An easyish & OTC hydroxymethylation of phenols

[Antoncho]

Take your phenol, dump into IPA, add some paraform and KOH - and here's your alcohol.... Of course, many assumptions are made when you put it this way; however, all looks very possible.

Patent GB893896

To a flask purged with nitrogen were added 18. 3 parts by weight of 2, 6-dimethylphenol, 42 parts by weight of 14. 3% w formaldehyde in tert. butyl alcohol, and 15 parts by volume of 2. 4% w KOH in tert. butyl alcohol. The phenol/formaldehyde/KOH molar ratios were therefore 1 : 1. 33 : 1/30.

This mixture was allowed to stand overnight at 20'C under nitrogen. To it was then added enough water to make a total of 500 parts by volume, the mixture acidified with HGl, and the organic phase taken up in methylene chloride. The aqueous phase was extracted with two successive portions of methylene chloride, and the methylene chloride fractions combined. The methylene chloride was then stripped off in vacuo at 35 C and the residue extracted with isopentane to leave an insoluble powdery white residue. Additional powdery white product was precipitated from the aqueous phase by further acidification. This was washed with isopentane.

The total yield of the 3, 5-dimethyl-4- hydroxybenzyl alcohol obtained in this manner was 14. 55 parts by weight, corresponding to a conversion based on the starting phenol of 64% and a yield on the same basis of 82%. The melting point of the product was 165-169 C.





Antoncho


P.S. Dear Rhodium! This post

Post 235445 (missing)

(Antoncho: "Formylations", Chemistry Discourse) is really not about formylation, but rather a hydroxymethylation - so will you please remove it from the formylation section of your site!


Sorry    

[Rhodium]

Uh, is it? the product is said to be 3-bromo-2-hydroxy-5-methoxy-benzaldehyde, so it looks like a formylation to me...

[YourMomma7111]

[Antoncho]

3-bromo-2-hydroxy-5-methoxy-benzaldehyde

Well, you see, the patent text was very confusing - they were preparing the alcohol by two different routes, one of them - from the aldehyde. I messed up the text beecause that example was followed by the aldehyde's red'n w/NaBH4 to alcohol and i thought that the product in the 1st stage was that algehyde

But this is definitely a methylolation - i've seen some such examples in other patents.


Antoncho

[Rhodium]

Ok, I'll checked the original patent, and it seems you are right - I'll remove that from my page. However, there were other interesting chemistry in the Patent, So I'll post selected partis of it here:

EXAMPLE 1

A suspension of 81.8 g of 2-bromo-4-methoxy-phenol and 24.9 g of boric acid in 55 ml of toluene is heated under reflux using a water separator until no further water separates off (approx. 12 hours). The thin light-brown suspension is then cooled to 90°C and in the course of 40 minutes 13 g of paraformaldehyde are added in portions. The mixture is stirred for 1 hour at 90°C and then cooled to 70°C; 100 ml of water are added and the mixture is then cooled further to 20°C and adjusted to pH 8.5 with concentrated sodium hydroxide solution. The brown suspension is stirred for 30 minutes and adjusted to pH 2.5 with concentrated sulfuric acid. The filter residue obtained after filtering with suction is washed twice with 50 ml of ethyl acetate each time. The combined filtrates are thoroughly mixed and the organic phase is separated off and concentrated by evaporation. The oily residue that remains is chromatographed on silica gel with toluene/ethyl acetate (4:1) as eluant. The 3-bromo-2-hydroxy-5-methoxybenzyl alcohol that is thus obtainable has an Rf value of 0.3; yield 50% of the theoretical yield.

EXAMPLE 2

In the course of I hour, at from 5°C to 10°C,18 g of sodium borohydride are added in portions to a solution of 160 g of 3-bromo-2-hydroxy-5-methoxy-benzaldehyde in 800 ml of ethanol. The resulting suspension is adjusted to pH 2.5 with sulfuric acid (10%) and the mixture is concentrated in vacuo to 500 ml. 200 ml of ethyl acetate are added thereto, the organic phase is separated off, the aqueous phase is extracted twice with 100 ml of ethyl acetate each time, and the combined organic phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The oily residue that is obtained is crystallised from toluene to yield 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in the form of colourless crystals mp 76°C. Yield 91% of the theoretical yield.

