GB1595699A - Halogenated benzylpinacolones and their use as intermediates - Google Patents

Description

(54) HALOGENATED BENZYLPINACOLONES AND THEIR USE AS INTERMEDIATES (71) We, IMPERIAL CHEMICAL INDUSTRIES LIMITED, Imperial Chemical House, Millbank, London, SW1P 35F, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to certain haloketone compounds useful as intermediates in the preparation of heterocyclic compounds which are imidazole or 1,2,4-triazole compounds having the properties of combating fungal diseases having the properties of combating fungal diseases in plants and of regulating the growth of plants.

The invention provides a compound of general formula (I)

wherein R1 is optionally substituted benzyl and X is halogen (preferably bromine or chlorine).

The compounds of the invention are useful as intermediates in the preparation of a compound of general formula (II)

wherein Rl is as defined above, Y is = N- or = CH-, R is t-butyl, and R3 is hydrogen, methyl or alkenyl, or an ester, an ether, an acid addition salt or a metal complex thereof.

The alkyl groups, which can be straight or branched chain, preferably have 1 to 5 carbon atoms; examples are methyl, ethyl, propyl (n or i-propyl) and butyl (n-, i- or t-butyl). Suitable alkenyl groups (which can also be straight or branched chain) are those having up to 7, preferably up to 4, carbon atoms, an example is allyl.

The benzyl group can be substituted in its alkyl and/or aryl moieties. Suitable substituents on its aryl moiety are halogen, C14 alkyl [e.g. methyl, erhyl, propyl (nor i-propyl) and butyl (n-, i- or t-butyl) j, halo-C1~4 alkyl), phenyl, halophenyl (e.g.

chlorophenyl), C3 cycloalkyl, nitro, cyano, C14 alkoxy (e.g. methoxy or ethoxy), (C1 < alkylene)dioxy (e.g. methylenedioxy), (C,4 alkoxy), (C1, alkyl) [e.g. 2methoxy- or ethoxy-ethyl], mercapto, (C,~, alkyl)thio [e.g. methyl or ethyl-thio], (C14 alkyl)sulphonyl, (C1~4 haloalkyl)sulphonyl) [e.g. trifluoromethylsulphonyl] , phenylsulphonyl, unsubstituted or mono- or di-(C14 alkyl) substituted sulphamoyl or carbamoyl, carboxy, (C1--4 alkoxy)carbonyl [e.g. methoxy- or ethoxy-carbonyl), unsubstituted or mono- or di- (C14 alkyl) substituted amino, (C2-e alkanoyl)-amino, N- (C1.1-alkyl) -substituted (C25 alkanoyl)amino, formylamino, N-(C1~4 alkyl )-substi- tuted formylamino), phenylethyl, phenoxy or benzyloxy. A suitable alkanoyl is acetyl or propionil. The benzyl group can have more than one ring substituent; examples of polysubstituted groups are those substituted with up to the maximum possible number (especially 1, 2 or 3) of for example halogen (paricularly chlorine) atoms and/or nitro, methyl or methoxy groups. Suitable substituents on the alkyl moiety of the benzyl group are halogen, C14 alkyl (e.g. methyl), phenyl or benzyl, both latter groups being optionally substituted as indicated above for aryl, cyano, (C14 alkoxy)carbonyl [eg.

methoxy- or ethoxy-carbonyl] or trihalomethyl (e.g. trifluoromethyl).

Examples of suitable benzyl groups are benzyl itself, a-methylbenzyl, a-methylchlorobenzyl (e.g. e-methyl-p-chlorobenzyl), Kz-methylfluorobenzyl [e.g. a-methyl-pchlorobenzyl), a-methyldichlorobenzyl (e.g. a-methyl-2,4-dichlorobenzyl), a-methyl fluorobenzyl [e.g. a-methyl-p-fluorobenzyl], chlorobenzyl (for example o-, m- or p- chloro-benzyl), dichlorobenzyl (e.g. 3,4-, 2,4- or 2,6-dichlorobenzyl), trichlorobenzyl (e.g. 2,3,6- or 2,4,5-trichlorobenzyl), tetrachlorobenzyl, pentachlorobenzyl, bromobenzyl (e.g. o-, m- or p-bromobenzyl), dibromobenzyl (e.g. 2,4-dibromodibromobenzyl), fluorobenzyl (e.g. o-, m- or p-fluorobenzyl), difluorobenzyl (e.g., 2,4-difluorobenzyl), pentafluorobenzyl), methylbenzyl (e.g., o-, m- or p-methylbenzyl), dimethylbenzyl (e.g. 2,5-dimethylbenzyl), cyanobenzyl (e.g. p-cyanobenzyl), nitro-benzyl (e.g. p-nitrobenzyl), (trifluoromethyf) benzyl [e.g. -trifluoromethyl)benzyl], methoxybenzyl (e.g. o-, m or p-methoxybenzyl), chloronitrobenzyl (e.g. 3nitro-4-chlorobenzyl), chlorofluorobenzyl (e.g. 2-chloro-4-fluorobenzyl, fluorobromobenzyl (e.g. 2-fluoro-4-bromo-benzyl), methoxybromobenzyl (e.g. 2-methoxy-5-bromo- benzyl and phenylbenzyl (e.g. p-phenylbenzyl).

