GB2138419A - Cyanophenols - Google Patents

Abstract

2-Cyanophenol is manufactured by: (1) reacting a substituted butadiene of formula (I) with a 2-haloacrylonitrile of formula (II> <IMAGE> wherein R in formula (I) is a leaving group; (2) hydrolysing the cyclohexene product thus formed to give the 3-hydroxy-4-halo-4- cyanocyclohexene; (3) oxidising the hydroxy product obtained from step 2 above to the corresponding 6-halo-6- cyanocyclohex-2-en-1-one; and (4) treating the 6-halo-6-cyanocyclohex-2-en-1-one product from step 3 above with a base to give the desired 2-cyanophenol.

Description

SPECIFICATION Cyanophenols This invention relates to cyanophenols and in particular to a process for the manufacture of 2-cyanophenol.

2-cyanophenol is a known product, useful in the manufacture of various products, in particular pharmaceutical products.

According to the present invention there is provided a process for the manufacture of 2cyanophenol which comprises the steps of: 1) reacting a substituted butadiene of formula (I) with a 2-haloacrylonitrile of formula (I I)

wherein R in formula (I) is a leaving group; 2) hydrolysing the cyclohexene product thus formed to give the 3-hydroxy-4-halo-4-cyanocyclohexene; 3) oxidising the hydroxy product obtained from step 2 above to the corresponding 6 halo-6-cyanocyclohex-2-en-1 -one; and 4) treating the 6-halo-6-cyanocyclohex-2-en1-one product from step 3 above with a base to give the desired 2-cyanophenol.

The leaving group R of the substituted butadiene of formula (I) may be any group which is removed on hydrolysis and is thereby replaced with a hydroxy group. Suitable leaving groups include acyl groups, aryl groups, heteroaryl groups, silyl groups, and phosphonate groups. Especially convenient leaving groups are lower acyl groups, for example the acetyl group.

An especially suitable 2-haloacrylonitrile is 2-chloroacrylonitrile.

The reaction between the substituted butadiene (I) and the 2-haloacrylonitrile (II) may take place at elevated pressures and temperatures in the absence of a solvent, or in the presence of a suitable solvent at atmospheric pressure. The reaction preferably takes place at a temperature in the range 50 to 1 50 "C. If a solvent is used, the reaction conventiently takes place under reflux. Thus suitable solvents for the reaction have a boiling point in the range 50 to 1 50 C, and include chlorinated hydrocarbon solvents, for example chlorobenzene.

Preferably there is used a catalyst for the Diels-Alder reaction, for example hydroquinone.

If desired, one or more of the reactants for step 1 may be prepared in situ. For example 1-acetoxybutadiene may be prepared by the reaction of crotonaldehyde and isopropenylacetate, p-toluenesulphonic acid and copper acetate (J.C.S. Perkin I, 1979, page 1897).

The 2-halo-acrylonitrile may be added to this reaction mixture, optionally in the presence of a suitable solvent, and the reaction of step 1 completed without the isolation of the 1acetoxybutadiene.

In step 2) of the process of the invention, the leaving group -R is hydrolysed and replaced by a -hydroxy group. Acidic or basic hydrolysis may be used, but preferably hydrolysis takes place in the presence of mineral acid, for example sulphuric or hydrochloric acid. Any solvent used in step 1) of the process is preferably removed prior to the hydrolysis step, since hydrolysis in a two phase reaction in the presence of the solvent tends to be slow.

In step 3) of the process of the invention, the -hydroxy group formed in step 2) is oxidised to the ketone. Any suitable oxidising agent may be used, but we have found that manganese dioxide is an especially effective oxidising agent for this reaction. The oxidisation reaction preferably takes place in the presence of an organic solvent, for example a chlorinated hydrocarbon solvent such as chloroform or chlorobenzene.

In step 4) of the process of the invention, the 6-halo-6-cyanocyclohex-2-en-1 -one product from step 3) is treated with base to eliminate hydrohalogen acid and form the desired 2-cyanophenol product. Especially preferred bases are organic amine bases, for example tirethylamine. The reaction conveniently takes place in the absence of a solvent, but a solvent may be used if desired.

The respective steps 1) to 4) of the process of the invention may take place consecutively with or without the isolation of the intermediate product of each step.

The invention is illustrated by the following Examples in which all parts and percentages are by weight unless otherwise stated.

