WO1998022417A1 - Process for the preparation of benzyl-ethers by use of phase transfer - Google Patents

Process for the preparation of benzyl-ethers by use of phase transfer Download PDF

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WO1998022417A1
WO1998022417A1 PCT/HU1997/000074 HU9700074W WO9822417A1 WO 1998022417 A1 WO1998022417 A1 WO 1998022417A1 HU 9700074 W HU9700074 W HU 9700074W WO 9822417 A1 WO9822417 A1 WO 9822417A1
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group
reaction
alkyl
halogen
general formula
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PCT/HU1997/000074
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French (fr)
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Géza ÁRVAI
Béla BERTÓK
Zsuzsanna KURUCZNÉ RIBAI
László PAP
István Székely
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Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt.
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Priority to AU50644/98A priority Critical patent/AU5064498A/en
Publication of WO1998022417A1 publication Critical patent/WO1998022417A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms

Definitions

  • This invention relates to the process for the preparation of the mixed ethers of general formula I, wherein
  • Ar represents an alicyclic, aromatic or one or more heteroatom-containing heterocyclic moiety, optionally substituted by one or more C ⁇ _ 4 alkoxy, methylenedioxy, C 1- alkyl, halogen, C ⁇ _ 4 haloalkyl or nitro-group, and/or condensed with a benzene ring,
  • R 1 means hydrogen, C,_ alkyl, C 1 -4 haloalkyl, C 2 . 4 alkenyl, phenyl, substituted phenyl, C 3 _ 6 cycloalkyl group
  • R 2 means C 6 alkyl, C 3 . 6 alkenyl, or C 3 _ 6 alkynyl group, optionally mono- or poly-substituted by C,_ 6 alkyl, C 1 -6 alkoxy, C 3 . 6 alkenyl, C 3 . 6 alkynyl, C 1-6 haloalkyl group, or by halogen atom; or a C ⁇ _ 4 alky loxy-C 1 -4 alky 1-oxy-
  • X means hydroxy, halogen or sulfonester leaving group, with the compounds of general formula III , wherein R has the same meaning as above
  • Y means hydroxy, halogen or sulfonester leaving group, with the proviso that one of the reaction partners is an alcohol.
  • Ar is favourably phenyl or naphthyl group
  • Ar as a heterocyclic moiety may contain one or more O, S, N heteroatoms, it may favourably represent benzodioxole-, benzodioxane-, 2-benzofuran-, 7-benzofuran- moieties.
  • the alicyclic group may favourably be condensed with a benzene ring, thus for instance may represent indane group, or 1,2,3,4-tetrahydronaphthyl group.
  • the carboximide group may favourably represent phthalimide moiety.
  • the aromatic, heterocyclic and alicyclic Ar groups are optionally substituted by C alkoxy-, methylenedioxy-,C,. 4 alkyl-, halogen-, C I -4 haloalkyl- or nitro group.
  • the ethers of general formula I are potential starting materials or active ingredients of a number of chemical products. Several representatives of them are arthropodicide synergists of outstanding activity (Hungarian patent application No 3318/95). With the exception of the methylenedioxy (MDP) synergists with saturated side-chain (such as PBO, i.e. 5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-l,3-benzodioxol), which have been known, the compounds are new, irrespective of their simple structures. Owing to their outstanding significance, their preparation and economical synthesis is of great importance.
  • MDP methylenedioxy
  • PBO i.e. 5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-l,3-benzodioxol
  • ethers can be prepared by the general methods known for the synthesis of ethers (Gy. Matolcsy, M. Nadasdy, V. Andriska; Pesticide Chemistiy, Akademia (1988); Hungarian patent application No 3318/95).
  • the essence of these methods is to react the alkali salt of the alcohol component with the partner, according to the rules of the nucleophilic substitution.
  • the partner contains a leaving group, which is usually a halogen, preferably bromo atom.
  • the reaction may be accomplished in two ways, depending on which part of the molecule is built up from the nucleophilic partner.
  • alkali hydroxides or alkali earth metal hydroxides favourably 2 molar equivalent of potassium hydroxide or sodium hydroxide in 10-40 w/w% aqueous solutions are applied, as for phase transfer catalyst various ammonium salts or hydroxides, favourably tetrabutylammonium bromide or iodide are used.
  • the reaction may be carried out without solvent or in an apolar aprotic solvent, in the temperature range of (-10)-(+100) °C, favourably at ambient temperature.
  • the reaction may be accomplished by reacting an activated benzyl derivative and an alcohol of general formula III, or in the other way round, by reacting an activated derivative of general formula III with a benzylalcohol of general formula II .
  • the leaving group (X or Y) is in a mobile e.g. benzyl or allyl position; or where elimination by-processes by the base are not possible.
  • a mobile e.g. benzyl or allyl position
  • elimination by-processes by the base are not possible.
  • R ⁇ is hydrogen or a substituent larger than hydrogen
  • the molecule does not contain an eliminable hydrogen in the beta position.
  • the method to choose is often determined by the availability and the price of the starting materials.
  • the ether formation under phase transfer conditions, compared to other solutions, also has the advantage that due to the low polarity of the medium, the above mentioned elimination side-reaction comes much less into prominence, thus even by using inexpensive reagents the product will be of high quality.
  • the R2 group depending on the stability of R2Y under the reaction conditions may be of numerous sort. It may vary from simple alkyl group through alkenyl or alkynyl group to various substituted e.g. halogenated, alkoxylated derivatives thereof, with straight or branched structures.
  • the method can favourably used for the reaction of 3,3-dichloro-butanyl derivatives where simultaneously with the ether formation a hydrogen halogenide elimination also takes place, resulting in one step the appropriate ether with unsaturated, e.g. 3-chloro-2-butenyl side-chain, which by further elimination may be transformed into the alkynyl ether.
  • the reaction is preferably carried out in an emulsion consisting of the aqueous alkali solution and a water-non-miscible organic solvent; or without solvent, in the emulsion of the starting materials and the resulting product.
  • This latter method which brings about faster reaction, is especially favourable in industrial use.
  • apolar aprotic e.g. halogenated solvents among them most preferably dichloroethane may be used.
