Synthesis, crystal structure, and herbicidal activity of pyrimidinyl benzylamine analogues containing a phosphonyl group

Article abstract of DOI:10.1002/hc.20589

A series of pyrimidinyl benzylamine analogues containing a phosphonyl group (2)was synthesized via the Mannich-type reactions of 2-(4,6- dimethoxypyrimidin-2-yloxy)benzoaldehyde l,aro- matic amines, and dialkyl phosphites or triphenyl phosphite in the pre

Full text of DOI:10.1002/hc.20589

Heteroatom Chemistry
Volume 21, Number 3, 2010
Synthesis, Crystal Structure, and Herbicidal
Activity of Pyrimidinyl Benzylamine Analogues
Containing a Phosphonyl Group
Wu Tang, Zhi-Hua Yu, and 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
Received 24 November 2009; revised 10 February 2010, 18 February 2010
INTRODUCTION
ABSTRACT: A series of pyrimidinyl benzylamine
analogues containing a phosphonyl group (2) was
synthesized via the Mannich-type reactions of 2-(4,6-
dimethoxypyrimidin-2-yloxy)benzoaldehyde 1, aro-
matic amines, and dialkyl phosphites or triphenyl
phosphite in the presence of Mg(ClO4)2. Their struc-
tures were characterized by spectroscopic data (in-
frared, 1H NMR, 31P NMR, and mass spectrome-
try) and elemental analyses, and compound 2b was
further determined by X-ray diffraction crystallogra-
phy. The results of preliminary bioassays (in vitro)
showed that most of title compounds 2 exhibited
higher herbicidal activities against dicotyledonous
weeds (Brassica campestris L.) than monocotyle-
donous weeds (Echinochloa crus-galli). Further bioas-
says (in vivo) indicated that some of 2 displayed as
good herbicidal activity against amaranth pigweed
(Amaranthus retroflexus) as the commercially avail-
able herbicide, Bispyribac-sodium, in both preemer-
gence and postemergence treatments at the dose of 1.5
Pyrimidinyl carboxylic acid derivatives are effec-
tive herbicides against barnyard grass in different
growth stages including preemergence treatment;
they also exhibit excellent safety on transplanted rice
crops, animals, and fish. These herbicides, which are
known as inhibitors of branched chain amino acid
(acetolactate or acetohydroxyacid) synthase, have
attracted considerable attention from the field of
pesticide scientists [1–5]. To date, several pyrimidyl
carboxylic acid derivatives, such as Pyriminobac-
methyl, have been used as commercially herbicides.
Furthermore, pyrimidyl benzylamine derivatives, for
example, N-[4-(propanoxycarbonyl)phenyl]-2-(4,6-
dimethoxypyrimidin-2-yloxy)benzylamine (ZJ0273),
have also been reported to show good herbicidal ac-
tivities and have been commercialized in China as a
prodrug herbicide [6]. Recently, α-amino phospho-
nic acid and their ester derivatives, as bioisosteres
of natural amino acids, have received an increas-
ing attention from the fields of medicinal chem-
istry and pesticide science because of their wide
biological activities such as enzyme inhibitors, an-
tibiotics, and haptens of catalytic antibodies, fungi-
cides, herbicides, plant regulators, and plant viru-
cides [7–13]. To find potent and selective herbi-
cide lead structures, we have synthesized a series of
novel pyrimidinyl benzylamine analogues contain-
ing a phosphonyl group (2) with structure similar
to ZJ0273 (Scheme 1). These contain the skeleton
of both pyrimidinyl benzylamine and α-amino phos-
phonate. We hypothesize that these compounds can
be oxidized to pyrimidinyl carboxamides and further
ꢀ
C
kg/ha.
2010 Wiley Periodicals, Inc. Heteroatom Chem
21:148–155, 2010; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20589
Correspondence to: De-Qing Shi; e-mail: chshidq@yahoo
.com.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20872046.
Contract grant sponsor: Natural Science Foundation of Hubei
Province.
Contract grant number: 2008CDB086.
2010 Wiley Periodicals, Inc.
c
ꢀ
148

Synthesis, Crystal Structure, and Herbicidal Activity of Pyrimidinyl Benzylamine Analogues Containing a Phosphonyl Group 149
H3CO
OCH3
H3CO
OCH3
H3C
NOCH3
COOCH3
N
O
N
N
N
O
P
OCH3
O
N
N
H
N
H
N
O
′
R
OCH3
OR
CO2Pr-n
OR
ZJ0273
Pyriminobac-methyl
SCHEME 1 Molecular designs of title compounds 2a–2r.
2
hydrolyzed to its carboxylic acid derivatives in plant
organisms, so they might also work as a prodrug of
pyriminidyl carboxylic acid herbicides. In this pa-
per, we reported the synthesis and their herbicidal
activities of title compounds 2.
