Synthesis and herbicidal activity of O,O-dialkyl(phenyl)-N-{1-[(6- chloropyridin-3-yl)methyl]-4-cyano-1H-1,2,3-triazol-5-yl}-1-amino-1- substitutedbenzyl-phosphonates

Article abstract of DOI:10.1080/10426507.2010.505594

A series of novel -amino phosphonate derivatives containing both pyridine and 1,2,3-triazole moieties 4 were synthesized via a multi-step reaction. First, the condensation of 5-amino-1-[(6-chloropyridin-3-yl) methyl]-4-cyano-1H-1,2,3- triazole with various aromatic aldehydes in the presence of magnesium perchlorate afforded imines 3 in moderate yields; second, imines 3 reacted with dialkyl phosphites or triphenyl phosphite to give the title compounds 4 in moderate to good yields. Their structures were elucidated by spectroscopic data (IR, ¹H NMR, ³¹P NMR, ESI-MS) and elemental analysis. The preliminary bioassay (in vitro) indicated that some of the title compounds 4 possessed moderate herbicidal activities against dicotyledonous plants (Brassica campestris L) at a concentration of 100 mg/L. However, compounds 4 did not exhibit herbicidal activities against Brassica campestris L at a concentration of 10 mg/L. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.505594

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Synthesis and Herbicidal Activity of O,O-
Dialkyl(phenyl)-N-{1-[(6-chloropyridin-3-
yl)methyl]-4-cyano-1H-1,2,3-triazol-5-
yl}-1-amino-1-substitutedbenzyl-
phosphonates
Wu Tang a & De-Qing Shi a
a Key Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry , Central China Normal University ,
Wuhan, Hubei, People's Republic of China
Published online: 07 Mar 2011.
To cite this article: Wu Tang & De-Qing Shi (2011) Synthesis and Herbicidal Activity of O,O-
Dialkyl(phenyl)-N-{1-[(6-chloropyridin-3-yl)methyl]-4-cyano-1H-1,2,3-triazol-5-yl}-1-amino-1-
substitutedbenzyl-phosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:3,
496-502, DOI: 10.1080/10426507.2010.505594
To link to this article: http://dx.doi.org/10.1080/10426507.2010.505594
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Phosphorus, Sulfur, and Silicon, 186:496–502, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.505594
SYNTHESIS AND HERBICIDAL ACTIVITY OF
O,O-DIALKYL(PHENYL)-N-{1-[(6-CHLOROPYRIDIN-3-
YL)METHYL]-4-CYANO-1H-1,2,3-TRIAZOL-5-YL}-1-
AMINO-1-SUBSTITUTEDBENZYL-PHOSPHONATES
Wu Tang and De-Qing Shi
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Wuhan, Hubei,
People’s Republic of China
GRAPHICAL ABSTRACT
N
N
N
N
ArCHO
N
N
CN
Cl
NCCH CN
2
CN
NH
Cl
Cl
CH N
2
CHAr
N
3
N
Mg(ClO )
N
4 2
2
K CO /DMSO
N
2
3
3
1
2
N
HPO(OR)
2
N
N
CN
Cl
O
OR
OR
P(OPh)
3
HN
P
N
Ar
4
Abstract A series of novel α-amino phosphonate derivatives containing both pyridine and
1,2,3-triazole moieties 4 were synthesized via a multi-step reaction. First, the condensation of
5-amino-1-[(6-chloropyridin-3-yl) methyl]-4-cyano-1H-1,2,3-triazole with various aromatic
aldehydes in the presence of magnesium perchlorate afforded imines 3 in moderate yields;
second, imines 3 reacted with dialkyl phosphites or triphenyl phosphite to give the title com-
pounds 4 in moderate to good yields. Their structures were elucidated by spectroscopic data
(IR, 1H NMR, 31P NMR, ESI-MS) and elemental analysis. The preliminary bioassay (in vitro)
indicated that some of the title compounds 4 possessed moderate herbicidal activities against
dicotyledonous plants (Brassica campestris L) at a concentration of 100 mg/L. However, com-
pounds 4 did not exhibit herbicidal activities against Brassica campestris L at a concentration
of 10 mg/L.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords α-Amino phosphonate; herbicidal activity; pyridine; triazole
Received 15 May 2010; accepted 28 June 2010.
The authors are grateful to the Natural Science Foundation of China (Grant No. 20872046) and the Natural
Science Foundation of Hubei Province (Grant No. 2008CDB086) for the financial support.
