New, promising route to DOX series?

[pHarmacist]

Ce qui fait que I'ancien bandagiste renie
Le compioir dont le faste alléchait les passants,
C'est son jardin d'Auteuil, ou, veufs de tout encens,
Les Zinnias ont I'air d'être en tôle vernie.

Hi Bees!

How about making a neet DOX-series precursor (2-allyl-1,4-dimethoxy-benzene or it's isomer) from p-methoxy-phenol? This potential route came to me yesterday while I was reading books and drinking a glas of wine.

Preparation of 2-allylphenol followed by isomerisation (a la safrol to isosafrol) is a well known, classic reaction, described in most practical org. chem. course books.

Can someone please follow below proposed procedure and report the results, that would bee super-great! I'm myself unable to preform this synth right now, yet I'm dying to know if it would work as planned as soon as possible. A true researcher can even take this to higher level and obtain some asymmetric ethers, like 2-ethoxy-5-methoxy^[5] just to name one, that would bee fun. The precursor described herein is perfect for that purpose!

Bandil, I was thinking about you when I came up with this! Wouldn't this bee a nice project for you since you are interested in DOX family! Have fun Bandil!!!
 

Outline:




Experimental:

[1]:

ATTENTION: Instead of using 47 g of phenol as described below, use 62 g of 4-methoxy-phenol and proceed! The product should bee 1-Allyloxy-4-methoxy-benzene. Distill under the reduced pressure and record the yield and the b.p.

Place 47 g (0.5 mol) of phenol, 60.5 g (0.5 mol) of allyl bromide, 69.1 g (0.5 mol) of anhydrous potassium carbonate and 100 mL of acetone in a 250-mL, two-necked round-bottomed flask fitted with a reflux condenser and sealed stirrer unit, and boil on a steam bath for 8 hours with stirring. Pour the reaction mixture into 500 mL of water, separate the organic layer and extract the aqueous layer with three 20 mL portions of ether. Wash the combined organic layer with 2 M sodium hydroxide solution, and dry over anhydrous potassium carbonate. Remove the ether with a rotary evaporator and distil the residue under reduced pressure. Collect the allyl phenyl ether, b.p. 85°C/19 mmHg; the yield is 57 g (85%).


[2]:

ATTENTION: Use 61.2 g of 1-Allyloxy-4-methoxy-benzene MW = 164 g/mol instead of allyl phenyl ether and proceed! Record the yield and b.p.

Boil 50 g of allyl phenyl ether gently in a RB flask fitted with an air reflux condenser. Determine the refractive index of the mixture at intervals; the rearrangemant is complete and the boiling is stopped when the refractive index has risen to 1.55 (about 6 hours are required). Dissolve the product in 100 mL of 5 M sodium hydroxide solution and extract with two 30 mL portions of light petroleum (b.p. 40-60°C) which removes the small amount of 2-methyldihydrobenzofuran formed as a by-product and which is neutral. Carefully acidify the alkaline solution with 5 M HCl (aq) with cooling and extract the mixture with one 50 mL portion and two 25 mL portions of ether. Dry the extract over anhydrous sodium sulphate and remove the ether with a rotary evaporator. Distil the residue under reduced pressure to give 2-allylphenol, b.p. 103-106°C/19 mmHg or b.p. 96°C/13 mmHg; refractive index 1.5440. The yield is 35 g (70%).

[3]:

ATTENTION: Instead of using 20 g p-hydroxybenzaldehyde as described below, use 26.9 g of 2-Allyl-4-methoxy-phenol and proceed! The product should bee 2-Allyl-1,4-dimethoxy-benzene. The yield should bee excellent. Record the yield!

20.g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at 75°-80° C. A total of 12 ml of water was added in small portions over the last hour. Work-up by addition of water, acidification and benzene extraction yielded 22.27 g of p-methoxybenzaldehyde (99.9%).

Patent US4065504

[4] (Optional, isomerisation):

ATTENTION: Use 26.7 g of 2-Allyl-1,4-dimethoxy-benzene MW = 178 g/mol instead of 20 g of 2-allylphenol and proceed. Record yield and b.p.

Prepare a saturated solution (about 50% w/v) of potassium hydroxide in 60 mL of methanol. Place this solution together with 20 g of 2-allylphenol in a RB flask fitted with a still-head and condenser set for downward distillation. Arrange a thermometer so that the bulb dips into the mixture and distil the latter slowly until the temperature reaches 110°C. Remove the still-head, attach an air condenser to the flask and boil the reaction mixture gently under reflux for 6 hours. Cool the mixture, cautiously acidify with concentrated HCl (aq) and extract the product with tree 30-mL portions of ether. Dry the extract, remove the ether and distil the residue under reduced pressure. Collect the 2-(prop-1-enyl)phenol as a fraction, b.p. 100-115°C/15 mmHg; it crystallises on cooling in an ice bath; yield 15 g (75%). Recrystallisation from dry light petroleum (b.p. 60-80°C) gives shining needles, m.p. 37°C.

