DE2116416A1 - Process for the preparation of 3,4-disubstituted "(5H) -furanones - Google Patents

Description

E. M e r c k, April 15, 1970

Darmstadt

Process for the preparation of 3,4-disubstituted 2 (SH) -furanones

It is known that 3,4-disubstituted 2 (5H) -furanones can be prepared by reacting cc-haloketones with alkali salts of acetic acid substituted with an electron-withdrawing group. Thus, 3-cyano ~ 4 ~ phenyl-2 (5H) -furanone was obtained in 39.4% yield by reaction of io ~ bromoacetophenone with sodium cyanacotate. It is also known that this and a number of related products are valuable intermediates for the preparation of polymethine dyes / Journal of Organic Chemistry, Volume 32 (1967), pages 173-17, 17 "> these compounds are also valuable intermediates for However, the preparation of pesticides. the known synthesis of 3,4-disubstituted 2 (5II) -furanones allowed because of this low yields to be achieved, does not exceed 47 ^c / o of theory, no economic production of these compounds.

It has now been found that 3,4-disubstituted 2 (5H) -furanones of formula I.

209843/1141

R ¹ X

wherein R is alkyl with 1-6 carbon atoms, phenyl or phenyl monosubstituted or polysubstituted by halogen, NO ₂ , CN and / or OR,

X CN or COOR ² and

ο
R denotes alkyl with 1-4 carbon atoms,

Surprisingly, produce them with good yields which enable these compounds to be used economically can that you a compound of formula II

R ¹ ^ -CO-CH ₂ -OCOCH ₃ (II)

where R has the same meaning as in formula I,

in a polar solvent in the presence of a basic condensing agent with a compound of formula III

X-CH ₂ -COOR ² (III)

2
wherein X and R have the meaning given above,

implements

209843/1141

The invention accordingly provides a process for the preparation of 3,4-disubstituted 2 (5H) -furanones Formula I, which is characterized in that an acetoxymethyl ketone of the formula II in a polar solvent Reacts in the presence of a basic condensing agent with a compound of the formula III

Although the most diverse acetoxymethyl ketones are involved in the reaction can be used, it is preferred to start from those derivatives which lead to compounds of the formula I with, for example lead the following substituents in the 4-position:

Methyl, ethyl, n-propyl, iso-propyl, n-, sec-, iso- and tert-butyl, amyl, iso-amyl, noopentyl, hexyl, phenyl, 2-, 3- or 4-chlorophenyl, 3- or 4-bromophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-ethoxyphenyl, 2,3-, 2,4-, 2,6-, 3,4- or 3,5-dichlorophenyl , 2,4- or 3,5-dinitrophenyl and 3-chloro ~ 4-methoxyphenyl. Among these radicals, the phenyls which are only substituted once or with two identical groups, and in particular the unsubstituted phenyl radical, are preferred Correspondingly, W-acetoxy-acetophenone and in the phenyl nucleus are single or twice the same with Cl, Dr, F, NO ₂ , CN, OCHo and OCoH ₅ Substituted üJ-Acetoxyacetophenone preferred starting compounds of the formula II. The acetoxymethyl ketones of the formula II are either known or can be prepared in a manner analogous to the known ones, for example by reacting the corresponding halomethylicetones with sodium acetate in acetic acid / acetic anhydride In many cases, it is not necessary to isolate the acetoxymethyl ketones produced in this way in pure form. It has been shown that the use of reaction mixtures obtained by this process and containing the acetoxymethyl ketones of the formula II, from which only the solvent has been removed, leads to good yields of compounds of the formula I in the process according to the invention.

209843 / 1U1

The following substituents in the 3-position of the 3,4'-disubstituted 2 (5H) -furanones which can be prepared according to the invention are embossed: CN, carbomethoxy, carboethoxy, carboprogoxy, Garbo-isopropoxy, Garbo-n-butoxy, Carboisobutoxy, Garbo- sec.butoxy and carbo-tert.butoxy. Preferred among these groups are CN, COOCH ₃ , COOC ₂ H ₅ , COO-nC-Hg and

Accordingly, preferred starting compounds of the formula are III to be mentioned: methyl cyanoacetate, ethyl cyanoacetate, Cyanoacetic acid n- · and iso-butyl ester ,. Halon, acid dimethyl ester, malonic acid diethyl ester, malonic acid-di-n- and isobutyl ester *

