Synthesis and herbicidal activities of 2-methylpropan-2-aminium methyl 1-(substituted phenoxyacetoxy) alkylphosphonates

Article abstract of DOI:10.1080/10426507.2012.736101

A series of 2-methylpropan-2-aminium methyl 1-(substituted phenoxyacetoxy) alkylphosphonates were selectively synthesized by reacting the corresponding dimethyl 1-(substitutedphenoxyacetoxy)alkylphosphonates with an excess of 2-methylpropan-2-amine. All the title compounds were identified by IR, ¹H NMR, and ³¹P NMR, some of them were further analyzed by ¹⁹F NMR and ¹³C NMR. Their herbicidal activity was investigated and the results showed that most of the demethylated aminium salts exhibited notable herbicidal activities against Brassica napus L. and Echinochloa crusgalli. Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures and tables.

Full text of DOI:10.1080/10426507.2012.736101

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Synthesis and Herbicidal Activities of
2-Methylpropan-2-Aminium Methyl
1-(Substituted Phenoxyacetoxy)
Alkylphosphonates
Ling Gao a , Xiaoyan Deng a , Xiaosong Tan a , Qingwu Long a , Hao
Peng a & Hongwu He a
a Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry , Central China Normal University ,
Wuhan , Hubei , P. R. China
Accepted author version posted online: 18 Oct 2012.
To cite this article: Ling Gao , Xiaoyan Deng , Xiaosong Tan , Qingwu Long , Hao Peng & Hongwu
He (2013) Synthesis and Herbicidal Activities of 2-Methylpropan-2-Aminium Methyl 1-(Substituted
Phenoxyacetoxy) Alkylphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:8,
989-994, DOI: 10.1080/10426507.2012.736101
To link to this article: http://dx.doi.org/10.1080/10426507.2012.736101
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Phosphorus, Sulfur, and Silicon, 188:989–994, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.736101
SYNTHESIS AND HERBICIDAL ACTIVITIES OF
2-METHYLPROPAN-2-AMINIUM METHYL
1-(SUBSTITUTED PHENOXYACETOXY)
ALKYLPHOSPHONATES
Ling Gao, Xiaoyan Deng, Xiaosong Tan, Qingwu Long, Hao
Peng, and Hongwu He
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan, Hubei, P. R. China
GRAPHICAL ABSTRACT
Abstract A series of 2-methylpropan-2-aminium methyl 1-(substituted phenoxyacetoxy)
alkylphosphonates were selectively synthesized by reacting the corresponding dimethyl
1-(substitutedphenoxyacetoxy)alkylphosphonates with an excess of 2-methylpropan-2-amine.
All the title compounds were identified by IR, 1H NMR, and 31P NMR, some of them were
further analyzed by 19F NMR and 13C NMR. Their herbicidal activity was investigated and
the results showed that most of the demethylated aminium salts exhibited notable herbicidal
activities against Brassica napus L. and Echinochloa crusgalli.
Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental
files: Additional text, figures and tables.
Keywords Synthesis; herbicidal activity; phosphonate; 2-Methylpropan-2-aminium
INTRODUCTION
1-Substituted alkylphosphonate derivatives have received considerable attention
in medicine and pesticide chemistry due to their biological activities over the past
Received 25 July 2012; accepted 23 September 2012.
This work was supported by the National Basic Research Program of China (2010CB126100), the National
Key Technologies R & D Program of China (No. 2011BAE06B03), and the National Natural Science Foundation
of China (No. 21172090 and No. 21002037). The research was supported in part by the PCSIRT (No. IRT0953).
Address correspondence to Hao Peng or Hongwu He, College of Chemistry, Central China Normal Univer-
sity, Wuhan, 430079, P. R. China. E-mail: penghao@mail.ccnu.edu.cn or he1208@mail.ccnu.edu.cn
989

