Synthesis and herbicidal activity of novel 1-(diethoxy-phosphoryl)-3-(4-one-1H-1,2,3-triazol-1-yl)-propan-2-yl carboxylic esters

Article abstract of DOI:10.3390/molecules20011088

A series of novel compounds, namely 1-(diethoxyphosphoryl)-3-(4-ones-1H-1,2,3-triazol-1-yl)propan-2-yl carboxylic esters, were designed on the basis of the diazafulvene intermediate of imidazole glycerol phosphate dehydratase (IGPD) and high-activity inhibitors of IGPD, and synthesized as inhibitors targeting IGPD in plants. Their structures were confirmed by ¹ H- NMR, ¹³C-NMR, 31P-NMR and HR-MS. The herbicidal evaluation performed by a Petri dish culture method showed that most compounds possessed moderate to good herbicidal activities. Six compounds were chosen for further herbicidal evaluation on barnyard grass by pot experiments. 1-(Diethoxyphosphoryl)-3-(4-phenyl- 1H-1,2,3-triazol-1-yl)propan-2-yl 2-(naphthalen-1-yl)acetate (5-A3) and ethyl 1-(2-acetoxy-3-(diethoxyphosphoryl)propyl)-1H-1,2,3-triazole-4-carboxylate (5-B4) showed good herbicidal activities. Compared with the compounds with the best herbicidal activity ever reported, both compounds 5-A3 and 5-B4, which can inhibit the growth of barnyard grass at the concentration of 250g/hm², efficiently gave rise to a nearly 4-fold increase of the herbicidal potency. However, their herbicidal activities were lower than that of acetochlor (62.5 g/hm²) in the pot experiments.

Full text of DOI:10.3390/molecules20011088

Molecules 2015, 20, 1088-1103; doi:10.3390/molecules20011088
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Herbicidal Activity of Novel 1-(Diethoxy-
phosphoryl)-3-(4-one-1H-1,2,3-triazol-1-yl)-propan-2-yl
Carboxylic Esters
1
,†
1,2,†
1,
3
1,
Yan Jin , Hanqing Zhao
Daoquan Wang 1
, Huizhe Lu *, Colleen M. Kuemmel , Jianjun Zhang * and
1
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China;
E-Mails: walterjin@126.com (Y.J.); zhaohanqing@bua.edu.cn (H.Z.); wangdq@cau.edu.cn (D.W.)
Department of Fundamental Science, Beijing University of Agriculture, Beijing 102206, China
Novo Nordisk, Inc., Princeton, NJ 08540, USA; E-Mail: colleenkuemmel@gmail.com
2
3
†
These authors contributed equally to this works.
*
Authors to whom correspondence should be addressed; E-Mails: luhz@cau.edu.cn (H.L.);
zhangjianjun@cau.edu.cn (J.Z.); Tel.: +86-106-273-1115 (J.Z.); Fax: +86-106-273-2219 (J.Z.).
Academic Editor: Derek J. McPhee
Received: 14 November 2014 / Accepted: 16 December 2014 / Published: 12 January 2015
Abstract: A series of novel compounds, namely 1-(diethoxyphosphoryl)-3-(4-ones-1H-
1,2,3-triazol-1-yl)propan-2-yl carboxylic esters, were designed on the basis of the diazafulvene
intermediate of imidazole glycerol phosphate dehydratase (IGPD) and high-activity
inhibitors of IGPD, and synthesized as inhibitors targeting IGPD in plants. Their structures
1
13
31
were confirmed by H-NMR, C-NMR, P-NMR and HR-MS. The herbicidal evaluation
performed by a Petri dish culture method showed that most compounds possessed
moderate to good herbicidal activities. Six compounds were chosen for further herbicidal
evaluation on barnyard grass by pot experiments. 1-(Diethoxyphosphoryl)-3-(4-phenyl-1H-
1
,2,3-triazol-1-yl)propan-2-yl 2-(naphthalen-1-yl)acetate (5-A3) and ethyl 1-(2-acetoxy-3-
(diethoxyphosphoryl)propyl)-1H-1,2,3-triazole-4-carboxylate (5-B4) showed good herbicidal
activities. Compared with the compounds with the best herbicidal activity ever reported,
both compounds 5-A3 and 5-B4, which can inhibit the growth of barnyard grass at the
2
concentration of 250g/hm , efficiently gave rise to a nearly 4-fold increase of the herbicidal
potency. However, their herbicidal activities were lower than that of acetochlor
2
(
62.5 g/hm ) in the pot experiments.

Molecules 2015, 20
Keywords: carboxylic esters; IGPD; synthesis; herbicidal activity
1089
1
. Introduction
Imidazole glycerol phosphate dehydratase (IGPD) was recently discovered as a new potential target
enzyme for the development of herbicides. It catalyzes the conversion of imidazole glycerol phosphate
IGP) to imidazole acetol phosphate (IAP) in the histidine biosynthetic pathway [1]. Since IGPD is
(
absent from mammals, its inhibition provides a safe and effective method for controlling weed growth [2].
Many high-activity inhibitors of IGPD such as (3-hydroxy-3-(1H-1,2,4-triazol-3-yl)propyl) phosphonic
acid (IRL1695, Mori et al. [3]) and (2-(3-phenoxypropanamido)-3-(1H-1,2,4-triazol-1-yl)propyl)
phosphonic acid (Schweitzer et al. [4]) were recently synthesized [5]. While these inhibitors exhibited
excellent enzymatic inhibitor activity, only the compound IRL1803 [3-hydroxy-3-(1H-[1,2,4]triazol-3-
yl)-cyclohexyl]-phosphonic acid (Mori et al. [6]) also elicited herbicidal activity, preventing weed
2
growth at a concentration of 1 kg/hm . Although many inhibitors of IGPD were reported, the
mechanism of the IGP dehydratase reaction is still unknown.
2
. Results and Discussion
2
.1. Design of the Target Molecules
IRL1695 was the first high-activity inhibitor of IGPD (IC50 = 130 nM, pH = 7.5, K
i
= 40 ± 6.5 nM,
3
K
m
/K
i
= 9.0 × 10 ). This compound was designed on the basis of the diazafulvene intermediate of
IGPD [3,7]. Then a series of novel β-carboxamido phosphonate compounds were synthesized, most of
which provided (Schweitzer et al. [8]) moderate to good enzymatic inhibitory activity. One in
particular, phenoxyacetamide 5a, displayed an inhibition constant of 80 nM. Schweitzer suggested that
the phenyl ring of â-carboxamido phosphates may contribute to a putative lipophilic interaction
between the inhibitor and IGPD. In this scenario, the phenyl ring may provide greater inhibition by
filling the enzymatic cavity better than five-membered rings or aliphatic groups. Alternatively, the
phenyl ring may be involved in a π-π interaction with an aromatic residue of the protein.
Inspired by these promising results, we decided to search for potential herbicidal activity in triazole
derivatives. By taking advantage of these active substructures and the diazafulvene intermediate of
IGPD [9], a series of novel 1-(diethoxyphosphoryl)-3-(4-one-1H-1,2,3-triazol-1-yl)propan-2-yl
carboxylic ester compounds (Figure 1) were designed and synthesized. In the structure of compound 5,
the triazole moiety and the methyldiethoxyphosphine were connected via a substituted alkyl. In order
to increase the osmosis of compounds into weeds, the phosphate of the diazafulvene intermediate and
the methanephosphonic acid of IRL1695 and 5a (Schweitzer et al. [8]) were replaced by
methyldiethoxyphosphine. The in vivo herbicidal activity of all the target compounds was also
evaluated. We report herein the preliminary results of these studies.

Molecules 2015, 20
1090
Figure 1. The design of the target molecules.
.2. Synthesis of the Title Compounds
2
The design of the target molecules was based on some highly active substructures and the
diazafulvene intermediate of IGPD [4] (Scheme 1).
Scheme 1. Synthesis of the target compounds 5.
Reagents and conditions: (a) (EtO)
c) NH Cl, NaN , CH OH-H
O, r.t, overnight; (d) sodium ascorbate, CuSO .
overnight, 60%–80% for 4; (e) DCC, CH Cl , reflux 8–14 h, 34%–80% for 5.
3
P, reflux., 4 h, 98% for 1; (b) m-CPBA, CH
2
Cl
2
, r.t, overnight 80% for 2;
(
4
3
3
2
4
5H
2
O, alkyne, CH
3
OH-H O, r.t,
2
2
2
All target compounds were synthesized via a five-step procedure (Scheme 1). The key intermediate,
diethyl(2-hydroxy-3-(4-one-1H-1,2,3-triazol-1-yl)propyl)phosphonate (4), was prepared as previously
described [10–13]. According to previous studies, compound 3 does not need to be purified. Thus, the
mixture from the third step was used to prepare compound 4 directly. Compound 4 was allowed to
react at room temperature with various carboxylic acids in the presence of DCC and DMAP as
catalysts to give the target compounds 5 in 34%–80% yields.. At first, carboxylic acids were converted
to acyl chlorides by oxalyl chloride, then reacted with compound 4 to give the target compounds.
However, the reactions gave low yields and the target compounds were difficult to separate. Their
1
structures were confirmed by H-NMR which showed the characteristic signals such as a single peak at
1
3
31
about δ 8.03 ppm for C-CH-N of 5A, C-NMR, P-NMR and HR-MS.