The halogen can be fluorine, chlorine, bromine or iodine.

A preferred class of compounds of general formula (II) are those wherein R is benzyl, a-methylbenzyl, a-methylchlorobenzyl, a-methyl-dichlorobenzyl, methyl fluorobenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, tetrachlorobenzyl, pentachlorobenzyl, bromobenzyl, dibromobenzyl, fluorobenzyl, difluorobenzyl, pentafluorobenzyl, methylbenzyl, dimetbyt-benzyl, cyanobenzyl, nitrobenzyl, trifluoromethylbenzyl, methoxybenzyl, chloronitrobenzyl, chlorofluorobenzyl, fluorobromobenzyl, methoxybromobenzyl or phenylbenzyl, Y is =N- R2 is t-butyl and R3 is hydrogen or methyl. Also preferred are corresponding compounds wherein Y is = CH-.

Particularly preferred are those compounds wherein R1 is benzyl, a-methyl-pchlorobenzyl, a-methyl-2,4-dichlorobenzyl, a-methyl-p-fluorobenzyl, o-, m- or pchlorobenzyl, 2,4-, 3,4- or 2,6-dichlorobenzyl, 2,4,5- or 2,3,6-trichlorobenzyl, pentachlorobenzyl, m- or p-bromobenzyl, 2,4-dibromobenzyl, o-, m- or p-fluorobenzyl, 2,4 difluorobenayl, o- or p-methylbenzyl, 2,5-dimethylbenzyl, p-nitrobenzyl, m- ( trifluoro- methyl)benzyl, o- or p-methoxybenzyl, 3-nitro-4-chlorobenzyl, 2-chloro-4-fluorobenzyl, 2-fluoro-4-bromo-benzyl, or 2-methoxy-5-bromobenzyl, Y is =N-, R2 is t-butyl, and Rs is hydrogen or methyl. Also particularly preferred are those compounds wherein R1 is benzyl, o-chlorobenzyl, 2,4-dichlorobenzyl, o- or p-fluorobenzyl, p-bromobenzyl, or 2-chloro-4-fluorobenzyl, Y is = CH-, R, is t-butyl and Rs is hydrogen or methyl.

Suitable salts of the compounds of general formula (II) are salts with inorganic or organic acids, e.g. hydrochloric, nitric, sulphuric, toluenesulphonic, acetic or oxalic acid. The esters are suitably alkanoates (e.g. acetates) and the ethers are suitably alkyl (e.g. methyl or ethyl), aryl (e.g. phenyl) or aralkyl (e.g. benzyl) ethers.

The metal complex is suitably one including copper, zinc, manganese or iron.

It preferably has the general formula:

wherein Y, R1, R2 and R3 are as defined above, M is a metal, A is an anion (e.g.

a chloride,, bromide, iodide, nitrate, sulphate or phosphate anion), n is 2 or 4, and y is 0 or an integer of 1 to 12.

Specific examples of the compounds of general formula (II) are given in Patent Applications Nos. 34590/76, 5524/80 and 5529/80 (Serial Nos. 1595696, 1595697, 1595698) which also give details of their fungicidal and plant growth regulating properties and fungicidal and plant growth regulating compositions containing them.

The compounds of general formula (II) can be prepared as follows from the compounds of the invention. The compounds of general formula (II) wherein Ra is hydrogen, or a salt thereof, can be prepared by reducing, preferably at 0 to 1000C and for 1 to 12 hours, a compound of general formula (III):

wherein Y, R1 and R2 are as defined above, or a salt thereof. Suitable reducing agents are sodium borohydride, lithium aluminium hydride or aluminium isopropoxide.

