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Journal of the Chilean Chemical Society

versão On-line ISSN 0717-9707

J. Chil. Chem. Soc. vol.56 no.4 Concepción dez. 2011 

J. Chil. Chem. Soc., 56, No 4 (2011), págs: 833-836





a Department of Chemistry, Payame Noor University, Tehran 19395-4697, I. R. of Iran .
b Department of Chemistry, Islamic Azad University, East Tehran Branch, 33955-163, Qiamdasht, Iran .* e-mail:
c Department of Chemistry, Arak University, Arak, Iran
Department of Chemistry, Guilan University, Rasht, Iran, 41335-1914


The one-pot reaction of halo-heterocycle, (R)-4-hydroxyphenoxy propionic acid and an alcohol, amine or sulfonamide is described as an efficient method for the synthesis of aryloxyphenoxy propionate hrerbicides by using 2,4,6-trichloro-1,3,5-triazine in the presence of (n-BU)4NI, as a homogeneous catalyst under mild conditions. The present procedure offers several advantages, such as good yields, short reaction times and easy workup.

Keywords: One-pot reaction, Catalyst, Aryloxyphenoxy propionate, Cyanuric chloride


The one-pot reaction is known as a reaction in which three or more easily accessible compounds are combined in a single reaction vessel.1-6 One-pot reactions increase the efficiency of reactants by combing several operational steps without isolation of intermediates or changing the reaction conditions. Speed, diversity, efficiency and environmental amiability are some of the major advantages of these reactions. They have emerged as valuable tools for the preparation of structurally diverse chemical libraries of drug-like heterocyclic compounds.7-9 Furthermore; aryloxyphenoxypropionates (APPs) are a highly effective class of herbicides due to their high activity, high selectivity and low toxicity. Up to now, more than 20 kinds of APPs such as clodinafop-propargyl 1, fenoxaprop-ethyl 2, fluazifop-butyl 3, haloxyfop-methyl 4, haloxyfop-etotyl 5, quizalofop-ethyl 6, have been commercialized and marketed by major agrochemical companies.10-17 They are used effectively in a number of crops including soybeans and cereal grains, such as wheat and rice, to control grass weeds.12 Commonly, there are three pathways (route A, B and C) described in the literature for preparation of desired APPs.14-16 These routes normally proceed via an aromatic nucleophilic substitution of proper halo-hetero cyclic compounds with (R)-4-hydroxyphenoxy propionic acid (4-HPPA) or it esters (Figure 1).

However, due to the low yield and purity of the A and B routes, commonly route C is chosen as the synthetic strategy for the synthesis of APPs such as clodinafop-propargyl 1 from corresponding halo-pyridine, 4-HPPA, and propargyl halides.16 Recently, a few efficient examples have been reported for the synthesis of APPs in ionic liquid media.18 The routes developed so far suffer from harsh and cumbersome conditions, long reaction times, the use of extremely anhydrous conditions, expensive and toxic reagents such as propargyl halide, the use of large excess of reagents, tedious work-up and by product formation. Because of the commercially importance of APPs, search for the development of a simple, mild, and efficient method is still highly demanded. On the other hand, over the past few years 2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride, CC) has been used in many chemical transformations19, especially in conversion of carboxylic acid to ester or amide20-22, hence using CC in preparation of APPs would be a challenge for the usual routes (A, B, C) being a valid alternative route.

In view of this report and also due to our attention in one-pot synthesis of organic compounds23,24, we are going to describe a practical and more economical method for large-scale preparation of APPs herbicides 1-12.


All used chemicals were purchased from Merck or Fluka Company. Melting points were determined using an electro thermal digital apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Galaxy series Fourier transform infrared (FT-IR) 5000 spectrometer using KBr discs. 1H NMR and 13C NMR spectra were recorded on Brucker spectrophotometer (300 MHZ) in CDCl3 or DMSO-d6 using Me4Si as an internal standard. Elemental analyses were performed on a Vario EL III elemental analyzer and mass spectra were recorded on Bruker Biflex Maldi-tof spectrometer.