[5]:

Diethyl Sulphate

This can bee found on rhodium.ws...

Ninety grams of sodium sulfate is placed in a dry 1 liter flask connected with a condenser and a receiver arranged for vacuum distillation. The flask is heated by means of an oil bath to 155-165°C. The apparatus is exhausted as nearly as possible by means of a filter pump, and misture of 50 grams of ethanol and 104.5 grams of concentrated sulfuric acid is allowed to drop through a capillary tube on the sodium sulfate at a rate of 120-150 drops per minute. The distillation of the mixture requires about one and one half hours for completion. The distillate, which consists of ethanol and diethyl sulfate is poured into a separatory funnel, the ethanol may be recovered for further use. The diethyl sulfate is washed with a dilute solution of sodium carbonate and then several times with cold water, then dried with anhydrous sodium sulfate, yielding 32.4 grams.

JACS 46, 999-1001 (1924)

References:

[1] Vogel's 5:th, page 986
[2] Vogel's, 5:th, page 984
[3] Us patent 4065504
[4] Vogel's, 5:th, page 984
[5] www.rhodium.ws

[hypo]

but someone had it before:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/25.meo.allylbenzene.html

for possible allyl iodide preparations see also this thread:

Post 402920

(hypo: "allyl iodide: is this article useful?", Chemistry Discourse)

[pHarmacist]

fuck.. this happens when you are offline.. sorry   ...


LOL!

[pHarmacist]

What about avoiding the isomerization, making a sec. alkyl halide and preforming a Delepine reaction? Are secondary alkyl halides of any use in Delepine? Does anyone have any reliable refs on use of sec. alkyl halides in Delepine reaction?

[hypo]

do you think MeI would work instead of DMS for the methylation reaction?
or is this phenol not activated enough?
(or would MeI react with the double bond?)

[pHarmacist]

I see no reason why it shouldn't methylate. Not activated? We even have a methoxy-function that is activating.

[Chimimanie]

Hey pH:

Look here

Post 406068

(Rhodium: "For 2,5-Dimethoxyallylbenzene prep", Novel Discourse)

And synth allyl bromide instead of the iodide, it is easier.

Glycerol -> allyl alcohol

https://www.thevespiary.org/rhodium/Rhodium/chemistry/allylalcohol.html

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0042

allyl alcohol -> allyl bromide

(A) ALLYL BROMIDE, CH2=CHCH2Br
In a 3-l. round-bottomed flask, a hydrobromic acid solution is prepared (p. 26) by the sulfur dioxide reduction of 480 g. (150.5 cc., 3 moles) of bromine in the presence of 510 g. of ice water or a mixture is made of 1 kg. (5.9 moles) of aqueous 48 per cent hydrobromic acid and 300 g. (162 cc.) of concentrated sulfuric acid. To this is added 385 cc. of aqueous allyl alcohol (p. 42), which, according to bromine titration, contains 233 g. (4 moles) of pure allyl alcohol. The 3-l. round-bottomed flask is fitted with a mechanical stirrer (Note 11), separatory funnel, and an efficient condenser set for downward distillation. Stirring is started, and 300 g. (162 cc.) of concentrated sulfuric acid is added gradually through the separatory funnel to the warm solution. The allyl bromide distils over completely in about one-half to one hour. The crude allyl bromide is washed with dilute sodium carbonate solution, dried over calcium chloride, and then distilled. The yield of product boiling at 69–72° from a number of experiments varies from 445–465 g. (92–96 per cent of the theoretical amount). A small high-boiling fraction is also obtained and examination has shown this to consist of propylene bromide.

from

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0025

If you wanna use allyl chloride, it is synthetised easily from allyl alcohol + HCl(aq) + CuCl(cat); the allyl chloride separate directly and is decanted in quantitative yield.

[hest]

Boiling allylbenzen in 48% HBr(aq) give's the wanted 2 bromide in almost quant. yeald. Im sure it will work for the 2,5-dimethoxy as well

[moo]

I found a few references about the allyl chloride synthesis from allyl alcohol, HCl and CuCl but haven't got access to any of the articles. I'll just post the chemical abstracts citations here, they are useful too. I'll have to look if someone had tried to use the same approach for the conversion of benzyl alcohol to benzyl chloride... Mere shaking with conc. HCl doesn't give quantitative yields.  Chimimanie, you wouldn't happen to speak about either of these refs?