  • phase transfer catalyst various tetra-substituted ammonium salts or hydroxides may preferably be used. Catalytic amount of them is sufficent.
  • the reaction is preferably carried out at ambient temperature under vigorous stirring.
  • the ether formation is fast even at low temperature, thus unwanted by- processes can be suppressed.
  • Reaction time may be shortened by applying small excess of the less expensive partner.
  • the product may be isolated from the reaction mixture by simple sedimentation.
  • the raw product thus obtained is of good quality. Its purity is 93-95%. It may of course be further purified by distillation, or if possible, by ciystallization but it may be used directly. To enhance its stability and hinder its acidic hydrolyzis it is suitable to wash the product to neutral and buffer it in basic pH region. For the sake of safer handling the addition of anti-oxidants of various type is advisable.
  • anti-oxidants e.g. TMQ; BHT; hydroquinone; hydroquinone monomethyl-ether; 2,2,6,6-tetramethyl-4-piperidinol-N-oxide may be used.
  • Piperonyl alcohol (45 g, 0.295 mol) is dissolved in benzene (550 ml), the solution is cooled to 5°C and 150 ml of aqueous 48%o hydrogen bromide solution is added to it.
  • the two phases are separated, the alkaline phase is extracted with 2x30 ml of benzene, the combined benzene layers are washed to neutral with 2x40 ml of 20%o ammonium chloride solution and with distilled water, then they are dried and evaporated.
  • the excess butynol (bp. 80°C/60 torr) is removed from the resulting oil in water-jet vacuo.
  • the raw product is purified by distillation in vacuo, with the help of a vacuum pump. According to GC analysis the fractions (48.0 g) collected between 110-120 °C (at 0.2 torr) are of 71.2%. purity. Distillation is then continued by applying a 10 cm long Vigreux-colonne. First nnings: p. 90-108°C /0.1 torr, 19.8 g, GC% approx. 68%.
  • IR ⁇ 3079, 2996, 2973, 2933, 2860, 2838, 1607, 1595, 1510,
  • Example 7 The procedure described in Example 7 is followed, with the difference that 1-[1- hydroxy-propyl]-3,4-dimethoxybenzene is applied.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The subject of the invention is the process for the preparation of mixed ethers of general formula (I), wherein Ar represents an alicyclic, aromatic or one or more heteroatom-containing heterocyclic moiety, optionally substituted by one or more C1-4 alkoxy, methylenedioxy, C1-4alkyl, halogen, C1-4haloalkyl or nitro-group, and/or condensed with a benzene ring; R1 means hydrogen, C¿1-4? alkyl, C1-4 haloalkyl, C2-4 alkenyl, phenyl, substituted phenyl, C3-6cycloalkyl group; R?2¿ means C¿1-6?alkyl, C3-6alkenyl, or C3-6alkinyl group, optionally mono- or poly-substituted by C1-6alkyl, C1-6alkoxy, C3-6alkenyl, C3-6alkinyl, C1-6haloalkyl group or by halogen atom; or a C1-4 alkyloxy-C1-4alkyl-oxy-C1-4alkyl group. n = 1,2 by the reaction of compounds of general formula (II), wherein R?1¿ and n have the same meaning as above; X means hydroxy, halogen or sulfonester leaving group, with the compounds of the general formula (III): R¿2?-Y, wherein R?2¿ has the same meaning as above; Y means hydroxy, halogen or sulfonester leaving group, with the proviso that one of the reaction partners of general formulae (II) and (III) is an alcohol, characterized by, that the reaction is performed under heterogenous conditions in presence of an aqueous base and a phase transfer catalyst, and the resulting product is optionally stabilized by the addition of a base and/or anti-oxidant.

Description

Process for the Preparation of Benzyl-ethers by Use of Phase transfer
This invention relates to the process for the preparation of the mixed ethers of general formula I, wherein
Ar represents an alicyclic, aromatic or one or more heteroatom-containing heterocyclic moiety, optionally substituted by one or more Cι_4 alkoxy, methylenedioxy, C1- alkyl, halogen, Cι_4 haloalkyl or nitro-group, and/or condensed with a benzene ring,
R1 means hydrogen, C,_ alkyl, C1 -4 haloalkyl, C2.4 alkenyl, phenyl, substituted phenyl, C3_6 cycloalkyl group, R2 means C 6 alkyl, C3.6 alkenyl, or C3_6 alkynyl group, optionally mono- or poly-substituted by C,_6 alkyl, C1 -6 alkoxy, C3.6 alkenyl, C3.6 alkynyl, C1-6 haloalkyl group, or by halogen atom; or a Cι_4 alky loxy-C1 -4 alky 1-oxy-
C alkyl group. n = 1, 2 under phase transfer conditions by the reaction of compounds of general formula II. , wherein R and n have the same meaning as above
X means hydroxy, halogen or sulfonester leaving group, with the compounds of general formula III , wherein R has the same meaning as above
Y means hydroxy, halogen or sulfonester leaving group, with the proviso that one of the reaction partners is an alcohol.
In the term Ar the aromatic group is favourably phenyl or naphthyl group, Ar as a heterocyclic moiety may contain one or more O, S, N heteroatoms, it may favourably represent benzodioxole-, benzodioxane-, 2-benzofuran-, 7-benzofuran- moieties. The alicyclic group may favourably be condensed with a benzene ring, thus for instance may represent indane group, or 1,2,3,4-tetrahydronaphthyl group. The carboximide group may favourably represent phthalimide moiety. The aromatic, heterocyclic and alicyclic Ar groups are optionally substituted by C alkoxy-, methylenedioxy-,C,.4 alkyl-, halogen-, CI -4 haloalkyl- or nitro group.
The ethers of general formula I are potential starting materials or active ingredients of a number of chemical products. Several representatives of them are arthropodicide synergists of outstanding activity (Hungarian patent application No 3318/95). With the exception of the methylenedioxy (MDP) synergists with saturated side-chain (such as PBO, i.e. 5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-l,3-benzodioxol), which have been known, the compounds are new, irrespective of their simple structures. Owing to their outstanding significance, their preparation and economical synthesis is of great importance.
