CA1339277C - Process for the aromatic ring acylation of 2-acyl-5-aryl-(heteroaryl)-3-hydroxycyclohex-2-en-1-ones - Google Patents
Process for the aromatic ring acylation of 2-acyl-5-aryl-(heteroaryl)-3-hydroxycyclohex-2-en-1-onesInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
- C07C49/543—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings to a six-membered ring
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Abstract
"Process for the Aromatic Ring Acylation of 2-acyl-5-aryl-(heteroaryl)-3-hydroxycyclohex-2-en-1-ones"
The invention concerns a process for the preparation of a compound of formula I
wherein:
the group represents an aryl group or a heteroaryl group optionally substituted with one or more electron donating groups;
R1 is selected from alkyl, fluoroalkyl, alkenyl, alkynyl and phenyl;
R2 is selected from hydrogen, halogen, alkyl, cyano and alkoxycarbonyl; and R3 is selected from alkyl, alkenyl, alkynyl, phenyl, substituted alkyl, substituted alkenyl, substituted alkynyl and substituted phenyl;
which process comprises:
reacting a compound of formula II
with an acid anhydride of formula III, an acid halide of formula IV or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula II, of anhydrous aluminium chloride.
The compounds of formula I are useful intermediates for the preparation of biologically active compounds.
The invention concerns a process for the preparation of a compound of formula I
wherein:
the group represents an aryl group or a heteroaryl group optionally substituted with one or more electron donating groups;
R1 is selected from alkyl, fluoroalkyl, alkenyl, alkynyl and phenyl;
R2 is selected from hydrogen, halogen, alkyl, cyano and alkoxycarbonyl; and R3 is selected from alkyl, alkenyl, alkynyl, phenyl, substituted alkyl, substituted alkenyl, substituted alkynyl and substituted phenyl;
which process comprises:
reacting a compound of formula II
with an acid anhydride of formula III, an acid halide of formula IV or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula II, of anhydrous aluminium chloride.
The compounds of formula I are useful intermediates for the preparation of biologically active compounds.
Description
- 13~9277 "Process for the Aromatic Ring Acylation of 2-acyl-5-aryl-(heteroaryl)-3-hydroxycyclohex-2-en-1-ones"
This invention relates to a process for the synthesis of organic compounds which are useful inter-mediates for the preparation of organic compounds havingbiological activity.
It has been found that certain cyclohexan-1,3-dione derivatives which have a 5-aryl or 5-heteroaryl substituent which is in turn substituted by at least one acyl group exhibit useful herbicidal activity. One of the intermediates useful for the preparation of these cyclohexan-1,3-dione derivatives are 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted hetero-aryl)-3-hydroxycyclohex-2-en-1-ones of formula I
R3Co OH
1 5 3~
n R2 0 R 3co in which the group ~ represents an acyl (X)n . . .
substituted aryl group or an acyl substituted heteroaryl group.
Prior to the present invention compounds of formula I have generally been made by:
5 (i) preparing an acyl substituted aromatic or hetero-aromatic compound by acylating the appropriate aromatic or heteroaromatic compound;
(ii) preparing an acyl substituted aromatic or heteroaromatic aldehyde by formylating the acyl substituted aromatic or heteroaromatic compound;
(iii) preparing a 5-(acyl substituted aryl)- or 5-(acyl substituted heteroaryl)-cyclohexan-1,3-dione by condensation and cyclization reactions on the aldehyde derivative; and ~5 (iv) preparing a 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted heteroaryl)-3-hydroxycyclohex-2-en-1-one by acylation of the 5-substituted cyclohexan-1,3-dione derivative.
The above process suffers from the disadvantage that once an acyl group is introduced into the aromatic or heteroaromatic ring (step (i)), formylation of the ring to give an aromatic or heteroaromatic aldehyde is difficult because the electro~withdrawing acyl group deactivates the ring towards further electrophilic aromatic substitution. Moreover, it has been found that the 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted heteroaryl)-3-hydroxycyclohex-2-en-1-one derivatives of formula I cannot be satisfactorily prepared from the corresponding 2-acyl-5-aryl- or 2-acyl-5-heteroaryl-3-hydroxycyclohex-2-en-1-ones using con-ventional acylation techni~ues unless the acyl group is the same on both ring systems. Attempts to carry out this acylation using conventional acylation techniques result in partial replacement of the 2-acyl substituent which leads to a mixture of compounds.
It has now been found that 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted hetero-aryl)-3-hydroxycyclohex-2-en-1-one derivatives of formula I can be prepared from the corresponding 2-acyl-5-aryl- or 2-acyl-5-heteroaryl-3-hydroxycyclohex-2-en-1-ones provided at least three molar equivalents of anhydrous aluminium chloride is used as the Lewis acid catalyst.
Accordingly the invention provides a process for the preparation of a compound of formula I
R CO OH
C~ I
~2 O
wherein:
the group ~ represents an aryl group or a heteroaryl group optionally substituted with one or more electron donating groups;
R3 is selected from the group consisting of: Cl to C6 alkyl; Cl to C6 alkoxy; Cl to C6 alkylthio; C2 to C6 alkenyl; C2 to C6 alkynyl; phenyl; and the groups Cl to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl and phenyl wherein each group is substituted with at least one substituent selected from the group consisting of halogen, hydroxy~ nitro, cyano, phenyl, Cl to C6 alkyl, Cl to C6 alkoxy, Cl to C6 alkylthio, (Cl to C6 alkoxy)-carbonyl,amino, N-(Cl to C6 alkyl)amino and N,N-di(Cl to C6 alkyl)amino;
R is selected from the group consisting of: Cl to C6 alkyl; Cl to C6 fluoroalkyl; C2 to C6 alkenyl; C2 to C6 alkynyl; and phenyl; and R2 is selected from the group consisting of: hydrogen;
halogen; cyano; Cl to C6 alkyl; and (Cl to C6 alkoxy)-carbonyl;
which process comprises reacting a compound of formula II
O ~ \ Rl II
with an acid anhydride of formula III, an acid halide of formula IV or a mixture thereof (R C02)0 R CO halide III IV
in the presence of at least three mole equivalents, based on the compound of formula II, of anhydrous aluminium chloride.
Suitable optionally substituted aryl and optionally substituted heteroaryl groups of formula ~ 5 ~ 1339277 ~ include:
phenyl groups of formula V
~ V
(X) 1 wherein:
X, which may be the same or different, are independently selected from the group consisting of: halogen; Cl to C6 alkyl; Cl to C6 alkyl substituted with a substituent selected from the group consisting of halogen, hydroxy, Cl to C6 alkoxy and Cl to C6 alkylthio; C2 to C6 alkenyl;
C2 to C6 alkynyl; hydroxy; Cl to C6 alkoxy; Cl to C6 alkoxy substituted with a substituent selected from halogen and Cl to C6 alkoxy; C2 to C6 alkenyloxy; C2 to C6 alkynyloxy; C~ to C6 alkylthio; and the group NR4R5 wherein R and R are independently selected from the group consisting of hydrogen, Cl to C6 alkyl, C2 to C6 alkanoyl, benzoyl and benzyl; and 1 is zero or an integer selected from 1 to 4;
benzocycloalkyl groups of formula VI
(W) m ~,~ ( CH 2 ) ~.~
(CH2) ~ VI
(X) p wherein:
W, which may be the same or different, are selected from the group consisting of Cl to C6 alkyl, C2 to C6 alkenyl and C2 to C6 alkynyl;
X is as hereinbefore defined;
m is zero or an integer selected from 1 to 4;
n is zero or an integer selected from 1 to 3; and p is zero or an integer selected from 1 and 2;
indenyl andbenzoheterocyclopentenyl groups of formula VII
(X) ~ ~ VII
(X)m wherein:
A is selected from CH and N; and B is selected frcm oxygen, sulfur, CH2 and the group ~-V wherein V is selected from the group consisting of hydrogen, Cl to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C7 cycloalkyl, benzyl and substituted benzyl wherein the benzene ring is substituted with from one to three substituents selected from the group consisting of halogen, nitro, Cl to C6 alkyl, Cl to C6 alkoxy and Cl to C6 haloalkyl; and , X and m are as hereinbefore defined; and q is zero or an integer sele~ted from 1 to 3, benzoazinyl groups of the formula VIII
VIII
~X)q 5 wherein:
D, E, G and J are independently selected from CH, N and N-Z wherein Z is selected from oxygen and the group -~An wherein Y is selected from Cl to C6 alkyl and benzyl and An is an anion selected from halide, tetra-10 fluoroborate, methosulfate and fluorosulfate, andprovided that at least one but no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G and J is selected from N-Z; and X and q are as hereinbefore defined;
15 naphthyl and cycloalkyl-, cycloalkenyl- and benzo-substituted azinyl groups of the formula IX
(X) q ~ D ~ IX
(X)m wherein:
D, E, G and J are independently selected from CH, N
and N-Z wherein Z is selected from oxygen and the group -YAn wherein Y is selected from Cl to C6 alkyl and benzyl and An is an anion selected from halide, tetra-fluoroborate, methosulfate and fluorosulfate, and provided that no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G and J is selected from N-Z;
Q is a saturated or unsaturated hydrocarbon chain containing from two to five carbon atoms; and X, m and q are as hereinbefore defined; and furyl and thienyl groups of formula X
(X)p ~ X
wherein;
L is selected from oxygen and sulfur; and 15 X and p are as hereinbefore defined.
