Method for producing bicyclic 1,3-diketones

Details Method for producing bicyclic 1,3-diketones Method for producing bicyclic 1,3-diketones

2003-01-06

2004-11-09

Qazi, Sabiha (Department: 1616)

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

Organic compounds

Oxygen containing

C568S031000, C568S042000, C568S043000, C568S304000, C504S236000, C504S237000, C504S238000, C504S296000, C504S348000

Reexamination Certificate

active

06815563

ABSTRACT:

The present invention relates to a process for preparing bicyclic 1,3-diketones of the formula I,
where
R
1
, R
2
, R
3
and R
4
are hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxycarbonyl, halogen, cyano, nitro, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylsulfenyl or C
1
-C
4
-alkylsulfonyl and
Z is C
1
-C
4
-alkylene, O, S, N—R
5
where
R
5
=C
1
-C
4
-alkyl or C
1
-C
4
-alkylcarbonyl,
novel intermediates and novel processes for preparing these intermediates.
Bicyclic 1,3-diketones are useful compounds which can be employed as intermediates in crop protection. U.S. Pat. No. 5,608,101, U.S. Pat. No. 5,536,703, JP 09052807, JP 10265441 and JP 10265415, for example, disclose bicyclooctanediones as intermediates for herbicidally active compounds.
The processes disclosed in JP 10 265 441 and JP 10 256 415 use highly expensive norbornanone as starting material. Owing to the high costs of the starting materials, these processes do not appear to be economical.
Other syntheses have also been described in the literature. They all suffer from the disadvantage that either a large number of synthetic steps are involved (Chem. Ber. 69 (1936), 1199) or that toxicologically and/or ecologically objectionable reagents are used (Can. J. Chem. 42 (1964), 260; Bull. Soc. Chim. Fr. 7-8 (1975), 1691), so that these syntheses are not acceptable from an industrial point of view.
This application is a 371 of PCT/EP01/07639 filed on Jul. 4, 2001.
It is an object of the present invention to provide an alternative process for preparing bicyclic 1,3-diketones of the formula I, which process does not have the disadvantages of the prior art.
We have found that this object is achieved by a process for preparing bicyclic 1,3-diketones of the formula I
where
R
1
, R
2
, R
3
and R
4
are hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy-carbonyl, halogen, cyano, nitro, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylsulfenyl or C
1
-C
4
-alkylsulfonyl and
Z is C
1
-C
4
-alkylene, O, S, N—R
5
where
R
5
is C
1
-C
4
-alkyl or C
1
-C
4
-alkylcarbonyl,
which comprises
a) reacting a bicyclic olefin of the formula II with haloform in the presence of a base to give the ring-expanded product of the formula III
 where
R
1
-R
4
and Z are as defined above and
X is halogen;
b) hydrolyzing the allylic halogen of the compound of the formula III to the allyl alcohol of the formula IV
c) oxidizing the allyl alcohol of the formula IV to the unsaturated ketone of the formula V
d) reacting the ketone of the formula V with a nucleophilic ion Y
−
which stabilizes a negative charge to give the ketone of the formula VI
e) hydrolyzing the ketone of the formula VI to the bicyclic 1,3-diketone of the formula I.
Furthermore, it has been found that, bypassing the hydrolysis step b), the allylic halogen of the compound of the formula III can be oxidized to the unsaturated ketone of the formula V.
Moreover, it has been found that the reaction of the ketone of the formula V with a nucleophilic ion Y
−
, which stabilizes a negative charge, to give the ketone of the formula VI can, without intermediate isolation, be hydrolyzed directly to give the bicyclic 1,3-diketone of the formula I.
Furthermore, we have found intermediates of the formula VI
where
R
1
, R
2
, R
3
and R
4
are hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy-carbonyl, halogen, cyano, nitro, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylsulfenyl or C
1
-C
4
-alkylsulfonyl and
Z is C
1
-C
4
-alkylene, O, S, N—R
5
where
R
5
is C
1
-C
4
-alkyl or C
1
-C
4
-alkylcarbonyl,
Y is cyano, sulfonate, C
1
-C
6
-alkylsulfonyl or unsubstituted or C
1
-C
3
-alkyl-, C
1
-C
3
-alkoxy-, C
1
-C
3
-alkylthio-, C
1
-C
3
-alkylsulfonyl-, halogen-, cyano-, nitro- or sulfonate-substituted phenylsulfonyl.