The above ethers can be prepared by the general methods known for the synthesis of ethers (Gy. Matolcsy, M. Nadasdy, V. Andriska; Pesticide Chemistiy, Akademia (1988); Hungarian patent application No 3318/95). The essence of these methods is to react the alkali salt of the alcohol component with the partner, according to the rules of the nucleophilic substitution. The partner contains a leaving group, which is usually a halogen, preferably bromo atom. The reaction may be accomplished in two ways, depending on which part of the molecule is built up from the nucleophilic partner. Due to the greater reactivity of benzyl halogenides, in the practice usually the alcoholate of the side-chain is reacted with benzyl bromide. This method is, however, limited when the alcoholate is for some reason hard to prepare. In these cases the inverse method may bring solution, but usually poorer reactions can be expected. This sort of ether preparation is known in the organic chemistiy as the classical Williamson synthesis (B.P Mundy, M.G. Ellerd, Name Reactions and Reagents in Organic Synthesis, Wiley (1988)). The reaction has, however, several drawbacks. The formation of the alcoholate is costly for the industry, it requires expensive reagents and refined technology with guaranteed water-free conditions or with a drying step (Hungarian patent specifications No. 180500, 190842).
For the preparation of ethers in general, further methods are also known. The oldest and most well-known among them is the acid-catalyzed dimerization of alcohols (Houben Weyl 6/3 1 1-19). According to the literature the reaction usually requires high temperature and to avoid decomposition the product has to be continuously removed from the reaction mixture. The oxonium cation formed on the action of the acid may easily take part in rearrangement reactions or it may be stabilized by the so called β-elimination of the hydrogen atom from the neighbouring carbon atom, giving rise to the appropriate olefine. This causes the formation of considerable amount of decomposition products, complicated by the fact the water which is formed in the reaction slows down the process. As a consequence, the performance of the reaction (yield, purity) is low. It is understandable therefore, that this method is not counted for when a synthesis is planned. It is rather taken into consideration as a side-reaction of acid-catalyzed processes (J. Am. Chem. Soc, 107, 1340, (1985)).
In the case of the dibenzyl ethers, to eliminate the draw-backs, the mefhylsulfoxide-induced dimerization method has been worked out (J. Org. Chem., 42, 2012, (1977)). Owing to the applied reagent and high temperature (175 °C), however, the method can not be utilized in industrial scale.
The production of the ethers is an extremely difficult task for the industiy. Not only because of expensive reagents and possible side reactions, but also because both the starting alcohols and the resulting ethers easily form peroxides and are potential explosives. In addition, the alkynyl compounds, due to the triple bond, are sensible to heat. At a large scale (1000 t/year) safe production is only conceivable if the reaction can be carried out under mild conditions and the end-product, which is in most cases a liquid, does not have to be further purified, distilled.
In the light of the above we investigated in details the possibilities of the preparation of asymmetric ethers of general formula I. The essence of our method which we worked out on the basis of our experimental results, is that the mixed ethers of general formula I., wherein the meaning of the substituents is the same as described above, can very favourably prepared by reacting the compounds of general formula II. , wherein X means hydroxy, halogen or sulfonester leaving group, with the compounds of general formula III wherein Y means hydroxy, halogen or sulfonester leaving group, in the presence of a phase transfer catalyst in aqueous medium, with the proviso, that one of the reactants is an alcohol. The resulting ether of general formula I is isolated, and if desired, stabilized by the addition of a base and/or an anti-oxidant.
1 2
In general formulae I II and III the meanings of Ar, R and R are the same as above. In a favourable embodient of the process the compounds of general formulae I
II and III are applied in molar ratios of 0.4-2.5, the base is taken in 1.0-10.0 molar equivalent amount, and the phase transfer calatalyst in 0.01-1.0 molar equivalent amount, favourable 0.1 molar equivalent amount.
As for base, alkali hydroxides or alkali earth metal hydroxides, favourably 2 molar equivalent of potassium hydroxide or sodium hydroxide in 10-40 w/w% aqueous solutions are applied, as for phase transfer catalyst various ammonium salts or hydroxides, favourably tetrabutylammonium bromide or iodide are used.
The reaction may be carried out without solvent or in an apolar aprotic solvent, in the temperature range of (-10)-(+100) °C, favourably at ambient temperature. The reaction may be accomplished by reacting an activated benzyl derivative and an alcohol of general formula III, or in the other way round, by reacting an activated derivative of general formula III with a benzylalcohol of general formula II .
In principle it is expedient to follow a way where the leaving group (X or Y) is in a mobile e.g. benzyl or allyl position; or where elimination by-processes by the base are not possible. Such an example is for instance when an activated benzyl derivative is reacted wherein R\ is hydrogen or a substituent larger than hydrogen, and the molecule does not contain an eliminable hydrogen in the beta position. In the practice, however, the method to choose is often determined by the availability and the price of the starting materials. The ether formation under phase transfer conditions, compared to other solutions, also has the advantage that due to the low polarity of the medium, the above mentioned elimination side-reaction comes much less into prominence, thus even by using inexpensive reagents the product will be of high quality.
The R2 group depending on the stability of R2Y under the reaction conditions may be of numerous sort. It may vary from simple alkyl group through alkenyl or alkynyl group to various substituted e.g. halogenated, alkoxylated derivatives thereof, with straight or branched structures. The method can favourably used for the reaction of 3,3-dichloro-butanyl derivatives where simultaneously with the ether formation a hydrogen halogenide elimination also takes place, resulting in one step the appropriate ether with unsaturated, e.g. 3-chloro-2-butenyl side-chain, which by further elimination may be transformed into the alkynyl ether.
The reaction is preferably carried out in an emulsion consisting of the aqueous alkali solution and a water-non-miscible organic solvent; or without solvent, in the emulsion of the starting materials and the resulting product. This latter method, which brings about faster reaction, is especially favourable in industrial use.
As for base, strong alkali or alkali earth metal hydroxides in small excess are applied. As for organic solvent, apolar aprotic e.g. halogenated solvents, among them most preferably dichloroethane may be used.
