04-19-00 15:58
No 122784
      Bromo-benzodifuranyl-isopropylamine -Lilienthal
(Rated as: excellent)

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Author  Topic:   Bromo-benzodifuranyl-isopropylamine 
Member   posted 01-08-99 05:42 AM          
This is the first compound more active than LSD in binding to human 5-HT2A receptors and in rat drug discrimination studies: Bromo-benzodifuranyl-isopropylamine, a cyclized analogue of DOB!
J. Med. Chem. 41, 5148 1998 M. A. Parker et al.
What do you think about another best-route-to contest? Additionaly, there are many possible analogues... Any ideas?
Member   posted 01-08-99 05:49 AM          
Nichols had a paper about it, too.

Member   posted 01-08-99 07:59 AM          
The paper is from the Nichols group.
rev drone
Member   posted 01-08-99 11:13 AM          
Are you sure this is the first compound to be more potent than LSD in this respect? I seem to remember reading in TiHKAL that a certain 2-bromo substituted lysergic compound to be stronger, not to mention the oh-so-frightening 2,5-dimethoxy-4-trifluoromethylphenylisopropylamine.
I've never seen the dehydrogenated comound, so I could be wrong. I know that if you hydrogenate the double bonds in the furanyl rings, you have something pretty hot. I guess I'll have to check this stuff out in the library.

What would be TRULY scary would be the trifluoromethylated analog -- prepared by acetylating the amine, trifluoromethylating with sodium trifluoroacetate and a copper salt catalyst, then hydrolyzing the amine. Now THAT would be a fun toy to play with.

-the good reverend drone

Member   posted 01-08-99 12:41 PM          
The synthesis of this cpd was reported in JMC 96 39(15):2953-61 I believe. I can't quite remember how it was accomplished, but howsabout start from hydroquinone, react with chloroacetic acid, then e.g. SOCl2 to give the di-acid chloride. Friedel-craft acylation followed by reduction by Zn/HCl. Reflux w/ Pd/C to aromatize. Next formylation, bromination, etc, etc. This is prob. close to what Nichols did and maybe a little bit clunky of a synth, got anything better than that?
Drone: Is 2,5-diMeO-4-trifluoromethyl cpd. that much stronger than DOB? Seems like Glennon first made this cpd and it wasn't that much hotter than Br, as you might expect since trifluoromethyl is electronically and sterically so similar.

I am unaware of the method that you mention for introduction of a trifluoromethyl group. Let me respond in kind by mention of another trifluoromethylation strategy that I am sure that you are unaware of: Nitriles are transformed into trifluoromethyl groups by reaction with BrF3. Yes you heard me right, not boron trifluoride, Bromine trifluoride. This is about as nasty of a reagent as you may ever hope to play with, but interesting rxn, no?

Administrator   posted 01-08-99 06:50 PM          
4-Trifluoromethyl-2,5-dimethoxyamphetamine (DOTFM) was synthesized by the Nichols group in JMC 37, 4346 (1997), and they also made the 2C-B analog (2C-TFM), which was found to be more potent than DOB! The DOB analog caused some problems with the lab rat tests, so an ED50 wasn't calculated.
The trifluoromethylation method mentioned by Drone was used to synthesize the compounds in question.

Administrator   posted 01-09-99 10:22 AM          
Another benzodifuran synth idea:
2,5-diformyl-hydroquinone is reacted with chloroacetic acid in basic solution to give 2,5-diformyl-1,4-acetoxybenzene, which is refluxed with Ac2O and NaOAc in AcOH to give the benzodifuran in good yields after vacuum distillation.

Ref: Vogel, 5th Ed, p 1160.

Member   posted 01-09-99 11:43 AM          
The tetrahydrobenzofurane analogue has 1/10 the potency of LSD in rat drug discrimination studies and at rat 5-HT2A receptors. Tetrahydrobenzodifuran was synthetized in the following way:
Hydrochinone with 1-bromo-2-chloroethane to hydrochinone-di-2-chloroethylether with Br2 to 2,5-bromo-hydrochinone-di-2-chloroethylether with BuLi at 0C to tetrahydrobenzodifuran (J. Med. Chem. 39, 2953 1996 A. P. Monte).
The 2-Br-lysergamides are inactive because they are antagonists. If I remember correctly, the trifluoromethylphenylisopropylamine has values comparable to DOB.
Member   posted 01-10-99 04:00 PM          
I did, they are not significantly different (aside from the animal disrupting activity of DOTFM). Look into the paper Rhodium gave.
rev drone
Member   posted 01-11-99 01:42 PM          
I thought DOTFM was considerably more potent. In fact I remember distinctly attending a conference, where Sasha himself said it was active in humans around 100 micrograms.
-the good reverend drone

