Method for preparing substituted styrene derivatives

Abstract

The present invention relates to a method for preparing substituted styrene derivatives.

Claims

1. A method for preparing substituted styrene derivative of formula (I): ##STR00005## where R.sup.1 is Cl (Ia), Br (Ib) or methyl (Ic), comprising reacting a dihydrobenzofuran derivative of formula (II) ##STR00006## where R.sup.1 is Cl, Br or methyl, by heating in the presence of an alkoxide or hydroxide base to give a compound of formula (I).

2. The method according to claim 1, wherein the radical definitions of formulae (I) and (II) are as follows: R.sup.1 is Cl.

3. The method according to claim 1, wherein the base used is potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium hydroxide.

4. The method according to claim 1, further comprising using one or more of an amide or ether solvent or mixtures of amide solvents with ethers or aromatic solvents as solvent.

5. The method according to claim 1, further comprising using one or more solvents comprising one or more of DMAc, DMF or diglyme or mixtures of DMAc or DMF with THF, 2-methyl-THF, dioxane, DME, toluene, xylene, chlorobenzene or 1,2-dichlorobenzene.

6. The method according to claim 1, wherein one of the following combinations of solvent and base is used for the reaction: a) diglyme in combination with potassium hydroxide b) DMAc in combination with potassium hydroxide c) DMF in combination with potassium hydroxide d) solvent mixture of DMAc with toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dioxane, DME, 2-methyl-THF or THF in combination with potassium hydroxide e) solvent mixture of DMF with toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dioxane, DME, 2-methyl-THF or THF in combination with potassium hydroxide f) DMAc, DMF, THF, 2-methyl-THF, dioxane, DME, anisole or diglyme or mixtures of these solvents in combination with potassium tert-butoxide g) potassium hydroxide as inorganic base and potassium tert-butoxide as organic base.

Description

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

(1) Preference is given to a method according to the invention in which the radical definitions of the formulae (I) and (II) are as follows:

(2) R.sup.1 is Cl.

Description of the Process

(3) The reaction according to the invention is shown in Scheme 1.

(4) ##STR00003##

(5) The desired styrene derivatives of the general formula (I) are obtained with good yields and in high purity by the method according to the invention.

(6) The method according to the invention has the advantage over the methods described above that the starting materials can be prepared on the industrial scale and, surprisingly, the method can be carried out successfully by using weaker bases such as potassium hydroxide.

(7) Useful solvents for the method according to the invention in principle include any organic solvents or solvent mixtures that are inert under the reaction conditions, including: ethers (such as: 1,2-dimethoxyethane (DME), diglyme, tetrahydrofuran (THF), 2-methyl-THF, anisole and 1,4-dioxane); amide solvents (such as: DMF, N,N-dimethylacetamide (DMAc)) and dipolar aprotic solvents (such as: DMSO). Preference is given to using THF, 2-methyl-THF, dioxane, DME, anisole, diglyme, DMF or DMAc or mixtures of DMAc with ethers or mixtures of DMAc with aromatic solvents (such as: toluene, xylene, chlorobenzene or 1,2-dichlorobenzene). Particular preference is given to using DMAc, DMF or diglyme or mixtures of DMAc or DMF with THF, 2-methyl-THF, dioxane, DME, toluene, xylene, chlorobenzene or 1,2-dichlorobenzene.

(8) Examples of useful alkoxide bases for the method according to the invention include the following: potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or potassium methoxide. Examples of useful hydroxide bases for the method according to the invention include the following: potassium hydroxide. Preference is given to using potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide or sodium methoxide. Particular preference is given to using potassium hydroxide or potassium tert-butoxide.

(9) Particularly preferred are the following combinations of the groups of solvents and bases described above: a) diglyme in combination with potassium hydroxide b) DMAc in combination with potassium hydroxide c) DMF in combination with potassium hydroxide d) solvent mixture of DMAc with toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dioxane, DME, 2-methyl-THF or THF in combination with potassium hydroxide e) solvent mixture of DMF with toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dioxane, DME, 2-methyl-THF or THF in combination with potassium hydroxide f) DMAc, DMF, THF, 2-methyl-THF, dioxane, DME, anisole or diglyme or mixtures of these solvents in combination with potassium tert-butoxide.

(10) Especially preferred for the method according to the invention is the following combination of solvents and base: DMAc or diglyme and potassium hydroxide.

(11) The temperature in the method according to the invention can be varied within wide limits. A customary operating temperature is from 20 C. to 120 C. The reaction is preferably conducted at a temperature in the range of 80 C. to 120 C. The reaction is particularly preferably conducted at a temperature in the range of 100 C. to 120 C.

(12) The method according to the invention is typically conducted at standard pressure. It is also possible to conduct the reaction under reduced pressure or at elevated pressure (positive pressure).

(13) The molar ratios of the compound of the formula (II) to bases of the group described above may be varied within wide limits. Typically, a molar ratio from 1:1 to 1:5 is employed. For organic bases such as potassium tert-butoxide, a molar ratio from 1:1 to 1:1.5 is preferred. Particular preference is given to a molar ratio of 1:1.1. For inorganic bases such as potassium hydroxide, a molar ratio from 1:2 to 1:4 is preferred. Particular preference is given to a molar ratio of 1:3.

