Process of preparing alkyl cis chrysanthemates

A process for the preparation of racemic or optically active isomers of alkyl esters of cis chrysanthemic of the formula ##STR1## wherein R is alkyl of 1 to 6 carbon atoms comprising reacting a racemic or optically active cis compound of the formula ##STR2## wherein R has the above definition with an aryl halothioformate of the formula ##STR3## wherein Hal is a halogen and Ar is aryl of 6 to 12 carbon atoms optionally substituted with at least one alkyl of 1 to 3 carbon atoms to obtain a compound of the formula ##STR4## of cis configuration and heating the latter optionally in an organic solvent to obtain the compound of formula I and novel intermediates.

STATE OF THE ART 
Majewski et al [Tetrahedron Letters, Vol. 23, No. 13, p. 1343-1346 (1982)] 
describe a route to a pyrethroid amide by a base-induced epoxyamide 
cyclization. Gerlach et al [J.C.S. Chem. Comm., 1972, p. 1215-1216] 
describe acylation of sterically hindered alcohols with 0-4-methylphenyl 
chlorothioformate. Published British application No. 2,085,428 describes 
forming a 3-vinyl side chain on cyclopropane carboxylates by reacting the 
corresponding 1-hydroxyethyl substituted compound with a phosphine. Also 
pertinent is DE-OS No. 2,639,777. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide a novel process for the 
preparation of alkyl esters of cis chrysanthemic acid. 
It is another object of the invention to provide novel intermediate 
products. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel process of the invention for the preparation of racemic or 
optically active isomers of alkyl esters of cis chrysanthemic of the 
formula 
##STR5## 
wherein R is alkyl of 1 to 6 carbon atoms comprises reacting a racemic or 
optically active cis compound of the formula 
##STR6## 
wherein R has the above definition with an aryl halothioformate of the 
formula 
##STR7## 
wherein Hal is a halogen and Ar is aryl of 6 to 12 carbon atoms optionally 
substituted with at least one alkyl of 1 to 3 carbon atoms to obtain a 
compound of the formula 
##STR8## 
of cis configuration and heating the latter optionally in an organic 
solvent to obtain the compound of formula I. 
Examples of R are alkyl such as methyl, ethyl, propyl, isopropyl and linear 
and branched butyl, pentyl and hexyl. 
In formula III, Hal is preferably chlorine but may be other halogens and Ar 
is preferably phenyl or naphthyl optionally substituted with at least one 
alkyl of 1 to 3 carbon atoms such as methyl or ethyl. The preferred 
compound of formula III is p-tolyl chlorothioformate. 
In a preferred mode of the process, the compound of formula IV is heated at 
100.degree. to 150.degree. C. in a non-polar, organic solvent, preferably 
a dichlorobenzene or trichlorobenzene. The heating can also be performed 
in the absence of a solvent. The compounds of formula II are known from 
Agr. Bio. Chem., Vol. 28 (7), p 456-4-6 (1964). 
A facet of the invention involves a process for the preparation of the 
racemic mixture or optically active compounds of formula II of cis 
configuration comprising reacting a racemic or optically active compound 
of the formula 
##STR9## 
with a carbonating reagent to obtain a compound of the formula 
##STR10## 
subjecting the latter to a selective reduction to obtain a compound of the 
formula cyclizing the latter to obtain a lactone of the formula 
##STR11## 
reacting the latter with diazo-2-propane to obtain a mixture of 
pyrazolines of the formulae 
##STR12## 
which, optionally separating the mixture and submitting the compound of 
formula IX.sub.a or the compound of formula IX.sub.b or their mixture to 
irradiation in the presence of a sensitizer to obtain a compound of the 
formula 
##STR13## 
and treating the latter with a basic agent and then with an esterification 
agent to obtain the corresponding compound of formula II. 
In a preferred mode of the latter process, the carbonation of the compound 
is effected with carbonic acid gas in the presence of a strong base such 
as a lithium alkyl and the reduction of the compound of formula VI is 
preferably effected with hydrogen in the presence of a catalyst. The 
cyclization of the compound of formula VII is either effected 
spontaneously or in the presence of an acid, preferably a mineral acid. 
The irradiation step may be effected with a mercury vapor lamp in the 
presence of a sensitizer such as benzophenone. The treatment of a compound 
of formula X is effected with a basic agent such as sodium hydroxide or 
preferably potassium hydroxide in an aqueous-alcohol solvent and the 
esterification may be effected in situ without isolution of the acid. 
