The most interesting CTH reaction ever documented?

[Regis]

Patent US6399828

:  Preparation of amphetamines from phenylpropanolamines. 

[Rhodium]

Wow - if there ever were a "double excellent" rating, this find would be worthy of it.

[SPISSHAK]

It's nice to have people around here are working to advance
The cause.

[Sunlight]

Very very good.

[Barium]

Awsome!! This opens up for some really smooth synthesis of various primary amines.

Phenylpropanolamines are readily made in high yields by CTH of 2-nitro-1-phenylpropan-1-ols, which in turn are made from the corresponding benzaldehyde and nitroethane much more easily than nitroalkenes. The O-acetyl could be inserted before the nitro group is reduced. By doing it this way the N-acetyl contaminant would not be generated.

2C-H could then be made by condensing 2,5-DMBA with nitromethane, acetylating the formed 2-nitro-1-(2,5-dimethoxyphenyl)ethan-1-ol to 1-acetoxy-2-nitro-1-(2,5-dimethoxyphenyl)ethane, which could be reduced in one step to 2C-H by CTH.

I´ll dig up some synths of phenylnitroethanols and -propanols. 
Catalytic hydrogenation freak

[Barium]

Preparation of various phenylnitroalkanols

Patent EP0960876

Patent US2597445

Patent US1973647

Patent US1356877

Patent US4496772

Patent GB353361

Catalytic hydrogenation freak

[Sunlight]

Do you think that is possible a direct CTH reduction of the acetyl nitroalcohol to the amine ? Even one pot after acetylation ?
Probably distillation will be necessary to remove the unreduced/unacetylated byproducts, but it could be a good way to make reasonable amounts with reasonable volumes.

[Barium]

I think it is possible. When nitroalcohol formation is complete just remove the benzaldehyde by steam distillation then acetylate. Acetylation of the isolated nitroalcohol should give 90%+ yields. The following CTH reduction of the -NO2 and hydrogenolysis of the acetoxy should give 90%+ yields as well. In the last step, just use excess of ammonium formate to push the hydrogenation/hydrogenolysis as far as possible.

Which of the useful benzaldehydes are not volatile with steam?
Catalytic hydrogenation freak

[Sunlight]

If the nitroalcohol doesn't precipitate, we should wash with sodium bisulphite, but I guess it may be just filtered.

[Mountain_Girl]

Hmmm..once again it's clear that I am not part of the Hive Illuminati.
While I can see that this process is useful, I'm having trouble figuring out exactly what the fuss is about.

For instance,

2C-H could then be made by condensing 2,5-DMBA with nitromethane, acetylating the formed 2-nitro-1-(2,5-dimethoxyphenyl)ethan-1-ol to 1-acetoxy-2-nitro-1-(2,5-dimethoxyphenyl)ethane, which could be reduced in one step to 2C-H by CTH.

Surely it would be simpler, cheaper & OTC to synth the nitrostyrene from 2,5-DMBA & nitromethane, & then reduce with Fe/HCl ?
(particularly for those that are acetic anhydride challenged)

Mountain Boy

[Barium]

Mountain_Girl:

The day you get something useful from reducing 2,5-dimethoxy-beta-nitrostyrene with Fe/HCl, please let me know. The basic idea is to have as many proven methods as possible to get the goodies from as many different precursors as possible. By aiming towards this goal we will get closer to the day when we can actually hear the screams out of pure frustration from the headquarters of Mr. Hutchinfuck. Because the more methods we develop the harder it gets for them to outlaw the stuff needed to make various sorts of honey.
Catalytic hydrogenation freak

[Mountain_Girl]

Barium:

Sorry, it was Zn not Fe that I was thinking of.
In particular :

Post 217679

(sunlight: "Russian patents works!!! Zn-HCl nitrostryrene rdxn", Novel Discourse)

I agree 100% with what you said & commend everybody's efforts in this regard. It's just that not being a chemist, I sometimes struggle to understand the significance of certain posts.
Also, I felt that the above procedure appealed mainly to those who have easy access to Acetic Anhydride, Pd/C and decent apparatus, i.e. non-OTC bees.
Mountain Boy

[Rhodium]

Mountain_Girl: There is no special apparatus needed for the above procedure, as it is a catalytic transfer hydrogenation. You only need a reflux condenser and a round-bottomed flask.

