FR2647440A1 - Process for the bromination of a phenol derivative - Google Patents

Abstract

The invention relates to the bromination at the ortho position of phenol derivatives of the guaiacol type, for example. This bromination is carried out by reacting the product to be brominated with a hypobromite, optionally in the presence of a primary or secondary amine.

Description

dans laquelle X représente l'hydrogène, OH, un radical alcoxy CH2 OH, CHO, CO2R, R etant un radical alkyle, alcényle, alkyloxy, ces radicaux pouvant être linéaires ou ramifiés, cycloalkyle, cycloalcényle, alkylcycloalcényle, benzyle, amine, terpénique, ou un radical alcoxy, R, et R2 sont identiques ou différents et représentent l'hydrogène, un halogène, un radical alkyle, acyle ou alcoxy, au moins un de X, Rf, R2 n'étant pas l'hydrogène.PROCESS FOR BROMINATING A PHENOL DERIVATIVE
The present invention relates to the bromination of a phenol derivative of formula (i)

in which X represents hydrogen, OH, an alkoxy radical CH2 OH, CHO, CO2R, R being an alkyl, alkenyl or alkyloxy radical, these radicals being able to be linear or branched, cycloalkyl, cycloalkenyl, alkylcycloalkenyl, benzyl, amine, terpenic, or an alkoxy radical, R, and R2 are identical or different and represent hydrogen, a halogen, an alkyl, acyl or alkoxy radical, at least one of X, Rf, R2 not being hydrogen.

 The problem which arises for the bromination of such products is twofold. On the one hand, in fact, we generally want to obtain an unobrominated and not brominated derivative. On the other hand, this bromination must be regio-selective because it is desired essentially to prepare the bronzed derivative in ortho. we can indicate on this subject that a bromination of a product such as guaiacol by bromine gives 80 t of brominated derivative in para and 20 t of brominated derivative in ortho only.

 The main object of the invention is therefore a process allowing in particular monobromation in ortho with an acceptable yield. However, the Applicant has realized that the problem could be resolved by using a specific brominating agent.

dans laquelle X représente l'hydrogène, OH, un radical alcoxy, CH2 OH, CHO, CO2R, R étant un radical alkyle, alcényle, alkyloxy, ces radicaux pouvant être linéaires ou ramifiés, cycloalkyle, cycloalcényle, alkylcycloalcényle, benzyle, amine, terpénique, Rt et
R2 sont identiques ou différents et représentent l'hydrogène, un halogène, un radical alkyle, acyle ou alcoxy, au moins un de X, Rt et R2 n'étant pas l'hydrogène.For this purpose, the process according to the invention for bromination of a phenol derivative is characterized in that a substrate of formula is reacted with a hypobromite

in which X represents hydrogen, OH, an alkoxy radical, CH2 OH, CHO, CO2R, R being an alkyl, alkenyl or alkyloxy radical, these radicals being able to be linear or branched, cycloalkyl, cycloalkenyl, alkylcycloalkenyl, benzyl, amine, terpenic , Rt and
R2 are identical or different and represent hydrogen, a halogen, an alkyl, acyl or alkoxy radical, at least one of X, Rt and R2 not being hydrogen.

 Under these conditions, a monobromo derivative in ortho is obtained with a yield of at least 30% and at least 40% according to preferred embodiments of the invention.

 Other characteristics, details and advantages of the invention will be better understood on reading the description and the concrete examples which will follow.

 The starting product or substrate is a phenol derivative corresponding to formula 1 above.

 The invention applies particularly well to products for which R1 and R2 are in the meta position and also to those for which RX and R2 both represent hydrogen.

 It will be noted that, as a particularly advantageous starting product, it is possible to use those for which X is an alkoxy radical, and inter alia those for which R1 and R2 are hydrogen, and more particularly those for which X is in the ortho position, in particular among these guaiacol (X = Oc2).

 As other interesting starting materials, salicylates can also be mentioned, that is to say the products for which X in the formula (1) is a CO2R radical, R being as defined above.

 By way of example, mention may be made of the products for which R1 and R2 are both hydrogen and in particular the salicylates of n-hexyl, of benzyl, of methyl, of amyl, of isoamyl, of ethyl-2 hexyl, cis-hexen-3 yl-1, glycol, prenyl, 2-ethyl butyl, 2-methyl pentyl, monomethylamine, 3,3,5 trimethyl cyclohexyl, 2-isopropyl cyclohexyl, beta-isopropoxyethyl, bronyl.

