Natural Science Forum / Chemistry / Organic Synthesis / February 2004

Make the imine with an aldehyde in situ in mildly acid aqueous buffer,
then reduce with NaBH3CN.  Or make the imine in anhydrous solvent
(toluene) with azeotropic water removal and then reduce it in any of a
number of ways.  

There aren't many routes to controlled incremental alkylation of
amines.   I suppose you could make the bis(benzanilide) or
bis(pivalanilide), deprotonate to the anion, and alkylate that.  Now
you have to crack the anilides (or reduce and get benzyl groups that
can be cleaved).

What color is your stuff?  If it isn't colorless or thereabouts you
want to clean it up as the hydrochloride (hello sep funnel, Norit, and
Celite) and liberate free base in the pot immediately prior to
derivatization.  A little zinc dust or sulfite with the charcoal might
help things along during the cleanup.

Didn't Aldrich sell a whole bunch of derivatized diaminofluorenones
(4,4'-diamonobenzophenones with an extra linkage) as immune system
diddlers?  Also maybe

Monatsh. Chem. 129(8/9) 915-920 (1998)

Using BuLi is not going to work.  It will add to the ketone.

What do you mean by "TLC showed nothin'"?

If EtI didn't work, increase the temperature or change the solvent
(e.g., DMF).  In either case you're going to get a mixture.

Steve Turner

I would add some mono-protecting group which can stabilise anion.
Since you have keto group in the molecule, I would suggest either
Alloc (intro: AllocCl, deprot: 20% Et2NH in THF with 3mol% Pd(PPh3)4)
or 2,4-dinitrobenzenesulfonyl (introduction: sulfonyl chloride,
deprotection: thiol+base, purification can be bitch with the second
case, check Greene Protection groups).

Alkylation: NaH + alkyl iodide, THF (or DMF), 0C to R.T.

The advantage would be that you could use this protected derivative as
a starting material for all alkylations and the deprotection would be
uniform.

Uncle Al's approach would be shorter, but it is less certain that it
will work. If you try it, make sure you form the imine (and that there
is not much aldehyde excess), to avoid forming mixtures.