The process of the present invention may be used to great advantage in the acylation of 2-acyl-3-hydroxy-5-phenylcyclohex-2-en-1-one derivatives of formula XI
(X) ~ ~5 r X~
to give 2-acyl-5-~acyl substituted phenyl)-3-hydroxy-cyclohex-2-en-1-one derivatives of formula XII
~ S \ Rl XII
and in the acylation of 2-acyl-5-naphthyl-3-hydroxy-cyclohex-2-en-1-one derivatives of formula XIII
(X) OH
~X~m~ ~ ~ ~
to give 2-acyl-5-(acyl substituted naphthyl)-3-hydroxy-cyclohex-2-en-1-one derivatives of formula XIV
R3Co q o m ~ = \
In the compound of formula I:
preferred values for Rl include: methyl; ethyl; and n-propyl;
preferred values for R2 include: hydrogen; and preferred values for R3 include: Cl to C6 alkyl;
C2 to C6 alkenyl; and phenyl.
In the groups of formulae V, VI, VII, VIII, IX, and X:
preferred values for X include: Cl to C6 alkyl; halogen;
Cl to C6 alkoxy; and Cl to C6 alkylthio;
preferred values for W include: methyl;
preferred values for A include: CH;
preferred values for B include: oxygen, sulfur and 15 N-(Cl to C6 alkyl);
preferred values for D, E, G and J include: CH and N;
preferred values for Q include: -(CH2)4-; and -~CH=CH ~;
preferred values for L include: oxygen and sulfur;
preferred values for 1 include: 2, 3 and 4;
preferred values for m include: zero, 1 and 2;
preferred values for n include: 1 and 2;
preferred values for p include: 1 and 2; and preferred values for q include: 1, 2 and 3.
The process of the present invention may be carried out under a wide range of operating conditions.
Preferably the reaction is carried out in the presence of a non-protic organic solvent. Suitable organic solvents include, for example, hydrocarbons, halocarbons and particularly chlorocarbons, halo-hydrocarbons and particularly chlorohydrocarbons, and aromatic solvents in which the aromatic ring is de-activated towards electrophilic aromatic substitution.
Specific examples of suitable solvents include cyclo-hexane, carbon tetrachloride, dichloromethane, dichloro-ethane, chlorobenzene, and nitrobenzene.
The specific reaction conditions required to effect the process of the present invention are not narrowly critical and depend to a large extent on the specific reactants and the solvent. ~owever, in general the reaction is carried out at a temperature in the range of from -20~C to 100~C and preferably from 0~C to 50~C.
If prior art acylation techniques are used to introduce an acyl group into the aromatic ring of a 2-acyl-5-aryl- or 2-acyl-5-heteroary1-3-hydroxycyclohex-2-en-1-one the resulting product comprises a mixture of compounds. For example, if 3-hydroxy-5-(2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one is acylated using a mole equivalent or a slight mole excess of acetyl chloride and a slight mole excess or even a 100% mole excess of a Lewis acid catalyst such 13~3277 as anhydrous aluminium chloride, the product comprises a mixture of compounds including a significant proportion of 2-acetyl-5-(3-acetyl-2,4,6-trimethyl-phenyl)-3-hydroxycyclohex-2-en-1-one as well as the de-sired 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one. Moreover, if, for example, 3-hydroxy-5-(2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one is acylated using a mole equivalent or a slight mole excess ofacetylchloride and a large mole excess (three fold or greater) of a Lewis acid catalyst other than aluminium chloride (eg ZnC12, SnC12 etc), the product still comprises a mixture of compounds including a significant proportion of 2-acetyl-5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-cyclohex-2-en-1-one, as well as the desired 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one.
Surprisingly, it has been found that using the process of the present invention the problem of acyl group exchange at the 2-position of the cyclohexan-1,3-dione ring can be alleviated or overcome. It is not fully understood why the process of the present in-vention alleviates or overc ~es the problem of acyl group exchange at the 2-position of the cyclohexan-1,3-dione ring. However, it is completely unexpected that the problem can be overcome provided that three or more mole equivalents of Lewis acid are used as acylation catalyst, and provided that the Lewis acid catalyst used is aluminium chloride.
~ 13 - 1339277 The invention is now illustrated by, but in no way limited to, the following Examples.
Example 1 Process for the Preparation of 5-(3-Acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (1) To a suspension of aluminium chloride (21.0 g, 0.158 mole) in dichloroethane (100 ml) at 0~C was added 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (14.3 g, 0.050 mole) in dichloroethane (70 ml). The mixture was stirred at 0~C for 30 minutes and then acetyl chloride (4.32 g, 0.055 mole) in dichloroethane (50 ml) was slowly added. Stirring was continued at 0~C for 30 minutes and then the mixture was allowed to come to room temperature. After 1.5 hours at this temperature the brownish solution was poured into cold hydrochloric acid (5 N, 100 ml). The mixture was stirred for 30 minutes. The two phases were separated and the aqueous portion extracted with dichloromethane (2 x 100 ml).
The combined organic extracts were washed with water, then evaporated to dryness. The brown oily residue was dissolved in toluene and extracted with 5% aqueous sodium hydroxide. The aqueous phase was washed with toluene and then acidified with hydrochloric acid (5 N).
The solid was collected, washed with water and air dried to give 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (13.93 g, 85%) as a brownish glassy solid. Proton magnetic resonance spectrum (CDC13; ~ in ppm): 1.20 (3H,t); 2.20 (3H, s);
2.24 (3H,s); 2.38 (3H,s); 2.45 (3H,s); 2.45-3.40 (6H,m);
3.90 (lH,m); 6.84 (lH,s); 18.25 (lH,s).
Example 2 Process for the Preparation of 5-(3-crotonyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (2) To a suspension of aluminium trichloride (4.0 g, 0.03 mole) in dichloroethane (20 ml) at 0~C was added 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (2.9 g, 0.01 mole) in dichloroethane (10 ml). The mixture was stirred at 0~C for five minutes and then crotonyl chloride (1.1 g, 0.01 mole) was added. Stirr-ing was continued at 0~C for 30 minutes and then at 20~C
for 3 hours. The brown solution was poured into cold dilute hydrochloric acid (2 M, 200 ml) and shaken occasional~y as it was allowed to warm to room tempera-ture. The organic phase was separated and the aqueous phase was shaken with chloroform (2 x 100 ml). The com-bined organic extracts were dried over magnesium sulphate and evaporated to give 5-(3-crotonyl-2,4,6-trimethyl-phenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (4.1 g, 83%) as a pale brown oil. Proton magnetic resonance spectrum (CDC13; ~ in ppm): 1.16 (3H,t); 1.93 (3H, d, J=7Hz); 2.07 (3H,s); 2.17 (3H,s); 2.38 (3H,s); 2.2-4.0 (7H,m); 6.1-6.8 (2H,m); 6.86 (lH,s); 18.20 (lH,s).
