A facile synthesis of novel optically active R,R-2-(4-(2-(4-(5-chloro-3- halo-pyridin-2-yloxy)-phenoxy)-propionyloxy)-phenoxy)-propionic acid esters using cyanuric chloride as potential herbicide

Article abstract of DOI:10.1016/j.cclet.2010.12.001

A facile method for the synthesis of a new series of R,R-2-(4-(2-(4-(5- chloro-3-halopyridin-2-yloxy)-phenoxy)-propionyloxy)-phenoxy)-propionic acid ester derivatives containing a halo-substituted pyridine carrying two R,R chiral centers from (R)-2-(4-hyd

Full text of DOI:10.1016/j.cclet.2010.12.001

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 535–538
www.elsevier.com/locate/cclet
A facile synthesis of novel optically active R,R-2-(4-(2-(4-(5-
chloro-3-halo-pyridin-2-yloxy)-phenoxy)-propionyloxy)-phenoxy)-
propionic acid esters using cyanuric chloride as potential herbicide
a
b
Hassan Tajik a, , Akbar Dadras , Shokufeh Aghabeygi
*
a Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
b Department of Chemistry, Islamic Azad University, East Tehran Branch, P.O. Box 33955-163, Qiamdasht, Iran
Received 26 August 2010
Available online 2 March 2011
Abstract
A facile method for the synthesis of a new series of R,R-2-(4-(2-(4-(5-chloro-3-halopyridin-2-yloxy)-phenoxy)-propionyloxy)-
phenoxy)-propionic acid ester derivatives containing a halo-substituted pyridine carrying two R,R chiral centers from (R)-2-(4-
hydroxyphenoxy)propionic acid, halopyridines and alcohols using base/cyanuric chloride/catalyst system is reported. Their
herbicidal activities against grass weeds and crops selectivity were evaluated.
# 2010 Hassan Tajik. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aryloxyphenoxypropionic acid; Chiral herbicide; Cyanuric chloride; Esters; R,R-Diastereomer
Modern high-yield agriculture relies on the effective control of pests and weeds to increase crop quality and yield.
Aryloxyphenoxypropionate herbicides (APPHs) have been an interesting and highly effective class of herbicides in the
international market over the past decade. Up to now, more than 20 kinds of APPHs, such as clodinafop propargyl, are
commercialized all over the world [1]. They are used effectively in a number of crops including soybeans and cereal
grains, such as wheat and rice, to control grass weeds [2]. APPH act via blocking the biosynthesis of fatty acids by
inhibiting acetyl-coenzyme A carboxylase [3,4]. However, continuous application of APPH has resulted in evolution
of weeds resistant [5] that means we need novel structure herbicides. Exploration of the structure–activity
relationships for the APPH by many agrochemical companies has led to the discovery of herbicides which vary only in
the type of aryl or alkyl group of the propionate ester moieties. All of these compounds contain one chiral R center that
comes from R-propionic acid portion of the molecule, and this chiral center is essential to the observed biological
effectiveness. It is well known that the R isomers of APPH have far greater herbicidal activity than the corresponding S
isomers [6].
Traditional APPHs have been prepared by coupling alcohols and acid chlorides generated from the parent
carboxylic acid [7]. The typical reagents employed to prepare an acid chloride from a carboxylic acid are corrosive
SOCl2, PCl3 or toxic phosgene. This method suffers from several disadvantages and can be cumbersome in a pilot
* Corresponding author.
E-mail addresses: tajik@guilan.ac.ir, hasan_tajik@yahoo.com (H. Tajik).
1001-8417/$ – see front matter # 2010 Hassan Tajik. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.001

