 7.23 (s, 1H, ArH), 7.07-6.98 (m, 2H, 2thiophene-H), 6.92 (t, J = 7.6 Hz,
1H, ArH), 5.93 (dd, J = 21.3, 9.4 Hz, 1H, CH), 4.02 (tdt, J = 37.2, 25.7, 8.8 Hz, 4H, 2CH2Me),
2.42 (s, 3H, ArCH3 ), 1.13 (t, J = 7.0 Hz, 3H, CH3), 1.08 (t, J = 7.0 Hz, 3H, CH3). 13C NMR: δC =
3
164.9 (d, JPC = 9.0 Hz), 150.8, 138.6, 130.9, 128.2, 127.5, 127.4, 126.8, 126.6, 121.9, 119.0,
63.5 (d, 2JPC = 6.7 Hz), 63.3 (d, 2JPC = 6.6 Hz), 50.4 (d, 1JPC = 160.6 Hz), 18.5, 16.8 (d, 3JPC = 5.1
3
31
Hz), 16.6 (d, JPC = 5.4 Hz). P NMR: 20.1. IR: 3223.2(NH), 1232.6(P=O), 1049.3(P-O-C);
Anal. calcd for C17H21N2O3PS2 (396.46): C, 51.50; H, 5.34; N, 7.07; found: C, 51.97; H, 5.09; N,
7.29.
Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4e): White
solid, mp 147-148 °C, yield, 72.9 %. 1H NMR: δH = 9.05 (d, J = 9.4 Hz, 1H, NH), 7.64 (dd, J =
8.7, 2.7 Hz, 1H, ArH), 7.50 (d, J = 5.1 Hz, 1H, ArH), 7.42 (dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.24
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(s, 1H, ArH), 7.07 (ddd, J = 15.4, 8.8, 3.8 Hz, 2H, 2thiophene-H), 5.90 (dd, J = 21.4, 9.4 Hz, 1H,
CH), 4.15 – 3.91 (m, 4H, 2CH2), 1.14 (dt, J = 14.0, 7.1 Hz, 6H, 2CH3). 13C NMR: δC = 165.8 (d,
3JPC = 8.6 Hz), 158.0 (d, 1JFC = 237.2 Hz), 148.6, 138.5, 132.5 (d, 3JFC = 11.0 Hz), 127.5, 127.4
(d, 2JPC = 6.5 Hz), 126.6, 119.5 (d, 3JFC = 8.8 Hz), 113.6 (d, 2JFC = 23.6 Hz), 108.6 (d, 2JFC = 27.2
Hz), 63.6 (d, 2JPC = 6.9 Hz), 63.3 (d, 2JPC = 6.7 Hz), 50.6 (d, 1JPC = 160.6 Hz), 16.8 (d, 3JPC = 5.2
Hz), 16.6 (d, 3JPC = 5.2 Hz). 31P NMR: 19.9. 19F NMR: 121.3. IR: 3213.6(-NH), 1231.6(P=O),
1052.2 (P-O-C); Anal. calcd for C18H19F2N2O3PS (400.42): C, 47.99; H, 4.53; N, 7.00; found: C,
47.86; H, 7.25; N, 7.17.
Diethyl [(2-chlorophenyl)(6-fluorobenzo[d]thiazol-2-ylamino)methyl]phosphonate (4f):
White solid, mp 146-148 °C, yield, 75.4 %. 1H NMR: δH = 9.10 (dd, J = 9.5, 3.4 Hz, 1H, NH),
7.66 (d, J = 7.7 Hz, 1H, ArH), 7.58 (dd, J = 8.7, 2.6 Hz, 1H ArH), 7.45 (d, J = 7.9 Hz, 1H ArH),
7.41-7.28 (m, 3H, ArH), 6.10 (dd, J = 21.3, 9.5 Hz, 1H, CH), 3.89 (m, J = 32.7, 25.6, 15.7, 8.1
Hz, 4H, 2CH2), 1.15 (t, J = 7.0 Hz, 3H, CH3), 1.00 (t, J = 7.0 Hz, 3H, CH3). 13C NMR: δC =
165.7 (d, 3JPC = 9.3 Hz), 158.0 (d, 1JFC = 237.0 Hz), 148.6, 134.5, 133.6 (d, 2JPC = 7.3 Hz), 132.5
(d,3JFC = 11.0 Hz), 130.1, 130.1, 129.8, 127.8, 119.6 (d, 3JFC = 8.6 Hz), 113.5 (d, 2JFC = 23.5 Hz),
108.5 (d, 2JFC = 27.3 Hz), 63.5 (d, 2JPC = 6.6 Hz), 63.2 (d, 2JPC = 6.8 Hz), 51.5 (d, 1JPC = 156.6
Hz), 16.8 (d, 3JPC = 4.9 Hz), 16.5 (d, 3JPC = 5.5 Hz). 31P NMR: 20.7. 19F NMR: 121.3. IR:
3245.5(NH), 1236.4(P=O), 1052.2 (P-O-C); Anal. calcd for C18H19ClFN2O3PS (428.84): C,
50.41; H, 4.47; N, 6.53; found: C, 49.97; H, 4.28; N, 6.57.