Bicyclic 1,3-diketones of the formula I can be present as keto-enol tautomers Ia and Ib. This present invention also relates to a process for preparing tautomers of the formulae Ia and Ib.
The process according to the invention for preparing compounds I comprises substantially one or more of the process steps a)-e). Also possible are such reaction sequences in which one or more of the process steps a)-e) are combined in one step (one-pot synthesis).
A possible reaction sequence leading to the preparation of the compounds I is compiled in the overview scheme below:
For the sake of clarity, only the synthesis of one enantiomer is described in each case. The process according to the invention also embraces the synthesis of the other enantiomer in each case.
The individual reaction steps are illustrated in more detail below:
Step a):
The reaction is carried out, for example, under the following conditions:
This step proceeds via a dihalocarbene, preferably dichlorocarbene, which is generated from haloform and a base.
Haloform, preferably chloroform, is used in the presence of a base, for example an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alkoxide or an alkali metal amide, preferably NaOH, KOH, sodium methoxide, and, if appropriate, a phase-transfer catalyst, for example tetrabutylammonium chloride, trimethylbenzylammonium chloride or Aliquat 336, in the absence of a solvent or in an inert hydrocarbon or halogenated hydrocarbon, for example hexane, heptane, petroleum ether, dichloromethane, carbon tetrachloride, dichloroethane or chlorobenzene, and, if appropriate, water.
The stoichiometric ratios are, for example, as follows: 1-4 equivalents of haloform, if appropriate 0.0001-0.10 equivalent of phase-transfer catalyst and 1-4 equivalents of base are used per equivalent of the compound II.
The addition is carried out, for example, in the following order: in the inert solvent, compound II and haloform are, if appropriate, admixed with phase-transfer catalyst and, at 0° C.-100° C., preferably 30-60° C., admixed with the base. Work-up is carried out, for example, by stirring the product mixture into water, followed by extraction and, if appropriate, distillation of the resulting residue under reduced pressure. Work-up can also be carried out without purification by distilling off the solvent and using the crude product directly for step b).
The preparation of exo-3,4-dichlorobicyclo[3.2.1]oct-2-ene has already been described in the literature. However, either the yields are unsatisfactory (J. Am. Chem. Soc. 1954, 6162; J. Org. Chem. 28 (1963), 2210; Recl. Trav. Chim. Pays-Bas 80, (1961) 740) or highly toxic phenyltrichloromethylmercury is used (Helv. Chim. Acta 55 (1972), 790; Org. Synth., Coll. Vol V, 1973, 969). The generation of carbene from ethyl trichloroacetate and base (Org. Synth. Coll. Vol. VI, 1988, 142) is highly exothermic: when this synthesis procedure was repeated, there was product outflow from the apparatus. carbene addition under phase-transfer catalysis is likewise already known in the literature (Houben/Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Vol. E19/b, 1989, 1527, Thieme Verlag, Stuttgart; Synthesis 9 (1972), 485). However, there is still scope for improvement with respect to yield and reaction time. When these procedures were checked, the yields obtained for larger batches were considerably lower. It has been observed that dichlorocarbene reacts with water to give carbon monoxide which, on an industrial scale, represents a potential danger.
Step b):
The hydrolysis is carried out, for example, under the following conditions: suitable solvents are water, with or without addition of a phase-transfer catalyst, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide. The hydrolysis is carried out, for example, using alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or alkaline earth metal hydroxides, for example magnesium hydroxide or calcium hydroxide; preference is given to NaOH and KOH.
The reaction is carried out at from 0° C. to the boiling point of the solvent, preferably at from room temperature to the reflux temperature of the solvent in question. The stoichiometric ratios are as follows: 1-5 equivalents of base, preferably 1-1.5 equivalents of base, are used per equivalent

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