Address correspondence to De-Qing Shi, Key Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University, Wuhan 430079, Hubei, People’s Republic of
China. E-mail: chshidq@mail.ccnu.edu.cn
496

SYNTHESIS OF α-AMINO PHOSPHONATE DERIVATIVES
497
CH3
NH
C2H5
CH3
CH2 N
CH2 N CH3
NH
Cl
CH2 N
HC CN
Nitenpyram
N CN
Acetamiprid
N
Cl
N
Cl
N
NNO2
Imidacloprid
Figure 1 Structures of some commercial pyridine-containing pesticides.
INTRODUCTION
α-Amino phosphonic acids and their ester derivatives, as bioisosteres of natural
amino acids, are receiving increasing attention in medicinal chemistry and pesticide sci-
ence, because some α-amino phosphonic acid derivatives have been found to exhibit a wide
range of biological activities such as enzyme inhibition, antibiotics, and haptens of cat-
alytic antibodies, fungicides, herbicides, plant regulators, and plant virucides [for example,
antiviral agent against tobacco mosaic virus (TMV)].1–7 For example, glyphosate is one
of the best-selling herbicides in the world agrochemical market. Moreover, nitrogen hete-
rocyclic compounds have played a major role in modern pesticide industry; it is reported
that more than 85% of pesticides with high activity and low toxicity were nitrogen hetero-
cyclic compounds. In the study of pharmaceuticals and agrochemicals, the introduction of
pyridine into the parent compounds may improve their properties and biological activities,
and many pyridine-containing compounds are known to possess a wide range of biologi-
cal and pharmacological activities as well as low toxicity toward mammals.8–11 Moreover,
5-(aminomethyl)-2-chloro-pyridine is an important pharmacophore in neonicotinoid insec-
ticides, and many derivatives containing the pyridine nucleus have been commercialized as
pesticides in plant protection (see Figure 1). Recently, click chemistry is a modular approach
that uses only the most practical and reliable chemical transformations. Its applications are
increasingly found in all aspects of drug discovery using bioconjugation reactions. It works
well in conjunction with structure-based design and combinatorial chemistry techniques,
and, through the choice of appropriate building blocks, can provide derivatives or mimics
of “traditional” pharmacophores, drugs, and natural products.12–15 However, the real power
of click chemistry lies in its ability to generate novel structures that might not necessarily
resemble known pharmacophores. The triazole products are more than just passive link-
ers; they readily associate with biological targets, through hydrogen bonding, and dipole
interactions. Moreover, it is well known that many 1,2,3-triazole-related molecules play
an important role in the development of agrochemicals such as insecticides, nematocides,
acaricides, and plant growth regulators.16–19 As a continuation of our research work—with
an attempt to find novel biologically α-amino phosphonate derivatives containing nitrogen
heterocycles,20,21 a series of novel α-amino phosphonate derivatives containing both 1,2,3-
triazole and pyridine moieties 4 were synthesized via a 1,2,3-triazole unit linking α-amino
phosphonate and (6-chloropyridin-3-yl)methyl moieties. Their preliminary herbicidal ac-
tivities were also evaluated in this article. The synthetic route is listed in Scheme 1.
RESULTS AND DISCUSSION
Synthesis and Structure Determination of Title Compounds 4
A series of novelα-amino phosphonate derivatives containing both pyridine and 1,2,3-
triazole moieties 4 were synthesized via the multistep reactions; 2-chloro-5-(chloromethyl)-

498
W. TANG AND D.-Q. SHI
N
N
Cl
Cl
NCCH2CN
N
ArCHO
CN
N
CN
Cl
N3
Cl
N
N
K2CO3/DMSO
N
N
N
Mg(ClO4)2
NH2
N CH Ar
1
2
3
N
CN
HPO(OR)2
or P(OPh)3
N
O
P
N
OR
OR
N
HN
4
Ar
R = Et, Ar = Ph (4a); R = Ph, Ar = Ph (4b); R = Et, Ar = 3,4-Cl2C6H3 (4c);
R = Ph, Ar = 3,4-Cl2C6H3 (4d); R = Ph, Ar = 4-NO2C6H4 (4e); R = Et, Ar = 4-CH3OC6H4 (4f);
R = CH3, Ar = 3,4-Cl2C6H3 (4g); R = Et, Ar = 4-ClC6H4 (4h); R = Ph, Ar = 4-ClC6H4 (4i).
