PROCESS FOR THE PRODUCTION OF 2-(SUBSTITUTED BENZOYL)1,3 CYCLOHEXANEDIONES

PROCEDE DE FABRICATION DE 2-(BENZOYL SUBSTITUE)-1,3 CYCLOHEXANEDIONES

English Abstract

A process for preparing a compound of formula
(I), where R1, R2, R3 R4, R5 and R6 are independently
hydrogen or C1-6 alkyl; R7 is halogen, cyano, NO2, C1-4
alkyl, C1-4 haloalkyl, C1-4 alkoxy or RaS in which Ra is
C1-4 alkyl; R8, R9 and R10 independently are hydrogen,
halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4
haloalkoxy, CN, NO2, phenoxy or substituted phenoxy;
R b S(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb
is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCOR c
in which Rc is C1-4 alkyl, NRdRe in which Rd and Re
indenpendently are hydrogen or C1-4 alkyl; RfC(O)- in
which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4
alkoxy; SO2NRgRh in which Rg and Rh independently
are hydrogen or C1-4 alkyl; or any two of R8, R9 and R10
together with the carbon atoms to which they are attached
form a 5 or 6 membered heterocyclic ring containing up to
three heteroatoms selected from O, N or S and which may
be optionally substituted by =NOC1-4 alkyl, C1-4 alkyl,
C1-4 haloalkyl, C1-4 alkoxy or halogen; which process
comprises the rearrangement of a compound of formula
(II) where R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10
are as defined in relation to formula (I), in a non-polar
solvent in the presence of a cyanide source, an alkali or
alkaline earth metal carbonate, a phase transfer catalyst
and 1-6 moles of water with respect to the compound of
formula (II).

French Abstract

La présente invention concerne la préparation d'un composé représenté par la formule (I) dans laquelle R<1>, R<2>, R<3>, R<4>, R<5> et R<6> sont indépendamment l'hydrogène ou un C1-6alkyle, R<7> est un halogène, cyano, NO2, C1-4alkyle, C1-4haloalkyle, C1-4alkoxy ou RaS où Ra est C1-4alkyle, R<8>, R<9> et R<10> sont indépendamment hydrogène, halogène, C1-4alkyle, C1-4alkoxy, C1-4haloalkyle, C1-4haloalkoxy, CN, NO2, phénoxy ou un phénoxy substitué, RbS(O)n Om où m est égal à 0 ou 1, n est égal à 0, 1 ou 2 et Rb est C1-4alkyle, C1-4haloalkyle, phényle ou benzyle, NHCOR<c> où Rc est C1-4alkyle, NRdRe où Rd et Re sont indépendamment hydrogène ou C1-4alkyle, RfC(O)- où Rf est hydrogène, C1-4alkyle, C1-4haloalkyle ou C1-4alkoxy, SO2NRgRh où Rg et Rh sont indépendamment hydrogène ou C1-4alkyle, ou toute paire d'éléments choisis parmi R<8>, R<9> et R<10>, associée aux atomes de carbone auxquels ils sont fixés, qui forme un cycle hétérocyclique à 5 ou 6 éléments contenant jusqu'à trois hétéroatomes choisis parmi O, N ou S et qui peut être éventuellement substitué par =NOC1-4alkyle, C1-4alkyle, C1-4haloalkyle, C1-4alkoxy, ou un halogène. Ledit procédé comprend également la réorganisation d'un composé représenté par la formule (II) dans laquelle R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9> et R<10> sont tels qu'ils ont été définis pour le composé représenté par la formule (I), cette réorganisation du composé représenté par la formule (II) ayant lieu dans un solvant non polaire en présence d'une source de cyanure, d'un carbonate d'alcali ou de métal alcalino-terreux, d'un catalyseur de transfert de phase et de 1 à 6 moles d'eau.