Example 3 The following (Tables la and lb) 2-acyl-5-(acyl substituted aryl)-3-hydroxycyclohex-2-en-1-ones were prepared from the appropriate 2-acyl-5-aryl-3-hydroxy-cyclohex-2-en-1-ones and the appropriate acid chloride following essentially the same procedure as that des-cribed in Example 1 or Example 2. The compounds were characterized by their proton nuclear magnetic resonance - 15 - 13~9277 spectra and spectroscopic data are recorded in Table 2 below.
TABLE la R CO
tX ~ C \ ~l XII
Substituents Com-pOund No (X)l R3Co Rl R2 3 2,4,6-(CH3)3 3-C6H5CO C2H5 H
This invention relates to a process for the synthesis of organic compounds which are useful inter-mediates for the preparation of organic compounds havingbiological activity.
It has been found that certain cyclohexan-1,3-dione derivatives which have a 5-aryl or 5-heteroaryl substituent which is in turn substituted by at least one acyl group exhibit useful herbicidal activity. One of the intermediates useful for the preparation of these cyclohexan-1,3-dione derivatives are 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted hetero-aryl)-3-hydroxycyclohex-2-en-1-ones of formula I
R3Co OH
1 5 3~
n R2 0 R 3co in which the group ~ represents an acyl (X)n . . .
substituted aryl group or an acyl substituted heteroaryl group.
Prior to the present invention compounds of formula I have generally been made by:
5 (i) preparing an acyl substituted aromatic or hetero-aromatic compound by acylating the appropriate aromatic or heteroaromatic compound;
(ii) preparing an acyl substituted aromatic or heteroaromatic aldehyde by formylating the acyl substituted aromatic or heteroaromatic compound;
(iii) preparing a 5-(acyl substituted aryl)- or 5-(acyl substituted heteroaryl)-cyclohexan-1,3-dione by condensation and cyclization reactions on the aldehyde derivative; and ~5 (iv) preparing a 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted heteroaryl)-3-hydroxycyclohex-2-en-1-one by acylation of the 5-substituted cyclohexan-1,3-dione derivative.
The above process suffers from the disadvantage that once an acyl group is introduced into the aromatic or heteroaromatic ring (step (i)), formylation of the ring to give an aromatic or heteroaromatic aldehyde is difficult because the electro~withdrawing acyl group deactivates the ring towards further electrophilic aromatic substitution. Moreover, it has been found that the 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted heteroaryl)-3-hydroxycyclohex-2-en-1-one derivatives of formula I cannot be satisfactorily prepared from the corresponding 2-acyl-5-aryl- or 2-acyl-5-heteroaryl-3-hydroxycyclohex-2-en-1-ones using con-ventional acylation techni~ues unless the acyl group is the same on both ring systems. Attempts to carry out this acylation using conventional acylation techniques result in partial replacement of the 2-acyl substituent which leads to a mixture of compounds.
It has now been found that 2-acyl-5-(acyl substituted aryl)- or 2-acyl-5-(acyl substituted hetero-aryl)-3-hydroxycyclohex-2-en-1-one derivatives of formula I can be prepared from the corresponding 2-acyl-5-aryl- or 2-acyl-5-heteroaryl-3-hydroxycyclohex-2-en-1-ones provided at least three molar equivalents of anhydrous aluminium chloride is used as the Lewis acid catalyst.
Accordingly the invention provides a process for the preparation of a compound of formula I
R CO OH
C~ I
~2 O
wherein:
the group ~ represents an aryl group or a heteroaryl group optionally substituted with one or more electron donating groups;
R3 is selected from the group consisting of: Cl to C6 alkyl; Cl to C6 alkoxy; Cl to C6 alkylthio; C2 to C6 alkenyl; C2 to C6 alkynyl; phenyl; and the groups Cl to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl and phenyl wherein each group is substituted with at least one substituent selected from the group consisting of halogen, hydroxy~ nitro, cyano, phenyl, Cl to C6 alkyl, Cl to C6 alkoxy, Cl to C6 alkylthio, (Cl to C6 alkoxy)-carbonyl,amino, N-(Cl to C6 alkyl)amino and N,N-di(Cl to C6 alkyl)amino;
R is selected from the group consisting of: Cl to C6 alkyl; Cl to C6 fluoroalkyl; C2 to C6 alkenyl; C2 to C6 alkynyl; and phenyl; and R2 is selected from the group consisting of: hydrogen;
halogen; cyano; Cl to C6 alkyl; and (Cl to C6 alkoxy)-carbonyl;
which process comprises reacting a compound of formula II
O ~ \ Rl II
with an acid anhydride of formula III, an acid halide of formula IV or a mixture thereof (R C02)0 R CO halide III IV
in the presence of at least three mole equivalents, based on the compound of formula II, of anhydrous aluminium chloride.
Suitable optionally substituted aryl and optionally substituted heteroaryl groups of formula ~ 5 ~ 1339277 ~ include:
phenyl groups of formula V
~ V
(X) 1 wherein:
X, which may be the same or different, are independently selected from the group consisting of: halogen; Cl to C6 alkyl; Cl to C6 alkyl substituted with a substituent selected from the group consisting of halogen, hydroxy, Cl to C6 alkoxy and Cl to C6 alkylthio; C2 to C6 alkenyl;
C2 to C6 alkynyl; hydroxy; Cl to C6 alkoxy; Cl to C6 alkoxy substituted with a substituent selected from halogen and Cl to C6 alkoxy; C2 to C6 alkenyloxy; C2 to C6 alkynyloxy; C~ to C6 alkylthio; and the group NR4R5 wherein R and R are independently selected from the group consisting of hydrogen, Cl to C6 alkyl, C2 to C6 alkanoyl, benzoyl and benzyl; and 1 is zero or an integer selected from 1 to 4;
benzocycloalkyl groups of formula VI
(W) m ~,~ ( CH 2 ) ~.~
(CH2) ~ VI
(X) p wherein:
W, which may be the same or different, are selected from the group consisting of Cl to C6 alkyl, C2 to C6 alkenyl and C2 to C6 alkynyl;
X is as hereinbefore defined;
m is zero or an integer selected from 1 to 4;
n is zero or an integer selected from 1 to 3; and p is zero or an integer selected from 1 and 2;
indenyl andbenzoheterocyclopentenyl groups of formula VII
(X) ~ ~ VII
(X)m wherein:
A is selected from CH and N; and B is selected frcm oxygen, sulfur, CH2 and the group ~-V wherein V is selected from the group consisting of hydrogen, Cl to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C7 cycloalkyl, benzyl and substituted benzyl wherein the benzene ring is substituted with from one to three substituents selected from the group consisting of halogen, nitro, Cl to C6 alkyl, Cl to C6 alkoxy and Cl to C6 haloalkyl; and , X and m are as hereinbefore defined; and q is zero or an integer sele~ted from 1 to 3, benzoazinyl groups of the formula VIII
VIII
~X)q 5 wherein:
D, E, G and J are independently selected from CH, N and N-Z wherein Z is selected from oxygen and the group -~An wherein Y is selected from Cl to C6 alkyl and benzyl and An is an anion selected from halide, tetra-10 fluoroborate, methosulfate and fluorosulfate, andprovided that at least one but no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G and J is selected from N-Z; and X and q are as hereinbefore defined;
15 naphthyl and cycloalkyl-, cycloalkenyl- and benzo-substituted azinyl groups of the formula IX
(X) q ~ D ~ IX
(X)m wherein:
D, E, G and J are independently selected from CH, N
and N-Z wherein Z is selected from oxygen and the group -YAn wherein Y is selected from Cl to C6 alkyl and benzyl and An is an anion selected from halide, tetra-fluoroborate, methosulfate and fluorosulfate, and provided that no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G and J is selected from N-Z;
Q is a saturated or unsaturated hydrocarbon chain containing from two to five carbon atoms; and X, m and q are as hereinbefore defined; and furyl and thienyl groups of formula X
(X)p ~ X
wherein;
L is selected from oxygen and sulfur; and 15 X and p are as hereinbefore defined.