For phase transfer catalyst various tetra-substituted ammonium salts or hydroxides may preferably be used. Catalytic amount of them is sufficent.
The reaction is preferably carried out at ambient temperature under vigorous stirring. The ether formation is fast even at low temperature, thus unwanted by- processes can be suppressed. Reaction time may be shortened by applying small excess of the less expensive partner. The product may be isolated from the reaction mixture by simple sedimentation.
The raw product thus obtained is of good quality. Its purity is 93-95%. It may of course be further purified by distillation, or if possible, by ciystallization but it may be used directly. To enhance its stability and hinder its acidic hydrolyzis it is suitable to wash the product to neutral and buffer it in basic pH region. For the sake of safer handling the addition of anti-oxidants of various type is advisable.
As for anti-oxidants e.g. TMQ; BHT; hydroquinone; hydroquinone monomethyl-ether; 2,2,6,6-tetramethyl-4-piperidinol-N-oxide may be used.
To demonstrate our process we give the following non limiting examples without the intention of being complete: Examples
1.) 5-(2-hut\>nyloxymethyl)-6-proj)yl-l,3-benzodioxole To 10 ml of 40w/v% potassium hydroxide solution under intensive stirring are added
1.6 g (0.0225 mol) of 2-butyn-l-ol dissolved in 5 ml of dichloromethane, followed by
3.2 g (0.015 ml) of chloromethyldihydrosafrole dissolved in 10 ml of dichloromethane and 0.5 g of tetrabutylammonium iodide. The mixture is stirred at room temperature for 4 hours. The reaction is followed by TLC method (eluent hexane-EtAc 15: 1). After separation of the phases the aqueous layer is washed with 2x5 ml of dichloromethane, the combined organic phases are washed to near neutral with 2x5 ml of saturated ammonium chloride solution. After drying and evaporation the resulting oil is purified by coloumn chromatography (eluent hexane-EtAc 15:1). Yield 3.0 g (0.01219 mol, 81.3%). TLC (eluent hexane-ethyl acetate 15:1) Rf=0.43.
GC (CP 9000, CP-SIL-5CB, 60 m x 0.53 mm, 5 ml/min N ,, FID, 220°C) tR = 9.7 min, approx. 94.5%).
IR (CHCl3, cm"1) u: 2950, 2867, 1602, 1502, 1485, 1355, 1260, 1068,
937, 866. iH-NMR (200 MHz, CDC13) δ: 0.96 (3H, t, J=7.3 Hz, CH3), 1.69 (2H, sextet, J=7.3
Hz, CH2-CH3), 1.87 (3H, t, J=2.3 Hz, C≡C-CH3), 2.56 (2H, t, J=7.6 Hz, aιyl-CH2)> 4.10 (2H, q, J=2.3 Hz, OCH2C≡C-), 4.48 (2H, s, CH O), 5.89 (2H, s, OCH2O), 6.66 and 6.83 (altogether 2H, s, aromatic). 13C-NMR (40 MHz, CDCI3) δ: 3.56 (C≡C- H3), 14.02 (CH3), 24.66 (CH2-CH3),
34.37 (aryl-CΗ2), 57.49 (OCΗ2C≡C~), 68.86 (CH2O), 75.21 (C≡C-CH3), 82.51 (C≡C-CH3), 100.77 (OCH2O), 109.49, 09.80 (C-4 and C-7), 128.26 (C-6), 135.53 (C-5), 145.44 (C-7a), 147.18 (C-3a). 2-) l-(2-ButvnvIox methyl)-3,4-dimethoxy-6-propyIbeιtzene
In 15 ml of dichloromethane 1.5 g (0.021 mol) of 2-butyn-l-ol and 3.0 g (0.0131 mol) of l ,2-dimethoxy-4-chloromethyl-5-propylbenzene are dissolved, and to the solution are added under vigorous stirring 10 ml of 40w/v%> potassium hydroxide solution and
0.4 g of tetrabutylammonium iodide. The mixture is stirred at room temperature for 2 hours. The reaction is followed by TLC method (eluent hexane-ethyl acetate 15:1).
After separation of the phases the aqueous layer is washed with 2x5 ml of dichloromethane, the combined organic phases are washed to near neutral pH with 2x5 ml of saturated ammonium chloride solution. Following diying and evaporation the resulting oil is purified by coloumn chromatography (eluent hexane-ethyl acetate
4: 1). Yield 3.1 g (0.01 18 mol, 90.3%).
TLC (hexane-ethyl acetate 4: 1) R 0.44 (PMA, UV) GC (CP 9000, CP-SIL-5CB, 60 m x 0.53 mm, 5 ml/min N2,, FID, 250°C) tR=7.9 min, approx. 93.8%. IR (CHC13, cm-l) υ: 2957, 2932, 2866, 2290, 2220, 1610, 1589, 1511,
1465, 1354, 1272, 1 136, 1 111, 1065, 997, 864. lH-NMR (200 MHz, CDCI3) δ: 0.98 (3H, t, J=7.3 Hz, CH3), 1.60 (2H, sextet, J=7.3 Hz, CH2-CH3), 1.88 (3H, t, J=2.3 Hz, C≡C-CH ),
2.59 (2H, t, J=7.6 Hz, aryl-CH2), 3.86 (6H, s, OCH3), 4.12 (2H, q, .1=2.3 Hz, OCH2C≡C-), 4.52 (2H, s, CH2O), 6.69 and 6.88 (altogether 2H, s, aromatic). 13C-NMR (50 MHz, CDCI3) δ: 3.52 (C≡C-CH3), 14.06 (CH3), 24.75 ( H2-CH3),
34.21 (aril-CH2), 55.84 (OCH3), 57.54 (O H2C=C-), 68.81 (CH2O), 75.22 (C≡C-CH3), 82.41 (C≡C-CH ), 112.64, 112.85 (C-3, C-6), 127.15 (C-4), 134.09 (C- 5), 146.76 (C-2), 148.41 (C-l). 3.) 5-(2-Butvnyloxymethy1)-l,3-henzodioxole
The two steps are carried out without the purification of the piperonyl bromide
Piperonyl alcohol (45 g, 0.295 mol) is dissolved in benzene (550 ml), the solution is cooled to 5°C and 150 ml of aqueous 48%o hydrogen bromide solution is added to it.
