FR2518999A1 - Heterocyclic ketone(s) prepn. - from heterocycle and acid with tri:fluoro:acetic anhydride and phosphoric catalyst - Google Patents

Abstract

Heterocyclic ketones of formula (I) (where X=N, O, S, NH or N-alkyl; Z=H, alkyl or alkenyl; R1=alkyl, aryl, furyl, thienyl, opt. substd. by a radical of the same gp or by halogen, cyano, amino, carbomethoxy or carboethoxy) are prepd. by reaction of a heterocycle (II) with trifluoracetic anhydride (III) and an organic acid R1COOH (IV) in the presence of a phosphoric catalyst (V) or (VI) (R2O)2P(:O)OH(V) or P2OP(:O)(OH)2 (where R2 is a hydrocarbon chain, which may be grafted to a polymeric support to form an ion exchange resin). Used as antibacterials and, after bromination, intermediates for the prepn.of epoxides. The process is easy to carry out and gives good yields.

Description

PROCESS FOR THE PIPING OF TONIC COMPOUNDS IN
PARTICULARLY OF FURANIC COMPOUNDS OR COMPOUNDS
CETONICS WITH LONG CHAINS, FURAN COMPOUNDS
AND CETONIC COMPOUNDS WITH LONG CHAINS PREPARED
BY IMPLEMENTING SAID METHOD.

où X est un hétéroatome du groupe N, O, S, NH ou N - alkyle, où Z est un radical du groupe suivant : hydrogène, alkyle, alkènyle, et où R est un radical du groupe : alkyle, alkényle, aryle, furyle, thiényle, substitué ou non par un radical du même groupe ou du groupe suivant : halogène, cyano, amino, carbométoxy, carbo-éthoxy.The invention relates to a process for the preparation of ketone compounds by transformation of a corresponding heteroaromatic compound, it more particularly to allow the preparation of ketone compounds of formula

where X is a heteroatom of the group N, O, S, NH or N-alkyl, where Z is a radical of the following group: hydrogen, alkyl, alkenyl, and where R is a radical of the group: alkyl, alkenyl, aryl, furyl , thienyl, substituted or unsubstituted by a radical of the same or the following group: halogen, cyano, amino, carbometoxy, carbo-ethoxy.

 The invention applies in particular to the transformation of furan compounds into furyl ketone compounds or to the production of long chain ketone compounds. It extends, as new products, to these long chain ketone compounds which have never been manufactured so far.

 The acylation reaction which has hitherto made it possible to obtain short chain ketone compounds has been the subject of numerous studies, in particular by using the particular properties of trifluoroacetic anhydride. The ketone compounds generally have antibacterial properties and are of great interest to carry out, especially after bromination, organic syntheses leading to the corresponding epoxides (bodies present in a large number of polymeric corruptions).

 The acylation reaction of the t) etheraromatic compounds consists of a condensation reaction of an organic acid on the hetero ring position of the hetero ring, the condensation generally taking place in the presence of trifluoroacetic anhydride. This compound can be isolated or react in situ with the heteroaromatic ring via the acylium ion created by its decomposition.

 In several articles by BOURNE et al (Journal of Chemical Society (1949, pp. 2976, 1951, pp. 718 and 826, 1952 pp. 1695 and 4014, 1953 pp. 735, 1954, pp. 4006, ...) it is shown that this The reaction is operative without catalyst, with long reaction times and medium yield and selectivity.

Very recently, a US patent of GS KUTA (American Cyanamid
Company No. 4,254,053, March 3, 1981) has used this technique and specifies the limits of the method as to the structure of the organic acid used. Moreover, in an article of
MARINO (Advances of Heterocyclic Chemistry, Volume 13, pages 235 1971), it is shown that an acid catalyst could be used in this type of reaction, these being rather selectively selective because of the presence of a significant amount of product. resulting from the trifluoroacetylation of the heteroatomic ring.Furthermore, in a recent GALLI article (Synthesis p.303, 1979), it is reported that 85% phosphoric acid, used as a catalyst, could reduce the reaction time, but that the introduction of water into the medium with a very corrosive catalyst seemed detrimental to the industrial development of such a process.