The esterification agent leading to the compounds of formula II can be any 
reagent known to an expert to obtain the desired esters. When it is 
desired to prepare a methyl ester, it is particularly convenient to use 
diazomethane. When it is desired to prepare other alkyl esters, the 
corresponding diazoalkanes can be used. 
The synthesis of cis chrysanthemic acids and their alkyl esters offers at 
the present time a quite particular interest, because they are used 
especially for the preparation of cyclopropane carboxylic acids with a 
dihalovinyl chain, certain esters of which are well known to possess a 
remarkable pesticidal activity, in particular insecticidal. The invention 
process provides a total synthesis of racemic or optically active alkyl 
esters of cis chrysanthemic acid, comprising a small number of steps with 
high yields. This synthesis is stereo-specific and in fact, the addition 
reaction and the cyclization leading to the pyrazolines of formulae 
IX.sub.a and IX.sub.b are stereo-specific, and the following stages do not 
cause any isomerization. 
The compound of formula II, and then the compounds of formulae IV and I of 
cis configuration are the only isomers obtained. Furthermore, the process 
of the invention presents a quite unexpected character in the light of the 
teaching of prior art. In fact, many authors, among them Matsui et al Agr. 
Biol. Chem. 28 456 (1964), Ficini et al Tet. Letters, 1976, 2441 and 
Snieckus et al Tet. Letters, 1982, 1343, did not succeed in dehydrating 
the cis configuration alcohol of formula II. The process of the present 
invention enables this dehydration to be effected with a total yield which 
can exceed 70%. 
The racemic or optically active compound of formula V utilized as a 
starting material is known and described, for example, in Tet. Letters No. 
29, p. 2683 (1979). 
The novel intermediates of the invention are the racemic and optically 
active compounds of formulae IV, VI, VII, IX.sub.a and IX.sub.b.

In the following examples there are described several preferred embodiments 
to illustrate the invention. However, it should be understood that the 
invention is not intended to be limited to the specific embodiments. 
EXAMPLE 1 
(1S,cis)methyl chrysanthemate 
STEP A: 4R-hydroxy-5-methyl-hex-2-ynoic acid 
195.6 ml of a 1.3M solution of butyl-lithium in hexane were added slowly to 
a solution of 10.5 g of 3R-hydroxy-4-methyl-pent-2-yne in 180 ml of 
tetrahydrofuran cooled to -78.degree. C. and when the addition was 
finished, an excess of solid carbon dioxide was added in small pieces. An 
abundant precipitate formed and after returning to ambient temperature, 
100 ml of water were added to dissolve the colloidal mass. The aqueous 
phase after separation from the organic phase was acidified with 
concentrated hydrochloric acid and was extracted with ether. The solvent 
is evaporated to obtain 21.05 g of 4R-hydroxy-5-methyl-hex-2-ynolic acid 
which was crystallized from benzene to obtain 8.9 g of the product in the 
form of white crystals melting at 80.degree. C. and a specific rotation of 
[.alpha.].sub.D.sup.20 =+10.6.degree. (c=2% in dioxane). 
STEP B: 5R-Isopropyl-2-(5H)-furanone 
A solution of 7.62 g of the product of Step A in 120 ml of methanol was 
hydrogenated at ordinary temperature and pressure in the presence of 500 
mg of palladium on barium sulfate and a few drops of quinoline and the 
hydrogenation was stopped when the theoretical quantity of hydrogen was 
consumed. The catalyst was filtered off and the filtrate was evaporated to 
dryness. The residue was dissolved in 20 ml of ether, and to this solution 
2 ml of concentrated HCl were added. The mixture was vigourously stirred 
and the ethereal phase was decanted, washed with sodium bicarbonate and 
with water. After drying over sodium sulfate, the ether was evaporated and 
the residue was distilled to obtain 5.70 g of 5R-isopropyl-2-(5H)-furanone 
with a boiling point of 78.degree.-79.degree. C. at 0.1 mm. mercury and 
having a specific rotation of [.alpha.].sub.D.sup.25 =-96.degree. C. (c=2% 
in dioxane). 
STEP C: 4,4-dimethyl-6R-isopropyl-7-oxa-2,3-diazabicyclo-oct-2-en-8-one 
(compound A) and 
4,4-dimethyl-8R-isopropyl-7-oxa-2,3-diazabicyclo-oct-2-en-6-one (compound 
B) 
25 ml of a 3.3M solution of diazo-2-propane in an ether ethylbenzene 
mixture prepared according to Dietrich-Buchecker et al (Tetrahedron, Vol. 