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Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(p-tolyl)methyl]phosphonate (4g): White solid,
mp 149-150 °C, yield, 74.7 %. 1H NMR: δH = 9.02 (dd, J = 9.7, 3.3 Hz, 1H, NH), 7.62 (dd, J =
8.7, 2.7 Hz, 1H, ArH), 7.43-7.35 (m, 3H, ArH), 7.19 (d, J = 8.0 Hz, 2H, ArH), 7.05 (td, J = 9.1,
2.7 Hz, 1H, ArH), 5.58 (dd, J = 21.4, 9.7 Hz, 1H, CH), 4.08-3.78 (m, 4H, 2CH2Me), 2.29 (s, 3H,
Ar-CH3), 1.15 (t, J = 7.0 Hz, 3H, CH3), 1.08 (t, J = 7.0 Hz, 3H, CH3). 13C NMR: δC = 165.9 (d,
3JPC = 9.9 Hz), 157.9 (d, 1JFC = 237.0 Hz), 148.8, 137.5, 133.3, 132.4(d, 3JFC = 11.0 Hz), 129.3,
129.3, 128.5, 128.5, 119.3 (d, 3JFC = 8.8 Hz), 113.4 (d, 2JFC = 23.7 Hz), 108.5 (d, 2JFC = 27.2 Hz),
63.2 (d, 2JPC = 6.8 Hz), 63.0 (d, 2JPC = 6.8 Hz), 54.8 (d, 1JPC = 154.0 Hz), 21.2, 16.8 (d, 3JPC = 5.0
Hz), 16.6 (d, 3JPC = 5.2 Hz). 31P NMR: 21.6. 19F NMR: 121.5. IR: 3213.6(NH), 1227.7(P=O),
1053.2 (P-O-C); Anal. calcd for C19H22FN2O3PS (408.11): C, 55.87; H, 5.43; N, 6.86; found: C,
55.85; H, 5.39; N, 6.90.
Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl]phosphonate (4h):
White solid, mp 148-150 °C, yield, 73.6 %. 1H NMR: δH = 8.96 (d, J = 12.8 Hz, 1H, NH), 7.57
(dd, J = 8.7, 2.6 Hz, 1H, ArH), 7.39 (d, J = 6.9 Hz, 2H, ArH), 7.34 (dd, J = 8.8, 4.8 Hz, 1H,
ArH), 7.01 (t, J = 9.0 Hz, 1H, ArH), 6.90 (d, J = 8.7 Hz, 2H, ArH), 5.52 (dd, J = 21.0, 9.7 Hz,
1H, CH), 4.04-3.74 (m, 4H, 2CH2), 3.70 (s, 3H, OCH3), 1.11 (t, J = 7.0 Hz, 3H, CH3), 1.03 (t, J
= 7.1 Hz, 3H, CH3). 13C NMR: δC = 165.9 (d, 3JPC = 10.0 Hz), 159.4, 157.9 (d, 1JFC = 237.0 Hz),
148.8, 132.4(d,3JFC = 11.3 Hz), 129.9, 129.8, 128.1, 119.3 (d, 2JFC = 8.6 Hz), 114.2, 114.2, 113.4
(d, 2JFC = 23.8 Hz), 108.5 (d, 2JFC = 27.3 Hz), 63.1 (d, 2JPC = 6.8 Hz), 62.9 (d, 2JPC = 6.8 Hz),
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55.6, 54.4 (d, 1JPC = 155.1 Hz), 16.8 (d, 3JPC = 5.1 Hz), 16.6 (d, 3JPC = 5.1 Hz). 31P NMR: 21.8.
19F NMR: 121.5. IR: 3221.3 (NH), 1225.8 (P=O), 1054.2 (P-O-C); Anal. calcd for
C19H22FN2O4PS (424.43): C, 53.77; H, 5.22; N, 6.60; found: C, 53.80; H, 5.25; N, 6.74.
Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(4-nitrophenyl)methyl]phosphonate (4i): White
solid, mp 124-125 °C, yield, 76.9 %. 1H NMR: δH = 9.22 (dd, J = 9.3, 4.4 Hz, 1H, NH), 8.28 (d,
J = 8.7 Hz, 2H, ArH), 7.80 (dd, J = 8.8, 1.9 Hz, 2H, ArH), 7.64 (dd, J = 8.7, 2.7 Hz, 1H, ArH),
7.37 (dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.06 (td, J = 9.1, 2.7 Hz, 1H, ArH), 5.83 (dd, J = 22.8, 9.3
Hz, 1H, CH), 4.16-3.86 (m, 4H, 2CH2), 1.17 (t, J = 7.0 Hz, 3H, CH3), 1.12 (t, J = 7.0 Hz, 3H,
CH3). 13C NMR: δC = 165.8 (d, 3JPC = 10.4 Hz), 158.0 (d, 1JFC = 237.4 Hz), 148.6, 147.6 (d, 4JFC
= 2.3 Hz), 144.4, 132.5 (d, 3JFC = 11.1 Hz), 129.7, 129.6, 124.0, 124.0, 119.6 (d, 3JFC = 9.0 Hz),
113.6 (d, 2JFC = 23.7 Hz), 108.6 (d, 2JFC = 27.3 Hz), 63.7 (d, 2JPC = 6.7 Hz), 63.4 (d, 2JPC = 6.7
Hz), 54.8 (d, 1JPC = 151.2 Hz), 16.8 (d, 3JPC = 5.1 Hz), 16.6 (d, 3JPC = 5.5 Hz). 31P NMR: 20.0.
19F NMR: 121.1. IR: 3215.5(-NH), 1239.3.6(P=O), 1046.4 (P-O-C); Anal. calcd for
C18H19FN3O5PS (439.40): C, 49.20; H, 4.36; N, 9.56; found: C, 48.96; H, 4.05; N, 9.69.
Diethyl [(6-methoxybenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4j):
White solid, mp 150-152 °C, yield, 76.7 %. 1H NMR: δH = 8.83 (dd, J = 9.5, 2.5 Hz, 1H, NH),
7.49 (d, J = 4.9 Hz, 1H, ArH), 7.34 (dd, J = 5.7, 2.8 Hz, 2H, ArH), 7.23 (s, 1H, thiophene-H),
7.03 (dd, J = 5.0, 3.6 Hz, 1H, thiophene-H), 6.84 (dd, J = 8.8, 2.6 Hz, 1H, ArH), 5.88 (dd, J =
21.5, 9.5 Hz, 1H, CH), 4.15-3.92 (m, 4H, 2CH2), 3.74 (s, 3H, OCH3), 1.16 (t, J = 6.5 Hz, 3H,
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CH3), 1.13 (t, J = 6.4 Hz, 3H, CH3). 13C NMR: δC = 164.2 (d, 3JPC = 8.7 Hz), 155.2, 146.0, 138.8,
132.5, 127.5, 127.3 (d, 2JPC = 6.7 Hz), 126.5, 119.4, 113.6, 106.1, 63.5 (d, 2JPC = 6.8 Hz), 63.2
(d, 2JPC = 6.9 Hz), 56.1, 50.6 (d, 1JPC = 160.6 Hz), 16.8 (d, 3JPC = 5.1 Hz), 16.6 (d, 3JPC = 5.5 Hz).
31P NMR: 20.0. IR: 3219.3(-NH), 1229.7(P=O), 1066.1 (P-O-C); Anal. calcd for C17H21N2O4PS2
(412.46): C, 49.50; H, 5.13; N, 6.79; found: C, 49.57; H, 4.74; N, 6.88.
Diethyl [(5-bromothiophen-2-yl)(6-fluorobenzo[d]thiazol-2-ylamino)methyl]phosphonate
(4k): White solid, mp 128-130 °C, yield, 78.3 %. 1H NMR: δH = 9.09 (dd, J = 9.3, 3.2 Hz, 1H,
NH), 7.70-7.61 (m, 2H, ArH, NH), 7.43 (dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.22-7.19 (m, 1H,
thiophene-H), 7.09 (td, J = 9.1, 2.8 Hz, 1H, thiophene-H), 5.85 (dd, J = 21.6, 9.3Hz, 1H, CH),
4.07 (qdd, J = 19.0, 13.8, 8.7 Hz, 4H, 2CH2), 1.19-1.17 (m, 3H, CH3), 1.17-1.15 (m, 3H, CH3).
13C NMR: δC = 165.7 (d, 3JPC = 9.2 Hz), 158.1 (d, 1JFC = 237.4 Hz), 148.5, 141.0, 132.6 (d, 3JFC
= 11.2 Hz), 129.3 (d, 2JPC = 6.7 Hz), 124.3, 119.66 (d, 3JFC = 8.7 Hz), 113.6 (d, 2JFC = 23.8 Hz),
108.7, 108.6 (d, 2JFC = 27.1 Hz), 108.6, 63.8 (d, 2JPC = 6.9 Hz), 63.5 (d, 2JPC = 6.6 Hz), 50.6 (d,
1JPC = 159.7 Hz), 16.8 (d, 3JPC = 5.2 Hz), 16.6 (d, 3JPC = 5.1 Hz). 31P NMR: 19.2. 19F NMR:
121.0. IR: 3211.6(-NH), 1223.9(P=O), 1050.2 (P-O-C); Anal. calcd for C16H17BrFN2O3PS2
(479.32): C, 40.09; H, 3.58; N, 5.84; found: C, 40.13; H, 3.51; N, 5.86.