 Moreover, these authors specify that the acylation processes with or above the catalyst mentioned above are not operative to prepare long-chain ketone compounds, in which the R 1 radical has more than 11 carbons.

 The present invention proposes to indicate an improved process for the preparation of ketone compounds having a general formula of the above-mentioned type, which process is free from defects or limitations of known processes.

 One of the objectives of the invention is, in particular, to indicate a process for the selective production of ketone compounds from the corresponding heteroaromatic compounds.

 Another objective is to indicate a process which can be carried out with excellent yields, whatever the length of the chain of the ketone compound to be prepared.

 Another objective is to suppress the trifluoroacetylation side reactions of the heteroaromatic compound and to obtain a totally selective reaction in ketone compound.

 Another objective is to eliminate the requirement of the anhydrous nature of the medium, which characterizes the known processes and constitutes one of the defects.

 Another object of the invention is to allow the conversion into corresponding heterocyclic ketone compounds, hydroxylated aromatic acids resulting from the oxidative degradation of lignin (vanillic acid, p-hydroxybenzoic acid, etc.).

 Another objective is to indicate a non-exothermic process, able to operate with light solvents, inexpensive, regenerable and forming a medium from which the reaction products and the catalyst are easily separable.

où X, Z et-R1 sont choisis parmi les groupes précédemment mentionnés, est du type consistant à faire réagir un composé hétéroaromatique de formule

avec de l'anhydride trifluoroacétique de formule

et avec un acide organique de formule

For this purpose, the process according to the invention for preparing ketone compounds of formula

where X, Z and -R1 are selected from the groups previously mentioned, is of the type consisting in reacting a heteroaromatic compound of formula

with trifluoroacetic anhydride of formula

and with an organic acid of formula

où R2 est une chaîne hydrocarbonée, fonctionnalisée ou non.According to the present invention the reaction is carried out in the presence of a catalyst consisting of a phosphoric reagent of formula

where R2 is a hydrocarbon chain, functionalized or not.

 The chain R2 may, where appropriate, be grafted onto a support polymer and have ion exchange properties; this chain can also be in free form, directly attached to the corresponding oxygen of the phosphoric reagent.

 The nature of the catalyst used makes it possible to work in a strictly organic medium: however, the experiments have shown that a limited amount of water is not detrimental to the good progress of the reaction and its yield. In practice, the reaction will preferably be carried out in an aprotic organic solvent in a medium with little or no hydration, the degree of hydration being controlled and less than 2 moles of water per mole of the aldehyde.

 Moreover, the presence of the catalyst targeted by the invention removes any limitation relating to the length of the alkyl chain of the organic acid used and makes it possible to obtain long-chain ketone compounds in which the radical R 1 possesses at least 11 carbons. .

 In this case, saturated or unsaturated natural fatty acids will preferably be used, combining lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, lactic acid and the like. which give a reaction having an excellent yield and make it possible to prepare ketone compounds whose hydrophilic properties are intermediate between those of the fatty acid and that of the corresponding alkane or alkene (whose aliphatic chain has the same number of carbons) and give these molecules a surfactant character.

 It should be noted that, when the organic acid used contains two acidic functions, the acylation takes place selectively on one of the two functions which constitutes a further advantage of the synthetic process of the invention compared with those of the art. prior.

 Moreover, the reaction which occurs in the presence of the catalyst proposed by the invention does not present any risk of sudden development; it takes place particularly efficiently in very short reaction times at a temperature close to ambient (10 to 50 ° C.) but nevertheless remains operating at -20 ° C. and at reflux of the most volatile compound of the medium (as the case may be: heteroaromatic compound or aprotic solvent).