The cooled mixture is vigorously stirred for 30 mins, while the reaction is followed by
TLC (hexane- ethyl acetate 2: 1). At the end of the reaction the phases are separated, the acidic layer is extracted with 50 ml of benzene, and the combined benzene layers are washed to neutral with ice-cold 2.5%> sodium hydrogen carbonate solution then with saturated sodium chloride solution. The solution is then concentrated on rotadest, approximately 350 ml of benzene is distilled off. As shown by TLC the raw product thus obtained contains the starting material only in traces.
To the benzene solution are added 31.5 g (0.45 mol) of 2-butyn-l-ol, 9 g of tetrabutylammonium iodide and 90 ml of 40 w/v %> aqueous potassium hydroxide solution. The mixture is vigorously stirred at room temperature for 1.5 hours. On TLC (hexane- ethyl acetate 9:1) the disappearance of the piperonyl bromide and the appearance of solely one product can be seen. The two phases are separated, the alkaline phase is extracted with 2x30 ml of benzene, the combined benzene layers are washed to neutral with 2x40 ml of 20%o ammonium chloride solution and with distilled water, then they are dried and evaporated. The excess butynol (bp. 80°C/60 torr) is removed from the resulting oil in water-jet vacuo. The raw product is purified by distillation in vacuo, with the help of a vacuum pump. According to GC analysis the fractions (48.0 g) collected between 110-120 °C (at 0.2 torr) are of 71.2%. purity. Distillation is then continued by applying a 10 cm long Vigreux-colonne. First nnings: p. 90-108°C /0.1 torr, 19.8 g, GC% approx. 68%.
Main fractions: bp. 108-1 10 °C /0.1 torr, 25.9 g, GC approx. 98%.
By repeated distillation of the first runnings further 13.4 g product can be gained.
Yield: 39.3 g (0.192 mol, 65.3%).
Figure imgf000010_0001
GC (CP 9000, CP-SIL-5CB, 60 m x 0.53 mm, 5 ml/min N2;, FID, 250°C): tR = 4.63 min, approx. 97.7%. Piperonyl alcohol contamination tR = 3.0 min, 1.5%. TLC (hexane- ethyl acetate 9: 1): Rf=0.39. Piperonyl alcohol contamination Rf=0.05. IR (CHCl3, cm-l) υ: 2997, 2946, 2921 , 2888, 2376, 1609, 1503, 1491 ,
1445, 1251, 1099, 1070, 1042, 937, 865, 810 ^-NMR (400 MHz, CDC13) δ: 1.87 (3H, t, J=2.3 Hz, Me), 4.10 (2H, q, J=2.3 Hz, O-Ci/2-C≡), 4.47, (2H, s, O-CH2-Ar), 5.94 (2H, s,
O-CH2-0), 6.76 (1H, d, J=8 Hz, H-7), 6.81 (1H, dd, J=8.15 Hz, H-6), 6.86 (1H, J=1.5 Hz, H-4) 13C-NMR (100 MHz, CDCI3) δ: 3.52 (Me), 57.29 (O-CH2-C≡), 71.15 (O-CH2-Ar),
82.54 (CH3-CV), 100.9C-2, 107.95, 108.71 (C- 4,7), 121.66 (C-6), 131.39, (C-5), 147.15,
147.66 (C3a, C-7a)
4.) l,2-Dimethoxy-4-fl-(Z-3-cIιIorobut-2-enyloxy)ethyl]benzene
1.0 g (5.5 mmol) of α-methylveratryl alcohol and 1.44 g (1 1 mmol) of 1,3- dichlorobut-2-ene (containing mainly the Z-isomer) are dissolved in 10 ml of benzene, to the mixture 1.23 g (22 mmol) of potassium hydroxide dissolved in 5 ml of water and 1.95 g (5.5 mmol) of benzyltributylammonium bromide are added and the mixture is stirred at room temperature for 2 days.
The phases are then separated, the aqueous layer is thoroughly extracted with benzene. The combined benzene layer is washed to neutral with diluted hydrochloric acid and with distilled water, then dried and evaporated. The raw material is purified by coloumn chromatography. Yield 0.47 g (1.7 mmol, 31.5%), homogenous according to GC analysis.
IR (CHC13, cm-!) υ: 2973, 2931, 2862, 2839, 1659, 1606, 1595, 1511,
1465, 1443, 1261, 1164, 1141, 1093, 1028. lH-NMR (200 MHz, CDCI3) δ: 1.43 (3H, d, J=6.5 Hz, CH-CH3), 1.97 (3H, t, J=0.5
Hz, =CC1-CΗ3), 3.80 (2H, m, OCH ), 3.87 and 3.89 (altogether 6H, each s , OCH3), 4.38 (2H, q, .1=6.5
Hz, Ar-CHO), 5.78 (1H, m, CH=CC1), 6.83 (2H, d, Ar), 6.87 (1H, d, Ar). 1 C-NMR (50 MHz, CDC13) δ: 21.23 (=CC1-CΗ3), 24.08 (CH-CH3), 55.84 (OCH3),
64.10 (OCH2), 77.05 (Ar-CHO), 108.92 (C-2),
110.91 (C-5), 118.74 (C-6), 124.43 (CH=CC1), 134.0 (CH=CC1), 135.89 (C-l), 148.49 and 149.23 (C-3 and
C-4).
5.) l-f2-(2-Butoxyethoxy)e1hoxymelhyI]-3,4-dimethoxybenzene To 3.0 g (17.83 mmol) of veratryl alcohol dissolved in 20.0 ml of benzene and cooled to 10 °C, 15.0 ml of 48% hydrogen bromide is added and the mixture is stirred for 30 mins. The phases are then separated in a separation funnel and the organic layer is neutralized with sodium hydrogen carbonate and concentrated to 2/3 of its volume by evaporation. To this solution are added 4.33 g (26.7 mmol) of diethylene glycol monobutyl ether, 4 ml of 50w/v%> potassium hydroxide solution and 0.65 g (1.75mmol) of tetrabutylammonium iodide, and the mixture is vigorously stirred at room temperature for one night. The phases are then separated in a separation funnel, the aqueous layer is extracted with benzene, the combined organic layer is washed to neutral with water, dried over magnesium sulfate and evaporated. The resulting oily raw product is purified by chromatography (eluent: n-hexane-ethyl acetate, 2: 1) R O.35.
