Production of cyclopentenone derivatives

A process for preparing cyclopentenone derivatives of the formula: ##STR1## wherein R.sup.1 is hydrogen, lower alkyl or lower alkenyl, R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted ar(lower)alkyl and A is the residue of a nucleophilic agent from which a hydrogen atom is excluded, which comprises reacting a 3-hydroxy-4-cyclopentenone compound of the formula: ##STR2## wherein R.sup.1 and R.sup.2 are each as defined above with a nucleophilic agent of the formula EQU A--H (III) wherein A is as defined above. The cyclopentenone derivatives of the formula (I) are useful as pharmaceuticals, agricultural chemicals, perfumes and as intermediates for the preparation of agricultural chemicals, pharmaceuticals and perfumes.

The present invention relates to cyclopentenone derivatives and their 
production. 
The said cyclopentenone derivatives are represented by the formula: 
##STR3## 
wherein R.sup.1 is a hydrogen atom, a lower alkyl group or a lower alkenyl 
group, R.sup.2 is a hydrogen atom, a lower alkyl group, a lower alkenyl 
group, a lower alkynyl group, a cycloalkyl group, a substituted or 
unsubstituted aryl group or a substituted or unsubstituted ar(lower)alkyl 
group and A is the residue of a nucleophilic agent from which a hydrogen 
atom is excluded. 
The residue of a nucleophilic agent from which a hydrogen atom is excluded 
may be, for instance, the residue of ammonia or an amine from which a 
hydrogen atom is eliminated, the residue of an alcohol from which a 
hydrogen atom is eliminated or the residue of hydrogen sulfide or a thiol 
from which a hydrogen atom is eliminated. Specifically, the substituent 
represented by the symbol A may be 
##STR4## 
--SR.sup.6 or the the like. R.sup.3 can be, for instance, a hydrogen atom, 
a hydrocarbon group (e.g. lower alkyl, lower alkenyl, cycloalkyl, aryl, 
ar(lower)alkyl) optionally bearing any substituent(s), a lower alkoxy 
group, a hydroxyl group or a heterocyclic group optionally bearing any 
substituent(s). R.sup.4 may be, for instance, a hydrogen atom or a 
hydrocarbon group (e.g. lower alkyl, lower alkenyl, aryl, ar(lower)alkyl) 
optionally bearing any substituent(s). Alternatively, R.sup.3 and R.sup.4 
may be taken together with the nitrogen atom to which they are attached to 
form a heterocyclic group optionally bearing any substituent(s). R.sup.5 
is the residue of a hydroxyl-containing compound excluding hydroxyl 
therefrom and may be a hydrocarbon group (e.g. lower alkyl, lower alkenyl, 
lower alkadienyl, cycloalkyl, aryl, ar(lower)alkyl) optionally bearing any 
substituent(s) or a heterocyclic group optionally bearing any 
substituent(s). R.sup.6 is the residue of a mercapto-containing compound 
excluding mercapto therefrom and may be a hydrogen atom, a hydrocarbon 
group (e.g. lower alkyl, lower alkenyl, cycloalkyl, aryl, ar(lower)alkyl) 
optionally bearing any substituent(s), an acyl group or a heterocyclic 
group optionally bearing any substituent(s). 
In the above significances, the term "lower" is intended to mean a group 
having not more than 12 carbon atoms, preferably not more than 8 carbon 
atoms. The term "cycloalkyl" is intended to mean the one having 3 to 8 
carbon atoms. The term "aryl" means phenyl, naphthyl, etc. Examples of the 
heterocyclic group are pyrrolidino, piperidino, morpholino, 
thiomorpholino, pyridyl, thienyl, furyl, etc. The substituent(s) which may 
be present on the aryl group, the ar(lower)alkyl group, the hydrocarbon 
group or the heterocyclic group are halogen, lower alkyl, lower alkenyl, 
lower alkoxy, lower alkoxycarbonyl, lower alkanoyloxy, hydroxyl, 
hydroxy(lower)alkyl, phenyl, thienyl, furyl, pyridyl, etc. In case of the 
alkyl group, the preferred substituent(s) which may be present thereon are 
hydroxyl, lower alkoxy, lower alkanoyloxy, phenyl, thienyl, furyl, 
pyridyl, etc. The favorable substituent(s) which can be present on the 
aryl group are lower alkyl, lower alkoxy, halogen, etc. The favored 
examples of the substituent(s) which can be present on the heterocyclic 
group are hydroxyl, hydroxy(lower)alkyl, lower alkoxycarbonyl, etc. The 
term "acyl" is intended to mean lower alkanoyl, optionally substituted 
benzoyl, optionally substituted phenylalkanoyl, alkoxycarbonyl, etc. 
