The Beckmann rearrangement is a chemical transformation that converts aldoximes and ketoximes into their corresponding amides in an acidic environment. This reaction is crucial in the industrial production of ε-caprolactam, a monomer used for making synthetic fibers.
Typically, the Beckmann rearrangement is conducted under harsh conditions, including high temperatures exceeding 130°C and the use of strong Brönsted acids such as H2SO4, HCl, Ac2O, and AcOH. Unfortunately, the non-catalytic nature of this process limits its applicability to sensitive substrates.
The stereochemical outcome of the Beckmann rearrangement is well-predicted: the R group opposite to the leaving group on the nitrogen atom migrates.
However, if the oxime undergoes isomerization during the reaction, a mixture of the two possible amides is formed. It’s important to note that the hydrogen atom does not migrate in this process, making it unsuitable for the synthesis of N-unsubstituted amides.
Mechanism
During the first step of the mechanism, the halo (X) group is converted into a leaving group through interaction with an electrophile. When the leaving group departs, it induces a [1,2]-shift of the R group located opposite to it. This results in the formation of a carbocation, which subsequently reacts with a nucleophile, either a water molecule or the departing leaving group itself.
This series of reactions ultimately lead to the formation of the amide after undergoing tautomerization.
With PCl5
Variations
Radical Beckmann rearrangement:
Organocatalytic Beckmann rearrangement with a boronic acid/perfluoro pinacol system under ambient conditions:
Cyanuric chloride assisted the Beckmann reaction:
The Beckmann rearrangement can be made catalytic with the assistance of cyanuric chloride and zinc chloride as co-catalysts. As an example, cyclododecanone can be transformed into the corresponding lactam, which serves as the monomer used in the production of Nylon 12.
The reaction mechanism for this process relies on a catalytic cycle in which cyanuric chloride activates the hydroxyl group through a nucleophilic aromatic substitution. The reaction product is displaced, and a new reactant takes its place through the formation of an intermediate Meisenheimer complex.
Synthetic Applications
1. Organoaluminum-Promotion
S. Mani and colleagues employed the organoaluminum-promoted modified Beckmann rearrangement in their efficient synthetic pathway to produce chiral 4-alkyl-1,2,3,4-tetrahydroquinoline. They obtained (4R)-4-ethyl-1,2,3,4-tetrahydroquinoline through the rearrangement of the ketoxime sulfonate derived from (3R)-3-ethylindan-1-one.
Subsequently, they reduced the resulting six-membered lactam product to the corresponding cyclic secondary amine using diisobutylaluminum hydride.
2. Total Synthesis of (+)-Codeine
In the research conducted by J.D. White’s laboratory, they successfully achieved the asymmetric total synthesis of the non-natural compound (+)-codeine through intramolecular carbenoid insertion. In the later stages of this total synthesis, there was a need to introduce a 6-membered piperidine moiety. To accomplish this, they utilized a Beckmann rearrangement of the oxime derived from a cyclopentanone intermediate.
Subsequently, they reduced the resulting 6-membered lactam to the corresponding amine using LAH. For this purpose, they prepared an oxime brosylate (Bs), which underwent a successful Beckmann rearrangement in acetic acid, yielding two isomeric lactams in a 69% yield with an 11:1 ratio in favor of the desired isomer.
3. Total Synthesis of (–)-Ibogamine
J.D. White and colleagues reported the total synthesis of (–)-ibogamine by initiating the process with the catalytic asymmetric Diels-Alder reaction of benzoquinone. This reaction established the azatricyclic framework of the molecule.
To further build upon this framework, they converted the resulting bicyclic ketone into the anti-oxime and subsequently subjected it to a Beckmann rearrangement in the presence of p-toluenesulfonyl chloride, yielding the 7-membered lactam.
Following this step, they elaborated on this lactam to create the aza tricyclic core of ibogamine, and in subsequent steps, synthesized the natural product itself, (–)-ibogamine.
4. Total Synthesis of (+)-Sparteine
In the final stages of their total synthesis of (+)-sparteine, J. Aubé and collaborators employed a novel variant of the photo-Beckmann rearrangement. They generated the hydroxylamine in situ, which then underwent an intramolecular reaction with the ketone to form a nitrone. Subsequent photolysis of this nitrone resulted in the desired lactam formation with a good yield.
Applications
- The Beckmann Rearrangement finds application in various industries, notably in the synthesis of paracetamol, a widely used pharmaceutical compound.
- This rearrangement involves the conversion of a ketone into a ketoxime, and it is facilitated by the use of hydroxylamine. It is a crucial step in the synthesis of numerous steroids and pharmaceutical drugs.
- Additionally, the Beckmann Rearrangement is instrumental in the production of specific chloro bicyclic lactams, making it a versatile reaction in organic synthesis.
Concepts Berg
What is the Beckmann rearrangement?
It’s a chemical reaction that converts oximes into amides.
Who is credited with discovering the Beckmann rearrangement?
Ernst Otto Beckmann, a German chemist.
What types of compounds are involved in the Beckmann rearrangement?
Oximes, which contain the C=N-O functional group, are the primary substrates.
What applications does the Beckmann rearrangement have in organic chemistry?
It is used for synthesizing amides, which are valuable building blocks in various industries, including pharmaceuticals and polymers.
References Books
- A Textbook of Strategic Applications of Named Reactions in Organic Synthesis book by Laszlo Kurti and Barbara Czako
- A Textbook of Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications book by Jie Jack Li
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