General one-pot procedure

To the stirred solution of (R)-2-(4-hydroxyphenoxy)-propionic acid (1.82 g, 0.01 mol) in 10 ml of DMF, potassium phosphate (2.12 g, 0.01mol) was added at 50°C. Then halo-heterocycle (0.01 mol) and tetrabutylammonium iodide (0.036 g, 1 mol %) was added, stirred at 50-60 °C for 2 h. After cooling the reaction mixture to 5 °C, cyanuric chloride (0.738 g, 0.004 mol) was added over 10 min, mixed for 1 h at 25 °C and subsequently 0.012 mol alcohol or amine was added. After completion of the reaction 1-2 h (monitored by thin-layer chromatography, TLC, eluent n-hexane: EtOAc = 2:1), the mixture was poured on 50 g of crushed ice with stirring and pH was adjusted to 8 with 25% NaOH and stirred for 10 min at 0-5 °C. The resulting solid was collected by filtration, purified by recrystallization from 90% ethanol.

Spectroscopic Data for new Compounds:

2-[4-(5-Chloro-3-fluoro-pyridin-2-yloxy)-phenoxy]-propionic acid hydrazide (10); IR (KBr): υmax= 3356, 3277 (N-H), 1677 (C=O), 1620, 1504 (C=N), 1453, 1239 (C=C), 1197 (C-O), 851 (C-Cl) cm-1; 1H NMR (CDCl3, 300 MHz): δC 7.82 (1H, s, Ar), 7.47 (1H, s, Ar), 7.05 (2H, d, J= 8.6 Hz, H h), 6.89 (2H, d, J= 8.6 Hz, Hph), 5.90 (1H, s, N-H), 5.25 (1H, q, J= 6.5 Hz ,cH), 4.70 (2H, br, NH2), 1.55 (3H, d, J= 6.5 Hz, CH3) ppm; 13C NMR (CDCl3, 75 MHz): δC 18.7, 74.1, 116.3, 122.5, 125.0, 140.5, 145.1, 147.2, 148.6, 151.2, 154.1, 172.19 (C=O) ppm; [M]+ m/z = 325.72. Found: MALDI-TOF-MS: [M+Na]+= 448.72; Anal Calcd for C14H13ClFN3O3: C, 51.62; H, 4.02; N, 12.90; Found: C, 51.44; H, 4.03; N, 12.95.

(R)-2-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)-N-(4,6-dimethoxy pyrimidin- 2-yl) propan amide (11): IR (KBr): υmax= 3409 (N-H), 2956 (C-H), 1719 (C=O), 1605, 1574 (C=N), 1450 (C=C),T166 (C-O) cm-1; 1H NMR (CDCl3, 300 MHz): δH 8.68 (1H, s, N-H), 7.81 (1H, s, Ar), 7.45 (1H, s, Ar), 7.09 (2H, d, J= 8.6 Hz, H h), 6.99 (2H, d, J= 8.6 Hz, H h), 5.76 (1H, s, H . ), 4.87 (1H, q, J= 6.5 Hz, CH), 3.90 (6H, s, OCH3), 1.65 (3H, d, J= 6.5 Hz, CH3) ppm; 13C NMR (CDCl3, 75 MHz): δC 18.5, 54.2, 76.0, 85.4, 116.7, 122.6, 124.1, 140.1, 145.1, 147.5, 148.6, 151.1, 154.1, 155.5, 169.9, 172.0 (C=O) ppm; Calcd: [M]+ m/z = 448.83; Found: MALDI-TOF-MS: [M+Na]+= 471.83; Anal Calcd for C20H18ClFN4O5: C, 53.52; H, 4.04; N, 12.48. Found: C, 53.71; H, 4.05; N, 12.48.