Synthesis of 2-(4,6-Dimethoxypyrimidin-
2-yloxy)Benzoaldehyde 1
A mixture of salicylaldehyde (1.22 g, 10 mmol), 4,6-
dimethoxypyrimidin-2-yl-methyl sulfoxide (2.18 g,
10 mmol), and anhydrous potassium carbonate
(2.07 g, 15 mmol) in dry tetrahydrofuran (15 mL)
was stirred under reflux for 8 h. The solid was fil-
tered off, and the liquid was poured into ice-cold
water (20 mL). The crude product was collected by
filtration. After recrystallization from ethanol/water
(/1:1 v/v), a light yellow crystal was obtained (2.25 g),
EXPERIMENTAL
Instruments
1
yield: 94%, mp: 61.5–62.5◦C. H NMR (CDCl3, 600
1H and 31P NMR spectra were obtained on a
Varian Mercury Plus-400 (400 MHz) or Varian Mer-
cury Plus-600 (600 MHz) spectrometer at room
temperature in CDCl3, with tetramethylsilane and
85% H3PO4 as the internal and external stan-
dards, respectively; chemical shift values (δ) were
in ppm. Elemental analyses were performed on a
Germany Elementar Vario EL III elemental analyzer
(Moselstraβe, Klotten, Germany). Mass spectra were
obtained on a Finnigan TraceMS 2000 spectrom-
eter (Hemel Hempstead, Hertfordshire, HP2 4TG,
UK) at 70 eV by EI method or Applied Biosys-
tems (Carlisle, Cumbria, CA6 4RD, UK) API 2000
LC/MS/MS (ESI-MS) spectrometer. The IR spectra
were recorded on a Nicolet NEXUS470 spectrome-
ter (Madison, WI 53711-4495, USA) as KBr pellets,
with absorption given in cm−1. X-ray diffraction was
carried out on a Bruker Smart 1000 CCD diffrac-
tometer (Karlsruhe, Germany). The melting points
were determined on an X-4 binocular microscope
melting point apparatus (Beijing Tech Instruments
Co., Beijing, China) and were uncorrected. Analyti-
cal thin-layer chromatography (TLC) was performed
on silica gel GF254 plates. Column chromatographic
purification was carried out with silica gel. Yields
were not optimized. Unless otherwise noted, all ma-
terials were commercially available and were used
directly without further purification. All solvents
were dried and redistilled before use.
MHz): δ 3.85 (s, 6H, 2OCH3), 5.84 (s, 1H, pyrimidine-
H), 7.22 (t, J = 7.8 Hz, 2H, ArH), 7.32 (t, J = 8.0 Hz,
1H, ArH), 7.60 (d, J = 7.2 Hz, 1H, ArH). Anal. Cacld.
for C13H12N2O4: C, 60.00; H, 4.65; N, 10.76. Found:
C, 59.82; H, 4.51; N, 10.97.
General Procedures for the Synthesis of
O,Oꢁ-Dialkyl (or Diphenyl)-[2-(4,6-
Dimethoxypyrimidin-2-yloxy)phenyl]
(Substituted Phenylamino)
Methylphosphonates 2
A
mixture
of
2-(4,6-dimethoxypyrimidin-2-
yloxy)benzoaldehyde 1 (0.78 g, 3 mmol), dialkyl
phosphite or triphenyl phosphite (3 mmol), sub-
stituted phenylamine (3.3 mmol), and Mg(ClO4)2
(0.033 g, 0.15 mmol) in anhydrous acetonitrile
(5 mL) was taken in a 25-mL flask, and the mixture
was stirred at 50 to 60◦C for 1 to 2 h (monitored
by TLC). The solid was filtered off, and the filtrate
was concentrated under vacuum. The residue was
purified by column chromatography on silica gel,
using petroleum ether and ethyl acetate (2:1 v/v) as
the eluent, to give 2 white or yellow crystals in 41%
to 87% yields (Scheme 2).
Data for 2a (R = Me, Rꢁ = H): yield, 78%; white
crystals; mp 150–151◦C; IR (KBr): ν 3312 (NH),
2958 (CH), 1604, 1497 (Ar), 1221, 1195 (P O), 1171
Heteroatom Chemistry DOI 10.1002/hc

150 Tang, Yu, and Shi
H CO
3
OCH
3
H CO
3
OCH
3
H CO
3
N
O
N
OCH
3
HPO(OR) or P(OPh)
2
3
K CO /THF
2
3
OH
N
N
O
P
N
N
+
O
H
N
NH
CHO
Mg(ClO ) ,
2
4 2
SO CH
2
3
′
R
′
R
CHO
OR
OR
1
2
SCHEME 2 Synthetic route of title compounds 2a–2r.
(P O C), 1061 (C O C) cm−1; 1H NMR (CDCl3, 600
MHz): δ 3.45 (d, J = 10.2 Hz, 3H, CH3O), 3.79 (s,
6H, 2CH3O), 3.82 (d, J = 10.8 Hz, 3H, CH3O), 5.26
(d, J = 24.0 Hz, 1H, PCH), 5.78 (s, 1H, pyrimidine-
H), 6.57 (d, J = 6.4 Hz, 2H, ArH), 6.65 (t, J = 6.4 Hz,
1H, ArH), 7.02 (t, J = 6.4 Hz, 2H, ArH), 7.21 (t,
J = 9.0 Hz, 2H, ArH), 7.30 (t, J = 7.8 Hz, 1H, ArH),
7.65 (d, J = 8.4 Hz, 1H, ArH); 31P NMR (CDCl3, 243
MHz): δ 25.60; EI-MS: m/z 445 (M+, 5.5), 337 (100),
335 (96.4), 304 (8.1), 197 (14.8), 196 (21.6), 77 (14.5).
Anal. Cacld. for C21H24N3O6P: C, 56.63; H, 5.43; N,
9.43. Found: C, 56.40; H, 5.69; N, 9.12.
ArH); 31P NMR (CDCl3, 243 MHz): δ 24.36. Anal.
Cacld. for C23H27N4O8P: C, 53.28; H, 5.25; N, 10.81.
Found: C, 53.45; H, 5.47; N, 10.76.
Data for 2d (R = Me, Rꢁ = 4-NO2): yield, 41%; yel-
low crystals; mp 175–176◦C; IR (KBr): ν 3310 (NH),
2985 (Ar H), 1606, 1492 (Ar), 1228 (P O), 1152
(P O C), 1068 (C O C) cm−1; 1H NMR (CDCl3,
600 MHz): δ 3.46 (d, J = 9.6 Hz, 3H, CH3O), 3.82
(d, J = 8.4 Hz, 3H, CH3O), 3.83 (s, 6H, 2CH3O), 5.30
(dd, J = 24.0 Hz, J = 7.2 Hz, 1H, PCH), 5.68 (s, 1H,
NH), 5.81 (s, 1H, pyrimidine-H), 6.59 (d, J = 7.8 Hz,
2H, ArH), 7.24 (d, J = 10.8 Hz, 2H, ArH), 7.35
(d, J = 7.2 Hz, 1H, ArH), 7.62 (d, J = 6.6 Hz, 1H,
ArH), 7.95 (d, J = 7.8 Hz, 2H, ArH); 31P NMR (CDCl3,
243 MHz): δ 23.64. Anal. Cacld. for C21H23N4O8P: C,
51.43; H, 4.73; N, 11.42. Found: C, 51.32; H, 4.90; N,
11.23.
