Ketone to amine: in search of a greener way...

So far the most common internet search for reduction of ketone to amine are pathways involving Hg or Cyanide.

A green/safe rxn should ideally:

1. avoid toxic fumes
2. avoid the use of toxic reagents (i.e. Hg, CN)
3. avoid the production of toxic byproducts
4. not involve "energetic materials" (i.e. CH3NO2)



Greener candidates:

Titanium(IV)isopropoxide

Palladium

NaBH4

Platinum on Carbon (10%) Catalyst (waaay too expensive no?)

What am I missing? Please help me flesh out this search.

And yes, I did a thorough search of the board before posting starting this topic.

Somebody mentioned the Eschweiler-Clarke reaction not too long ago in another thread... I.e. amination of ketone or aldehyde with formic acid as the reducing agent. That's not too bad, is it? It's acidic alright, but hardly *toxic*. Also, I don't remember whether the thread concluded that the reaction is versatile or not... Which is to say whether a variety of carbonyl and amine compounds can be used or not.

Other than that, an extremely nifty method if you ask me - Grignard reagent on intermediate imine (from keton/aldehyde and ammonia derivative) to give the amine.

RMgX + R'-N=CR"R'" =(1. anhydrous conditions 2. weak acid)=> HR'N-CRR"R"'.

IIRC someone applied this method to benzylmagnesium chloride and methylacetimine and succesfully made methamphetamine with a 80% yield. It's in the Rhodium archives I think.

I believe the exact words from the author was "this method beats the hell out of any P2P amination", or something like that :-P

I really really like the last one. Very nice


- Furch

[Edited on 2-2-2007 by Furch]

Quote:

It's in the Rhodium archives I think. I believe the exact words from the author was "this method beats the hell out of any P2P amination", or something like that :-P I really really like the last one. Very nice - Furch [Edited on 2-2-2007 by Furch]

Quote from March's Advanced organic chemistry, 4th ed., p. 935 on the topic of "The addition of organometallic compounds to C=N bonds";

"For the addition of an organometallic compound to an imine to give a primary amine, R' in RCH=NR' would have to be H, and such compounds are seldom stable. However, the conversion has been done, for R = aryl, by the use of the masked reagents (ArCH=N)2SO2 [prepared from an aldehyde RCHO and sulfamide (NH2)2SO2]. Addition of R"MgX or R"Li to these compounds gives ArCHR"NH2 after hydrolysis."

On page 896 on the topic of "Formaldehyde-hexamethylenetetramine transformation" is stated that "However, these compounds [simple imines] are generally unstable. Most imines with a hydrogen on the nitrogen, sponaneously polymerize."

Hence, as usual, this route is not functional when it comes to preparing primary amines, rather secondary ones.

Concerning the methylenedioxy functions sensitivity to acids, it's not a problem in this case, since by "weak acid" I ment an acid with a pKa of water, that general area... Only enough to free the amine from the R-NR'MgX intermediate.

I don't know for certain, but if cleavage of the methylenedioxy bridge competes with alkylation of the imine function, I'd say the latter is the most probable outcome... Judging from the general electrophilicity of the two in comparison. You might want to research that a bit more thoroughly though, as I don't know for sure.

To answer the question, by the way, I don't know whether this method has ever been applied to any substance containing the methylenedioxy function...

[Edited on 3-2-2007 by Furch]

Quote:

Originally posted by Furch To answer the question, by the way, I don't know whether this method has ever been applied to any substance containing the methylenedioxy function... [Edited on 3-2-2007 by Furch]

Then the search pushes on for a method to swap that ketone for an amine on the methylenedioxy variety.

Im looking into reductive animation using titanium(IV)isopropoxide and NaBH4 via the Rhodium site.

Yes, cleavage of those ether bridges is something of a problem, rather fragile. What is the strength of those bonds in relation to the ketone? I should be able to find this out since it's just CHem I stuff.

the methoxy-grop is very stable, ethers are protective groups, to be cleaved, when the more reactive group of a molecule has reacted.

There have to be brute forces, strong acids, strong bases, pressure and alike appllied to cleave and I doubt that a condition for amination of a ketone meets the criteria for ether-cleavage, even partially (exclusion AlI3, which partially destroys the methylene-bond of the aryl molecule).

there are "green" ways for reductive amination, but I doubt, that NaBH4 is "gentle" or not toxic, also, the Hg toxicity of amalgam sems to be overstated and the amount of poisenous salts is usually little, compared to the amounts used in gold-mining in south-america. (dieelectric heating? *hint*)

[Edited on 3-2-2007 by nightflight]

[Edited on 4-2-2007 by nightflight]

Here's a link:

http://www.organic-chemistry.org/chemicals/reductions/sodium...

Wow Isomeric_Fred, you are the man!