Sciencemadness Discussion Board

2-methylbutanal to 2-amino-butane synthesis

Quantum_Dom - 24-12-2008 at 17:32

Hi guys, I have undertaken the conversion of 2-methylbutanal into 2-amino-butane (see scheme provided below).



As a reactionnal scheme I have thought about the following:

1- Formation of the aldoxime by reaction with hydroxylamine, followed by a Beckmann rearrangment, in order to obtain the corresponding terminal amide.[1,2]

2-Perform an Hoffman rearrangment on the latter amide in order to eliminate a carbon and therefore obtain the desired amine.[3]

I have tried the first step but I am afraid that I always get the nitrile which hydrolyze to a useless carboxylic acid afterwards.

I was wondering if anyone could help me find an alternative method to perform the latter synthesis or maybe improve the mentionned scheme by giving me valuable pointers. It would be very much appreciated. Thanks !

[1] Synthesis 2002, No. 8, p 1057. 2002.
[2]Organic Syntheses, Coll. Vol. 2, p.371 (1943); Vol. 17, p.60 (1937).
[3]Tetrahedron Letters, Vol. 38, No. 3, pp. 313-316, 1997





[Edited on 24-12-2008 by Quantum_Dom]

[Edited on 24-12-2008 by Quantum_Dom]

not_important - 24-12-2008 at 20:09

Why not start with the corresponding acid, and that that to the amide by your favorite method?

The proper name of the target would be 2-amino-butane, always find the longest carbon chain first and build from that.

UnintentionalChaos - 24-12-2008 at 22:06

Perhaps someone could dig up this paper: http://pubs.acs.org/doi/abs/10.1021/ja064315b

Very similar to reductive amination, but not quite. You oxidize the intermediate hemiaminal generated in-situ to the amide.

Perhaps other oxidants can stand in for tert-butyl hydroperoxide.

You might also consider oxidation followed by the hunsdiecker reaction, then vast excess of ammonia to favor the monosubstituted product.

Also, this wouldn't happen to have anything to do with a phenyl group that's not being drawn, does it....

Quantum_Dom - 24-12-2008 at 22:26

Quote:
Originally posted by not_important
Why not start with the corresponding acid, and that to the amide by your favorite method?


Because I dont have access to DCC, is there any (reasonable yielding) OTC procedures to generate primary amides out of a carboxylic acid ?
Quote:
Originally posted by not_important
The proper name of the target would be 2-amino-butane, always find the longest carbon chain first and build from that.


Thanks, will edit the mistake.

Quantum_Dom - 24-12-2008 at 22:30

Quote:
Originally posted by UnintentionalChaos
Perhaps someone could dig up this paper: http://pubs.acs.org/doi/abs/10.1021/ja064315b

Very similar to reductive amination, but not quite. You oxidize the intermediate hemiaminal generated in-situ to the amide.

Perhaps other oxidants can stand in for tert-butyl hydroperoxide.


Thanks I have access to the paper:
http://rapidshare.com/files/176579765/Highly_Efficient_Oxida...

It seems that this procedure works best for aromatic aldehydes :(. The authors are only using substituted benzaldehydes and the only aliphatic aledhyde used yields 39 % of amide.
Quote:

You might also consider oxidation followed by the hunsdiecker reaction, then vast excess of ammonia to favor the monosubstituted product.


I like it! I like it a lot. Silver nitrate, bromine, nice and OTC. Thank you very much for this ! :D
Quote:

Also, this wouldn't happen to have anything to do with a phenyl group that's not being drawn, does it....


I have no idea of what you are talking about ;)





[Edited on 24-12-2008 by Quantum_Dom]

[Edited on 25-12-2008 by Quantum_Dom]

S.C. Wack - 24-12-2008 at 22:59

Quote:
Originally posted by UnintentionalChaos
Also, this wouldn't happen to have anything to do with a phenyl group that's not being drawn, does it....


Methylenedioxyphenyl seems more certain.

Quantum_Dom - 24-12-2008 at 23:07

Quote:
Originally posted by S.C. Wack

Methylenedioxyphenyl seems more certain.