Data for 2b (R = Et, Rꢁ = H): yield, 73%; white
crystals; mp 103–104.5◦C; IR (KBr): ν 3305 (NH),
2986 (Ar H), 1604, 1497 (Ar), 1362, 1223 (P O),
1192, 1165 (P O C), 1056 (C O C) cm−1; 1H NMR
(CDCl3, 600 MHz): δ 1.06 (t, J = 7.2 Hz, 3H, CH3),
1.29 (t, J = 7.2 Hz, 3H, CH3), 3.69–3.73 (m, 1H,
CH2), 3.79 (s, 6H, 2CH3O), 3.90–3.94 (m, 1H, CH2),
4.18–4.22 (m, 2H, CH2), 5.22 (d, J = 24.0 Hz, 1H,
PCH), 5.77 (s, 1H, pyrimidine-H), 6.55 (d, J = 7.8 Hz,
2H, ArH), 6.64 (t, J = 7.2 Hz, 1H, ArH), 7.00
(t, J = 7.2 Hz, 2H, ArH), 7.18–7.21 (m, 2H, ArH),
7.28 (d, J = 6.6 Hz, 1H, ArH), 7.65 (d, J = 7.2 Hz,
1H, ArH); 31P NMR (CDCl3, 243 MHz): δ 23.27; EI-
MS: m/z 473.5 (M+, 3.7), 337 (100), 335 (94.5), 304
(6.2), 198 (64.7), 196 (49.9), 195 (21.6), 139 (9.5),
138 (13.6), 77 (25.5). Anal. Cacld. for C23H28N3O6P:
C, 58.35; H, 5.96; N, 8.88. Found: C, 58.28; H, 6.14;
N, 9.21.
Data for 2e (R = Me, Rꢁ = 4-Br): yield, 72%; white
crystals; mp 138–139◦C; IR (KBr): ν 3302 (NH),
2991 (Ar H), 1608, 1502 (Ar), 1223 (P O), 1165
(P O C), 1056 (C O C) cm−1; 1H NMR (CDCl3, 600
MHz): δ 3.45 (d, J = 10.8 Hz, 3H, CH3O), 3.80 (s,
6H, 2CH3O), 3.82 (d, J = 11.4 Hz, 3H, CH3O), 5.19
(d, J = 24.0 Hz, 1H, PCH), 5.80 (s, 1H, pyrimidine-
H), 6.45 (d, J = 8.4 Hz, 2H, ArH), 7.09 (d, J = 9.6 Hz,
2H, ArH), 7.21 (d, J = 7.2 Hz, 2H, ArH), 7.31
(d, J = 7.8 Hz, 1H, ArH), 7.61 (d, J = 7.8 Hz, 1H,
ArH); 31P NMR (CDCl3, 243 MHz): δ 25.12; ESI-MS:
m/z 546 (M+ + Na − 1, 16), 524 (M+, 100), 415 (21).
Anal. Cacld. for C21H23BrN3O6P: C, 48.11; H, 4.42; N,
8.01. Found: C, 48.30; H, 4.45; N, 7.85.
Data for 2c (R = Et, Rꢁ = 4-NO2): yield, 51%; yel-
low crystals; mp 145–146◦C; IR (KBr): ν 3308 (NH),
2982 (Ar H), 1600, 1496 (Ar), 1225 (P O), 1162
(P O C), 1050 (C O C) cm−1; 1H NMR (CDCl3,
600 MHz): δ 1.06 (t, J = 7.8 Hz, 3H, CH3), 1.30
(t, J = 6.8 Hz, 3H, CH3), 3.68–3.73 (m, 1H, CH2),
3.80 (s, 6H, 2CH3O), 3.91–3.95 (m, 1H, CH2), 4.16–
4.21 (m, 2H, CH2), 5.25 (d, J = 23.4 Hz, 1H, PCH),
5.55 (s, 1H, NH), 5.80 (s, 1H, pyrimidine-H), 6.57
(d, J = 9.0 Hz, 2H, ArH), 7.24 (d, J = 8.4 Hz,
2H, ArH), 7.35 (t, J = 8.4 Hz, 1H, ArH), 7.60
(d, J = 7.8 Hz, 1H, ArH), 7.94 (d, J = 8.4 Hz, 2H,
Data for 2f (R = Et, Rꢁ = 4-Br): yield, 68%; white
crystals; mp 117–118◦C; IR (KBr): ν 3308 (NH), 2975
(Ar H), 1598, 1514 (Ar), 1225 (P O), 1160 (P O C),
1
1062 (C O C) cm−1; H NMR (CDCl3, 600 MHz):
δ 1.06 (t, J = 7.2 Hz, 3H, CH3), 1.29 (t, J = 7.2 Hz,
3H, CH3), 3.71–3.76 (m, 1H, CH2), 3.79 (s, 6H,
2CH3O), 3.91–3.93 (m, 1H, CH2), 4.19 (t, J = 7.2 Hz,
2H, CH2), 5.15 (d, J = 23.4 Hz, 1H, PCH), 5.79 (s,
1H, pyrimidine-H), 6.44 (d, J = 8.4 Hz, 2H, ArH),
7.07 (d, J = 9.0 Hz, 2H, ArH), 7.20 (d, J = 8.4 Hz,
2H, ArH), 7.29 (d, J = 7.2 Hz, 1H, ArH), 7.62
Heteroatom Chemistry DOI 10.1002/hc

Synthesis, Crystal Structure, and Herbicidal Activity of Pyrimidinyl Benzylamine Analogues Containing a Phosphonyl Group 151
(d, J = 7.2 Hz, 1H, ArH); 31P NMR (CDCl3, 243 MHz):
δ 25.06. Anal. Cacld. for C23H27BrN3O6P: C, 50.01; H,
4.93; N, 7.61. Found: C, 49.83; H, 4.69; N, 7.50.
