IE41513B1

IE41513B1 - Process for the production of 2,3-dihydrobenzofurans

Info

Publication number: IE41513B1
Application number: IE182175A
Authority: IE
Original assignee: Fisons Ltd
Priority date: 1974-09-05
Filing date: 1975-08-18
Publication date: 1980-01-16
Also published as: HU173992B; IL47922A0; PL103396B1; DK398275A; IE41513L; DD121934A5; IL47922A

Description

lhe present invention relates to a chemical process for preparing compounds of the general formula: [in whioh R^ and R2 may be the same or different and each is selected from hydrogen or an alkyl group (notably an alkyl group containing 1 to 6 carbon atoms, e.g. methyl, ethyl or propyl groups) or R^ and R2 together form an alkylene chain (e.g. one containing 2 to 5 carbon atoms); M is an alkyl group; R^, Rg and Rg may be the same or different and each is selected from hydrogen, an alkyl (e.g. lower alkyl) or an alkoxy (e.g. lower alko;y) group or a halogen atom; and R? is an alkyl group (e.g. lower alkyl, notably methyl, ethyl or propyl)]. These compounds find use as herbicides.

The term lower is used herein with respect to alkyl and alkoxy groups to denote that these groups contain from 1 to 6 carbon atoms.

Accordingly, the present invention provides a process for preparing a compound of formula I which comprises reacting a compound of formulas [wherein R^, R2< R4, Rg, Rg and Ry have the values above and R1Q and R^ may be the same or different and each is selected from a lower alkyl group or R^Q and R^ together with the nitrogen atom form a heterocyclic ring] with a mixture of a strong acid as hereinafter defined and a compound of the formula HOM wherein M has the values given above. , The invention is of especial application in the production of compounds of formula I wherein R^^ and R2 are both lower alkyl groups (notably methyl or ethyl groups); R4, Rg and Rg are hydrogen; R-, is methyl and M is lower alkyl, notably methyl, ethyl, propyl or isopropyl. The preferred starting material of formula II has Rlo and R^ together with the nitrogen atom forming a heterocyclic ring selected from piperidino, pyrrolidine, and notably morpholino.

The term strong acid as used herein is to denote a mineral acid or an organic acid; a) which does not take part in deleterious side reactions during the process, apart from forming a salt with the amine HNR^qR^^ released during the process; and b) whioh preferably dissociates in water to give at least 1 gram equivalent of H per gram mol of acid. Thus, suitable strong acids for present use include hydrochloric, sulphuric and phosphoric acids, but do not include nitric acid whioh may oxidise the reagents 42.52.3 and/or products. The strong acid may be used in the form of an aqueous solution thereof or in an anhydrous form.

The strong mineral acid for present use is preferably hydrochloric acid which desirably provides not less than 20 parts by weight of HCL per 80 parts of water in the reaction mixture.

I The compound HOM is, as indicated in the preferred compounds which it is desired to produce, preferably an alkanol, notably methanol, ethanol, propanol or iso-propanol.

The process of the invention is carried out in a liquid medium which may be merely an excess of the alkanol reagent. However, the process is conveniently carried out by adding a solution of the compound of formula II (e.g. in a non-polar organic solvent, notably benzene, xylene, toluene or hexane) to an agitated mixture of the strong acid and alkanol so as to form a two phase reaction mixture. The addition may take place in one or more stages or may be on a continuous basis where the process is operated continuously. The reaction may be carried out at elevated temperatures, although it is preferred to use temperatures below 40°C.

We have found that the relative proportions of strong acid, alkanol, and compound of formula II affect the yield and quality of the product. We prefer to employ more than 1.5 molar proportions of alkanol and more than 1.2 molar equivalent proportions of strong acid per molar proportion of compound of formula II. Whilst the process may be carried out under substantially anhydrous conditions, as when HjSO^ is used as the strong acid, water may be preferred with some strong acids, e.g. when HCl is present. In this case we prefer to use more than 0.35 parts by weight of HCl per part of water in the reaction mixture. - 5 41613 It is preferred to agitate the reaction mixture and it will be appreciated that all weights and proportions are in respect of t^ie total reaction mixture not just the organic or aqueous phase.