Therefore, examples of the ar(lower)alkyl group optionally bearing any 
substituent(s) may include benzyl, .alpha.-methylbenzyl, phenethyl, 
naphthylmethyl, 4-methylphenylmethyl, 4-methoxyphenylmethyl, 
4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, etc. 
Some analogous compounds to the cyclopentenone derivatives (I) and their 
production are known and can be summarized as follows: 
##STR5## 
wherein R is hydrogen or methyl and R' is C.sub.7 H.sub.15 or C.sub.11 
H.sub.23. 
##STR6## 
wherein R" is --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, 
--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --. 
In these procedures, however, the yields of the products are poor. Further, 
the references (1) and (2) disclose 4-methoxy compounds only and are 
entirely silent on other compounds having any group other than methoxy at 
the 4-position. The procedure in the reference (3) is disadvantageous for 
the production of 4-substituted compounds, because 5-substituted compounds 
are by-produced in addition to the 4-substituted compounds. Particularly 
when alkylamines such as diethylamine are used as the reagent, there are 
obtained a mixture of various products, and in fact, their isolation and 
identification have not been made. Furthermore, none of the said 
references discloses any use of the products therein. 
The cyclopentenone derivatives (I) are useful as pharmaceuticals, 
agricultural chemicals, perfumes, etc. and their intermediates. For 
instance, the cyclopentenone derivatives (I) are reacted with 
chrysanthemic acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid, 
p-chlorophenylisovaleric acid, etc. to give their esters or amides, which 
are useful as agricultural chemicals. Further, for instance, the 
cyclopentenone derivatives (I) may be reacted with .alpha.-substituted 
phenyl acetic acids to give their esters or amides, which are useful as 
anti-inflammatory agents. Furthermore, for instance, they can be used as 
intermediates for the synthesis of novel derivatives of prostaglandins. 
Moreover, they are advantageous for pharmaceutical use, because they are 
more lipophilic than their known analogous compounds. Moreover, those 
wherein R.sup.5 is geranyl are useful as perfumes having good odor or 
their intermediates. 
The cyclopentenone derivatives of the formula (I) can be readily produced 
in excellent yields by reacting a 3-hydroxy-4-cyclopentenone compound of 
the formula: 
##STR7## 
wherein R.sup.1 and R.sup.2 are each as defined above with a nucleophilic 
agent of the formula: 
EQU A--H (III) 
wherein A is as defined above. This reaction is per se novel. 
The starting 3-hydroxy-4-cyclopentenone compound (II) is known and can be 
produced, for instance, from the corresponding furan-carbinol by 
rearrangement as shown in the following formulas: 
##STR8## 
wherein R.sup.1 and R.sup.2 are each as defined above. 
Examples of the 3-hydroxy-4-cyclopentenone compound (II) are as follows: 
2-methyl-3-hydroxy-4-cyclopentenone, 2-ethyl-3-hydroxy-4-cyclopentenone, 
2-n-propyl-3-hydroxy-4-cyclopentenone, 
2-isopropyl-3-hydroxy-4-cyclopentenone, 
2-n-butyl-3-hydroxy-4-cyclopentenone, 
2-n-pentyl-3-hydroxy-4-cyclopentenone, 
2-n-hexyl-3-hydroxy-4-cyclopentenone, 
2-n-heptyl-3-hydroxy-4-cyclopentenone, 2-allyl-3-hydroxy-4-cyclopentenone, 
2-(2'-cis-butenyl)-3-hydroxy-4-cyclopentenone, 
2-(2'-cis-pentenyl)-3-hydroxy-4-cyclopentenone, 
2-(3'-cis-hexenyl)-3-hydroxy-4-cyclopentenone, 
2-(2'-trans-pentenyl)-3-hydroxy-4-cyclopentenone, 
2-propargyl-3-hydroxy-4-cyclopentenone, 
2-(2'-pentynyl)-3-hydroxy-4-cyclopentenone, 
2-benzyl-3-hydroxy-4-cyclopentenone, 