Data for 2g (R = Me, Rꢁ = 4-CH3O): yield, 63%;
white crystals; mp 156–157◦C; IR (KBr): ν 3302 (NH),
2978 (Ar H), 1602, 1570 (Ar), 1356 (P O), 1228
(P O C), 1060 (C O C) cm−1; 1H NMR (CDCl3, 600
MHz): δ 3.46 (d, J = 10.2 Hz, 3H, CH3O), 3.67 (s, 3H,
CH3O), 3.78 (s, 6H, 2CH3O), 3.82 (d, J = 10.8 Hz,
3H, CH3O), 5.20 (d, J = 24.0 Hz, 1H, PCH), 5.78 (s,
1H, pyrimidine-H), 6.53 (d, J = 7.8 Hz, 2H, ArH),
6.59 (d, J = 8.4 Hz, 2H, ArH), 7.21 (d, J = 8.4 Hz,
2H, ArH), 7.28 (d, J = 7.8 Hz, 1H, ArH), 7.65
(d, J = 7.8 Hz, 1H, ArH); 31P NMR (CDCl3, 243 MHz):
δ 25.35. Anal. Cacld. for C22H26N3O7P: C, 55.58; H,
5.51; N, 8.84. Found: C, 55.17; H, 5.54; N, 8.99.
Data for 2h (R = Et, Rꢁ = 4-CH3O): yield, 77%;
white crystals; mp 129–130◦C; IR (KBr): ν 3301
(NH), 2988 (Ar H), 1608, 1568, 1515 (Ar), 1360
(P O), 1223 (P O C), 1058 (C O C) cm−1; 1H NMR
(CDCl3, 600 MHz): δ 1.06 (t, J = 6.6 Hz, 3H, CH3),
1.30 (t, J = 7.2 Hz, 3H, CH3), 3.67 (s, 3H, CH3O),
3.73–3.74 (m, 1H, CH2), 3.78 (s, 6H, 2CH3O), 3.91–
3.94 (m, 1H, CH2), 4.20 (t, J = 7.2 Hz, 2H, CH2), 5.16
(d, J = 24.0 Hz, 1H, PCH), 5.77 (s, 1H, pyrimidine-
H), 6.52 (d, J = 8.4 Hz, 2H, ArH), 6.58 (d, J = 9.0 Hz,
2H, ArH), 7.20 (d, J = 8.4 Hz, 2H, ArH), 7.28
(d, J = 8.4 Hz, 1H, ArH), 7.66 (d, J = 6.6 Hz, 1H,
ArH); 31P NMR (CDCl3, 243 MHz): δ 24.86; EI-MS:
m/z 504 (M+, 14.0), 367 (76.9), 365 (100), 227 (73.6),
225 (56.0), 139 (19.5), 138 (14.5). Anal. Cacld. for
C24H30N3O7P: C, 57.25; H, 6.01; N, 8.35. Found: C,
57.13; H, 6.17; N, 8.44.
ArH), 7.18–7.23 (m, 3H, ArH), 7.29 (d, J = 8.0 Hz,
1H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH); 31P
NMR (CDCl3, 162 MHz): δ 25.18. Anal. Cacld. for
C23H27ClN3O6P: C, 54.39; H, 5.36; N, 8.27. Found: C,
54.16; H, 5.48; N, 8.42.
Data for 2k (R = Me, Rꢁ = 3-Br): yield, 72%; white
crystals; mp 154–155◦C; IR (KBr): ν 3304 (NH), 2984
(Ar H), 1607, 1572, 1516 (Ar), 1355 (P O), 1224
(P O C), 1056 (C O C) cm−1; 1H NMR (CDCl3, 600
MHz): δ 3.46 (d, J = 10.2 Hz, 3H, CH3O), 3.79 (s,
6H, 2CH3O), 3.82 (d, J = 10.2 Hz, 3H, CH3O), 5.22
(d, J = 23.4 Hz, 1H, PCH), 5.77 (s, 1H, pyrimidine-
H), 6.48 (d, J = 6.8 Hz, 1H, ArH), 6.67 (s, 1H, ArH),
6.76 (d, J = 7.6 Hz, 1H, ArH), 6.86 (t, J = 7.4 Hz, 1H,
ArH), 7.21–7.25 (m, 2H, ArH), 7.32 (t, J = 6.6 Hz, 1H,
ArH), 7.64 (d, J = 7.2 Hz, 1H, ArH); 31P NMR (CDCl3,
243 MHz): δ 25.20. Anal. Cacld. for C21H23BrN3O6P:
C, 48.11; H, 4.42; N, 8.01. Found: C, 48.37; H, 4.51;
N, 7.84.
Data for 2l (R = Et, Rꢁ = 3-Br): yield, 73%; white
crystals; mp 115–116◦C; IR (KBr): ν 3308 (NH), 2982
(Ar H), 1612, 1581, 1519 (Ar), 1361 (P O), 1226
(P O C), 1051 (C O C) cm−1; 1H NMR (CDCl3,
400 MHz): δ 1.06 (t, J = 6.8 Hz, 3H, CH3), 1.30 (t,
J = 6.8 Hz, 3H, CH3), 3.70–3.79 (m, 1H, CH2), 3.80
(s, 6H, 2CH3O), 3.85–3.92 (m, 1H, CH2), 4.17–4.21
(m, 2H, CH2), 5.18 (d, J = 23.6 Hz, 1H, PCH), 5.77
(s, 1H, pyrimidine-H), 6.47 (d, J = 6.0 Hz, 1H, ArH),
6.66 (t, J = 6.4 Hz, 1H, ArH), 6.75 (d, J = 6.8 Hz, 1H,
ArH), 6.85 (t, J = 8.0 Hz, 1H, ArH), 7.21–7.31 (m,
3H, ArH), 7.65 (d, J = 7.6 Hz, 1H, ArH); 31P NMR
(CDCl3, 162 MHz): δ 25.36; ESI-MS: m/z 574 (M+ +
Na − 1, 8), 552 (M+, 100), 413 (26). Anal. Cacld. for
C23H27BrN3O6P: C, 50.01; H, 4.93; N, 7.61. Found: C,
50.25; H, 4.72; N, 7.80.
