microswitch
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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.
\"Conspiracies hatched in hell do not have angels as witnesses,\" Hough said.
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Furch
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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]
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microswitch
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| 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] |
Many thanks for the kindly and insightful advice. I was looking at the Titanium(IV)isopropoxide, but I have heard of the Grignard reagent and will
start snooping around.
Also, in response:
About the acidity....acidic aqueous solutions are very hard on a methoxy group (the ether bridges no?).
Also,
"Grignard reagent on intermediate imine (from keton/aldehyde and ammonia derivative) to give the amine."
Has this been shown to be the case with the methylenedioxy species?
Thanks in advance,
\"Conspiracies hatched in hell do not have angels as witnesses,\" Hough said.
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Furch
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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]
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microswitch
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| 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. 
\"Conspiracies hatched in hell do not have angels as witnesses,\" Hough said.
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nightflight
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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]
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Furch
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Nightflight, I agree with your reasoning, however the critical point for the methylenedioxy bridge in the above mentioned reaction sequence is the
presence of a benzylmagnesiumhalide... I.e. a strong base, which according to your reason may potentially damage the MD-bridge.
Indeed, the more reactive imine will exclusively react with the benzylmagnesiumhalide, IF it is present. This is not the case when it comes to the
MDMA synthesis with which the discussion is concerned... As 3,4-MD-benzylmagnesiumhalide would probably be prepared separate from the methylacetimine.
Would the MD-bridge withstand, say, a benzylmagnesiumhalide at temperatures around 60 °C, i.e. that of refluxing THF? I still have faith in the
stability of the methylenedioxy bridge... Call me naive if you will.
- Furch
[Edited on 4-2-2007 by Furch]
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microswitch
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So my next search string: Enantioselective Synthesis reduction of ketones to yield amines
New and efficient catalysts for enantioselective borohydride reduction of ketones and imines
Abstract Optically active aldiminato cobalt(II) complexes have been found to catalyze the enantioselective reduction of ketones with sodium
borohydride affording the corresponding optically active secondary alcohols in high chemical yields with high enantioselectivities. The
enantioselective borohydride reduction is also applicable to not only C=O bonds in aromatic ketones but also to C=N bonds in aromatic imines.
Takushi Nagata1, Kiyoaki D. Sugi1, Kiyotaka Yorozu1, Tohru Yamada2 and Teruaki Mukaiyama3
(1) Chemical Synthesis Laboratories, Mitsui Petrochemical Industries, Ltd., Waki-cho, Kuga-gun, Yamaguchi, 740, Japan
(2) Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, 223, Japan
(3) Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo, 162, Japan
Journal Catalysis Surveys from Japan
Publisher Springer Netherlands
ISSN 1384-6574 (Print) 1572-8803 (Online)
Subject Chemistry and Materials Science
Issue Volume 2, Number 1 / March, 1998
DOI 10.1023/A:1019005803704
Pages 47-57
SpringerLink Date Tuesday, November 30, 2004
\"Conspiracies hatched in hell do not have angels as witnesses,\" Hough said.
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MEXCHEM2006
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This journal article was posted by Solo on 9-11-2006 in the Wanted References and Needed Translations section
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Isomeric_Fred
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apperently sodium triacetoxy borohydride (prepared in-situ from sodium borohydride +3 acetic acid) is a very good and versatile reagent and
reductivaly aminating most ketones/aldehydes.
It is though taking roughly 20 hours to complete the reaction, but is reported to give extremely good yields.
It is compatible with most ketones and aldehydes, and even works well for weakly basic amines. ill pull out the refs for you later on...
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microswitch
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Here's a link:
http://www.organic-chemistry.org/chemicals/reductions/sodium...
Wow Isomeric_Fred, you are the man!
\"Conspiracies hatched in hell do not have angels as witnesses,\" Hough said.
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Isomeric_Fred
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attached is a rar file with interesting refs about nabh4 and additive as reductive amination reagents -
1. Direct and indirect reductive amination of aldehydes
and ketones with solid acid-activated sodium borohydride
under solvent-free conditions, B. T. Cho, S. K. Kang / Tetrahedron 61 (2005) 5725–5734 (main idea is a powerful system for reductive amination in
solid state with nabh4 + boric acid).
2. Sodium borohydride in carboxylic acid media: a phenomenal
reduction system, G.W. Gribble/Chemical Society Reviews, 1998, volume 27
3. Reductive Amination of Aldehydes and Ketones with Sodium
Triacetoxyborohydride. Studies on Direct and Indirect Reductive
Amination Procedures, Ahmed F. Abdel-Magid,* Kenneth G. Carson, Bruce D. Harris, Cynthia A. Maryanoff, and
Rekha D. Shah/J. Org. Chem. 1996, 61, 3849-3862
More to come as i find them in my archives.
Attachment: red.amin.rar (1MB)
This file has been downloaded 657 times
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