Scheme 1 Synthesis route of the title compounds 4.
pyridine reacted with sodium azide to generate 5-(azidomethyl)-2-chloro-pyridine 1, which
reacted with malononitrile in the presence of potassium carbonate to yield 5-amino-1-[(6-
chloropyridin-3-yl)methyl]-4-cyano-1H-1,2,3-triazole 2. When we choose the Mannich-
type reaction of amine 2, aromatic aldehydes, and dialkyl phosphites or triphenyl phosphite
in the presence of magnesium perchlorate to synthesize the target compounds 4—α-amino
phosphonate derivatives containing both pyridine and 1,2,3-triazole moieties, only inter-
mediate imines 3 were formed. Finally, imines 3 reacted with excess dialkyl phosphites or
triphenyl phosphite to give 4 in moderate to good yields. Their structures were deduced
from their spectral data (IR, 1H NMR, 31P NMR, ESI-MS) and elemental analysis. In the
1H NMR spectra of 4, the methine proton linking with the phosphonyl group was displayed
as a doublet of doublets due to coupling with P and NH with coupling constants of 24 and
10 Hz, respectively. The methylene protons exhibited two doublets because of their differ-
ent chemical surroundings and coupling with each other with a coupling constant of 16 Hz,
while the NH proton appeared as a broad singlet with a variable chemical shift δ 6.0–7.0, in
some cases, the NH signal peaks disappeared in 1H NMR spectrum. For 31P NMR spectra,
all compounds displayed a singlet in the range δ 13–20. The IR spectra of compounds
4 showed the expected stretching absorption bands indicating the existence of the NH
(3200–3300 cm−1), C N (∼2230 cm−1), P O (∼1225 cm−1), P O C (∼1025 cm−1
)
moieties. The ESI-MS of compounds 4 revealed the existence of their strong molecular ion
peaks, which were in accordance with the given structures of products 4.
Herbicidal Activities
The herbicidal activity values of the title compounds 4 against Brassica campestris
L (rape) and Echinochloa crus-galli (barnyard grass) have been investigated at dosages of
100 mg/L and 10 mg/L compared with the commercially available herbicide, glyphosate,
according to the method described in the Supplemental Materials (available online).
CONCLUSION
In summary, we have synthesized a series of novel α-amino phosphonate derivatives
containing both pyridine and 1,2,3-triazole moieties 4 via a multistep reaction. Finally,

SYNTHESIS OF α-AMINO PHOSPHONATE DERIVATIVES
499
imines 3 reacted with dialkyl phosphites or triphenyl phosphite to generate the title com-
pounds 4 in moderate to good yields. The preliminary bioassay (in vitro) indicated that some
of the title compounds 4 possessed moderate herbicidal activities against dicotyledonous
plants (Brassica campestris L) at the concentration of 100 mg/L. However, compounds 4
did not exhibit herbicidal activities against Brassica campestris L at the concentration of
10 mg/L.
EXPERIMENTAL
Instruments
The melting points of the products were determined on an XT-4 binocular microscope
(Beijing Tech Instrument Co., Beijing, China) and were uncorrected. The IR spectra were
recorded on a Nicolet NEXUS470 spectrometer as KBr pellets with absorption given in
cm−1. 1H and 31P NMR spectra were performed on a Varian Mercury Plus-400 (400 MHz)
or Varian Mercury Plus-600 (600 MHz) spectrometer at room temperature in CDCl3 with
TMS and 85% H3PO4 as the internal and external standards, respectively. Mass spectra
were measured on an Applied Biosystems API 2000 LC/MS/MS (ESI-MS) spectrometer.
Elemental analysis was taken on a Vario EL III elemental analysis instrument. Analytical
TLC was performed on silica gel GF254. Column chromatographic purification was carried
out using silica gel. Unless otherwise noted, all materials were commercially available and
were used directly without further purification. All solvents were dried and redistilled before
use. 5-(Azidomethyl)-2-chloro-pyridine 1 was prepared by the nucleophilic substitution of
2-chloro-5-(chloromethyl)-pyridine with sodium azide in refluxing ethanol in 95% yield
according to the reported procedure.22
Synthesis of 5-Amino-1-[(6-chloropyridin-3-yl)methyl]-4-cyano-1H-
1,2,3-triazole 223
Compound 1 (8.4 g, 5 mmol), malononitrile (3.3 g, 5 mmol), and anhydrous potassium
carbonate (20.7 g, 15 mmol) in DMSO (50 mL) were stirred at 40–50◦C for 1 h (monitored
by TLC). The mixture was poured into water (250 mL), and the solid was filtered, then
washed with ethanol and ethyl ether, respectively. Compound 2 was obtained as a light
yellow solid, yield: 90%; mp 215–217◦C.