EXAMPLE 3

In the course of 30 minutes, at from 40°C to 60°C. 67 g of hydrogen chloride are introduced into a solution of 459 g of triphenylphosphane and 387 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 600 ml of ethyl acetate. The reaction mixture is then stirred for 5 hours at 75°C, the product beginning to crystallise after 30 minutes. The reaction mixture is cooled to 0° and stirred for a further one hour and then at that temperature the crystals are filtered off with suction. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)-methyl]-triphenyl-phosphonium chloride is thus obtained in the form of colourless crystals [m.p.: 257°C (decomposition); yield 89% of the theoretical yield.

EXAMPLE 4

In the course of 1.5 hours, at 5°C,16 g of bromine are added dropwise to a solution of 50 g of [(2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium bromide in 1l of methanol. The solution is then concentrated in vacuo at 20°C to 130 ml, 250 ml of ethyl acetate are added thereto in the course of 2 hours, the resulting yellow suspension is stirred for 2 hours at 0°, and the slightly yellow crystals are filtered off with suction and recrystallised from methanol. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)-methyl]-triphenyl-phosphonium bromide is thus obtained in the form of colourless crystals [mp 259°C; yield 76% of the theoretical yield

EXAMPLE 5

In the course of 30 minutes. at from 40°C to 60°C. 18 g of hydrogen chloride are introduced into a solution of 49.8 g of 2-hydroxy-5-methoxy-benzyl alcohol and 115.8 g of triphenylphosphane in 150 ml of acetonitrile. The reaction mixture is then stirred for 5 hours at 75°C, the product beginning to crystallise after approx.. 30 minutes. The reaction mixture is cooled to 0°C, stirred for a further one hour and then at that temperature the crystals are filtered off with suction. [(2-Hydroxy-5-methoxy-phenyl)methyl]-triphenylphosphonium chloride is thus obtained in the form of colourless crystals [mp.: 270°C (decomposition);

EXAMPLE 6

In the course of 1.5 hours, at 5°C,13 g of bromine are added dropwise to a solution of 35 g of [(2-hydroxy-5-methoxyphenyl)methyl]-triphenylphosphonium chloride in 700 ml of methanol. The solution is concentrated in vacuo at 20°C to 110 ml, 220 nil of ethyl acetate are added thereto in the course of 2 hours, the resulting yellow suspension is stirred for 2 hours at 0°C. and the slightly yellow crystals are filtered off with suction and recrystallised from methanol. A mixture of colourless crystals (mp 210°C) which according to AgNO3 titre comprises 22.4% by weight [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl ]-triphenyl-phosphonium chloride and 77.6% by weight [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium bromide is obtained; yield 76 % of the theoretical yield.

EXAMPLE 15

In the course of 30 minutes, at room temperature. 20 g of hydrogen bromide are introduced into a suspension of 50 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 300 ml of anhydrous acetic acid. The reaction mixture is stirred for 5 hours at room temperature and the resulting solution is concentrated by evaporation. The black-brown oily residue. which crystallises slowly when left to stand at room temperature, is crystallised from ethyl acetate/cyclohexane (5:1) with the addition of a small amount of activated charcoal. 3-Bromo-2-hydroxy-5-methoxy-benzyl bromide is thus obtained

EXAMPLE 16

8.8 g of trimethyl phosphite are added to 20.0 g of 3-bromo-2-hydroxy-5-methoxy-benzyl bromide and, with stirring, the mixture is heated for 3 hours at 140°C (complete conversion according to TLC). The resulting oil is filtered with toluene/ethyl acetate (4:1) as eluant over a small amount of silica gel. [(3-Bromo-2-hydroxy-5-methoxyphenyl)methyl]phosphonic acid dimethyl ester is thus