(14) The reaction time is short and is in the range from about 0.5 to about 5 hours. A longer reaction time is possible, but is not economically worthwhile.

(15) The compounds of the formula (I) are not isolated. The compounds of the formula (I) are further reacted to compounds of the formula (III) (Scheme 2), either directly (when using potassium tert-butoxide as base) or after an intermediate work-up (when using potassium hydroxide as base). The reaction to give compounds of the formula (III) is carried out as described in WO 2015/189114.

(16) The following reaction sequence is preferably carried out for preparing the compound of the formula (III):

(17) ##STR00004##

Examples

(18) The present invention is elucidated in more detail by the examples which follow, without restricting the invention to these examples.

3-Chloro-2-vinylphenol (Ia)

(19) Potassium hydroxide powder (85%, 22.6 g, 342.9 mmol) is added to a solution of 4-chloro-2,3-dihydro-1-benzofuran (IIa) (19.0 g, 114.3 mmol) in N,N-dimethylacetamide (75 ml) at 20 C., the mixture is heated to 120 C. and stirred at this temperature for 1 hour. The reaction mixture was cooled to ca. 10-15 C., diluted with water (150 ml) and brought to a pH of 1 by slow addition of 37% hydrochloric acid (40 ml). The aqueous phase was extracted twice with toluene (100 ml each time), the combined organic phases washed once with 10% hydrochloric acid (30 ml) and concentrated under reduced pressure to a residual volume of ca. 100 ml. The solution thus obtained is used directly in the next step. Analytical data for 3-chloro-2-vinylphenol are as follows: .sup.1H-NMR (CDCl.sub.3, 400 MHz) (ppm)=7.08 (dd, J=8.0, 8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.79 (dd, J=12.0 Hz, 12.0 Hz, 1H), 5.74 (d, J=12.0 Hz, 1H), 5.73 (s, 1H), 5.68 (d, J=12.0 Hz, 1H).

3-Bromo-2-vinylphenol (Ib)

(20) .sup.1H-NMR (DMSO-d6, 400 MHz) (ppm)=10.20 (s, 1H), 7.08 (dd, J=8.0, 1.3 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.89 (dd, J=8.0, 1.0 Hz, 1H), 6.77 (dd, J=17.8, 12.1 Hz, 1H), 6.08 (dd, J=17.8, 2.5 Hz, 1H), 5.51 (dd, J=12.1, 2.5 Hz, 1H).

3-Methyl-2-vinylphenol (Ic)

(21) .sup.1H-NMR (DMSO-d6, 400 MHz) (ppm)=9.45 (s, 1H), 6.93 (t, J=7.8 Hz, 1H), 6.73 (dd, J=17.9, 11.8 Hz, 1H), 6.69 (d, J=7.8, 1.0 Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 5.76 (dd, J=17.9, 2.5 Hz, 1H), 5.41 (dd, J=11.9, 2.5 Hz, 1H), 2.27 (s, 3H).

3-Chloro-2-vinylphenyl Methanesulphonate (IIIa)

(22) The toluene solution of Ia obtained in the step above was cooled to 0-5 C. and triethylamine (17.5 ml, 125.7 mmol) was added. A 50% solution of methanesulphonyl chloride (9.7 ml, 125.7 mmol) in toluene was metered in over a period of 1 hour at a temperature of 0-5 C. and, after addition was complete, the mixture was stirred at 20 C. for 30 min. Subsequently, the reaction mixture was brought to a pH of 1 by slow addition of 10% hydrochloric acid (50 ml) at 10-15 C. and the aqueous phase extracted twice with a mixture of toluene/tert-butyl methyl ether 4:1 (50 ml each time). The combined organic phases were concentrated under reduced pressure and the residue was recrystallized from ethanol (15 ml) (23.7 g, 89% of theory). .sup.1H-NMR (CDCl.sub.3, 400 MHz) (ppm)=7.36 (dd, J=8.0, 1.2 Hz, 1H), 7.34 (dd, J=8.0, 1.2 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.76 (dd, J=18.0 Hz, 11.7 Hz, 1H), 5.91 (dd, J=18.0, 1.6 Hz, 1H), 5.73 (dd, J=11.8, 1.4 Hz, 1H), 3.11 (s, 3H).

3-Bromo-2-vinylphenyl Methanesulphonate (IIIb)

(23) .sup.1H-NMR (CDCl.sub.3, 400 MHz) (ppm)=7.56 (dd, J=8.1, 1.1 Hz, 1H), 7.38 (dd, J=8.1, 1.1 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 6.72 (dd, J=18.0 Hz, 11.8 Hz, 1H), 5.84 (dd, J=18.0, 1.4 Hz, 1H), 5.71 (dd, J=11.6, 1.4 Hz, 1H), 3.11 (s, 3H).

3-Methyl-2-vinylphenyl Methanesulphonate (IIIc)

(24) .sup.1H-NMR (CDCl.sub.3, 400 MHz) (ppm)=7.23 (dd, J=7.8, 1.8 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.14 (dd, J=7.5, 1.4 Hz, 1H), 6.71 (dd, J=17.8 Hz, 11.8 Hz, 1H), 5.65 (dd, J=11.8, 1.6 Hz, 1H), 5.63 (dd, J=17.8, 1.6 Hz, 1H), 3.09 (s, 3H), 2.37 (s, 3H).