Claims

-7-
CLAIMS
1. A process for preparing a compound of formula (I):
<IMG>
where R1, R2, R3, R4, R5 and R6 are independently hydrogen or C1-6
alkyl; R7 is halogen, cyano, NO2, C1-4 alkyl, C1-4 haloalkyl, C1-4
alkoxy or RaS in which Ra is C1-4 alkyl; R8, R9 and R10 independently
are hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4
haloalkoxy, CN, NO2, phenoxy or substituted phenoxy; R b S(O)n Om in
which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-4 alkyl, C1-4
haloalkyl, phenyl or benzyl, NHCOR c in which Rc is C1-4 alkyl, NRdRe
in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(O)-
in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
SO2NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl;
or any two of R8, R9 and R10 together with the carbon atoms to which
they are attached form a 5 or 6 membered heterocyclic ring containing
up to three heteroatoms selected from O, N or S and which may be
optionally substituted by =NOC1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl,
C1-4 alkoxy or halogen; which process comprises the rearrangement of a
compound of formula (II) where R1, R2, R3, R4, R5, R6, R7, R8, R9 and
R10 are as defined in relation to formula (I), in a non-polar solvent
in the presence of a cyanide source, an alkali or alkaline earth metal
carbonate, a phase transfer catalyst and 1-6 moles of water with
respect to the compound of formula (II):

-8-
<IMG>
2. A process according to claim 1 where R1, R2, R3, R4, R5 and R6 are
independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, NO2, C
alkyl, C1-4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl;
R8, R9 and R10 independently are hydrogen, halogen, C1-4 alkyl, C1-4
alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, phenoxy or
substituted phenoxy; R b S(O)n Om in which m is 0 or 1, n is 0, 1 or 2
and Rb is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCOR c in
which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are
hydrogen or C1-4 alkyl; RfC(O)- in which Rf is hydrogen, C1-4 alkyl,
C1-4 haloalkyl or C1-4 alkoxy; or SO2NRgRh in which Rg and Rh
independently are hydrogen or C1-4 alkyl.
3. A process according to claim 1 or claim 2 where R1, R2, R5 and R6 are
hydrogen and R3 and R4 are independently hydrogen or methyl.
4. A process according to any one of the preceding claims where R7 is
halogen or NO2.
5. A process according to any one of the preceding claims where R8 is
hydrogen.
6. A process according to any one of the preceding claims where R9 is
hydrogen or C1-4 alkoxy.

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7. A process according to any one of the preceding claims where R10 is a
group CH3SO2 attached to the benzoyl group at the 4- position.
8. A process according to any one of the preceding claims where the
cyanide source is an alkali metal cyanide.
9. A process according to any one of the preceding claims where the
solvent is toluene.
10. A process according to any one of the preceding claims where the phase
transfer catalyst is tetrabutyl ammonium bromide.

Description

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PROCESS FOR THE PRODUCTION OF 2-(SUBSTITUTED BENZOYL)1,3 CYCLOHEXANEDIONES
The present invention relates to the production of 2-(substituted
a
benzoyl)-1,3-cyclohexanedione compounds.
2-(substituted benzoyl)-1,3-cyclohexanediones are known as herbicides
from for example US Patent No. 4,780,127, US Patent No. 4,806,146,
US Patent No. 4,946,981, US Patent No. 5,006,158, WO 9408988 and
VJO 9404524. One method of producing these compounds is by re-arrangement
of an enol ester. This method is described in US Patent No. 4,780,127 and
US Patent No. 4,695,673.
This process provides a means to obtain the desired compounds but
generally employs organic bases such as triethylamine or employs polar
aprotic solvents when alkali metal carbonates are used as base. The use of
organic 'eases and polar aprotic solvents present problems on an industrial
scale due to the need to recover these materials efficiently. It has
surprisingly been found that non-polar solvents in combination with
inorganic bases can be employed if a critical amount of water is added to
the reaction medium.
According to the present invention there is provided a process for
preparing a compound of formula (I) where R1, R2, R3, R4, R5 and R6 are
independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, N02,
C~-4 91ky1, ia-4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl;
R , R and R independently are hydrogen, halogen, C1-4 alkyl, C1-4
alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, N02, phenoxy or substituted
phenoxy; RbS(0)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1_4
alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl,
NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(0)-
in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
S02NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl; or
any two of R8, R9 and R10 together with the carbon atoms to which they are
attached form a 5 or 6 membered heterocyclic ring containing up to three
heteroatoms selected from 0, N or S and which may be optionally substituted
by C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =NOC1-4 alkyl or halogen; which
process comprises the rearrangement of a compound of formula (II) where R1,
R2, R3, R4, R5, R6, R7, Ra, R9 and R10 are as defined in relation to
formula (I), in a non-polar solvent in the presence of a cyanide source, an

