(Official Hive Translator)
07-03-02 08:53
No 328346
      A cool, funny :-) route to fluoro-substituted PEAs
(Rated as: excellent)

Oh my beeloved brethren!

As many lately noted, the chemistry forums run somewhat shallow these days... If not for Barium, itd stop altogether, I guesssmile. Perhaps, that is the reason that even some of the best-winged have turned to the Couch to engage into activities otherwise seen only from people of a plebic mindsetsmiletongueshocked

Anyways, i thought i'd pull smth curious from the depths of my HD so as to ease the atmosphere a little. It's certainly a somewhat complicated synth and requires some expensive/sparse catalysts, but the chemistry is neat enough to keep you amused, i hopesmile

Especially that last step, Hoffmann degradation of Ph-propionamide to the PEA.

Patent US6255528

Fluorine-containing phenethylamines are obtained in an advantageous manner by reacting fluorine-containing bromobenzenes with acrylamide in the presence of a palladium catalyst, hydrogenating the resulting arylacrylamides catalytically and then rearranging the arylamides obtained.

Example 1

275 ml of dry dimethylformamide were flushed with nitrogen for 1 hour. 100 g of 1-bromo-4-(trifluoromethoxy)-benzene, 29.4 g of acrylamide, 101 mg of palladium(II) acetate, 216 mg of triphenylphosphine and 67.8 g of sodium acetate were then added successively, and the mixture was stirred at C. for 20 hours. After cooling, the mixture was filtered, the filtrate was concentrated, the filter residue was combined with the concentrated filtrate and the mixture was suspended in 200 ml of water and filtered again. The resulting filter residue was washed with 200 ml of n-hexane and air-dried. This gave 84 g of 3-[4-(trifluoromethoxy)-phenyl]-acrylamide. According to GC, stated in area percent, the product was 95.9% pure. This corresponds to a yield of 83% of theory.

Now, from the patent it isn't clear if this condensation is specific for fluorine-substituted nuclei - has anyone ever seen smth similar performed on other bromobenzenes?

Example 2

In a stirred autoclave, 250 g of the 3-[4-(trifluoromethoxy)-phenyl]-acrylamide obtained according to Example 1 were initially charged dissolved in 1250 ml of tetrahydrofuran, 6.2 g of palladium-on-carbon (10% by weight) were added, and the acrylamide was hydrogenated at C. and a hydrogen pressure between 5 and 10 bar until the reaction had gone to completion (3 hours). The catalyst was then filtered off and the solvent removed by distillation. This gave 221 g of 3-[4-(trifluoromethoxy)-phenyl]-propionamide. According to GC, stated in area percent, the product was 98.1% pure. This corresponds to a yield of 86% of theory.

Obviously, there are other then pressure hydrogenation ways to reduce that double bond, not touching the amide function. Anyone has propositions? Would ordinary NaBH4 do the job?

Example 5
(in the previous two examples they did the same rearrangement under different conditions, this one having by far the best yield.)

21.1 g of sodium hydroxide and 20 g of 3-[4-(trifluoromethoxy)-phenyl]-propionamide, prepared according to Example 2, were initially charged in 70 ml of water, and 15 g of bromine were added dropwise at room temperature. The mixture was then heated under reflux for 3 hours. The reaction mixture was subsequently admixed with 200 ml of water and worked up and purified as described in Example 3. This gave 12.9 g of 2-[4-(trifluoromethoxy)-phenyl]-ethylamine which distilled over at from 84 to C. and 10 mbar. According to GC, stated in area percent, the resulting product was 99% pure. This corresponds to a yield of 72% of theory.

As it has probably become by now evident to most of the bees (yes, Ba, Im writing this specifically for you!wink), such posts more-often-then-not get NO responses at all laugh well, such is life, I guesssmile. So, please, dont bother replying to this, Im quite content with my silent submission of knowledgelaughlaughlaugh.


(Chief Bee)
07-03-02 09:27
No 328357
      Great, Antoncho! The reaction seems to be a ...  Bookmark   

Great, Antoncho!

The reaction seems to be a really novel route to our beloved phenetylamines. I see no reason for the reaction not to work on other bromo- or iodobenzenes without fluorine substituents.

Please note that acrylamide is a carcinogen.
(Hive Bee)
07-04-02 03:12
No 328653
      AlH 3 reduces alpha , beta -unsaturated amides to ...  Bookmark   

AlH3 reduces alpha,beta-unsaturated amides to allylic amines Tetrahedron 35, 567 (1979)
alpha,beta-unsaturated amides -> saurated amides by Li or K(s-Bu)3BH JOC 41, 2194 (1976) and JOC 60, 6198 (1995)
NaCNBH3 reduces alpha,beta-unsaturated amides that are geminally substituted by another electron withdrawing group to saturated compounds JOC 41, 3328 (1976)

Sodium hypophosphite-Pd/C reduces a shitload of alkenes to alkanes without touching carbonyl groups, carboxylic acids and derivatives, alkyl nitriles or halogen substituents on aromatic nuclei and the yield are generally in the range 80-95%. Tet. Lett. vol 25, no 40, pp4565-4568, 1984.

Might be that Red-Al could reduce both the double bond and the amide. Excess Red-Al in refluxing toulene should do the job. But this is just a guess.  

Acrylamide is seriously nasty indeed. Just ask Rhone Poulanc how much trouble it can causewink.

I refuse to degrade to a couch-hog just because its vacation. My vacation will be in the grave winkcool
(Hive Bee)
07-08-02 19:02
No 330180
      Heck coupling
(Rated as: excellent)

This is a Heck Coupling, not a condensation. In a heck coupling, you have two subtrates. One, a sp2 hybridized halide or triflate, and a electron deficient terminal alkene. The two are coupled, and the product posseses a trans geometry.

The Pd(OAc)2 is the pre-catalyst, the PPh3 is the ligand, and the Sodium Acetate acts as a base and buffer. The Pd(OAc)2 disassocites the -OAc, and forms a Pd(PPh3)n species in situ. These low valent 14 (n=2)& 16 (n=3) electron species are very reactive, and oxidativly add a Bromobenzene to form Pd(PPh3)2BrPh, where Pd has inserted into the Ph-Br bond. It then loses a -Br, and coordinates in a eta-2  fashion to the pi system of the terminal alkene to give Pd(PPh3)2(CH2CHCONH2)Ph. The acetate then acts as a base when the terminal end of the alkene and the arene are coupled. The product is then reductivly eliminated, and the catalytic cycle continues. If you'll notice, the catalyst loading in this reaction is very low (101mg).

This reaction would apply to any substituted Bromo-, Iodo-, or Triflate substituted benzene.
(Master Whacker)
07-16-02 22:32
No 333501
      Wow!  Bookmark   


Your knowledge continuously amazes me!  Please keep up the fantastic posts.  I can only imagine how many hours you have invested in studying inorganic to be so fluent in this area.  I am a HUGE fan of Pd chemistry and really enjoy your detailed explanations of these reactions.  I'm not trying to kiss your ass, I just want you you to know that your time spent posting here is greatly appreciated!smile


Thank you so much for posting that Hofmann degradation.  SWIM has been looking for a high-yielding ref on this reaction for ages!smile