Diethyl [(6-fluorobenzo[d]thiazol-2-ylamino)(thiophen-3-yl)methyl]phosphonate (4l): White
solid, mp 147-150 °C, yield, 78.1 %. 1H NMR: δH = 8.91 (dd, J = 9.6, 1.5 Hz, 1H, NH), 7.55
(ddd, J = 12.6, 8.3, 2.8 Hz, 3H, ArH), 7.36 (dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.21 (d, J = 4.9 Hz,
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1H, ArH), 7.03 (td, J = 9.1, 2.7 Hz, 1H, ArH), 5.74 (dd, J = 20.4, 9.7 Hz, 1H, CH), 4.05-3.80 (m,
4H, 2CH2), 1.08 (dt, J = 17.9, 7.0 Hz, 6H, 2CH3). 13C NMR: δC = 165.8 (d, 3JPC = 8.2 Hz), 157.9
(d, 1JFC = 236.7 Hz), 148.8, 136.5, 132.4 (d, 3JFC = 11.0 Hz), 128.1 (d, 3JPC = 3.1 Hz), 126.9,
124.1 (d, 2JPC = 8.8 Hz), 119.4 (d, 3JFC = 8.7 Hz), 113.5 (d, 2JPC = 23.8 Hz), 108.5 (d, 2JFC = 27.2
Hz), 63.2 (d, 2JPC = 6.7 Hz), 63.0 (d, 2JPC = 6.5 Hz), 51.2 (d, 1JPC = 157.4 Hz), 16.8 (d, 3JPC = 5.2
Hz), 16.6 (d, 3JPC = 5.5 Hz). 31P NMR: 20.9. 19F NMR: 121.5. IR: 3215.5(NH), 1250.9(P=O),
1049.3 (P-O-C); Anal. calcd for C16H18FN2O3PS2 (400.42): C, 47.99; H, 4.53; N, 7.00; found: C,
48.04; H, 4.42; N, 7.19.
Diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(2-fluorophenyl)methyl]phosphonate (4m):
White solid, mp 114-115 °C, yield, 71.5 %. 1H NMR: δH = 9.44 (d, J = 8.7 Hz, 1H, NH), 7.74 (s,
1H, ArH), 7.62 (d, J = 10.7 Hz, 1H, ArH), 7.46-7.38 (m, 2H, ArH), 7.28 (dd, J = 15.1, 7.9 Hz,
6H, ArH), 7.16 (d, J = 5.6 Hz, 2H, ArH), 7.05 (t, J = 11.3 Hz, 3H, ArH), 6.90 (d, J = 7.9 Hz, 2H,
ArH), 6.41 (dd, J = 22.0, 9.7 Hz, 1H, CH). 13C NMR: δC = 165.7 (d, 3JPC = 9.7 Hz), 161.1, 158.2
2
(d, 1JFC = 237.6 Hz), 150.4 (d, JPC = 9.8 Hz), 150.2 (d, 2JPC = 10.0 Hz), 148.4, 132.5 (d, 3JFC =
11.1 Hz), 131.3, 130.5, 130.4, 130.2, 126.1, 126.1, 125.5, 122.4, 122.5, 120.8, 120.8, 120.6,
3
2
2
120.6, 119.9 (d, JFC = 8.9 Hz), 116.1 (d, JFC = 20.7 Hz), 113.7 (d, JFC = 23.9 Hz), 108.6 (d,
1
31
19
2JFC = 27.5 Hz), 48.4 (d, JPC = 163.5 Hz). P NMR: 13.8. F NMR: 116.1, 120.9. IR:
3264.7(NH), 1207.5(P=O), 953.8 (P-OPh); Anal. calcd for C26H19F2N2O3PS (508.48): C, 61.42;
H, 3.77; N, 5.51; found: C, 60.98; H, 3.72; N, 5.60.