 With regard to the stoichiometry of the components which are brought together at the beginning of the reaction, the organic acid used as a reference value is advantageously used under the following conditions, the heteroaromatic compound is used in approximately stoichiometric proportion relative to that in particular in slight excess, particularly in the case of volatile heteroaromatic compounds such as furan; the trifluoroacetic anhydride is used in a proportion of between the stoichiometric proportion and 3 times the latter, while the catalyst is itself used so as to involve at least 10 moles of H + ions per 1 mole of heteroaromatic compound; an amount of catalyst close to 8.1 × 1 equivalent H + per mole of heteroaromatic compound seems to provide in most cases the best results, the reaction ratio of reactive components / organic solvent being close to 1/3.

 It should be noted, moreover, that the catalyst used does not undergo any alteration in the reaction and can be reused without regeneration, after filtration if it is a polymeric catalyst, after distil latic if it is is an alkylphosphate.

dans lesquels R1 est un radical du groupe dé7à évoqué, possèdant au moins ll carbones,
et les composés furylcétoniques même formule générale, t dans lesquels Z est constitué par/hydrogène et R1 par le radical CH3(CH2)n où n ) ltJ
L'invention exposée sous sa forme générale ci-dessus est illustrée ci-après par des exemples non limitatifs de mise en oeuvre.The invention extends, as such, to new products that can be manufactured by the method referred to above, in particular
ketone compounds with long chains of formulas

in which R 1 is a radical of the group mentioned above, having at least 11 carbons,
and the furylketonic compounds of the general formula, wherein Z is hydrogen and R 1 is CH 3 (CH 2) n where n)
The invention set forth in its general form above is illustrated hereinafter by non-limiting examples of implementation.

EXAMPLE 1
Synthesis of tet: hyl furyl-2 ketone from furan and propanoic acid.

In a 1-liter reactor equipped with a condenser, a mechanical stirrer and an addition funnel, 1.25 moles of furan, 1 mole of propanoic acid, 2.25 moles of anhydride are placed in a reactor of 1 liter. trifluroacetic acid and 5 × 10 2 H + equivalent in the form of macroporous polystyrene resin of reference "DUOLITE ES 467" (functional groups niels - NH - CH 2 PO 3 H 2) previously put in acid form and containing about 1 molecule of water per active site in 100 ml nitromethane nitromethane
After 10 minutes of reaction at 20 C the yield is close to 96%. The reaction is totally selective. The resin is filtered and recycled. The solvent and trifluoroacetic acid are evaporated and recycled. The concentrated medium is washed with K 2 CO 3 solution and dried over MgSO 4.

The ketone obtained then distilled at 87-88 ° / 12 mm Hg.

 If the level of hydration of the medium (controlled by the Karl FISHER method) is increased, the yield of ethyl furyl ketone decreases, and is then only 30% under experimental conditions rigorously identical to those described above for a resin containing 3 molecules of water per active site.

EXAMPLE 2
Synthesis of Pentyl Furyl-2 Ketone from Furan and Hexanoic Acid

 A 1-liter reactor equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a reactor: 1.25 × 10 1 mole of furan, 1 × 10 1 mole of hexanoic acid, 2.25 moles trifluoroacetic anhydride and 5-H + equivalent in the form of di (2-ethylhexyl) phosphate (BAYER alkylphosphate) in 100 ml of nitromethane.

 After 1 hour of reaction at 30 ° C., the yield is 85%. The reaction is completely selective, the resin is filtered and recycled. The solvent, trifluoroacetic acid and phosphonic ester are removed and recycled. The concentrated phase is washed with a K 2 CO 3 solution, dried over anhydrous MgSO 4 and then distilled. Pentyl furyl-2-ketone is separated at 120-123 ° / 18 mm Hg.

The addition of water to the medium substantially reduces the yield in a homogeneous medium, and it is only 10% for a degree of hydration close to 3 molecules of water per H ion.
EXAMPLE 3
Synthesis of 7-oxethyl-7-heptanolic acid from heptanedioic acid (pimelic acid).