Molecules 2015, 20
.3. Herbicidal Activity of Compounds 5
The herbicidal evaluation was performed using wheat and rape as model plants by the reported Petri
1091
2
dish culture method [14]. Most compounds were found to possess moderate to good herbicidal
activities. Compounds 5-A3, 5-B3, 5-B4, 5-C2, 5-C3 and 5-D3 were screened further by using a pot
experiment with barnyard grass. Of these, 1-(diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-
yl)propan-2-yl 2-(naphthalen-1-yl)acetate (5-A3) and ethyl 1-(2-acetoxy-3-(diethoxyphosphoryl)-
propyl)-1H-1,2,3-triazole-4-carboxylate (5-B4) showed good herbicidal activity. However, their
herbicidal activities were lower than that of acetochlor. The herbicidal evaluation on barnyard grass
had two parts, pre-emergence treatment and post-emergence treatment, which is described in the
Experimental Section. The activity data are listed in Tables 1 and 2.
Table 1. The percent inhibitory ratios against the growth of root and stalk of wheat and
rape of 5 at different concentrations.
Relative Inhibition (Root %/Stalk %)
Comp.
R
1
R
2
Rape Wheat
10 mg/L
100 mg/L
100 mg/L 10 mg/L
73.4/63.1 24.3/23.3
78.5/74.5 39.2/12.8
69.6/53.6 56.9/30.9
66.2/53.7 37.0/16.0
71.8/51.7 36.5/14.0
78.4/70.7 32.4/16.6
76.8/67.3 24.5/12.2
71.3/56.2 51.3/37.4
75.2/58.5 49.7/28.7
85.6/72.6 49.7/47.9
95.8/86.7 85.0/51.0
83.9/77.3 56.9/40.3
78.3/72.5 44.4/30.1
5-A1
5-A2
5-A3
5-A4
5-A5
5-A6
5-A7
5-A8
5-B1
5-B2
5-B3
5-B4
5-B5
5-B6
5-B7
5-B8
5-C1
5-C2
5-C3
5-C4
5-C5
C
C
C
C
C
C
C
C
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
-
-
-
-
-
-
-
-
C
6
H
5
-
87.4/61.3
79.2/61.6
92.5/75.7
84.0/43.8
89.0/75.0
90.2/64.0
84.4/57.5
69.5/21.6
84.2/61.6
84.3/71.2
97.7/82.5
92.3/75.5
77.7/50.7
75.5/57.8
62.3/21.9
70.6/29.5
89.9/64.7
70.2/25.4
95.8/82.8
46.3/21.3
75.4/46.5
30.3/7.1
20.3/11.4
84.6/64.5
41.7/11.6
59.8/25.1
34.5/14.1
34.3/18.1
26.5/0.0
4-NO
2
C
6
H -
4
α-C10
H
7
CH -
2
CH
3
-
2-FC
6
H
4
-
2-ClPy-3-
4-OCH
3,5-(NO
3
C
6
H -
4
2
)
2
C
6
H -
3
EtOOC-
EtOOC-
EtOOC-
EtOOC-
EtOOC-
EtOOC-
EtOOC-
EtOOC-
t-Bu
C
6
H
5
-
43.5/25.4
51.0/7.4
4-NO
2
C
6
H -
4
α-C10
H
7
CH
2
-
93.0/68.8
43.0/18.9
34.3/7.4
CH
3
-
2-FC
6
H
4
-
2-ClPy-3-
4-OCH
3,5-(NO
25.5/11.2
43.7/7.5
64.6/44.3
61.8/47.4
5.2/0.0
12.1/7.4
27.1/5.1
3
C
6
H
4
-
2
)
2
C
6
H
3
-
18.6/-11.8 73.2/67.2
C
6
H
5
-
56.6/32.2
26.8/11.8
92.7/64.8
18.5/-7.2
26.5/0.0
66.8/47.7 32.1/14.1
86.3/77.7 53.6/42.8
90.7/77.0 75.4/37.4
71.3/67.0 32.3/16.1
75.7/70.3 29.9/14.9
t-Bu
4-NO
2
C
6
H -
4
t-Bu
α-C10
H
7
CH -
2
t-Bu
CH
3
-
t-Bu
2-FC
6
H
4
-

Molecules 2015, 20
1092
Table 1. Cont.
Relative Inhibition (Root %/Stalk %)
Rape Wheat
10 mg/L 100 mg/L 10 mg/L
59.2/51.5 24.7/7.1
Comp.
R
1
R
2
1
00 mg/L
5
5
5
5
5
5
5
5
5
-C6
-C7
-D1
-D2
-D3
-D4
-D5
-D6
-D7
t-Bu
t-Bu
4-OCH
3
C
6
H
4
-
84.0/64.5
70.0/36.3
75.3/57.6
74.4/50.7
97.6/86.8
77.3/50.5
64.4/29.6
82.3/61.7
72.2/32.2
30.9/18.9
48.8/14.8
25.6/29.4
48.3/32.2
93.4/57.8
28.5/18.8
31.3/7.9
3,5-(NO
2
)
2
6
C H
3
-
58.6/44.2 32.8/30.5
68.7/63.4 51.5/40.1
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
2
-
-
-
-
-
-
-
C
6
H -
5
2
2
2
2
2
2
4-NO
2
C
6
H
4
-
76.8/72.8
92.1/77.0
66.5/60.9
66.3/53.8
22.7/2.1
36.4/9.8
22.9/5.0
20.9/9.2
α-C10
H
7
CH -
2
CH
2-FC
4-OCH
3,5-(NO
3
-
6
H
4
-
3
C
6
H
4
-
28.7/-4.8
34.8/21.3
63.6/56.2 36.0/19.5
71.6/53.8 7.0/7.2
2
)
2
6
C H
3
-
Table 2. The fresh weight reduction ratios of Barnyard grass at different concentrations of 5.
Fresh Weight Reduction Ratios of Barnyard Grass (%)
Comp.
Pre-Emergence Treatment
Post-Emergence Treatment
4
kg/hm2 1 kg/hm2 250 g/hm2 62.5 g/hm2 4 kg/hm2 1 kg/hm2 250 g/hm2 62.5 g/hm2
Acetochlor
99.0
−2.5
4.2
99.0
68.3
4.6
5
-A3
40.4
51.4
34.3
28.7
49.8
26.9
13.3
30.5
11.8
19.0
21.4
13.3
4.0
11.0
6.2
99.3
68 .1
97.6
55.1
81.0
64.1
93.1
47.1
88.1
30.9
72.0
38.4
79.1
15.7
74.8
4.1
5
5
-B3
-B4
4.8
30.7
0.0
5
5
5
-C2
-C3
-D3
0.0
−4.1
2.7
2.2
55.5
11.0
23.1
11.4
0.0
2.1
The preliminary bioassay results showed that most compounds 5 possess moderate to good
herbicidal activity. When evaluating the inhibitory activity of compounds 5 at a concentration of
1
9
00 mg/L against the root growth of wheat, compounds 5-B3, 5-C3 and 5-D3 exhibited more than
0% inhibitory activity and 20 compounds exhibited more than 70% inhibitory activity. At 10 mg/L,
compounds 5-B3 and 5-C3 exhibited more than 70% inhibitory activity against the root growth of
wheat. When evaluating the inhibitory activity of compounds 5 at 100 mg/mL against the stalk growth
of wheat, 11 compounds exhibited more than 70% inhibitory activity. At 10 mg/L, all compounds 5
exhibited slight inhibitory activity against the stalk growth of wheat, while compound 5-B3 was the
best, exhibiting 51% inhibitory activity.
According to the Figure 2, evaluation of the inhibitory activity of compounds 5 at 100 mg/L against
the root growth of rape showed compounds 5-A3, 5-A6, 5-B3, 5-B4, 5-C3 and 5-D3 exhibited more
than 90% inhibitory activity and 29 compounds exhibited more than 70% inhibitory activity. At
1
0 mg/L, compounds 5-B3, 5-C3 and 5-D3 exhibited more than 90% inhibitory activity. Investigation
of the inhibitory activities of compounds against the stalk growth of rape showed compounds 5-A3,
-A5, 5-B2, 5-B3, 5-B4, 5-C3 and 5-D3 exhibited more than 70% inhibitory activity at 100 mg/L,
5
while at 10 mg/L, all the compounds 5 exhibited slight inhibitory activity against the stalk growth of rape.
Interestingly, compounds 5-B3 also exhibited the best inhibitory activity against the stalk growth of
rape among all compounds 5.