990
L. GAO ET AL.
Scheme 1
two decades.1–7 In our previous work, a series of 1-(substituted phenoxyacetoxy)
alkylphosphonate derivatives, as potent pyruvate dehydrogenase complex (PDHc)
inhibitors, were synthesized and showed notable herbicidal activities.8–11 Apparently, the
salts of alkylphosphonic acids show higher inhibitory activity against PDHc E1 than the
corresponding esters of alkylphosphonic acids do, because the salts are more analogous
to the pyruvic acid which acts as the substrate of pyruvate dehydrogenase complex. Up
to now, some monosalts of the alkylphosphonic acid derivatives like lithium, sodium, and
potassium salts (Scheme 1) were synthesized.12,13 2-Methylpropan-2-aminium salts are
often introduced in the design of bioactive compounds and the synthesis of 2-methylpropan-
2-aminium phosphonate is relatively mild, clean, and cheap.14,15 Therefore, a series of
2-methylpropan-2-aminium methyl 1-(substituted phenoxyacetoxy)alkylphosphonates
were designed and synthesized to investigate the relationship of structure-herbicidal
activity.
RESULTS AND DISCUSSION
Synthesis
A detailed synthetic route for the title compounds 5 is outlined in Scheme 2. Dimethyl
phosphite was used directly as obtained commercially. Substituted phenoxyacetic acids
1, substituted phenoxyacetyl chlorides 2, and dimethyl 1-hydroxyalkylphosphonates 3
were prepared according to the methods previously reported.16–19 Dimethyl 1-(substituted
phenoxyacetoxy)alkylphosphonates 4 were synthesized by the reaction of 2 with 3 us-
ing pyridine as a catalyst. 2-Methylpropan-2-aminium methyl 1-(substituted phenoxy-
acetoxy)alkylphosphonates 5 (Table 1) were obtained by the reaction of dimethyl 1-
(substituted phenoxyacetoxy)alkylphosphonates 4 with 2-methylpropan-2-amine in the
yields of 78∼54%. The structures of 5a–5m were confirmed by comprehensive elemental
analysis, IR, 1H NMR, and 31P NMR and some of them were further identified by 19F NMR
and 13C NMR.
Herbicidal Activity
The herbicidal activities of title compounds against the roots and stems of Brassica
napus L. and Echinochloa crusgalli were tested at the dosage of 10 and 100 μg/g. The results
showed that some of the synthesized compounds displayed notable herbicidal activities
against the tested plants, and they displayed higher inhibitory activities against the growth
of the root than that of the stem. For example, 5a–5e showed 95–96% inhibitory rate against
the root of B. napus L. at the dosage of 10 μg/g, but only 69–85% inhibitory rate against
the stem of B. napus L. at the same dosage. The inhibitory activities of title compounds
against dicotyledon were higher than those against monocotyledon. For example, 5a–5e
showed 95–96% inhibitory rate against the root of dicotyledon B. napus L. at the dosage of

SYNTHESIS AND HERBICIDAL ACTIVITIES
991
Scheme 2
10 μg/g, but they displayed 75–88% inhibitory effect against the root of monocotyledon E.
crusgalli at the same dosage.
By comparison of herbicidal activities among the title compounds, it was found that
different R groups have little effect on herbicidal activity. For example, the inhibitory
activities of 5a–5e against B. napus L. or E. crusgalli were almost the same. However,
the X and Y groups have some impact on the herbicidal activity. The 5a–5e with 2-F,
4-Cl, or 5k–5m with 2-Cl, 4-F as X and Y exhibit significant herbicidal activities against
tested plants, while 5f–5j only with 2-Cl on the phenoxy ring show weak inhibitory activity.
Apparently, the introduction of 4-Cl or 4-F on the phenoxy ring is beneficial to the herbicidal
activity.
Table 1 Physical Constants of Compound 5
Compd.
X
Y
R
Appearance
mp/◦C
Yield/%
5a
5b
5c
5d
5e
5f
5g
5h
5i
F
F
F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
F
Me
Et
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
108–110
115–117
132–134
111–1112
68–70
133–135
112–114
122–124
12–122
128–130
115–117
119–121
108–110
70
63
65
63
58
71
73
74
68
66
73
66
67
n-Pr
n-Bu
i-Pr
Me
Et
n-Pr
n-Bu
i-Pr
Me
Et
5j
5k
5l
F
F
5m
i-Pr

