AU3507301A - Process for preparing 2-(thiosubstituted)-4-haloacetophenones - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

Name of Applicant: Actual Inventors: Address for Service: Invention Title: Rhone-Poulenc Agriculture Ltd.

CRAMP, Susan Mary DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Process for preparing 2-(thiosubstituted)-4-haloacetophenones The following statement is a full description of this invention, including the best method of performing it known to us: O:'OPERPDB;DIVISIONALS\2405650 DIV.DOC 9!4/01 P OPER PDB Spei 2405650 di 099doc-09 04 01 -1A- This application is a divisional application derived from Australian Patent Application No. 18723/97, the entire contents of which are incorporated herein by reference.

This invention relates to a process for preparing certain 2-thiosubstituted acetophenone derivatives, which are useful as intermediates in the preparation of herbicidally active compounds.

Cooper et al, Synthetic Communications, Vol. 25(6), pages 899-906 (1995) describe the preparation of 2-ethylthio-4-chlorobenzamides and 2-ethylthio-3,4dichlorobenzamides by reacting the corresponding 2,4-dichloro- and 2,3,4- 10 trichlorobenzamides respectively with ethanethiol in N,N-dimethyl formamide (DMF) in the presence of potassium carbonate. These reactions were reported as proceeding with i ortho-selectivity, except where the benzamide was a tertiary amide. Fink et al, Tetrahedron Letters, Vol. 34(41) pages 6525-6528 (1993) and EP-A-0 536 512 describe the preparation of 4-fluoro-2-(phenylmethylthio)acetophenone from 2,4- 15 difluoroacetophenone. The reaction is performed in tetrahydrofuran (THF) with benzyl mercaptan and potassium t-butoxide. This is described as proceeding in a yield of 63% with a ratio of ortho/para products of 8.6:1 89% ortho, 11% para). It is however desirable to provide intermediates which are used in multi-step reaction schemes in high yields and with high isomeric purity.

It is therefore an object of this invention to provide a process for preparing 2thiosubstituted acetophenones proceeding in high yield.

It is a further object of this invention to provide an improved process for preparing 2-thiosubstituted acetophenones with a greater ortho selectivity.

Surprisingly, the present invention allows these objects to be met in whole or in part.

Thus, the present invention provides a process for preparing a 2-(thiosubstituted)-4-(halo)acetophenone which comprises reacting a 2, 4 -(dihalo)acetophenone with a thiolating agent under substantially anhydrous conditions with less than about 5% by volume water content, optionally in the presence of a base.

Surprisingly, it has been found that the reaction proceeds in good yield and with high regioselectivity under such conditions.

It will be understood that the halogen atoms in the 2,4-(dihalo)acetophenone may be the same or different, and that the 10 acetophenone may be optionally substituted by from one to three groups in the 3- and/or 5- and/or 6- positions of the benzene ring.

By the term "substantially anhydrous" is meant that water not deliberately introduced into the reaction mixture the thiolating agent used is not provided in an aqueous solution or suspension). Preferably from about 0.01 to about 0.5% by volume of water is present. It will however be understood that in certain cases slightly more or less water may be tolerated, depending on the nature of the solvents used, the 2-thiosubstituted acetophenone derivative to be prepared and other reaction conditions.

The reaction is preferably performed in an ether solvent such as THF, diisopropyl ether, tert-butyl methyl ether (MTBE), diglyme and diethyl ether.

Preferred solvents are THF, diisopropyl ether and MTBE, the latter two being preferred when the process is performed on a large scale, for reasons of cost and availability.

Preferably the 2 -(thiosubstituted)-4-haloacetophenone is a compound of formula

SR

1 0

R

2

CH

3

R

3

(I)

wherein

R

1 is lower alkyl, or phenyl optionally substituted by from one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy and

R

2 is hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, 10 lower haloalkoxy or -S(O)nR 5

R

3 is halogen; n is zero, one or two; and

R

5 is lower alkyl or phenyl optionally substituted by from one to five groups which may be the same or different selected from halogen, lower S alkyl, lower haloalkyl, lower alkoxy, lower haloalkyl and -S(O)n-alkyl; the 2 4 -dihaloacetophenone is a compound of formula (II): 4

R

4 0 CH3

R

3

(II)

where R 2 and R 3 are as defined above and R 4 is halogen; and the thiolating agent is a compound of formula (III):

R

1 S-X (m) wherein R 1 is as defined above and X is hydrogen or a metal cation.

By the term 'lower' is meant radicals comprising at least one 4 hydrocarbon chain, it being understood that such radicals contain from one to six carbon atoms linked together in a straight- or branched- carbon chain.