Synthesis of 5-(Arylmethyleneamino)-1-[(6-chloropyridin-
3-yl)methyl]-4-cyano-1H-1,2,3-triazoles 3
Compound 2 (0.7g, 3 mmol), substituted benzaldehyde (3 mmol), magnesium per-
chlorate (0.03 g, 0.15 mmol) in toluene (20 mL), and DMSO (2 mL) were stirred under
refluxing. The water formed was removed until no further water was formed or the reaction
was complete as monitored by TLC. The mixture was concentrated under vacuum, and
the crude product was purified by column chromatography on silica gel using a mixture of
petroleum ether and acetone (4:1) as an eluent to give 3 as yellow solids in 69–83% yields,
which can be used without further purification.

500
W. TANG AND D.-Q. SHI
General Synthetic Procedures for O,O-Dialkyl(phenyl)-N-{1-[(6-
chloropyridin-3-yl)methyl]-4-cyano-1H-1,2,3-triazol-5–yl}-1-amino-1-
substitutedbenzyl Phosphonates 4
Compound 3 (1 mmol) and dimethyl phosphite, diethyl phosphite, or triphenyl phos-
phite (10 mmol) were stirred under reflux (90–160◦C) for 3–12 h (monitored by TLC). The
mixture was concentrated under vacuum, and the crude product was purified by column
chromatography on silica gel using a mixture of petroleum ether and acetone (4:1) as an
eluent to give 4 as white or yellow solids in 46–87% yields.
Data for 4a (R = Et, Ar = C6H5). Yield 81%, white solid, mp 154–156◦C; IR
(KBr): υ 3215 (N-H), 3024 (Ar), 2246 (CN), 1263 (P O), 1042 (P O C) cm−1; 1H NMR
(CDCl3, 400 MHz): δ 1.04 (t, J = 7.2 Hz, 3H, CH2CH3), 1.30 (t, J = 7.2 Hz, 3H, CH2CH3),
3.54–3.58 (m, 1H, OCH2), 3.80–3.84 (m, 1H, OCH2), 4.07–4.15 (m, 2H, OCH2), 5.19 (dd,
J = 10.0 Hz, J = 23.2 Hz, 1H, PCH), 5.42 (d, J = 15.6 Hz, 1H, CH2), 5.48 (d, J = 15.6 Hz,
1
1H, CH2), 6.75 (s, 1H, NH), 7.27–7.43 (m, 7H, ArH, PyH), 8.37 (s, 1H, PyH); 31P { H}
NMR (CDCl3, 162 MHz): δ 18.6; ESI-MS: m/z 498 (M+K-1, 12), 482 (M+Na-1, 59), 460
(M+, 100). Anal. Calcd for C20H22ClN6O3P: C 52.12, H 4.81, N 18.24; found C 52.31, H
4.76, N 18.35.
Data for 4b (R = C6H5, Ar = C6H5). Yield 87%, light yellow crystals, mp
183–184◦C; IR (KBr): υ 3262 (N-H), 3077 (ArH), 2232 (CN), 1584, 1488, 1455 (Ar),
1251 (P O), 1158 (P O C), 952, 927 cm−1; 1H NMR (CDCl3, 400 MHz): δ 5.09 (d, J =
15.6 Hz, 1H, CH2), 5.17 (d, J = 15.6 Hz, 1H, CH2), 5.60 (dd, J = 10.0 Hz, J = 24.2 Hz, 1H,
PCH), 6.42 (d, J = 8.0 Hz, 2H, ArH), 7.01–7.14 (m, 8H, ArH), 7.23–7.43 (m, 5H, ArH),
1
7.58 (d, J = 7.6 Hz, 2H, PyH), 7.95 (s, 1H, PyH); 31P { H} NMR (CDCl3, 243 MHz): δ
13.4; ESI-MS: m/z 578 (M+Na-1, 16), 556 (M+, 100). Anal. Calcd for C28H22ClN6O3P:
C 60.38, H 3.98, N 15.09; found C 60.10, H 3.91, N 15.24.