EXAMPLE 19

In the course of from 30 to 45 minutes, at 200, with stirring, 43.9 g of bromine are added dropwise to a solution of 45.9 g of 2-hydroxy-5-methoxy-benzoic acid methyl ester in 125 ml of heptane. The reaction mixture is then stirred for a further 3 to 4 hours, then diluted with 1l0 ml of water and stirred for a further one hour and then 295 ml of heptane and 46 ml of tent-butyl methyl ether are added thereto. The mixture is then heated to from 50°C to 55°C and the aqueous phase is separated off. The organic phase is extracted twice with 1l4 nil of water each time and cooled to -20°C. The crystals which precipitate are filtered off and dried under a high vacuum. 3-Bromo-2-hydroxy-5-methoxy-benzoic acid methyl ester is thus obtained; yield 82.5% of the theoretical yield

EXAMPLE 20

In the course of 1 hour, at 20°C. with stirring, a solution of 57 g of 3-bromo-2-hydroxy-5-methoxy-benzoic acid methyl ester in 110 ml of tetrahydrofuran are added dropwise to a solution of 8 g of sodium borohydride in 280 ml of tetrahydrofuran.  The reaction mixture is stirred for a further 2.5 hours, hydrolysed with 105 ml of 2N hydrochloric acid and adjusted to pH 2.5. The aqueous phase is separated off. The organic phase is extracted three times with 90 ml of sodium chloride solution (10%) each time. concentrated by evaporation using a rotary evaporator, diluted with 100 ml of toluene. concentrated to 100 g using a rotary evaporator and in the course of 30 minutes, at 60°C, added to a suspension, heated to from 70°C to 80°C, of 55.1 g of triphenylphosphane, 8.8 g of hydrogen chloride and 42 ml of toluene. The reaction mixture is stirred for a further 7 hours and then cooled to from 0°C to -5°C. The crystals that have formed are filtered off washed four times with 40 ml of toluene each time and dried under a high vacuum. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride, which is identical to the product obtainable according to Example 3, is obtained; yield 79% of the theoretical yield.

[Antoncho]

I'll remove that from my page.

Well, actually, i didn't say 'from your page' - i said 'from the 'Formylations' section of your page'    

You could move it to the 'methylolation' section

There's already four nice hydroxymethylations posted only by me - this one, the other one, and two more in

Post 300201

(Antoncho: "3-methyl-2,5-diMeO-benzaldehyde", Novel Discourse). Considering that BzOH-BzCl-BzCN transformation is a one-pot and easy (albeit toxic) procedure and reductions of nitriles are multiple and well-documented, that might bee worth doing....... for the future generations, maybee


Antoncho

[Rhodium]

I have a methylolation section? Hmmm... Oh well, if I don't, perhaps I should make myself one?

[Antoncho]

something like that

[Osmium]

> Take your phenol, dump into IPA, add some paraform and
> KOH - and
> here's your alcohol.... Of course, many assumptions are made when
> you put it this way; however, all looks very possible.

Unfortunately not!
Phenolates will react with formaldehyde under basic condition producing hydroxymethylated products. Unfortunately you cannot stop this reaction at the mono-substitution step. It only works in this case because the 2 and 6-position are already occupied, otherwise these sites would react too. If you do this with plain phenol you will hydroxymethylate the shit out of the molecule producing a polymer.
Same thing also happens with acid catalysis. These products are some of the oldest known polymers, phenol-formaldehyde resins, bakelite etc, and their manufacture requires attention to carefully stay inside a window of reaction parameters unless you want to remove the final product mechanically with power tools from your reaction kettle since the polymer finally becomes unmeltable. It's also pretty pyrolysis resistant, that's why such polymers are used for rocket nozzle and burning chamber heat insulation, vehicle brake pads, unburnable high-voltage insulators etc so burning the polymer off doesn't work either.