Rhodium
(Chief Bee)
12-03-01 17:04
No 243844
      Tryptamine reductive alkylation with NaBH(OAc)3
(Rated as: excellent)
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It seems like sodium triacetoxyborohydride can indeed be used for reductive alkylation of tryptamine without the usual reduction of the indole to an indoline. In J. Org. Chem. 63, 968 (1998) there is an example of tryptamine being alkylated with a ketone to form a secondary amine. Using more of the carbonyl compound and more of the borohydride may give the dialkylated tryptamine in good yield.

Sodium triacetoxyborohydride can be made by mixing 1 mole of NaBH4 with 3 moles of glacial acetic acid in an inert solvent, and evaporating in vacuo. Care must be taken not to leave any residual acetic acid in there, as in JACS 96, 7812 (1974) they show that NaBH4 in neat acetic acid (equivalent to triacetoxyborohydride plus excess acetic acid) reduced indoles to indolines.

Experimental:

To tryptamine (13.2g, 82.4 mmol) in 1500ml dichloroethane at room temperature was added 1,4-cyclohexanedione monoethyleneglycol acetal (1.1g, 77.5 mmol), sodium triacetoxyborohydride (25g, 117.9 mmol) and glacial acetic acid (4.4 ml, 77.1 mmol). The reaction was stirred for 24h, the solvent distilled off under reduced pressure, the residue taken up in 700ml DCM, washed with saturated Na2CO3 followed by water, and then dried over MgSO4 and the solvent distilled off under reduced pressure. After recrystallization from DCM, the N-alkyl-tryptamine was isolated in 87% yield (20.2g).
 
 
 
 
    slappy
(Hive Bee)
12-04-01 21:59
No 244362
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

To reiterate the words of a great chemist, "Triacetoxy is the shit." It is so much more selective and gentle than NaBH4, which will give the alcohol. It's even better than NaCNBH3 for reductive amination, and it doesn't give off HCN.

Steric effects most certainly played a role in the monosubstitution. The Cyclohexadione monoacetal is pretty bulky, and I can almost guarantee the with a smaller ketone such as formaldehyde or acetaldehyde, you would get the tertiary amine.
 
 
 
 
    terbium
(Old P2P Cook)
12-05-01 19:21
No 244758
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

I thought that the problem with reductive alkylation of tryptamine was cyclization to the beta-carboline, not indoline formation. Wouldn't reductive alkylation with formaldehyde or acetaldehyde likely result in the beta-carboline when using triacetoxyborohydride just as with NaBH4?

Post 68441 (Lilienthal: "Re: Melatonin->5-MeO-MET", Tryptamine Chemistry)
 
 
 
 
    Rhodium
(Chief Bee)
12-06-01 02:24
No 244901
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

KrZ has shown to us that reductive amination of Tryptamine with NaBH3CN works in moderate yield (was it 60%?) even with a little addition of acetic acid (Eschweiler-clarke results in betacarbolines though). Many people has wondered if NaBH4 or any of the "enhanced" versions of it would work instead, but all those "enhanced" varieties, both acetoxyborohydrides and the mixtures that gives free diborane seem to make the indoline - until I found this reference.
 
 
 
 
    foxy2
(Distinctive Doe)
12-06-01 02:37
No 244904
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

Here is what I want.

Reductive amination of indoleacetaldehyde with dialkylamines!!!

Do Your Part To Win The War
 
 
 
 
    Rhodium
(Chief Bee)
12-06-01 02:46
No 244910
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

That should not be too hard, except the unstableness of the aldehyde: ../rhodium/chemistry /indoleacetaldehyde.html
 
 
 
 
    foxy2
(Distinctive Doe)
12-06-01 03:31
No 244918
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

Actually I have a reference, I just have to haul my ass to the library and get it.  The product is an unsaturated(ethylene) dialkyltryptamine which has to bee hydrogenated.  Wonder if Al/Hg can do it?

Do Your Part To Win The War
 
 
 
 
    Rhodium
(Chief Bee)
12-06-01 09:21
No 244980
      Re: Tryptamine reductive alkylation with NaBH(OAc)  Bookmark   

Very interesting... An ethylenic DMT would be an enamine, conjugated with the rest of the aromatic rings. I wounder if that would be active in its own special way, or if it would be totally inactive because one of the electronic structures that can be drawn for it, there is a positive charge on the nitrogen. Go get the ref! smile