Molecules 2015, 20
1093
CK
A3
0 mg/L
A3
B3
B3
C3
C3
D3
D3
1
100 mg/L 10 mg/L 100 mg/L
10 mg/L 100 mg/L 10 mg/L 100 mg/L
Figure 2. Photographs showing the lateral root and stalk development of dicotyledon rape
with compounds 5-A3, 5-B3, 5-C3, 5-D3 at different concentrations.
Overall, the inhibitory activity against root growth was stronger than the inhibitory activity against
stalk growth. Interestingly, compound 5-B3 exhibited the best inhibitory activity in both wheat and
rape, even at the concentration of 10 mg/L, where inhibitory activity against root growth of rape was
9
3%. Aside from compound 5-B3, compounds whose R
2
is α-naphthylmethylene (5-A3, 5-B3, 5-C3,
5
-D3) also exhibited much better inhibitory activity than other target compounds. This observation
builds on the conclusion of Schweitzer, where the naphthyl ring fills the volume of the enzymatic
cavity even more efficiently than the phenyl ring. Alternatively, the π-π interaction of the naphthyl ring
with an aromatic residue of the protein may be stronger than with the phenyl ring.
In the pot experiment, we chose six compounds (5-A3, 5-B3, 5-B4, 5-C2, 5-C3, 5-D3) which
exhibited more than 90% inhibitory activity against stalk growth or root growth. According to the
Figure 3, the pot experiment on barnyard grass shows that compounds 5-A3 and 5-B4 exhibited good
inhibitory activity with post-emergence treatment. But all the six compounds (5-A3, 5-B3, 5-B4, 5-C2,
5
-C3, 5-D3) only exhibited slight inhibitory activity in pre-emergence treatment. Compared with
IRL1803, which exhibits the best herbicidal activity ever reported, compounds 5-A3 and 5-B4 both
gave displayed a nearly a 4-fold increase in inhibition. These compounds can also efficiently inhibit
2
the growth of barnyard grass at a concentration of 250 g/hm . The increase of herbicidal activity
maybe the result of the ester group in 5-A3 which increases the osmosis of compounds into weeds.
blank A3 A3 A3 A3 acetochlor B4 B4 B4 B4
4
kg/ha 1 kg/ha 250 g/ha 62.5 g/ha 62.5 g/ha 4 kg/ha 1 kg/ha 250 g/ha 62.5 g/ha
Figure 3. Photographs showing the lateral development of monocotyledon barnyard grass
with compounds 5-A3, 5-B4 at different concentrations with a pot experiment.

Molecules 2015, 20
1094
3
. Experimental
3
.1. General Methods
All starting materials and reagents were commercially available and used without further
1
13
31
purification except as indicated. H-NMR (300 MHz), C-NMR (75.5 MHz) and P-NMR (121.5 MHz)
spectra was recorded in CDCl or DMSO-d with a Bruker DPX300 spectrometer, using TMS as internal
3
6
standard; Mass spectra were obtained with Agilent 1100 series LC/MSD mass spectrometer.
High-resolution mass spectra (HRMS) was performed by the Peking University. Melting points were
measured on a Yanagimoto melting-point apparatus and are uncorrected.
3
.2. Chemical Synthesis
General Procedure for the Synthesis of Compounds 4
A mixture of diethyl (oxiran-2-ylmethyl)phosphonate (1.65 g, 10 mmol), sodium azide (1.30 g,
20 mmol) and ammonium chloride (1.06 g, 20 mmol) was dissolved in 1:1 mixture of methanol and
water (30 mL), and stirred at room temperature overnight. Dichloromethane (50 mL) was added and
then the organic phase was washed with water (3 × 50 mL). The organic phase was dried with
anhydrous Na
methanol and water (30 mL), CuSO
and then alkyne (11 mmol) was added. The mixture was stirred at room temperature overnight.
Dichloromethane was then added and the mixture was washed with water, dried with Na SO , and
2
SO
4
and concentrated under vacuum. The residue was dissolved in a 1:1 mixture of
4
·5H O (0.16 g, 1 mmol) and sodium ascorbate (0.20 g, 1 mmol)
2
2
4
concentrated by vacuum. The desired product was obtained by purification on a silica gel column with
petroleum ether–ethyl acetate.
Diethyl (2-hydroxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl)phosphonate (4-A). Yield: 89%. White
1
solid. H-NMR (CDCl
3
) δ 1.26 (t, J = 7.1 Hz, 6H), 1.95–2.05 (m, 2H), 3.98–4.10 (m, 4H), 4.38–4.49
(
m, 2H), 4.57–4.61 (m, 1H), 5.37 (d, J = 4.4Hz, 1H), 7.26–7.39 (m, 3H), 7.76–7.79 (m, 2H), 8.03 (S,
13
1
6
1
3
H); C-NMR (CDCl ) δ 15.90 (d, JC-P = 6.2 Hz), 30.51 (d, JC-P = 140.0 Hz), 55.70 (d, JC-P = 15.5 Hz),
1.60 (d, JC-P = 6.4 Hz), 61.79 (d, JC-P = 6.3 Hz), 65.07 (d, JC-P = 3.2 Hz), 121.25, 125.18, 127.62,
31
28.38, 130.18, 146.92; P-NMR (CDCl ) δ 29.04.
3
Ethyl 1-(3-(diethoxyphosphoryl)-2-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate (4-B). Yield: 79%.
1
White solid. H-NMR (CDCl
3
) δ 1.30–1.43 (m, 9H), 1.78–1.87 (m, 1H), 1.95–2.08 (m, 1H), 4.05–4.17
1
3
(
m, 4H), 4.39–4.50 (m, 4H), 4.59–4.64 (m, 1H), 8.31 (s, 1H); C-NMR (CDCl
3
) δ 14.23, 16.24 (d,
J
C-P = 3.4 Hz), 16.32 (d, JC-P = 3.3 Hz), 30.47 (d, JC-P = 140.7 Hz), 55.99 (d, JC-P = 18.3 Hz), 61.19, 62.27
31
(d, JC-P = 6.8 Hz), 62.39 (d, JC-P = 6.6 Hz), 65.17 (d, JC-P = 4.1 Hz), 129.16, 140.07, 160.68; P-NMR
CDCl ) δ 29.03.
(
3
Diethyl (3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropyl)phosphonate (4-C). Yield: 69%.
1
White solid. H-NMR (CDCl
3
) δ 1.26–1.35 (m, 15H), 1.84–2.09 (m, 2H), 4.05–4.16 (m, 4H), 4.36–4.45
1
3
(
m, 2H), 4.53–4.57 (m, 1H), 7.51 (s, 1H) ; C-NMR (CDCl ) δ 16.10 (d, JC-P = 2.5 Hz), 16.19 (d,
3

Molecules 2015, 20
1095
J
C-P = 2.3 Hz), 30.14, 30.48, 30.60 (d, JC-P = 140.0 Hz), 55.51 (d, JC-P = 16.1 Hz), 61.94 (d, JC-P = 6.9 Hz),
3
1
6
2.03 (d, JC-P = 7.3 Hz), 65.41 (d, JC-P = 3.6 Hz), 120.20, 157.21; P-NMR (CDCl ) δ 29.09.
3
Diethyl (3-(4-(chloromethyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropyl)phosphonate (4-D). Yield: 74%.
1
White solid. H-NMR (CDCl
3
) δ 1.20–1.25 (m, 6H), 1.81–2.03 (m, 2H), 3.95–4.07 (m, 4H), 4.31–4.38
1
3
(
m, 2H), 4.49–4.56 (m, 1H), 4.61 (s, 2H), 5.20 (d, J = 6.9 Hz, 1H), 7.83 (s, 1H); C-NMR (CDCl
3
) δ
1
5.75 (d, JC-P = 1.2 Hz), 15.83 (d, JC-P = 1.1 Hz), 30.36 (d, JC-P = 139.8 Hz), 35.59, 55.50 (d,
J
C-P = 14.9 Hz), 61.55 (d, JC-P = 6.6 Hz), 61.70 (d, JC-P = 6.4 Hz), 64.78 (d, JC-P = 3.1 Hz), 124.17,
3
1
1
43.51; P-NMR (CDCl ) δ 28.61.
3
General Procedure for the Synthesis of Compounds 5
A mixture of carboxylic acid (5 mmol) and DCC (1.07 g, 5.5 mmol) was dissolved in
dichloromethane (40 mL), stirred at room temperature for 1 h. Then the mixture was placed in ice-bath
and DMAP (0.06 g, 0.5 mmol), compounds 4 (4 mmol) was added, stirred for 10 min. Then the mixture
was stirred at room temperature overnight. The desired product was obtained by purification on a silica
gel column with petroleum ether/ethyl acetate.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl benzoate (5-A1). Yield: 79%.
1
White solid. H-NMR (CDCl
3
) δ 1.24 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 2.25–2.34 (m, 2H),
4
7
1
6
1
4
.05–4.18 (m, 4H), 4.91–4.93 (m, 2H), 5.72–5.79 (m, 1H), 7.27–7.44 (m, 5H), 7.52–7.55 (m, 1H),
1
3
.77–7.80 (m, 2H), 7.98 (s, 1H), 8.00–8.03 (m, 2H); C-NMR (CDCl ) δ 15.77 (d, JC-P = 6.0 Hz),
3
5.85 (d, JC-P = 6.0 Hz), 27.69 (d, JC-P = 140.9 Hz), 52.14 (d, JC-P = 7.9 Hz), 61.68 (d, JC-P = 1.2 Hz),
1.76 (d, JC-P = 1.7 Hz), 67.64, 120.75, 125.18, 127.65, 128.04, 128.32, 128.76, 129.23, 130.01,
3
1
+
33.03, 147.22, 164.74; P-NMR (CDCl
3
) δ 25.53; HR-MS: for C22
H
26
N
3
O P [M+H] calculated m/z
5
44.16, found m/z 444.1682839.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl 4-nitrobenzoate (5-A2). Yield:
1
8
0%. White solid. H-NMR (CDCl
3
) δ 1.28 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.0 Hz, 3H), 2.28 (d,
J = 6.7 Hz, 1H), 2.34 (d, J = 6.8 Hz, 1H), 4.07–4.21 (m, 4H), 4.94–4.97 (m, 2H), 5.74–5.81 (m, 1H),
1
3
7
.30–7.43 (m, 3H), 7.78–7.81 (m, 2H), 8.00 (S, 1H), 8.17–8.20 (m, 2H), 8.23–8.27 (m, 2H); C-NMR
CDCl ) δ 16.18 (d, JC-P = 3.9 Hz), 16.26 (d, JC-P = 4.1 Hz), 28.11 (d, JC-P = 141.1 Hz), 52.28 (d,
C-P = 7.2 Hz), 62.25 (d, JC-P = 6.6 Hz), 68.93, 125.54, 128.18, 128.73, 130.12, 130.82, 134.49, 147.80,
(
3
J
1
3
1
+
50.65, 163.44; P-NMR (CDCl
3
) δ 25.06; HR-MS: for C22
H
25
N
4
O P [M+H] calculated m/z 489.15,
7
found m/z 489.1533621.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl 2-(naphthalen-1-yl)acetate (5-A3).
1
Yield: 73%. White solid. H-NMR (CDCl
3
) δ 1.27 (t, J = 7.1 Hz, 6H), 1.98–2.10 (m, 2H), 4.01–4.11
(
m, 6H), 4.55 (d, J = 4.6 Hz, 2H), 5.49–5.53 (m, 1H), 7.17 (s, 1H), 7.29–7.40 (m, 8H), 7.62–7.74 (m, 4H),
1
3
7
5
1
.86–7.89 (m, 1H); C-NMR (CDCl ) δ 15.91 (d, JC-P = 5.7 Hz), 27.58 (d, JC-P = 141.0 Hz), 38.52,
3
2.04 (d, JC-P = 8.1 Hz), 61.68 (d, JC-P = 4.4 Hz), 61.77 (d, JC-P = 4.3 Hz), 67.45, 120.22, 123.09,
24.96, 125.34, 125.44, 126.09, 127.61, 127.81, 128.21, 128.28, 129.33, 129.95, 131.42, 131.56,