 A 1-liter reactor equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a 1.25 mole of furan, 1 mole of pimelic acid and 2.25 mole of anhydride. trifluoroacetic acid and 1 × 10 equivalent H + in the form of "DUOLITE ES 467" resin in acid form in 100 ml of nitromethane.

 After 15 minutes of reaction at 30 C the yield is of the order of 80%. The resin is filtered and recycled. The solvent and trifluoroacetic acid are evaporated and recycled; the ketonic acid obtained distils at 210-215 / 14 mmHg.

EXAMPLE 4
Synthesis of p-hydroxyphenyl 2-furyl ketone from p-hydroxybenzoic acid and furan.

 A 1-liter reactor equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a reactor: 1.25 × 10 1 mole of furan, 1 × 10 1 mole of hydroxybenzoic acid, 2 × 10 moles trifluoroacetic anhydride and 1 equivalent + as "DUOLITE ES 467" resin in acid form in 100 ml of acetonitrile.

 After 45 minutes of reaction at 30 ° C., the yield is approximately 85%. The resin is filtered and recycled.

The solvent and trifluoroacetic acid are evaporated and recycled, the product obtained after recrystallization melts at 164 ° C.

EXAMPLE 5
Synthesis of Pentadecanyl Furyl - 2 Ketone from Palmitic Acid and Furan.

 In a 1-liter reactor equipped with a condenser, a mechanical stirrer and an addition funnel, 1.25 molar 10-1 mol of furan, 1.10-1 mol of palmitic acid, 2.25 mol. trifluoroacetic anhydride and 1 equivalent equivalent H in the form of "DUOLITE ES 467" resin in acid form in 100 ml of nitromethane.

 After 15 minutes of reaction at 20 ° C., the resin is filtered and recycled. The solvent and trifluoroacetic acid are evaporated and recycled. Pentadecanylfuryl ketone is obtained after recrystallization with a yield of 91% (melting temperature: 50 ° C.).

EXAMPLE 6
Synthesis of p-nitrebenzyl furyl-2-ketone from p-nitrophenyl-2 ethanoic acid and furan.

 A 1-liter flask equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a 1-liter flask: 1.25 mol of furan, 1 mol of 2-hydroxyphenyl-2-ethanol acid, , 1 mol of trifluoroacetic anhydride and 5-H + equivalent as "ES 467" resin in acid form in 100 ml of methylene chloride.

 After 30 minutes of reaction at 30 C the resin is filtered and recycled. The solvent and trifluoroacetic acid are evaporated and recycled. P-Hydroxybenzyl furyl ketone is obtained after recrystallization, with a yield of 86%.

EXAMPLE 7
Synthesis of N-methyl 2-pyrryl-2-furyl ketone from N-methyl-carboxylic acid and furan.

 A 1,1-liter flask equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a 1-liter flask: 1.25 × 10 -2 mole of furan, 1.10 1 mole of N-methylpyrrole carboxylic acid, 2.25 × 10 1 moles of trifluoroacetic anhydride and 1.10 1 equivalent H + in the form of resin "ES 467" in acid form in 100 ml of nitromethane.

 After 30 minutes of reaction at 30 ° C., the yield of S-methylpyrryl-2-furylketone is close to 90%.

The resin is filtered and recycled. The solvent and trifluoroacetic acid are evaporated and recycled, the ketone distilled at 162/13 mm Hg.

EXAMPLE 8
Synthesis of thienyl - 2 undecanyl ketone from lauric acid and thiophene.

 A 1-liter flask equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a 1-liter flask: 1.10 1 mole of thiophene, 1.10 1 mole of lauric acid, 2 moles of trifluoroacetic anhydride, presence of 1 × 10 equivalent H + in the form of resin "ES 467" in acid form in 100 ml of nitromethane.

