Author Topic: Making 2-C-TFM  (Read 2311 times)

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Alphabeta121

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Making 2-C-TFM
« on: September 11, 2000, 06:46:00 PM »
I "asked-a-scientist" how to add a triflouromethyl group to an electron rich aromatic ring (such as 1,4 Dimethoxy Benzene) and I got the following responce:

In order to add a CF3 group to an aromatic ring, one usually employs the
following reactions:

1) Radical attack of CF3(.)
2) Addition of CF3-copper species to ArI
3) conversion of other halogens into F (i.e. ArCCl3 + SbPh(2)F3 -> ArCF3)
4) conversion of carbonyl and carboxylic acid groups into CF3 using SF4

What seems the most facile starting with either dimethoxybenzene or dimethoxybenzaldehyde?
Pretend Reagent aquisition is no problem.


Alphabeta121

hest

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Re: Making 2-C-TFM
« Reply #1 on: September 13, 2000, 07:34:00 AM »
I think that TFA (trifluroacetic acid) and brombenzen is the best, and most safe, way
boil Brombezen and TFA in N-Methylpyrrolidin-on with some Cu(I)I or Cu(I)Br
See J.Chem.Soc.Perkin Trans.1 1988 p921-926

smiley_boy

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Re: Making 2-C-TFM
« Reply #2 on: November 09, 2000, 08:29:00 AM »
You identified many of the challenges in this synthesis, though I think there are a few things you have have overlooked. Why not take a closer look at your synthetic route? This seems like the logical approach to me. Okay, the goal is 2C-TFM. There already has been a paper on this very subject by Nichols (J. Med. Chem. 37(25) 4346-4351; 1994), though I admit his route may not be the best one.

Yes, trifluoromethylating is a problem with a starting material like 2C-B or 2C-I, since all the traditional trifluoromethylating procedures are developed for electron-deficient, aprotic systems (and these phenethylamines are definately not that.) So, why not look towards a different approach? Brominating 2,5-dimethoxybenzaldehyde with elemental bromine in acetic acid at room temperature is simple enough (much more higher-yielding than brominating 2C-H too), and that aldehyde group will give you all the electron withdrawing power you need -- and its even in the most ideal spot on the ring too -- the para-position. The procedure can be found inOrg.Prep.Proced.Int. 23(4) 419 - 424; 1991. Trifluoromethylation via copper(I) salt-catalyzed nucleophilic aromatic substitution is a well-established procedure, with hundreds of examples available to follow. After trifluoromethylation, you have 4-trifluoromethyl-2,5-dimethoxybenzaldehyde: a quick Knoevenhagel condensation, followed by a selective reduction (perhaps either BH3.THF complex, or AlH3, which generated in situ by treating LiAlH4 with a quantitative amount of concentrated H2SO4), and you have your desired free base.



Its just a suggestion; I hope this helps...


twitchin' the night away...

mocket

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Re: Making 2-C-TFM
« Reply #3 on: November 14, 2000, 04:51:00 AM »
Errrmm... Could someone remind me of the effects of this PEA? As Sasha said, 'the 4 position is where the action is'.
At a tangent, anyone considered replacing the benzene ring with a 5-membered ring? I saw an amphetamine analogue with a saturated 5-member ring. Can't help but wonder what substitution would do... besides being legal ;-)

Mocket says 'NO' to industrial GHB ;-)

smiley_boy

  • Guest
Re: Making 2-C-TFM
« Reply #4 on: December 01, 2000, 05:34:00 PM »
As far as I know, I don't think there have been any human tests on 2C-TFM. I think its safe to say is probobly not for the average tourist.

Regarding replacing the benzene ring, there are countless examples of 5-membered ring aryl ethylamines, with a huge range of biological activities. The geometry is completely different, and so each family of aryl ethylamine essentially has its own set of QSAR's.

To put it another way, consider this: phenethylamines are ethylamines with a 6-memeberd aromatic ring structure, tryptamines are ethylamines with a 7-memeberd aromatic ring structure. The two classes of compounds contain thousands of enormously active biological compounds, but little more than that essential structure -- aromatic ring, -ethyl, -amine -- really connects them.

Its not an entirely bad idea. Don't forget, 6-membered heterocyclic rings (like pyridine) are still a possibility, as are many others. With the right chemist (and the right budget), an entire library of "iKAL's" could be written. With the addition of a heteroatom, the ethylaminee chain could be added in multiple places, adding the possibility for countless more arylethylamines! Here are a few "new" books that came to mind:

BiKAL: benzofuranylethylamines I have known and loved
FiKAL: furanylethylamines i Have Known and Loved (you have to love the sound of that acronym ;) )
NiKAL: napthylethylamines i Have Known and Loved
PyiKAL: Pyridinylethylamines i Have Known and Loved
ThFiKAL: Thiofuranylfuranylethylamines i Have Known and Loved ("ThFi-" is the sound you make when you smell these compounds - ick..)

Alphabeta121

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Re: Making 2-C-TFM
« Reply #5 on: January 29, 2001, 02:24:00 PM »
would the henry reaction succeed w/ 4-TFM-2,5-DMB?  the paper using ethylenediamine diacetate said that the reaction failed on the four TFM benzaldehyde.

alphabeta121

Rhodium

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Re: Making 2-C-TFM
« Reply #6 on: January 29, 2001, 03:42:00 PM »
Yes, I think the henry reaction would work with 4-TFM-2,5-DMBA, at leas with a little tweaking of the reaction conditions. If the failure with 4-TFM-BA is due to the strong electron-withdrawing effects of the CF3 group, this should be outweighed by the two methoxy groups, and if ethylenediammonium diacetate (EDDA) fails, just try another catalyst. EDDA fails with piperonal too, but cyclohexylamine and NaOH works for it.


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