If desired, catalytic hydrogenation using a suitable metal catalyst can be used. When the compound of general formula (III) is a sterically hindered ketone, a Grignard reagent, for example butylmagnesium halide (e.g. bromide or iodide) can be used as the reducing agent; when a reagent such as a butylmagnesium halide is used, single diastereoisomers are often produced. Further details of this reduction are given in Patent Application No. 34590/76 (Serial No. 1595696).

The compounds of general formula (III) wherein R3 is methyl or alkenyl, or a salt thereof, can be prepared by reacting, preferably at 15 to 800C and for 6 to 12 hours, a. compound of general formula (III) or a salt thereof with the appropriate Grignard reagent e.g. a methyl or alkenyl magnesium halide such as methyl or allyl magnesium bromide or iodide. This reaction can be performed by methods known in the art.

The compound of general formula (III) may be made by reacting imidazole or 1,2,4-triazole, or a salt thereof, with a,lg-haloketone of general formula (1) wherein Rl and X are as defined above. This process may be carried out by heating the reactants together in the absence of a solvent or diluent, but preferably a solvent is present.

Suitable solvents are non-hydroxylic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, sulpholane and tetrahydrofuran. Hydroxylated solvents, for example, methanol and ethanol, may be used in certatn circumstances when the presence of the hydroxyl group does not interfere with the reaction. The process can be carried out in the presence of a base such as sodium hydride, sodium ethoxide, excess imidazole or triazole, or an alkali metal carbonate (e.g. potassium carbonate).

The reaction temperature will depend upon the choice of reactants, solvents and base, but generally the reaction mixture is heated under reflux. The process generally consists of dissolving the reactants in a solvent and then isolating the product by removal of the reactant solvent in vacuo. Unreacted imidazole of triazole can be removed by extraction of the product with a suitable solvent which is then washed with water.

A crystallisation or other purification procedure may then be carried out if desired.

The ,ce-halo ketones may be made by known methods.

The following Examples illustrate the invention; the temperatures are given in degtees Centigrade (O).

EXAMPLE 1.

Stage I. 4-Chlorobenzaldehyde (140.5 g) and pinacolone (100 g) in industrial methylated spirit (IMS; 200 ml) were added dropwise over 25 minutes to sodium hydroxide (40 g) in water (70 ml) and IMS (150 ml) with extemal cooling (ice/water) applied to maintain a temperature of not more than 25". The resulting creamy suspension was stirred for a further 3 hours at 18 and was then filtered.

The residue was washed with aqueous IMS and dried to give 4-chlorobenzal pinacolone, m.p. 8384 . The filtrate was concentrated under reduced pressure and allowed to stand for 2 days to give more of the chalcone product, m.p. 8384 .

Stage 11. The chalcone (22.25 g) was suspended in ethyl acetate (125 ml) and Raney nickel (6 g) added after washing with ethyl acetate (4 X 15 ml). The apparatus was evacuated at the water pump and hydrogen was introduced to atmospheric pressure. The mixture was then shaken vigorously at room temperature. After 14.5 hours, hydrogenation ceased when the recorded uptake of gas was 2303 ml. The catalyst was filtered off, taking care not to allow the residue to become dry, and the filtrate concentrated in vacuo to afford crude 4-chlorobenzylpinacolone.

Stage 111. 4-chlorobenzylpinacolone (11.2 g) in carbon tetrachloride (80 ml) was cooled to about 50 and bromine (8 g) in carbon tetrachloride (20 ml) added dropwise at that temperature over 2 hours. Care was taken to keep free bromine to a minimum n the reaction mixture in order to avoid byproduct formation. The solution was washed with saturated aqueous sodium bicarbonate and with water, dried (magnesium sulphate), and concentrated in vacuo to afford, as a white crystalline solid, crude 1,4'-chlorophenyl-2-bromo-4,4-dimethylpentan-3-one, m.p. 4850 .

Stage IV. The product (0.69 g) of Stage III and 1,2,4-triazole (0.17 g) were mixed with potassium carbonate (0.52 g) in acetone (10 ml) and the mixture refluxed for 2 hours. After cooling to room temperature the inorganic material was filtered off and the filtrate concentrated in vacuo to afford crude -p-chlorobenzyl a-1,2,4- triazol-1-yl pinacolone which can be reduced to give 1-t-butyl-2-(1,2,4-triazol-1 yl)-2-p-chlorobenzylethanol.

EXAMPLE 2.