536
H. Tajik et al. / Chinese Chemical Letters 22 (2011) 535–538
plant. Due to the vigorous conditions and formation of strong acid during the process, sensitivity of optically active
carboxylic acids and the disadvantages associated with the use of acid chlorides, esterification of carboxylic acids is an
active area of research. A common approach involves treatment of the carboxylic acid with a reagent to form an
activated intermediate, which is then treated in situ with an alcohol to form the ester product. Carboxylic acids
activated by cyanuric chloride (CC) have been used in many chemical transformations [8–10] and can be a valid
alternative route to the classical preparation method of APPH. In this article, we have developed a facile process
suitable for large-scale preparation of APPH using carboxylic acids, CC as a mild and inexpensive reagent and
benzyltriphenylphosphonium bromide (BTPPB) as a phase transfer catalyst (PTC).
On the other hand, to the best of our knowledge the synthesis of aryloxyphenoxypropionic esters containing double
R,R chiral center has not been reported and previous studies were based upon using one R chiral spacer between aryl
and ester groups. In this study, we have tried to develop new herbicides based on biochemical reasoning and report the
synthesis of new titled compounds by introducing second chiral R center which can be used as bioisosteric group in
order to obtain better herbicidal activity (Scheme 1).
1. Results and discussions
Initially, halo pyridines 1a–b, R-2-(4-hydroxyphenoxy) propionic acid 2, R-2-(4-(5-chloro-3-halopyridin-2-
yloxy)-phenoxy)-propionic acids 3a–b was prepared according to the literature methods [11,12]. The R chiral
compounds 4–13 and novel final target compounds 14–23 were synthesized from the compounds 3a–b, CC, base,
PTC, ROH in an inert solvent (Scheme 1). New products 14–23 were characterized by 1H NMR, 13C NMR, FT-IR,
MALDI-TOF-MS spectroscopy and elemental analysis, which are given in Section 2 [13].
The herbicidal activities of the new compounds 14–23 were evaluated at a rate of 125 g a.i./ha in a set of experiment
in greenhouse according to the known method [14] and compared to the results obtained in distilled water and
monochiral compounds 4–13 (from which some are the commercially available herbicides). They were tested for post-
emergence inhibitory effect against Alopecurus myosuroides (Alo), Echinochloa cruss-galli (Ech), Avena fatua (Ave)
weeds. The seed of weeds were collected from different provinces exhibited resistance to commercial herbicides.
Inspection of Table 1 reveals that fluorine-containing compounds displayed much better herbicidal activities than
chlorine-containing compounds. For example, compounds 14–16 showed higher inhibition rate in comparison to 20–
22. Ethyl ester showed better herbicidal activity than the corresponding methyl ester and n-propyl ester in general. The
presence of propargyl ester was useful for the improvement of herbicidal activity and selectivity for crop protection.
Propargylester 19 showed better inhibition rate against the A. fatua and A. myosuroides grass in comparison to
propylester 16. It is also interesting to note that in many cases the introduction of second chiral center as R,R
diastereomer slightly increase herbicidal activity and improved crop selectivity. As results listed in Table 1,
[()TD$FIG]
Y
Y
HO
O
OH
F
O
O
O
OH
DMF/K2CO3
HCl
+
N
N
O
Cl
Cl
3a-b
1a-b
2
1) CC, Base, PTC
1) CC, Base, PTC
2) ROH
HO
O
O
OH
2)
3) ROH
O
Y
Y
O
O
O
OR
O
O
O
O
OR
N
N
Cl
Cl
O
4-13
14-23
R = -CH3, -CH2CH3, -CH2CH2CH3,-CH(CH3)2 -CH2CH2CH2CH3, -CH2-C ≡ CH; Y= Cl, F
Scheme 1.