Again, I have no clues of what you guys are referring to. :cool:

I just like to synthesize primary amines to stink up my lab ! :D

[Edited on 24-12-2008 by Quantum_Dom]

not_important - 24-12-2008 at 23:36

Back some time ago there was a bit of discussion on using a nickel salt and hypochlorite bleach or swimming pool chlorinating chemicals to oxidise aldehydes or primary alcohols to the carboxylic acid, yields in the 80 to 95 percent range for aliphatic aldehydes in the C4 to C8 range.

https://sciencemadness.org/talk/viewthread.php?tid=8215&...

After that there converting it to the acid chloride, if you've access to SOCl2 or other such compounds, or first convert to the ester and then react that with concentrated aqueous ammonia to form the amide, or convert the acid to the ammonium salt and dehydrate that by azeotropic removal of water using toluene or xylene and boric acid as a catalyst.

Quantum_Dom - 24-12-2008 at 23:47

Quote:
Originally posted by not_important
Back some time ago there was a bit of discussion on using a nickel salt and hypochlorite bleach or swimming pool chlorinating chemicals to oxidise aldehydes or primary alcohols to the carboxylic acid, yields in the 80 to 95 percent range for aliphatic aldehydes in the C4 to C8 range.

https://sciencemadness.org/talk/viewthread.php?tid=8215&...

After that there converting it to the acid chloride, if you've access to SOCl2 or other such compounds, or first convert to the ester and then react that with concentrated aqueous ammonia to form the amide, or convert the acid to the ammonium salt and dehydrate that by azeotropic removal of water using toluene or xylene and boric acid as a catalyst.


Ouch! Thionyl chloride is pretty hard to get for me and I rather keep away from that thing as much as I can. I guess azeotropic dehydration would be the best call in my case.

Many thanks, for the oxidation procedure. Looks extremely versatile and OTC !

[Edited on 24-12-2008 by Quantum_Dom]

Klute - 25-12-2008 at 03:58

Well, even plain hypochlorite and a PTC will do that easily i think. If you have the opportunity, you can add a little tempo catalyst in there too.

not_important - 25-12-2008 at 23:20

Simple hypochlorite tends to halogenate the alpha carbon. Think of making chloroform from ethanol and bleach, first is oxidation of acetaldehyde followed by replacement of the alpha hydrogens be chlorine, then cleavage of the C-C bond.

[Edited on 26-12-2008 by not_important]

Quantum_Dom - 26-12-2008 at 00:09

Quote:
Originally posted by not_important
Simple hypochlorite tends to halogenate the alpha carbon. Think of making chloroform from ethanol and bleach, fixed is oxidation of acetaldehyde followed by replacement of the alpha hydrogens be chlorine, then clevage of the C-C bond.


I actually thought about alpha-halogenating the aldehyde too. Then oxidize to the carboxylic acid (maybe in one-pot ?).

Then, nucleophilic substitution with sodium nitrite to generate the alpha-nitro compound, reduction of the nitro group with zinc dust/ammonium formate and finally decarboxylation to the amine

But for "alpha-halogenating" a carboxylic acid, I think a phosphorous halide is required.








[Edited on 26-12-2008 by Quantum_Dom]

not_important - 26-12-2008 at 04:14

The generally only works well with primary bromides and iodides. With tertiary halides that generally yields almost entirely the nitrous ester or dehydrohalogenation products, even secondary bromides or iodides tend to give the ester as the majority product.

But truthfully for this compound I'd just do reductive amination of MEK with a large excess of ammonia, or pass sec-butyl alcohol and ammonia over heated Ni-Cu catalyst, and fractionate the products to get the mono-substituted amine. Ammonia, MEK, and sec-BuOH all are cheap and easy to come by.

Quantum_Dom - 26-12-2008 at 06:44

Quote:
Originally posted by not_important
The generally only works well with primary bromides and iodides. With tertiary halides that generally yields almost entirely the nitrous ester or dehydrohalogenation products, even secondary bromides or iodides tend to give the ester as the majority product.

But truthfully for this compound I'd just do reductive amination of MEK with a large excess of ammonia, or pass sec-butyl alcohol and ammonia over heated Ni-Cu catalyst, and fractionate the products to get the mono-substituted amine. Ammonia, MEK, and sec-BuOH all are cheap and easy to come by.


Good call. Thanks ! Although the challenge was to start from 2-methylbutanal, I clearly see and understand your point.

[Edited on 26-12-2008 by Quantum_Dom]