rev drone
Member   posted 01-13-99 07:54 PM          
Nichols used yet another trifluoromethylation method. Still based on an Ulmann-type reaction, but with chlorodifluoroacetate, and a little KF, I think. The use of sodium trifluoroacetate seems more logical to me, but hey, I'm not the one currently getting funds from the NIH.

If anyone's interested, I have a big compendium on trifluoromethylation procedures I'd be willing to share. Personally, I've heard some rumors about human tests of DOTFM that have me quite scared, but hey, whatever floats your boat (the US military is currently testing certain unnamed high-powered PEA's as incapacitating agents in chem warfare. Due to their stability, these ones can deliver what LSD only promised to warfare in the 50's and 60's. Still, these aren't the rumors that have me as nervous.)

-the good reverend drone

Administrator   posted 01-14-99 11:22 AM          
Yes, please share your TFM references. I would also be interested in hearing more about those DOTFM rumours.
Member   posted 01-15-99 05:14 AM          
Chemistry Letters, pp. 1719-20, 1981
"Regispecific trifluoromethylation by substitution of the halogen in aromatic halides was achieved by the use of sodium trifluoroacetate and copper(I) iodide. The reaction proceeded smoothly in dipolar aprotic solvents in good to high yields."

A mixture of iodobenzene (5mmol), sodium trifluoroacetate (20mmol), and copper (I) iodide (10mmol) in N-methylpyrrolidone (NMP) (40ml) was heated under argon athmosphere. Evolution of CO2 began at around 140C. After 4H stirring at 160C, work-up of the resulting mixture afforded trifluoromethylbenzene in 72% yield (GLC). The reaction can be carried out in glass apparatus under normal pressure.

m-bromotoluene ---> m-trifluoromethyl-toluene 58%
2-bromopyridine ---> trifluoromethylpyridine 41%

Member   posted 01-15-99 08:58 AM          
Rhodium, could you give the whole title and author of your reference (Vogel, 5th Ed, p 1160). How would one synthetize 2,5-diformyl-hydroquinone?

Administrator   posted 01-15-99 04:19 PM          
They aren't quoting any reference in Vogel for that reaction. They are using it to prepare benzofuran, but I see no reason why it couldn't be used to make dibenzofuran.
Synth of the precursor? Formylate hydroquinone twice? Or run the reaction with 2,5-dihydroxybenzaldehyde to give the OH-substituted benzofuran, formylate that, and run the reaction once again.

Quote from Vogel:


Equip a 1-litre three-necked flask with an efficient double surface reflux
condenser, a mechanical stirrer and a thermometer, the bulb of which is within
2cm of the bottom of the flask. Place a warm solution of 80g of sodium hydroxide
in 80 ml of water in the flask, add a solution of 25g (0.266 mol) of phenol in
25 ml of water and stir. Adjust the temperature inside the flask to 60-65C
(by warming on a water bath or by cooling, as may be found necessary); do not
allow the crystalline sodium phenoxide to separate out. Introduce 60g (40.5 ml,
0.5 mol) of chloroform in three portions at intervals of 15 minutes down the
condenser. Maintain the temperature of the well-stirred mixture at 60-70C
during the addition by immersing the flask in hot or cold water as may be
required. Finally heat on a boiling water bath for 1 hour to complete the
reaction. Remove the excess of chloroform from the alkaline solution by steam
distillation. Allow to cool, acidify the orange-colored liquid cautiously with
dilute sulfuric acid and again steam distill the almost colorless liquid until
no more oily drops are collected. Extract the distillate at once with ether,
remove most of the ether from the extract by distillation on a water bath using
a rotary evaporator. Transfer the residue, which contains phenol as well as
salicylaldehyde, to a small glass-stoppered flask, add about twice the volume
of saturated sodium metabisulfite solution, and shake vigorously (preferably
mechanically) for at least half an hour, and allow to stand for 1 hour. Filter
the paste of bisulfite compound at the pump, wash it with a little alcohol, and
finally with a little ether (to remove the phenol). Decompose the bisulfite
compound by warming in a round-bottomed flask on a water bath with dilute
sulfuric acid, allow to cool, extract the salicylaldehyde with ether and
dry the extract with anhydrous magnesium sulfate. Remove the ether by
flash distillation and distill the residue collecting the salicylaldehyde
(a colorless liquid) at 195-197C. The yield is 12g (37%).

o-Formylphenoxyacetic acid.

