In the bad old days, reductive amination of secondary amines to form tertiary amines was not so good. Via halides was often low yielding and slow.
Forming an amide and then reducing with LAH used, well, LAH.
Recently there seems to be a raft of new routes which, in general, seem to proceed via the formation of iminium and then reduction using borohydride,
cyanoborohydride and similarly unexotic and toxic/explosive hydrides (or hydrogen itself). In many routes, lithium perchlorate is used as a catalyst
(and can be reused!).
Has anyone come across other general routes to the tertiary amines that is quick, high yielding & safe?solo - 6-12-2008 at 07:30
Reference Information
New Method of Making Tertiary Amines Reviewed by Trevor Laird
Most modern chemists wishing to make aromatic tertiary amines will try the Buchwald Hartwig methodologies involving displacement of a halide or other
leaving group by an amine under palladium or copper catalysis. A new method. developed by the group of Knochel at Munich, involves reacting a Grignard
reagent with an N-chloroamine. The Nchloroamines are easily prepared by reaction of a secondary amine with N-chlorosuccinimide in hexane. The
Grignards need to be prepared by the exchange reaction, which is typical of Knochel’s excellent procedures, namely reaction of an aryl halide with
I-PrMgCl-LiCl.
The aminations occur rapidly at minus 45 degrees within 15 minutes with moderate to good yields. Some biaryl is formed as a byproduct in some cases.
The strategy is a useful alternative method of making tertiary amines, particularly when all three groups on the nitrogen are different. (P Sinha
and P Knochel, SynLett, 2006, 19, 3304-3308). If there is a chiral center adjacent to N in the N-chloroamine, then
chirality is retained.
Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines Colin J. Dunsmore, Reuben Carr, Toni Fleming, and Nicholas J. Turner J. Am. Chem. Soc., 2006, 128 (7), pp 2224–2225
Abstract
However, in contrast to primary and secondary amines, there are relatively few methods reported for the preparation of enantiomerically pure tertiary
amines. ... 6 Although lipase-catalyzed kinetic resolution is a favored method for obtaining enantiomerically pure primary amines,7 this method can
only be applied to specific classes of secondary amine8 and is unavailable for tertiary amines. ... In light of the lack of a general method for the
preparation of optically active tertiary amines, we sought to adapt our recently developed chemo-enzymatic deracemization procedure to accommodate
chiral tertiary amine substrates. ...
Well, there are several good routes for methylations to tertiary amines: HCHO/HCOOH, trimethylphosphate, etc
But usually when alkylating with a alkyl halide (or sulfonate) superior to ethyl, quaternary ammonium salt formation is very minimal if your
substrate is even slightly hindered.
Reductive amiantions can also be done using CTH conditions, so no need of hydrides or hydrogen under pressure, even though I find reductive aminations
with NaBH4 very practical, safe and often high yielding.grind - 11-12-2008 at 01:18
Quote:
The Grignards need to be prepared by the exchange reaction, which is typical of Knochel’s excellent procedures, namely reaction of an aryl halide
with I-PrMgCl-LiCl.
Exchange reaction? And they get Ar2MgCl/LiCl? What a strange compound with 3-valent magnesium... (?).
Does anyone have the original article?
A simple route to tertiary amines is the acylation of a secondary amine with following reduction (like Piglet said).
But there is often no need for LAH, in most cases modified NaBH4 does the job.
Advantages:
- no sensitive intermediates (like imines or enamines)
- cheap and easy to handle reducing agent (NaBH4) and modification agents
- dependent on modification agent of NaBH4 working under non-inert conditions is no problem
- in contrast to triacyloxyborohydrides there is often no "waste" of active H
- in contrast to LAH, where the workup is a mess, you can basify and have a clear phase (instead of an Al(OH)3 slurry which disturbs the workup
considerably)
Disadvantage:
- introduction of aryl groups is not possible
[Edited on 11-12-2008 by grind]Klute - 11-12-2008 at 09:19
Well, you could introduce a arene by acylating an aniline, and then reducing the amide.
I agree on the modified borohydride, borane reductions often go smooth and high yielding.