The process of the present invention may be used to great advantage in the acylation of 2-acyl-3-hydroxy-5-phenylcyclohex-2-en-1-one derivatives of formula XI
(X) ~ ~5 r X~
to give 2-acyl-5-~acyl substituted phenyl)-3-hydroxy-cyclohex-2-en-1-one derivatives of formula XII
~ S \ Rl XII
and in the acylation of 2-acyl-5-naphthyl-3-hydroxy-cyclohex-2-en-1-one derivatives of formula XIII
(X) OH
~X~m~ ~ ~ ~
to give 2-acyl-5-(acyl substituted naphthyl)-3-hydroxy-cyclohex-2-en-1-one derivatives of formula XIV
R3Co q o m ~ = \
In the compound of formula I:
preferred values for Rl include: methyl; ethyl; and n-propyl;
preferred values for R2 include: hydrogen; and preferred values for R3 include: Cl to C6 alkyl;
C2 to C6 alkenyl; and phenyl.
In the groups of formulae V, VI, VII, VIII, IX, and X:
preferred values for X include: Cl to C6 alkyl; halogen;
Cl to C6 alkoxy; and Cl to C6 alkylthio;
preferred values for W include: methyl;
preferred values for A include: CH;
preferred values for B include: oxygen, sulfur and 15 N-(Cl to C6 alkyl);
preferred values for D, E, G and J include: CH and N;
preferred values for Q include: -(CH2)4-; and -~CH=CH ~;
preferred values for L include: oxygen and sulfur;
preferred values for 1 include: 2, 3 and 4;
preferred values for m include: zero, 1 and 2;
preferred values for n include: 1 and 2;
preferred values for p include: 1 and 2; and preferred values for q include: 1, 2 and 3.
The process of the present invention may be carried out under a wide range of operating conditions.
Preferably the reaction is carried out in the presence of a non-protic organic solvent. Suitable organic solvents include, for example, hydrocarbons, halocarbons and particularly chlorocarbons, halo-hydrocarbons and particularly chlorohydrocarbons, and aromatic solvents in which the aromatic ring is de-activated towards electrophilic aromatic substitution.
Specific examples of suitable solvents include cyclo-hexane, carbon tetrachloride, dichloromethane, dichloro-ethane, chlorobenzene, and nitrobenzene.
The specific reaction conditions required to effect the process of the present invention are not narrowly critical and depend to a large extent on the specific reactants and the solvent. ~owever, in general the reaction is carried out at a temperature in the range of from -20~C to 100~C and preferably from 0~C to 50~C.
If prior art acylation techniques are used to introduce an acyl group into the aromatic ring of a 2-acyl-5-aryl- or 2-acyl-5-heteroary1-3-hydroxycyclohex-2-en-1-one the resulting product comprises a mixture of compounds. For example, if 3-hydroxy-5-(2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one is acylated using a mole equivalent or a slight mole excess of acetyl chloride and a slight mole excess or even a 100% mole excess of a Lewis acid catalyst such 13~3277 as anhydrous aluminium chloride, the product comprises a mixture of compounds including a significant proportion of 2-acetyl-5-(3-acetyl-2,4,6-trimethyl-phenyl)-3-hydroxycyclohex-2-en-1-one as well as the de-sired 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one. Moreover, if, for example, 3-hydroxy-5-(2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one is acylated using a mole equivalent or a slight mole excess ofacetylchloride and a large mole excess (three fold or greater) of a Lewis acid catalyst other than aluminium chloride (eg ZnC12, SnC12 etc), the product still comprises a mixture of compounds including a significant proportion of 2-acetyl-5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-cyclohex-2-en-1-one, as well as the desired 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one.
Surprisingly, it has been found that using the process of the present invention the problem of acyl group exchange at the 2-position of the cyclohexan-1,3-dione ring can be alleviated or overcome. It is not fully understood why the process of the present in-vention alleviates or overc ~es the problem of acyl group exchange at the 2-position of the cyclohexan-1,3-dione ring. However, it is completely unexpected that the problem can be overcome provided that three or more mole equivalents of Lewis acid are used as acylation catalyst, and provided that the Lewis acid catalyst used is aluminium chloride.
~ 13 - 1339277 The invention is now illustrated by, but in no way limited to, the following Examples.
Example 1 Process for the Preparation of 5-(3-Acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (1) To a suspension of aluminium chloride (21.0 g, 0.158 mole) in dichloroethane (100 ml) at 0~C was added 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (14.3 g, 0.050 mole) in dichloroethane (70 ml). The mixture was stirred at 0~C for 30 minutes and then acetyl chloride (4.32 g, 0.055 mole) in dichloroethane (50 ml) was slowly added. Stirring was continued at 0~C for 30 minutes and then the mixture was allowed to come to room temperature. After 1.5 hours at this temperature the brownish solution was poured into cold hydrochloric acid (5 N, 100 ml). The mixture was stirred for 30 minutes. The two phases were separated and the aqueous portion extracted with dichloromethane (2 x 100 ml).
The combined organic extracts were washed with water, then evaporated to dryness. The brown oily residue was dissolved in toluene and extracted with 5% aqueous sodium hydroxide. The aqueous phase was washed with toluene and then acidified with hydrochloric acid (5 N).
The solid was collected, washed with water and air dried to give 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (13.93 g, 85%) as a brownish glassy solid. Proton magnetic resonance spectrum (CDC13; ~ in ppm): 1.20 (3H,t); 2.20 (3H, s);
2.24 (3H,s); 2.38 (3H,s); 2.45 (3H,s); 2.45-3.40 (6H,m);
3.90 (lH,m); 6.84 (lH,s); 18.25 (lH,s).
Example 2 Process for the Preparation of 5-(3-crotonyl-2,4,6-trimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (2) To a suspension of aluminium trichloride (4.0 g, 0.03 mole) in dichloroethane (20 ml) at 0~C was added 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (2.9 g, 0.01 mole) in dichloroethane (10 ml). The mixture was stirred at 0~C for five minutes and then crotonyl chloride (1.1 g, 0.01 mole) was added. Stirr-ing was continued at 0~C for 30 minutes and then at 20~C
for 3 hours. The brown solution was poured into cold dilute hydrochloric acid (2 M, 200 ml) and shaken occasional~y as it was allowed to warm to room tempera-ture. The organic phase was separated and the aqueous phase was shaken with chloroform (2 x 100 ml). The com-bined organic extracts were dried over magnesium sulphate and evaporated to give 5-(3-crotonyl-2,4,6-trimethyl-phenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (4.1 g, 83%) as a pale brown oil. Proton magnetic resonance spectrum (CDC13; ~ in ppm): 1.16 (3H,t); 1.93 (3H, d, J=7Hz); 2.07 (3H,s); 2.17 (3H,s); 2.38 (3H,s); 2.2-4.0 (7H,m); 6.1-6.8 (2H,m); 6.86 (lH,s); 18.20 (lH,s).
Example 3 The following (Tables la and lb) 2-acyl-5-(acyl substituted aryl)-3-hydroxycyclohex-2-en-1-ones were prepared from the appropriate 2-acyl-5-aryl-3-hydroxy-cyclohex-2-en-1-ones and the appropriate acid chloride following essentially the same procedure as that des-cribed in Example 1 or Example 2. The compounds were characterized by their proton nuclear magnetic resonance - 15 - 13~9277 spectra and spectroscopic data are recorded in Table 2 below.