H. Tajik et al. / Chinese Chemical Letters 22 (2011) 535–538
537
Table 1
Herbicidal activity of compounds 4–13 and 14–23 homologues (relative inhibition of growth percent for post-emergence treatment)/dosage 125 g
a.i./ha.
[TD$INLINE]
O
Cl
N
O
O
RO
n
n= 1, 2
Y
.
No.
n
R
Y
Yield (%)
Barley
Wheat
Alo
Ech
Ave
4
14
5
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
Me
F
85
82
87
78
84
81
83
80
85
82
83
80
86
82
88
83
85
82
83
80
35
10
27
10
35
15
30
12
25
10
20
0
10
0
75
80
82
90
76
79
73
78
54
62
88
100
30
42
45
52
35
36
57
60
80
80
75
80
62
70
57
65
55
54
82
92
40
44
51
54
40
45
45
53
90
90
90
93
84
89
81
85
62
63
95
100
30
43
50
54
45
50
47
50
Me
F
Et
F
5
15
6
Et
nPr
nPr
F
0
F
10
0
16
7
F
isoPr
isoPr
nBu
nBu
Propyn
Propyn
Me
F
10
0
17
8
F
F
15
5
18
9a
19
10
20
11
21
12
22
13
23
F
F
0
F
0
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
30
15
25
15
18
10
20
5
10
0
Me
Et
10
0
Et
nPr
nPr
15
0
Propyn
Propyn
0
0
a
Herbicidal activity of clodinafop propargyl a commercially available herbicide has been evaluated for comparison.
fluorine-containing compound 19 that included propargyl ester moiety displayed much better herbicidal activity and
crop selectivity.
2. Experimental
2.1. General procedure for the synthesis of compounds (4–13)
N,N-Dimethylamino pyridine (DMAP) (0.01 mol) was added to a solution of 3a–b (0.01 mol), 0.01% mol BTPPB,
and CC (0.005 mol) in acetone (60 mL) at 25 8C. After stirring for 2 h, the alcohol (0.011 mol) was added to the
reaction mixture, and stirred for 2 h. The salt was filtered off and the acetone was removed by rotary evaporator. The
crude product poured in an ice water bath, filtered and crystallized in EtOH to the average yield of 85%.
2.2. General procedure for the synthesis of compounds (14–23)
To the stirred solution of DMAP (0.025 mol), 0.01% mol BTPPB and CC (1.8 g 0.01 mol) in acetone (30 mL), 3a–
b (0.01 mol) was added during 10 min and mixed for an hour at 25 8C. Reaction mixture was then treated with 2
(1.82 g, 0.01 mol) for 2 h and followed by the addition of ROH (0.011 mol). After completion of the reaction (about 2–
3 h, monitored by thin-layer chromatography, TLC, eluent n-hexane:EtOAc 2:1), the mixture was poured on ice water
adjusted at pH 8 and the obtained precipitate was filtered and crystallized in EtOH.
For herbicidal activity tests, an emulsion concentrate as EC 8% was formulated by mixing 8 parts of the active
ingredients (a.i.), 14 parts of blended emulsifiers MS and FF4 (trade name), 10 part of cyclohexanone, 30 part of pine
oil and sun flower oil was added up to 100 mL. Herbicidal testing carried out at the rate of 125 g a.i./ha with a spelling