Molecules 2015, 20
1096
P [M+H] calculated m/z
3
1
+
1
5
33.21, 147.13, 169.69; P-NMR (CDCl
08.19, found m/z 508.199584.
3
) δ 25.49; HR-MS: for C27
H
30
N
3
O
5
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl acetate (5-A4). Yield: 71%.
1
White solid. H-NMR (CDCl
3
) δ 1.34 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 2.06 (s, 3H),
2
7
.08–2.13 (m, 1H), 2.15–2.19 (m, 1H), 4.09–4.19 (m, 4H), 4.69–4.85 (m, 2H), 5.46–5.53 (m, 1H),
1
3
.31–7.36 (m, 1H), 7.40–7.45 (m, 2H), 7.82–7.85 (m, 2H), 7.92 (S, 1H); C-NMR (CDCl
3
) δ:15.90 (d,
J
C-P = 6.1 Hz), 20.37, 27.72 (d, JC-P = 141.1 Hz), 52.00 (d, JC-P = 7.1 Hz), 61.71 (d, JC-P = 1.1 Hz), 61.80
31
(d, JC-P = 1.1 Hz), 66.99, 120.32, 125.24, 127.75, 128.36, 129.94, 147.37, 169.18; P-NMR (CDCl
3
)
+
δ:25.61; HR-MS: for C17
H
24
N
3
O
5
P [M+H] calculated m/z 382.15, found m/z 382.1526338.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl
2-fluorobenzoate
(5-A5).
1
Yield: 73%. White solid. H-NMR (CDCl
3
) δ 1.26 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 3.5 Hz, 3H),
2
.24–2.34 (m, 2H), 4.06–4.19 (m, 4H), 4.93 (d, J = 5.2 Hz, 2H), 5.74–5.82 (m, 1H), 7.09–7.21 (m,
H), 7.30–7.42 (m, 3H), 7.47–7.55 (m, 1H), 7.80–7.83 (m, 2H), 7.91–7.94 (m, 1H), 8.06 (S, 1H);
) δ:15.90 (d, JC-P = 5.8 Hz), 15.98 (d, JC-P = 5.6 Hz), 27.77 (d, JC-P = 140.7 Hz),
2.28 (d, JC-P = 7.2 Hz), 61.88 (d, JC-P = 1.4 Hz), 62.00 (d, JC-P = 1.5 Hz), 68.28, 116.65 (d, JC-F = 22.3
Hz), 117.40 (d, JC-F = 9.6 Hz), 120.89 (d, JC-F = 2.6 Hz), 123.92 (d, JC-F = 3.9 Hz), 125.34, 127.79,
2
13C-NMR (CDCl
3
5
1
28.46, 130.18, 132.00, 134.85 (d, JC-F = 9.1 Hz), 147.46, 159.86, 162.62 (d, JC-F = 3.5 Hz), 163.31;
31P-NMR (121.5MHz, CDCl
) δ:25.26; HR-MS: for C22
H25FN
O
5
P [M+H] calculated m/z 462.15,
+
3
3
found m/z 462.1588621.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl 2-chloronicotinate (5-A6).
1
Yield: 75%. White solid. H-NMR (CDCl
3
) δ 1.30 (t, J = 6.3 Hz, 3H), 1.34 (t, J = 6.3 Hz, 3H),
2
7
.25–2.34 (m, 2H), 4.08–4.21 (m, 4H), 4.86–5.00 (m, 2H), 5.76–5.83 (m, 1H), 7.30–7.35 (m, 2H),
1
3
.38–7.43 (m, 2H), 7.79–7.82 (m, 2H), 8.04 (S, 1H), 8.24–8.27 (m, 1H), 8.48–8.50 (m, 1H); C-NMR
) δ 16.06 (d, JC-P = 3.2 Hz), 16.14 (d, JC-P = 3.2 Hz), 27.95 (d, JC-P = 141.5 Hz), 52.21 (d,
C-P = 8.0 Hz), 62.08 (d, JC-P = 3.1 Hz), 62.17 (d, JC-P = 2.9 Hz), 68.83, 120.89, 122.13, 125.43, 125.76,
(CDCl
3
J
1
3
1
28.01, 128.59, 130.01, 140.49, 147.65, 149.52, 152.00, 162.85; P-NMR (CDCl
3
) δ 24.87; HR-MS:
+
for C21
H24ClN
4
O
5
P [M+H] calculated m/z 479.12, found m/z 479.1245606.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl 4-methoxybenzoate (5-A7).
1
Yield: 65%. White solid. H-NMR (CDCl
3
) δ 1.25 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H),
2
.23–2.32 (m, 2H), 3.81 (s, 3H), 4.05–4.18 (m, 4H), 4.89–4.91 (m, 2H), 5.67–5.75 (m, 1H), 6.87–6.90
1
3
(m, 2H), 7.27–7.41 (m, 3H), 7.78–7.80 (m, 2H), 7.95–7.98 (m, 3H); C-NMR (CDCl
3
) δ:16.00 (d,
J
6
1
C-P = 5.9 Hz), 16.08 (d, JC-P = 5.6 Hz), 27.95 (d, JC-P = 140.6 Hz), 52.36 (d, JC-P = 7.2 Hz), 55.16,
1.88 (d, JC-P = 1.6 Hz), 61.98 (d, JC-P = 1.7 Hz), 67.51, 113.55, 120.80, 121.22, 125.41, 127.86,
3
1
28.52, 130.21, 131.59, 147.48, 163.58, 164.70; P-NMR (CDCl
3
) δ 25.72; HR-MS: for C23
H
28
N
3
O P
6
+
[M+H] calculated m/z 474.17, found m/z 474.1788486.
1
-(Diethoxyphosphoryl)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-yl 3,5-dinitrobenzoate (5-A8). Yield:
1
77%. White solid. H-NMR (CDCl
3
) δ 1.32 (t, J = 6.9 Hz, 3H), 1.34 (t, J = 6.9Hz, 3H), 2.36 (d,
J = 6.7 Hz, 1H), 2.42 (d, J = 6.7 Hz, 1H), 4.11–4.21 (m, 4H), 4.92–5.05 (m, 2H), 5.84–5.91 (m, 1H),