Stage 1. Pinacolone (10 g) in dry diethyl ether (30 ml) was added slowly to a suspension of sodamide (4.1 g) in dry diethyl ether (15 ml). The mixture was then stirred overnight at room temperature and then stirred and refluxed for 16 hours (the mixture was by this time orange-coloured). Benzyl chloride (13.2 g) was then added dropwise and the mixture refluxed for 24 hours. Water (100 ml) was added and the ethereal layer separated, and washed with water, dilute hydrochloric acid and again with water; it was then dried (sodium sulphate). The ether was evaporated under reduced pressure and then the residue was distilled to give oc-benzylpinacolone, b.p. 78--80"/0.06 mm Hg.

Stage 11. Bromine (1.4 ml) was added dropwise to lce-benzylpinacolone (5.2 g) in diethyl ether (80 ml) at about 10 . The solution was then stirred for 1 hour at room temperature and the ether was evaporated in vacuo to give a red liquid which was distilled in a bulb to give, as a slightly coloured liquid, a-bromo-a-benzyl pinacolone, b.p. 100 /0.1 mm Hg.

Stage III. 1,2,4-Triazole (0.28 g) in dimethyl formamide (5 ml) was added dropwise to a suspension of sodium hydride (0.1 g of 100%) in dimethyl formamide (2 ml). The reaction mixture was stirred for 2 hours and then a-bromo-a-benzyl pinacolone (1.0 g) in dimethylformamide (5 ml) was added. The reaction mixture was stirred at room temperature overnight and then poured into water (75 ml) to give, as a white crystalline solid, a-(1,2,4-triazol-1-yl)-a-benzyl pinacolone, m.p. 69710.

Stage IV r-1,2,4-Triazol-1-yl-r-benzylpinacolone (2.0 g) in methanol (20 ml) was treated portionwise with sodium borohydride (0.26 g). The mixture was then refluxed for one hour. The solvent was removed in vacuo and hydrochloric acid (1 N; 40 ml) was added to the residue. The white precipitate was filtered off, washed with water, dried and crystallised from aqueous ethanol to give, as a whit crystalline solid, 1 -t-butyl-2- ( 1,2,4-triazol- 1 -yl) -2-benzylethanol.

Patent Specification No. 1252533 discloses a compound of general formula (I) wherein X is bromine and R1 is o-bromobenzyl. In this Specification we make no claim to said compound of Patent Specification No. 12522533.

Subject to the foregoing disclaimer, WHAT WE CLAIM IS:1. A compound of general formula (I):

wherein R1 is optionally substituted benzyl and X is halogen.

2. A compound according to claim 1 wherein R1 is benzyl optionally ring substituted with halogen, C14 alkyl, halo (C1~4 alkyl), phenyl, halophenyl, C;--B cycloalkyl, nitro, cyano, C14 alkoxy, (C14 alkylene)dioxy, (C14 alkoxy), (C,, alkyl), mercapto, (C1 alkylthio, (C1~4 alkyl) sulphonyl, (C14 haloalkyl)sulphonyl, phenyl sulphonyl, unsubstituted or mono- or di- (C14 alkyl) substituted sulphamoyl or carbamoyl, carboxy, (C1 alkoxy)carbonyl, unsubstituted or mono- or di-(C1-4 alkyl) substituted amino, (C26 alkanoyl)amino, N-(C1~4 alkyl)-substituted (C2~^ alkanoyl) amino, formylamino, N- ( C14 alkyl)-substituted formylamino, phenylethyl, phenoxy or benzyloxy, the number of ring - substituents being 1, 2 or 3, and/or optionally substituted on the carbon atom with one halogen or C1-4 alkyl or phenyl or benzyl optionally substituted as recited above for benzyl, C14 alkyl, cyano, (C1 alkoxy)carbonyl or trihalomethyl.

3. A compound according to claim 2 wherein R1 is benzyl, a-methylbenzyl, xr-methyldichloro-benzyl, a-methyldichloro-benzyl, &alpha;-methylfluorobenzyl, chlorobenzyl, dichloro-benzyl, trichlorobenzyl, tetrachlorobenzyl penta-chlorobenzyl, bromobenzyl, dibromobenzyl, fluoro-benzyl, difiuorobenzyl, pentafluorobenzyl, methylbenzyl, dimethylbenzyl, cyanobenzyl, nitrobenzyl, trifluoromethylbenzyl, methoxybenzyl, chloronitrobenzyl, chlorofluorobenzyl, fluorobromobenzyl, methoxybromobenzyl or phenylbenzyl.