TABLE la R CO
tX ~ C \ ~l XII
Substituents Com-pOund No (X)l R3Co Rl R2 3 2,4,6-(CH3)3 3-C6H5CO C2H5 H
4 2,4,6-(CH3)3 3-ClCH2CO C2H5 H
2,4,6-(CH3)3 3-(4-CH30C6H4CO)C2H5 H
6 2,4,6-(CH3~3 3-(4-02NC6H4CO)C2H5 H
7 2,4,6-(CH3)3 3-(4-NCC6H4CO) C2H5 H
8 2,4,6-(CH3)3 3-(C6H5CH2CO C2H5 H
9 2,4,6-(CH3)3 3-C2HsOCOCH2COC2H5 H
2,4,6-(CH3)3 3-CH3SCH2CO C2H5 H
11 2,4,6-(CH3)3 3-C2HsSCO C2H5 H
12 2,4,6-(CH3)3 3-BrCH2CO C2H5 H
13 2,4,6-(CH3)3 3-C2H5CO C2H5 H
14 2,4,6-(C2Hs)3 3-CH3CO C2H5 H
2,6-(CH3)2 3-CH3CO C2H5 H
16 2,4-(CH3)2 5-CH3CO C2H5 H
- 16 - ~ 1339277 TABLE la - continued Substituents Com-pound No (X)l R3Co Rl R2 18 4-CH3 3-CH3CO n-c3H7 H
1~ 3-CH3 4-CH3CO C2H5 H
6-F-2,3,4-(CH3)3 5-CH3CO C2H5 H
21 5-Br-2,4,6-(CH3)3 3-CH3CO C2H5 H
22 4-Br-2,6-(CH3)2 3-CH3CO C2H5 H
TABLE lb CH3?~ Cs~C2H5 23 H 3C~-- ~C~C2H5 24 ~ OH
CH3CO ~--~C~~2H5 25 TABLE lb - continued 3 ~H 3 ~OH
CH3 _r _ ~~ 26 ~f ~
OH
6 5 ~ C ~~ 27 OH
Ch- 3 CH= CH CO ~--C 2 8 - l9- 133~277 Compound Proton Chemical Shift No ~ in ppm 3 1.16(3H,t); 2.04(3H,s); 2.15(3H,s);
2.44(3H,s); 2.2-4.0(7H,m); 6.94(1H, s); 7.1-7.8(5H,m); 18.22(lH,s).
4 1.18(3H,t); 2.17(3H,s); 2.23(3H,s);
2.39(3H,s); 2.2-4.0(7H,m); 4.37(2H, s); 6.90(lH,s); 18.23(lH,s).
1.16(3H,t); 2.04(3H,s); 2.13(3H,s);
2.43(3H,s); 2.3-4.0(7H,m); 3.83(3H, s), 6.88(3H,m); 7.71(2H,d); 18.14 (lH,s).
6 1.16(3H,t); 2.03(3H,s); 2.13(3H,s);
2.45(3H,s); 2.3-4.0(7H,m); 6.93(1H, s); 7.8-8.4(4H,dofd); 18.20(1H,s).
7 1.16(3H,t); 2.02(3H,s); 2.13(3H,s);
2.44(3H,s); 2.3-4.0(7H,m); 6.92(1H, s); 7.79(4H,dofd); 18.15(1H,s).
8 1.16(3H,t); 2.06(3H,s); 2.10(3H,s);
2.36(3H,s); 2.2-4.1(7H,m); 3.95(2H, s); 6.86(1H,s); 7.0-7.3(5H,m); 18.18 (lH,s).
- 20 - 133~277 TABLE 2 - continued Compound Proton Chemical Shift No ~ in ppm 9 1.16(3H,t); 1.33(3H,t); 2.0-2.3(9H, m); 2.3-4.0(7H,m); 4.20(2H,q); 5.10 (lH,s): 6.90(1H,s); 12.38(1H,s);
18.25(lH,s).
l.lS(3H,t); 2.22(6H,s); 2.30(3H,s);
2.40(3H,s); 2.3-4.0(9H,m); 6.89(1H, s); 18.25(1H,s).
11 1.15(3H,t~; 1.37(3H,t); 2.23(3H,s);
2.33(3H,s); 2.39(3H,s); 2.4-4.1(9H, m); 6.89(1H,s); 18.17(1H,s).
12 1.13(3H,t); 2.16(3H,s); 2.26(3H,s);
2.41(3H,s); 2.2-4.0(7H,m); 4.27(2H, s); 6.89(lH,s); 18.17(lH,s).
13 1.16(3H,t); 1.42(3H,t); 2.27(3H,s);
2.33(3H,s); 2.44(3H,s); 2.3-3.9(7H,m); 4.40(2H,q); 7.04(1H,s);
18.19(lH,s).
14 0.9-1.2(12H,m); 2.2-3.9(13H,m); 2.50 (3H,s); 6.94(1H,s); 18.16(1H,s).
1.16(3H,t); 2.43(6H,s); 2.54(3H,s);
2.2-4.0(7H,m); 6.97(2H,dofd); 18.18 - (lH,s).
TABLE 2 - continued Compound Proton Chemical Shift No ~ in ppm 16 1.16(3H,t); 2.37(3H,s); 2.48(3H,s);
2.56(3H,s); 2.3-3.8(7H,m); 7.09(1H, s); 7.53(1H,s); 18.27(1H,s).
17 1.15(3H,t); 2.41(3H,s); 2.55(3H,s);
2.4-3.7(7H,m); 7.15-7.92(3H,m);
18.17(1H,s).
18 0.98(3H,t); 1.4-1.8~2H,m); 2.49(3H, s); 2.57(3H,s); 2.4-3.6(7H,m); 7.20 (2H,bs); 7.54(1H,bs); 18.18(1H,s).
19 1.16(3H,t); 2.54(3H,s); 2.58(3H,s);
2.4-3.6(7H,m); 7.1-7.8(3H,m); 18.17 (lH,s).
1.16(3H,t); 2.16(6H,s); 2.27(3H,s);
2.49(3H,d); 2.3-3.9(7H,m); 18.20(lH, s ) .
21 1.16(3H,t); 2.21(3H,s); 2.27(3H,s);
2.45(3H,s); 2.54(3H,s); 2.4-4.0(7H, m); 18.18(lH,s).
22 0.99(3H,t); 1.5-1.8(2H,m); 2.27(3H, s); 2.39(3H,s); 2.53(3H,s); 2.4-4.0 (7H,m); 7.27(1H,s); 18.22(1H,s).
TABLE 2 - continued Compound Proton Chemical Shift No ~ in ppm 23 1.16(3H,t); 2.27(3H,s); 2.33(3H,s):
2.43(3H,s); 2.0-4.0(13H,m); 18.16 (lH,s).
24 1.15(3H,t); 1.16(6H,s); 2.07(3H,s);
2.24(3H,s); 2.48(3H,s); 2.5-3.6(11H, m); 18.17(lH,s).
1.16(3H,t); 2.15-3.9(16H,m); 7.1-8.4(4H,m); 18.16(1H,s).
26 1.02(3H,t); 1.64(2H,m); 2.29(3H,s);
2.39(3H,s); 2.46(3H,s); 2.58(3H,s);
2.4-4.0(7H,m); 7.51(1H,s); 18.16(lH, s ) .
27 1.15(3H,t); 2.6-3.8(7H,m); 6.24(1H, d); 7.07(1H,d); 7.4-7.9(5H,m); 18.18 (lH,s).
28 1.16(3H,t); 1.98(3H,d); 2.2-3.8(7H, m); 6.22(lH,d); 6.80(lH,d); 6.9-7.0 (2H,m); 18.16(lH,s).
Comparative Example The procedure described in Example 1 was re-peated using 10.0 9 (0.075 mole) of aluminium chloride.
The yield of 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxypropionylcyclohex-2-en-1-one obtained was 1.6 y (9.8%). The major organic product recovered from the reaction was unreacted 3-hydroxy-5-mesityl-2-propionyl-cyclohex-2-en-1-one.
The Example clearly illustrates that even with a 1.5 fold molar excess of aluminium chloride (standard molar excess used fro acylation rections is around 1.1) very poor yields of the desired product are obtained.