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alkali or alkaline earth metal carbonate, a phase transfer catalyst and 1-6
moles of water with respect to the compound of formula (II).
As used herein the term "alkyl", refers to straight or branched
chains. The term "haloalkyl" refers to an alkyl group substituted by at
least one halogen. Similarly the term "haloalkoxy" refers to an alkoxy
group substituted by at least one halogen. As used herein the term
"halogen" refers to fluorine, chlorine, bromine and iodine.
Suitable optional substituents for phenoxy groups R8, R9 and RIO
include halogen such as fluorine and chlorine and C1_4 haloalkyl.
A preferred group of compounds of formula (I) are those where RI, R2,
R3, R4, R5 and R6 are independently hydrogen or C1_6 alkyl; R~ is halogen,
cyano, N02, C -4 alkyl, C -4 haloalkyl, CI-4 alkoxy or RaS in which Ra is
CI-4 alkyl; R~, R9 and Rlb independently are hydrogen, halogen, CI_4 alkyl,
Cl-4 alkoxy, CI_4 haloalkyl, CI_4 haloalkoxy, CN, N02, phenoxy or
substituted phenoxy; RbS(0)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb
is CI-4 alkyl, CI-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is CI-4
alkyl, NRdRe in which Rd and Re independently are hydrogen or CI-4 alkyl;
RfC(0)- in which Rf is hydrogen, CI-4 alkyl, CI-4 haloalkyl or C1-4 alkoxy;
or S02NRgRh in which Rg and Rh independently are hydrogen or CI_4 alkyl.
Preferably RI, R2, R3, R4, R5 and R6 are independently hydrogen or
C1_4 alkyl. More preferably R1, R2, R5 and R6 are hydrogen and R3 and R4
are independently hydrogen or methyl.
R~ is preferably halogen or N02. A preferred value for R8 is
hydrogen.
R9 is preferably hydrogen or CI-4 alkoxy, especially ethoxy. Most
preferably Rg is hydrogen.
Preferably R10 is a group RbS(0)nOm where Rb, n and m are as defined
above. More preferably m is zero, n is 2 and Rb is CH3 or C2H5. Most
preferably RIO is a group CH3S02 attached to the benzoyl group at the 4-
position.
The term "cyanide source" refers to a substance or substances which
under the rearrangement conditions consists of or generates hydrogen
cyanide and/or cyanide anion. '
Preferred cyanide sources are alkali metal cyanides such as sodium and
potassium cyanide; cyanohydrins of methyl alkyl ketones having from 1-4
carbon atoms in the alkyl groups, such as acetone or methyl isobutyl ketone

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cyanohydrins; benzaldehyde cyanohydrin; cyanohydrins of C2-C5 aliphatic
aldehydes such as acetaldehyde cyanohydrin, propionaldehyde cyanohydrin,
etc; cyclohexaneone cyanohydrin; triethylamine-HCN complex; tetrabutyl
ammonium bromide/CN mixtures; lactonitrile; lower alkyl silyl cyanides,
notably di- and tri-(lower alkyl)silyl cyanides such as dimethyl and
trimethyl-silyl cyanides; potassium ferricyanide; and hydrogen cyanide
itself. More preferably the cyanide source is an alkali metal cyanide most
preferably sodium cyanide. The cyanide source is used in an amount up to
about 50 mole percent based on the enolester. It may be used in as little
as about 1 mole percent to produce an acceptable rate of reaction at about
40°C, on a small scale. Larger scale reactions give more reproducible
results with slightly higher catalyst levels of about 5 mole percent.
Generally about 1-10 mole % of the cyanide source is preferred.
The process is conducted with a molar excess, with respect to the enol
ester compound of formula (II), of an alkali or alkaline earth metal
carbonate, preferably sodium carbonate. ,
The alkali or alkaline earth metal carbonate is used in an amount of
from about 1 to about 4 moles per mole of enol ester, preferably about 2
moles per mole.
A number of different solvents may be usable in this process,
depending on the nature of the reactants. A preferred solvent for this
reaction is toluene. Other solvents which may be employed, depending on
the reactants or products include alkyl aromatics such as xylene, cumene,
and cymene or alkanes such as hexane or cycloaikanes such as cyclohexane.
The selection of a suitable phase transfer catalyst can be determined
by routine procedures well known to the skilled chemist. Known phase
transfer catalysts include tetralkyl ammonium halides and phosphonium
salts. Preferred catalysts are tetralkyl ammonium halides, especially
tetrabutyl ammonium bromide. The phase transfer catalyst is generally used
at 1-10 mol%.
t~later is preferably used at 2-6, especially 4, moles per mole of enol
ester.
In general, depending on the nature of the reactants and the cyanide
source, the rearrangements may be conducted at temperatures from 0°C,
up to
about 100°C. Preferably the temperature is at a maximum of about
80°C.
Most preferably the temperature is from about 20°C, to about
70°C. In some