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Diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4n):
White solid, mp 138-139 °C, yield, 78.9 %. 1H NMR: δH = 9.37 (d, J = 9.5 Hz, 1H, NH), 7.63
(dd, J = 8.7, 2.7 Hz, 1H, ArH), 7.55 (d, J = 5.0 Hz, 1H, ArH), 7.43 (dd, J = 8.8, 4.8 Hz, 1H,
ArH), 7.36 (s, 1H, thiophene-H), 7.34-7.27 (m, 4H, ArH), 7.16 (dd, J = 15.9, 7.7 Hz, 2H), 7.05
(ddd, J = 27.5, 13.9, 7.9 Hz, 6H, thiophene-H), 6.37 (dd, J = 21.9, 9.5 Hz, 1H, CH). 13C NMR: δC
= 165.6 (d, 3JPC = 8.8 Hz), 158.1 (d, 1JFC = 237.5 Hz), 150.4 (d, 2JPC = 9.7 Hz), 150.2 (d, 2JPC =
9.6 Hz), 148.4, 136.8, 132.6 (d, 3JFC = 11.0 Hz), 130.5, 130.5, 130.4, 130.4, 128.5, 128.4, 127.8,
127.5, 126.0 (d, 2JPC = 7.4 Hz), 120.9, 120.9, 120.9,120.9, 119.8 (d, 3JFC = 8.7 Hz), 113.7 (d, 2JFC
= 23.8 Hz), 108.7 (d, 2JFC = 27.3 Hz), 51.0 (d, 1JPC = 165.4 Hz). 31P NMR: 13.2. 19F NMR:
120.9. IR: 3240.6 (NH), 1202.7 (P=O), 948.0 (P-OPh); Anal. calcd for C24H18FN2O3PS2
(496.51): C, 58.06; H, 3.65; N, 5.64; found: C, 58.10; H, 3.58; N, 5.90.
Diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(phenyl)methyl]phosphonate (4o): White
solid, mp 123-124 °C, yield, 76.2 %. 1H NMR: δH = 9.44 (dd, J = 9.8, 2.7 Hz, 1H, NH),
7.71-7.64 (m, 3H, ArH), 7.48-7.41 (m, 3H, ArH), 7.38 (dd, J = 8.9, 7.1 Hz, 1H, ArH), 7.35-7.29
(m, 4H, ArH), 7.18 (t, J = 7.4 Hz, 2H, ArH), 7.09 (td, J = 9.1, 2.7 Hz, 1H, ArH), 7.03 (d, J = 8.6
Hz, 2H, ArH), 6.95 (d, J = 8.7 Hz, 2H, ArH), 6.16 (dd, J = 22.1, 9.8 Hz, 1H, CH). 13C NMR : δC
= 165.8 (d, 3JPC = 8.1 Hz), 158.1 (d, 1JFC = 237.2 Hz), 150.5 (d, 2JPC = 10.1 Hz), 150.3 (d, 2JPC =
9.8 Hz), 148.6 (d, 4JFC = 1.3 Hz), 134.9, 132.5 (d, 3JFC = 11.2 Hz), 130.4, 130.4, 130.3, 130.3,
129.1, 129.1, 129.0, 128.9, 125.9, 125.9, 120.9, 120.9, 120.8, 120.8, 119.7 (d, 3JFC = 8.7 Hz),
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113.6 (d, 2JFC = 23.7 Hz), 108.6 (d, 2JFC = 27.3 Hz), 55.4 (d, 1JPC = 157.2 Hz). 31P NMR: 14.9.
19F NMR: 121.1. IR: 3269.5 (-NH), 1194.0 (P=O), 948.0 (P-OPh); Anal. calcd for
C26H20FN2O3PS (490.49): C, 63.67; H, 4.11; N, 5.71; found: C, 63.57; H, 3.90; N, 5.97.
Diphenyl [(2-chlorophenyl)(6-fluorobenzo[d]thiazol-2-ylamino)methyl]phosphonate (4p):
White solid, mp 109-112 °C, yield, 72.4 %. 1H NMR: δH = 9.47 (d, J = 9.6 Hz, 1H, NH), 7.81 (d,
J = 7.6 Hz, 1H, ArH), 7.63 (d, J = 8.7 Hz, 1H, ArH), 7.51 (d, J = 8.0 Hz, 1H, ArH), 7.41 (ddd, J
= 30.3, 15.8, 7.4 Hz, 3H, ArH), 7.29 (dt, J = 12.1, 8.0 Hz, 4H, ArH), 7.15 (dd, J = 16.6, 7.8 Hz,
2H, ArH), 7.05 (d, J = 8.8 Hz, 3H, ArH), 6.87 (d, J = 8.0 Hz, 2H, ArH), 6.63 (dd, J = 22.0, 9.6
Hz, 1H, CH). 13C NMR: δC = 165.6 (d, 3JPC = 9.6 Hz), 158.1 (d, 1JFC = 237.6 Hz), 150.4 (d, 2JPC
= 9.8 Hz), 150.2 (d, 2JPC = 9.5 Hz), 148.4, 133.7, 133.2, 132.6 (d, 3JFC = 11.2 Hz), 130.8, 130.5,
130.5, 130.4, 130.4, 130.4, 130.1, 128.3, 126.1, 126.0, 120.9, 120.9, 120.5, 120.5, 119.9 (d, 3JFC
= 8.8 Hz), 113.7 (d, 2JFC = 23.6 Hz), 108.7 (d, 2JFC = 27.4 Hz), 51.9 (d, 1JPC = 160.8 Hz). 31P
NMR: 13.9. 19F NMR: 120.8. IR: 3253.1 (-NH), 1205.6 (P=O), 948.0 (P-OPh); Anal. calcd for
C26H19ClFN2O3PS (524.93): C, 59.49; H, 3.65; N, 5.34; found: C, 59.50; H, 3.63; N, 5.70.
Diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl]phosphonate (4q):
White solid, mp 133-134 °C, yield, 76.2 %. 1H NMR: δH = 9.35 (dd, J = 9.8, 2.3 Hz, 1H, NH),
7.65 (dd, J = 8.7, 2.7 Hz, 1H, ArH), 7.59 (dd, J = 8.7, 1.9 Hz, 2H, ArH), 7.44 (dd, J = 8.8, 4.8
Hz, 1H, ArH), 7.36-7.28 (m, 4H, ArH), 7.18 (dd, J = 8.2, 6.6 Hz, 2H, ArH), 7.09 (td, J = 9.1, 2.7
Hz, 1H, ArH), 7.05-6.95 (m, 6H, ArH), 6.06 (dd, J = 21.5, 9.8 Hz, 1H, CH), 3.76 (s, 3H, OCH3).
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13C NMR: δC = 165.8 (d, 3JPC = 9.7 Hz), 159.8, 158.0 (d, 1JFC = 237.4 Hz), 150.6 (d, 2JPC = 9.9
Hz), 150.4 (d, 2JPC = 9.8 Hz), 148.6, 132.5 (d, 3JFC = 11.4 Hz), 130.4, 130.4, 130.3, 130.3, 130.3,
130.2, 126.7, 125.9, 125.9, 120.9, 120.9, 120.9, 120.8, 119.6 (d, 3JFC = 8.9 Hz), 114.6, 114.6,
113.6 (d, 2JFC = 23.7 Hz), 108.6 (d, 2JFC = 27.4 Hz), 55.7, 54.8 (d, 1JPC = 158.6 Hz). 31P NMR:
15.2. 19F NMR: 121.1. IR: 3252.1 (-NH), 1218.1 (P=O), 953.8 (P-OPh); Anal. calcd for
C27H22FN2O4PS (520.52): C, 62.30; H, 4.26; N, 5.38; found: C, 61.95; H, 4.02; N, 5.55.
Diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(o-tolyl)methyl]phosphonate (4r): White
solid, mp 137-138 °C, yield, 79.5 %. 1H NMR: δH = 9.45 (dd, J = 9.6, 2.9 Hz, 1H, NH), 7.72 (d,
J = 7.6 Hz, 1H, ArH), 7.65 (dd, J = 8.7, 2.7 Hz, 1H, ArH), 7.44 (dd, J = 8.8, 4.8 Hz, 1H, ArH),
7.37-7.25 (m, 7H, ArH), 7.22-7.15 (m, 2H, ArH), 7.1-7.06 (m, 3H, ArH), 6.87 (d, J = 8.6 Hz,
2H, ArH), 6.30 (dd, J = 22.1, 9.6 Hz, 1H, CH), 2.55 (s, 3H, CH3). 13C NMR: δC = 165.9 (d, 3JPC
= 11.1 Hz), 158.1 (d, 1JFC = 237.4 Hz), 150.5 (d, 2JPC = 9.8 Hz), 150.2 (d, 2JPC = 9.6 Hz), 148.5,
137.1 (d, 3JPC = 8.1 Hz), 133.9, 132.5 (d, 3JFC = 11.3 Hz), 130.9, 130.4, 130.4, 130.4, 130.4,
128.9, 128.7, 126.9, 126.0, 121.0 (d, 3JPC = 3.5 Hz), 121.0, 120.9, 120.7, 120.7, 119.7 (d, 2JPC =
9.0 Hz), 113.6 (d, 2JFC = 23.8 Hz), 108.6 (d, 2JFC = 27.2 Hz), 51.4 (d, 1JPC = 158.8 Hz), 20.0. 31P
NMR: 15.6. 19F NMR: 121.1. IR: 3246.3 (-NH), 1200.7 (P=O), 941.3 (P-OPh); Anal. calcd for
C27H22FN2O3PS (504.52): C, 64.28; H, 4.40; N, 5.55; found: C, 64.43; H, 4.07; N, 5.65.
