As we have mentioned several times throughout this series, functional group interconversion
is essential in organic synthesis. The ability to take a cheap or conveniently available substrate
and turn one of its functional groups into another one is a fundamental strategy in the synthesis of
complex organic molecules. In a previous tutorial, we introduced a reaction called the Curtius
rearrangement. This reaction was first described by German chemist Theodor Curtius in 1885. Curtius
converted an acid chloride into an acyl azide by reacting it with azide salts like sodium azide.
Forming the acyl azide is the first step of the Curtius reaction. The rearrangement itself
consists of heating the substance to a temperature of about 100oC, where it then decomposes to form
an isocyanate. This process is now believed to be concerted, with the R group migrating to
the nitrogen atom at the same time as diatomic nitrogen is released, leaving this isocyanate.
With this context we can introduce the Schmidt reaction. One simple version of
the Schmidt reaction involves the direct reaction of carboxylic acids with HN3, or hydrazoic acid.
This leads directly to the acyl azide, without having to preform the acid chloride, which then
reacts via Curtius rearrangement to give the isocyanate as we just discussed. But a much
more interesting extension of this chemistry was first described by German chemist Karl Friedrich
Schmidt in 1924, and deals with the reaction of hydrazoic acid with ketones, yielding amides in
a process referred to as the Schmidt reaction. There are generally two mechanisms proposed for
this reaction, and it is believed that they may operate simultaneously in many cases. In the first
pathway, the nitrogen that bears the proton on hydrazoic acid attacks the protonated carbonyl
to give this intermediate, and this is followed by the simultaneous migration of an R group and
loss of the very stable N2 molecule, to yield the amide. This is called the Baeyer-Villiger pathway,
because it is analogous to the mechanism for this reaction, which we covered in a previous tutorial.
The second pathway starts the same way, but then further proton transfer takes place so as to kick
off a water molecule and produce this diazoiminium ion intermediate. At this point, we again see the
migration of an alkyl group to kick off nitrogen gas, while the nitrogen that remains generates a
third C-N bond to maintain neutrality of the adjacent carbon. That gives us this nitrilium
cation. This is readily hydrated by the water generated during the first step, and that again
brings us to the amide. This second pathway is called the Beckmann pathway, because it resembles
the mechanism for the Beckmann rearrangement, which we also discussed in another tutorial.
Now, an immediately obvious problem that needs resolution is the selectivity of alkyl migration
in non-symmetrical ketones. If R1 is the same as R2, then there is no ambiguity. But the situation
is more complex when R1 is not the same as R2. It is believed that in the Beckmann pathway
the diazoiminium intermediate forms two possible isomers, where the R1 group can be either cis or
trans with respect to the diazonium group, which will be of differing stabilities depending on
sterics. Then the migration proceeds in anti fashion with respect to the departing group,
as is depicted here. This becomes trickier when we realize that the two isomers of the diazoiminium
ion interconvert under acid catalysis, when this nitrogen becomes protonated, giving this
C-N bond considerable single bond character and thus the ability to rotate. But in any case,
as a general rule, the more substituted alkyl group migrates preferentially, whether proceeding
via the Baeyer-Villiger or Beckmann pathways. So bulkier alkyl groups migrate preferentially over
smaller alkyl groups, and aryl groups migrate preferentially over alkyl groups.
An interesting observation which is quite recent, is that alkyl azides undergo the
same reaction as hydrazoic acid under acidic conditions, whether using Brønsted-Lowry acids
like trifluoroacetic acid, or Lewis acids like tin tetrachloride. In some cases,
the substrate may contain both reacting functionalities, a ketone and an alkyl azide,
and some acid treatment may be enough to activate the substrate toward a regiospecific Schmidt
rearrangement. This strategy has been applied broadly in the synthesis of natural products.
We can further illustrate this brilliant innovation by reporting work from Professor Jeff
Aubé, now at the University of North Carolina. In this example, the target is the alkaloid stenine.
Professor Aubé found that he could combine a Lewis-acid catalyzed Diels-Alder reaction
with a Schmidt reaction, using the same Lewis acid for both reactions. When he reacted the
following diene and dienophile, the cycloaddition gave this intermediate, an azido ketone. We will
notice that the regiochemistry of the Diels-Alder reaction is governed by the rules we discussed in
a previous tutorial on this reaction, namely that the electron-withdrawing group of the dienophile,
in this case the ketone, ends up opposite the electron-donating substituent in the diene,
in this case the trimethylsilyl enol ether. In addition, the endo transition
state prevails over the exo, and therefore the four stereocenters that are generated
must have this specific configuration out of the eight that are geometrically possible.
Under these same reaction conditions, the Lewis acid induces the Schmidt rearrangement,
with regioselectivity and stereospecificity. Finally, hydrolysis of the TMS enol ether
yields the following ketoamide. This was then converted to stenine via five additional steps
that we will not discuss. Note how this brilliant approach, with the Diels-Alder cycloaddition
and Schmidt reaction happening all in one pot, allows for the establishment of the
correct stereochemistry and the construction of the skeleton of the natural alkaloid.
A complex strategy such as this one illustrates first of all how organic chemists like to combine
reactions in “domino” sequences to assemble complex molecular structures very quickly
and efficiently. It also illustrates how the old Schmidt reaction can be extended to quite
complex situations, where its regioselectivity and stereospecificity can help create complicated
molecular structures. Thus, this venerable old reaction is still very much of current interest
to synthetic organic chemists, and every student of organic synthesis should be familiar with it.