In a preferred aspect of the invention each of R 2

R

3 and R 4 are chlorine.

In another preferred aspect of the invention

R

2 and R 4 are halogen (preferably chlorine) and R 3 is hydrogen.

In another preferred embodiment

R

2 is selected from hydrogen, halogen, lower alkoxy methoxy) and lower haloalkoxy (e.g.

10 2 ,2-difluoroethoxy).

Preferably R 1 is lower alkyl (most preferably methyl).

X is preferably hydrogen or an alkaline earth metal or alkali metal cation lithium or sodium). Where X is hydrogen the presence of a base is preferred, for example an alkali or alkaline earth base (such as sodium hydride, potassium carbonate or potassium t-butoxide).

The reaction is generally performed at a temperature from -80 0 C to the boiling of the solvent, more preferably from -20 0 C to 60 0 C, from about 100 to about 550 being especially preferred.

The molar ratio of the 2,4-dihaloacetophenone: thiolating agent is generally from 1:1 to 1:2, preferably from 1:1 to 1:1.5, even more preferably from 1:1.1 to 1:1.3.

The following non-limiting examples illustrates the invention.

Example 1 Preparation of 3 4 -dichloro-2-(methylthio)acetophenone (small scale) Sodium thiomethoxide (0.2g, 0.0028M) was added to a solution of 2 3 trich loroace tophe none (0.5g, 0.0022M) in THF (lOMIn). The mixture was stirred at room temperature for 3 hours then diluted with diethyl ether, washed with water, dried over magnesium sulphate, filtered and evaporated to give 3 4 -dichloro-2-(methylthio)acetophenone (0.

4 3g, 82%) as a yellow oil, H' NMR (CDCI 3 2.4(s,3H), 7.15(d,LH), 7.5(d,1H).

NMR

analysis indicated that there was less than 1% of the para product present.

By proceeding in a similar manner were prepared: 4 -chloro- 2 -(methylthio)acetophenone as a fawn solid, m.p. 63 0

C,

NMR analysis indicated a purity starting from 2,4dichioroacetophenone; and 4-rm--22dfurehx)2(ehlhoaeohnn as a red oil, H' NMR (CDCI 3 2.45(s,3H), 2.6(s,3H), 4.3(t,d,2H), 6.25(t,t,1IH), 7.05(d,1IH), 7.55(d, 1H), starting from 2,4-dibromo-3-(2,2difluoroethoxy)acetophenone. NMR analysis indicated a purity >98%.

Example 2 Preparation of3 4 -dichloro-2-( ethvlthio)acetophenone arger 2 3 ,4-Trichloroacetophenone (20.03g, 89.6mM) was dissolved in TIF (200m1d) and dry sodium thiomethoxide (8.06g, 1 15.l1mM)was added.

The mixture was stirred for 6.8 hours at 25 0 C. Water (lO0rni) and MTBE (lO0mil) were then added and the resulting two phases separated. The aqueous phase was re-extracted with MTBE (lO0m!) and the combined organic phases were washed with brine (2 x 50m.1). The solvent was removed under reduced pressure to give of 3,4-dichloro-2- (methylthio)acetophenone as a brown liquid (20.70g, 94% yield). Less than 1% of the para isomer was detected.

Example 3 The effect of the presence was analysed in the following experiment.

The conditions of Example 1 were repeated replacing 2, 3 4 -trichloroacetophenone with 2 4 -dichloroacetophenone [to give 4 -chloro-2-(methylthio)acetophenone], except that the reaction mixture was stirred overnight and the THF (which had less than 0.1% by volume water

S

10 content when received from the suppliers and which was stored over 4 .o Angstrom molecular sieves) was evaporated prior to work up. Various quantities of water were added and the reaction yield and regioselectivity determined (the approximate proportion of each regioisomer present was determined by measuring H' NMR peaks).

The following results were obtained. Note that in Tables 1 and 2 below 'SM' means starting material 2 4 -dichloroacetophenone), 'Prod' means desired product 4 -chloro-2-(methylthio)acetophenone) and 'Isomer' means the para-product 2 -chloro-4-(methylthio)acetophenone).

The percentages for the water are by volume and the percentages for the compounds are based on the theoretical yield from the starting material.

