Author Topic: Benzodioxin MDA analogue?  (Read 9222 times)

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  • Guest
Well, after one of those nightmarish ...
« Reply #40 on: August 11, 2004, 09:49:00 PM »
Well, after one of those nightmarish post-reaction workups, I finally recovered the bromoethyl ether from the reaction mixture in good yield.  It is very soluble in water; Et2O would hardly even touch the product in the aqueous..


  • Guest
"very soluble in water"?
« Reply #41 on: August 12, 2004, 10:52:00 AM »
OK, phenethyl_man, lets make it clear - you`re talking about 4-(2-bromoethoxy)-3-methoxybenzaldehyde, aren`t you?
 The strange thing here is that the estimated logP for that compound is 2,36 but now you`re telling us that your product is "very soluble in water"! I`m not sure if the real logP is the same and if someone has any info, please, share it.
 Just informatively:
logP(vanillin)= 1,26
logP(4-(2-hydroxyethoxy)-3-methoxybenzaldehyde)= 1,01(estimated); 0,58(experimental) - maybe your product :(


  • Guest
You guessed it; not the expected product..
« Reply #42 on: August 12, 2004, 02:40:00 PM »
You guessed it; not the expected product.. just another failure to add to the list.

In the first reaction, the HBr cleaved the ether of butyl cellosolve leaving the bromohydrin, however the hydroxy group was not replaced by bromine as expected (merely adding some H2SO4 to catalyze this reaction almost surely would have overcome this problem.)

Thus, the subsequent alkylation left me with 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde..  and if only I didn't have that damn formyl group to worry about, then I could oxidize this to a phenoxyacetaldehyde and condense/cyclize with HOAc/ZnCl2 to get the unsaturated furan, but oh well..

I giveth up for now..


  • Guest
Failed cyclialkylation
« Reply #43 on: September 10, 2004, 10:30:00 PM »
I tried and failed in my attempt to cyclise and formylate 2-(2,4-dibromophenoxy)ethyl chloride to 2,3-dihydrobenzofuran-5-carboxaldehyde in one-pot.

Bearing in mind the results azole recently posted (

Post 522253

(azole: "3-Br-4-(2-chloroethoxy)BA failed to cyclize", Novel Discourse)
), it seems the reaction may not be possible to do without the use of BuLi. The cyclisation of 2-(2-bromophenoxy)ethyl chloride with Mg is clearly possible (

Post 510718

(Kinetic: "2,3-Dihydrobenzofurans without BuLi", Novel Discourse)
) but the extra bromide on the ring may interfere in this case. It could well be that the Parham cyclisation only works with 2-(2,4-dibromophenoxy)ethyl chloride because it selectively metalates the position ortho- to the stabilising oxygen first. If Mg is not selective in this way, then the para- position may well react first instead. This could interfere with the subsequent Grignard formation and Wurtz-type coupling which is necessary to form the dihydrobenzofuran ring.

After the above failures, I am leaning more towards the synthesis of the dehydrogenated aromatic analogue 5-(2-aminopropyl)benzofuran. I will post a proposal for the synthesis of the precursor aldehyde soon: via para-bromination of phenoxyacetic acid, followed by cyclisation (either via the acid chloride followed by Lewis acid, or simply with polyphosphoric acid), then reduction of the formed benzofuranone and dehydration to 5-bromobenzofuran. The dehydration will happen readily as the product is aromatic, and it should be possible to react the product with Mg followed by DMF to give the benzaldehyde.

Below is the synthesis of 2-(2,4-dibromophenoxy)ethyl chloride. This will hopefully be useful for anyone who wants to make 2,3-dihydrobenzofuran-5-carboxaldehyde from it using BuLi (see the very interesting Tet Lett article posted above in

Post 499729

(Kinetic: "An interesting possiblilty", Novel Discourse)
for this), but also because the two steps are similar to the etherification of hydroquinone with 1,2-dichloroethane followed by dibromination to give 1,4-bis(2-chloroethoxy)2,5-dibromobenzene; this of course is an intermediate in the synthesis of Nichols' super-potent DOX analogues.

2-Phenoxyethyl chloride

23.5g phenol (250mmol)
30.0g NaOH (750mmol)
5g aliquat 336 (12.5mmol, 5mol%)
2.5g sodium metabisulfite (12.5mmol, 5mol%)
200ml 1,2-dichloroethane
200ml water

A biphasic solution of the above was vigorously stirred at reflux for 12 hours, then allowed to cool and acidified with a small amount of concentrated HCl. The phases were separated, the organic layer washed with 2x100ml water and then dried over MgSO4. Removal of the solvent left a liquid which was distilled at 93-107oC (using a water pump) to give the title product as a clear, colourless liquid.

Yield: 28.2g (180mmol, 72%)

Notes: The product is a solid in the fridge but melts rather quickly on warming to room temperature. According to the literature the product should melt at around 25oC, but the product is pure enough to use in the next step.
The product smells identical to an authentic sample of 2-phenoxyethyl bromide.

2-(2,4-Dibromophenoxy)ethyl chloride

31.3g 2-phenoxyethyl chloride (200mmol)
70.3g bromine (440mmol)
60.0g anhydrous zinc chloride (440mmol)
Acetic acid

A solution of the 2-phenoxyethyl chloride and zinc chloride in 150ml acetic acid was cooled to around 5oC. The flask was covered in aluminium foil to exclude the contents from light and, with ice-bath cooling, a solution of bromine in 25ml acetic acid was added over 1 1/4 hours. The flask was then removed from the ice-bath and stirring was continued for a further 3 hours. The clear orange solution was then added to 800ml water, and the pale semi-liquid which precipitated was extracted with 2x60ml DCM. The combined orange extracts were washed in succession with 100ml water, 100ml 0.5M sodium metabisulfite solution, 2x100ml 1M potassium carbonate solution and 100ml brine. After drying over MgSO4 and removing the solvent, a very pale, colourless oil remained. This quickly set to sparkling crystals weighing 49.5g (crude yield: 157mmol, 79%). Recrystallisation from 50ml methanol provided the title product as absolutely clear, sparkling plates.

Yield: 43.3g (138mmol, 69%)

Notes: The two equivalents of zinc chloride appear to be necessary, as when a catalytic amount was used, the yield was lower and the product refused to crystallise at room temperature. As this product had a similar smell to 4-bromoanisole (aniseed), this was probably due to incomplete bromination.
The sodium metabisulfite removes all of the remaining orange (bromine) colour.
The first potassium carbonate wash takes on a very slight yellow tint, and the second does not change colour. Phenolic byproducts therefore appear to be negligible.
Using more methanol for the recrystallisation leads to a large amount of the product being held up in solution, even on standing in the freezer.