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.