We have recently discussed two important multicomponent reactions.
These are the Passerini reaction and the Ugi reaction, and we have explained that they
are very useful in the creation of large chemical libraries for screening in the search for
biological activity.
We will now learn a third multi-component reaction which has attracted a lot of attention
lately, although the reaction itself is over a century old.
This reaction was invented by Italian chemist Pietro Biginelli in 1891, while working at
the University of Florence.
It involves combining an aromatic aldehyde, urea, and a beta-keto ester, in this case
ethyl acetoacetate, to produce a heterocyclic compound called dihydropyrimidinone.
The reaction is catalyzed by Brønsted or Lewis acids.
Since we have not yet discussed this particular heterocyclic system, let us take a step back
and introduce it.
We have previously discussed the properties and the synthesis of pyridines.
These are important compounds in nature and in drug design.
To formally obtain the pyridine ring, you simply replace a carbon atom of benzene, or
more precisely a methine, with a nitrogen atom.
Pyridine is the trivial name given by chemists to this system.
If we replace a second methine group in pyridine, we get three possible isomers, depending on
which is replaced.
These will be pyridazine, if the two nitrogen atoms are 1,2 with respect to each other,
pyrimidine if they are in a 1,3 relationship, and pyrazine if they are 1,4.
These are also just trivial names invented by chemists, which simply have to be memorized,
because they bear no clear relationship to the molecular structure as an IUPAC name would.
Of the three systems with two nitrogen atoms, the most important one is certainly the pyrimidine,
which provides the skeleton of the pyrimidine bases contained in nucleic acids like DNA
and RNA.
It is therefore quite interesting that the Biginelli reaction constitutes a rapid entry
into these systems.
However, the product above is not a fully aromatic pyrimidine, but rather a more complex
one.
Let us look at the numbering, highlight the differences, and engage in a simple nomenclature
exercise.
When numbering pyrimidines, the nitrogens must be positions 1 and 3.
Looking at our Biginelli product, first of all, the double bond between N3 and C4 is
missing in our target, so we call this a 3,4-dihydropyrimidine, which means we have added two hydrogen atoms
to positions 3 and 4, the one visible on the nitrogen and the implied hydrogen on the carbon.
There is also a carbonyl at C2, and this necessarily adds a hydrogen atom at N1 as well.
We finish with an aryl group at C4 and an ethyl ester group at C5.
Therefore, the complete name is: 4-aryl-5-carbethoxy-3,4-dihydropyrimidin-2(1H)-one.
A lot of these Biginelli products can be further modified into interesting substances which
are biologically active, such as calcium-channel blockers.
This explains their frequent utilization as library products for screening.
Now let’s talk more about the reaction itself.
The mechanism actually is not known in precise detail, but let’s go over a reasonable candidate.
The first step is the establishment of an equilibrium by reaction of urea as a nucleophile
with an aldehyde, the electrophile.
This forms a hemiaminal which loses water due to acid catalysis, where this hydroxyl
is protonated and then water is kicked off by the lone pair on this nitrogen.
This yields a very electrophilic protonated species, a carbamoyl iminium ion.
This reacts with the best nucleophile left, the beta-keto ester, probably via its enol
form given the acidic conditions.
As we can see, the alpha carbon attacks this carbon atom, and this pi bond goes to neutralize
the nitrogen.
This yields an adduct that quickly reacts by intramolecular imine formation, which we
can also call a dehydration, in order to form the ring.
This final step is highly favored kinetically due to the intramolecular nature of the two
reacting partners.
The initially formed acylimine tautomerizes quickly to give the expected product, in which
the double bond enjoys conjugation with the ester group and is therefore more stable.
And that’s one possibility for this mechanism.
Now, if you are familiar with the Hantzsch synthesis of pyridines which we have previously
discussed, you may know that beta-ketoesters react with aldehydes very readily, at least
under basic conditions, and therefore an alternative mechanism is, in principle, possible.
Thus, the beta-keto ester, via its enol form, may attack the aldehyde first.
Dehydration promoted by acid would yield the alpha,beta-unsaturated ketoester, which then
would undergo conjugate addition by the urea nucleophile, and the end stage would be identical
as with the first mechanism.
This mechanism was originally proposed, but all current evidence points to the first one
as the correct one, at least under typical Biginelli conditions.
However, if one prepares and isolates the alpha,beta-unsaturated ketoacid described
above, reaction with nucleophiles like O-methyl isourea will yield, under acidic conditions,
the Biginelli product, showing that the mechanism can be steered by changing the experimental
protocol.
Just as with the previous two reactions we investigated, you likely will have noticed
that this reaction forms a chiral product, containing a stereogenic center at the carbon
that was previously the carbonyl carbon of the aldehyde.
Given that this reaction is of great synthetic importance for medicinal chemists, it is not
surprising that chemists have tried to create an enantioselective version.
Many of the attempts have used catalytic reactions, and more precisely chiral acids as promoters.
If one looks at the protonated carbamoyl iminium intermediate of the reaction, the presence
of a bulky chiral anion in the vicinity of the electrophile, most likely by formation
of a tight ion pair, may trigger diastereoface selection during the attack of the enol nucleophile
onto the iminium spcies.
As an example of this type of research, we will highlight the recent work of Professor
Liu-Zhu Gong, at the Chengdu Institute of Organic Chemistry in China.
By using 10 mole percent of a readily available chiral phosphoric acid as a catalyst, he was
able to perform this reaction and preferentially obtain the R enantiomer in a ratio of 98.5
to 1.5, which means a very impressive enantiomeric excess of 97%.
Note that the catalyst, despite not possessing any chiral centers, is dissymmetric by virtue
of its axial chirality, and quite enantiomerically stable, because rotation around the carbon-carbon
bond connecting the two aromatic rings is hindered.
There are many other enantioselective applications of the Biginelli reaction, and in addition
to chiral phosphoric acids one can use a variety of Lewis acids, though we will stop our survey
of this type of chemistry here.
Finally, we should note that the reaction also works with aliphatic aldehydes, but generally
in lower yields, especially if one uses enolizable aldehydes.
Demonstrating that great reactions never go out of fashion, this old and venerable reaction
is still of great interest today, and a hot topic in modern organic synthesis.