Process for Preparing 2,6-Substituted Phenols

Abstract

The present invention relates to a process for preparing 2,6-substituted phenols, and in particular to a process for preparing 2,6-diphenylphenol. This process is a doubling coupling of a boronic acid and a 2,6-dihalogenphenol in a Suzuki-Miyaura reaction on sterically hindered ortho positions. In a preferred embodiment, this process takes place in a continuous flow system. The present invention further relates to the composition obtained by this process, and to the use of this composition for preparing poly(2,6-diphenylphenylene oxide), for the manufacture of dyes, drugs, plastics, insulating materials and/or insecticides, and for use in medical applications and material research.

##STR00001##

Claims

1. A process for preparing a compound of formula (I), ##STR00005## wherein R represents phenyl, substituted aryl, alkyl, or substituted alkyl, comprising, reacting a compound of formula (II) ##STR00006## wherein R represents phenyl, substituted aryl, alkyl, or substituted alkyl, with a compound of formula (III) ##STR00007## wherein R and/or R represents a halogen, in the presence of a catalyst, which process is a double coupling of a boronic acid and a 2,6-dihalogenphenol in a Suzuki-Miyaura reaction on a sterically hindered position.

2. The process according to claim 1, wherein one or both of the halogens is iodine, bromide or chloride.

3. The process according to claim 1, wherein the compound of formula (I) is 2,6-diphenylphenol, the compound of formula (II) is phenyl boronic acid and the compound of formula (III) is 2,6-diiodophenol.

4. The process according claim 1, wherein the catalyst is a palladium catalyst.

5. The process according claim 1, wherein the catalyst is SiliaCat-DPP-Pd.

6. The process according claim 1, wherein the reaction takes place in a continuous flow system.

7. The process according claim 1, wherein the reaction time is less then 6 hours.

8. The process according claim 1, wherein the yield of the compound of formula (III) is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% by weight.

9. Composition A composition obtained by the process according to claim 1.

10. A method for preparing poly(2,6-diphenylphenylene oxide), the method comprising using a composition according to claim 9.

11. The method according to claim 10, wherein the method is a method for the manufacture of dyes, drugs, plastics, insulating materials, and/or insecticides.

12. The method according to claim 10, wherein the method is applied in medical applications or material research.

13. A method for preparing a 2,6-substituted phenol, in particular 2,6-diphenylphenol, the method comprising using a palladium catalyst.

14. The method according to claim 13, wherein the preparation of the 2,6-substituted phenol involves a double coupling of a boronic acid and a 2,6-dihalogenphenol in a Suzuki-Miyaura reaction on a sterically hindered position, in particular on the sterically hindered ortho positions of the 2,6-dihalogenphenol.

15. The method according to claim 13, wherein the palladium catalyst is SiliaCat-DPP-Pd.

Description

FIGURES

[0038] FIG. 1 is a schematic overview of the Suzuki Miyaura reaction of phenyl boronic acid and 2,6-diiodophenol.

EXAMPLES

Example 1. Preparation of 2,6-Diphenylphenol

Provision of Phenyl Boronic Acid

[0039] Phenyl boronic acid is available on the market through several suppliers. Alternatively, phenyl boronic acid may be prepared by reacting bromobenzene and n-BuLi in the presence of B(OMe).sub.3, followed by hydrolysis with sulfuric acid. The reaction can be performed as a batch reaction, but may also be performed in a continuous flow system.

Preparation of 2,6-Diiodophenol

[0040] 2,6-Diiodophenol was prepared by reacting 1 eq phenol and 1.5 eq iodine (I.sub.2) and 2 eq 30% hydrogen peroxide (H.sub.2O.sub.2) for 24 hours at room temperature, in accordance with the protocol described in Rafael D. C. Gallo, Karimi S. Gebara, Rozanna M. Muzzi and Cristiano Raminelli, J. Braz. Chem. Soc., Vol. 21, No. 4, 770-774, 2010. The reaction was performed as a batch reaction. The reaction may also be performed in a continuous flow system.

Preparation of 2,6-diphenylphenol

[0041] Phenyl boronic acid and 2,6-diiodophenol were used in a Suzuki-Miyaura reaction as shown in FIG. 1.

[0042] A mixture of 346 mg (1 mmol) 2,6-diiodophenol, 305 mg (2.5 mmol) phenyl boronic acid, 414 mg potassium carbonate (3 mmol) and 80 mg (1 mol %) SiliaCat-DPP-Pd was suspended in 25 ml of a mixture of methanol/water=8/2. This mixture was stirred at 55 C. for 1 hour.

[0043] The reaction was frequently followed on TLC (eluens: hexane/dichloromethane=8/2). After 10 minutes 80% conversion had taken place. When the reaction was completed, the catalyst was filtered off and water was added to the filtrate.

[0044] The solution was extracted with ethylacetate, dried on magnesium sulphate and concentrated in vacuum.

[0045] The crude mixture was purified on a silicagel column using hexane/dichloromethane=8/2 as eluens to give 191 mg of pure 2,6-diphenylphenol (78% yield).

Example 2

Preparation of 2,6-diphenylphenol in a Continuous Flow System

[0046] By utilising continuous flow, the aim was to assess if it is possible to perform the Suzuki-Miyaura reaction between 2,6-diiodophenol and phenyl boronic acid in the presence of Si-DPP-Pd catalyst to afford 2,6-diphenylphenol in a shorter time than the analogous batch reaction as described in Example 1. Additional targets included a desire to increase the reaction yield and to reduce the need for separation steps in order to purify the products.

[0047] The reaction was assessed utilising a packed-bed flow reactor wherein the effect of flow rate (5-20 l min1) and reactor temperature (25 to 100 C.) are assessed on the formation of 2,6-diphenylphenol, using aq. MeOH as the reaction solvent and potassium carbonate as the base.