Yield: 3.62g (11.59 mmol, 65.1%)
IR (CHCI3, cm"1) υ: 2999, 2958, 2935, 2913, 2870, 2448, 2371 , 1722, 1608, 1595, 1513, 1466, 1443, 1420, 1353, 1328, 1265, 1239, 1157, 1140, 1094, 1029, 982, 951, 918, 889, 862, 809, 725, 640, 592, 477
!H-NMR (200 MHz, CDCI3) 8: 0.91 (3H, t, J=7.2Hz, -O-CH2-CH2-CH2-CH3), 1.36
(2H, m, -O-CH2-CH2-CH2-CH3), 1.55 (2H, m, -O-
CH2-CH2-CH2-CH3), 3.46 (2H, t, -O-CH2-CH2-
CH2-CH3) 3.63 (8H, m, -0-CH2-CH2-0), 3.86 and 3.88 (6H, s, CH3O ), 4.50 (2H, s, C 2-Aή, 6.79-6.91
(3H, m, Ar) 13C-NMR (50 MHz, CDC1 ) δ: 13.81 (-O-CH2-CH2-CH2- H3), 19.4 (-O-CH2-CH2-
CH2-CH3), 31.62 (-O-CH2- H2-CH2-CH3), 55.71 and 55.81 (OCH3), 69.06, 70.0, 70.58, 71.10, (-O-
CH2), 73.02 (Ar-CΗ2-O), 110.81 (Ar-C-2), 111.04 (Av-C-4), 120.21 (Ar-C-6), 130.79 (Ar-C-7), 148.49 and 148.94 (Ar-C-3 and Ar-C-4)
6.) l-[2-(2-Butoxyethoxy)ethoxymethyl]-3,4-dimethoxy-6-woηylbenzene
To 5.02 g (21.6 mmol) of l ,2-dimethoxy-4-chloromethyl-5-propylbenzene, dissolved in 25 ml of dichloromethane, 5.96 g (36.74 mmol) diethylene glycol monobutyl ether, 0.4 g of n-tributylammonium iodide and 17 ml of 40%> sodium hydroxide solution are added. The mixture is stirred at room temperature for one night, then the two phases are separated in a separation funnel, the aqueous phase is extracted with dichloromethane, the combined organic layers are washed to alkali-free with water, dried over MgSO4 and evaporated. The raw product is purified by chromatography (eluent: benzene-ethyl acetate 9: 1) R =0.32 Yield: 5.63g (15.88 mmol, 74.47%).
IR (CHC13, cm" 1) υ: 3315, 2998, 2959, 2933, 2871 , 2418, 2374, 2035, 1617,
1350,1272, 1224, 1112, 1035, 997, 893, 867, 839, 641, 556. iH-NMR (200 MHz, CDCI3) δ: 0.91 and 0.96 (3H, t, J=7.2 Hz, -O-(CH2)3-CH , and
Ar-(CH2)2-CH3), 1.33-1.61 (6H, m, -O-CH2-CH2- CH2-CH3, -CH2-CH2-CH3), 2.57 (2H, m, Av-CH2-
CH2-CH3), 3.45 (2H m, - -CH2), 3.57-3.67 (8H, m,
4xH2C-O) 3.68 and 3.86 (6H, s, OCH3), 4.52 (2H, m, Ar-CH2-0) 6.69 and 6.89 (2H, m, aromatic)
13C-NMR (50 MHz, CDCl3) δ: 13.82 (-CH2-CH2- Η3) 14.03 (-O-CH2-CH2-CH2- 6Η3), 19.18 (-O-CH2-CH2- Η2-CH3), 24.57 (-CH2-
CH2-CH3) 31.63 (-O-CH2-CH2-CH2-CH3), 34.15 (- CH2-CH2-CH3), 55.83 (OCH3), 69.27, 70.02, 70.60 and 70.67 (-O- H2), 71.12 (Ar-CH2-O), 112.51 (Ar- C-2), 112.64 (Aτ-C-4), 127.74 (Ar-C-7), 133.69 (Ar- C-6), 146.75 and 148.22 (Ar-C-3 and Aτ-C-4)
7.) l-fl-(But-2-ynyloxy)ethyl]-3,4-dimethoxybenzene
To 1.0 g (5.5 mmol) of α-methylveratryl alcohol, dissolved in 10 ml of dichloromethane, are added 1.09 g (8.2 mmol) of 1 -bromo-2-butyne, 0.2 g of n- tributylammonium iodide and 10 ml of 40% sodium hydroxide solution. The mixture is stirred at room temperature for 1 night and the two phases are separated in a separation funnel. The organic layer is extracted with dichloromethane, the combined organic layer is washed to alkali-free with water, dried over MgSO4 and evaporated. The raw product (1.15 g) is purified by chromatography. Yield: 0.8 g (3.42 mmol, 62.1%). nD 2° 1.5282.
IR CCHCls cm"1) v:
2976, 2855, 2837, 1605, 1595, 1514, 1465, 1419, 1371, 1353, 1311, 1260, 1164, 1 141, 1086, 1027, 864 1 H-NMR (200 MHz, CDCI3) δ :
1.46 (3H, d, J=6.5Hz, CH-C//3), 1.85 (3h, t, J=2.3Hz, ≡C-Ci/3), 3.83 and 4.01
(2H, ABX3, JAB=15-° HZ > JAX=JBX=2-3 HZ, ≡C-CJ 2-O), 3.87 and 3.89 (altogether 6H, each s, O-CH3), 4.55 (2H, q, J=6.5 Hz, Ar-CH-O), 6.80-6.89 (3H, m, aromatic). 13C-NMR (50 MHz, CDCI3) δ:
3.61, (=C-CΗ ), 23.76 (CH-CH3), 55.87 (O- H3), 55.96 (≡C-CH2-O). 75.36 (≡ C-CH2), 76.40 (Ar-CH-O), 81.91 (≡C-CH ), 109.06 (C-2), 110.86 (C-5), 118.94 (C-6), 135,30 (C-l), 148.52 (C-3), 149.19 (C-4). 8.)