Example 1 Step 1) 1-Acetoxybutadiene (1.12g; 0.01 mole), 2chloroacrylonitrile (0.8ml; 0.01 mole) and hydroquinone (0. 1g; 0.001 mole) were sealed in a Carius tube and heated at 1 30 C for 24h.

The reaction mixture was dissolved in ether and filtered. The filtrate was allowed to stand and there crystallised 1 .01g of 3-acetoxy-4chloro-4-cyanocyclohexene, melting point 86"C. The structure of the product was confirmed by infra-red spectroscopy and elemental analysis.

Step 2) The product from step 1 (0.5g; 0.0025M) was added to 20ml of 2N sulphuric acid and heated under reflux for 1 hour. After this time, the mixture was extracted using chloro form and the organic layer separated, dried and the solvent removed in vacuo to give pale brown crystals (0.49) of 3-hydroxy-4-chloro-4cyanocyclohexene.

Step 3) The product from step 2) (2.159; 0.0137mole was dissolved in chloroform (50 ml) and manganese dioxide (59; 0.057mole) was added. The mixture was stirred for 7 hours and filtered. The solvent was removed to leave 2.19 of a pale yellow oil whose structure was confirmed by infra-red spectroscopy and nmr spectroscopy to be 6-chloro-6cyanocyclohex-2-en-1 -one.

Step 4) Triethylamine (3ml; 0.02mole) was added to the product from step 3) (0.79; 0.0045mole) at room temperature. After approximately 1 minute an exothermic reaction occurred. After 10 minutes, the mixture was evaporated and partitioned between acid and ether. The etherial layer was washed with water, dried and the solvent evaporated to give 0.59 2-cyanophenol, melting point 92-94"C.

Example 2 The procedure of Example 1 was repeated except that in step 1) the reaction took place in chlorobenzene as solvent. The details of step 1) were as follows:- 1-Acetoxybutadiene (4.95g; 0.44mole) and hydroquinone (0.449; 0.004mole) were added to 35ml chlorobenzene and heated under reflux. 2-chloroacrylonitrile (5.3ml; 0.066mole) was added dropwise over half an hour and the mixture was heated for a further 3 hours. The reaction mixture was cooled to room temperature and the insoluble material removed by filtration. The solvent was removed in vacuo to leave 6.039 of pale brown needles of 3-acetoxy-4-chloro-4-cyanohexene.

Example 3 The procedure of Example 1 was repeated except that in step 1), the 1-acetoxybutadiene was prepared in situ. The details were as follows: Crotonaldehyde (1.49; 0.02mole), isopropenylacetate (3.26ml; 0.03mole), p-toluenesulphonic acid (0.049; 0.02mole) and cupric acetate (0.01g; 0.00005mole) were added to chlorobenzene (20ml) and heated under reflux for 4 hours. 2-Chloroacrylonitrile (2.4ml; 0.03mole) was added dropwise and the mixture was heated for a further 4 hours. After filtration the solvent was removed to give 3.289 of a brown oil which yielded 1.769 of 3-acetoxy-4-chloro-4-cyanocyclohexene on chromatographic purification.

Example 4 The procedure of Example 1 was repeated except that in step 2), the hydrolysis took place using hydrochloric acid. The details were as follows:- 3-Acetoxy-4-chloro-4-cyanocyclohexene from step 1) (39; 0.015mole) was added to 50 ml of 2N hydrochloric acid and the mixture was heated under reflux for 8 hours. The reaction mixture was filtered and the filtrate extracted with chloroform to give, after removal of solvent, 2.159 of 3-hydroxy-4chloro-4-cyanocyclohexene.

Claims (1)

1. Process for the manufacture of 2-cyanophenol which comprises the steps of: 1) reacting a substituted butadiene of formula (I) with a 2-halocrylonitrile of formula (II)

wherein R in the formula (I) is a leaving group; 2) hydrolysing the cyclohexene product thus formed to give the 3-hydroxy-4-halo-4-cyanocyclohexene; 3) oxidising the hydroxy product obtained from step 2 above to the corresponding 6 halo-6-cyanocyclohex-2-en-1 -one; and 4) treating the 6-halo-6-cyanocyclohex-2-en1-one product from step 3 above with a base to give the desired 2-cyanophenol.