Apart from the reagents and solvents, the reaction mixture may contain minor amounts of other non-deleterious materials. Thus, the compound of formula II need not be in pure form but may be used in the form of the reaction product from an earlier process step as outlined below.

The compound of formula I may be recovered from the reaction mixture by allowing the mixture to separate into organic and aqueous phases, removing the organic layer and recovering the product therefrom, e.g. by distillation (to remove excess alkanol and solvent when present), washing with a mild alkali (e.g. an alkali-metal, notably sodium, carbonate) and further distillation, preferably under reduced pressure, to remove final amounts of solvent. The isolated product may then be purified by conventional techniques .

As indicated above, the compound of formula II may be used in the form of the reaction mixture in which it is produced. The preferred method for producing the compound is by the reaction of a compound of formula: III ZliBS.3 with a compound of formula R^SO2Hal where Hal is halogen, preferably in the presence of an acid acceptor to remove the H-Hal as it is formed. Suitable acid acceptors include tertiary amines, notably trialkylamines, e.g. trimethylamine or triethylamine; aromatic tertiary amines, e.g. dimethylaniline; and pyridine and its homologues.

Whilst the reagents may be used in substantially the stoichiometric amounts, we prefer to use a small excess, e.g. up to 20% molar excess, of the compound R^SC^Hal based on the compound of formula III and an excess, e.g. 10 to 50% molar excess, of acid acceptor based on the amount of H-Hal which would theoretically be liberated.

The reaction may be carried out merely by mixing together the R^SC^Hal and compound of formula III simultaneously or sequentially and in one or more stages. Desirably the reaction temperature is less than 100°C, preferably within the range 30 to 80°C. However, to aid uniform reaction we prefer to carry out the reaction in an organic solvent as reaction medium or in an excess of the acid acceptor. Suitable solvents include non-polar organic solvents, e.g. benzene, toluene, xylene, or hexane.

When the reaction is substantially complete, as evidenced by analysis of a sample showing little or no remaining compound of formula III, the product compound of formula II may be recovered using conventional techniques. However, we prefer not to isolate the product but merely to extract the halogen salt of the acid acceptor from the reaction mixture by water extraction and separate off the organic layer containing the compound of formula II for use in preparing the compound of formula I.

The compound of formula III may be prepared in a number of ways, but it is preferably prepared by reacting a suitably substituted benzoquinone with an enamine of formula R^CHNR^ Thus, where R4, Rg and Rg are all hydrogen the compound of formula III may be prepared by reacting para-benzoquinone with an appropriate enamine, e.g. (ch3)2c=ch-n Preferably the reaction is carried out in an organic solvent, e.g. benzene, toluene or hexane, under reflux.

The reaction product of formula III may be recovered from the reaction mixture using conventional techniques, e.g. filtration followed by washing and the product then reslurried in the organic solvent to be used in the preparation of the compound of formula II, although this need not be done and the reaction mixture may be used directly.

The enamine to be used in the production of the compound of formula III is conveniently prepared by the reaction of the appropriate amine H-NR^ R^ with the appropriate aldehyde R1R2CHCH0 in a suitable solvent, e.g. benzene, toluene or hexane. The reaction is preferably carried out under reflux and driven to completion by removal of water from the system, e.g. by removing the water layer obtained by condensing the solvent/water azeotrope which distils off. The enamine product may be recovered from the reaction mixture and purified for use in the production of the compound of formula III using conventional techniques.

A particularly preferred process for preparing the compound of formula III comprises reacting the enamine and the appropriate benzoquinone in the presence of the aldehyde R-^RjCHCHO, the enamine preferably being present in an excess i 42.52.3 over the benzoquinone. The presence of the aldehyde may be achieved either by adding the aldehyde to the reaction mixture as a separate reagent; or by having aldehyde present in the enamine used, e.g. by using excess aldehyde during the preparation of the enamine.