 After 30 minutes of reaction at 40 ° C., the yield is approximately 92%. The resin is filtered and recycled.

The solvent and trifluoroacetic acid are evaporated and recycled. The 2 - thienyl undecanyl ketone / distilled at 162/1 mm Hg.

EXAMPLE 9
Synthesis of bromo - 5 - pentyl furyl ketone from 6 - bromo hexanoic acid and furan.

 A 1-liter flask equipped with a condenser, a mechanical stirrer and an addition funnel is placed in a 1-liter flask: 1 mole of 6-bromo hexanoic acid, 1.25 mole of furan and 2 mole of 10 mol of trifluoroacetic anhydride in the presence of 710 1 H + equivalent in the form of retina "ES 467" in acid form in 100 ml of nitromethane.

 10 minutes this reaction at 20 C the yield is about oc 95. The resin is filtered and recreated.

The solvent and trifluoroacetic acid are evaporated and recycled. 5-Bromo pentyl furyl ketone / distilled at 115 -120 C by 0.1 mm Hg.

Claims (12)

 1 / - Process for preparing ketone compounds of formula

 where X is a heteroatom of the group N, O, S, NH or N-alkyl, where Z is a radical of the following group: hydrogen, alkyl, alkylen, and where R1 is a radical of the group: alkyl, aryl, furyl, thienyl substituted or unsubstituted by a radical of the same or the following group: halogen, cyano, amino, carbo methoxy, carbo ethoxy,  said method comprising reacting a heteroaromatic compound of the formula

 with trifluoroacetic anhydride of formula

 and with an organic acid of formula

 and being characterized in that the reaction is carried out in the presence of a catalyst consisting of a phosphoric reagent of formula

 where R2 is a hydrocarbon chain, functionalized or not.  2 - Process according to the rev-ndication i, characterized in that ase is used co catalyst a phosphoric active precatéf formula, grafted on a polymer-sup port, said catalyst having ion exchange properties.  3 / - The method of claim 1, characterized in that the reaction is carried out in an aprotic organic solvent, little or not hydrated, the hydration rate being less than 2 moles of water per mole of alhyde.  4 / - Process according to one of claims 1 or 2, characterized in that the heteroaromatic compound and. the organic acid are dissolved in the presence in approximately stoichiometric proportion with respect to each other, the trifluoroacetic anhydride being brought into the presence of these bodies in a proportion comprised between the stoichiometric proportion and 3 times the latter, while the catalyst is itself brought into contact with said bodies so as to involve at least 10 moles of H + ions for one mole of heteroaromatic compound.  5 / - Method according to one of claims 1, 2, 3 or 4, characterized in that it is carried out at a temperature between approximately 10 C and 50 C.  6 / - Method according to one of claims 1, 2, 3, 4 or 5, for preparing long chain ketone compounds of formula above, wherein the R1 radical has at least 11 carbons, characterized in that the one of the following fatty acids is used in the reaction: lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid.  7 / - Method according to one of claims 1, 2, 3, 4, 5 or 6, for preparing-furylketonic compounds, characterized in that a compound is used. heteroaromatic formula

 where Z is a radical of the aforementioned type.  8. The process as claimed in claim 7, wherein the furan is used in the reaction as a heteroaromatic compound.

 9 / - Process according to claim 8, for preparing long-chain furyl ketone compounds of formula

 where n> 10, characterized in that furan is used in the reaction as a heteroatomic compound and, as organic acid, natural fatty acids of formula

 10 / - Method according to one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, characterized in that it uses in the reaction an organic acid,  in which R1 is a radical of the following group: C2H5,

 11 / - Long-chain ketone compound of the formula

 manufactured by carrying out the process according to claim 6, characterized in that R1 is a radical of the aforementioned group having at least 16 carbons.  12 / - Furyl-ketonic compound of formula

 manufactured by carrying out the process according to claim 9, characterized in that Z is hydrogen and R1 is (CH2) nCH3 where n> 10.