Process for producing 2,2,4,4-tetra-substituted...

Details Process for producing 2,2,4,4-tetra-substituted... Process for producing 2,2,4,4-tetra-substituted...

2001-11-29

2003-05-06

Richter, Johann (Department: 1621)

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

Organic compounds

Oxygen containing

C568S347000, C568S351000, C568S353000, C556S436000

Reexamination Certificate

active

06559343

ABSTRACT:

This application is a 371 of PCT/EP00/04567 filed May 19, 2000, now WO 00/75095, published Dec. 12, 2000.
The present invention relates to a process for the preparation of 2,2,4,4-tetrasubstituted 1,3,5-cyclohexanetriones of the formula I.
2,2,4,4-Tetrasubstituted 1,3,5-cyclohexanetriones of the formula I are used as intermediates for the preparation of herbicidally active compounds, such as described, for example, in EP-B 283 152.
Processes for their preparation are therefore of particular interest.
To date, the following syntheses are known as processes for the preparation of 2,2,4,4-tetrasubstituted 1,3,5-cyclohexanetriones:
1. The reaction of 2,4,6-trihydroxyacetophenone with an excess of methyl iodide and sodium methanolate and subsequent deacetylation by means of hydrochloric acid. The total yield of 2,2,4,4-tetramethyl-1,3,5-cyclohexanetrione (based on 2,4,6-trihydroxyacetophenone) is 37%. (EP-B 283 152).
2. Starting from dimethyl acetonedicarboxylate, dimethyl tetra-C-methylacetonedicarboxylate was obtained by methylation, and this was converted into the dicarboxylic acid methyl ester chloride and then methylated with dimethylcadmium. The methyl 2,2,4,4-tetramethyl-3,5-dioxohexanecarboxylate obtained was cyclized in the presence of sodium methanolate. The total yield (based on dimethyl acetonedicarboxylate) is 0.01% (Chem. Ber. 92, 2033 (1959)).
3. Ethyl 2,4,4-trimethyl-3-oxo-pentanecarboxylate was converted into the silyl enol ether at −78° C., acetylated in the presence of ZnCl
2
and then cyclized in the presence of lithium diisopropylamide. The total yield (based on ethyl 2,4,4-trimethyl-3-oxo-pentanecarboxylate) is 50% (M. Benbakkar et al., Synth. Commun. 19 (18) 3241).
It is furthermore known that
4. Silyl ketene acetals rearrange under thermal stress to give silyl enol ethers. If the silyl ketene acetal of methyl isobutyrate is thermolyzed at 200° C. without solvent, methyl 2,4,4-trimethyl-3-(trimethylsilyloxy)-pent-2-enecarboxylate is obtained in 75% yield. 2,2,4,4-Tetramethyl-1,3-cyclobutadiene, inter alia, is formed as a by-product (C. Ainsworth et al., J. Orgmetal. Chem. 46 (1972) 59).
Both the first and the second abovementioned synthesis route yield 2,2,4,4-tetramethyl-1,3,5-cyclohexanetrione in unsatisfactory yields. Moreover, toxic dimethylcadmium is employed in the multistage 2
nd
reaction sequence.
In the 3
rd
synthesis variant, two equivalents of base are needed for the preparation of the silyl ether. The reaction must furthermore be carried out at low temperatures (−78° C.), so that this process is also problematical from technical points of view.
The preparation of methyl 2,4,4-trimethyl-3-(trimethylsilyloxy)-pent-2-enecarboxylate according to sequence 4 necessitates working in a bomb tube—this is laborious, complicated and relatively expensive. Moreover, the silyl ketene acetals needed are laborious to prepare.
As a consequence, these synthesis routes can be unsatisfactory as economical and efficient processes for the preparation of 2,2,4,4-tetrasubstituted 1,3,5-cyclohexanetriones.
It is an object of the present invention, therefore, to find an alternative synthesis process for the preparation of 2,2,4,4-tetrasubstituted 1,3,5-cyclohexanetriones, which does not have the abovementioned disadvantages of the preparation methods known until now.
We have found that this object is achieved by the process according to the invention for the preparation of 2,2,4,4-tetrasubstituted 1,3,5-cyclohexanetriones of the formula I
in which
R
1
, R
2
, are C
1
-C
6
-alkyl or C
3
-C
6
-cycloalkyl, where these two radicals can be unsubstituted or partially or completely halogenated and/or substituted by the following radicals:
C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio or di(C
1
-C
4
-alkyl)amino;
C
1
-C
6
-alkoxy, C
2
-C
6
-alkenyl or C
2
-C
6
-alkynyl;