Molecules 2015, 20
.22–7.35 (m, 3H), 7.66–7.69 (m, 2H), 8.11 (S, 1H), 8.99–9.04 (m, 3H); C-NMR (CDCl
1097
1
3
7
3
) δ:16.06 (d,
J
J
1
C-P = 5.9 Hz), 27.95 (d, JC-P = 141.8 Hz), 52.12 (d, JC-P = 8.9 Hz), 62.12 (d, JC-P = 6.6 Hz), 62.20 (d,
C-P = 6.5 Hz), 69.72, 120.88, 122.30, 125.14, 127.98, 128.48, 129.12, 129.73, 132.57, 147.43, 148.16,
3
1
+
61.22; P-NMR (CDCl
3
) δ 24.82; HR-MS: for C22
H
24
N
5
O P [M+H] m/z calculated 534.13, found
9
m/z 534.1384403.
Ethyl 1-(2-(benzoyloxy)-3-(diethoxyphosphoryl)propyl)-1H-1,2,3-triazole-4-carboxylate (5-B1). Yield:
1
7
8%. White solid. H-NMR (CDCl
3
) δ 1.21–1.41 (m, 9H), 2.23–2.29 (m, 2H), 4.06–4.20 (m, 4H), 4.40
(
q, J = 7.1 Hz, 2H), 4.97 (d, J = 4.9 Hz, 2H), 5.67–5.75 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.56–7.61
13
(m, 1H), 7.98–8.01 (m, 2H), 8.29 (s, 1H); C-NMR (CDCl
3
) δ:14.08, 16.09 (d, JC-P = 6.3 Hz), 16.17 (d,
J
J
1
C-P = 6.3 Hz), 28.01 (d, JC-P = 140.5 Hz), 52.60 (d, JC-P = 6.3 Hz), 61.07, 62.05 (d,
C-P = 10.2 Hz), 62.16 (d, JC-P = 6.5 Hz), 67.72, 128.40, 128.61, 128.84, 129.60, 133.48, 140.20,
3
1
+
60.37, 165.04; P-NMR (CDCl
3
) δ 25.19; HR-MS: for C19
H
26
N
3
O P [M+H] calculated m/z 440.15,
7
found m/z 440.1581131.
Ethyl 1-(3-(diethoxyphosphoryl)-2-((4-nitrobenzoyl)oxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5-B2).
1
Yield: 73%. yellow solid. H-NMR (CDCl
3
) δ 1.28–1.44 (m, 9H), 2.23–2.34 (m, 2H), 4.10–4.24 (m,
4
H), 4.43 (q, J = 7.1 Hz, 2H), 5.00–5.03 (m, 2H), 5.73–5.81 (m, 1H), 8.18–8.22 (m, 2H), 8.29–8.34
13
(m, 3H); C-NMR (CDCl
3
) δ 13.99, 16.00 (d, JC-P = 6.3 Hz), 16.08 (d, JC-P = 6.3 Hz), 27.90 (d,
J
C-P = 140.6 Hz), 52.53 (d, JC-P = 6.6 Hz), 60.95, 61.95 (d, JC-P = 9.2 Hz), 62.05 (d, JC-P = 6.7 Hz), 67.63,
3
1
1
28.30, 128.58, 128.76, 129.49, 133.38, 140.06, 160.28, 164.93; P-NMR (CDCl
3
) δ 24.63; HR-MS:
+
for C19
H
25
N
4
O
9
P [M+H] calculated m/z 485.14, found m/z 485.1431913.
Ethyl 1-(3-(diethoxyphosphoryl)-2-(2-(naphthalen-1-yl)acetoxy)propyl)-1H-1,2,3-triazole-4-carboxylate
1
(
5-B3). Yield: 68%. White solid. H-NMR (CDCl
3
) δ 1.31 (t, J = 7.1 Hz, 6H), 1.42 (t, J = 7.1 Hz, 3H),
2
.01 (d, J = 6.7 Hz, 1H), 2.08 (d, J = 6.7 Hz, 1H), 4.05–4.16 (m, 6H), 4.43 (q, J = 7.1 Hz, 2H), 4.66
(
d, J = 4.8 Hz, 2H), 5.43–5.51 (m, 1H), 7.34 (d, J = 6.1 Hz, 1H), 7.40–7.55 (m, 3H), 7.71 (s, 1H),
1
3
7
3
1
1
.79–7.88 (m, 3H); C-NMR (CDCl ) δ 14.19, 16.22 (d, JC-P = 5.9 Hz), 27.95 (d, JC-P = 140.6 Hz),
3
8.81, 52.43 (d, JC-P = 6.3 Hz), 61.07, 62.16 (d, JC-P = 6.2 Hz), 62.24 (d, JC-P = 6.0 Hz), 67.52, 123.31,
25.31, 125.75, 126.43, 127.95, 128.27, 128.31, 128.69, 129.40, 131.69, 133.62, 140.05, 160.28,
3
1
+
70.03; P-NMR (CDCl
3
) δ 24.39; HR-MS: for C24
H
30
N
3
O P [M+H] calculated m/z 504.18, found
7
m/z 504.1894132.
Ethyl 1-(2-acetoxy-3-(diethoxyphosphoryl)propyl)-1H-1,2,3-triazole-4-carboxylate (5-B4). Yield:
1
7
4%. White solid. H-NMR (CDCl
3
) δ: 1.27–1.44 (m, 9H), 2.04 (s, 3H), 2.05–2.20 (m, 2H), 4.09–4.21
1
3
(
m, 4H), 4.42 (q, J = 7.1 Hz, 2H), 4.76–4.93 (m, 2H), 5.45–5.54 (m, 1H), 8.33 (s, 1H); C-NMR
CDCl ) δ:13.83, 15.93 (d, JC-P = 6.0 Hz), 20.33, 27.71 (d, JC-P = 141.1 Hz), 52.33 (d, JC-P = 7.7 Hz),
0.77, 61.77 (d, JC-P = 3.0 Hz), 61.86 (d, JC-P = 2.8 Hz), 66.77, 128.37, 139.79, 160.14, 169.07; P-NMR
(
3
31
6
+
(CDCl
3
) δ: 25.13; HR-MS: for C14
H
24
N
3
O P [M+H] calculated m/z 378.14, found m/z 378.1424631.
7
Ethyl 1-(3-(diethoxyphosphoryl)-2-((2-fluorobenzoyl)oxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5-B5).
1
Yield: 78%. yellow solid. H-NMR (CDCl
3
) δ 1.26–1.41 (m, 9H), 2.26 (d, J = 6.6 Hz, 1H), 2.33 (d,
J = 6.5 Hz, 1H), 4.08–4.21 (m, 4H), 4.40 (q, J = 7.1 Hz, 2H), 5.00–5.01 (m, 2H), 5.72–5.80 (m, 1H),

