Process for the preparation of benzyl-ethers

Details Process for the preparation of benzyl-ethers Process for the preparation of benzyl-ethers

1999-07-13

2001-11-20

Keys, Rosalynd (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S626000, C568S659000, C568S660000, C568S661000, C568S662000, C568S663000

Reexamination Certificate

active

06320085

ABSTRACT:

This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/HU97/00073 which has an International filing date of Nov. 12, 1997 which designated the United States of America.
SUMMARY OF THE INVENTION
This invention relates to the process of 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
1-4
alkoxy, methylenedioxy, C
1-4
alkyl halogen, C
1-4
haloalkyl or nitro-group, and/or condensed with a benzene ring,
R
1
and R
2
independently mean hydrogen, C
1-4
alkyl, C
1-4
haloalkyl, C
2-4
alkenyl, phenyl, substituted phenyl, C
3-6
cycloalkyl group,
R
3
means C
3-6
alkynyl group, optionally substituted by one or more C
1-6
alkyl, C
3-6
alkenyl, C
3-6
alkynyl, C
1-6
haloalkyl group, or halogen atom; or a C
1-4
alkyloxy-C
1-4
alkyl-oxy-C
1-4
alkyl group,
under acidic conditions, by the reaction of compounds of general formula II, wherein
X means hydroxy, halogen or sulfonester leaving group, with compounds of general formula III , wherein
R
3
has the same meaning as above.
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
1-4
alkoxy-, methylenedioxy-, C
1-4
alkyl-, halogen-, C
1-4
haloalkyl- or nitro group.
FIELD OF THE INVENTION
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 having saturated side-chain (such as PBO, i.e. 5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-1,3-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.
BACKGROUND OF THE INVENTION
The above ethers can be prepared by the general methods known for the synthesis of ethers (Gy. Matolesy, M. Nádasdy, V. Andriska;
Pesticide Chemistry
, Akadémia (1988); Hungarian patent specifications 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 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 chemistry 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 applications No. 180500, 190842).
The preparation of the halogenide or of the partner containing the leaving group requires a separate step and the use of further costly reagents. In case the alpha carbon atom contains additional substituents (R
1
and/or R
2
is different from hydrogen) the preparation of the activated, for example halogen derivative involves difficulties as the product is susceptible to elimination reaction or side reactions, for instance aromatic electrophilic substitution. The yield of the coupling strongly depends on the reactivity of the partner and the resulting product needs further purification.
For the preparation of ethers in general, further methods are also known. The oldest and most well-known among them is the acid catalyzed dimerisation of alcohols (Houben Weyl 6/3 11-19). 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 &bgr;-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 that 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 (
Chem. Pharm. Bull
. 31, 3024, (1983)).
In the case of the dibenzyl ethers, to eliminate the draw-backs, the methyl sulfoxide-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.
It was a major break-through when it was revealed that, in addition to the fact that the ether formation can be catalyzed by Lewis acids, the reaction with zinc(II) chloride in dichloroethane can be performed under relatively mild conditions (
J. Org. Chem
. 52, 3917, (1987)). The method, however, has been worked out practically only for dimerization and intramolecular cyclization reactions. For mixed ethers the reproducibility of the reaction, as well as the quality and yield of the product are poor. With benzyl(p-methoxybenzyl)alcohol, containing an aromatic substituent, the reaction proceeds in low yield due to polymerization; the mixed ether with unsaturated chain (&agr;-methylbenzyl allyl ether)—unlike its saturated analogue—can be obtained again, only in poor yield, because of dimerization. In a published version of the reaction the benzyl halogenide was reacted with the nucleophilic reagent in the presence of zinc oxide (
Tetrahedron
, 38, 1843, (1982)), but applicability of this reaction for the compounds of general formula I is not known.
The acid-catalyzed ether formation takes place through the appropriate cationic intermediate. Stability of ring-substituted 1-phenylethyl carbocations and their reaction with nucleophilic reagents in trifluoroethanol/water=1./I model system has been studied (
J. Am. Chem. Soc
., 106, 1361, ((1984); 106, 1373, (1984). The two references, however do not give examples on the preparation of compounds of general formula I., and do not give a hint concerning their synthesis respect to the reaction media (polarity, solvation), which—as shown by the two references—play major role in the reaction and even small modifications may disturb the sensible equilibria. Authors of the above two references in their later theoretical work have published that ethers, similar type to general formula I., are surprisingly sensible to acids, differing from other ethers. Ether formation proceeds in a reversible reaction, which increases the possibility of by-product formation, deteriorating purity and yield of the product. As shown by the data published, alkoxyalcohols, such as ethylene glycol monomethyl ether, have poor reactivity, unsaturated alcohols e,g. propargyl alcohol have medium reactivity, falling well behind the reactivit

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