.7-/7- (Prop-2-en yloxy) eth ylJ-3, 4-dimeth oxybenzene,
(l-(3',4'-dimethoxyphenyl)ethyl allyl ether) The procedure described in Example 7 is followed, with the difference that 3.0 g (0.0164 mol) of α-methylveratryl alcohol and 1.38g (0.018 mol) of allyl chloride are applied.
Yield: 2.5 g (68.6%).
GC (CP 9000, CP-SIL-5CB, 60 m x 0.53 mm, 5 ml/min N2,, FID, 250°C) tR = 3.4 min (cca. 95%).
IR
Figure imgf000015_0001
υ: 3079, 2996, 2973, 2933, 2860, 2838, 1607, 1595, 1510,
1465, 1443, 1419, 1311, 1260, 1164, 1 141, 1089, 1027, 996, 928, 860. ΪH-NMR (200 MHz, CDC13) δ: 1.45 (3H, d, J=6.4 Hz, CH3), 3.83 AB mid. (2H, ABdt, JAB= 12-7 Hz, J=1.3, 6.0 Hz, OCH2CH=), 3.89 and 3.87 (altogether 6H, each s, CH3O), 4.41 (2H, q,
J=6.4 Hz, CH-O), 5.11-5.29 (2H, m), 5.81-6.0 (1H, m), 6.83 (2H, s), 6.89 (1H, s).
13C-NMR (50 MHz, CDCI3) δ: 24.0 (CH-CH3), 55.77 (OCH3), 69.17 (OCH2=), 108.94 (C-2), 110.82 (C-5), 116.58 (CH=CH2),
118.58 (C-6), 135.0 (C-l), 136.26 (CH=CH2), 148.29 and 149.11 (C-3 and C-4).
9.) l-fl-(2-butyιιyloxy)propyl]-3.4-dimethoxybenzene
The procedure described in Example 7 is followed, with the difference that 1-[1- hydroxy-propyl]-3,4-dimethoxybenzene is applied.
Yield: 77%
Purity (GC): CP 9000, CP-SIL-5CB, 60 mxθ.53 μm, 5 ml/min N25, FID, 220°C tR = 13.0 min, >95%. IR (CHCI3, cm"1) υ: 2999, 2959, 2935, 2875, 2856, 2839, 2240, 1608,
1595, 1513, 1465, 1261 , 1234, 1 162, 1142, 1061 , 1028. iH-NMR (200 MHz, CDCI3) δ: 0.84 (3H, t, =7.4 Hz, CH2C77r 3), 1.65 and 1.83 (altogether 2H, each m, CH2CH3), 1.82 (3H, t,
J=2.3 Hz, C=C-CH3), 3.84 and 3.86 (altogether 6H, s, CH3O), 3.78 and 3.99 (altogether 2H, ABX3, JAB=15-° HZ > AX=JBX=2.3 HZ, OCH2), 4.22 (1H, t, .1=6.8 Hz, CH-O), 6.80-6.83 (3H, m, aromatic) (signals of ethyl acetate may be seen at
1.22 (t), 2.01 (s) and 4.08 (q) ppm). i3C-NMR (50 MHz, CDCI3) δ: 3.55 (C=C-CH ), 10.23 (CH2CH3), 30.58
(CH2CH3), 55.77 (OCH3), 56.03 (OCH2), 75.41
(C=C-CH3), 81.71 (C=C-CH3), 82.24 (CH-O), 109.34, 110.64 (C-2, C-5), 119.63 (C-6), 133.95
(C-l), 148.44 and 149.09 (C-3, C-4).
10.) l-fl-(2-butynyloxy)-2-methylpropyl]-3,4-dimethoxybenzene The procedure described in Example 7 is followed, with the difference that, 1-(1- hydroxy-2-methylpropyl)-3,4-dimethoxybenzene is applied. Yield: 65%
Purity (GC): CP 9000, CP-SIL-5CB, 60 mxθ.53 μm, 5 ml/min
N25, FID, 220°C, tR = 14.0.0 min, >91%. IR (CHCI3, cm"1) υ: 3029, 2995, 2958, 2937, 2871, 2857, 2839, 2238,
1606, 1595, 1510, 1466, 1443, 1420, 1263, 1238, 1157, 1142, 1062, 1028. ^-NMR (400 MHz, CDCI3) δ: 0.65 and 0.97 (altogether 6H, each d, J = 6.8 Hz,
CH(CH3)2), 1.77 (3H, t, J = 2.3 Hz, C=C-CH3), 1.87 (1H, m, C77(CH3)2), 3.80 and 3.81
(altogether 6H, s, OCH3), 3.71 and 3.95 (altogether 2H, ABX3, JAB=15-0 Hz, JAχ = JBχ= 2.3 Hz,
OCH2), 3.90 (1H, d, J = 8.1 Hz, CH-O), 6.68-6.78
(3H, m, aromatic). 13C-NMR (100 MHz, CDC13) δ: 3.39 (C≡C-CH3), 18.87 and 19.16 ((CH(CH3)2), 34.32 (CH(CH ) ), 55.61 (OCH3), 56.11 (OCH ),
75.44 (C≡C-CH3), 81.37 (G-1C-CH3), 86.25 (CH-
O), 109.76 (C-
5), 110.32 (C-2), 120.19 (C-6), 132.91 (C-l),
148.24 (C-4) and 148.80 (C-3).
11.) l-(But-2-ynyloxymethyl)naphthaleιιe
To the solution of 1.50 g (21.4 mmol) of 2-butyn-l-ol in 10 ml of dichloromethane are added 3.71 g (21.0 mmol) of 1-chloromethylnaphthalene, 0.4 g of n- tributylammonium iodide and 10 ml of 40% potassium hydroxide solution. The mixture is stirred at room temperature for one night, then the two phases are separated in a separation funnel. The organic layer is extracted with dichloromethane, the combined organic layer is washed to alkali-free with water, dried on MgSO4 and evaporated. The raw product, 3.61 g (17.2 mmol, 81.8%), is homogeneous as shown by GC analysis.