2-p-chlorobenzyl-3-hydroxy-4-cyclopentenone, 
2-p-methoxybenzyl-3-hydroxy-4-cyclopentenone, 
2-phenyl-3-hydroxy-4-cyclopentenone, 
2-cyclopentyl-3-hydroxy-4-cyclopentenone, 
2-cyclohexyl-3-hydroxy-4-cyclopentenone, 
2-(.alpha.-methylallyl)-3-hydroxy-4-cyclopentenone, 
2-(3',4'-methylenedioxyphenyl)-3-hydroxy-4-cyclopentenone, 
2-allyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-(2'-cis-pentenyl)-3-hydroxy-3 -methyl-4-cyclopentenone, 
2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-(2'-cis-butenyl)-3-hydroxy-3-methyl-4-cyclopentenone, 
2-n-hexyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-(3'-cis-hexenyl)-3-hydroxy-3-methyl-4-cyclopentenone, 
2-cyclopentyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-cyclohexyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-phenyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-p-chlorophenyl-3-hydroxy-4-cyclopentenone, 
2-p-methoxyphenyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-benzyl-3-hydroxy-3-methyl-4-cyclopentenone, 
2-(3',4'-dimethoxybenzyl)-3-hydroxy-3-methyl-4-cyclopentenone, 
2-n-pentyl-3-allyl-3-hydroxy-4-cyclopentenone, etc. 
Examples of the nucleophilic agent (III) include amines, 
hydroxyl-containing compounds, sulfur compounds, etc. Specific examples of 
the amines are ammonia, hydroxylamine, o-methylhydroxylamine, 
N-methylhydroxylamine, methylamine, ethylamine, n- or iso-propylamine, n- 
or sec-butylamine, n-, iso- or tert-pentylamine, n-, sec- or 
tert-octylamine, cyclopropylamine, octadecylamine, aminoadamantane, 
allylamine, dimethylamine, diethylamine, di-n-propylamine, 
cyclohexylamine, cyclopentylamine, aminoethanol, aminobutanol, 
3-amino-1-propanol, 1-amino-2-propanol, L-2-amino-1-propanol, 
N-aminopiperidine, .omega.-amino-.beta.-picoline, 4(6)-aminouracil, 
3-aminopropionitrile, 2-aminopyridine, 2-aminomethylpyridine, 
aminomethylthiophene, furfurylamine, aniline, 4-chloroaniline, 
2,4-dichloroaniline, 4-methylaniline, 3- or 4-hydroxyaniline, 
4-methoxyaniline, N-methylaniline, o-, m- or p-nitroaniline, 
4-hydroxyaniline, 3,4-methylenedioxyaniline, 3,4-dimethoxyaniline, 
benzylamine, .beta.-phenethylamine, .alpha.-methylbenzylamine, 
d-.alpha.-methylbenzylamine, ethylenediamine, 
2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropyl-1-methylamine, 
l-2-hydroxymethylpyrrolidine, l-2-methoxycarbonylpyrrolidine, 
l-2-methoxycarbonyl-4-hydroxypyrrolidine, etc. As the organic 
hydroxyl-containing compounds, there may be exemplified alcohols (e.g. 
isopropanol, n-propanol, n-butanol, n-octanol, dodecanol, ethylene glycol, 
1,3-propanediol, allyl alcohol, 2-pentenyl alcohol, 3-hexenyl alcohol, 
geraniol, nerol, farnesyl alcohol, cyclopentanol, cyclohexanol, 
2-cyclohexenyl alcohol, cyclopropyl methyl alcohol, l-menthol, propargyl 
alcohol, 2-pentyn-1-ol, 1,4-cyclohexanediol, dimethylaminoethanol, 
dimethylaminopropanol, diethylaminoethanol, furfuryl alcohol, thenyl 
alcohol, 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropyl-1-methanol), 
phenols (e.g. phenol, cresol, 4-chlorophenol, 2,4-dichlorophenol, 
4-dimethylaminophenol, 4-sulfamoylphenol, catechol, resorcinol, 
hydroquinone, sesamol, 4-methoxyphenol), aralkyl alcohols (e.g. benzyl 
alcohol, l-.alpha.-methylbenzyl alcohol, d-.alpha.-methyl-benzyl alcohol, 
3,4-methylenedioxybenzyl alcohol, 2,4-dichlorobenzyl alcohol, 
3,4-dimethoxybenzyl alcohol, .beta.-phenethyl alcohol), diisopropylidene 
mannose, diisopropylidene glucose, glycolic acid ethyl ester, mandelic 
acid methyl ester, pantoyl lactone, etc. As the sulfur compounds, there 
may be exemplified alkyl, alkenyl or cycloalkyl mercaptans (e.g. 
