Sciencemadness Discussion Board

Primary amine to primary alcohol

ttso - 16-2-2011 at 21:52

Hello everyone. I have a question about "Primary amine to primary alcohol"

I've tried that the primary amine add NaNO2 and Ac2O in AcOH for 17h , then used NaOMe to give primary alcohol .

Indeed,it can work,but the yields and convertion are low.

I also read some literature that used KOH and diethylene glycol/ 210 oC. I think the temp is too harsh for my substrate . ( six-ring azasugar, functional group contaning Cbz and OBn and a allyl chain)

Can anyone else help me to figure out this problem or give me some suggestion in transformation?

Thanks a lot.




[Edited on 17-2-2011 by ttso]

Magic Muzzlet - 16-2-2011 at 22:01

Well.... What is the substrate?

DJF90 - 16-2-2011 at 22:27

Amines can be converted to leaving groups using pyrylium salts: http://curlyarrow.blogspot.com/2009/09/how-to-turn-amine-int...

I suppose the nitrogen can then be displaced by hydroxide, although you may also experience elimination (depending on the substrate)

Melgar - 17-2-2011 at 10:17

Strong oxidizers like sodium hypochlorite can remove the amino group on amino acids, which then undergoes a rearrangement that creates an aldehyde. In any case, the -NH2 can be oxidized to -NO2 by something like potassium permanganate, which may be easier to replace with a hydroxyl group since it makes a better leaving group.

DJF90 - 20-2-2011 at 02:58

Primary amines are seldom converted to nitro compounds in good yield, especially with something like permanganate. I also doubt very much that the nitro group would be a better leaving group, or even a leaving group at all. You might try diazotisation in aqueous conditions, but I wouldnt expect too much from it; just an idea.

Nicodem - 20-2-2011 at 12:02

Quote: Originally posted by DJF90  
Amines can be converted to leaving groups using pyrylium salts: http://curlyarrow.blogspot.com/2009/09/how-to-turn-amine-int...

I suppose the nitrogen can then be displaced by hydroxide, although you may also experience elimination (depending on the substrate)

Due to some (work related) coincidence I just stumbled into Katritzky et al. article on the same topic as the one referred in that blog and thought to reply here (the article is attached). That is a very interesting reaction described in that blog. C-Alkylation of 2-nitropropane is highly unusual. I have only seen it done with p-nitrobenzyl halides or other very electron poor ArylCH2X (but that is a classical example of SRN1 mechanism),* while normal alkylating reagents always start with O-alkylation followed by the decomposition of the resulting O-alkyl nitronate to aldehydes or ketones (e.g., JACS, 77, 1114 or JACS, 71, 1767).

I don't think the author of the blog even realizes the exceptionality of his 2-nitropropane alkylation (despite some replies pointing it out). If it turns out that it is the 2,4,6-triphenylpyridinium leaving group that somehow causes the reaction to go via SRN1 mechanism (accepting an electron from the nitronate?), it would make for an interesting discovery that would allow the C-benzylation of nitroalkanes with any benzyl group, not just limited to the nitro substituted ones. Seems like a perfect research project for amateur chemists (and highly publishable also!).

* For such examples see:
http://euch6f.chem.emory.edu/nucleophilic.html
DOI: 10.1021/ja01178a066
DOI: 10.1021/jo01168a002
DOI:10.1016/S0040-4039(99)00790-X
DOI:10.1016/S0040-4020(63)80038-1

PS: Otherwise the general umpolung methodology for primary amines is the N-ditosylation which gives the electrophilic N,N-ditosylamines that are able to undergo SN2 substitutions with ease provided they are of -CH<sub>2</sub>NTs<sub>2</sub> type. In this case one would alkylate potassium acetate in DMF to obtain the alkyl acetate and hydrolyse that to the alcohol. But regarding the question of the original poster, I have no idea without first seeing the structure of the substrate, but I do know "KOH and diethylene glycol/ 210 oC" is no method for such conversions (seems like someone confused the hydrolysis of amides with amines->alcohol transformation).

Attachment: Preparation of azides, phthalimides, and sulphonamides from primary amines.pdf (121kB)
This file has been downloaded 1883 times

smaerd - 15-10-2012 at 12:45

@Nicodem - can you find a reference for the n,n-ditosylation of primary amines? I'm very curious about this and am having a hard time finding anything.

Nicodem - 16-10-2012 at 07:42

Quote: Originally posted by smaerd  
@Nicodem - can you find a reference for the n,n-ditosylation of primary amines? I'm very curious about this and am having a hard time finding anything.

I can hardly belive you can't find much. There is plenty of literature examples on the synthesis of primary alkylamine N,N-disulfonimides. Admittedly, this is classically done via a two step synthesis, first making the sulfonamide, deprotonating it (e.g., with NaH) and sulfonating it again to get to the imide. Though, there is a limited number of examples where the N,N-disulfonation occurs directly with the arenesulfonyl chloride and triethylamine. An arenesulfonyl chloride with NaH/DMF or Cs2CO3/MeCN can also give N,N-disulfonimides directly.

A cursory literature search gives this variety of methods:

DOI: 10.1021/je60075a025
DOI: 10.1002/adsc.201100285
DOI: 10.1016/j.tetlet.2008.08.054
DOI: 10.1002/hlca.19800630806
DOI: 10.1021/ja061606b
DOI: 10.1073pnas.0904264106
and many others...

smaerd - 16-10-2012 at 15:48

Really appreciate the DOI's. I did find one example using THF and NaH but that was about where it stopped, think my nomenclature is lacking. This seemed to be the most useful DOI: 10.1002/hlca.19800630806 .

Learning new synthetic techniques day by day,

Thanks for taking the time and replying as always.

Nicodem - 21-11-2012 at 08:48

Quote: Originally posted by Nicodem  
That is a very interesting reaction described in that blog. C-Alkylation of 2-nitropropane is highly unusual. I have only seen it done with p-nitrobenzyl halides or other very electron poor ArylCH2X (but that is a classical example of SRN1 mechanism),* while normal alkylating reagents always start with O-alkylation followed by the decomposition of the resulting O-alkyl nitronate to aldehydes or ketones (e.g., JACS, 77, 1114 or JACS, 71, 1767).

I don't think the author of the blog even realizes the exceptionality of his 2-nitropropane alkylation (despite some replies pointing it out). If it turns out that it is the 2,4,6-triphenylpyridinium leaving group that somehow causes the reaction to go via SRN1 mechanism (accepting an electron from the nitronate?), it would make for an interesting discovery that would allow the C-benzylation of nitroalkanes with any benzyl group, not just limited to the nitro substituted ones. Seems like a perfect research project for amateur chemists (and highly publishable also!).

Well, it turns out that, in his blog, Curly Arrow cited the not most relevant of the Katritzky et al. papers on the topic of alkylations with pyridinium salts. I just stumbled to the paper where this type of alkylations of nitronates (derived from nitromethane, nitroethane or 2-nitropropane) with 1-benzyl and 1-alkyl-2,4,6-triphenylpyridiniums is studied:

Carbon-alkylation of simple nitronate anions by N-substituted pyridiniums
Alan R. Katritzky, George De Ville, Ranjan C. Patel
Tetrahedron 1981, 37, Supplement 1, 25–30. DOI: 10.1016/0040-4020(81)85037-5

Attachment: 0025-0030.pdf (383kB)
This file has been downloaded 1366 times

smaerd - 21-11-2012 at 09:42

I did read this entry on the their blog. Really interesting. Thanks for uploading the according article.