Data for 2i (R = Me, Rꢁ = 2-Cl): yield, 57%; white
crystals; mp 101–102◦C; IR (KBr): ν 3305 (NH), 2992
(Ar H), 1605, 1520 (Ar), 1356 (P O), 1225 (P O C),
Data for 2m (R = Me, Rꢁ = 4-Cl): yield, 74%;
white crystals; mp 142–143◦C; IR (KBr): ν 3305
(NH), 2991 (Ar H), 1604, 1566, 1519 (Ar), 1354
(P O), 1220 (P O C), 1051 (C O C) cm−1; 1H
NMR (CDCl3, 600 MHz): δ 3.45 (d, J = 10.8 Hz, 3H,
CH3O), 3.79 (s, 6H, 2CH3O), 3.82 (d, J = 10.8 Hz,
3H, CH3O), 5.19 (d, J = 24.0 Hz, 1H, PCH), 5.79 (s,
1H, pyrimidine-H), 6.49 (d, J = 8.4 Hz, 2H, ArH),
6.95 (d, J = 9.0 Hz, 2H, ArH), 7.21 (d, J = 7.8 Hz,
2H, ArH), 7.31 (d, J = 6.6 Hz, 1H, ArH), 7.61
(d, J = 6.6 Hz, 1H, ArH); 31P NMR (CDCl3, 243 MHz):
δ 25.19. Anal. Cacld. for C21H23ClN3O6P: C, 52.56; H,
4.83; N, 8.76. Found: C, 52.68; H, 4.94; N, 8.97.
Data for 2n (R = Et, Rꢁ = 4-Cl): yield, 87%; white
crystals; mp 119–121◦C; IR (KBr): ν 3308 (NH), 2992
(Ar H), 1603, 1569, 1520 (Ar), 1358 (P O), 1222
(P O C), 1053 (C O C) cm−1; 1H NMR (CDCl3,
400 MHz): δ 1.06 (t, J = 7.2 Hz, 3H, CH3), 1.30 (t,
J = 7.2 Hz, 3H, CH3), 3.70–3.77 (m, 1H, CH2), 3.80
(s, 6H, 2CH3O), 3.82–3.93 (m, 1H, CH2), 4.16–4.23
1
1062 (C O C) cm−1; H NMR (CDCl3, 400 MHz): δ
3.50 (d, J = 10.2 Hz, 3H, CH3O), 3.79 (s, 6H, 2CH3O),
3.83 (d, J = 10.2 Hz, 3H, CH3O), 5.30 (d, J = 23.6 Hz,
1H, PCH), 5.78 (s, 1H, pyrimidine-H), 6.54–6.61 (m,
2H, ArH), 6.89 (t, J = 7.8 Hz, 1H, ArH), 7.19–7.25
(m, 3H, ArH), 7.32 (d, J = 11.4 Hz, 1H, ArH), 7.64
(d, J = 11.4 Hz, 1H, ArH); 31P NMR (CDCl3, 162
MHz): δ 24.86. Anal. Cacld. for C21H23ClN3O6P: C,
52.56; H, 4.83; N, 8.76. Found: C, 52.74; H, 5.02; N,
8.85.
Data for 2j (R = Et, Rꢁ = 2-Cl): yield, 75%; white
crystals; mp 93–94◦C; IR (KBr): ν 3307 (NH), 2991
(Ar H), 1604, 1564, 1518 (Ar), 1362 (P O), 1224
(P O C), 1055 (C O C) cm−1; 1H NMR (CDCl3,
400 MHz): δ 1.11 (t, J = 7.6 Hz, 3H, CH3), 1.29 (t,
J = 7.6 Hz, 3H, CH3), 3.79 (s, 6H, 2CH3O), 3.81–
4.04 (m, 2H, CH2), 4.18–4.22 (m, 2H, CH2), 5.25
(d, J = 23.6 Hz, 1H, PCH), 5.77 (s, 1H, pyrimidine-
H), 6.53–6.60 (m, 2H, ArH), 6.88 (t, J = 7.6 Hz, 1H,
Heteroatom Chemistry DOI 10.1002/hc

152 Tang, Yu, and Shi
(m, 2H, CH2), 5.16 (d, J = 23.6 Hz, 1H, PCH),
5.79 (s, 1H, pyrimidine-H), 6.49 (d, J = 7.2 Hz,
2H, ArH), 6.94 (d, J = 8.8 Hz, 2H, ArH), 7.20–
7.24 (d, J = 6.8 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz,
1H, ArH), 7.62 (d, J = 8.0 Hz, 1H, ArH); 31P NMR
(CDCl3, 162 MHz): δ 25.54; ESI-MS: m/z 530 (M+ +
Na − 1, 11), 508 (M+, 100), 369 (18). Anal. Cacld. for
C23H27ClN3O6P: C, 54.39; H, 5.36; N, 8.27. Found: C,
54.13; H, 5.09; N, 7.91.