The reaction of an acetoxymethyl ketone of the formula II with a compound of the formula III vrlrä. carried out in polar solvents in the presence of a basic condensing agent. It has proven particularly advantageous to use the reactants of the formulas II and III and the basic condensing agent in approximately equimolar amounts. Suitable polar solvents are preferably lower aliphatic alcohols such as methanol, ethanol, isopropanol and butanol, which can optionally also contain water; dimethylformamide and dimethyl sulfoxide are also suitable. However, methanol and ethanol, which may also contain small amounts of water, are particularly preferred. According to the invention, alkali metal and alkaline earth metal hydroxides and the alkali metal alcoholates of lower aliphatic alcohols are used as basic condensing agents. Preference is given to using NaOH, KOH, NaOCH ₃ , KOCH ₃ , NaOC ₂ II ₃ and KOC ₂ II ₅ . The reaction is conducted at temperatures between -10 ⁰ C and +50 ⁰ C, preferably between ⁰ · pre- C and +40 ⁰ C durchgeführtk The reaction time is generally between 30 minutes and 20 hours.

20 9843/1 14 1

After the end of the reaction, the reaction mixture is adjusted to a pH between 1 and 6 by adding acid, preferably a mineral acid such as hydrochloric acid or sulfuric acid, the desired compound of the formula I precipitating in pure form. The yields are between 60 and 100 %. the theory,

If one compares the reactivities of the reaction partners used in the known synthesis of the 3,4-disubstituted 2 (5H) -furanones, halomethyl ketone and sodium cyanacetate with those of the reaction partners used according to the invention, acetoxymethyl ketone and cyano- or carbalkoxy-acetic acid esters, then it must be It should be considered surprising that in the process according to the invention the 2 (5H) -furanones of the formula I are obtained in yields which are relatively 30-100 <fo higher than in the known process. that in the reaction-determining step with elimination of sodium halide from the methyl halide ketone and the sodium salt of cyanoacetic acid an oc-oxoalkyl ester is formed, which is then cyclodehydrated to 2 (5Il) -furanone.This ester formation is a reaction that is known to be easily accessible primary in such nucleophilic substitution reactions Halides, like the halomethyl ketones, have high yields In contrast, in the process according to the invention, such an α-oxoalkyl ester can only be formed from the acotoxymethyl ketone of the formula II and the cyano- or carbalkoxy-acetic acid ester of the formula III by a double transesterification. Such reactions are hardly known to date; Furthermore, it was not to be expected that such a double transesterification would proceed with such high yields as is found in the process according to the invention. This is all the more true as here the two esters reacting with one another are used in approximately equivalent amounts; Even with simple transesterifications, high yields of the desired new ester can only be obtained if the corresponding alcohol is used in large excess.

■ 209843/1 UI

The production of the 3,4-disubstituted 2 (5H) -furanones of the formula I by the process according to the invention enables the economical production of a number of valuable substances, in particular of dyes and pesticides. The preparation of dyes from intermediates of the formula I is described in the Journal of Organic Chemistry, Volume 32 (1967), pages 173-176. The 3-cyano-5-diaethylaiainoinethylene-4-phenyl-2 (5H) -furanone also described there, which according to the German patent application P 19 65 134 also has an excellent herbicidal activity, can be obtained from 3-cyano-4r-phenyl-2 (5H ) ~ iuranon (formula I; R ₁ = phenyl, X = CN) can be produced by reaction with dimethylformamide and a chlorinating agent such as POCl ₃ , SOCl ₂ , COCl ₂ , PCl ₅ or SO ₂ Cl ₂

example 1

A solution of 89 gui-acetoxyacetophenone and 70.5 g of isobutyl cyanoacetate in 400 ml of methanol is mixed with a likewise cooled solution of 22 g of sodium hydroxide in 300 ml of methanol while cooling with ice water. After allowing the reaction mixture to stand for 4 hours at room temperature for 20 $ * hydrochloric acid is added until a pH of 5 «The precipitating cream colored material is filtered off, washed with water, ethanol and Diäthylather and dried at 90 ⁰ C in vacuum; there are 77 g of 3 'cyano-4-phenyl-2 (5H) -furanone (83.3 fi of theory) which are uniformly thin-layer chromatography and melts at 164 ⁰ C ·

209843 / 1U1

Example 2

77.5 gto-chloroacetophenone and 50 g of sodium acetate are refluxed for 6 hours in a mixture of 100 ml of glacial acetic acid and 15 ml of acetic anhydride 400 ml of methanol are added. A cold solution of 22 g of sodium hydroxide in 300 ml of methanol is added to the mixture, which has been cooled with ice water and, after 4 hours, the procedure is as in Example 1. 76.2 g of 3-cyano-4-phenyl-2 are obtained (5H) -furanone (82.5 # of theory), F. 163 ⁰ C ₁ obtained «