33 p. 745 (1977) were added in 5 ml portions to a solution of 20 ml of 
ether and 5.30 g of the product of Step B, while the temperature was kept 
at about -10.degree. C. After 2 hours at ambient temperature, the ether 
was evaporated at ambient temperature and the residue was chromatographed 
over silica gel. Elution with hexane with 20% of ether yielded a first 
fraction of compound B which was crystallized (m.p. 78.degree.-82.degree. 
C. with decomposition), followed by 300 mg of a mixture of compounds A and 
B, and a final fraction of 4.37 g of compound A in the form of a colorless 
liquid. 
STEP D: (1S,3R,4R)6,6-dimethyl-4-isopropyl-3-oxabicyclohexan-2-one 
A solution of 2.38 g of compound B of Step C and 4.8 g of benzophenone in 
200 ml of benzene was irradiated with a mercury vapor lamp type Philips 
HPK125 until the stochiometric quantity of nitrogen had been given off. 
After evaportation of the solvent, the residue was chromatographed over 
silica gel and eluted with hexane with 20% of ether to obtain 1.28 g of 
(1S,3R,4R)6,6-dimethyl-4-isopropyl-3-oxabicyclo-hexan-2-one having a 
specific rotation of [.alpha.].sub.D.sup.20 =+80.degree. (chloroform). 
Photolysis under the same conditions of 4.30 g of compound A in the 
presence of 9.0 g of benzophenone in solution in 1 liter of benzene and 
after total evolution of the nitrogen and isolation as previously, 3.30 g 
of the same cyclopropane lactone as above were obtained with a specific 
rotation of [.alpha.].sub.D.sup.20 =+70.degree. (chloroform). 
STEP E: 
Methyl(1S,3R)2,2-dimethyl-3-(1-hydroxy-2-methyl)-propyl-1-cyclopropane 
carboxylate 
A solution of 4.2 g of the product of Step D in 55 ml of ethanol was mixed 
with a solution of 11.3 g of potassium hydroxide in 30 ml of water. After 
48 hours at ambient temperature and elimination of the greater part of the 
ethanol under reduced pressure, water was added and the aqueous solution 
was washed with ether. Then the aqueous phase was acidified with 10% 
hydrochloric acid, and extracted with ether. The organic extract was dried 
and then treated immediately with an ethereal solution of diazomethane, 
slightly in excess. After one hour at ambient temperature, the solvent was 
evaporated under reduced pressure to obtain 5.0 g of 
methyl(1S,3R)2,2-dimethyl-3-(1-hydroxy-2-methyl)-propyl-1-cyclopropane 
carboxylate which was used as is in the continuation of the synthesis. 
STEP F: 
Methyl(1S,3R)2,2-dimethyl-3-[1-(4-methyl-phenoxy-carbonothioyloxy)-2-methy 
lpropyl]-1-cyclopropane-carboxylate 
2.4 ml of O-paratolyl chlorothioformate were added dropwise to a mixture of 
2.80 g of the product of Step E and 1.5 ml of pyridine in 40 ml of 
methylene chloride. After 48 hours at ambient temperature, the reaction 
mixture was diluted with 200 ml of ether and was washed with water. After 
drying and evaporation of the solvents, the residue was chromatographed 
over silica gel and eluted with hexane with 5% of ether to obtain 2.34 g 
of methyl(1S,3R)2,2-dimethyl-3-[1-(4-methyl-phenoxy-carbonothioyloxy)-2-me 
thylpropyl]-1-cyclopropane-carboxylate. 
STEP G: Methyl(1S cis)chrysanthemate 
A solution of 1.725 g of the product of Step F in 20 ml of 
1,2,4-trichloro-benzene was heated slowly to 140.degree. C. and then kept 
at this temperature for 15 minutes. After cooling, the solution was 
chromatographed over silica gel and eluted with hexane with 2% of ether to 
obtain 692 mg of methyl (1S,cis) chrysanthemate having a specific rotation 
of [.alpha.].sub.D.sup.20 =-60.5.degree. C. (benzene) of (1S,3R) 
configuration. 
EXAMPLE 2 
Methyl(1R,cis)chrysanthemate 
Using the procedure of Example 1, 3S-hydroxy-4-methyl-pent-2-yne was 
reacted with the same succession of stages to obtain 
methyl(1R,cis)chrysanthemate having a specific rotation of 
[.alpha.].sub.D.sup.20 =+66.5.degree. (benzene). 