2CH3O), 3.81–3.89 (m, 1H, CH2), 4.09–4.14 (m, 2H,
CH2), 5.23 (d, J = 23.6 Hz, 1H, PCH), 5.77 (s, 1H,
pyrimidine-H), 6.58 (d, J = 8.4 Hz, 2H, ArH), 7.20–
7.24 (m, 4H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 7.65
(d, J = 8.0 Hz, 1H, ArH); 31P NMR (CDCl3, 162 MHz):
δ 25.16; ESI-MS: m/z 619 (M+ + Na − 1, 11), 597.6
(M+, 100), 404 (26). Anal. Cacld. for C29H35F3N3O6P:
C, 56.28; H, 5.90; N, 7.03. Found: C, 56.46; H, 5.81;
N, 6.94.
Data for 2o (R = Me, Rꢁ = 4-CF3): yield, 84%;
yellow crystals; mp 107–108◦C; IR (KBr): ν 3307
(NH), 3001 (Ar H), 1611, 1563, 1485 (Ar), 1361
(P O), 1216 (P O C), 1064 (C O C) cm−1; 1H NMR
(CDCl3, 400 MHz): δ 3.46 (d, J = 10.4 Hz, 3H, CH3O),
3.79 (s, 6H, 2CH3O), 3.82 (d, J = 10.4 Hz, 3H, CH3O),
5.09 (s, 1H, NH), 5.27 (d, J = 24.0 Hz, 1H, PCH),
5.79 (s, 1H, pyrimidine-H), 6.60 (d, J = 8.0 Hz, 2H,
ArH), 7.22–7.36 (m, 5H, ArH), 7.63 (d, J = 8.0 Hz,
1H, ArH); 31P NMR (CDCl3, 162 MHz): δ 25.68. Anal.
Cacld. for C22H23F3N3O6P: C, 51.47; H, 4.52; N, 8.18.
Found: C, 51.25; H, 4.61; N, 8.39.
Crystal Structure Determination
In the determination of the structure of the sin-
gle crystal, X-ray intensity data were recorded on
a Bruker SMART CCD area detector diffractome-
ter with graphite monochromated MoKα radiation
◦
◦
˚
(λ = 0.71073 A). In the range 1.61 ≤ θ ≤ 26.50 ,
10,172 independent reflections were obtained. In-
tensities were corrected for Lorentz and polariza-
tion effects and empirical absorption, and all data
were corrected using the SADABS [14] program.
The structure was solved by direct method using
the SHELXS-97 program [15]. All of the nonhy-
drogen atoms were refined on F2 anisotropically
by a full-matrix, least-squares method. The hydro-
gen atoms were located from the difference Fourier
map, but their positions were not refined. The con-
tributions of these hydrogen atoms were included in
structure factor calculations. The weighting scheme
was w = 1/[σ2(Fo2) + (0.0714P)2 + 0.0000P], where
P = [(Fo)2 + 2Fc2]/3. The maximum and minimum
difference peaks and holes are 0.24 and –0.26
Data for 2p (R = Et, Rꢁ = 4-CF3): yield, 87%;
white crystals; mp 124–125◦C; IR (KBr): ν 3305
(NH), 2996 (Ar H), 1605, 1561, 1486 (Ar), 1357
(P O), 1214 (P O C), 1060 (C O C) cm−1; 1H NMR
(CDCl3, 400 MHz): δ 1.06 (t, J = 7.2 Hz, 3H, CH3),
1.30 (t, J = 7.2 Hz, 3H, CH3), 3.70–3.79 (m, 1H, CH2),
3.81 (s, 6H, 2CH3O), 3.90–3.94 (m, 1H, CH2), 4.19 (t,
J = 7.2 Hz, 2H, CH2), 5.08 (s, 1H, NH), 5.23 (d, 1H,
J = 23.2 Hz, PCH), 5.78 (s, 1H, pyrimidine-H), 6.59
(d, J = 8.4 Hz, 2H, ArH), 7.20–7.32 (m, 5H, ArH),
7.64 (d, J = 8.0 Hz, 1H, ArH); 31P NMR (CDCl3, 162
MHz): δ 24.79; ESI-MS: m/z 541.6 (M+, 100). Anal.
Cacld. for C24H27F3N3O6P: C, 53.24; H, 5.03; N, 7.76.
Found: C, 53.37; H, 5.20; N, 7.86.
−3
˚
e A , respectively, S= 0.89, and (ꢀ/σ)max = 0.00.
Atomic scattering factors and anomalous disper-
sion corrections were taken from the Interna-
tional Table for X-ray Crystallography [16]. X-ray
diffraction indicated that the crystal (C23H28N3OP,
Data for 2q (R = Ph, Rꢁ = 4-CF3): yield, 61%;
white crystals; mp 153–154◦C; IR (KBr): ν 3306
(NH), 3022 (Ar H), 1609, 1569, 1487 (Ar), 1362
(P O), 1217 (P O C), 1188, 1061 (C O C) cm−1;
1H NMR (CDCl3, 400 MHz): δ 3.70 (s, 6H, 2CH3O),
5.21 (d, J = 7.6 Hz, 1H, NH), 5.72 (dd, J = 8.8 Hz,
J = 24.0 Hz, 1H, PCH), 5.76 (s, 1H, pyrimidine-H),
6.65 (d, J = 8.4 Hz, 2H, ArH), 6.75 (d, J = 8.4 Hz, 2H,
ArH), 7.03–7.37 (m, 13H, ArH), 7.71 (d, J = 7.6 Hz,
1H, ArH); 31P NMR (CDCl3, 162 MHz): δ 25.82; ESI-
MS: m/z 659 (M+ + Na − 1, 12), 637.6 (M+, 87), 404
(100). Anal. Cacld. for C32H27F3N3O6P: C, 60.29; H,
4.27; N, 6.59. Found: C, 60.13; H, 4.37; N, 6.73.