Thus, from another aspect the present invention provides a process for preparing a compound of formula OM [wherein R^, R^, R^, R^, Rg, R? and M have the values given above] which comprises Stage (a) reacting a benzoquinone with an enamine of formula: Ειε2ο=οη-νη1οΚιι IV [wherein R^, R2, R^^ and R^ have the values given above] in the presence of a compound of formula R^R2CHCH0, the enamine of formula IV preferably being present at substantially all times during the reaction in more than the stoichiometric amount required to react with the benzoquinone; whereby there is produced a compound of formula III? Stage (b) reacting this with a compound of formula RySOjHal to give a compound of formula II; and Stage (c) reacting this with a mixture of a strong acid as herein defined and a compound of formula HOM (where M has the values given above), whereby there is - 9 produced a compound of formula I.

The presence of the requisite amount of enamine in the reaction mixture for Stage (a) of the above process can be achieved by, for example, adding the benzoquinone to a reaction mixture containing the desired amount of enamine or by adding the benzoquinone and enamine in the desired proportions to a continuously operated process. Preferably the enamine is employed in an overall small excess, e.g. from 1 to 10%, notably from 1 to 4% molar excess, although it will be appreciated that higher excesses may be used if desired. The addition is preferably carried out with I agitation and the reaction is desirably carried out at a temperature of from 20 to 60°C, notably at 40 to 50°C, although lower or higher temperatures may be used, e.g. up to the reflux temperature of the reaction mixture. Where reaction is carried out at below the reflux temperature of the reaction mixture, it may be desired to heat the mixture to 100-120°C in the final stages to assist completion of reaction.

As indicated above, the reaction is carried out in the presence of a compound ί^Ι^ΟΙΚΗΟ. This is desirably one in which R^ and R2 are the same as in the enamine used, e.g. R^ and R2 are both methyl groups, in which case the aldehyde is isobutyraldehyde. Desirably the aldehyde is present as a 10 to 200 molar percent based on the enamine used. The aldehyde may be added as a separate ingredient or as a solvent for one of the other reagents, e.g. for the enamine.

Stage (a) is usually carried out in a liquid medium. Suitable liquid media for present use include aromatic hydrocarbons, e.g. benzene, toluene or xylene; aliphatic hydrocarbons, e.g. cyclohexane or petroleum ethers; halogenated hydrocarbons and aliphatic ketones, e.g. acetone or methyl ethyl ketone. It is however preferred that the liquid medium be one in which the compound of formula III and water are only slightly soluble or miscible and the aromatic hydrocarbons are exemplary of such liquids.

The Reagents for use in Stage (a) are known materials and may be prepared by known processes. However, we have found it particularly advantageous if the enamine of formula IV is prepared by the reaction of a compound of formula H-NR^R^ with an excess of a compound of formula R^RgCHCHO in the presence of a solvent and the reaction mixture, preferably after removal of water therefrom as described above, is used as such in the process of the invention since in this manner the presence of the compound of formula R^R^CHCHO, notably isobutyraldehyde, is ensured during the process of the invention.

The reaction mixture from Stage (a) contains the compound of formula III or a derivative thereof. The compound of formula III may be recovered from the reaction mixture using conventional techniques, e.g, by filtration followed by washing and the product then reslurried in the organic solvent to be used in the preparation of the compound of formula I, although this need not be done and the reaction mixture may be used directly in Stage (b).

In Stage (b) of the process the compound of formula III is treated as described above to convert the hydroxy group in the 5-position to a R^SC^O- group; and in Stage (c) of the process the group in the 2-position is hydrolysed and alkoxylated by treatment with a mixture of a strong acid and an alkanol as described above.

From the above, it will be seen that the production of the compound of formula I may be summarised as: Stage 1 RjR CHCHO Γ HNRioRn H Stage 2 Stage 3 + a benzoquinone Ψ Stage 4 Stages (a) and Cb) described above give rise to intermediate products of formulae II and III of improved purity. The compounds of formula I prepared therefrom are described and claimed in the Specification of Patent Application No. 1822/75.