538
H. Tajik et al. / Chinese Chemical Letters 22 (2011) 535–538
volume of 1000 L/ha. All the treatments were replicated three times in a completely randomized design. Three weeks
after treatment, the plants were cut at the soil surface and their fresh weight was determined. The herbicidal activity
was calculated as the inhibition percent in comparison to the distilled water. Range 0% means no effect, 100% means
complete killing (Table 1).
Acknowledgments
We wish to express our deep gratitude to Guilan University and also to the Persian Gulf University research council
for the partial support of this project.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/
j.cclet.2010.12.001.
References
[1] H.P. Li, Pestic. Sci. Adm. 25 (2004) 28.
[2] K.T. Ren, Y.H. Li, H.Z. Yang, Chin. J. Pestic. 38 (1999) 1.
[3] X.L. Zhu, L. Zhang, Q. Chen, J. Wan, G.F. Yang, J. Chem. Inf. Model 46 (2006) 1819.
[4] X.L. Zhu, G.F. Hao, C.G. Zhang, G.F. Yang, J. Chem. Inf. Model 49 (2009) 1936.
[5] E. Zand, F. BenaKashani, H.M. Alizadeh, et al. Iranian J. Weed Sci. 2 (2006) 17.
[6] R.W. Brown, J. Agric. Food Chem. 8 (1990) 269.
[7] R. Schurter, H. Rempfler, US PT 4,713,109, 1987.
[8] B. Mokhtari, R. Azadi, A. Azhdari, Chin. Chem. Lett. 21 (2010) 171.
[9] K. Venkataraman, D.R. Wagle, Tetrahedron Lett. 32 (1979) 3037.
[10] G. Blotny, Tetrahedron 62 (2006) 9507.
[11] K.Y. Chen, C.T. Huang, Int. J. Appl. Sci. Eng. 2 (3) (2004) 286.
[12] P. Zhong, H. Hu, S. Guo, Synth. Commun. 34 (2004) 4301.
[13] Selected data of compounds: (R,R)(+)-2-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)propionic acid 4-(1-methoxycarbonylethoxy)phenyl
ester (14): Yield 82%, [a]20 +90 (acetone, c 2), mp 75–76 C. H NMR: 7.88 (s, 1H), 7.52 (d, 1H), 7.20 (d, 2H, J = 8.7 Hz), 7.05 (d, 2H,
J = 8.7 Hz), 6.98 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 4.94 (q, 1H, J = 6.5 Hz), 4.73 (q, 1H, J = 6.5 Hz), 3.75 (s, 3H), 1.78 (d, 3H,
1
D
J = 6.5 Hz); 1.62 (d, 3H, J = 6.5 Hz); IR (max, KBr): 3075, 2950, 1749, 1508, 1226, 1191 cmÀ1 13C NMR (100 MHz, CDCl3): 18.5(2C), 52.3,
;
73.0, 73.2, 115.8, 116.2, 122.1, 122.3, 124.8, 125.0, 140.1, 144.3, 145.2, 147.2, 148.7, 154.8, 155.4, 170.8, 172.4; Calcd. (M)+ m/z 489.8.
Found: MALDI-TOF-MS: (M+Na) + 512.2. Anal. calcd. for C24H21ClFNO7 (489.88): C, 58.84; H, 4.32; N, 2.86. Found: C, 58.64; H, 4.24; N,
2.75. (R,R)(+)-2-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)propionic acid 4-(1-ethoxycarbonyl-ethoxy)-phenyl ester (15):Yield 78%,
[a]20D + 90 (acetone, c 2), mp 60–62 C. 1H NMR: 7.88 (s, 1H), 7.50 (d, 1H), 7.12 (d, 2H, J = 8.6 Hz), 7.01 (d, 2H, J = 8.6 Hz), 6.96 (d, 2H,
J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 4.94 (q, 1H, J = 6.5 Hz), 4.72 (q, 1H, J = 6.5 Hz), 4.22 (q, 2H, J = 6.9 Hz), 1.78 (d, 3H, J = 6.5 Hz); 1.61
(d, 3H, J = 6.5 Hz); 1.25(t, 3H, J = 6.9 Hz), IR (max, KBr): 3035, 2993, 1758, 1505, 1195, 1099 cmÀ1 13C NMR (100 MHz, CDCl3): 14.1,
;
18.5(2C), 61.3, 73.1, 73.2, 115.9, 116.2, 122.0, 122.3, 124.8, 125.0, 140.1, 144.3, 145.2, 147.2, 148.7, 154.8, 155.5, 170.8, 172.4; Calcd. (M)+
m/z 504.2. Found: MALDI-TOF-MS: (M+Na)+ 527.2. Anal. calcd. for C25H23ClFNO7 (503.90): C, 59.59; H, 4.60; N, 2.78. Found: C, 59.84; H,
4.64; N, 2.74. Further information is given in Supporting information.
[14] T. Chen, P. Shen, Y. Li, H. He, J. Fluorine Chem. 127 (2006) 291.