Data for 2r (R = n-Bu, Rꢁ = 4-CF3): yield, 71%;
yellow crystals; mp 71–72◦C; IR (KBr): ν 3292 (NH),
2963 (Ar H), 1599, 1567, 1469 (Ar), 1367 (P O),
1228, 1194 (P O C), 1104, 1060 (C O C) cm−1; 1H
NMR (CDCl3, 400 MHz): δ 0.81 (t, J = 7.6 Hz, 3H,
CH3), 0.87 (t, J = 7.6 Hz, 3H, CH3), 1.15–1.62 (m,
8H, 2CH2CH2), 3.64–3.67 (m, 1H, CH2), 3.78 (s, 6H,
M = 473.45) is of triclinic, space group P1 with a =
r
˚
˚
˚
9.685(1) A, b = 16.366(2) A, c= 16.998(2) A, α =
98.954(3)◦, β = 101.436(3)◦, γ = 104.859(2)◦, V =
3
3
˚
2491.0(6) A , Z = 4, Dc = 1.262 g/cm , F(000) = 1000,
μ(MoKα) = 0.152 mm−1. Crystallographic data (ex-
cluding structure factors) for the structure have
been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publica-
tion CCDC No. 729200 (available free of charge at
http://www.ccdc.cam.ac.uk/conts/retrieving/html or
from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK).
Biological Assay
Herbicidal Activity (In Vitro). The herbicidal
evaluation of compounds 2 was undertaken accord-
ing to the previously reported method [17] and
Heteroatom Chemistry DOI 10.1002/hc

Synthesis, Crystal Structure, and Herbicidal Activity of Pyrimidinyl Benzylamine Analogues Containing a Phosphonyl Group 153
TABLE 1 The Herbicidal Activities of Compounds 2a–2r (In Vitro, % Inhibition)
Brassica campestris
Echinochloa crus-galli
Compound
100 mg/L (Root/Stalk)
10 mg/L (Root/Stalk)
100 mg/L (Root/Stalk)
10 mg/L (Root/Stalk)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
78.9/68.1
84.4/76.6
74.4/44.7
64.4/48.9
83.3/68.1
74.4/68.1
73.3/57.4
78.9/51.1
82.2/70.2
65.5/63.8
68.9/53.2
68.9/51.1
74.4/51.1
77.8/51.1
95.5/89.4
93.3/80.8
64.4/55.3
64.4/55.3
77.8/53.2
43.3/31.9
66.7/38.3
53.3/40.4
72.2/44.7
68.9/57.4
67.8/38.3
73.3/46.8
51.1/44.7
45.5/46.8
53.3/31.9
43.3/36.2
45.5/14.9
57.8/21.3
48.9/46.8
64.4/48.9
63.0/31.9
54.4/38.3
68.6/58.9
37.1/51.3
71.4/56.4
65.7/46.2
57.1/64.1
60.0/61.5
57.1/69.2
51.4/64.1
62.8/66.7
48.6/56.4
71.4/61.5
37.1/48.7
51.4/51.3
37.1/33.3
80.0/53.8
74.3/53.8
65.7/53.8
65.7/41.0
51.4/43.6
20.0/51.3
48.6/48.7
48.6/43.6
40.0/43.6
37.1/41.0
34.3/35.9
37.1/48.7
22.8/30.8
22.8/38.5
42.8/38.5
5.7/30.8
34.3/38.5
31.4/20.5
28.6/38.5
34.3/30.8
28.6/0
45.7/35.9
carried out in the Laboratory of Biological Activities
Test, College of Chemistry, Central China Normal
University, Wuhan, People’s Republic of China. The
results are listed in Table 1.
Preemergence Treatment. Sandy clay (100 g) in
a plastic box (11 cm × 7.5 cm × 6 cm) was moistened
with water. Fifteen sprouting seeds of the weed un-
der test were planted in fine earth (0.6-cm depth) in
the glasshouse and sprayed with the test compound
solution.
Herbicidal Activity (In Vivo). The herbicidal ac-
tivities of some of 2 were evaluated using the com-
mercially available herbicide, Bispyribac-sodium, as
the control drug according to a previously reported
procedure [18,19].
Postemergence Treatment. Seedlings (one leaf
and one stem) of the weed were sprayed with the test
compounds at the same rate as that used in the pre-
emergence test. For both methods, the fresh weights
were determined 21 days later and the percentage in-
hibition relative to the controls was calculated. The
herbicidal activity is summarized in Table 2.
Plant Material. Two dicotyledonous crops, rape
(Brassica campestris L.) and amaranth pigweed
(Amaranthus retroflexus), and two monocotyle-
donous crops, barnyard grass [Echinochloa crus-
galli] and hairy crabgrass [Digitaria sanguinalis (L.)
Scop.], were used to test the herbicidal activities of
compounds. The seeds of amaranth pigweed were re-
produced outdoors and stored at room temperature.
Seeds of rape, barnyard grass, and hairy crabgrass
were purchased from the Institute of Crop, Tianjin
Agriculture Science Academy (Tianjin, China).
RESULTS AND DISCUSSION
Synthesis
Salicylaldehyde
dimethoxypyrimidin-2-yl-methylsulfone
reacted
with
4,6-
the
in
presence of potassium carbonate to generate 2-(4,6-
dimethoxypyrimidin-2-yloxy)benzoaldehyde 1 in a
high yield. Target compounds 2 were synthesized via
the Mannich-type reactions of 1, aromatic amines,
and dialkyl phosphites or triphenyl phosphite in
the presence of Mg(ClO4)2 in moderate to good
yields. It was found that Mg(ClO4)2 can reduce the
reaction time and improve the yields of products
2 greatly. The structures of target compounds 2
were confirmed from their spectroscopic data (in-
Treatment. The emulsions of purified com-
pounds were prepared by dissolving them in N,N-
dimethylformamide (100 μL) with the addition of a
little Tween 20 and proper water. There were three
replicates for each treatment. The mixture of the
same amount of water, N,N-dimethylformamide,
and Tween 20 was used as the control.