[0048] The following reagents were used: potassium carbonate; 2,6-diiodophenol; Si-DPP-Pd (Silicycle); phenyl boronic acid; 2,6-diphenylphenol; HPLC grade methanol (Fischer Scientific, UK) and de-ionised water.

[0049] A Varian GC-MS fitted with a Zebron ZB-5 (30 m (long)0.25 mm (i.d.)0.25 m (film thickness)) capillary column (Phenomenex (UK)) was employed for analysis and quantification of the samples generated using Labtrix Start. Flow reactions were executed using a standard Labtrix Start system fitted with a catalyst set upgrade having PEEK, glass and FFKM wetted parts. The system is capable of investigating flow reactions over a thermal range of 20 to 195 C. at 20 bar and having additional independent pump lines where required. A hand held pressure meter was fitted to inlet A, behind the check valve and ahead of the micro reactor holder, in order to measure the pressure within the reactor during reactions. A glass micro reactor containing a packed-bed (Device 3026) was employed herein.

[0050] The internal standards phenyl boronic acid, 2,-6-diiodophenol and 2,6-diphenylphenol were analysed by GC using the following methodology: column=Zebron ZB-5, injection volume=1 l, split ratio=100:1, injector temperature=200 C., oven temperature 75 C. for 3 min, ramping to 200 C. at 10 C. min.sup.1 and held for 5.50 min (21 min total run time); helium flow rate=1.0 ml min.sup.1. A 2.0 min filament delay was employed and afforded a total run time of 23.5 min.

TABLE-US-00001 TABLE 1 Summary of the retention times obtained for the key analytes of interest as determined via GC-MS analysis. Analyte Retention time (Min) 2,6-Diiodophenol 1 15.05 Phenyl boronic acid 2 19.37 2,6-Diphenylphenol 4 21.30 Biphenyl 7 11.97 Mono-phenylphenol 6 18.34

[0051] The continuous flow reactions were performed using aq. MeOH (8:2 MeOH:H.sub.2O) as reaction solvent and potassium carbonate as the inorganic base. For reasons of limited product solubility at room temperature, a reduced concentration of reactants was employed in the flow reactor (Table 2).

TABLE-US-00002 TABLE 2 Composition of reactant solutions. Solution # Composition Standard A 96.2 mg 2,6-diiodophenol 1 & 82.8 mg K.sub.2CO.sub.3 5/5 ml 8:2 (MeOH:H.sub.2O) Standard B 61 mg phenyl boronic acid 2/5 ml 8:2 (MeOH:H.sub.2O)

[0052] Prior to performing any reactions, the flow reactor was packed with the catalyst (13.3 mg). In order to avoid damage to the reactor any fines (<45 m) were removed by sieving prior to use. The void volume of the reactor was measured and found to be 24 l. The reactor was initially flushed with reaction solvent in order to wet the catalyst bed. Subsequently, the reactant solutions were introduced into the reactor at equal flow rates, in order to maintain the reagent stoichiometry utilised in batch (1 eq. 2,6-diiodophenol:2.5 eq. phenyl boronic acid:3 eq. K.sub.2CO.sub.3). Preliminary investigations were performed using a total flow rate of 5 l min1 at 25 C. and the reaction product was analysed using offline GC-MS analysis.

[0053] Subsequently, the reaction temperature was increased to 50 C., then 75 C. and finally 100 C. At 25 C., two additional analyte peaks were observed at 11.97 min and 18.34 min. Analysis of the mass spectra revealed that these were biphenyl and the mono-phenylphenol intermediate. On increasing the reaction temperature, the mono-phenylphenol intermediate was completely converted to the target 2,6-diphenylphenol. Whilst it was quoted to assess 1 l min1, the fact that complete conversion was obtained, this was substituted with 20 l min1 to evaluate how short a reaction time was possible.

[0054] Table 3 summarises the reaction conversion and selectivities obtained over the conditions assessed. Interestingly, consumption of 2,6-diiodophenol remained high throughout. However, the proportion of mono-phenylphenol intermediate increased with increasing flow rate. This insinuates insufficient residence time within the catalyst bed. A longer reaction time at an elevated temperature is therefore thought to be advantageous. The residence time can be calculated based on the total flow and void volume.

[0055] It is assumed that all components have the same relative response factor by GC-MS.

TABLE-US-00003 TABLE 3 Reaction conversion at different flow rates and temperatures. Total flow Temperature 1 Conv. Mono-6 Di-4 Run ID (l/min.sup.1) ( C.) (%) (%) (%) 1 5 25 74.1 21.5 87.5 2 5 50 88.3 0 100 3 5 75 Quant. 0 100 4 5 100 Quant. 0 100 5 7.5 100 98.7 0.4 99.6 6 7.5 75 85.2 6.2 93.8 7 7.5 50 85.0 14.7 85.3 8 10 50 80.1 22.8 77.2 9 10 75 78.9 9.8 90.2 10 10 100 87.4 4.3 95.7 11 20 100 83.9 7.7 92.3 12 20 75 81.0 11.1 88.9 13 20 50 79.9 33.6 66.4

[0056] Using a continuous flow reactor, it was thus observed that 2,6-diiodophenol can be converted to 2,6-diphenylphenol at high conversion rates at temperatures >50 C. When reactions were performed at lower temperatures and shorter reaction times, a significant proportion of the mono-intermediate was obtained, indicating incomplete reaction. Based on void volume, the reaction times employed herein ranged from 1.2 to 4.8 min.

[0057] This is a significant decrease in reaction time and yield when compared to the analogous batch reaction, which achieved a 85% conversion in 30 minutes.