The above process stages may be carried out as distinct and separate steps but, as indicated above, readily lend themselves to sequential operation in that reaction products from one stage may be used directly in a later stage. Furthermore, it is possible to recover excess reagents and solvents for re-use. Thus, acid acceptor may be recovered from the aqueous phase from stage 3 by treatment of the halogen salt with alkali (e.g. NaOH) and subsequent distillation; the organic phase of the reaction mixture from stage 4 may be fractionally distilled to recover alkanol and solvent, and the aqueous phases may be distilled to recover alkanol and, possibly, acid, the residue then being treated with alkali to liberate the amine and the acid acceptor which may have been carried over in the organic phase from stage 3 to stage 4 and this residue fractionally distilled to recover amine for use in stage 1 and acid acceptor for use in stage 3.

The process of the invention will now be illustrated by the following Example, in which all parts and percentages are given by weight unless stated otherwise: 41613 Example 1 Stage 1 - Preparation of enamine To a stirred mixture of 332 parts of isobutyraldehyde with 867.5 parts of toluene was added 200.5 parts of morpholine. The temperature rose from 20°C to 41°C. The mixture was refluxed with continuous separation and removal of the aqueous phase from the returning solvent stream.

To complete the water removal, the final stages were carried out with a fractionation column. The total time at reflux was 4.8 hours. The excess isobutyraldehyde was removed from the product by distillation.

Stage 2 - Preparation of 2,3-dihydro-3,3-dimethyl-5hydroxy-2-morpholinobenzofuran The solution of enamine in toluene produced in Stage 1 was added to 238.2 parts of technical benzoquinone in 226 parts of toluene over a period of 1.2 hours. The temperature was maintained at 35-45°C throughout the additions by heating or cooling as required. When the heat of reaction was no longer observed, the reaction mixture was raised to the boiling point and maintained at reflux for 0.5 hours. After cooling to 25°C the insoluble product was filtered off, and washed with 670 parts of toluene.

The solvent-wet filtered solid was reslurried in 1083 parts of toluene for stage 3.

Stage 3 - Preparation of 2,3-dihydro-3,3-dimethyl-2morpholinobenzofuran-5-yl methanesulphonate The slurry from stage 2 was heated to 40°C with adequate mechanical agitation. Methane sulphonyl chloride (258 parts) and triethylamine (228 parts) were added simultaneously but separately to the reaction mixture, which was maintained at 4O-46°C with external cooling, over a period of 0.35 hours. A further 23 parts of triethylamine were added, followed by 585 parts of water.

The two phase reaction mixture was then heated to 5O-55°C and allowed to settle. After separation of the lower layer of triethylamine hydrochloride solution, the upper solvent layer was passed to stage 4.

Stage 4 - Preparation of 2,3-dihydro-3,3-dimethyl-2ethoxy-benzofuran-5-yl methane sulphonate To the solution from stage 3 were added 350 parts of ethyl alcohol, 43 parts of water, and 655 parts of 30% w/w hydrochloric acid. The temperature rose to 47°C.

The two-phase reaction mixture was agitated for 16 hours with cooling to 20°C and, after settling, the lower aqueous layer was removed.

The upper solvent layer was distilled to remove the bulk of the unreacted ethyl alcohol, and washed with sodium carbonate solution to remove traces of hydrochloric acid. The solution was then distilled to remove the remaining toluene leaving 564 parts of product of 98% purity by GLC analysis, equivalent to 87.5% yield on technical benzoquinone . I Example 2 Preparation of 2,3-dihydro-3,3-dimethyl-2-methoxy-benzofuran-5-yl methane sulphonate 2,3-Dihydro-3,3-dimethyl-5-hydroxy-2-morpholinobenzofuran (62.3 parts), 98.0% pure produced as in Example 1) was slurried in 180 parts of commercial mixed xylenes. Methane sulphonyl chloride (31.25 parts) and triethylamine (27.6 parts) were added simultaneously but separately to the reaction mixture, which was maintained at 40-45°C with external cooling, over a period of 0.6 hours. After agitating for a further 0.5 hours, 66 parts of water and 41613 a further 3.5 parts of triethylamine were added. The twophase reaction mixture was then heated to 60-65°C and allowed to settle. After separation of the lower layer of triethylamine hydrochloride solution, the upper solvent layer was allowed to evaporate to constant weight. Crude yield, 80.2 parts, purity by G.L.C. 98%, equivalent to 98.2 mole % yield.