methylmercaptan, ethylmercaptan, n- or iso-propylmercaptan, n- or 
iso-butylmercaptan, mercaptodecane, mercaptononane, mercaptocyclopentane, 
mercaptocyclohexane, 3-mercapto-1-propene), aryl or aralkylmercaptans 
(e.g. thiophenol, o-, m- or p-mercaptotoluene, p-chlorothiophenol, 
.omega.-mercaptotoluene, .beta.-mercaptonaphthalene), carboxy- or 
hydroxy-substituted alkyl or aryl mercaptans (e.g. mercaptoacetic acid, 2- 
or 3-mercaptopropionic acid, o-mercaptobenzoic acid, 
p-hydroxymercaptobenzene, 2-hydroxyethylmercaptan, 
3-mercapto-1,2-propanediol), thiocarboxylic acids (e.g. thioacetic acid, 
thiopropionic acid), heterocyclic ring-containing mercaptans (e.g. 
mercaptobenzothiazole, 2- or 4-mercaptopyridine, 
2-mercapto-5-thiazolidone, 2-mercaptothiazoline, 2-mercaptobenzoxazole, 
2-mercaptothiophene), etc. 
The reaction between the 3-hydroxy-4-cyclopentenone compound (II) and the 
nucleophilic agent (III) is carried out in the presence or absence of an 
inert solvent, when desired, in the presence of a catalyst. 
As the inert solvent, there may be used water, ethers (e.g. dioxane, 
tetrahydrofuran, diethyl ether, di-n-propyl ether), ketones (e.g. acetone, 
methylethylketone), esters (e.g. methyl acetate, ethyl acetate), 
dimethylformamide, dimethylsulfoxide, hydrocarbons (e.g. benzene, 
toluene), halogenated hydrocarbons (e.g. chloroform, dichloromethane), 
etc. Their mixtures are also usable. Further, excess of the nucleophilic 
agent (III) may be used as the reaction medium. 
When the nucleophilic agent (III) is a hydroxyl-containing compound or a 
sulfur compound, it is preferred to effect the reaction under anhydrous 
conditions for achievement of a higher reaction rate or a better yield. 
Thus, the operation in such an organic solvent as tetrahydrofuran, 
chloroform, dioxane or toluene in the presence of a catalyst is 
recommended. When the nucleophilic agent (III) is an amine, anhydrous 
conditions are not necessarily recommended, and particularly when the 
amine is water-soluble, an aqueous solution of such amine is frequently 
and favorably used. In this case, the combined use of any organic solvent 
with water is also permissible. In case of the amine being not 
water-soluble, however, the operation in an organic solvent, especially 
under anhydrous conditions, is usually preferred. 
As the catalyst, there may be used any one chosen from alkali metals (e.g. 
sodium, potassium, lithium) and their salts (e.g. nitrate, sulfate, 
chloride, phosphate), oxides, alkoxides, hydrides and amides, tertiary 
amines (e.g. pyridine, triethylamine, quinine), quaternary ammonium salts, 
etc. When the nucleophilic agent (III) is an amine, such amine itself 
plays a role of the catalyst. Even in such case, any other compound which 
serves as the catalyst may be added to the reaction medium. The use of the 
catalyst is normally effective for enhancement of the reaction rate and 
increase of the conversion. While any particular limitation is not present 
on the amount of the catalyst, it is usual to employ the catalyst in an 
amount of 1/1000 to 2 parts by weight, preferably of 1/500 to 1/2 part by 
weight, to 1 part by weight of the 3-hydroxy-4-cyclopentenone compound 
(II). 
The reaction temperature is usually from -20.degree. to 150.degree. C., 
preferably from -10.degree. to 120.degree. C. Any special limitation is 
not present on the reaction time. 
As the result of the above reaction, there is readily produced the 
objective cyclopentenone derivative (I) in an excellent yield. Recovery of 
the cyclopentenone derivative (I) from the reaction mixture may be 
attained by a per se conventional separation procedure such as extraction, 
fractionation, condensation, distillation or recrystallization.