(R)-2-Ethanesulfonyl-imidazo [1,2-a] pyridine-3-sulfonic acid [2-[4-(5-chloro- 3-fluoro-pyridin-2-yloxy)-phenoxy]-propionyl]-amide (12): IR (KBr): υmax= 3275 (N-H), 1640 (C=O), 1605, 1457, (C=N, C=C), 1313 (S=O), 1167m(C-O), 735 (C-Cl) cm-1; 1H NMR (DMSO-d6, 300 MHz): δH 8.97 (1H, s, NH), 8.15 (1H, m, Himida), 8.00 (1H, Ar), 7.73 (1H, m, Himida.) 7.50 (1H, Ar), 7.19 (2H, m, Himida ™6.95 (2H, d, J= 8.6 Hz, Hph), 6.60 (2H, d, J= 8.6 Hz, H h), 4.36 (1H, q,'J= 6.5 Hz, CH), 3.66 (2H, m, CH2), 1.31 (3H,d, J= 6.5 Hz, cH3), 1.13 (3H, m, CH3) ppm; 13C NMR (DMSO-d6, 75 MHz): δC 7.2, 19.4, 39.1, 40.7, 48.8, 75.9, 114.9, 115.6, 118.5, 122.4, 124.6, 125.9, 127.0, 128.4, 129.1, 140.7, 142.4, 142.7, 145.9, 155.7, 178.0 (C=O) ppm; Calcd: [M]+ m/z = 582.04; Found: MALDI-TOF-MS: [M+Na]+ = 605.02; Anal Calcd for C23H20ClFN4O7S2: C, 47.38; H, 3.46; N, 9.61; S, 11.00; Found: C, 47.14; H, 3.45; N, 9.63; S, 11.08.


In this work we attempted to synthesize some APPs via a one pot reaction employing CC/K3PO4 as a mild and inexpensive reagent in the presence of TBAI as a homogeneous catalyst.

Initially, to evaluate a one-pot process, we prepared ester 1 by reaction between 5-chloro-2,3-difluoro pyridine, (R)-4-hydroxyphenoxy propionic acid and propargyl alcohol using base/CC / 60 °C, these conditions were selected as a model reaction. For optimization, the reaction was carried out with different bases and solvents under the same conditions to increase the product yield. The results are depicted in Table 1. As results showed employing K3PO4 as base in DMF (Table 1, entry 4) afforded moderate yield of the corresponding ester.

We also studied the role of various catalysts on the model reaction and the results are summarized in Table 2. The results show that using 1 mol% of (n-BUt)4NI at temperature of 60 °C, in DMF for 4h afforded the corresponding product in 89% yield (Table 2: entry 6). To study the effect of catalyst, the reaction was carried out in absence and presence of catalyst under the same conditions. The reaction product in absence of catalyst, even under longer reaction times was obtained in moderated yield (Table 1: entry 4). It was also found that a higher amount of catalyst did not improve the yield of reaction.

To examine the generality and efficiency of this simple protocol, we synthesized several APP proven herbicides and three new compounds (the new compounds are very likely to have herbicide activity, but haven't been tested), employing a one-pot reaction of halo-heterocycle, (R)-4-hydroxyphenoxy propionic acid and an alcohol, amine or sulfonamide (Figure 2).

As showed in Figure 2, various halo-heterocyclic compounds were reacted efficiently with 4-HPPA in DMF/ K3PO4/TBAI to yield APPA salts, which subsequently underwent insitu esterification, amidation, or sulfonamidation reactions, which proceeded efficiently by using CC. It is noteworthy to mention that the cyanuric acid can be easily recovered at the end of reaction. The results are listed in Table 3.

The structure of new products (10-12) was characterized by the spectroscopic data. The IR, 1H- and 13C-NMR spectra of all new synthesized APPs are consistent with their structures. The obtained elemental analysis data are in good agreement with the theoretical values. The IR spectra of 10 showed an N-H stretching absorption near 3356, 3277 cm-1 and also C=O stretching band at 1677 cm-1. Its 1H-NMR spectra showed a singlet at 5.90 and 4.70 ppm for CONH and NH2 groups, respectively. The IR and 1H-NMR spectra of 11 showed an amidic N-H group in stretching absorption at 3409 cm-1 and 8.68 ppm respectively. The other signals were observed at the expected regions. The 13C-NMR spectrum of 12 showed 21 carbon signals and MALDI-TOF-MS spectrum revealed [M+Na]+ at 605.02 which elucidate the structure of the reaction product.


In conclusion, by using K3PO4/TBAI/DMF/CC, a convenient general one-pot new protocol has been developed to convert various heterocyclic halide/ 4-HPPA/ alcohol, amine or sulfamide directly to the corresponding ester, amide or sulfonamide derivatives under mild condition.


We wish to express our deep gratitude to the Payame Noor University Research council and also Industrial Pesticide Research Center Karaj for the partial support of the work.



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(Received: September 15, 2010 - Accepted: June 20, 2011)

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