In the previous tutorial, we reviewed the Diels-Alder reaction in considerable
detail. Now let’s examine some modifications that can be made to this important reaction.
As we recall, any Diels-Alder reaction involves a diene and a dienophile
going to generate cyclohexene. Up until now, the six atoms participating in the cycloaddition
have been carbon atoms, but interestingly, they do not need to be. We can utilize dienophiles
in which one of the two atoms is not carbon, but is rather oxygen or nitrogen, and in doing so we
can produce a variety of heterocycles. Let’s see some examples of 1,3-butadiene reacting
with various dienophiles and the heterocycles they produce. If using aldehydes or ketones,
we can produce dihydropyrans. If using imines, we can produce tetrahydropyridines. If using thiones,
the sulfurous analogs of ketones, we can produce dihydrothiapyrans. So as we can see,
the utility of Diels-Alder chemistry goes far beyond the generation of cyclohexenes alone.
Now we should also understand that the same trends regarding kinetics that we
learned for the standard reaction will apply here. Electron-withdrawing groups on the dienophile will
accelerate the reaction. Take this N-tosylimine for example, recalling that tosyl functionality
will withdraw electron density. This will react with cyclopentadiene even at room temperature.
If using a diene substituted with electron-donating functionality, such as methoxy,
then the methoxy and tosyl groups can end up either ortho or para to one another, but not meta.
We can replace carbon atoms with heteroatoms not just on the dienophile, but on the diene as well.
For example, let’s take our standard butadiene and replace the terminal carbon with a nitrogen. That
gives us this alpha-beta unsaturated imine. This can react with something like maleic anhydride
to produce this tetrahydropyridine derivative. Now with hetero Diels-Alder reactions understood,
it’s time to look at an extension of this reaction, which is called a 1,3-dipolar
cycloaddition. This is where the diene is replaced by a 1,3-dipole. What does this mean exactly? This
term refers to a three-atom fragment which can only be written as a zwitterion. So we will first
represent this in a general manner, with A, B, and C, one pi bond, and formal positive and negative
charges on B and C respectively. This can react with a standard dienophile, such as ethene shown
here, undergoing a cycloaddition under thermal conditions to produce a five-membered ring.
The reason this is considered an extension of Diels-Alder is that this is also a
[4 + 2] cycloaddition. Though we don’t have a diene with two pi bonds, we have a 1,3-dipole
with one pi bond and one lone pair. The lone pair also qualifies as two pi electrons, so there’s
our four, and the dienophile is the two as usual. When we push the negative charge over to the other
fragment, we are generating a new sigma bond, the pi bond on the dienophile goes to generate the
other new sigma bond, and the existing pi bond will go to neutralize this central atom here.
These reactions are stereospecific and subject to clear regiochemical laws,
so let’s see some specific examples. We recently learned a bit about diazomethane,
and this will work well as a 1,3-dipole. Let’s react this with methyl acrylate,
and we will produce this substituted pyrazoline, which refers to the fact that these two nitrogen
atoms have a double bond between them. For reasons regarding frontier orbitals that we
won’t elaborate on for the moment, the ester must end up adjacent to the terminal nitrogen,
it can’t be on the carbon opposite the nitrogen atoms, so there’s the regiochemistry we mentioned.
Looking at one more example, let’s use a nitrile oxide. This is a nitrile where the
nitrogen atom is positively charged and bound to an oxyanion. These are regularly produced
via dehydration of nitroalkanes, typically in situ, meaning that we will produce them
and immediately react them with olefins, which is just another word for alkenes.
This strategy allows for the avoidance of dipole decomposition,
as it is very reactive. The nitrile oxide reacts with the olefin by precisely the mechanism we just
outlined, to produce an iso-oxazoline. Notice that these are cis to one another on the product,
given that they were cis on the reagent. This can be cleaved at the weak N-O bond by Raney
nickel and then protonated in aqueous acidic workup to generate this Aldol-type product.
The key thing we must realize is that this was done with strong regio and stereoselectivity. This
would be very difficult to achieve using standard enolate chemistry, thereby making it difficult to
ensure the status of these stereocenters. But with 1,3-dipolar cycloaddition it’s no problem,
and therein lies the real utility of this technique in the chemistry lab.
This just scratches the surface of this synthetic technique,
and we could continue to use any number of different dipoles with different heteroatoms,
which is why this approach is so common in natural product and drug synthesis. But for now,
with this reaction understood, let’s move on to some other interesting pericyclic reactions.