2,4,6-(CH3)3 3-(4-CH30C6H4CO)C2H5 H
6 2,4,6-(CH3~3 3-(4-02NC6H4CO)C2H5 H
7 2,4,6-(CH3)3 3-(4-NCC6H4CO) C2H5 H
8 2,4,6-(CH3)3 3-(C6H5CH2CO C2H5 H
9 2,4,6-(CH3)3 3-C2HsOCOCH2COC2H5 H
2,4,6-(CH3)3 3-CH3SCH2CO C2H5 H
11 2,4,6-(CH3)3 3-C2HsSCO C2H5 H
12 2,4,6-(CH3)3 3-BrCH2CO C2H5 H
13 2,4,6-(CH3)3 3-C2H5CO C2H5 H
14 2,4,6-(C2Hs)3 3-CH3CO C2H5 H
2,6-(CH3)2 3-CH3CO C2H5 H
16 2,4-(CH3)2 5-CH3CO C2H5 H
- 16 - ~ 1339277 TABLE la - continued Substituents Com-pound No (X)l R3Co Rl R2 18 4-CH3 3-CH3CO n-c3H7 H
1~ 3-CH3 4-CH3CO C2H5 H
6-F-2,3,4-(CH3)3 5-CH3CO C2H5 H
21 5-Br-2,4,6-(CH3)3 3-CH3CO C2H5 H
22 4-Br-2,6-(CH3)2 3-CH3CO C2H5 H
TABLE lb CH3?~ Cs~C2H5 23 H 3C~-- ~C~C2H5 24 ~ OH
CH3CO ~--~C~~2H5 25 TABLE lb - continued 3 ~H 3 ~OH
CH3 _r _ ~~ 26 ~f ~
OH
6 5 ~ C ~~ 27 OH
Ch- 3 CH= CH CO ~--C 2 8 - l9- 133~277 Compound Proton Chemical Shift No ~ in ppm 3 1.16(3H,t); 2.04(3H,s); 2.15(3H,s);
2.44(3H,s); 2.2-4.0(7H,m); 6.94(1H, s); 7.1-7.8(5H,m); 18.22(lH,s).
4 1.18(3H,t); 2.17(3H,s); 2.23(3H,s);
2.39(3H,s); 2.2-4.0(7H,m); 4.37(2H, s); 6.90(lH,s); 18.23(lH,s).
1.16(3H,t); 2.04(3H,s); 2.13(3H,s);
2.43(3H,s); 2.3-4.0(7H,m); 3.83(3H, s), 6.88(3H,m); 7.71(2H,d); 18.14 (lH,s).
6 1.16(3H,t); 2.03(3H,s); 2.13(3H,s);
2.45(3H,s); 2.3-4.0(7H,m); 6.93(1H, s); 7.8-8.4(4H,dofd); 18.20(1H,s).
7 1.16(3H,t); 2.02(3H,s); 2.13(3H,s);
2.44(3H,s); 2.3-4.0(7H,m); 6.92(1H, s); 7.79(4H,dofd); 18.15(1H,s).
8 1.16(3H,t); 2.06(3H,s); 2.10(3H,s);
2.36(3H,s); 2.2-4.1(7H,m); 3.95(2H, s); 6.86(1H,s); 7.0-7.3(5H,m); 18.18 (lH,s).
- 20 - 133~277 TABLE 2 - continued Compound Proton Chemical Shift No ~ in ppm 9 1.16(3H,t); 1.33(3H,t); 2.0-2.3(9H, m); 2.3-4.0(7H,m); 4.20(2H,q); 5.10 (lH,s): 6.90(1H,s); 12.38(1H,s);
18.25(lH,s).
l.lS(3H,t); 2.22(6H,s); 2.30(3H,s);
2.40(3H,s); 2.3-4.0(9H,m); 6.89(1H, s); 18.25(1H,s).
11 1.15(3H,t~; 1.37(3H,t); 2.23(3H,s);
2.33(3H,s); 2.39(3H,s); 2.4-4.1(9H, m); 6.89(1H,s); 18.17(1H,s).
12 1.13(3H,t); 2.16(3H,s); 2.26(3H,s);
2.41(3H,s); 2.2-4.0(7H,m); 4.27(2H, s); 6.89(lH,s); 18.17(lH,s).
13 1.16(3H,t); 1.42(3H,t); 2.27(3H,s);
2.33(3H,s); 2.44(3H,s); 2.3-3.9(7H,m); 4.40(2H,q); 7.04(1H,s);
18.19(lH,s).
14 0.9-1.2(12H,m); 2.2-3.9(13H,m); 2.50 (3H,s); 6.94(1H,s); 18.16(1H,s).
1.16(3H,t); 2.43(6H,s); 2.54(3H,s);
2.2-4.0(7H,m); 6.97(2H,dofd); 18.18 - (lH,s).
TABLE 2 - continued Compound Proton Chemical Shift No ~ in ppm 16 1.16(3H,t); 2.37(3H,s); 2.48(3H,s);
2.56(3H,s); 2.3-3.8(7H,m); 7.09(1H, s); 7.53(1H,s); 18.27(1H,s).
17 1.15(3H,t); 2.41(3H,s); 2.55(3H,s);
2.4-3.7(7H,m); 7.15-7.92(3H,m);
18.17(1H,s).
18 0.98(3H,t); 1.4-1.8~2H,m); 2.49(3H, s); 2.57(3H,s); 2.4-3.6(7H,m); 7.20 (2H,bs); 7.54(1H,bs); 18.18(1H,s).
19 1.16(3H,t); 2.54(3H,s); 2.58(3H,s);
2.4-3.6(7H,m); 7.1-7.8(3H,m); 18.17 (lH,s).
1.16(3H,t); 2.16(6H,s); 2.27(3H,s);
2.49(3H,d); 2.3-3.9(7H,m); 18.20(lH, s ) .
21 1.16(3H,t); 2.21(3H,s); 2.27(3H,s);
2.45(3H,s); 2.54(3H,s); 2.4-4.0(7H, m); 18.18(lH,s).
22 0.99(3H,t); 1.5-1.8(2H,m); 2.27(3H, s); 2.39(3H,s); 2.53(3H,s); 2.4-4.0 (7H,m); 7.27(1H,s); 18.22(1H,s).
TABLE 2 - continued Compound Proton Chemical Shift No ~ in ppm 23 1.16(3H,t); 2.27(3H,s); 2.33(3H,s):
2.43(3H,s); 2.0-4.0(13H,m); 18.16 (lH,s).
24 1.15(3H,t); 1.16(6H,s); 2.07(3H,s);
2.24(3H,s); 2.48(3H,s); 2.5-3.6(11H, m); 18.17(lH,s).
1.16(3H,t); 2.15-3.9(16H,m); 7.1-8.4(4H,m); 18.16(1H,s).
26 1.02(3H,t); 1.64(2H,m); 2.29(3H,s);
2.39(3H,s); 2.46(3H,s); 2.58(3H,s);
2.4-4.0(7H,m); 7.51(1H,s); 18.16(lH, s ) .
27 1.15(3H,t); 2.6-3.8(7H,m); 6.24(1H, d); 7.07(1H,d); 7.4-7.9(5H,m); 18.18 (lH,s).
28 1.16(3H,t); 1.98(3H,d); 2.2-3.8(7H, m); 6.22(lH,d); 6.80(lH,d); 6.9-7.0 (2H,m); 18.16(lH,s).
Comparative Example The procedure described in Example 1 was re-peated using 10.0 9 (0.075 mole) of aluminium chloride.
The yield of 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxypropionylcyclohex-2-en-1-one obtained was 1.6 y (9.8%). The major organic product recovered from the reaction was unreacted 3-hydroxy-5-mesityl-2-propionyl-cyclohex-2-en-1-one.
The Example clearly illustrates that even with a 1.5 fold molar excess of aluminium chloride (standard molar excess used fro acylation rections is around 1.1) very poor yields of the desired product are obtained.
