fluoro compound using sandmeyer on aminoacid

[poix]

I would like to know if some bee think it may work:

The post n° 221895 say that the sandmeyer reaction can be done on aminoacid to make an alpha-bromo carboxylic acid, I wonder if the fluorination can be done this way:

H2SO4 + 2NaNO2 -> 2HONO + Na2SO4         aqueous environment
2 NaBF4 + H2SO4 -> 2 HBF4 +  Na2SO4
glycine  H2NCH2COOH +  NaNO2 +  H2SO4 +  NaBF4 -> FCH2COOH + ...
alanine CH3CH(NH2)COOH + NaNO2 +  H2SO4 +  NaBF4 -> CH3CHFCOOH + ...

FCH2COOH + SOCl2 -> FCH2COCl + ...
CH3CHFCOOH + SOCl2 -> CH3CHFCOCl + ...



FCH2COCl   +  1,4 dimethoxybenzene + AlCl3  ->   2,5 dimethoxy beta fluoroacetophenone   =A   
CH3CHFCOCl    +  1,4 dimethoxybenzene  + AlCl3 -> 2,5 dimethoxy beta fluoropropiophenone =B


A+H- -> 2,5 dimethoxy beta fluoroethyl benzene =C
B +H- -> 2,5 dimethoxy beta fluoropropyl benzene =D

C + POCl3 (or dichloromethyl methyl ether) -> 2,5-dimethoxy-4-(2-fluoroethyl)-benzaldehyde =E
D + POCl3 (or dichloromethyl methyl ether) -> 2,5-dimethoxy-4-(2-fluoropropyl)-benzaldehyde =F

E + CH3NO2 + reduction ->>> 2C-EF "It would be every bit as much a treasure and ally as is 2C-B or 2C-I
E + CH3CH2NO2 + reduction ->>> DOEF potent hallucinogen dosage 2-3.5 mg duration 12-16h
E + CH3CH2CH2NO2 + reduction ->>> 4C-DOEF cognitive enhancer

F + CH3NO2 + reduction ->>> 2C-PF Not in Pihkal but 2C-P is very potent (6-10mg) so I bet it will be even more potent
F + CH3CH2NO2 + reduction ->>> DOPF Not in Pihkal but surely very potent
F + CH3CH2CH2NO2 + reduction ->>> 4C-DOPF cognitive enhancer

So I hope that this method work because the synth for DOEF in pihkal is not very interesting nor easy


Question with the sandmeyer: how can we avoid side reaction like formation of alpha hydroxy carboxylic acid, anyone as a ref.  for  the fluorination using sandmeyer?

poix

[Rhodium]

Generally, the sandmeyer reaction can easily form fluorides with aromatic diazonium salts, and hydroxyl formation can be suppressedc pretty good by keeping the temperature down, as well as keeping the amount of water down. In don't know about aliphatic fluorides, or if the pyrolysis of the fluoroborate salt will be accompanied by decarboxylation.

If I were to make an alpha-fluorinated acetophenone, I would alpha-brominate the acetophenone with NBS, and then do a halogen exchange on the bromine with KF (perhaps with a dash of PbF2) in refluxing polyethyleneglycol. The yields are usually very high, and certainly very higher than if using your reaction scheme. Reduction of the ketone must be done with the wolff-kishner method, or you'll destroy the molecule.

[poix]

thank rhodium

yes alpha-fluorinated sorry

Do you have some ref I can lookup in the library?

I thought that with NBS we brominate para of the ketone, like with 2,5 dmb +NBS -> 4br-2,5 dmb.

How can I make some alpha difluoro compound? Would NBS brominate two times at the same site?

I think they could be as interesting as 2C-TFM

[Rhodium]

The alpha-position of an acetophenone is more reactive than the 4-position of the aromatic ring, so with carefully selected reaction conditions, it is possible to selectively brominate there with NBS as far as I know. If that is not possible to control enough, then CuBr2 can brominate acetophenones without any effect on the ring.

1,1-Difluoroalkylbenzenes are made by treating the corresponding carbonyl compound with DAST (diethylaminosulfur tetrafluoride).

I don't have any references handy, but do a search on gem-difluorides on

http://www.scirus.com

[poix]

I found that FCH2COOH can be made from ClCH2COOH by an halogen exchange, this is more easy than my method. BUT after a little search in merck index, I found that FCH2COOH is a violent poison, neurotoxic and it is not something you want around you. So I think Rhod's route is better.
 
Rhod :'Reduction of the ketone must be done with the wolff-kishner method, or you'll destroy the molecule.'
The yields are shitty with ZN/HCl in pihkal (2C-P) but they are better than with hydrazine in triethyleneglycol (2C-E).
It will be really cool if CTH worked, otherwise maybe DMSO as solvent and hydrazine, the conditions are milder but the yields are better aren't they?

I've got a new idea last week, it's surprising I haven't got it before: what about reacting trifluoroacetic acid with SOCl2, then FC it with 1,4dmbenzene, reducing the acetophenone, formylate the alcane,get 2,5-dimethoxy-4-(2-trifluoroethyl)-benzaldehyde nitr/reduct it and get the 'I am sure of it very cool' 2C-TFE(or 2C-ETF)? If it work it will be easier to do it than to do 2C-EF because trifluoroacetic acid is commercially avaiable, no need to do some nasty fluorination.

Well what are the major pitfall in this synthesis?
-F/C TFacetyl chloride with 1,4dmbenzene: Do someone know if this would be a problem? But i bet it will work.
-Reduction of the ketone: well if there is a pitfall I think it will be there, is the TFacetophenone more sensitive than acetophenone?

P iX

[Rhodium]

It should work to acylate p-diMeO-benzene with trifluoroacetyl chloride, but I don't know how good electrophile it would be in a FC reaction as the fluorine atoms are pretty electron-withdrawing.

[Rhodium]

Preparation of 3-Trifluoromethyl-?,?,?-trifluoroacetophenone

Patent US3748361

50.5 g (2.1 moles) of magnesium turnings were charged to a 2 liter flask fitted with a mechanical stirrer, reflux condenser, addition tube and thermometer. One ml of ethyl bromide in 50 ml. ether was added as an activator. 450 g (2.0 moles) of meta trifluoromethyl bromobenzene in 1200 ml of ether were added dropwise to the magnesium. The addition time was 5 hrs. The temperature was maintained between 25-30°C. To this dark reaction mixture were added 76 g (0.66 mole) of trifluoroacetic acid in 750 ml of anhydrous ether over a two-hour period. The reaction temperature was 35°C. The reaction mixture was then refluxed for 2 hours after addition was complete and cooled to 0°C.; then 100 ml of H₂O were added to the mixture slowly, followed by 200 ml of concentrated HCl dissolved in 300 ml. of H₂O. The temperature was maintained between 0-10°C.

The. ether layer was separated and washed twice with 10% Na₂CO₃ solution. The ether layer was then dried over anhydrous MgSO₄, filtered, and the filtrate concentrated on a roto-evaporator. The residue was vacuum distilled at 89°C/80mmHg to give 119 g (85%) of the ketone and then analyzed.