1
frared, H NMR, 31P NMR, EI-MS, or ESI-MS) and
Heteroatom Chemistry DOI 10.1002/hc

154 Tang, Yu, and Shi
TABLE 2 The Herbicidal Activities of Some of 2 (In Vivo, 1.5 kg/ha, % Inhibition)
Preemergence Treatment
Postemergence Treatment
Amaranthus Echinochloa
Brassica
Amaranthus Echinochloa
Digitaria
Brassica
Digitaria
sanguinalis
Compound campestris retroflexus
crus-galli
sanguinalis campestris retroflexus
crus-galli
2b
2o
2p
61.6
36.4
62.3
99.9
100
81.8
51.1
100
87.9
33.7
6.0
90.3
33.7
5.0
87
25.3
9.3
100
54.7
39.8
100
90.7
24.9
18.6
100
62.0
23.2
10.0
100
Bispyribac-
sodium
95.5
96.7
100
elemental analyses. In addition, the crystal structure
of compound 2b was further determined by X-ray
single-crystal diffraction analyses. As shown in
Fig. 1, the dihedral angels between pyrimidine
and phenyl [C(7) C(9) C(11)] rings, pyrimidine
and phenyl [C(15) C(17) C(19)] rings, two phenyl
rings are 89.28, 25.43, and 68.55◦, respectively. In
addition, some intra- and intermolecular hydrogen
bonds were observed, such as N(3) H(3A)· · ·O(4)
Herbicidal Activities
The preliminary herbicidal activity (in vitro) of
compounds 2 against B. campestris L. (rape) and
Echinochloa crus-galli (barnyard grass) has been
investigated at the dosages of 100 and 10 mg/L,
respectively. The results indicated that some of 2
possessed good herbicidal activities against dicotyle-
donous plants (B. campestris L.) at the concentra-
tion of 100 mg/L. For example, compounds 2o and
2p possessed 95.5% and 93.3% inhibitory activities
against the root of B. campestris L. and 89.4% and
80.8% against the stalk at the concentration of 100
mg/L, respectively. Further bioassays (in vivo) indi-
cated that some compounds of 2 exhibited as good
◦
˚
˚
[2.15(2) A, 164.9 (2) ], C(11) H(11)· · ·N(3) [2.59 A,
◦
◦
˚
100 ], C(13) H(13)· · ·O(1)[2.45 A, 102 ], C(15) H
◦
˚
(15)· · ·O(12) [2.57 A, 138 ], C(20) H(23B)· · ·O(3)
◦
◦
˚
˚
[2.59 A, 157 ], C(23) H(23B)· · ·O(3) [2.59 A, 132 ],
in crystal 2b.
FIGURE 1 Molecular structure of compound 2b.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis, Crystal Structure, and Herbicidal Activity of Pyrimidinyl Benzylamine Analogues Containing a Phosphonyl Group 155
[6] (a) Lv, L.; Chen, J.; Wu, J.; Ling, W.; Mao, L. S.; Li,
M. Z.; Cai, X.; Peng, W. L.; Wu, Y.; Wu, S. G.; Wang,
H. J.; Wang, G. C.; Cui, H.; Han, S. D.; Qiu, W. L.;
Wang, Y. H. US Patent 6,800,590 B2, 2004; (b) Lv, L.;
Wu, J.; Chen, J.; Ling, W.; Peng, W. L.; Mao, L. S.;
Wang, G. C.; Li, M. Z. ZL Patent 0,0130,735.5, 2003;
(c) Wu, J.; Cheng, J.; Lu, L. J Agric Food Chem 2006,
54(16), 5954–5957.
herbicidal activity against A. retroflexus as the com-
mercially available herbicide, Bispyribac-sodium, at
a dose of 1.5 kg/ha. For example, compound 2b
showed 100% inhibition against amaranth pigweed
(A. retroflexus) in both preemergence and poste-
mergence treatments at the dose of 1.5 kg/ha and
compound 2o exhibited 81.8% inhibition against
amaranth pigweed (A. retroflexus) in preemergence
treatments at the same concentration.
[7] Kuhkar, V. P.; Hudson, H. R. (Eds.). Synthesis of
α-Aminoalkanephosphonic and α-Aminophosphinic
Acids; Wiley: Chichester, UK, 2000.
[8] Palacios, F.; Alonso, C.; de los Santos, J. M. Chem
Rev 2005, 105, 899–931.
[9] Gioia, P. L.; Chuah, P. H.; Sclapari, T. WO Patent
2,007,054,540, 2007.
CONCLUSIONS
[10] Kafarski, P.; Lejczak, B. Curr Med Chem Anti-Cancer
Agents 2001, 1, 301–312.
[11] Lintunen, T.; Yli-Kauhaluoma, J. T. Bioorg Med
Chem Lett 2000, 10, 1749–1750.
[12] Kafarski, P.; Lejczak, B. Phosphorus Sulfur 1991, 63,
193–215.
[13] 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.
[14] Sheldrick, G. M. Program for Empirical Absorp-
tion Correction of Area Detector Data; University of
Go¨ttingen: Germany, 1996.
[15] Sheldrick, G. M. SHELXTL V5.1, Software Reference
Manual; Bruker AXS: Madison, WI, 1997.
[16] Wilson, A. J. International Table for X-ray Crystal-
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Vol. C, Tables 6.1.1.4 (pp. 500–502) and 4.2.6.8
(pp. 219–222).
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Huang, R.; Wang, Q. J Agric Food Chem 2007, 55,
3011–3017.
We synthesized a series of pyrimidinyl benzylamine
analogs containing a phosphonyl group (2) via the
Mannich-type reaction. The results of preliminary
bioassays showed that some of 2 displayed good
herbicidal activity against the root of B. campestris
L. at the concentration of 100 mg/L. Further bioas-
says (in vivo) indicated that some of 2 exhibited
as good herbicidal activity against amaranth pig-
weed (A. retroflexus) as the commercially avail-
able herbicide, Bispyribac-sodium, in both preemer-
gence and postemergence treatments at the dose of
1.5 kg/ha.
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Heteroatom Chemistry DOI 10.1002/hc