Data for 4c (R = Et, Ar = 3,4-Cl2C6H3). Yield 80%, white solid, mp 183–185◦C;
IR (KBr): υ 3212 (N-H), 3070, 2980 (Ar), 2229 (CN), 1594, 1461, 1396, 1336 (Ar), 1238
1
(P O), 1023 (P O C) cm−1; H NMR (CDCl3, 400 MHz): δ 1.14 (t, J = 7.2 Hz, 3H,
CH2CH3), 1.26 (t, J = 7.2 Hz, 3H, CH2CH3), 3.69–3.75 (m, 1H, OCH2), 3.90–3.96 (m,
1H, OCH2), 4.04–4.08 (m, 2H, OCH2), 5.12 (dd, J = 9.2 Hz, J = 23.8 Hz, 1H, PCH), 5.48
(d, J = 16.0 Hz, 1H, CH2), 5.57 (d, J = 16.0 Hz, 1H, CH2), 6.43 (s, 1H, NH), 7.23–7.50
1
(m, 4H, ArH, PyH), 7.51 (d, J = 8.4 Hz, 1H, PyH), 8.46 (s, 1H, PyH); 31P { H} NMR
(CDCl3, 162 MHz): δ 18.6; ESI-MS: m/z 551 (M+Na, 5), 529 (M+1, 100). Anal. Calcd
for C20H20ClN6O3P: C 45.35, H 3.81, N 15.86; found C 45.17, H 3.92, N 15.93.
Data for 4d (R = C6H5, Ar = 3,4-Cl2C6H3). Yield 77%, light yellow solid, mp
193–195◦C; IR (KBr): υ 3215 (N-H), 2986 (Ar), 2231 (CN), 1597, 1465, 1354 (Ar), 1235
(P O), 1028 (P O C) cm−1; 1H NMR (CDCl3, 400 MHz): δ 5.06 (d, J = 15.2 Hz, 1H,
CH2), 5.19 (d, J = 15.6 Hz, 1H, CH2), 5.53 (dd, J = 10.0 Hz, J = 24.2 Hz, 1H, PCH),
6.65 (s, 1H, NH), 6.74 (d, J = 7.6 Hz, 2H, PyH), 7.03 (d, J = 7.2 Hz, 2H, ArH), 7.13–7.40
1
(m, 10H, ArH), 7.55 (s, 1H, PyH), 8.21 (s, 1H, ArH); 31P { H} NMR (CDCl3, 162 MHz):
δ 19.4; ESI-MS: m/z 647 (M+Na, 12), 626.5 (M+2, 81), 624.6 (M+, 100), 403 (35), 327
(42), 274 (51). Anal. Calcd for C28H20Cl3N6O3P: C 53.74, H 3.22, N 13.43; found C 53.68,
H 3.15, N 13.50.
Data for 4e (R = C6H5, Ar = 4-NO2C6H4). Yield 46%, white solid, mp
210–211◦C; IR (KBr): υ 3210 (N-H), 2995 (Ar), 2237 (CN), 1591, 1464, 1352 (Ar),
1238 (P O), 1040 (P O C) cm−1; 1H NMR (CDCl3, 400 MHz): δ 5.09 (d, J = 15.6 Hz,
1H, CH2), 5.17 (d, J = 15.6 Hz, 1H, CH2), 5.97 (dd, J = 9.6 Hz, J = 23.6 Hz, 1H, PCH),

SYNTHESIS OF α-AMINO PHOSPHONATE DERIVATIVES
501
6.28 (s, 1H, NH), 6.65 (d, J = 8.4 Hz, 2H, PyH), 7.09 (d, J = 8.0 Hz, 2H, ArH), 7.16
1
(d, J = 8.0 Hz, 2H, ArH), 7.19–7.43 (m, 10H, ArH), 8.11 (s, 1H, PyH); 31P { H} NMR
(CDCl3, 162 MHz): δ 20.2; ESI-MS: m/z 622 (M+Na-1, 69), 601 (M+, 100). Anal. Calcd
for C28H21ClN7O5P: C 55.87, H 3.52, N 16.29; found C 55.98, H 3.31, N 16.50.