IR (CHCI3, cm"1) υ: 3044, 3001 , 2945, 2920, 2854, 1598, 1509, 1356,
1166, 1086, 1067 iH-NMR (400 MHz, CDCI3) δ: 1.93 (3H, t, J=2.3 Hz, C≡C-CH3), 4.22 (2H, q,
J=2.1 Hz, O-CH2-C≡C), 5.06 (2H, s, C10H7-CH2- O), 7.45 (1Η, t, J=8 Ηz), 7.53 (3Η, m), 7.84 (1H, d,
J=8.1 Hz), 7.88 (3H, m), 7.88 (1H, d, J=7.7 Hz),
8.19 (1H, d, J=8.2 Hz). 13C-NMR (100 MHz, CDCI3) δ: 3.6 (OC-CH3), 57.71 (O-CΗ2-c≡c)> 69-72
C10H7-CH2-O), 75.10 (O-CH2-C≡C), 82.76 (O- CH2-C=C), 124.03, 125.10, 125.72, 126.19,
126.85, 128.43, 128.72, 131.79 (C-8a), 133.06,
133.70 12.)
5-f2-(2-bιιtoxyethoxy)ethoxymethyl]-6-propyl-l,3-benz dioxol, PBO
Into an apparatus supplied with magnetic stirrer are placed 2.98 g (14.02 mmol) of 5- chloromethyldihydrosafrole, 2.72 g (16.82 mmol) of diethylene glycol monobutyl ether, 15 ml of dichloromethane, 10 ml of 40%> potassium hydroxide solution and 0.51 g (1.38 mmol) of tetrabutylammonium iodide. The emulsion is reacted under intensive stirring for 4 hours, while the reaction is followed by TLC chromatography. After the disappearance of the starting chloromethyl derivative the mixture is allowed to settle, the phases are separated, the organic layer is washed to alkali-free with water, dried and evaporated. The product is distilled in vacuo. Bp: 180°C/lHgmm. The material is identical with the PBO obtained from the market. Yield: 4.0g (90%>). Purity (GC) 98%.

Claims

Claims
1. Process for the preparation of mixed ethers of general formula I., wherein Ar represents an alicyclic, aromatic or one or more heteroatom-containing heterocyclic moiety, optionally substituted by one or more C alkoxy, methylenedioxy, C,.4 alkyl, halogen, C1-4 haloalkyl or nitro-group, and/or condensed with a benzene ring, R1 means hydrogen, C,.4 alkyl, C,_4 haloalkyl, C2.4 alkenyl, phenyl, substituted phenyl, C3.6 cycloalkyl group,
R2 means C1-6 alkyl, C3.6 alkenyl, or C3.6 alkinyl group, optionally mono- or poly-substituted by C1-6 alkyl, C1-6 alkoxy, C3_6 alkenyl, C3.6 alkinyl, C1-6 haloalkyl group or by halogen atom; or a C1.4 alkyloxy-C1.4 alkyl-oxy- C1-4 alkyl group. n = 1 , 2 by the reaction of the compounds of general formula II, wherein R and n have the same meaning as above X means hydroxy, halogen or sulfonester leaving group, with the compounds of general formula III , wherein R has the same meaning as above
Y means hydroxy, halogen or sulfonester leaving group, with the proviso that one of the reaction partners of general formulae II. and III. is an alcohol, characterized by, that the the reaction is performed under heterogenous conditions in the presence of an aqueous base and a phase transfer catalyst, and the resulting product is optionally stabilized by the addition of a base and/or an anti- oxidant.
2. The process according to claim 1., characterized by, that the compounds of general formulae II. and III. are applied in molar ratios of 0.4 - 2.5
3. The process according to claims 1.- 2. characterized by, that 1.0 -10.0 molar equivalent amount of a base, preferably alkali or alkali earth metal hydroxide, preferably 2.0 molar equivalent of potassium hydroxide or sodium hydroxide in 10- 40 w/v%> aqueous solutions are applied.
4. The process according to claims 1.- 3. characterized by, that as phase transfer catalyst various ammonium salts or hydroxides, preferably tetrabutyl ammonium bromide or iodide are applied.
5 The process according to claims 1.- 4. characterized by, that the phase transfer catalyst is applied in 0.01-1.0 molar equivalent amount, preferably 0.1 molar equivalent amount.
6. The process according to claims 1.- 5. characterized by, that the reaction is carried out without solvent, or in the presence of an apolar aprotic solvent, preferably dichloroethane.
7. The process according to claims 1.- 6. characterized by, that the reaction is carried out at a temperature of (-10)-(+100) °C, preferably at room temperature.
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US6596870B2 (en) 2000-07-13 2003-07-22 Brandeis University Asymmetric synthetic methods based on phase transfer catalysis
CN1124246C (en) * 2000-09-01 2003-10-15 中国科学院上海有机化学研究所 Process for preparing 4-(2-alkoxyethyl) phenol by phase-transfer catalysis
WO2011020848A1 (en) 2009-08-18 2011-02-24 Endura S.P.A. Substituted alkynyl phenoxy compounds as new synergists in pesticidal compositions
EP2289889A1 (en) 2009-08-18 2011-03-02 Endura S.p.a. Substituted alkynyl phenoxy compounds and their uses
WO2012123714A1 (en) * 2011-03-11 2012-09-20 Rothamsted Research Limited Compositions and methods for controlling pesticide resistant pests
AP3523A (en) * 2011-03-11 2016-01-11 Rothamsted Res Ltd Compositions and methods for controlling pesticide resistant pests
US10104890B2 (en) 2011-03-11 2018-10-23 Rothamsted Research Limited Compositions and methods for controlling pesticide resistant pests
WO2014147387A1 (en) * 2013-03-21 2014-09-25 Rothamsted Research Limited Compositions and methods for controlling herbicide resistant weeds

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