Hope everyone has enjoyed their celebrations, but it's back to the grindstone now!
I've been spending a fair bit of time pondering secondary amine formation.
There are a number of methodologies to achieve this.
Conventionally alkylating gives a mixture of secondary and tertiary amines, and if it's the secondary amine you want, it will be the last of the column, making large scale prep a bit of a nightmare.
Reductive amination always crops up when discussing this topic, and it is a good way of stopping at the secondary amine, with a small amount of collateral damage usually. It can also be useful for the suppression of quaternisation in tertiary amine formation.
The problem I have with it I think, is working with a lot of amines, is purification. Column chromatography on amines is best avoided, especially on scales above a few mmol. I will only ever column derivatised or protected amines unless it's on a small scale for analytical purposes.
The other qualm I have with this is that the aldehyde partners I require most often are not commercially available, nor are trivial to synthesise, often several steps with protection/deptrotection and purification.
The best method hands-down is the aza-Michael reaction. A lovely procedure I follow includes an equimolar ratio of amine to acrylonitrile in protic solvent, overnight at rt, rotovap, quantitative. But, I am all too aware of it's limited scope.
I have seen recently this paper in JOC that uses CsOH to suppress over-alkylation. I tried it with my substrate and I saw up to 4:1 selectivity by LC/MS, but, after a column only achieved 2:1, not the 10:1 they claim in the paper. And again, for me, a column is best avoided.
The method I have settled for recently is to nosylate the amine and alkylate with pot carb, then column. Deprotection (without thiophenol!) gives essentially pure amine with a basic wash.
Nice and easy, and no free amine to column. The best thing is the nosyl group can be used orthogonal to the Boc group.
if your molecule can withstand it, amide coupling followed by good old LAH reduction could be a simple alternative, and you get directly a free base amine from the H2O/15%NaOH/H2O Fieser quench and filtration
ReplyDeleteThat's also true, a kind of brute force reductive amination. The trouble I would have is that it would apply to unsymmetrical polyamine synthesis - there's likely to be nitrile around. I have considered using an orthogonally protected gamma-aminobutyric to couple, reduce and deptrotect, to introduce a 4-C spacer. Only trouble would be a base-labile protecting group that could withstand LithAl. Does Fmoc?
DeleteFmoc definitely does not survive LAH. Fmoc would survive borane.THF reduction (but I do not like amide reductions with borane because it is not always clean and you end up with amine borane complexes that you need to decompose by anh. HCl in MeOH or with Raney nickel).
DeleteAlso a problem with Fmoc for polyamine monoprotection is that the protected product is unstable in its free base form due to Fmoc getting chopped off by an amine. Have you considered using an azido-substituted piece instead? Simple alkyl azides are not really dangerous once you get above ratio 6 carbon+oxygen atoms per azide
Also, have you seen this preparation of cyclen? It is quite wasteful on DIBAL but i loved the ring expansion trick they used:
http://www.orgsyn.org/orgsyn/prep.asp?prep=v78p0073
Didn't think it would.
DeleteI've considered azides, especially since their reduction can be affected much more mildly than that a nitrile, but I already have a large stock of bromoalkyl nitriles to use. Howver, azide preparation is easy enough, I use it as an amine surrogate in other chemistry - it could prove useful for polyamines though, perhaps a Staudinger in the presence of a nosyl protected amine.
For my purposes though, it's better to have a fully Boc-protected amine (less one reactive site) as I require the salt after deprotection, so I alkylate with the nosyl, and do a quick PG exchange with Boc.
That's a neat prep, I might send it on to someone I know who makes macrocylic ligands for MRI - could save a bit of money buying in DOTA!