4. A compound according to claim 3 wherein R1 is benzyl, a-methyl-p-chlorobenzyl, a-methyl-2,4-dichloro.benzyl, a-methyl-p-fiuorobenzyl, o-, m- or p-chlorobenzyl, 2,4-, 3,4- or 2,6-dichlorobenzyl, 2,4,5- or 2,3,6-trichlorobenzyl, pentachlorobenzyl, m- or p-bromobenzyl, 2,4-dibromobenzyl, o-, m- or p-fluorobenzyl, 2,4difluorobenzyl, o- or p-methylbenzyl, 2,5-dimethylbenzyl, p-nitrobenzyl, m- (trifluoro methyl)benzyl, o- or p-methoxybenzyl, 3-nitro-4-chlorobenzyl, 2-chloro-4-fiuoro- benzyl, 2-fluoro-4-bromobenzyl, or 2-methoxy-5-bromobenzyl.

5. A compound according to any one of the preceding claims wherein X is bromine or chlorine.

6. 1-(4'-Chloropbenyl)-2-bromo-4,4-dimethylpentan-3-one.

7. &alpha;-Bromo-&alpha;-benzylpinacolone.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (7)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   Subject to the foregoing disclaimer, WHAT WE CLAIM IS:1. A compound of general formula (I):

   wherein R1 is optionally substituted benzyl and X is halogen.
2. 2. A compound according to claim 1 wherein R1 is benzyl optionally ring substituted with halogen, C14 alkyl, halo (C1~4 alkyl), phenyl, halophenyl, C;--B cycloalkyl, nitro, cyano, C14 alkoxy, (C14 alkylene)dioxy, (C14 alkoxy), (C,, alkyl), mercapto, (C1 alkylthio, (C1~4 alkyl) sulphonyl, (C14 haloalkyl)sulphonyl, phenyl sulphonyl, unsubstituted or mono- or di- (C14 alkyl) substituted sulphamoyl or carbamoyl, carboxy, (C1 alkoxy)carbonyl, unsubstituted or mono- or di-(C1-4 alkyl) substituted amino, (C26 alkanoyl)amino, N-(C1~4 alkyl)-substituted (C2~^ alkanoyl) amino, formylamino, N- ( C14 alkyl)-substituted formylamino, phenylethyl, phenoxy or benzyloxy, the number of ring - substituents being 1, 2 or 3, and/or optionally substituted on the carbon atom with one halogen or C1-4 alkyl or phenyl or benzyl optionally substituted as recited above for benzyl, C14 alkyl, cyano, (C1 alkoxy)carbonyl or trihalomethyl.
3. 3. A compound according to claim 2 wherein R1 is benzyl, a-methylbenzyl, xr-methyldichloro-benzyl, a-methyldichloro-benzyl, &alpha;-methylfluorobenzyl, chlorobenzyl, dichloro-benzyl, trichlorobenzyl, tetrachlorobenzyl penta-chlorobenzyl, bromobenzyl, dibromobenzyl, fluoro-benzyl, difiuorobenzyl, pentafluorobenzyl, methylbenzyl, dimethylbenzyl, cyanobenzyl, nitrobenzyl, trifluoromethylbenzyl, methoxybenzyl, chloronitrobenzyl, chlorofluorobenzyl, fluorobromobenzyl, methoxybromobenzyl or phenylbenzyl.
4. 4. A compound according to claim 3 wherein R1 is benzyl, a-methyl-p-chlorobenzyl, a-methyl-2,4-dichloro.benzyl, a-methyl-p-fiuorobenzyl, o-, m- or p-chlorobenzyl, 2,4-, 3,4- or 2,6-dichlorobenzyl, 2,4,5- or 2,3,6-trichlorobenzyl, pentachlorobenzyl, m- or p-bromobenzyl, 2,4-dibromobenzyl, o-, m- or p-fluorobenzyl, 2,4difluorobenzyl, o- or p-methylbenzyl, 2,5-dimethylbenzyl, p-nitrobenzyl, m- (trifluoro methyl)benzyl, o- or p-methoxybenzyl, 3-nitro-4-chlorobenzyl, 2-chloro-4-fiuoro- benzyl, 2-fluoro-4-bromobenzyl, or 2-methoxy-5-bromobenzyl.
5. 5. A compound according to any one of the preceding claims wherein X is bromine or chlorine.
6. 6. 1-(4'-Chloropbenyl)-2-bromo-4,4-dimethylpentan-3-one.
7. 7. &alpha;-Bromo-&alpha;-benzylpinacolone.