Hydrolysis/alkoxylation stage 65.4 Parts of 2,3-dihydro-3,3-dimethyl-2-morpholino10 benzofuran-5-yl methane sulphonate prepared as above were dissolved in 150 parts of commercial mixed xylenes. To this solution were added 24 parts of methyl alcohol, 13 parts of water, and 47.8 parts of 36% w/w hydrochloric acid. The temperature rose to 28°C. The two-phase reaction mixture was agitated for 16 hours at ambient temperature and, after settling, the lower aqueous layer was removed.

The upper solvent layer was evaporated to constant weight to give 53.3 parts of 2,3-dihydro-3,3-dimethyl-2methoxy-benzofuran-5-yl methane sulphonate of 95% purity by G.L.C. analysis, equivalent to 94.8 mole % yield on 2,3-dihydro-3,3-dimethyl-2-morpholinobenzofuran-5-yl methane sulphonate.

Claims

1. CLAIMS:1. A process for preparing a compound of the formula [in which R^ and may be the same or different and each is selected from hydrogen or an alkyl group or R^ and R 2 together form an alkylene chain: M is an alkyl group; R a , Rg and Rg may be the same or different and each is selected from hydrogen, an alkyl, or.an alkoxy group or a halogen atom; and Ry is an alkyl group] which comprises reacting a compound of the formula: II [wherein R^, R 2 , R^, Rg, Rg and R? have the values above and R^ Q and R^ may be the same or different and each is selected from a lower alkyl group or R^q and R^

2. A process as claimed in claim 1 wherein the strong acid is selected from those which dissociate in water to give at least 1 gram equivalent of H + per gram mol of acid.

3. A process as claimed in claim 1 wherein the

4. A process as claimed in any one of the preceding claims wherein the reaction is carried out in a two phase reaction mixture.

5. Above), whereby there is produced a compound of formula I. 5 R^, Rg and Rg may be the same or different and each is selected from hydrogen, an alkyl, or an alkoxy group or a halogen atom; and R? is an alkyl group] which comprises: Stage (a) reacting a benzoquinone with an enamine of formula: 5 10. A process as claimed in claim 9 wherein the acid acceptor is present in a 10 to 50% molar excess based on the amount of H-Hal theoretically liberated. 5 strong acid is selected from sulphuric, hydrochloric and phosphoric acids.

6. A process as claimed in any one of the preceding claims wherein more than 1.2 molar proportions of strong

7. A process as claimed in any one of the preceding claims wherein the strong acid used is hydrochloric acid and more than 0.35 parts by weight of HCl are used per part

8. A process as claimed in any one of the preceding claims wherein the compound of formula II has been prepared by the reaction of a compound of formula with a compound of formula R^SO^Hal where Hal is halogen.

9. A process as claimed in claim 8 wherein the compounds of formula III and RySC^Hal are reacted in the presence of an acid acceptor.