aryl, aryloxy or heterocyclyl, which has up to three heteroatoms from the group consisting of O, S and N, where the aryl, the aryloxy and the heterocyclyl radical can be unsubstituted or partially or completely halogenated and/or substituted by the following radicals: C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy or C
1
-C
4
-alkoxycarbonyl;
or two radicals R
1
and R
2
, which are bonded to the same carbon, together form a —(CH
2
)
2-6
— chain, which can be substituted by the following radicals: halogen, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy or C
1
-C
4
-alkoxycarbonyl;
which comprises
a) reacting a cyclobutane-1,3-dione of the formula II
where R
1
and R
2
have the abovementioned meanings, with an O or N nucleophile, if appropriate in the presence of a base, and a silylating reagent to give the silyl enol ether of the formula III,
where
R
3
is C
1
-C
8
-alkoxy, amino, C
1
-C
6
-alkylamino or di(C
1
-C
6
-alkyl)amino;
R
4
is C
1
-C
6
-alkyl or phenyl;
R
1
and R
2
have the abovementioned meanings;
b) converting the compound III by acetylation, if appropriate in the presence of a Lewis acid, into the tricarbonyl compound of the formula IV,
 where R
1
to R
3
have the abovementioned meanings;
c) cyclizing the compound IV in the presence of a base to give the 2,2,4,4-tetrasubstituted cyclohexanetrione of the formula I.
The reaction sequence for the preparation of the 2,2,4,4-tetrasubstituted 1,3,5-cyclohexanetriones of the formula I is compiled in the following scheme:
In what follows, the individual reaction stages and preferred embodiments are explained in greater detail. The preferred embodiments of the individual reaction stages apply not only on their own but also in combination with the other process stages:
In this reaction, suitable O nucleophiles are C
1
-C
8
-alcohols, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methylpropan-1-ol, 2-methylpropan-2-ol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methylbutan-1-ol, 3-methylbutan-1-ol, 1,1-dimethylpropan-1-ol, 1,2-dimethylpropan-1-ol, 2,2-dimethylpropan-1-ol, 1-hexanol, 2-hexanol, 3-hexanol or 2-ethylhexanol.
Suitable N nucleophiles are ammonia, C
1
-C
6
-alkylamines, such as methylamine, ethylamin, 1-propylamine, 2-propylamine, 1-butylamine, 2-butylamine, 2-methylprop-1-ylamine, 2-methylprop-2-ylamine, 1-pentylamine, 2-pentylamine, 3-pentylamine, 2-methylbut-1-ylamine, 3-methylbut-1-ylamine, 1,1-dimethylprop-1-ylamine, 1,2-dimethylprop-1-ylamine, 2,2-dimethylprop-1-ylamine, 1-hexylamine, 2-hexylamine or 3-hexylamine or di(C
1
-C
6
-alkyl)amines such as dimethylamine, diethylamine, di(1-propyl)amine, di(2-propyl)amine, di(1-butyl)amine, di(2-butylamine), di(2-methylprop-1-yl)amine, di(2-methylprop-2-yl)amine, di(1-pentylamine), di(2-pentyl)amine, di(3-pentylamine), di(2-methylbut-1-yl)amine, di(3-methylbut-1-yl)amine, di(1,1-dimethylprop-1-yl)amine, di(1,2-dimethylprop-1-yl)amine, di(2,2-dimethylprop-1-yl)amine, di(1-hexyl)amine, di(2-hexyl)amine, di(3-hexyl)amine, N-methyl-N-ethylamine, N-methyl-N-1-propylamine, N-methyl-N-2-propylamine, N-methyl-N-1-butylamine, N-methyl-N-2-butylamine, N-methyl-N-2-methylprop-1-ylamine, N-methyl-N-2-methylprop-2-ylamine, N-methyl-N-pentylamine, N-methyl-N-2-pentylamine, N-methyl-N-3-pentylamine, N-methyl-N-2-methylbut-1-ylamine, N-methyl-N-3-methylbut-1-ylamine, N-methyl-N-1,1-dimethylprop-1-ylamine, N-methyl-N-1,2-dimethylprop-1-ylamine, N-methyl-N-2,2-dimethylprop-1-ylamine, N-methyl-N-1-hexylamine, N-methyl-N-2-hexylamine, N-methyl-N-3-hexylamine, N-ethyl-N-2-propylamine, N-ethyl-N-2-propylamine, N-ethyl-N-1-butylamine, N-ethyl-N-2-butylamine, N-ethyl-N-2-methylprop-1-ylamine, N-ethyl-N-2-methylprop-2-ylamine, N-ethyl-N-pentylamine, N-ethyl-N-2-pentylamine, N-ethyl-N-3-pentylamine, N-ethyl-N-2-methylbut-1-ylamine, N-ethyl-N-3-methylbut-1-ylamine, N-ethyl-N-1,1-dimethylprop-1-ylamine, N-ethyl-N-1,2-dimethylprop-1-ylamine, N-ethyl-N-2,2-dimethylprop-1-ylamine, N-ethyl-N-1-hexylamine, N-ethyl-N-2-hexylamine or N-ethyl-N-3-hexylamine.
Likewise, the alkali metal or alkaline earth metal salts of the C
1
-C
8
-alcohols, C
1
-C
6
-alkylamines or di(C
1
-C
6
-alkyl)amines and of ammonia are suitable, i.e., for e

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