992
L. GAO ET AL.
Experimental details and the herbicidal activities (Tables S1 and S2) are presented in
the Supplemental materials.
CONCLUSION
In conclusion, a series of 2-methylpropan-2-aminium methyl 1-(substituted phenoxy-
acetoxy)alkylphosphonates were selectively synthesized by the reaction of dimethyl 1-
(substituted phenoxyacetoxy)alkylphosphonates with 2-methylpropan-2-amine. Their her-
bicidal activities against the roots and stems of dicotyledonous B. napus L. and mono-
cotyledon E. crusgalli were evaluated. Most of the synthesized compounds showed good
inhibitory activities to the tested plants and they exhibited higher herbicidal activities against
dicotyledon than monocotyledon. Structure-activity relationships indicated that different R
group had little effect on herbicidal activity, while the introduction of 2-F, 4-Cl, or 2-Cl,
4-F as X and Y on the phenoxy ring is beneficial to the herbicidal activity.
EXPERIMENTAL
Column chromatography was carried out with Merck silica gel (230–400 mesh). Thin-
layer chromatography (TLC) was performed on silica gel GF-254. Melting points (mp) were
measured on an electrothermal melting-point apparatus and uncorrected. Infrared spectra
were recorded in potassium bromide pellets with a Nicolet Avatar 360 Fourier transform
1
infrared (FTIR) spectrophotometer. H, 31P, 19F, and 13C NMR spectra were recorded on
a Varian Mercury-Plus400 or 600 spectrometer with CDCl3 or DMSO-d6 as the solvent
and TMS as the internal standard. Elemental analyses were performed by a Vario EL III
elemental analyzer. The results of elemental analyses for C, H, and N were within 0.5% of
the theoretical values. All the solvents must be absolutely anhydrous. Pyridine and thionyl
chloride were distilled before use. Potassium fluoride, alumina should be dried in an oven
before the reaction.
Synthesis of Compounds 4
To a stirred mixture of dimethyl 1-hydroxyalkylphosphonates 3 (0.010 mol) and
pyridine (0.012 mol) in dichloromethane (25 mL), a solution of substituted phenoxyacetyl
chlorides 2 (0.012 mol) in dichloromethane (15 mL) was added dropwise at 0–5◦C. The
resultant mixture was stirred for 3–4 h at room temperature and then washed with diluted
hydrochloric acid, saturated sodium hydrogen carbonate solution, and brine, dried, and
concentrated. The residue was purified by column chromatography on silica gel and elution
with a mixture of petroleum ether and acetone (v:v 4:1) to give compounds 4 in yields of
80–89%.
General Synthesis of Title Compounds 5a–5m
Dimethyl 1-(substituted phenoxyacetoxy)alkylphosphonates 4 (0.0025 mol) were
added to 2-methylpropan-2-amine (5 mL). The resultant mixture was stirred at room tem-
perature for 20–36 h or reflux at 46 ◦C for 6–8 h. Then, the excess 2-methylpropan-2-amine
was removed under reduced pressure and washed with acetone to afford crud products as
white solids. Further recrystallization from acetonitrile or flash-column chromatography
on silica gel using a mixture of petroleum ether and ethanol (v:v 3:1) afford 5 as white