[Sunlight]

With the Zn HCl procedure you can easily make a 10 gr batch, and it is worth for 2CH, but is nothing if you would be playing with 3,4,5 TMNS. Thinking in a 100 gr or bigger batch, this could be interesting.

[Ritter]

Barium,
Yes, adding the acetyl group to the nitroalcohol before reduction to the amine to prevent the formation of the amide is an excellent concept, good work!  The only thing I'm concerned with in that scenario is that if acetic anhydride is employed for the esterification, you most definitely would dehydrate some if not all of the nitro- alcohol to the nitropropene.  If you insist on making the acetyl ester, I recommend that the reaction be run in an ice bath using pyridine/triethylamine as solvent/halogen scavenger and acetyl chloride as the esterifying agent.  A better, less watched reagent for preparation of the ester is benzoyl chloride.  The benzoyl group should undergo hydrogenolysis just as in the case of the benzoylmandelonitrile to phenethylamine reduction.  Other possible leaving groups are tosylates and mesylates.

[Rhodium]

Speaking of mandelonitrile esters - is there any chance they could be reduced via CTH to phenethylamines?

[SpicyBrown]

Would plain formic acid work in place of ammonium formate in this procedure? (The established CTH, not the theoretical 2CH preparation although that sounds particularly useful as well..) SWIM has seen several instances where formic acid is used in place of other formates; The removal of an allyl carbamate is an example, a Palladium(0) catalyst (Though usually something mroe exotic such as Palladium Tetrakis-Triphenylphosphine or Pd(dba)-CHCl3 complex) complexes with the allyl group, removing it from the protected molecule, then reduction comes into play by reducing free'd allyl group, releasing the Palladium atom. This worked best in literature with ammonium formate as the source of H- but formic acid worked with acceptable yields as well..

This could be completely un-useful for this procedure, SWIM isn't sure.

SpicyBrown

[Ritter]

Unbelievably I just happened to stumble across a reference which uses acetic anhydride in a tertiary amine at 0'C to   dehydrate a nitroaldol to the corresponding nitroalkene.
See: J. Org. Chem., Vol. 53, p2147, 1988  compound (

Now we know for a fact that acetic anhydride definitely won't acetylate the nitroaldol.  Bring on the acyl chlorides!!!

Rh:  I have seen a few reductions of mandelonitrile and its esters in the literature over the years.  They were mostly catalytic hydrogenations and used plenty of sulfuric acid in combination with an alcoholic solvent.  My thoughts on the CTH are if it can run in the presence of H2SO4 than it will probably do the trick for sure, however I have never seen a successful CTH in the lit. which used strong mineral acid as a reactant.

Perhaps mandelonitriles will reduce under standard CTH conditions and not require added acid, who'll be the first to find out?

[Barium]

Ritter:

Dear god I´m stupid. Of course the nitroalcohol will be dehydrated to the nitroalkene. Sigh! So it´s time to bring out those nasty acid chlorides, together with pyridine or triethylamine - the lingering stench of hardcore chemistry.
But you are, as always, right. It´s almost scary  

CTH in the presence of strong mineral acids is rarely seen. This is mostly because formic or hypophosphorous acids are decomposed by HCl or H2SO4. In order to perform CTH under such conditions we need to find other donors. Cyclohexene can be used if it´s ok to work with benzene which is produced.

Spicy:

Formic acid is by far a less active hydrogen donor than its salts.
Just neutralize the formic acid with ammonium or sodium carbonate, bicarbonate or hydroxide. The potassium salts are even better hydrogen donors than the sodium salts.

Catalytic hydrogenation freak

[Sunlight]

The conditions are really different if we use acetic anhydride in acetic acid or in a tertiary amine. Are you reasonabaly sure that it won't work ? Using chlorides and tertiary amines is not so attractive...