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cases, for instance when there is a possible problem of excessive
by-product formation (for instance, when using an orthonitro benzoyl
halide) the temperature should be kept at about 40°C maximum.
The process may be carried out using the enol ester as the starting
material, or with generation of the enol ester in situ, for instance by
reaction of a compound of formula (III) where RI, R2, R3, R4, R5 and R6 are
as defined in relation to formula (I) with a compound of formula (IV) where
R~, R8, R9 and RIB are as defined in relation to formula (I) and Z is a
halo, preferably chioro.
Nlhen the enol ester is utilised as a starting material it may be
prepared by any of a number of known means, including acylation of a
compound of formula (III) with, a compound of formula (IV).
The production of compounds of formula (I) according to this
invention, may be advantageously carried out starting with compounds of
formula (III) and formula (IV) and may be carried out with or without
isolation of the intermediate enol ester (II). When carried out in two
steps, the compound of formula (III) and the compound of formula (IV) are
reacted in the presence of a alkali or alkali earth metal carbonate.
The enol ester isolated from the resulting product mix by known
techniques, for instance washing the resultant solution with acid and base,
and with saturated sodium chloride solution, and drying. Such a technique
is advantageous when a different solvent is preferred for the second step -
the rearrangement of the enol ester to the compound of formula (I). The
dried enol ester may be mixed with an appropriate solvent such as
acetonitrile, 1,2-dichloroethane, or toluene and contacted with the
appropriate amounts of cyanide source, phase before catalyst, sodium
carbonate and water, and heated to an temperature, to produce the final
product.
In a preferred alternative the enol ester may be retained in the
reaction product and the second stage may be carried out (using the same
solvent) by adding a cyanide source, water and additional base if necessary
to produce the compound of formula (I).
Comparable yields can be obtained either with or without isolation of
the enol ester.

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The compound of formula (I) is obtained~from this reaction in the form
of its salt. The desired acylated compound of formula (I) may be obtained
with acidification and extraction with an appropriate solvent.
The process of the invention is illustrated by the following example.
EXAMPLE_ 1
J
Toluene (22g) was charged to a 4 necked 250m1 flamed dried round
bottomed flask previously purged with N2 and sealed to a Drierite guard
tube and oil bubbler. 1,3 Cyclohexanedione (5.0g) and sodium carbonate
powder (12.0g) were charged to give a red slurry. This mass was heated to
55-57°C and held for 20 minutes. 2-chloro-4-(methylsuiphonyl) benzoyl
chloride (ll.Og) was added to toluene (25g) and heated to obtain a complete
solution. This solution was added to the mass dropwise, via a heated
dropping funnel, over 20 minutes at 55-57°C to give a pale yellow
slurry.
This mass was held at 55-57°C for 2 hours. Sodium cyanide (0.103g),
tetra
n-butylammonium in bromide (0.13g) and water (2.9g) were added and the
reaction held on temperature for a further three hours. A solid formed on
the base of the flask which could not be agitated so the reaction mass was
screened and the paste and liquors analysed. The required compound of
formula (I) as the sodium salt was produced in 81.6% yield.
The above procedure was repeated but omitting the water and none of
the required product was obtained.
The procedure of Example 1 was repeated a second time using 8 moles of
water with respect to the enol ester and the yield of the required product
was less than 1%.

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CHEMICAL FORMULAE
(IN DESCRiPTiCN)
R2 ~ Rio
R, O 2°
(I) ,
R' Re
R O
R' R~ O
R3
Rio
Ra ~ °
Rs \R° O- (II)
R8
' Z
R R O
'
R
(III)
a
R
s
R
R O
Rio
R°
v
CI~
O w Ra
R;

Representative Drawing