Claims (10)
1. A process for the preparation of a compound of formula I
which process comprises:
reacting a compound of formula II
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula II, of anhydrous aluminium chloride wherein the group of formula o is selected from:
phenyl groups of formula V
wherein:
X, which may be the same or different, are independently selected from the group consisting of:
halogen; C1 to C6 alkyl; C1 to C6 alkyl substituted with a substituent selected from the group consisting of halogen, hydroxy, C1 to C6 alkoxy and C1 to C6 alkylthio; C2 to C6 alkenyl; C2 to C6 alkynyl;
hydroxy; C1 to C6 alkoxy; C1 to C6 alkoxy substituted with a substituent selected from halogen and C1 to C6 alkoxy; C1 to C6 alkenyloxy; C2 to C6 alkynyloxy;
C1 to C6 alkylthio; and the group NR4R5 wherein R4 and R5 are independently selected from the group consisting of hydrogen, C1 to C6 alkyl, C2 to C6 alkanoyl, benzoyl and benzyl; and 1 is zero or an integer selected from 1 to 4;
benzocycloalkyl groups of formula VI
wherein:
W, which may be the same or different, are selected from the group consisting of C1 to C6 alkyl, C2 to C6 alkenyl and C2 to C6 alkynyl;
X is as hereinbefore defined;
m is zero or an integer selected from 1 to 4;
n is zero or an integer selected from 1 to 3; and p is zero or an integer selected from 1 and 2;
indenyl and benzoheterocyclopentenyl groups of formula VII
wherein:
A is selected from CH and N; and B is selected from oxygen, sulfur, CH2 and the group N-V wherein V is selected from the group consisting of hydrogen, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C7 cycloalkyl, benzyl and substituted benzyl wherein the benzene ring is substituted with from one to three substituents selected from the group consisting of halogen, nitro, C1 to C6 alkyl, C1 to C6 alkoxy and C1 to C6 haloalkyl; and X and m are as hereinbefore defined; and q is zero or an integer selected from 1 to 3;
benzoazinyl groups of the formula VIII
VIII
wherein:
D,E,G and J are independently selected from CH, N and N-Z wherein Z is selected from oxygen and the group -YAn wherein Y is selected from C1 to C6 alkyl and benzyl and An is an anion selected from halide, tetrafluoroborate, methosulfate and fluorosulfate, and provided that at least one but no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G, and J is selected from N-Z;
and X and q are as hereinbefore defined;
naphthyl and cycloalkyl-, cycloalkenyl- and benzo-substituted azinyl groups of the formula IX
wherein:
D, E, G and J are independently selected from CH, N and N-Z wherein Z is selected from oxygen and the group -YAn wherein Y is selected from C1 to C6 alkyl and benzyl and An is an anion selected from halide, tetrafluoroborate, methosulfate and fluorosulfate, and provided that no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G and J is selected from N-Z;
Q is a saturated or unsaturated hydrocarbon chain containing from two to five carbon atoms; and X, m and q are as hereinbefore defined; and furyl and thienyl groups of formula X
>
wherein:
L is selected from oxygen and sulfur; and X and p are as hereinbefore defined; and R1 is selected from the group consisting of: C1 to C6 alkyl; C1 to C6 fluoroalkyl; C2 to C6 alkenyl;
C2 to C6 alkynyl; and phenyl; and R2 is selected from the group consisting of:
hydrogen; halogen; cyano; C1 to C6 alkyl; and (C1 to C6 alkoxy)carbonyl; and R3 is selected from the group consisting of: C1 to C6 alkyl; C1 to C6 alkoxy; C1 to C6 alkylthio; C2 to C6 alkenyl; C2 to C6 alkynyl; phenyl; and the groups C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl and phenyl wherein each group is substituted with at least one substituent selected from the group consisting of halogen, hydroxy, nitro, cyano, phenyl, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, (C1 to C6 alkoxy)carbonyl, amino, N-(C1 to C6 alkyl)-amino and N,N-di(C1 to C6 alkyl)amino.
which process comprises:
reacting a compound of formula II
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula II, of anhydrous aluminium chloride wherein the group of formula o is selected from:
phenyl groups of formula V
wherein:
X, which may be the same or different, are independently selected from the group consisting of:
halogen; C1 to C6 alkyl; C1 to C6 alkyl substituted with a substituent selected from the group consisting of halogen, hydroxy, C1 to C6 alkoxy and C1 to C6 alkylthio; C2 to C6 alkenyl; C2 to C6 alkynyl;
hydroxy; C1 to C6 alkoxy; C1 to C6 alkoxy substituted with a substituent selected from halogen and C1 to C6 alkoxy; C1 to C6 alkenyloxy; C2 to C6 alkynyloxy;
C1 to C6 alkylthio; and the group NR4R5 wherein R4 and R5 are independently selected from the group consisting of hydrogen, C1 to C6 alkyl, C2 to C6 alkanoyl, benzoyl and benzyl; and 1 is zero or an integer selected from 1 to 4;
benzocycloalkyl groups of formula VI
wherein:
W, which may be the same or different, are selected from the group consisting of C1 to C6 alkyl, C2 to C6 alkenyl and C2 to C6 alkynyl;
X is as hereinbefore defined;
m is zero or an integer selected from 1 to 4;
n is zero or an integer selected from 1 to 3; and p is zero or an integer selected from 1 and 2;
indenyl and benzoheterocyclopentenyl groups of formula VII
wherein:
A is selected from CH and N; and B is selected from oxygen, sulfur, CH2 and the group N-V wherein V is selected from the group consisting of hydrogen, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C7 cycloalkyl, benzyl and substituted benzyl wherein the benzene ring is substituted with from one to three substituents selected from the group consisting of halogen, nitro, C1 to C6 alkyl, C1 to C6 alkoxy and C1 to C6 haloalkyl; and X and m are as hereinbefore defined; and q is zero or an integer selected from 1 to 3;
benzoazinyl groups of the formula VIII
VIII
wherein:
D,E,G and J are independently selected from CH, N and N-Z wherein Z is selected from oxygen and the group -YAn wherein Y is selected from C1 to C6 alkyl and benzyl and An is an anion selected from halide, tetrafluoroborate, methosulfate and fluorosulfate, and provided that at least one but no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G, and J is selected from N-Z;
and X and q are as hereinbefore defined;
naphthyl and cycloalkyl-, cycloalkenyl- and benzo-substituted azinyl groups of the formula IX
wherein:
D, E, G and J are independently selected from CH, N and N-Z wherein Z is selected from oxygen and the group -YAn wherein Y is selected from C1 to C6 alkyl and benzyl and An is an anion selected from halide, tetrafluoroborate, methosulfate and fluorosulfate, and provided that no more than three of D, E, G and J are selected from N and N-Z and no more than one of D, E, G and J is selected from N-Z;
Q is a saturated or unsaturated hydrocarbon chain containing from two to five carbon atoms; and X, m and q are as hereinbefore defined; and furyl and thienyl groups of formula X
>
wherein:
L is selected from oxygen and sulfur; and X and p are as hereinbefore defined; and R1 is selected from the group consisting of: C1 to C6 alkyl; C1 to C6 fluoroalkyl; C2 to C6 alkenyl;
C2 to C6 alkynyl; and phenyl; and R2 is selected from the group consisting of:
hydrogen; halogen; cyano; C1 to C6 alkyl; and (C1 to C6 alkoxy)carbonyl; and R3 is selected from the group consisting of: C1 to C6 alkyl; C1 to C6 alkoxy; C1 to C6 alkylthio; C2 to C6 alkenyl; C2 to C6 alkynyl; phenyl; and the groups C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl and phenyl wherein each group is substituted with at least one substituent selected from the group consisting of halogen, hydroxy, nitro, cyano, phenyl, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, (C1 to C6 alkoxy)carbonyl, amino, N-(C1 to C6 alkyl)-amino and N,N-di(C1 to C6 alkyl)amino.
2. A process according to claim 1 wherein said reaction is carried out in the presence of an aprotic organic solvent at a temperature in the range of from -20°C to 100°C.
3. A process according to claim 1 for the preparation of a compound of formula I wherein:
in the groups of formula V, VI, VII, VIII, IX and X:
X is selected from C1 to C6 alkyl, halogen, C1 to C6 alkoxy and C1 to C6 alkylthio;
W is methyl;
A is CH;
B is selected from oxygen, sulfur and N-(C1 to C6 alkyl);
D, E, G and J are selected from CH and N;
Q is selected from -(CH2)4- and -(CH=CH)2-;
L is selected from oxygen and sulfur;
1 is selected from the integers 2 to 4;
m is selected from zero and the integers 1 and 2;
n and p are independently selected from the integers 1 and 2; and q is selected from the integers 1 to 3;
R1 is selected from methyl, ethyl and n-propyl;
R2 is hydrogen; and R3 is selected from C1 to C6 alkyl, C2 to C6 alkenyl and phenyl.
in the groups of formula V, VI, VII, VIII, IX and X:
X is selected from C1 to C6 alkyl, halogen, C1 to C6 alkoxy and C1 to C6 alkylthio;
W is methyl;
A is CH;
B is selected from oxygen, sulfur and N-(C1 to C6 alkyl);
D, E, G and J are selected from CH and N;
Q is selected from -(CH2)4- and -(CH=CH)2-;
L is selected from oxygen and sulfur;
1 is selected from the integers 2 to 4;
m is selected from zero and the integers 1 and 2;
n and p are independently selected from the integers 1 and 2; and q is selected from the integers 1 to 3;
R1 is selected from methyl, ethyl and n-propyl;
R2 is hydrogen; and R3 is selected from C1 to C6 alkyl, C2 to C6 alkenyl and phenyl.