Molecules 2015, 20
1098
1
3
7
1
6
.12–7.25 (m, 2H), 7.54–7.61 (m, 1H), 7.90–7.95 (m, 1H), 8.40 (s, 1H); C-NMR (CDCl
3
) δ 13.85,
5.85 (d, JC-P = 5.8 Hz), 15.93 (d, JC-P = 5.9 Hz), 27.67 (d, JC-P = 140.5 Hz), 52.41 (d, JC-P = 6.7 Hz),
0.78, 61.96 (d, JC-P = 6.6 Hz), 67.96, 116.64 (d, JC-F = 22.2 Hz), 117.14 (d, JC-F = 9.4 Hz), 123.89 (d,
J
C-F = 3.9 Hz), 128.67 (d, JC-F = 2.1 Hz), 131.92, 134.93 (d, JC-F = 9.3 Hz), 139.88, 160.00 (d,
J
C-F = 27.0 Hz), 162.46 (d, JC-F = 3.5 Hz), 163.27; 31P-NMR (CDCl
3
) δ:24.83; HR-MS: for
+
C
H25FN O
19 3 7
P [M+H] calculated m/z 458.14, found m/z 458.1486913.
1
-(Diethoxyphosphoryl)-3-(4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)propan-2-yl 2-chloronicotinate
1
(
5-B6). Yield: 76%. yellow solid. H-NMR (CDCl
3
) δ 1.29–1.42 (m, 9H), 2.25–2.34 (m, 2H),
4
.10–4.23 (m, 4H), 4.41 (q, J = 7.1 Hz, 2H), 4.93–5.08 (m, 2H), 5.75–5.82 (m, 1H), 7.36–7.40 (m,
H), 8.25–8.29 (m, 1H), 8.40 (s, 1H), 8.53–8.55 (m, 1H); 13C-NMR (CDCl
) δ: 13.90, 15.95 (d,
C-P = 3.5 Hz), 16.03 (d, JC-P = 3.5 Hz), 27.76 (d, JC-P = 141.3 Hz), 52.30 (d, JC-P = 7.6 Hz), 60.95,
2.09 (d, JC-P = 4.5 Hz), 62.18 (d, JC-P = 4.4 Hz), 68.49, 122.08, 125.45, 128.64, 139.97, 140.42,
1
3
J
6
1
31
O
P [M+H]+
49.46, 152.01, 160.10, 162.64; P-NMR (CDCl
3
) δ: 24.53; HR-MS: for C18
H24ClN
4
7
calculated m/z 475.11, found m/z 475.1143897.
Ethyl 1-(3-(diethoxyphosphoryl)-2-((4-methoxybenzoyl)oxy)propyl)-1H-1,2,3-triazole-4-carboxylate
1
(
5-B7). Yield: 80%. White solid. H-NMR (CDCl
3
) δ 1.20–1.41 (m, 9H), 2.20–2.29 (m, 2H), 3.86 (s,
3
6
1
H), 4.07–4.20 (m, 4H), 4.40 (q, J = 7.1 Hz, 2H), 4.96 (d, J = 4.8 Hz, 2H), 5.66–5.70 (m, 1H),
13
3
.89–6.94 (m, 2H), 7.92–7.96 (m, 2H), 8.29 (s, 1H); C-NMR (CDCl ) δ:13.98, 16.00 (d, JC-P = 5.7 Hz),
6.07 (d, JC-P = 6.0 Hz), 27.89 (d, JC-P = 140.5 Hz), 52.55 (d, JC-P = 6.3 Hz), 55.20, 60.97, 62.08 (d,
J
C-P = 6.5 Hz), 67.24, 113.58, 120.96, 128.52, 131.62, 140.05, 160.30, 163.66, 164.63; 31P-NMR
+
(CDCl
3
) δ 25.16; HR-MS: for C20
H
28
N
3
O
8
P [M+H] calculated m/z 470.16, found m/z 470.1686778.
Ethyl 1-(3-(diethoxyphosphoryl)-2-((3,5-dinitrobenzoyl)oxy)propyl)-1H-1,2,3-triazole-4-carboxylate
1
(
5-B8). Yield: 76%. White solid. H-NMR (CDCl
3
) δ 1.31–1.40 (m, 9H), 2.37 (d, J = 6.7 Hz, 1H), 2.44
(
d, J = 6.7 Hz, 1H), 4.13–4.23 (m, 4H), 4.37 (q, J = 7.1 Hz, 2H), 5.01–5.14 (m, 2H), 5.84–5.92 (m, 1H),
1
3
8
6
.45 (s, 1H), 9.09 (d, J = 2.1 Hz, 2H), 9.20–9.22 (m, 1H); C-NMR (CDCl
3
) δ 13.87, 16.05 (d, JC-P =
.0 Hz), 27.93 (d, JC-P = 141.6 Hz), 52.35 (d, JC-P = 8.8 Hz), 60.99, 62.18 (d, JC-P = 7.2 Hz), 62.28 (d,
3
1
J
C-P = 6.9 Hz), 69.54, 122.50, 128.64, 129.29, 132.55, 139.97, 148.35, 160.07, 161.20; P-NMR (CDCl ) δ
3
+
2
4.38; HR-MS: for C19
H
24
N O11P [M+H] calculated m/z 530.12, found m/z 530.1282694.
5
1
6
4
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl benzoate (5-C1). Yield:
1
8%. White solid. H-NMR (CDCl
3
) δ: 1.23–1.35 (m, 15H), 2.20–2.33 (m, 2H), 4.06–4.19 (m, 4H),
.76–4.87 (m, 2H), 5.65–5.73 (m, 1H), 7.36–7.47 (m, 3H), 7.56–7.61 (m, 1H), 7.99–8.03 (m, 2H);
) δ: 16.02 (d, JC-P = 6.3 Hz), 16.10 (d, JC-P = 6.3 Hz), 28.01 (d, JC-P = 140.7 Hz),
0.03, 30.41, 52.04 (d, JC-P = 7.6 Hz), 61.87 (d, JC-P = 1.4 Hz), 61.95 (d, JC-P = 1.4 Hz), 67.95, 119.79,
28.25, 129.03, 129.45, 133.27, 157.44, 164.95; 31P-NMR (CDCl
) δ: 25.58; HR-MS: for
13C-NMR (CDCl
3
3
1
3
+
C
20
H
30
N
3
O P [M+H] calculated m/z 424.19, found m/z 424.199584.
5
1
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl4-nitrobenzoate (5-C2). Yield:
1
76%. White solid. H-NMR (CDCl
3
) δ: 1.26–1.38 (m, 15H), 2.27 (d, J = 6.6 Hz, 1H), 2.33 (d,
J = 6.6 Hz, 1H), 4.08–4.21 (m, 4H), 4.83–4.86 (m, 2H), 5.69–5.76 (m, 1H), 7.42 (s, 1H), 8.17–8.21

Molecules 2015, 20
1099
1
3
(
m, 2H), 8.27–8.31 (m, 2H); C-NMR (CDCl
3
) δ: 16.18 (d, JC-P = 4.0 Hz), 16.26 (d, JC-P = 3.6 Hz),
2
1
8.16 (d, JC-P = 141.4 Hz), 30.15, 30.56, 52.05 (d, JC-P = 7.6 Hz), 62.21 (d, JC-P = 6.5 Hz), 68.96,
19.81, 123.48, 130.78, 134.58, 150.65, 157.75, 163.36; 31P-NMR (CDCl
) δ: 24.99; HR-MS: for
3
+
C
20
H
29
N
4
O
7
P [M+H] calculated m/z 469.18, found m/z 469.1846622.
1
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 2-(naphthalen-1-yl)acetate
1
(5-C3). Yield: 61%. White solid. H-NMR (CDCl
3
) δ: 1.21–1.33 (m, 15H), 1.91-2.13 (m, 2H), 4.03–4.15
(
m, 6H), 4.55–4.56 (m, 2H), 5.42–5.51 (m, 1H), 6.89 (s, 1H), 7.36–7.56 (m, 4H), 7.79–7.87 (m, 2H),
1
3
7
3
1
.94–7.97 (m, 1H); C-NMR (CDCl
3
) δ: 16.31 (d, JC-P = 6.3 Hz), 27.98 (d, JC-P = 141.2 Hz), 30.23,
0.53, 38.99, 52.26 (d, JC-P = 8.0 Hz), 62.09 (d, JC-P = 3.8 Hz), 62.18 (d, JC-P = 3.9 Hz), 68.02, 119.39,
31
23.54, 125.40, 125.87, 126.53, 128.03, 128.28, 128.75, 129.73, 131.90, 133.74, 157.71, 170.22; P-NMR
+
(CDCl
3
) δ: 25.39; HR-MS: for C25
H
34
N
3
O
5
P [M+H] calculated m/z 488.22, found m/z 488.2308841.
1
7
4
2
6
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl acetate (5-C4). Yield:
1
1%. White solid. H-NMR (CDCl
3
) δ 1.26–1.37 (m, 15H), 2.03–2.21 (m, 5H), 4.08–4.19 (m, 4H),
1
3
.58–4.76 (m, 2H), 5.41–5.47 (m, 1H), 7.37 (s, 1H); C-NMR (CDCl
0.60, 28.02 (d, JC-P = 141.2 Hz), 30.11, 30.47, 52.02 (d, JC-P = 7.9 Hz), 61.92 (d, JC-P = 6.3 Hz),
7.34, 119.48, 157.53, 169.36; 31P-NMR (CDCl P [M+H]+
) δ 26.22; HR-MS: for C15
3
) δ 16.16 (d, JC-P = 6.1 Hz),
3
H
28
N
3
O
5
calculated m/z 362.18, found m/z 362.183934.
1
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 2-fluorobenzoate (5-C5).
1
Yield: 66%. yellow solid. H-NMR (CDCl
3
) δ: 1.25–1.38 (m, 15H), 2.18–2.33 (m, 2H), 4.08–4.20 (m,
4
7
H), 4.82–4.84 (m, 2H), 5.70–5.74 (m, 1H), 7.11–7.25 (m, 2H), 7.49 (s, 1H), 7.54–7.57 (m, 1H),
13
.90–7.95 (m, 1H); C-NMR (CDCl ) δ: 15.99 (d, JC-P = 5.9 Hz), 16.07 (d, JC-P = 5.9 Hz), 27.92 (d,
3
JC-P = 141.0 Hz), 30.01, 30.41, 52.11 (d, JC-P = 7.6 Hz), 61.99 (d, JC-P = 1.2 Hz), 62.07 (d, JC-P = 1.4 Hz),
6
8.42, 116.72 (d, JC-F = 22.3 Hz), 117.55 (d, JC-F = 9.5 Hz), 119.91 (d, JC-F = 2.3 Hz), 123.96 (d,
3
1
J
C-F = 3.9 Hz), 132.07, 134.90 (d, JC-F = 9.2 Hz), 157.45, 162.67 (d, JC-F = 3.5 Hz), 163.40; P-NMR
+
(CDCl
3
) δ:24.90; HR-MS: for C20
H29FN
3
O
5
P [M+H] calculated m/z 442.18, found m/z 442.1901622.
1
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 4-methoxybenzoate (5-C6).
1
Yield: 43%. yellow solid. H-NMR (CDCl
3
) δ 1.21–1.37 (m, 15H), 2.19–2.29 (m, 2H), 3.87 (s, 3H),
4
.05–4.18 (m, 4H), 4.78–4.80 (m, 2H), 5.58–5.67 (m, 1H), 6.89–6.94 (m, 2H), 7.35 (s, 1H), 7.93–7.98
m, 2H); 13C-NMR (CDCl
) δ: 16.23 (d, JC-P = 6.0 Hz), 16.30 (d, JC-P = 5.9 Hz), 28.27 (d,
C-P = 140.7 Hz), 30.24, 30.62, 52.28 (d, JC-P = 7.4 Hz), 55.41, 62.05 (d, JC-P = 1.9 Hz), 62.13 (d,
(
3
J
J
3
1
C-P = 2.0 Hz), 67.82, 113.73, 119.89, 121.55, 131.78, 157.68, 163.79, 164.91; P-NMR (CDCl
3
) δ
+
2
5.68; HR-MS: for C21
H
32
N
3
O
6
P [M+H] calculated m/z 454.20, found m/z 454.2101487.
1
-(4-(tert-Butyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 3,5-dinitrobenzoate (5-C7).
1
Yield: 63%. White solid. H-NMR (CDCl
3
) δ: 1.24–1.37 (m, 15H), 2.27–2.35 (m, 2H), 4.10–4.21 (m, 4H),
1
3
4
.77–4.89 (m, 2H), 5.76–5.84 (m, 1H), 7.42 (s, 1H), 9.09–9.10 (m, 2H), 9.23–9.24 (m, 1H); C-NMR
CDCl ) δ: 16.33 (d, JC-P = 5.8 Hz), 28.39 (d, JC-P = 141.9 Hz), 30.19, 30.66, 52.06 (d, JC-P = 8.6 Hz),
2.34 (d, JC-P = 6.8 Hz), 62.43 (d, JC-P = 6.8 Hz), 69.96, 119.69, 122.65, 129.43, 133.06, 148.65,
(
3
6