Diphenyl [(6-methoxybenzo[d]thiazol-2-ylamino)(thiophen-2-yl)methyl]phosphonate (4s)
[23]: White solid, mp 118–120 °C, yield, 74.7 %. 1H NMR: δH = 9.20 (d, J = 17.6 Hz, 1H, NH),
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7.58 (d, J = 5.1 Hz, 1H, ArH), 7.42-7.30 (m, 7H, ArH), 7.20 (dd, J = 15.8, 7.6 Hz, 2H, ArH),
7.11-7.03 (m, 5H, ArH), 6.87 (dd, J = 8.8, 2.6 Hz, 1H, thiophene-H), 6.39 (dd, J = 22.0, 9.5 Hz,
1H, CH), 3.75 (s, 3H, OCH3). 13C NMR: δC = 164.1 (d, 3JPC = 9.3 Hz), 155.4, 150.5 (d, 2JPC =
9.7 Hz), 150.3 (d, 2JPC = 9.8 Hz), 145.8, 137.1, 132.6, 130.5, 130.5, 130.4, 130.4, 128.4, 128.3,
127.8, 127.4, 126.0, 126.0, 125.9, 120.9, 120.9, 119.6, 113.8, 106.2, 56.1, 51.0 (d, 1JPC = 165.6
Hz). 31P NMR: 13.5. IR: 3247.3 (NH), 1211.4 (P=O), 949.0 (P-OPh)); Anal. calcd for
C25H21N2O4PS2 (508.55): C, 59.05; H, 4.16; N, 5.51; found: C, 58.78; H, 3.81; N, 5.67.
Diphenyl [(2-fluorophenyl)(6-methoxybenzo[d]thiazol-2-ylamino)methyl]phosphonate (4t):
White solid, mp 116-118 °C, yield, 70.1 %.1H NMR: δH = 9.30 (dd, J = 9.8, 2.3 Hz, 1H, NH),
7.80 (t, J = 7.6 Hz, 1H, ArH), 7.45 (dd, J = 12.7, 6.7 Hz, 1H, ArH), 7.40 (d, J = 8.9 Hz, 1H,
ArH), 7.38-7.36 (m, 1H, ArH), 7.34 (d, J = 8.0 Hz, 4H, ArH), 7.33-7.27 (m, 2H, ArH), 7.20 (dd,
J = 13.2, 7.2 Hz, 2H, ArH), 7.08 (d, J = 8.4 Hz, 2H, ArH), 6.96 (d, J = 8.3 Hz, 2H, ArH), 6.87
(dd, J = 8.8, 2.6 Hz, 1H, CH), 3.75 (s, 3H, OCH3). 13C NMR: δC = 164.1 (d, 2JPC = 9.7 Hz),
160.1 (dd, 1JFC = 246.5, 3JPC = 6.5 Hz), 155.41, 150.44 (d, 2JPC = 9.7 Hz), 150.2 (d, 2JPC = 9.7
Hz), 145.8, 132.5, 131.2 (d, 3JFC = 8.2 Hz), 130.5, 130.5, 130.4, 130.4, 130.2, 126.0, 126.0,
125.4, 122.7, 122.6, 120.9, 120.9, 120.7, 120.6, 116.1 (d, 2JFC = 22.1 Hz), 113.8, 106.2, 56.1,
48.3 (d, 1JPC = 163.8 Hz). 31P NMR: 14.1. IR: 3259.8 (NH), 1206.5 (P=O), 948.1 (P-OPh); Anal.
calcd for C27H22FN2O4PS (520.52): C, 62.30; H, 4.26; N, 5.38; found: C, 62.11; H, 3.98; N, 5.44.
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Diphenyl [(5-bromothiophen-2-yl)(6-fluorobenzo[d]thiazol-2-ylamino)methyl]phosphon ate
(4u): White solid, mp 123-124 °C, yield, 74.7 %. 1H NMR: δH = 9.46 (dd, J = 9.5, 2.5 Hz, 1H,
NH), 7.75-7.67 (m, 2H, ArH), 7.49 (dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.42-7.32 (m, 5H, ArH), 7.22
(dt, J = 11.2, 7.4 Hz, 2H, ArH), 7.17-7.06 (m, 5H, ArH, thiophene-H), 6.47 (dd, J = 22.2, 9.4 Hz,
1H, CH). 13C NMR: δC = 165.6 (d, 2JPC = 9.3 Hz), 158.2 (d, 1JFC = 237.7 Hz), 150.4 (d, 2JPC =
9.7 Hz), 150.2 (d, 2JPC = 9.7 Hz), 148.4, 139.3, 132.7 (d, 3JFC = 11.3 Hz), 130.5, 130.5, 130.4,
130.4, 130.3, 126.2, 126.1, 125.2, 120.9, 120.9, 120.8, 120.8, 119.9 (d, 3JFC = 8.7 Hz), 113.8 (d,
2JFC = 23.7 Hz), 108.9, 108.75 (d, 2JFC = 27.4 Hz), 51.0 (d, 1JPC = 164.7 Hz). 31P NMR: 12.5. 19F
: 120.6. IR: 3238.6 (NH), 1204.6 (P=O), 949.0 (P-OPh); Anal. calcd for C24H17BrFN2O3PS2
(575.41): C, 50.10; H, 2.98; N, 4.87; found: C, 50.20; H, 3.01; N, 5.22.