4. A process for the preparation of a compound of formula XII
XII
wherein:
X is selected from the group consisting of C1 to C6 alkyl, halogen, C1 to C6 alkoxy and C1 to C6 alkylthio;
R1 is selected from the group consisting of methyl, ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of:
C1 to C6 alkyl; C2 to C6 alkenyl; phenyl; C1 to C6 alkoxy; C1 to C6 alkylthio; C1 to C6 alkyl substituted with one or more substituents selected from the group consisting of halogen, (C1 to C6 alkoxy)carbonyl, C1 to C6 alkoxy, C1 to C6 alkylthio and phenyl; and phenyl substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1 to C6 alkyl and C1 to C6 alkoxy; and 1 is selected from the integers 2 to 4;
which process comprises:
reacting a compound of formula XI
XI
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XI, of anhydrous aluminium chloride.
XII
wherein:
X is selected from the group consisting of C1 to C6 alkyl, halogen, C1 to C6 alkoxy and C1 to C6 alkylthio;
R1 is selected from the group consisting of methyl, ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of:
C1 to C6 alkyl; C2 to C6 alkenyl; phenyl; C1 to C6 alkoxy; C1 to C6 alkylthio; C1 to C6 alkyl substituted with one or more substituents selected from the group consisting of halogen, (C1 to C6 alkoxy)carbonyl, C1 to C6 alkoxy, C1 to C6 alkylthio and phenyl; and phenyl substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1 to C6 alkyl and C1 to C6 alkoxy; and 1 is selected from the integers 2 to 4;
which process comprises:
reacting a compound of formula XI
XI
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XI, of anhydrous aluminium chloride.
5. A process for the preparation of a compound of formula XII
XII
wherein:
X is selected from the group consisting of halogen, methyl and methoxy;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of methyl, ethyl, chloromethyl, bromomethyl, ethoxycarbonylmethyl, methylthiomethyl, benzyl, allyl, ethylthio, phenyl, methoxyphenyl, nitrophenyl and cyanophenyl; and l is selected from the integers 2 to 4;
which process comprises:
reacting a compound of formula XI
XI
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XI, of anhydrous aluminium chloride.
XII
wherein:
X is selected from the group consisting of halogen, methyl and methoxy;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of methyl, ethyl, chloromethyl, bromomethyl, ethoxycarbonylmethyl, methylthiomethyl, benzyl, allyl, ethylthio, phenyl, methoxyphenyl, nitrophenyl and cyanophenyl; and l is selected from the integers 2 to 4;
which process comprises:
reacting a compound of formula XI
XI
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XI, of anhydrous aluminium chloride.
6. A process for the preparation of a compound of formula XII
XII
wherein:
X is methyl;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is methyl; and l is selected from the integers 3 and 4;
which process comprises:
reacting a compound of formula XI
XI
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XI, of anhydrous aluminium chloride.
XII
wherein:
X is methyl;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is methyl; and l is selected from the integers 3 and 4;
which process comprises:
reacting a compound of formula XI
XI
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XI, of anhydrous aluminium chloride.
7. A process for the preparation of a compound of formula XIV
XIV
wherein:
X is selected from the group consisting of C1 to C6 alkyl, halogen, C1 to C6 alkoxy and C1 to C6 alkylthio;
R1 is selected from the group consisting of methyl, ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of: C1 to C6 alkyl; C2 to C6 alkenyl; phenyl;
C1 to C6 alkoxy; C1 to C6 alkylthio; C1 to C6 alkyl substituted with one or more substituents selected from the group consisting of halogen, (C1 to C6 alkoxy)carbonyl, C1 to C6 alkoxy, C1 to C6 alkylthio and phenyl; and phenyl substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1 to C6 alkyl and C1 to C6 alkoxy;
, - 36 -m is selected from zero and the integers 1 and 2; and q is selected from the integers 1 to 3;
which process comprises:
reacting a compound of formula XIII
XIII
R
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XIII, of anhydrous aluminium chloride.
XIV
wherein:
X is selected from the group consisting of C1 to C6 alkyl, halogen, C1 to C6 alkoxy and C1 to C6 alkylthio;
R1 is selected from the group consisting of methyl, ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of: C1 to C6 alkyl; C2 to C6 alkenyl; phenyl;
C1 to C6 alkoxy; C1 to C6 alkylthio; C1 to C6 alkyl substituted with one or more substituents selected from the group consisting of halogen, (C1 to C6 alkoxy)carbonyl, C1 to C6 alkoxy, C1 to C6 alkylthio and phenyl; and phenyl substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1 to C6 alkyl and C1 to C6 alkoxy;
, - 36 -m is selected from zero and the integers 1 and 2; and q is selected from the integers 1 to 3;
which process comprises:
reacting a compound of formula XIII
XIII
R
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XIII, of anhydrous aluminium chloride.
8. A process for the preparation of a compound of formula XIV
XIV
wherein:
X is selected from the group consisting of halogen, methyl and methoxy;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of methyl, ethyl, chloromethyl, bromomethyl, ethoxycarbonylmethyl, methylthiomethyl, benzyl, allyl, ethylthio, phenyl, methoxyphenyl, nitrophenyl and cyanophenyl;
m is selected from zero and the integers 1 and 2;
and q is selected from the integers 1 to 3;
which process comprises:
reacting a compound of formula XIII
XIII
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XIII, of anhydrous aluminium chloride.
XIV
wherein:
X is selected from the group consisting of halogen, methyl and methoxy;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is selected from the group consisting of methyl, ethyl, chloromethyl, bromomethyl, ethoxycarbonylmethyl, methylthiomethyl, benzyl, allyl, ethylthio, phenyl, methoxyphenyl, nitrophenyl and cyanophenyl;
m is selected from zero and the integers 1 and 2;
and q is selected from the integers 1 to 3;
which process comprises:
reacting a compound of formula XIII
XIII
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XIII, of anhydrous aluminium chloride.
9, A process for the preparation of a compound of formula XIV
XIV
wherein:
X is methyl;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is methyl;
m is selected from zero and the integers 1 and 2; and q is selected from the integers 1 to 3;
which process comprises:
reacting a compound of formula XIII
XIII
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XIII, of anhydrous aluminium chloride.
XIV
wherein:
X is methyl;
R1 is selected from ethyl and n-propyl;
R2 is hydrogen;
R3 is methyl;
m is selected from zero and the integers 1 and 2; and q is selected from the integers 1 to 3;
which process comprises:
reacting a compound of formula XIII
XIII
with an acid anhydride of formula III, an acid halide of formula IV, or a mixture thereof (R3CO)2O R3COhalide III IV
in the presence of at least three mole equivalents, based on the compound of formula XIII, of anhydrous aluminium chloride.
10. A process according to claim 4 or claim 7 wherein said reaction is carried out in the presence of an aprotic organic solvent at a temperature in the range of from -20°C to 100°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPG.2208 | 1983-11-04 | ||
| AUPG220883 | 1983-11-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1339277C true CA1339277C (en) | 1997-08-12 |
Family
ID=3770387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000466547A Expired - Fee Related CA1339277C (en) | 1983-11-04 | 1984-10-29 | Process for the aromatic ring acylation of 2-acyl-5-aryl-(heteroaryl)-3-hydroxycyclohex-2-en-1-ones |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR920002250B1 (en) |
| BR (1) | BR8405564A (en) |
| CA (1) | CA1339277C (en) |
-
1984
- 1984-10-25 KR KR1019840006635A patent/KR920002250B1/en not_active IP Right Cessation
- 1984-10-29 CA CA000466547A patent/CA1339277C/en not_active Expired - Fee Related
- 1984-10-31 BR BR8405564A patent/BR8405564A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR850004091A (en) | 1985-07-01 |
| BR8405564A (en) | 1985-09-10 |
| KR920002250B1 (en) | 1992-03-20 |
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