Table 1 Water <0.1 10.0 Percentage present SM Prod Isomer Trace >99% Trace >98% <1% 15 84 1 51 48.5 0.5 95 5 Trace 98 2 Trace Ratio Prod:Isomer >99:1 >98:1 84:1 97:1 >5:1 >2:1 This indicates that at higher concentrations of water, the reaction did not proceed to completion at room temperature.

Example 4 The effect of the heating the reaction and the presence of water was analysed in the following experiment. The conditions of Example 3 were repeated, except that the reaction mixture was heated at from about 50 0 C to about 55 0 C overnight.

The following results were obtained: Table 2 Water <0.1 10.0 20.0 50.0

SM

Trace Trace 7% 38% 52% 71% 78% 80% obtained Prod Isomer >99% Trace >99% Trace 93% Trace 60% 2.50% 40% 8% 22% 7% 13% 9% 10% 10% Ratio Prod:Isomer >99:1 >99:1 >93:1 25:1 5:1 3.2:1 1.5:1 1:1 These results show that at higher reaction temperatures, the regioselectivity decreases significantly when the reaction is performed in the presence of substantial quantities of water.

The above experiments therefore clearly demonstrate the advantage of the process of the invention over the prior art, both in terms of a higher yield and a greater selectivity, and the effect of water on the reaction.

The compounds obtained by the process of the present invention may be used in the preparation of herbicidally active compounds for example, as part of one of the following reaction schemes:-

SR

1 O O O R2 R11 OMe R3-

(IV)

R

1 0 2 S 0 0 SO R'

R

2

CO

2 H SOC1, R 1 I R1COCH2CO 2 tBuR3/

R

3 PTSA (V) Compounds of formulae (IV) and are known the literature as intermediates in the preparation of herbicidally active compounds. Both the diones of formula above and the herbicidally active compounds which they be used to prepare are described, for example, in European Patent Publication Nos. 0418175, 0487353, 0527036, 0560482, 0609798 and 0682659.

Claims (12)

1. A process for preparing a 2-(thiosubstituted)-4-haloacetophenone of formula SR' O R 2 R CH 3 R wherein R' is lower alkyl, or phenyl optionally substituted by from one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy and -S(O)nR 5 R 2 is hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy -S(0)-R 5 SR3 is halogen; n is zero, one or two; R is lower alkyl or phenyl optionally substituted by from one to five groups which may be the same of different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy and -S(O)n-alkyl; wherein, 'lower' means a radical comprising at least one straight or branched hydrocarbon chain containing from one to six carbon atoms; which comprises reacting a 2,4-dihaloacetophenone of formula (II): R4 0O R2 2 CH3 R 3 (II) P:OPERPDB Spei 2405650 di' 099 doc-09 04 01 where R 2 and R 3 are as defined above and R 4 is halogen, with a thiolating agent of formula (III): R'S-X (III) oO.. ooo. ooeo *eee eee *eee e *e wherein R' is as defined above and X is hydrogen or a metal cation: under substantially anhydrous conditions in which the volume of water present is less than about 1 percent.

2. A process according to claim 1 in which the reaction is performed in the presence 10 of a base.-

3. A process according to claim 1 or 2 in which the volume of water present is from about 0.01 to about 0.5 percent.

4. A process according to any one of the preceding claims in which the reaction is performed in an ether solvent.

A process according to claim 4 in which the ether solvent is selected from tetrahydrofuran, diisopropyl ether, tert-butyl methyl ethe, diglyme and diethyl ether.

6. A process according to claim lower alkoxy and lower haloalkoxy. 1 in which R 2 is selected from hydrogen, halogen,

7. A process according to claim 1 in which R 3 and R 4 are halogen and R 2 is hydrogen.

8. A process according to claim 1 in which R 2 R 3 and R 4 are chlorine.

9. A process according to claim 1 in which X is hydrogen or an alkali metal cation.

10. A process according to claim 1 in which R' is lower alkyl. P: OPER\PDB Spci 2405650 div 099 doc-09 0401 -11

11. A process according to any one of the preceding claims in which the reaction is performed at a temperature from -80 0 C to the boiling point of the solvent, preferably from 0 C to 60 0 C.

12. A process according to any one of the preceding claims in which the molar ratio of the 2,4-dihaloacetophenone: thiolating agent is from 1:1 to 1:2, preferably from 1:1 to 1:1.5. DATED this 9th day of April, 2001 10 Rhone-Fulenc Agriculture Limited By DAVIES COLLISON CAVE Patent Attorneys for the applicant *oooo *00