Example 3

A solution of 8.4 g of potassium hydroxide in 75 ml of methanol ^{is added at 0} ° C. to 37.5 g of tI-acetoxyveratrone (3,4-dimetkoxyphenyl acetoxymethyl ketone) and 17 g of ethyl cyanoacetate in 150 ml of methanol. The mixture remains at room temperature for 2 hours; then it is diluted with 250 ml of water and bit concentrated hydrochloric acid is acidified. The 3-cyano-4- (3,4-dimethoxyphonyl) -2 (5H) ~ furanone which precipitates is filtered off with suction and recrystallized from acetonitrile; M.p. 221 ° C, yield 30 g (81.5 # of theory).

The following are obtained analogously:

from acetoxyethyl tert-butyl ketone and ethyl cyanoacetate 4-tert-butyl-3-cyano-2 (5H) -furanone; F. 64 ° C, yield 64.3 f »

the theory,

from acetoxyacetone and ethyl cyanoacetate 3 ~ cyano-4- »ethyl-2 (5H) -furanone; M.p. 122 ° C, yield 61 #

the theory.

209843/1141

Example 4 '

To a solution of 16 g of 4-chloro-W-acetoxyacetophenone and 8> g of cyanoacrylate in 75 ml of methanol, a cooled sodium methylate solution prepared from 1.8 g of sodium and 30 ml of methanol is added at 0 ° C .; the temperature rises to about 38 ° G. After standing for 2 hours, the precipitated gray-green product is filtered off with suction, dissolved in water and treated with 3 ml of concentrated hydrochloric acid. The thereby precipitated 4- (4-chlorophenyl) -3-cyano-3 (5H) -furanone Fe is filtered off with suction and recrystallized from acetonitrile; P. 233 ⁰ C, yield 12 g (73 % of theory).

Example 5

To a solution of 445 g of u-acetoxyacetophenone and 400 g of malonic acid dietyloster in 1.5 1 of ethanol, a sodium ethylate solution freshly prepared from 57.5 g of sodium and 1.5 1 of ethanol is allowed to run in as quickly as possible at 5 ° C. while cooling with ice The reaction mixture is poured into 10 liters of water overnight and acidified with concentrated hydrochloric acid, 3-Carboethoxy-4- phenyl-2 (51l) -furanone separating out as a greenish oil, which crystallizes after a while, is filtered off with suction and converted into ethanol Is recrystallized in the presence of activated charcoal; P. 82 ⁰ C, yield 394 g (67.6 ^c / o of theory).

209843/1 UI

Claims (1)

Claims A process for preparing compounds of formula I B ¹ X XC XC. <■> wherein R is alkyl with 1-6 carbon atoms, phenyl or through Halogen, NO ₂ , CN and / or OR mono- or polysubstituted phenyl, X CN or COOR ² and R denotes alkyl with 1-4 carbon atoms, characterized in that a compound of the formula II R ^1- -CO-CH ₂ -OCOCH ₃ (II) where R has the meaning given above, in a polar solvent in the presence of a basic one Condensing agent with a compound of formula III X-CH ₂ -COOR ² (III) 2
wherein X and R have the meaning given above, implements 2098A3 / 1141 2. Process according to claim 1, characterized in that the reaction is carried out at a temperature between »10 C and +50 ⁰ C · 3 · Process for the preparation of _{3-cyano ~ 4 ~ phenyl ~ 2 (5H) · furanones optionally substituted once or twice by halogen, NO 31} CN and / or alkoxy with up to 4 carbon atoms in the phenyl nucleus, characterized in that that one optionally substituted one or two times in the phenyl nucleus by halogen, NO ₃₁ CN and / or alkoxy with up to 4 carbon atoms oj-acetoxyacetophenone in an optionally hydrous aliphatic alcohol with 1-3 carbon atoms in the presence of an alkali metal hydroxide or - alcoholate reacts with a cyanoacetic acid ester with 4 - 7 carbon atoms at a temperature between ⁰ ° C. and 40 ^° C. 4 «Process for the preparation of 3« cyano-4-phenyl-2 (5H) -furanone, characterized in that UJ -. Acetoxyacetophenone in methanol or ethanol in the presence of an equivalent of sodium or potassium hydroxide with an approximately equimolar amount of ethyl cyanoacetate at a temperature between ⁰ ° C. and 30 ^° C. 209 84 3/114