To a mixture of 35 ml (40 g, 0.33 mol) of salicylaldehyde, 31.5 g (0.33 mol) of
chloroacetic acid and 250 ml of water contained in a 500-ml, two-necked round-
bottomed flask fitted with a stirrer unit, add slowly with stirring a solution
of 26.7 g (0.66 mol) of sodium hydroxide in 700 ml of water. Heat the mixture
to boiling with stirring and reflux for 3 hours. The solution acquires a
red-brown color. Cool and acidify the solution with 60 ml of concentrated
hydrochloric acid and steam distill to remove unreacted salicylaldehyde; 12ml
(14g) are thus recovered. Cool the residual liquor which first deposits some
dark red oil which then solidifies; on standing, almost colorless crystals
appear in the supernatant solution. Decant the supernatant solution and crystals
and filter off the crystals, and air dry; the yield of almost pure product,
m.p. 132-133C, is 21 g. The solidified red oil may be extracted with small
quantities of hot water, the extracts treated with decolorizing charcoal and
cooled, to yield a further 6g of product; total yield 27g.


Heat under reflux for 8 hours a mixture of 20 g (0.11 mol) of o-formylphenoxy-
acetic acid, 40g of anhydrous sodium acetate, 100 ml of acetic anhydride and
100ml glacial acetic acid. Pour the light brown solution into 600 ml of iced
water, and allow to stand for a few hours with occasional stirring to aid the
hydrolysis of acetic anhydride. Extract the solution with three 150 ml portions
of ether and wash the combined ether extracts with 5 per cent aqueous sodium
hydroxide until the aqueous layer is basic; the final basic washing phase
acquires a yellow color. Wash the ether layer with water until the washings
are neutral, dry the ethereal solution over anhydrous calcium chloride and
remove the ether on a rotary evaporator. Distil the residue and collect the
benzofuran as a fraction of b.p. 170-172C. The yield of colourless product
is 9.5g (91%).

Member   posted 01-15-99 05:20 PM          
Sorry Rhodium, I was asking for the whole title and author of "Vogel" 
Administrator   posted 01-15-99 10:19 PM          
A. I. Vogel, Textbook of Practical Organic Chemistry, 5th Ed., Longman (1989)
Member   posted 01-16-99 10:40 AM          
Thanks. What do you think of oxidizing 2,5-dimethyl-p-hydrochinone (The Cook 01-15-99 and patent link some replies later)? I think, double-Vilsmeyer won't work.
rev drone
Member   posted 01-17-99 11:02 AM          
The DOTFM rumor is that, one of the old-time neuronauts got their hands on some, and it took a week or two for them to come down from 100 micrograms. That trifluoromethyl is impossible for the human body to metabolize, and it just sits in those serotonin receptors with no intention of leaving.
Just to cut to the chase, and make life a lot easier for those who haven't picked it up, I recommend a thorough reading of JMC. The total synthesis of this compound is nicely described by the nichols group. Here's the general overview:

1)hydroquinone + bromochloroethane -> 1,4-(bis-2-cholroethoxy)-benzene

2)bromination of aforementioned product, yielding 1,4-dibromo-2,5-bis-(2-chloro-ethoxy)-benzene

3)cyclization with n-BuLi, producing

4)formylation, yielding 2,3,6,7-tetrahydro-benzo(1,2-b;4,5-b')difuran-4-carbaldehyde

5)Knoevenhagel with nitroethane

6)Reduction to the amine

7) Bromination, yeilding finally the desired product.

Honestly, I really think this is a really elegant synthesis, and I can't imagine improving on the general route. The only improvements I see are in the details: reaction conditions could be tweaked to make them higher-yielding or more facile to undertake, but that's about it. If you can figure out a better way, feel perfectly free to prove me wrong.