Chemical Abstracts 40, 6948 (1946)
Velocity of allyl chloride formation from allyl alcohol and commercial hydrochloric acid in the presence of cuprous chloride. Jean Jacques. Bull. soc. chim. Fr. 12, 843-5 (1945). -- Mixts. of 2 cc. com. allyl alc. (d₁₈ 0.8695) and 6 cc. HCl (d 1.19) were treated with varying amts. of CuCl, ranging from 5 to 250 mg., at 18°. Between 3.75 and 70 mg. the catalyst had a marked effect on the rate of allyl chloride (I) formation; above and below this range the effect was relatively slight. In the absence of catalyst, no appreciable I was formed within 48 hrs. I is conveniently prepd. by treating 1 vol. allyl alc. with 3 vols. concd. HCl in the presence of 2-3% CuCl. The reaction is completed in less than 6 hrs. Reaction velocities are illustrated graphically.

Chemical Abstracts 25, 2412 (1931)
Preparation of some allyl derivatives. R. Breckpot. Bull. soc. chim. Belg. 39, 462-9 (1930). -- Allyl chloride is prepd. with a quant. yield and in very short time from allyl formate or allyl alc. and concd. HCl. The presence of water does not harm the reaction. CuCl is used as a catalyst, together with a small quantity of H₂SO₄. Very pure vinylacetonitrile is obtained with almost quant. yield, from allyl chloride and CuCN or from a mixt. of CuCN, concd. aq. HCl and allyl alc., or allyl formate, or both. The reaction is fast. Exptl. conditions are given.



It is also possible to synthesize allyl chloride with only allyl alcohol, conc. HCl and enough time.


J. Am. Chem. Soc 51, 225 (1929):

The Action of Sulfuric Acid in the Preparation of Certain Alkyl Halides

[...] Allyl chloride and allyl bromide are commonly prepared by the aid of heat, and also by the use of sulfuric acid. These halides, as ordinarily prepared, soon develop an extremely pungent odor, becoming lachrymators, and the bromide also develops a color. A simple cold process has been worked out for preparing these halides. The high-boiling residue is very small in this process. Furthermore, one distillation gives a product which remains for months water-white and maintains a perfectly clean odor, without any trace of sharpness, when stored in the dark in an ordinary bottle. The yields are poorer than those obtained in "Organic syntheses," but our process is recommended when one wishes to sacrifice yield for quality, in making these halides for special work. The process also involves a minimum apparatus and hardly any attention, although it requires a few days' time.

Experimental

    Allyl Alcohol. -- Solid potassium carbonate is aded to Eastman practival allyl alcohol. The upper layer is removed and given the same treatment. After twenty-four hours it is filtered and used without distillation.
    Allyl Chloride. -- The alcohol is mixed with 8 times its volume of commercial hydrochloric acid (sp. gr., 1.19) in a suitable well-corked bottle. After ten days the upper layer is washed once with 10% sodium hydroxide and twice with 15% sodium chloride, which minimizes emulsion formation. It is dried over calcium chloride and distilled. The yield of material boiling from 45-47° is from 55-65%. As an example: 204 cc. of crude alcohol with 1632cc. of acid gave 144g. of chloride.
    If a small amount of halide is wanted in a hurry, the reaction is carried out in a sealed Pyrex bottle immersed in hot water (60°). Most of the yield, over 80%, is obtained in three hours.

[Chimimanie]

I have read the two Bull soc chim refs, but I dont have them at hand now, because the bigger part of my refs is away.

They described a process to do allyl chloride, from the alcohol, with HCL, and with or without CuCl and/or H2SO4.

There was a plot in one of the ref with the relative amount of CuCl and the yield in time. The relationship between the quantity of CuCl and the reaction time was antiproportional. They said that H2SO4 was detrimental to the quality of the product, the better is to not use it. HCl alone did not do the trick. When some 3 vol HCl and 1 vol allyl alcohol are used, without CuCl nothing react. They add the CuCl and directly another layer form, this layer is allyl chloride. They did different test with different quantity of catalyst and found that 2-3% is the best quantity. Reaction is over in 5-6 hours with that quantity of catalyst if I remember well. Yield is quantitative . That is truly a good synthesis of it!

Just do what they said in their abstract, take 3 vol concentrated aqueous HCl, 1 vol allyl alcohol, add the catalytic amount of CuCl, the solution will beecome trouble, then a layer will form on top (I think), just wait 6 hours and then decant it off, dry it or distill it whatever and thats all, allyl chloride easy.  If really you are interested in the article I can rephotocopy it, traduct it and post it.

I have a ref from those bull soc chim articles where they had a better yield for the glycerol=> allyl alcohol production than the ref in orgsyn too.

[catastrophe]

Could this work? Would a clemmensen reduce the allylbenzene to a propylbenzene? One could then chloromethylate as Chimimanie described for 2,5-Dimethoxytoluene(don't think the CH3CH2CH2 would make much difference from CH3), then follow by a Sommelet to obtain the final aldehyde.

Thanks