EXAMPLE 3 
Methyl cis chrysanthemate 
STAGE A: 4,4-dimethyl-6-isopropyl-7-oxa-2,3-diazabicyclo-oct-2-en-8-one 
(compound C) and 
4,4-dimethyl-8-isopropyl-7-oxa-2,3-diazabicyclo-oct-2-en-6-one (compound 
D) 
40 ml of a 3M solution of diazo-2-propane in an ether-ethylbenzene mixture 
[prepared according to Dietrich-Buchecker et al Tetrahedron., Vol. 33, p. 
745 (1977)] were added in portions of 5 ml to a solution of 7.70 g of 
5(RS)isopropyl-2(5H)furanone obtained as described in Example 1 beginning 
with 3(RS)hydroxy-4-methyl-pent-2-yne in 20 ml of ether while keeping the 
temperature at about -10.degree. C. After 2 hours at ambient temperature, 
the ether was evaporated at ambient temperature and the residue was 
chromatographed over silica gel. Elution with hexane with 20% of ether 
yielded one fraction of 4.45 g of compound D crystallized (m.p. 
68.degree.-69.degree. C.) and one fraction of 7.25 g of compound C in the 
form of a colorless liquid. 
STEP B: 6,6-dimethyl-4-isopropyl-3-oxabicyclohexan-2-one 
A solution of 3.50 g of the D compound of Step A and of 7.00 g of 
benzophenone in 1 liter of benzene was irradiated with a mercury vapour 
lamp of Philips type HPK125 until the stochiometric quantity of nitrogen 
had evolved. After evaporation of the solvent, the residue was 
chromatographed over silica gel and eluted with hexane first with 5% and 
then with 10% of ether to obtain 2.73 g of 
6,6-dimethyl-4-isopropyl-3-oxabicyclohexan-2-one with a boiling point of 
47.degree.-48.degree. C. at 0.05 mm Hg. 
Photolysis under the same conditions of 4.30 g of compound C in the 
presence of 9.0 g of benzophenone in solution in 1 liter of benzene and 
after total evolution of nitrogen and separation as previously yielded 
3.30 g of the same cyclopropane lactone. 
STEP C: Methyl cis 
2,2-dimethyl-3-(1-hydroxy-2-methyl)-propyl-1-cyclopropane carboxylate 
A solution of 2.7 g of the product of Step B in 40 ml of ethanol was mixed 
with a solution of 7.5 g of potassium hydroxide in 20 ml of water. After 
48 hours at ambient temperature and elimination of the greater part of the 
ethanol under reduced pressure, water was added and the aqueous solution 
was washed with ether. The aqueous phase was then acidified with 10% 
hydrochloric acid and was extracted with ether. The organic extract was 
dried and evaporated to dryness and the residue of 2.9 g was immediately 
treated with an ethereal solution of diazomethane in slight excess. After 
one hour at ambient temperature, the solvent was evaporated under reduced 
pressure to obtain 3.10 g of methyl cis 
2,2-dimethyl-3-(1-hydroxy-2-methyl)-propyl-1-cyclopropane carboxylate 
melting at 58.degree.-59.degree. C. after crystallization from an ethyl 
ether-hexane mixture. 
STEP D: Methyl cis 
2,2-dimethyl-3-[1-(4-methyl-phenoxycarbonothioyloxy)-2-methylpropyl]-1-cyc 
lopropane carboxylate 
0.3 ml of O-p-tolyl chlorothioformate was added dropwise at 0.degree. C. to 
a mixture of 0.2 g of the product of Step C and 0.16 ml of pyridine in 6 
ml of dry methylene chloride. After 48 hours, the reaction mixture was 
adsorbed at 0.degree. C. on a minimal quantity of silica (.perspectiveto.2 
g) and then was chromatographed over silica gel. Elution with hexane with 
2% of ether yielded 0.383 g of methyl cis 
2,2-dimethyl-3-[1-(4-methyl-phenoxycarbonothioyloxy)-2-methylpropyl]-1-cyc 
lopropane carboxylate melting at 92.degree.-93.degree. C. after 
crystallization from hexane. 
STEP E: Methyl cis chrysanthemate 
A solution of 0.693 g of the product of Step D in 10 ml of 
1,2,4-trichloro-benzene was heated slowly at 140.degree. C. and then 
maintained for fifteen minutes at this temperature. After cooling, the 
solution was poured directly onto a column of silica gel and eluted with 
hexane with 2% of ether to obtain 0.323 g of methyl cis-chrysanthemate. 
Various modifications of the products and processes of the invention may be 
made without departing from the spirit or scope thereof and it should be 
understood that the invention is intended to be limited only as defined in 
the appended claims.