Molecules 2015, 20
1100
P [M+H] calculated m/z 514.16,
31
+
1
58.11, 161.37 ; P-NMR (CDCl
3
) δ:24.65; HR-MS: for C20
H
28
N
5
O
9
found m/z 514.1697404.
1
7
1
7
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl benzoate (5-D1). Yield:
1
3
6%. White solid. H-NMR (CDCl ) δ 1.20–1.35 (m, 6H), 2.22 (d, J = 6.5 Hz, 1H), 2.28 (d, J = 6.5 Hz,
H), 4.06–4.19 (m, 4H), 4.69 (s, 2H), 4.88–4.90 (m, 2H), 5.65–5.73 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H),
13
.56–7.61 (m, 1H), 7.78 (s, 1H), 7.98–8.01 (m, 2H); C-NMR (CDCl ) δ: 16.12 (d, JC-P = 6.3 Hz), 16.20
3
(
d, JC-P = 6.3 Hz), 28.04 (d, JC-P = 140.7 Hz), 35.90, 52.45 (d, JC-P = 6.8 Hz), 62.13 (d, JC-P = 6.6 Hz),
31
6
7.86, 123.99, 128.41, 128.95, 129.61, 133.46, 144.68, 165.09; P-NMR (CDCl
3
) δ: 25.14; HR-MS:
+
for C17
H23ClN
3
O
5
P [M+H] calculated m/z 416.11, found m/z 416.1136615.
1
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 4-nitrobenzoate (5-D2).
1
Yield: 78%. White solid. H-NMR (CDCl
3
) δ: 1.29 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 2.26 (d,
J = 6.9 Hz, 1H), 2.32 (d, J = 7.1 Hz, 1H), 4.08–4.21 (m, 4H), 4.70 (s, 2H), 4.91–4.94 (m, 2H),
.72–5.76 (m, 1H), 7.83 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 1.9 Hz, 1H), 8.27 (d,
5
1
3
J = 2.0 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H); C-NMR (CDCl
3
) δ: 16.15 (d, JC-P = 3.8 Hz), 16.23 (d,
J
J
C-P = 3.7 Hz), 28.04 (d, JC-P = 141.1 Hz), 35.85, 52.28 (d, JC-P = 7.0 Hz), 62.20 (d, JC-P = 1.7 Hz), 62.28 (d,
C-P = 1.5 Hz), 68.77, 123.49, 124.00, 130.79, 134.39, 144.75, 150.64, 163.32; 31P-NMR (CDCl
)
3
+
δ:24.70; HR-MS: for C17
H22ClN
4
O
7
P [M+H] calculated m/z 461.09, found m/z 461.0987397.
1
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 2-(naphthalen-1-yl)acetate
1
(
5-D3). Yield: 80%. White solid. H-NMR (CDCl
3
) δ: 1.26–1.35 (m, 6H), 1.94–2.04 (m, 2H),
4
.06–4.16 (m, 6H), 4.41–4.46 (m, 2H), 4.51–4.53 (m, 2H), 5.41–5.44 (m, 1H), 6.59 (s, 1H), 7.37–7.57
1
3
(m, 4H), 7.84–7.96 (m, 3H); C-NMR (CDCl
3
) δ: 16.28 (d, JC-P = 5.9 Hz), 27.90 (d, JC-P = 141.0 Hz),
3
1
5.67, 39.11, 52.39 (d, JC-P = 7.4 Hz), 62.16 (d, JC-P = 6.6 Hz), 62.25 (d, JC-P = 6.5 Hz), 67.72, 123.50,
25.48, 126.01, 126.63, 128.22, 128.27, 128.75, 129.70, 131.80, 133.67, 144.29, 169.87; 31P-NMR
+
(CDCl
3
) δ: 25.14; HR-MS: for C22
H
27ClN
3
O
5
P [M+H] calculated m/z 480.14, found m/z 480.1449616.
1
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl acetate (5-D4). Yield:
1
5
4%. White solid. H-NMR (CDCl
3
) δ 1.31–1.38 (m, 6H), 2.05–2.15 (m, 2H), 2.06 (s, 3H), 4.09–4.20
) δ 16.31 (d,
C-P = 6.0 Hz), 20.76, 28.14 (d, JC-P = 141.0 Hz), 36.00, 52.44 (d, JC-P = 6.9 Hz), 62.17 (d,
(
m, 4H), 4.65–4.82 (m, 4H), 5.41–5.48 (m, 1H), 7.74 (s, 1H); 13C-NMR (CDCl
3
J
J
3
1
C-P = 3.3 Hz), 62.26 (d, JC-P = 3.2 Hz), 67.31, 123.85, 144.81, 169.54; P-NMR (CDCl
3
) δ 25.19;
+
HR-MS: for C12
H21ClN
3
O
5
P [M+H] calculated m/z 354.09, found m/z 354.0980115.
1
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 2-fluorobenzoate (5-D5).
1
Yield: 52%. White solid. H-NMR (CDCl
3
) δ 1.25–1.38 (m, 6H), 2.23–2.31 (m, 2H), 4.08–4.20 (m, 4H),
4
1
.70 (s, 2H), 4.89–4.91 (m, 2H), 5.70–5.74 (m, 1H), 7.12–7.25 (m, 2H), 7.55–7.58 (m, 1H), 7.85 (s,
1
3
H), 7.89–7.95 (m, 1H); C-NMR (CDCl ) δ 16.05 (d, JC-P = 5.9 Hz), 16.13 (d, JC-P = 5.9 Hz), 27.93
3
(d, JC-P = 140.8 Hz), 35.86, 52.46 (d, JC-P = 6.8 Hz), 62.18 (d, JC-P = 6.5 Hz), 68.29, 116.84 (d,
J
C-F = 22.3 Hz), 124.06 (d, JC-F = 2.1 Hz), 124.09 (d, JC-F = 1.9 Hz), 132.13, 135.05 (d, JC-F = 9.1 Hz),
1
44.58, 160.04, 162.71 (d, JC-F = 3.5 Hz), 163.48; 31P-NMR (CDCl
3
) δ 25.02; HR-MS: for
+
C
17
H
22ClFN
3
O
5
P [M+H] calculated m/z 434.10, found m/z 434.1042397.