SYNTHESIS AND HERBICIDAL ACTIVITIES
993
solids. Selected characterizations for 5a, 5f, and 5m are presented here; others are located
in the Supplemental Materials. Figures S1–S6 show sample 1H, 31P, and 19F NMR of some
products
2-methylpropan-2-aminium methyl (1-(2-(4-chloro-2-fluorophenoxy)acetoxy)
ethyl)phosphonate (5a). White solid; 1H NMR (600 MHz CDCl3) δ: 1.35 (s, 9H,
C(CH3)3), 1.41∼1.46 (m, 3H, CHCH3), 3.59 (d, J = 10.2 Hz, 3H, OCH3), 4.66, 4.70 (q,
AB system, JAB = 16.2 Hz, 2H, OCH2), 5.22 (t, J = 7.2 Hz, 1H, CHCH3), 6.87∼7.11 (m,
3H, Ph–H), 8.29 (s, 3H, NH3); 19F NMR (376 MHz, DMSO-d6) δ: −131.55; 31P NMR
(160 MHz, DMSO-d6) δ: 12.08, IR (υ/cm−1): 3296, 2979, 2919, 2192, 1755, 1652, 1499,
1454, 1377, 1316, 1196, 1060, 898, 779, 650; Elemental Anal. Calcd. for C15H24ClFNO6P:
C, 45.06, H, 6.05, N, 3.50; Found: C, 45.36, H, 6.29, N, 3.32.
2-methylpropan-2-aminium methyl (1-(2-(2-chlorophenoxy)acetoxy)ethyl)phos-
phonate (5f). White solid; 1H NMR (400 MHz CDCl3) δ: 1.33 (s, 9H, C(CH3)3), 1.36∼1.48
(m, 3H, CHCH3), 3.59 (d, J = 10.4Hz, 3H, OCH3), 4.59, 4.62(q, AB system, JAB = 16.4 Hz,
2H, OCH2), 5.24 (t, J = 7.2 Hz, 1H, CHCH3), 6.80∼7.27 (m, 4H, Ph–H), 8.35 (s, 3H,
NH3); 31P NMR (160 MHz, DMSO-d6) δ: 12.17; IR (υ/cm−1): 3427, 2977, 2918, 2192,
1755, 1634, 1538, 1494, 1399, 1376, 1199, 1068, 829, 780; Elemental Anal. Calcd.for
C15H25ClNO6P: C, 47.19, H, 6.60, N, 3.67; Found: C, 47.39, H, 6.89, N, 3.76.
2-methylpropan-2-aminium methyl (1-(2-(2-chloro-4-fluorophenoxy)acetoxy)-
1
2-methylpropyl)phosphonate (5m). White solid; H NMR (400MHz CDCl3) δ: 0.97
(d, J = 6.8 Hz, 3H, CHCH3), 1.02 (d, J = 6.8 Hz, 3H, CHCH3), 1.35 (s, 9H, C(CH3)3),
2.16∼2.23 (m, 1H, CH(CH3)2), 3.58 (d, J = 10.0 Hz, 3H, OCH3), 4.73 (s, 2H, OCH2),
5.01 (t, J = 8.0 Hz, 1H, CHCH(CH3)2), 6.84∼7.15 (m, 3H, Ph–H), 8.26 (s, 3H, NH3); 19
F
NMR (376 MHz, DMSO-d6) δ: –121.57; 31P NMR (160 MHz, DMSO-d6) δ: 13.09; 13C
NMR (100 MHz, DMSO-d6) δ: 18.51, 20.38, 27.07, 50.34, 51.47, 65.67, 74.64 (d, JP-C
=
152.0 Hz), 114.40 (d, JF-C = 22.5 Hz), 117.07, 117.33, 121.90 (d, JF-C = 10.3 Hz), 149.91,
156.02 (d, JF-C = 238.5 Hz); IR (υ/cm−1): 3403, 2979, 2828, 2173, 1756, 1636, 1575,
1490, 1374, 1310, 1204, 1061, 860, 760; Elemental Anal. Calcd.for C17H28ClFNO6P: C,
47.72, H, 6.60, N, 3.27; Found: C, 47.94, H, 6.34, N, 3.07.
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