Data for 4f (R = Et, Ar = 4-MeOC6H4). Yield 62%, white solid, mp 169–170◦C;
IR (KBr): υ 3218 (N-H), 2991 (Ar), 2238 (CN), 1591, 1455, 1380 (Ar), 1235 (P O), 1037
(P O C) cm−1; 1H NMR (CDCl3, 600 MHz): δ 1.04 (t, J = 7.2 Hz, 3H, CH2CH3), 1.30
(t, J = 7.2 Hz, 3H, CH2CH3), 3.50–3.52 (m, 1H, OCH2), 3.78 (s, 3H, OCH3), 3.80–3.84
(m, 1H, OCH2), 4.06–4.12 (m, 2H, OCH2), 5.06 (dd, J = 9.0 Hz, J = 23.1 Hz, 1H, PCH),
5.42 (d, J = 16.2 Hz, 1H, CH2), 5.51 (d, J = 16.2 Hz, 1H, CH2), 6.00 (s, 1H, NH), 6.82
(d, J = 8.0 Hz, 2H, ArH), 7.24 (d, J = 8.4 Hz, 2H, ArH), 7.31 (d, J = 8.4 Hz, 1H,
1
PyH), 7.48 (d, J = 8.0 Hz, 1H, PyH), 8.42 (s, 1H, PyH); 31P { H} NMR (CDCl3, 243
MHz): δ 20.6; ESI-MS: m/z 512 (M+Na-1, 18), 490 (M+, 52), 257 (100). Anal. Calcd for
C21H24ClN6O4P: C 51.38, H 4.93, N 17.12; found C 51.53, H 4.99, N 17.35.
Data for 4g (R = CH3, Ar = 3,4-Cl2C6H3). Yield 67%, white solid, mp
175–176◦C; IR (KBr): υ 3212 (N-H), 2995 (Ar), 2241 (CN), 1585, 1452, 1376 (Ar),
1236 (P O), 1042 (P O C) cm−1; 1H NMR (CDCl3, 600 MHz): δ 3.54 (d, J = 10.8 Hz,
3H, OCH3), 3.76 (d, J = 10.8 Hz, 3H, OCH3), 5.14 (dd, J = 9.0 Hz, J = 24.0 Hz, 1H,
PCH), 5.47 (d, J = 16.2 Hz, 1H, CH2), 5.56 (d, J = 15.6 Hz, 1H, CH2), 6.36 (s, 1H, NH),
7.22 (d, J = 7.6 Hz, 1H, PyH), 7.35 (d, J = 8.4 Hz, 1H, ArH), 7.42 (s, 1H, ArH), 7.44 (d,
1
J = 8.4 Hz, 1H, ArH), 7.50 (d, J = 7.6 Hz, 1H, PyH), 8.44 (s, 1H, PyH); 31P { H} NMR
(CDCl3, 243 MHz): δ 20.3; ESI-MS: m/z 522 (M+Na-1, 12), 500 (M+, 100). Anal. Calcd
for C18H16Cl3N6O3P: C 43.09, H 3.21, N 16.75; found C 42.94, H 3.07, N 16.90.
Data for 4h (R = Et, Ar = 4-ClC6H4). Yield 72%, white solid, mp 176–178◦C;
IR (KBr): υ 3241 (N-H), 3070, 2987 (Ar), 2227 (CN), 1591, 1492, 1459, 1340 (Ar), 1228
1
(P O), 1019 (P O C) cm−1; H NMR (CDCl3, 600 MHz): δ 1.09 (t, J = 7.2 Hz, 3H,
CH2CH3), 1.28 (t, J = 7.2 Hz, 3H, CH2CH3), 3.61–3.63 (m, 1H, OCH2), 3.85–3.88 (m,
1H, OCH2), 4.05–4.12 (m, 2H, OCH2), 5.13 (dd, J = 9.6 Hz, J = 23.7 Hz, 1H, PCH), 5.46
(d, J = 15.6 Hz, 1H, CH2), 5.53 (d, J = 15.6 Hz, 1H, CH2), 6.53 (s, 1H, NH), 7.27–7.33
1
(m, 5H, ArH, PyH), 7.48 (d, J = 7.6 Hz, 1H, PyH), 8.42 (s, 1H, PyH); 31P { H} NMR
(CDCl3, 243 MHz): δ 19.3; ESI-MS: m/z 532 (M+K-1, 38), 516 (M+Na-1, 8), 494 (M+,
100). Anal. Calcd for C20H21Cl2N6O3P: C 48.50, H 4.27, N 16.97; found C 48.27, H 4.34,
N 16.76.