You're absolutely right about the vilsmeyer reaction. Formyl groups are deactivating, and that's why you can only get one of them on there at a time through Vilsmeyer, Duff, Reimer-Tiemann, etc.

-the good reverend drone

Member   posted 01-17-99 01:22 PM          
Drone, please read carefully! You forgot the last steps (if I remember right):
- protecting the amine.
- dehydrogenation (aromatization) from tetrahydrodifuranyl to difuranyl.
- deprotection.
Try to count the steps for the whole synthesis...
Member   posted 01-17-99 04:06 PM          
It is hard for me to rationalize why DOTFM might have such a long duration of action. DOB would just as resistant to metabolic inactivation. Maybe some kind of very efficient H bonding interaction at the receptor? Interesting stuff, this.
Member   posted 01-18-99 04:54 AM          
The substances we talk about are not only classical pharmaceuticals with defined somatic effects but (and that's the reason why we are interested in this stuff) also cause powerful psychic effects and reactions. And these reactions may continue or emerge after the pharmacological effects are over. Did you ever read Stanislav Grof, LSD Psychotherapy? He talks about many strange cases and bizarre effects (aside from his questionable theories about the human psychology).
There are some (more complex) substances with exceptional long duration at the receptor(e.g. salmeterol), but their effects never last for a week. And there are slow-releasing formulations/prodrugs, but the DOTFM used was definately none.

Administrator   posted 01-18-99 03:52 PM          
Lilienthal: I think Drone is talking about the compound BDFLY, which is p-bromo-tetrahydrobenzodifuranylisopropylamine, which was invented in JMC 39, 2953 (1996) by Nichols group, rather than the difuran compound in the picture at the top of this page.
rev drone
Member   posted 01-19-99 10:39 AM          

Rh, Lilienthal,
Yep, I wasn't interested in the dehydrogenated product so much; I just didn't see it being greatly advantageous over the saturated one.


The trifluoromethyl group is unique for a number of reasons biologically. Its ridiculously electronegative, And still very hydrophobic -- it CAN'T hydrogen bond to anything. No enzyme can bind to it. As Dr. Shulgin put it "its the world's shortest length of teflon", and essentially that is what it is.

-the good reverend drone

Member   posted 01-19-99 11:58 AM          
Drone, why are you interested in the dehydrogenated product? It seems to have only the same activity as DOB. The dehydrogenated seems to be about ten times more active!
The only reasonable way to 2,5-methyl-parahydrochinone I found is the Elbs persulphate oxidation of 2,5-dimethylphenol (cheap educt, easy procedure, 42% yield):
J. Chem. Soc. 2303 1948W. Baker, N. C. Brown

Administrator   posted 01-20-99 03:56 PM          
What do you want the 2,5-dimethyl-p-hydroquinone for? oxidize it to the dialdehyde? What about my other idea of making hydroxy-benzofuran from 2,5-dihydroxybenzaldehyde, formylate the product and run the ring closure rxn once more?
Still, making 2,5-dimethoxy-4,6-methyl-amphetamine (6-Me-DOM) from 2,5-dimethyl-p-hydroquinone would be very interesting. The compound should be really active.

Member   posted 01-23-99 06:27 AM          
Rhodium, the double-Vilsmayer should work. But I'm not sure if the formylation will be very selective. The rate of the competing 4-substitution depends on the steric hindrance there.
The synthesis is very tricky, maybe the original one is not so bad. I think the main problem is that electrophilic aromatic substitution (like bromination or Vilsmayer formylation) will yield high amounts of furan-2-substituted products. So the benzodifuran seems not to be an optimal intermediate.

Does someone have infos about the on the acid sensitivety or the metabolic resistance of benzofurans?

What do you think about 5-methoxybenzofurans with the sidechain in 4 or 7 position. Maybe the next paper from the Nichols group is about these compounds.

Member   posted 01-23-99 04:30 PM          
What do you think about this synthesis:
Administrator   posted 02-03-99 03:39 PM          
Nice, but all the ways to this compound seems long and tedious.
What about the synth of the following two probably very active compounds:

* Methylate the OH's after step A, formylate, condense with EtNO2 and reduce.
* Same thing, but first carry out step B before doing as above.

Much shorter and easier, and still very interesting.

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