Next up in our survey of name reactions is the Favorskii rearrangement,
not to be confused with the Favorskii reaction, which is actually something completely different.
As applied to ring systems, it is a classical reaction inducing
ring contraction, meaning that a ring is getting smaller.
The reaction was invented by Russian chemist Alexei Favorskii in 1894. It applies to enolizable
alpha-chloro ketones, including acyclic substrates, but it is used in synthesis
mainly as a ring contraction tool. Let’s take a look at how this works now.
To begin, we see formation of an enolate at the carbon opposite the halogen. Then the nucleophilic
carbon from the enolate attacks the carbon that bears the chloro group, thus producing the very
strained cyclopropanone intermediate. This is immediately attacked by the hydroxide base
at the carbonyl carbon, and when these electrons come back down to reform the carbonyl,
the new three-membered ring pops open, and the electrons in this bond remain with this carbon.
This leaves a carboxylic acid with a carbanion moiety next door. Rapid proton transfer from
the carboxyl group to the carbanion gives the following product. A key element of regiochemistry
we must understand is that in a case such as this when the system is not symmetrical, opening
of the ring usually occurs to yield the less substituted and therefore more stable carbanion.
This mechanism is consistent with the fact that isomeric alpha-haloketones yield the
same carboxylate, such as here where the structural difference between these two
starting materials doesn’t matter, because enolate attack onto the bromide gives the
same cyclopropanone in both cases, although it is too strained and unstable to be isolated.
This scheme illustrates two other facts. First, the reaction works for alpha-bromo
ketones as well as chloro ketones, although generally in lower yield. And second, when
anhydrous alkoxides are used as bases, esters are obtained instead of the carboxylate salt.
An elegant way to confirm that a symmetrical intermediate is formed is shown in the following
scheme. As we can see, alpha-chlorocyclohexanone was labeled at the Cl-bearing position with a
14C label. Favorskii rearrangement gave the cyclopentanecarboxylate, in which the label
was then found equally distributed in the alpha and the beta positions, confirming
the intermediacy of the cyclopropanone, which can be opened both ways with equal probability.
Applications for this chemistry in synthesis are plentiful, especially when a larger ring size is
easy to make, and ring-contraction leads to rather strained systems.
In Eaton’s famous synthesis of the very strained cubane,
the final cube structure was established with a Favorskii ring contraction. The last
step was a simple thermal decarboxylation, which yielded the target cubic structure.
Another ring-contraction was applied to the lab synthesis of the poisonous alkaloid epibatidine,
found in frogs. This time we start from another natural product, the protected tropinone we see
here. This is alpha-brominated to yield a mixture of exo and endo alpha-bromides.
Ring contraction using methoxide yields the desired 2.2.1 skeleton from the 3.2.1 precursor.
Rather standard chemistry then converts the ester to the desired target epibatidine as a racemate.
With many ring-contraction strategies as applications, the Favorskii rearrangement
continues to be a useful tool in the synthesis of natural products and other structures of interest.