10. 17 wherein the compound R^R 2 CHCH0 is present in from 10 to 200 molar percent based on the enamine used. 10 IV [wherein R^, R 2 , R 1Q and R^^ have the values given above] in the presence of a compound of formula R^RjCHCHO, whereby there is produced a compound of formula: 10 reacted together in a non-polar organic solvent reaction medium. 10 wherein the compounds of formulae III and R^SOjHal are 10 5. A process as claimed in any one of the preceding claims wherein more than 1.5 molar proportions of HOM are used per molar proportion of the compound of formula II. 11. Wherein the reaction mixture containing the compound of formula II is used in the process of claims 1 to 7 without

11. A process as claimed in any one of claims 8 to

12. A process as claimed in any one of claims 8 to

13. A process as claimed in claim 8 wherein the compound of formula III has been prepared by the reaction of a suitably substituted benzoquinone with an enamine of formula r 1 r 2 c=chnr 10 r 11 . 20

14. A process as claimed in claim 13 wherein the benzoquinone and the enamine are reacted in the presence of a compound of formula R^R 2 CHCHO. 15. Formula R^CHCHO. 15 Stage (b) reacting a compound of formula III with a compound of formula R^SO 2 Hal wherein Hal is a halogen, to give a compound of formula:

15. A process as claimed in either of claims 13 or 14 wherein the enamine is present at substantially all 15 isolation of the compound of formula II therefrom. 15 acid are used per molar proportion of the compound of formula II. 15 together with the nitrogen atom form a heterocyclic ring] with a mixture of a strong acid as hereinbefore defined and a compound of the formula HOM wherein M has the values given above.

16. A process for preparing a compound of the formula [in which R^ and R 2 may be the same or different and each is selected from hydrogen or an alkyl group or R^ and R 2 together form an alkylene chain; M is an alkyl group;

17. A process as claimed in any one of claims 13 to 16 wherein the enamine is employed in an overall excess of from 1 to 10 molar percent based on the benzoquinone.

18. A process as claimed in any one of claims 14 to

19. A process as claimed in any one of claims 13 to 18 wherein the enamine has been prepared by the reaction of a compound of formula HNR^ Q R^^ with a compound of

20. A process as claimed in claim 19 wherein an excess of R^R 2 CHCH0 is reacted with HNR^ Q R^^ whereby there is produced a reaction mixture containing the enamine and the compound R^R^HCHO. 20 - 20 II r, R r ? so 2 o R. R. '10 R, ‘6 '11 and Stage (c) reacting the compound of formula II with a mixture of a strong acid as herein defined and a compound of formula HOM (where M has the values given 20 by weight of water in the reaction mixture.

21. A process as claimed in claim 20 wherein water is removed from the reaction mixture and the reaction mixture is used to provide the enamine and compound r 1 r 2 chcho.

22. A process as claimed in any one of the preceding

23. A process as claimed in any one of the preceding claims wherein the groups R 4 , R 5 and R g are all hydrogen.

24. A process as claimed in any one of the preceding claims wherein the R? group is a methyl group.

25. A process as claimed in any one of the preceding claims wherein the group M is a methyl, ethyl or propyl group. 25 claims wherein the groups R^ and R 2 are both the same and are selected from lower alkyl groups. 25 times during the reaction in an overall excess over the stoichiometric amount required to react with the benzoquinone .

26. A process as claimed in any one of the preceding claims wherein the group -NR^R.^ is selected from morpholino, piperidino and pyrrolidino.

27. A process as claimed in any one of the preceding claims wherein the compound of formula 1 is. 2,3-dihydro-3,3dimethyl-2-ethoxy-benzofuran~5-yl methane sulphonate.

28. A process for preparing a compound of the formula which comprises reacting p-benzoquinone with from 1 to 4% molar overall excess of the enamine (ch 3 ) 2 c=ch-n' in the presence of from 10 to 200 molar % of isobutyraldehyde (based on the enamine) in an aromatic hydrocarbon medium? reacting the reaction product with CH 3 SO 2 C1 in the presence of an acid acceptor; and reacting the reaction product with a mixture of ethyl alcohol and a mineral acid selected from sulphuric acid, hydrochloric acid or phosphoric acid.

29. A process according to claim 1 for producing a compound of formula I substantially as hereinbefore described.

30. A process according to claim 1 for producing a 5 compound of formula I substantially as hereinbefore described in the Examples.

31. A compound of formula I whenever produced by a process as claimed in any one of the preceding claims.