Molecules 2015, 20
1101
1
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl
4-methoxybenzoate
1
(
5-D6). Yield: 34%. White solid. H-NMR (CDCl
3
) δ: 1.24–1.38 (m, 6H), 2.19 (d, J = 6.6 Hz, 1H),
2
.25 (d, J = 6.6 Hz, 1H), 3.87 (s, 3H), 4.06–4.19 (m, 4H), 4.69 (s, 2H), 4.86–4.88 (m, 2H), 5.62–5.66 (m,
H), 6.90–6.95 (m, 2H), 7.74 (s, 1H), 7.93–7.98 (m, 2H); 13C-NMR (CDCl
) δ: 16.26 (d,
C-P = 6.0 Hz), 16.33 (d, JC-P = 5.7 Hz), 28.20 (d, JC-P = 140.5 Hz), 36.04, 52.62 (d, JC-P = 6.4 Hz),
1
3
J
31
55.45, 62.24 (d, JC-P = 6.6 Hz), 67.63, 113.83, 121.35, 124.03, 131.87, 144.83, 163.90, 164.93; P-NMR
+
(
CDCl
) δ:25.39; HR-MS: for C18H25ClN O
3 3 6
P [M+H] calculated m/z 446.12, found m/z 446.1242262.
1
-(4-(Chloromethyl)-1H-1,2,3-triazol-1-yl)-3-(diethoxyphosphoryl)propan-2-yl 3,5-dinitrobenzoate (5-
1
D7). Yield: 76%. White solid. H-NMR (CDCl
3
) δ 1.26–1.38 (m, 6H), 2.32 (d, J = 6.8 Hz, 1H), 2.39
(
d, J = 7.0 Hz, 1H), 4.12–4.23 (m, 4H), 4.68 (s, 2H), 4.88–5.02 (m, 2H), 5.79–5.87 (m, 1H), 7.87 (s,
1
3
1
P
H), 9.09–9.10 (m, 2H), 9.21–9.22 (m, 1H); C-NMR (CDCl
3
) δ 16.18 (d, JC-P = 5.9 Hz), 28.13 (d, JC-
= 141.8 Hz), 35.76, 52.24 (d, JC-P = 8.4 Hz), 62.30 (d, JC-P = 6.8 Hz), 62.40 (d, JC-P = 6.6 Hz), 69.71,
1
22.60, 124.00, 129.38, 132.73, 144.74, 148.49, 161.27; 31P-NMR (CDCl
3
) δ 24.38; HR-MS: for
+
C
17
H21ClN
5
O
9
P [M+H] calculated m/z 506.08, found m/z 506.0838179.
3
.3. In Vivo Herbicidal Activity
For the preliminary herbicidal activity screen the growth inhibition effect on the dicotyledon rape
and the monocotyledon wheat was examined with a standard Petri dish test. Briefly, the compounds to
®
be tested were dissolved in DMF and emulsified with Tween 80, and the solutions were diluted with
water to the concentrations of 100 mg/L and 10 mg/L, respectively. The solution (9 mL) was added to
a Petri dish and two pieces of filter paper were placed on the dish bottom. Twenty seeds of each of
rape and wheat were placed on the filter paper. The covered Petri dish was transferred into an artificial
climate incubator, where the condition was controlled-temperature 25 °C , room humidity 80%, light
intensity 10 Klux, and photoperiod 12 h/day. The incubation was continued for 5 days. The lengths of
all roots and stalks were measured and the percentage inhibition was calculated relative to controls
using distilled water.
Further herbicidal activity was examined using a pot experiment with barnyard grass [6]. Briefly,
the compounds to be tested (5-A3, 5-B3, 5-B4, 5-C2, 5-C3, 5-D3) were dissolved in DMF and
®
emulsified with Tween 80, and the solutions were diluted with water to the concentrations of
2
2
2
2
4
kg/hm , 1 kg/hm , 250 g/hm and 62.5 g/hm , respectively. Ten germinated seeds of barnyard grass
were 5 mm below the soil in each 8 cm × 8 cm flowerpot. Pre-emergence and post-emergence
treatment was applied for each compound at concentration. For pre-emergence treatment, plants were
treated with compounds 10 days after seeds were sowed while for post-emergence, plants were treated
with compounds 24 h after seeds were sowed. The pottings were transferred into an artificial climate
incubator, where the condition was controlled at temperature 25 °C, room humidity 80%, light
intensity 10 Klux, and photoperiod 12 h/day. The incubation was stopped two weeks after plants were
treated. The fresh weight were measured and the fresh weight reduction ratios were calculated relative
2
to controls using distilled water, compared with 62.5 g/hm acetochlor.

Molecules 2015, 20
. Conclusions
In summary, a series of novel 1-(diethoxyphosphoryl)-3-(4-one-1H-1,2,3-triazol-1-yl)propan-2-yl
1102
4
carboxylic esters were synthesized and their herbicidal activities were evaluated. The bioassays
showed that most of the tested compounds have good herbicidal activities against rape and wheat at
1
00 mg/L. Among all the novel compounds tested, compounds 5-A3 and 5-B4 displayed better
herbicidal activities than IRL1803 ([3-hydroxy-3-(1H-[1,2,4]triazol-3-yl)-cyclohexyl]-phosphonic acid,
2
1
000 g/hm ) which has the best herbicidal activity ever reported. Both compounds 5-A3 and 5-B4,
2
which can efficiently inhibit the growth of barnyard grass at the concentration of 250 g/hm , displayed
a nearly 4-fold increase in the herbicidal potency. Furthermore, using the preliminary bioassay,
compounds whose R is α-naphthylmethylene (5-A3, 5-B3, 5-C3, 5-D3) exhibited much better
2
inhibitory activity than other target compounds. This observation supports the conclusion of
Schweitzer, whereby the naphthyl ring fills the volume of the cavity in the enzyme even more
efficiently than the phenyl ring, or the π-π interaction of the naphthyl ring with an aromatic residue of
the protein may be stronger than with the phenyl ring. This may help us develop new herbicides based
on the new potential target enzyme imidazole glycerol phosphate dehydratase (IGPD).
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/01/1088/s1.
Acknowledgments
We acknowledge financial support of this investigation by the National High Technology Research
and Development Program of China (2011AA10A206, 2011BAE06B02-01), the Chinese Universities
Scientific Fund (15054705), the NSFC of China (21172257) and Key laboratory of Horticultural Crops
Genetic Improvement, Ministry of Agriculture in China.
Author Contributions
Yan Jin and Hanqing Zhao performed research, analyzed the data and wrote the manuscript together.
Colleen M. Kuemmel provided help in the synthesis experiments and bioassay experiments; Huizhe Lu
and Jianjun Zhang provided guidance and suggestions for all the experiments and they also provided
proper suggestions when wrote and revised the manuscript; Daoquan Wang provided guidance and
suggestions in the synthesis experiments. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
References
1
.
Glynn, S.E.; Baker, P.J.; Sedelnikova, S.E.; Davies, C.L.; Eadsforth, T.C.; Levy, C.W.; Rodgers, H.F.;
Blackburn, G.M.; Hawkes, T.R.; Viner, R.; et al. Structure and Mechanism of Imidazoleglycerol-
Phosphate Dehydratase. Structure 2005, 13, 1809–1817.

Molecules 2015, 20
1103
2
3
.
.
Sinha, S.C.; Chaudhuri, B.N.; Burgner, J.W.; Yakovleva, G.; Davisson, V.J.; Smith, J.L. Crystal
Structure of Imidazole Glycerol-phosphate Dehydratase. J. Boil. Chem. 2004, 279, 15491–15498.
Mori, I.; Iwasaki, G.; Kimura, Y.; Matsunaga, S.; Ogawa, A.; Nakano, T.; Buser, H.P.; Hatano, M.;
Tada, S.; Hayakawa, K. Synthesis of inhibitors of imidazoleglycerol phosphate dehydratase.
J. Am. Chem. Soc. 1995, 117, 4411–4412.
4
5
6
7
.
.
.
.
Schweitzer, B.A.; Loida, P.J.; Thompson-Mize, R.L.; CaJacob, C.A.; Hegde, S.G. Design and
synthesis of β-carboxamido phosphonates as inhibitors of imidazoleglycerol phosphate
dehydratase. Bioorg. Med. Chem. Lett. 1999, 9, 2053–2058.
Shen, T.; Du, F.-P.; Liu, T. Molecular Simulation of the Interaction between Imidazole Glycerol
Phosphate Dehydratase and Nitrogen-containing Heterocyclic Phosphate Inhibitors. Acta Phys.
Chim. Sin. 2011, 27, 1831–1838.
Mori, I.; Matsunaga, S.; Fonne-Pfister, R.; Tada, S.; Kimura, Y.; Iwasaki, G.; Mano, J.; Hatano, M.;
Hatano, M.; Koizumi, S.; et al. A novel class of herbicide: Specific inhibitors of imidazoleglycerol
phosphate dehydratase. Plant Physiol. 1995, 107, 719–723.
Mori, I.; Iwasaki, G.; Hayakawa, K. Rational design of a new herbicide by inhibition of histidine
biosynthesis Design and synthesis of inhibitors of imidazole glycerol phosphate dehydratase.
Yuki Gosei Kagaku Kyokaishi 1996, 54, 514–524.
8.
Schweitzer, B.A.; Loida, P.J.; Cajacob, C.A.; Chott, R.C.; Collantes, E.M.; Hegde, S.G.;
Mosier, P.D.; Profeta, S. Discovery of imidazoleglycerol phosphate dehydratase inhibitors through
3-D database searching. Bioorg. Med. Chem. Lett. 2002, 12, 1743–1746.
9.
Gohda, K.; Kimura, Y. Theoretical evidence of the existence of a diazafulvene interm ediate in the reaction
pathway of imidazoleglycerol phosphate dehydratase. Biochim. Biophys. Acta 1998, 1385, 107–114.
1
0. Lindell, S.D.; Earnshaw, C.G.; Wright, B.J.; Carver, D.S.; O’Mahony, M.J.; Saviile-Stones, E.A.
Synthesis of inhibitors of imidazoleglycerol phosphate dehydratase. Bioorg. Med. Chem. Lett.
1
996, 6, 547–552.
1
1
1. Cox, J.M.; Hawkes, T.R.; Bellini, P.; Ellis, R.M.; Barrett, R.; Swanborough, J.J.; Russell, S.E.;
Walker, P.A.; Barnes, N.J.; Knee, A.J. The Design and Synthesis of Inhibitors of Imidazoleglycerol
Phosphate Dehydratase as Potential Herbicides. Pestic. Sci. 1997, 50, 297–311.
2. Saika, H.; Fruh, T.; Iwasaki, G.; Koizumi, S.; Mori, I.; Hayakawa, K. Synthesis of (2R,3R)-,
(2S,3S)-, (2R,3S)-, and (2S,3R)-imidazole glycerol phosphates (IGP): Substrates for IGP-dehydratase
(IGPD). Bioorg. Med. Chem. Lett. 1993, 3, 2129–2134.
1
1
3. Głowacka, I.E. Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-
-yl)propylphosphonates. Tetrahedron 2009, 20, 2270–2278.
1
4. Zhu, Y.Q.; Wu, C.; Li, H.B.; Zou, X.M. Design, synthesis and quantitative structure-activity
relationship study of herbicidal analogues of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)-ones. J. Agric.
Food Chem. 2007, 55, 1364–1369.
Sample Availability: Samples of the compounds 5 are available from the authors.
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