 An essential characteristic of the process of the invention is the nature of the brominating agent.

 According to the invention, this brominating agent is a hypobromite.

Generally, an alkali metal hypobromite is used, more particularly sodium hypobromite.

 Furthermore, there is a variant of the invention which makes it possible to increase the yield of brominated product.

 This variant consists in carrying out the bromination reaction in the presence of the hypobromite and of an additional compound.

 This compound can be chosen first of all from the group of primary or secondary amines, in particular aliphatic amines, more particularly alkylamines. Examples of the latter are those for which the alkyl radical or radicals are methyl, ethyl, n-propyl, n-butyl, isobutyl, cyclohexyl, tert-butyl.

 This compound can also be chosen from the group of imides, lactams, amides as well as urea derivatives and cyanuric and isocyanuric acids.

 As regards the imides, mention may be made of succinimide, phthalimide, saccharin.

 For lactams, caprolactam can be mentioned.

 Among the amides, acetamide can be used, sulfonamides such as tosylsulfonamide.

 For urea derivatives, ureines, ureides or cyclic derivatives thereof such as hydantoin can be used.

 Generally, the reaction is carried out in an aqueous medium, the hypobromite generally being introduced in the form of an aqueous solution.

 However, it is possible to work in a two-phase environment.

 The product & bromer is present in solution in a solvent, the second phase, aqueous phase, being for example that of the aqueous hypobromite solution.

 As solvent, it is possible to use halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated or not, ethers.

 Mention may be made in this connection of carbon tetrachloride, dichlo romethane, chloroethane, dichlorobenzene.

 For ethers, mention may more particularly be made of isopropyl ether, butyl oxide and hexyxide.

 A particular embodiment can be mentioned. It consists in forming a two-phase medium comprising on the one hand the solvent of the above type and the starting substrate, and on the other hand as the second phase of water and the additional compound described above. The reaction is carried out by injecting the hypobromite into the aqueous phase.

 Preferably, the aqueous phase is maintained at a pH close to neutrality.

 Another embodiment consists in forming a two-phase medium comprising an organic solvent of the aforementioned type and an aqueous phase with the hypobromite and the additional compound. The reaction is carried out by introducing the bromine product into the solvent.

 The reaction is generally carried out at a temperature close to ambient.

 The concentration of phenol derivative (starting product) is usually between 5.1 and 10 moles / l.

 The process of the invention is particularly advantageous for carrying out a monobromation in which case a quantity of brominating agent between 0.8 and 1.2 equivalent of reactive bromine is generally used.

 Generally, the amount of additional compound used with hypobromite can vary widely.

This amount can thus range from 0.01 to 10 moles, more particularly 0.1 to 1 mole per mole of starting material to be brominated.

 This process is also very advantageous for carrying out bromination in ortho of the substrates of formula (1) for which of course there is a free position in ortho of the OH group.

 Once the reaction is complete, the product can be separated from the reaction medium by any known means after, if necessary, conventional treatment for the transition from its salt form to the desired form. An example of treatment consists in adding an acid solution to the reaction medium and in increasing the temperature in order to hydrolyze the precipitate formed during the reaction.

 Concrete but non-limiting examples now go between data.

In these examples, TT denotes the Rate of Transformation, i.e. the ratio:
number of moles transformed
number of moles entered
It defines the quantity of starting product transformed during the reaction.

RR denotes the yield of the reaction, i.e. the ratio
number of moles obtained
number of theoretical moles
It indicates the percentage of a compound present in the reaction mixture.

RT denotes the Yield compared to the processed product or the ratio
RR
TT
It reflects the selectivity of a reaction for a compound.

EXAMPLE 1
A solution of sodium hypobromite containing 0.075 moles of Dr (measured by iodometry) is added to a solution of 9.3 g (0.075 moles) of guaiacol dissolved in 100 ml of isopropyl ether.

Stirring is continued for four hours at a temperature between 15 and 20 ° C. The mixture is treated with 100 ml of 2N & 5O0C sulfuric acid. The organic phase is washed and dried overnight over calcium chloride.