Diphenyl [(6-fluorobenzo[d]thiazol-2-ylamino)(thiophen-3-yl)methyl]phosphonate (4v):
White solid, mp 138-140 °C, yield, 75.8 %. 1H NMR: δH = 9.34 (d, J = 9.7 Hz, 1H, NH), 7.79 (s,
1H, ArH, ArH), 7.68 (dd, J = 8.7, 2.7 Hz, 1H, ArH), 7.63 (dd, J = 5.0, 3.0 Hz, 1H, ArH), 7.47
(dd, J = 8.8, 4.8 Hz, 1H, ArH), 7.40 (d, J = 5.0 Hz, 1H, ArH), 7.37-7.30 (m, 4H, ArH), 7.19 (q, J
= 7.2 Hz, 2H, ArH), 7.11 (td, J = 9.1, 2.7 Hz, 1H, thiophene-H), 7.06-6.98 (m, 4H, ArH,
thiophene-H), 6.32 (dd, J = 20.7, 9.8 Hz, 1H, CH). 13C NMR: δC = 165.7 (d, 2JPC = 8.0 Hz),
158.1 (d, 1JFC = 237.3 Hz), 150.5 (d, 2JPC = 10.1 Hz), 150.4 (d, 2JPC = 9.8 Hz), 148.6, 134.9,
132.4 (d, 3JFC = 11.3 Hz), 130.4, 130.4, 130.3, 130.3, 128.2, 127.5, 125.9, 125.4, 125.3, 120.9,
120.9, 120.9, 120.9, 119.6 (d, 3JFC = 8.9 Hz), 113.7 (d, 2JFC = 23.6 Hz), 108.7 (d, 2JFC = 27.3 Hz),
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51.7 (d, 1JPC = 161.1 Hz). 31P NMR: 14.4. 19F NMR: 121.0. IR: 3250.2 (-NH), 1209.4 (P=O),
943.2 (P-OPh); Anal. calcd for C24H18FN2O3PS2 (496.51): C, 58.06; H, 3.65; N, 5.64; found: C,
57.98; H, 3.48; N, 5.60.
Conclusion
A series of a-aminophosphonates were synthesized through multicomponent reaction of
2-aminobenzothiazole, diphenyl phosphate (or dialkyl phosphate) and aldehydes. In general the
method is very green, cheap and convenient. The structures of compounds were verified by IR,
NMR and elemental analyses and their antiviral activities against TMV and PVY were evaluated.
The results showed that 4b, 4j and 4q exhibit higher antiviral activities against TMV and PVY in
vivo than Ribavirin, and are similar to Dufulin. As far as we know, this was the first indication
that this kind of compounds may possess potential anti-PVY activity. Further studies on the
structural optimization, design, and development of new antiviral agents are underway.
Acknowledgments
The authors gratefully acknowledge the National Natural Science Foundation of China (Nos.
21362004, 21562013) and Subsidy Project for Outstanding Key Laboratory of Guizhou Province
in China (20154004) and Collaborative Innovation Center for Natural Products and Biological
Drugs of Yunnan for supporting the project.
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Research highlights:
 a-aminophosphonates with 6-fluorobenzothiazole unit were synthesized.
 The analogs display good activities against tobacco mosaic virus.
 Compound 4q showed similar curative and protective activity against potato virus Y (PVY)
to Dufulin.
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Table 1: Optimization reaction conditions for the synthesis of a-aminophosphonates
temperature（°C
Entry
solvent
Time（min）
Yield(%)
）
1
2
acetonitrile
DMF
80
20
20
20
20
20
20
20
20
20
20
20
20
20
20
30
40
60
nr
80
4.3
3
DMSO
Pyridine
ethyl alcohol
toluene
toluene
toluene
NMP
80
nr
4
80
4.8
5
80
nr
6
80
9.4
7
90
12.8
20.3
25.6
33.1
37.9
42.7
46.8
47.0
51.6
66.5
67.9
8
100
100
120
130
140
150
160
150
150
150
9
10
11
12
13
14
15
16
17
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
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Reaction condition: aldehydes (1.0 mmol), amine (1.0 mmol) and phosphate (1.2 mmol) in
organic solvent (1.0 mL) under microwave irradiation at 60 W power.
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Table 2: Antiviral activities of the test compounds against tobacco mosaic virus (TMV) in vivo
at 500 μg/mL
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