Data for 4i (R = C6H5, Ar = 4-ClC6H4). Yield 84%, white solid, mp 110–112◦C;
IR (KBr): υ 3242 (N-H), 2986 (Ar), 2225 (CN), 1588, 1461, 1345 (Ar), 1231 (P O), 1024
1
(P O C) cm−1; H NMR (CDCl3, 600 MHz): δ 4.98 (s, 2H, CH2), 5.49 (dd, J = 9.6
Hz, J = 24.6 Hz, 1H, PCH), 6.63 (d, J = 8.4 Hz, 2H, ArH), 6.98 (s, 1H, NH), 7.02–7.33
1
(m, 12H, PyH, ArH), 7.43 (d, J = 8.4 Hz, 2H, ArH), 8.04 (s, 1H, PyH); 31P { H} NMR
(CDCl3, 243 MHz): δ 19.7; ESI-MS: m/z 612 (M+Na-1, 35), 590 (M+, 100). Anal. Calcd
for C28H21Cl2N6O3P: C 56.87, H 3.58, N 14.21; found C 56.93, H 3.47, N 14.39.
REFERENCES
1. Kuhkar, V. P.; Hudson, H. R. Eds. Synthesis of α-Aminoalkanephosphonic and α-
Aminophosphinic Acids; John Wiley and Sons: Chichester, UK, 2000.
2. Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899–931.
3. Gioia, P. L.; Chuah, P. H.; Sclapari, T. WO Patent 2007,054,540, 2007.
4. Kafarski, P.; Lejczak, B. Curr. Med. Chem. Anti-Cancer Agents 2001, 1, 301–312.

502
W. TANG AND D.-Q. SHI
5. Lintunen, T.; Yli-Kauhaluoma, J. T. Bioorg. Med. Chem. Lett. 2000, 10, 1749–1750.
6. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193–215.
7. Chen, M. H.; Chen, Z.; Song, B. A.; Bhadury, P. S.; Yang, S.; Cai, X. J.; Hu, D. Y.; Xue, W.;
Zeng, S. J. Agric. Food Chem. 2009, 57, 1383–1388.
8. Liu, M. C.; Lin, T. S.; Cory, J. G.; Cory, A. H.; Sartorelli, A. C. J. Med. Chem. 1996, 39,
2586–2593.
9. Finkelstein, B. L.; Martz, M. A.; Strock, C. J. Pestic. Sci. 1997, 50, 319–323.
10. Li, G. Y.; Qian, X. H.; Cui, J. N.; Huang, Q. C.; Zhang, R.; Guan, H. J. Agric. Food Chem. 2006,
54, 125–129.
11. Jo, Y. W.; Im, W. B.; Rhee, J. K.; Shim, M. J.; Kim, W. B.; Choi, E. C. Bioorg. Med. Chem. 2004,
12, 5909–5915.
12. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8(24), 1128–1137.
13. Kolb, H. C. Angew. Chem. Int. Ed. Engl. 2001, 40, 2004–2021.
14. Sneader, W., Ed. Drug Prototypes and Their Exploitation; John Wiley & Sons: Chichester, UK,
1996.
15. Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887–2893.
16. Ogura, T.; Numata, A.; Ueno, H.; Masuzawa, Y. WO Patent 039 106, 2000.
17. Najim, A. A.; Yaseen, A. A.; Asmehan, A. Heteroat. Chem. 2004, 15, 380–387.
18. Banks, B. J.; Chubb, N. A. EP Patent 957 094, 1999.
19. Shuto, A.; Kisida, H.; Tsuchiya, T.; Takada, Y.; Fujimoto, H. WO Patent 9 529 175, 1996.
20. Tang, W.; Yu, Z. H.; Shi, D. Q. Heteroat. Chem. 2010, 21(3), 148–155.
21. Tang, W.; Shi, D. Q. J. Heterocycl. Chem. 2010, 47(1), 162–166.
22. (a) Schneider, P. EP Patent 256990, 1988; (b) Zhu, X. F.; Chen, X. B.; Yan, M.; Shi, D. Q.; Ding,
K. R. Heteroat. Chem. 2008, 19(1), 15–20.
23. Cottrell, I. F.; Hands, D.; Houghton, P. G.; Humphrey, G. R.; Wright, S. H. B. J. Heterocycl.
Chem. 1991, 28, 301–307.