A brown liquid is obtained which is analyzed by HPLC and CPG. The results are as follows:
TT = 63.2%
Bromo-6 guaiacol RR = 20.8% RT = 32.9%
Bromo-4 gaiacol RR = 3.8%
It can be noted that the bromo-6 ratio is 5.47
bromo-4
This is an interesting value insofar as these are products whose separation poses the most problems.

EXAMPLE 2
This example describes a bromination in the presence of an amine.

 Bromination is carried out in a two-phase medium, in the presence of different molar concentrations of tert-butylamine and using sodium hypobromite as a brominating agent.

 0.075 moles (9.3 g) of guaiacol plus different amounts of tert-butylamine are dissolved in 100 ml of isopropyl ether and 20 ml of water.

 0.075 moles of hypobromite are added dropwise. The mixture is left stirring for 4 hours.

 The temperature is maintained between 15 and 200C. The compound is hydrolyzed with 50 cm3 of 4N sulfuric acid at 500C.

 The organic phase is washed and dried over calcium chloride.

 The products are separated by CPG and HPLC and identified by interpretation of the NMR spectra.

For 1/8 mole of amine per mole of guaiacol, the results are as follows
TT = 64.1%
Bromo-6 guaiacol RR = 27% RT = 42%
Bromo-4 guaiacol RR = 6.9%
For 1/4 mole of amine per mole of guaiacol, the results are as follows:
TT = 66.7%
Bromo-6 guaiacol RR = 30.9% RT = 46.4%
Bromo-4 guaiacol RR = 6.7%
For 1/2 mole of amine per mole of guaiacol, the results are as follows:
TT = 79%
Bromo-6 gaiacol RR = 44.1% RT = 55.8%
Bromo-4 gaiacol RR = 11%
EXAMPLE 3
This example describes a reaction by adding guaiacol to a hypobromite solution containing an amine.

 An aqueous hypobromite solution containing 0.075 mole of Br and 30 ml of isopropyl ether is cooled to OOC. First 0.7 g of tert-butylamine is added thereto, then 9.3 g of guaiacol, the latter being dissolved in 70 ml of isopropyl ether. The temperature is maintained & OOC. Excess reactive bromine is neutralized with 10% sodium sulfite. The mixture is treated with 50 ml of 4N sulfuric acid at 500C. the organic phase is washed and dried overnight over calcium chloride. It is then analyzed by CPG.

 An R T of 61.8% is obtained for 6-bromo galacol.

Claims (10)

1. Process for the bromination of a phenol or a phenol derivative  characterized in that one reacts with a hypobromite a  formula substrate

 or alkoxy, at least one of X, R, and R2 not being hydrogen.  represent hydrogen, a halogen, an alkyl, acyl radical  glycolic, Rl and R2 are the same or different and  cycloalkenyl, alkylcycloalkenyl, benzyl, amine, terpene,  these radicals possibly being linear or branched, cycloalkyl,  CH2OH, CHO, COUR, R being an alkyl, alkenyl, alkyloxy radical,  in which X represents hydrogen, OH, an alkoxy radical, 2. Method according to claim 1, characterized in that  uses a hypobromite of an alkali metal, in particular sodium. 3. Method according to claim 1 or 2, characterized in that  conducts the bromination reaction in the presence additionally of a  additional compound selected from the group comprising  primary or secondary amines. 4. Method according to one of claims 1 or 2, characterized in that  that the bromination reaction is carried out in the presence of a  additional compound selected from the group comprising  imides, lactams, amides, urea derivatives and  cyanuric and isocyanuric acids. 5. Method according to one of the preceding claims, characterized  in that the bromination reaction is carried out in a medium  biphasic comprising a solvent and water. 6. Method according to one of the preceding claims, characterized  in that an ortho bromination of the substrate of  Formula 1). 7. Method according to one of the preceding claims, characterized  in that a substrate of formula (1) is reacted in which  R, and R2 are in the meta position. 8. Method according to one of the preceding claims, characterized  in that a substrate of formula (1) is reacted in which  Rl r R2 = H. 9. Method according to one of the preceding claims, characterized  in that a substrate of formula (1) is reacted in which  X is an alkoxy radical. 10. Method according to one of the preceding claims, characterized  in that a substrate of formula (1) is reacted in which  X is in ortho position.